A Type 2 Diabetes Study of the Longer-Term Glycemic Effect of AVANDAMET vs. Metformin

A Randomized, Parallel Group, Double-blind, Multi-center Study Comparing the Efficacy and Safety of AVANDAMET and Metformin After 80 Weeks of Treatment.

Status

Completed

Phases

Phase 4

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00386100

Enrollment

688

Registered

2006-10-11

Start date

2006-10-31

Completion date

2009-09-30

Last updated

2016-11-23

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Diabetes Mellitus, Type 2

Keywords

Fasting Plasma Glucose, Dual energy X ray absorptiometry (DXA), Drug-naive, Type 2 diabetes mellitus, Bone Mineral Density, Hyperglycemia, HbA1c

Brief summary

This study will evaluate the longer-term glycemic effect of two medicines approved for initial treatment of type 2 diabetes. The study consists of a 2 week screening period (2 study visits), followed by an 80 week double-blind treatment period (11 study visits). Also, a sub-study was included to look at changes in bone mineral density (BMD) at the lumbar spine.

Detailed description

This was a phase IV, randomized, double-blind, global, multi-centre study. The study consisted of a 2 week screening period followed by an 80 week double-blind treatment period. Subjects who met all eligibility requirements were randomized in a 1:1 ratio, stratified by country, gender (male and female) and pre-screening HbA1c (≤9% or\>9) either to MET or AVM. When the substudy was added, a new randomization was created for the participating centers. Those subjects in the bone sub-study were stratified by country, gender (male, premenopausal female, and postmenopausal female), pre-screening HbA1c (i.e., ≤9%; \>9%), and either to MET or AVM. At randomization, Visit 3 (Week 0), subjects were initiated at Dose Level 1. Treatment with AVM was initiated at a dose of 4 mg/500 mg and titrated up to a maximum total daily dose of AVM 8 mg/2000 mg. Treatment with MET therapy was initiated at a dose of 500 mg and titrated up to a maximum daily dose of 2000mg.

Interventions

DRUGAvandamet 6 mg/1500 mg (ttd)

One 2 mg/ 500 mg capsule will be taken in the AM with the morning meal Two 2 mg/ 500 mg capsules will be taken in the PM with the evening meal

DRUGAvandamet 4 mg/1000 mg (ttd)

One 2 mg/500 mg capsule will be taken in the AM with the morning meal. One 2 mg/500 mg capsule will be taken in the PM with the evening meal.

DRUGAvandamet 2 mg/500 mg (ttd)

one placebo capsule will be taken in the AM with the morning meal one 2 mg/ 500 mg capsule will be taken in the PM with the evening meal.

DRUGAvandamet 8 mg/ 2000 mg (ttd)

Two 2 mg/ 500 mg capsules will be taken in the AM with the morning meal. Two 2 mg/ 500 mg capsules will be taken in the PM with the evening meal.

DRUGMetformin 500 mg (ttd)

One placebo capsule will be taken in the AM with the morning meal. One 500 mg capsule will be taken in the PM with the evening meal.

DRUGMetformin 1000 mg (ttd)

One 500 mg capsule will be taken in the AM with the morning meal. One 500 mg capsule will be taken in the PM with the evening meal.

DRUGMetformin 1500 mg (ttd)

One 500 mg capsule will be taken in the AM with the morning meal. Two 500 mg capsules will be taken in the PM with the evening meal.

DRUGMetformin 2000 mg (ttd)

Two 500 mg capsule will be taken in the AM with the morning meal. Two 500 mg capsule will be taken in the PM with the evening meal.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to 75 Years

Healthy volunteers

Inclusion criteria

* The subject provides written informed consent. * The subject is male or female and 18 to 75 years of age at the time of pre-screening. * The subject has an established clinical diagnosis of type 2 diabetes according to recommended guidelines (e.g., American Diabetes Association, International Diabetes Federation, World Health Organization, Canadian Diabetes Association, or American Association of Clinical Endocrinologists). * The subject is currently treated with diet and exercise, and has not taken more than 2 weeks of an anti-diabetic monotherapy or insulin in the past 6 months. * The subject has a BMI \>25 kg/m2 at pre-screening. * The subject has a Quest HbA1c 7.5% to 10.5% at pre-screening. * The subject has a fasting capillary blood glucose 126 mg/dL (7mmol/L), as measured by the site staff at week 0. * If the subject is a pre-menopausal female of child-bearing potential, she agrees to practice acceptable contraceptive measures (e.g. oral birth control pills, Norplant, Depo-Provera, an intrauterine device (IUD), a diaphragm with spermicide or a condom with spermicide, or abstinence) at least 1 month before screening, during the study, and for 30 days after the last dose of study medication is taken * The subject is able and willing to perform self-monitoring of blood glucose as specified in this protocol.

Exclusion criteria

* The subject has taken an oral anti-diabetic monotherapy or insulin for more than 14 days in the past 6 months. * The subject has presence of clinically significant renal or hepatic disease (serum creatinine 1.5 mg/dL (132.6 mol/L) for males and 1.4 mg/dL (123.8 mol/L) for females): ALT, AST, total bilirubin, or alkaline phosphatase \>2.5 times the upper limit of the normal (ULN) reference range. * The subject has anemia defined by hemoglobin concentration \<11g/dL (110g/L) for males or \<10g/dL (100g/L) for females. * Presence of unstable or severe angina, coronary insufficiency or New York Heart Association (NYHA) class III-IV or any congestive heart failure requiring pharmacologic treatment. * The subject has systolic blood pressure \>160 mmHg or diastolic blood pressure \>90 mmHg * The subject has a chronic disease requiring intermittent or chronic treatment with oral, intravenous, or intra-articular corticosteroids (i.e., only use of topical, inhaled or nasal corticosteroids is permitted). * The subject has acute or chronic metabolic acidosis or a history of diabetic ketoacidosis. * The subject has a clinically significant abnormality which in the judgment of the investigator makes the subject unsuitable for inclusion in the study (e.g., physical examination, laboratory tests, or electrocardiogram, etc). * The subject has used an investigational agent within 30 days or 5 half-lives (whichever was longer) prior to pre-screening. * The subject is a female who is lactating, pregnant, or planned to become pregnant. * The subject has a prior history of severe edema or a medically serious fluid related event (e.g., heart failure). * The subject has a history of macular edema. * The subject has significant hypersensitivity (e.g., difficulty swallowing, difficulty breathing, and tachycardia or skin reaction) to TZDs, biguanides, or compounds with similar chemical structures. * The subject has a diagnosis of cancer (other than squamous, basal cell, or cervical cancer in-situ) in the past 3 years and is receiving treatment for cancer. * The subject has a history or suspicion of drug abuse or alcohol abuse within the last 6 months. * The subject is known to have severe lactose intolerance. * The subject is not willing to comply with visits and procedures described in the protocol. * The subject has a disease that may affect bone turnover including, but not limited to: Paget's disease, hypercalcemia, hypocalcemia, hyperparathyroidism, hyperthyroidism, osteomalacia, metastatic bone disease * The subject has a weight of greater than 300 lbs (136.4 kg). * The subject has received treatment with bisphosphonates (≥1 month cumulative treatment within the last 12 months) or fluoride (dose greater than 10mg/day within the previous 5 years).

Design outcomes

Primary

Measure	Time frame	Description
Change From Baseline in HbA1c at Week 80	Baseline and Week 80	Blood was taken for serum HbA1c measurements. Change from baseline was calculated as the Week 80 value minus the baseline value. Last observation carried forward (LOCF) was not used for this analysis.

Secondary

Measure	Time frame	Description
Number of Participants Achieving HbA1c <=6.5% and <7% at Week 80	Week 80	Blood was taken for serum Hb1AC measurements. Hb1AC responders were described as participants having achieved Hb1AC \<=6% and \<7% at Week 80 with LOCF from Week 32.
Change in Fasting Plasma Glucose (FPG) From Baseline at Week 80	Baseline and Week 80	Blood was taken for serum FPG measurements. Change from baseline was calculated as the Week 80 value minus the baseline value.
Change From Baseline in FPG at Week 80	Baseline and Week 80	Blood was taken for serum FPG measurements. Change from baseline was calculated as the Week 80 value minus the baseline value with LOCF from Week 32 for withdrawn participants or missing values.
Number of Participants Achieving FPG <=6 mmol/L (110 mg/dL) and <=7 mmol/L (126 mg/dL) at Week 80	Week 80	Blood was taken for serum FPG measurements. FPG responders were described as participants having achieved FPG \<=6 mmol/L (110 mg/dL) and \<7 mmol/L (126 mg/dL) Hb1AC at Week 80 with LOCF from Week 32.
Number of Participants Achieving Treatment Failure	Randomization to treatment failure (up to Week 80)	Treatment failure was defined as an HbA1c level \>= 7% after Week 32 or withdrawal due to insufficient therapeutic effect (ITE) at any time.
Percent Change From Baseline in Total Cholesterol, Low-density Lipoprotein (LDL) Cholesterol, High-density Lipoprotein (HDL) Cholesterol, and Triglycerides at Week 80	Baseline and Week 80	Blood was taken for measurement of total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides. Percent change from baseline at Week 80 was based on log transformed data. Geometric mean, GM; standard error, SE. n is the number of evaluable participants, which is the number of participants with a value at baseline and at the specified visit for the parameter of interest.
Percent Change From Baseline in Adiponectin at Week 80 (United States [US] and Mexico Subset of Participants )	Baseline and Week 80	Blood was taken for measurement of adiponectin. Percent change from baseline at Week 80 was based on log transformed data. This outcome measure was analyzed for a subset of participants in the US and Mexico only.
Percent Change From Baseline in C-reactive Protein (CRP) at Week 80 (US and Mexico Subset of Participants)	Baseline and Week 80	Blood was taken for measurement of CRP. Percent change from baseline at Week 80 was based on log transformed data. This outcome measure was analyzed for a subset of participants in the US and Mexico only.
Percent Change in Free Fatty Acids (FFA) From Baseline at Week 80 (US and Mexico Subset of Participants).	Baseline and Week 80	Blood was taken for measurement of FFA. Percent change from baseline at Week 80 was based on log transformed data. This outcome measure was analyzed for a subset of participants in the US and Mexico only.
Change in Fasting Insulin From Baseline at Week 80 (US and Mexico Subset of Participants)	Baseline and Week 80	Blood was taken for fasting insulin measurements. Change from baseline was calculated as the Week 80 value minus the baseline value, with LOCF from Week 32 for withdrawn participants or missing values. This outcome measure was analyzed for a subset of participants in the US and Mexico only.
Change in C-peptide From Baseline at Week 80 (US and Mexico Subset of Participants)	Baseline and Week 80	Blood was taken for C-peptide measurements. Change from baseline was calculated as the Week 80 value minus the baseline value with LOCF from Week 32 for withdrawn participants or missing values. This outcome measure was analyzed for a subset of participants in the US and Mexico only.
Percent Change From Baseline in in HOMA-S and HOMA-B to Week 80 (US and Mexico Subset of Participants)	Baseline and Week 80	Blood was taken for measurement of homeostasis model assessment for insulin sensitivity (HOMA-S) and beta-cell function (HOMA-B). Percent change from baseline at Week 80 was based on log transformed data. This outcome measure was analyzed for a subset of participants in the US and Mexico only. GM, geometric mean; SE, standard error.
Slope of Delta-cell Function as Estimated by the Ratio deltaI/deltaG	Baseline and Week 80	The ratio Delta I/Delta G is calculated based on the oral glucose tolerance test (OGTT), where Delta I = (30 minute immunoreactive insulin minus 0 minute immunoreactive insulin) and Delta G = (30 minute plasma glucose minus 0 minute plasma glucose). The 0 minute values are fasting insulin and glucose; the 30 minute values are taken 30 minutes after the oral glucose challenge. This outcome measure was analyzed for a subset of participants in the US and Mexico only.
Mean Change From Baseline in HbA1c at Week 80	Baseline and Week 80	Blood was taken for serum Hb1AC measurements. Change from baseline was calculated as the Week 80 value minus the baseline value, with LOCF from Week 32 for withdrawn participants or missing values.
Percent Change From Baseline in Lumbar Spine Bone Mass Density (BMD) at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Baseline and Weeks 20, 56, and 80	BMD was measured by dual X-ray absorptiometry (DXA). The percent change from baseline in BMD at a given timepoint was defined at the participant level by the following formula: percent change = (BMD at given week minus BMD at baseline)/BMD at baseline x 100%. This outcome measure was analyzed for a subset of participants in the bone study only.
Percent Change From Baseline in Total Hip BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Baseline and Weeks 20, 56, and 80	BMD was measured by dual X-ray absorptiometry (DXA). The percent change from baseline in BMD at a given timepoint was defined at the participant level by the following formula: percent change = (BMD at given week minus BMD at baseline)/BMD at baseline x 100. This outcome measure was analyzed for a subset of participants in the bone study only.
Percent Change From Baseline in Trochanter BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Baseline and Weeks 20, 56, and 80	BMD was measured by dual X-ray absorptiometry (DXA). The percent change from baseline in BMD at a given timepoint was defined at the participant level by the following formula: percent change = (BMD at given week minus BMD at baseline)/BMD at baseline x 100. This outcome measure was analyzed for a subset of participants in the bone study only.
Percent Change From Baseline in Femoral Neck BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Baseline and Weeks 20, 56, and 80	BMD was measured by dual X-ray absorptiometry (DXA). The percent change from baseline in BMD at a given timepoint was defined at the participant level by the following formula: percent change = (BMD at given week minus BMD at baseline)/BMD at baseline x 100. This outcome measure was analyzed for a subset of participants in the bone study only.
Percent Change From Baseline in Distal Radius BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Baseline and Weeks 20, 56, and 80	BMD was measured by dual X-ray absorptiometry (DXA). The percent change from baseline in BMD at a given timepoint was defined at the participant level by the following formula: percent change = (BMD at given week minus BMD at baseline)/BMD at baseline x 100. This outcome measure was analyzed for a subset of participants in the bone study only.
Percent Change From Baseline in Total Body BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Baseline and Weeks 20, 56, and 80	BMD was measured by dual X-ray absorptiometry (DXA). The percent change from baseline in BMD at a given timepoint was defined at the participant level by the following formula: percent change = (BMD at given week minus BMD at baseline)/BMD at baseline x 100. This outcome measure was analyzed for a subset of participants in the bone study only.
Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Baseline and Weeks 12, 32, 56, and 80	Blood was taken for measurement of serum calcium. Percent change from baseline was based on log transformed data. Geometric mean, GM; standard error, SE. This outcome measure was analyzed for a subset of participants in the bone study only. n is the number of evaluable participants, which is the number of participants with a value at baseline and at the specified visit for the parameter of interest.
Percent Change From Baseline in Intact Parathyroid Hormone at Week 80	Baseline and Week 80	Blood was taken for measurement of intact parathyroid hormone. Percent change from baseline was based on log transformed data. Standard error, SE; Wk, Week; %, percent. This outcome measure was analyzed for a subset of participants in the bone study only. n is the number of evaluable participants, which is the number of participants with a value at baseline and at the specified visit for the parameter of interest.
Percent Change From Baseline in 25-hydroxy Vitamin D at Week 80	Baseline and Week 80	Blood was taken for measurement of 25-hydroxy vitamin D. Percent change from baseline was based on log transformed data. Standard error, SE; Wk, Week; %, percent. This outcome measure was analyzed for a subset of participants in the bone study only. n is the number of evaluable participants, which is the number of participants with a value at baseline and at the specified visit for the parameter of interest.
Percent Change From Baseline in Estradiol at Weeks 20, 56, and 80	Baseline and Weeks 20, 56, and 80	Blood was taken for measurement of estradiol. Percent change from baseline was based on log transformed data. Standard error, SE; Wk, Week; %, percent. This outcome measure was analyzed for a subset of female participants in the bone study only. n is the number of evaluable participants, which is the number of female participants with a value at baseline and at the specified visit for the parameter of interest.
Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Baseline and Weeks 20, 56, and 80	Blood was taken for measurement of CTX. Percent change from baseline was based on log transformed data. Standard error, SE; Wk, Week; %, percent. This outcome measure was analyzed for a subset of participants in the bone study only. n is the number of evaluable participants, which is the number of participants with a value at baseline and at the specified visit for the parameter of interest.
Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Baseline and Weeks 20, 56, and 80	Blood was taken for measurement of P1NP. Percent change from baseline was based on log transformed data. Standard error, SE; Wk, Week; %, percent. This outcome measure was analyzed for a subset of participants in the bone study only. n is the number of evaluable participants, which is the number of participants with a value at baseline and at the specified visit for the parameter of interest.
Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Baseline and Weeks 20, 56, and 80	Blood was taken for measurement of BSAP. Percent change from baseline was based on log transformed data. Standard error, SE; Wk, Week; %, percent. This outcome measure was analyzed for a subset of participants in the bone study only. n is the number of evaluable participants, which is the number of participants with a value at baseline and at the specified visit for the parameter of interest.
Number of Participants at Final Dose Level	Baseline to Week 80 or withdrawal	—

Countries

Argentina, Brazil, Canada, Mexico, Pakistan, Philippines, South Korea, Taiwan, United States

Participant flow

Participants by arm

Arm	Count
Metformin Beginning dose of Metformin (MET) 500 milligrams (mg) once a day. Dose could be increased up to a maximum dose of MET 2000 mg.	334
Avandamet Beginning dose of Avandamet (AVM) 4 mg/500 mg once a day. Dose could be increased up to a maximum dose of 8 mg/2000 mg.	344
Total	678

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	7.6% bone loss	1	0
Overall Study	Adverse Event	15	25
Overall Study	Bad metabolic control & patient security	1	0
Overall Study	BMD <2.5	1	0
Overall Study	Bone loss by DXA bone scan	1	0
Overall Study	Bone mass density (BMD) loss >6%	4	4
Overall Study	Consecutive elevated Hba1C	1	0
Overall Study	DBP 93 mmHg at randomization	1	0
Overall Study	Death	0	1
Overall Study	Did not receive study medication	6	4
Overall Study	Didn't meet entry criteria	1	1
Overall Study	Excessive bone loss vs. baseline value	0	1
Overall Study	Hb1Ac >8%	0	1
Overall Study	Insufficient therapeutic effect	30	6
Overall Study	Laboratory findings	1	0
Overall Study	Lost to Follow-up	29	29
Overall Study	Non-compliance	18	19
Overall Study	Osteoporosis	0	1
Overall Study	Osteoporosis findings on Visit 2 DXA	0	1
Overall Study	Out of country for 5 months	1	0
Overall Study	Participant moving out of state	2	0
Overall Study	Participant randomized in error	1	0
Overall Study	Participant's concern due to CPK levels	1	0
Overall Study	Participant's PCP wanted to stop drug	1	0
Overall Study	Positive pregnancy test	1	3
Overall Study	Protocol Violation	5	3
Overall Study	Visit 11 DXA showed excessive bone loss	0	1
Overall Study	Withdrawal by Subject	32	31

Baseline characteristics

Characteristic	Metformin	Avandamet	Total
Age, Continuous	50.7 years STANDARD_DEVIATION 10.49	51.5 years STANDARD_DEVIATION 10.52	51.1 years STANDARD_DEVIATION 10.5
Duration of Diabetes	2.570 years STANDARD_DEVIATION 3.2671	2.293 years STANDARD_DEVIATION 3.0774	2.429 years STANDARD_DEVIATION 3.1729
Race/Ethnicity, Customized African America/African	13 participants	17 participants	30 participants
Race/Ethnicity, Customized American Indian or Alaskan Native	3 participants	7 participants	10 participants
Race/Ethnicity, Customized Asian - Central/South Asian	23 participants	22 participants	45 participants
Race/Ethnicity, Customized Asian - East Asian	44 participants	51 participants	95 participants
Race/Ethnicity, Customized Asian - Japanese	0 participants	1 participants	1 participants
Race/Ethnicity, Customized Asian - South East Asian	48 participants	48 participants	96 participants
Race/Ethnicity, Customized Mixed Race	5 participants	5 participants	10 participants
Race/Ethnicity, Customized Not Specified	9 participants	7 participants	16 participants
Race/Ethnicity, Customized White - Arabic/North African	4 participants	3 participants	7 participants
Race/Ethnicity, Customized White - White/Caucasian/European	185 participants	183 participants	368 participants
Sex: Female, Male Female	158 Participants	160 Participants	318 Participants
Sex: Female, Male Male	176 Participants	184 Participants	360 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	159 / 334	145 / 344
serious Total, serious adverse events	27 / 334	28 / 344

Outcome results

Primary

Change From Baseline in HbA1c at Week 80

Blood was taken for serum HbA1c measurements. Change from baseline was calculated as the Week 80 value minus the baseline value. Last observation carried forward (LOCF) was not used for this analysis.

Time frame: Baseline and Week 80

Population: Intent-to-Treat (ITT) Population: all participants who were randomized, received at least one dose of study medication, and had both a baseline and at least one on-therapy value. Only evaluable participants, defined as the number of participants with a baseline and at least one post baseline assessment, were analyzed.

Arm	Measure	Group	Value (MEAN)	Dispersion
Metformin	Change From Baseline in HbA1c at Week 80	Baseline	8.64 percent change	Standard Error 0.053
Metformin	Change From Baseline in HbA1c at Week 80	Change from Baseline	-1.36 percent change	Standard Error 0.073
Avandamet	Change From Baseline in HbA1c at Week 80	Baseline	8.64 percent change	Standard Error 0.055
Avandamet	Change From Baseline in HbA1c at Week 80	Change from Baseline	-1.85 percent change	Standard Error 0.07

p-value: <0.000195% CI: [-0.69, -0.3]Repeated measures analysis

Secondary

Change From Baseline in FPG at Week 80

Blood was taken for serum FPG measurements. Change from baseline was calculated as the Week 80 value minus the baseline value with LOCF from Week 32 for withdrawn participants or missing values.

Time frame: Baseline and Week 80

Population: Week 32 Evaluable Population with LOCF. Only evaluable participants, defined as participants with a value at baseline and at the specified visit for the parameter of interest, were analyzed.

Arm	Measure	Group	Value (MEAN)	Dispersion
Metformin	Change From Baseline in FPG at Week 80	Baseline	10.37 mmol/l	Standard Deviation 3.268
Metformin	Change From Baseline in FPG at Week 80	Change from Baseline	-2.53 mmol/l	Standard Deviation 3.165
Avandamet	Change From Baseline in FPG at Week 80	Baseline	10.13 mmol/l	Standard Deviation 2.927
Avandamet	Change From Baseline in FPG at Week 80	Change from Baseline	-3.39 mmol/l	Standard Deviation 2.908

p-value: <0.00195% CI: [-1.425, -0.71]ANCOVA

Secondary

Change in C-peptide From Baseline at Week 80 (US and Mexico Subset of Participants)

Blood was taken for C-peptide measurements. Change from baseline was calculated as the Week 80 value minus the baseline value with LOCF from Week 32 for withdrawn participants or missing values. This outcome measure was analyzed for a subset of participants in the US and Mexico only.

Time frame: Baseline and Week 80

Population: Week 32 Evaluable Population with LOCF for US and Mexico subset. Only evaluable participants, defined as participants with a value at baseline and at the specified visit for the parameter of interest, were analyzed.

Arm	Measure	Value (MEAN)	Dispersion
Metformin	Change in C-peptide From Baseline at Week 80 (US and Mexico Subset of Participants)	-0.244 mmol/l	Standard Error 0.0518
Avandamet	Change in C-peptide From Baseline at Week 80 (US and Mexico Subset of Participants)	-0.473 mmol/l	Standard Error 0.0502

p-value: 0.000695% CI: [-0.359, -0.099]ANCOVA

Secondary

Change in Fasting Insulin From Baseline at Week 80 (US and Mexico Subset of Participants)

Blood was taken for fasting insulin measurements. Change from baseline was calculated as the Week 80 value minus the baseline value, with LOCF from Week 32 for withdrawn participants or missing values. This outcome measure was analyzed for a subset of participants in the US and Mexico only.

Time frame: Baseline and Week 80

Arm	Measure	Value (MEAN)	Dispersion
Metformin	Change in Fasting Insulin From Baseline at Week 80 (US and Mexico Subset of Participants)	-1.5 picomoles per Liter (pmol/l)	Standard Error 9.18
Avandamet	Change in Fasting Insulin From Baseline at Week 80 (US and Mexico Subset of Participants)	-35.2 picomoles per Liter (pmol/l)	Standard Error 8.79

p-value: 0.004295% CI: [-56.666, -0.99]ANCOVA

Secondary

Change in Fasting Plasma Glucose (FPG) From Baseline at Week 80

Blood was taken for serum FPG measurements. Change from baseline was calculated as the Week 80 value minus the baseline value.

Time frame: Baseline and Week 80

Population: ITT Population. Only evaluable participants, defined as the number of participants with a baseline and at least one post baseline assessment, were analyzed. Last observation carried forward (LOCF) was not used for this analysis.

Arm	Measure	Group	Value (MEAN)	Dispersion
Metformin	Change in Fasting Plasma Glucose (FPG) From Baseline at Week 80	Baseline	10.52 millimoles per Liter (mmol/l)	Standard Error 0.184
Metformin	Change in Fasting Plasma Glucose (FPG) From Baseline at Week 80	Change from Baseline	-2.25 millimoles per Liter (mmol/l)	Standard Error 0.147
Avandamet	Change in Fasting Plasma Glucose (FPG) From Baseline at Week 80	Baseline	10.17 millimoles per Liter (mmol/l)	Standard Error 0.162
Avandamet	Change in Fasting Plasma Glucose (FPG) From Baseline at Week 80	Change from Baseline	-3.41 millimoles per Liter (mmol/l)	Standard Error 0.139

p-value: <0.000195% CI: [-1.54, -0.77]Repeated measures analysis

Secondary

Mean Change From Baseline in HbA1c at Week 80

Blood was taken for serum Hb1AC measurements. Change from baseline was calculated as the Week 80 value minus the baseline value, with LOCF from Week 32 for withdrawn participants or missing values.

Time frame: Baseline and Week 80

Population: Week 32 Evaluable Population with LOCF: a subset of the ITT Population with LOCF starting at Week 32. Only participants with assessment(s) at Week 32 or later were included in this population. Only evaluable participants, defined as participants with a value at baseline and at the specified visit for the parameter of interest, were analyzed.

Arm	Measure	Group	Value (MEAN)	Dispersion
Metformin	Mean Change From Baseline in HbA1c at Week 80	Baseline	8.59 percent change	Standard Deviation 0.898
Metformin	Mean Change From Baseline in HbA1c at Week 80	Change from Baseline	-1.42 percent change	Standard Deviation 0.07
Avandamet	Mean Change From Baseline in HbA1c at Week 80	Baseline	8.66 percent change	Standard Deviation 0.954
Avandamet	Mean Change From Baseline in HbA1c at Week 80	Change from Baseline	-1.91 percent change	Standard Deviation 0.069

p-value: <0.000195% CI: [-0.669, -0.305]ANCOVA

Secondary

Number of Participants Achieving FPG <=6 mmol/L (110 mg/dL) and <=7 mmol/L (126 mg/dL) at Week 80

Blood was taken for serum FPG measurements. FPG responders were described as participants having achieved FPG \<=6 mmol/L (110 mg/dL) and \<7 mmol/L (126 mg/dL) Hb1AC at Week 80 with LOCF from Week 32.

Time frame: Week 80

Arm	Measure	Group	Value (NUMBER)
Metformin	Number of Participants Achieving FPG <=6 mmol/L (110 mg/dL) and <=7 mmol/L (126 mg/dL) at Week 80	FPG <=6.1 mmol/l	31 participants
Metformin	Number of Participants Achieving FPG <=6 mmol/L (110 mg/dL) and <=7 mmol/L (126 mg/dL) at Week 80	FPG <=7.0 mmol/l	55 participants
Avandamet	Number of Participants Achieving FPG <=6 mmol/L (110 mg/dL) and <=7 mmol/L (126 mg/dL) at Week 80	FPG <=6.1 mmol/l	83 participants
Avandamet	Number of Participants Achieving FPG <=6 mmol/L (110 mg/dL) and <=7 mmol/L (126 mg/dL) at Week 80	FPG <=7.0 mmol/l	133 participants

p-value: <0.000195% CI: [2.94, 6.81]Regression, Logistic

p-value: <0.000195% CI: [2.25, 4.92]Regression, Logistic

Secondary

Number of Participants Achieving HbA1c <=6.5% and <7% at Week 80

Blood was taken for serum Hb1AC measurements. Hb1AC responders were described as participants having achieved Hb1AC \<=6% and \<7% at Week 80 with LOCF from Week 32.

Time frame: Week 80

Arm	Measure	Group	Value (NUMBER)
Metformin	Number of Participants Achieving HbA1c <=6.5% and <7% at Week 80	<=6.5%	97 participants
Metformin	Number of Participants Achieving HbA1c <=6.5% and <7% at Week 80	<7%	133 participants
Avandamet	Number of Participants Achieving HbA1c <=6.5% and <7% at Week 80	<=6.5%	128 participants
Avandamet	Number of Participants Achieving HbA1c <=6.5% and <7% at Week 80	<7%	184 participants

p-value: 0.004695% CI: [1.18, 2.46]Regression, Logistic

p-value: <0.000195% CI: [1.75, 3.81]Regression, Logistic

Secondary

Number of Participants Achieving Treatment Failure

Treatment failure was defined as an HbA1c level \>= 7% after Week 32 or withdrawal due to insufficient therapeutic effect (ITE) at any time.

Time frame: Randomization to treatment failure (up to Week 80)

Population: ITT Population. Only evaluable participants, defined as the number of subjects with a baseline and at least one post baseline assessment, were analyzed. Last observation carried forward (LOCF) was not used for this analysis

Arm	Measure	Value (NUMBER)
Metformin	Number of Participants Achieving Treatment Failure	156 participants
Avandamet	Number of Participants Achieving Treatment Failure	114 participants

p-value: <0.000195% CI: [0.45, 0.74]Regression, Cox

Secondary

Number of Participants at Final Dose Level

Time frame: Baseline to Week 80 or withdrawal

Population: Safety population. This population consisted of all participants who were randomized and received at least one dose of the study medication.

Arm	Measure	Group	Value (NUMBER)
Metformin	Number of Participants at Final Dose Level	Dose level 1 AVM 4 mg/500 mg, MET 500 mg	17 participants
Metformin	Number of Participants at Final Dose Level	Dose level 2 AVM 4 mg/1000 mg, MET 1000 mg	16 participants
Metformin	Number of Participants at Final Dose Level	Dose level 3 AVM 6 mg/1500 mg, MET 1500 mg	27 participants
Metformin	Number of Participants at Final Dose Level	Dose level 4 AVM 8 mg/2000 mg, MET 2000 mg	236 participants
Avandamet	Number of Participants at Final Dose Level	Dose level 4 AVM 8 mg/2000 mg, MET 2000 mg	242 participants
Avandamet	Number of Participants at Final Dose Level	Dose level 1 AVM 4 mg/500 mg, MET 500 mg	19 participants
Avandamet	Number of Participants at Final Dose Level	Dose level 3 AVM 6 mg/1500 mg, MET 1500 mg	34 participants
Avandamet	Number of Participants at Final Dose Level	Dose level 2 AVM 4 mg/1000 mg, MET 1000 mg	18 participants

Secondary

Percent Change From Baseline in 25-hydroxy Vitamin D at Week 80

Blood was taken for measurement of 25-hydroxy vitamin D. Percent change from baseline was based on log transformed data. Standard error, SE; Wk, Week; %, percent. This outcome measure was analyzed for a subset of participants in the bone study only. n is the number of evaluable participants, which is the number of participants with a value at baseline and at the specified visit for the parameter of interest.

Time frame: Baseline and Week 80

Population: Week 20 Evaluable for the Bone Sub-study Population. This is a subset of the bone sub-study with LOCF from Week 20. Only participants with 25-hydroxy vitamin D measurements at Week 20 or later were included.

Arm	Measure	Group	Value (NUMBER)
Metformin	Percent Change From Baseline in 25-hydroxy Vitamin D at Week 80	Wk80 % change, males n=16, 21	-4.4369 percent change
Metformin	Percent Change From Baseline in 25-hydroxy Vitamin D at Week 80	Wk 80 % change - SE, females n= 29, 17	-24.8664 percent change
Metformin	Percent Change From Baseline in 25-hydroxy Vitamin D at Week 80	Wk80 % change, overall n=45, 38	-13.9678 percent change
Metformin	Percent Change From Baseline in 25-hydroxy Vitamin D at Week 80	Wk80 % change + SE, premenopausal females n=13, 7	-2.0833 percent change
Metformin	Percent Change From Baseline in 25-hydroxy Vitamin D at Week 80	Wk80 % change - SE, males n=16, 21	-16.1896 percent change
Metformin	Percent Change From Baseline in 25-hydroxy Vitamin D at Week 80	Wk80 % change, premenopausal females n= 13, 7	-15.3838 percent change
Metformin	Percent Change From Baseline in 25-hydroxy Vitamin D at Week 80	Wk80 % change + SE, males n=16, 21	8.9639 percent change
Metformin	Percent Change From Baseline in 25-hydroxy Vitamin D at Week 80	Wk80 % change - SE, premenopausal females n=13, 7	-26.8776 percent change
Metformin	Percent Change From Baseline in 25-hydroxy Vitamin D at Week 80	Wk80 % change + SE, females n= 29, 17	-7.1080 percent change
Metformin	Percent Change From Baseline in 25-hydroxy Vitamin D at Week 80	Wk80 % change+ SE, postmenopausal females n=16, 10	8.8368 percent change
Metformin	Percent Change From Baseline in 25-hydroxy Vitamin D at Week 80	Wk 80 % change - SE, overall n= 45, 38	-20.4091 percent change
Metformin	Percent Change From Baseline in 25-hydroxy Vitamin D at Week 80	Wk80 % change, postmenopausal females n=16, 10	-7.1318 percent change
Metformin	Percent Change From Baseline in 25-hydroxy Vitamin D at Week 80	Wk80 % change, females n=29, 17	-16.4578 percent change
Metformin	Percent Change From Baseline in 25-hydroxy Vitamin D at Week 80	Wk80% change - SE, postmenopausal females n=16, 10	-20.7575 percent change
Metformin	Percent Change From Baseline in 25-hydroxy Vitamin D at Week 80	Wk80 % change + SE, overall n= 45, 38	-7.0053 percent change
Avandamet	Percent Change From Baseline in 25-hydroxy Vitamin D at Week 80	Wk80% change - SE, postmenopausal females n=16, 10	-19.3620 percent change
Avandamet	Percent Change From Baseline in 25-hydroxy Vitamin D at Week 80	Wk80 % change + SE, overall n= 45, 38	-4.6305 percent change
Avandamet	Percent Change From Baseline in 25-hydroxy Vitamin D at Week 80	Wk80 % change, overall n=45, 38	-12.9210 percent change
Avandamet	Percent Change From Baseline in 25-hydroxy Vitamin D at Week 80	Wk 80 % change - SE, overall n= 45, 38	-20.4909 percent change
Avandamet	Percent Change From Baseline in 25-hydroxy Vitamin D at Week 80	Wk80 % change + SE, males n=16, 21	-4.2837 percent change
Avandamet	Percent Change From Baseline in 25-hydroxy Vitamin D at Week 80	Wk80 % change, males n=16, 21	-14.1507 percent change
Avandamet	Percent Change From Baseline in 25-hydroxy Vitamin D at Week 80	Wk80 % change - SE, males n=16, 21	-23.0005 percent change
Avandamet	Percent Change From Baseline in 25-hydroxy Vitamin D at Week 80	Wk80 % change + SE, females n= 29, 17	4.7124 percent change
Avandamet	Percent Change From Baseline in 25-hydroxy Vitamin D at Week 80	Wk80 % change, females n=29, 17	-9.0412 percent change
Avandamet	Percent Change From Baseline in 25-hydroxy Vitamin D at Week 80	Wk 80 % change - SE, females n= 29, 17	-20.9882 percent change
Avandamet	Percent Change From Baseline in 25-hydroxy Vitamin D at Week 80	Wk80 % change + SE, premenopausal females n=13, 7	0.3546 percent change
Avandamet	Percent Change From Baseline in 25-hydroxy Vitamin D at Week 80	Wk80 % change, premenopausal females n= 13, 7	-16.2325 percent change
Avandamet	Percent Change From Baseline in 25-hydroxy Vitamin D at Week 80	Wk80 % change - SE, premenopausal females n=13, 7	-30.0781 percent change
Avandamet	Percent Change From Baseline in 25-hydroxy Vitamin D at Week 80	Wk80 % change+ SE, postmenopausal females n=16, 10	17.3807 percent change
Avandamet	Percent Change From Baseline in 25-hydroxy Vitamin D at Week 80	Wk80 % change, postmenopausal females n=16, 10	-2.7100 percent change

p-value: 0.906995% CI: [-17.6057, 24.3392]ANCOVA

p-value: 0.511895% CI: [-35.6298, 25.3742]ANCOVA

p-value: 0.581695% CI: [-20.2636, 48.6692]ANCOVA

p-value: 0.958795% CI: [-35.928, 52.959]ANCOVA

p-value: 0.833795% CI: [-34.4741, 67.4901]ANCOVA

Secondary

Percent Change From Baseline in Adiponectin at Week 80 (United States [US] and Mexico Subset of Participants )

Blood was taken for measurement of adiponectin. Percent change from baseline at Week 80 was based on log transformed data. This outcome measure was analyzed for a subset of participants in the US and Mexico only.

Time frame: Baseline and Week 80

Population: Week 32 Evaluable Population with LOCF for US and Mexico subset. Only evaluable participants, defined as the number of participants with a value at baseline and at the specified visit for the parameter of interest, were analyzed.

Arm	Measure	Group	Value (NUMBER)
Metformin	Percent Change From Baseline in Adiponectin at Week 80 (United States [US] and Mexico Subset of Participants )	Percent change from baseline + SE	18.58 percent change
Metformin	Percent Change From Baseline in Adiponectin at Week 80 (United States [US] and Mexico Subset of Participants )	Percent change from baseline	12.96 percent change
Metformin	Percent Change From Baseline in Adiponectin at Week 80 (United States [US] and Mexico Subset of Participants )	Percent change from baseline - SE	7.61 percent change
Avandamet	Percent Change From Baseline in Adiponectin at Week 80 (United States [US] and Mexico Subset of Participants )	Percent change from baseline + SE	139.28 percent change
Avandamet	Percent Change From Baseline in Adiponectin at Week 80 (United States [US] and Mexico Subset of Participants )	Percent change from baseline	128.44 percent change
Avandamet	Percent Change From Baseline in Adiponectin at Week 80 (United States [US] and Mexico Subset of Participants )	Percent change from baseline - SE	118.10 percent change

p-value: <0.000195% CI: [79.23, 128.19]ANCOVA

Secondary

Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80

Blood was taken for measurement of BSAP. Percent change from baseline was based on log transformed data. Standard error, SE; Wk, Week; %, percent. This outcome measure was analyzed for a subset of participants in the bone study only. n is the number of evaluable participants, which is the number of participants with a value at baseline and at the specified visit for the parameter of interest.

Time frame: Baseline and Weeks 20, 56, and 80

Population: Week 20 Evaluable for the Bone Sub-study Population. This is a subset of the bone sub-study with LOCF from Week 20. Only participants with BSAP measurements at Week 20 or later were included.

Arm	Measure	Group	Value (NUMBER)
Metformin	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk80 % change + SE, overall n=72, 64	-21.19 percent change
Metformin	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk80 % change, overall n=72, 64	-24.23 percent change
Metformin	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk80 % change - SE, overall n=72, 64	-27.15 percent change
Metformin	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk56 % change + SE, overall n=72, 64	-18.29 percent change
Metformin	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk56 % change, overall n=72, 64	-21.52 percent change
Metformin	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk56 % change - SE, overall n=72, 64	-24.61 percent change
Metformin	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk20 % change + SE, overall n=66, 59	-24.16 percent change
Metformin	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk20 % change, overall n=66, 59	-26.46 percent change
Metformin	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk20 % change - SE, overall n=66, 59	-28.70 percent change
Metformin	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk80 % change + SE, males n=30, 32	-15.44 percent change
Metformin	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk80 % change, males n=30, 32	-20.35 percent change
Metformin	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk80 % change - SE, males n=30, 32	-24.97 percent change
Metformin	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk56 % change + SE, males n=30, 32	-12.22 percent change
Metformin	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk56 % change, males n=30, 32	-17.05 percent change
Metformin	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk56 % change - SE, males n=30, 32	-21.62 percent change
Metformin	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk20 % change + SE, males n=26, 29	-16.27 percent change
Metformin	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk20 % change, males n=26, 29	-20.50 percent change
Metformin	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk20 % change - SE, males n=26, 29	-24.51 percent change
Metformin	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk80 % change + SE, females n=42, 32	-24.30 percent change
Metformin	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk80 % change, females n=42, 32	-28.11 percent change
Metformin	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk80 % change - SE, females n=42, 32	-31.74 percent change
Metformin	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk56 % change + SE, females n=42, 32	-22.54 percent change
Metformin	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk56 % change, females n=42, 32	-26.75 percent change
Metformin	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk56 % change - SE, females n=42, 32	-30.73 percent change
Metformin	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk20 % change + SE, females n=40, 30	-26.82 percent change
Metformin	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk20 % change, females n=40, 30	-30.23 percent change
Metformin	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk20 % change - SE, females n=40, 30	-33.48 percent change
Metformin	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk80 % change + SE, premenopausal females n=19, 10	-13.89 percent change
Metformin	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk80 % change, premenopausal females n=19, 10	-19.28 percent change
Metformin	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk80 % change - SE, premenopausal females n=19, 10	-24.33 percent change
Metformin	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk56 % change + SE, premenopausal females n=19, 10	-12.43 percent change
Metformin	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk56 % change, premenopausal females n=19, 10	-16.84 percent change
Metformin	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk56 % change - SE, premenopausal females n=19, 10	-21.02 percent change
Metformin	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk20 % change + SE, premenopausal females n=17, 10	-24.73 percent change
Metformin	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk20 % change, premenopausal females n=17, 10	-29.57 percent change
Metformin	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk20 % change - SE, premenopausal females n=17, 10	-34.10 percent change
Metformin	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk80 % change+ SE, postmenopausal females n=23, 22	-29.10 percent change
Metformin	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk80 % change, postmenopausal females n=23, 22	-34.39 percent change
Metformin	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk80% change - SE, postmenopausal females n=23, 22	-39.29 percent change
Metformin	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk56 % change+ SE, postmenopausal females n=23, 22	-27.51 percent change
Metformin	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk56 % change, postmenopausal females n=23, 22	-34.04 percent change
Metformin	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk56% change - SE, postmenopausal females n=23, 22	-39.99 percent change
Metformin	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk20 % change+ SE, postmenopausal females n=23, 20	-28.14 percent change
Metformin	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk20 % change, postmenopausal females n=23, 20	-32.70 percent change
Metformin	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk20% change - SE, postmenopausal females n=23, 20	-36.97 percent change
Avandamet	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk56 % change, females n=42, 32	-28.77 percent change
Avandamet	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk80 % change + SE, overall n=72, 64	-23.30 percent change
Avandamet	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk56 % change+ SE, postmenopausal females n=23, 22	-23.61 percent change
Avandamet	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk80 % change, overall n=72, 64	-26.37 percent change
Avandamet	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk56 % change - SE, females n=42, 32	-33.17 percent change
Avandamet	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk80 % change - SE, overall n=72, 64	-29.31 percent change
Avandamet	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk20 % change, premenopausal females n=17, 10	-37.68 percent change
Avandamet	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk56 % change + SE, overall n=72, 64	-24.39 percent change
Avandamet	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk20 % change + SE, females n=40, 30	-31.60 percent change
Avandamet	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk56 % change, overall n=72, 64	-27.48 percent change
Avandamet	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk20 % change+ SE, postmenopausal females n=23, 20	-32.02 percent change
Avandamet	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk56 % change - SE, overall n=72, 64	-30.45 percent change
Avandamet	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk20 % change, females n=40, 30	-35.23 percent change
Avandamet	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk20 % change + SE, overall n=66, 59	-31.02 percent change
Avandamet	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk20 % change - SE, premenopausal females n=17, 10	-42.32 percent change
Avandamet	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk20 % change, overall n=66, 59	-33.31 percent change
Avandamet	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk20 % change - SE, females n=40, 30	-38.66 percent change
Avandamet	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk20 % change - SE, overall n=66, 59	-35.53 percent change
Avandamet	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk56 % change, postmenopausal females n=23, 22	-31.20 percent change
Avandamet	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk80 % change + SE, males n=30, 32	-21.18 percent change
Avandamet	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk80 % change + SE, premenopausal females n=19, 10	-23.69 percent change
Avandamet	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk80 % change, males n=30, 32	-25.34 percent change
Avandamet	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk80 % change+ SE, postmenopausal females n=23, 22	-25.82 percent change
Avandamet	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk80 % change - SE, males n=30, 32	-29.27 percent change
Avandamet	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk80 % change, premenopausal females n=19, 10	-29.89 percent change
Avandamet	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk56 % change + SE, males n=30, 32	-21.97 percent change
Avandamet	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk20% change - SE, postmenopausal females n=23, 20	-41.50 percent change
Avandamet	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk56 % change, males n=30, 32	-25.87 percent change
Avandamet	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk80 % change - SE, premenopausal females n=19, 10	-35.59 percent change
Avandamet	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk56 % change - SE, males n=30, 32	-29.57 percent change
Avandamet	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk80 % change, postmenopausal females n=23, 22	-31.93 percent change
Avandamet	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk20 % change + SE, males n=26, 29	-26.59 percent change
Avandamet	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk56 % change + SE, premenopausal females n=19, 10	-27.74 percent change
Avandamet	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk20 % change, males n=26, 29	-30.05 percent change
Avandamet	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk56% change - SE, postmenopausal females n=23, 22	-38.04 percent change
Avandamet	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk20 % change - SE, males n=26, 29	-33.35 percent change
Avandamet	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk56 % change, premenopausal females n=19, 10	-32.47 percent change
Avandamet	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk80 % change + SE, females n=42, 32	-23.20 percent change
Avandamet	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk80% change - SE, postmenopausal females n=23, 22	-37.54 percent change
Avandamet	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk80 % change, females n=42, 32	-27.60 percent change
Avandamet	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk56 % change - SE, premenopausal females n=19, 10	-36.89 percent change
Avandamet	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk80 % change - SE, females n=42, 32	-31.74 percent change
Avandamet	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk20 % change, postmenopausal females n=23, 20	-36.94 percent change
Avandamet	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk56 % change + SE, females n=42, 32	-24.09 percent change
Avandamet	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Wk20 % change + SE, premenopausal females n=17, 10	-32.69 percent change

p-value: 0.517695% CI: [-10.97, 6.06]ANCOVA

p-value: 0.36295% CI: [-18.62, 7.97]ANCOVA

p-value: 0.911595% CI: [-11.39, 14.48]ANCOVA

p-value: 0.195695% CI: [-30.35, 8.31]ANCOVA

p-value: 0.674995% CI: [-13.09, 23.85]ANCOVA

Secondary

Percent Change From Baseline in C-reactive Protein (CRP) at Week 80 (US and Mexico Subset of Participants)

Blood was taken for measurement of CRP. Percent change from baseline at Week 80 was based on log transformed data. This outcome measure was analyzed for a subset of participants in the US and Mexico only.

Time frame: Baseline and Week 80

Arm	Measure	Group	Value (NUMBER)
Metformin	Percent Change From Baseline in C-reactive Protein (CRP) at Week 80 (US and Mexico Subset of Participants)	Percent change from baseline + SE	-6.49 percent change
Metformin	Percent Change From Baseline in C-reactive Protein (CRP) at Week 80 (US and Mexico Subset of Participants)	Percent change from baseline	-10.63 percent change
Metformin	Percent Change From Baseline in C-reactive Protein (CRP) at Week 80 (US and Mexico Subset of Participants)	Percent change from baseline - SE	-14.59 percent change
Avandamet	Percent Change From Baseline in C-reactive Protein (CRP) at Week 80 (US and Mexico Subset of Participants)	Percent change from baseline + SE	14.28 percent change
Avandamet	Percent Change From Baseline in C-reactive Protein (CRP) at Week 80 (US and Mexico Subset of Participants)	Percent change from baseline	-17.96 percent change
Avandamet	Percent Change From Baseline in C-reactive Protein (CRP) at Week 80 (US and Mexico Subset of Participants)	Percent change from baseline - SE	-21.49 percent change

p-value: 0.13895% CI: [-18.04, 2.82]ANCOVA

Secondary

Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80

Blood was taken for measurement of CTX. Percent change from baseline was based on log transformed data. Standard error, SE; Wk, Week; %, percent. This outcome measure was analyzed for a subset of participants in the bone study only. n is the number of evaluable participants, which is the number of participants with a value at baseline and at the specified visit for the parameter of interest.

Time frame: Baseline and Weeks 20, 56, and 80

Population: Week 20 Evaluable for the Bone Sub-study Population. This is a subset of the bone sub-study with LOCF from Week 20. Only participants with CTX measurements at Week 20 or later were included.

Arm	Measure	Group	Value (NUMBER)
Metformin	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk80 % change + SE, females n=41, 30	-12.9 percent change
Metformin	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk20 % change, overall n=61, 56	-5.5 percent change
Metformin	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk80 % change, females n=41, 30	-20.1 percent change
Metformin	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk20 % change+ SE, postmenopausal females n=22, 18	4.1 percent change
Metformin	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk80 % change - SE, females n=41, 30	-26.6 percent change
Metformin	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk20 % change - SE, overall n=61, 56	-9.9 percent change
Metformin	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk56 % change + SE, females n=40, 30	-8.5 percent change
Metformin	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk80 % change - SE, overall n=79, 62	-24.2 percent change
Metformin	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk56 % change, females n=40, 30	-15.8 percent change
Metformin	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk80 % change + SE, males n=28, 32	-11.0 percent change
Metformin	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk56 % change - SE, females n=40, 30	-22.5 percent change
Metformin	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk20% change - SE, postmenopausal females n=22, 18	-14.7 percent change
Metformin	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk20 % change + SE, females n=38, 27	-2.5 percent change
Metformin	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk80 % change, males n=28, 32	-20.7 percent change
Metformin	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk20 % change, females n=38, 27	-8.9 percent change
Metformin	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk56 % change + SE, overall n=68, 62	-5.3 percent change
Metformin	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk20 % change - SE, females n=38, 27	-15.0 percent change
Metformin	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk80 % change - SE, males n=28, 32	-29.2 percent change
Metformin	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk80 % change + SE, premenopausal females n=18, 9	-18.6 percent change
Metformin	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk56% change - SE, postmenopausal females n=22, 21	-13.0 percent change
Metformin	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk80 % change, premenopausal females n=18, 9	-27.8 percent change
Metformin	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk56 % change + SE, males n=28, 32	-11.5 percent change
Metformin	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk80 % change - SE, premenopausal females n=18, 9	-36.0 percent change
Metformin	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk56 % change, overall n=68, 62	-11.4 percent change
Metformin	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk56 % change + SE, premenopausal females n=18, 9	-25.5 percent change
Metformin	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk56 % change, males n=28, 32	-20.0 percent change
Metformin	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk56 % change, premenopausal females n=18, 9	-31.8 percent change
Metformin	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk80 % change + SE, overall n=69, 62	-12.7 percent change
Metformin	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk56 % change - SE, premenopausal females n=18, 9	-37.5 percent change
Metformin	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk56 % change - SE, males n=28, 32	-27.7 percent change
Metformin	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk20 % change + SE, premenopausal females n=16, 9	-4.2 percent change
Metformin	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk56 % change - SE, overall n=68, 62	-17.1 percent change
Metformin	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk20 % change, premenopausal females n=16, 9	-14.0 percent change
Metformin	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk20 % change + SE, males n=23, 29	4.8 percent change
Metformin	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk20 % change - SE, premenopausal females n=16, 9	-22.8 percent change
Metformin	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk20 % change, postmenopausal females n=22, 18	-5.8 percent change
Metformin	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk80 % change+ SE, postmenopausal females n=23, 21	-11.5 percent change
Metformin	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk20 % change, males n=23, 29	-3.1 percent change
Metformin	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk80 % change, postmenopausal females n=23, 21	-21.0 percent change
Metformin	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk20 % change + SE, overall n=61, 56	-0.8 percent change
Metformin	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk80% change - SE, postmenopausal females n=23, 21	-29.5 percent change
Metformin	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk20 % change - SE, males n=23, 29	-10.3 percent change
Metformin	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk56 % change+ SE, postmenopausal females n=22, 21	10.3 percent change
Metformin	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk80 % change, overall n=69, 62	-18.7 percent change
Metformin	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk56 % change, postmenopausal females n=22, 21	-2.1 percent change
Avandamet	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk56 % change - SE, females n=40, 30	-16.4 percent change
Avandamet	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk56% change - SE, postmenopausal females n=22, 21	-18.4 percent change
Avandamet	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk20 % change+ SE, postmenopausal females n=22, 18	-3.2 percent change
Avandamet	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk20 % change, postmenopausal females n=22, 18	-13.6 percent change
Avandamet	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk20% change - SE, postmenopausal females n=22, 18	-22.8 percent change
Avandamet	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk80 % change + SE, overall n=69, 62	-7.5 percent change
Avandamet	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk80 % change, overall n=69, 62	-14.0 percent change
Avandamet	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk80 % change - SE, overall n=79, 62	-20.1 percent change
Avandamet	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk56 % change + SE, overall n=68, 62	3.7 percent change
Avandamet	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk56 % change, overall n=68, 62	-3.2 percent change
Avandamet	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk56 % change - SE, overall n=68, 62	-9.6 percent change
Avandamet	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk20 % change + SE, overall n=61, 56	-0.8 percent change
Avandamet	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk20 % change, overall n=61, 56	-5.9 percent change
Avandamet	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk20 % change - SE, overall n=61, 56	-10.7 percent change
Avandamet	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk80 % change + SE, males n=28, 32	-1.8 percent change
Avandamet	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk80 % change, males n=28, 32	-10.9 percent change
Avandamet	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk80 % change - SE, males n=28, 32	-19.1 percent change
Avandamet	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk56 % change + SE, males n=28, 32	6.5 percent change
Avandamet	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk56 % change, males n=28, 32	-2.2 percent change
Avandamet	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk56 % change - SE, males n=28, 32	-10.2 percent change
Avandamet	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk20 % change + SE, males n=23, 29	13.2 percent change
Avandamet	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk20 % change, males n=23, 29	5.8 percent change
Avandamet	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk20 % change - SE, males n=23, 29	-1.1 percent change
Avandamet	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk80 % change + SE, females n=41, 30	-8.2 percent change
Avandamet	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk80 % change, females n=41, 30	-16.9 percent change
Avandamet	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk80 % change - SE, females n=41, 30	-24.8 percent change
Avandamet	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk56 % change + SE, females n=40, 30	1.2 percent change
Avandamet	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk56 % change, females n=40, 30	-8.0 percent change
Avandamet	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk56 % change, postmenopausal females n=22, 21	-7.4 percent change
Avandamet	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk20 % change + SE, females n=38, 27	-8.3 percent change
Avandamet	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk20 % change, females n=38, 27	-15.3 percent change
Avandamet	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk20 % change - SE, females n=38, 27	-21.7 percent change
Avandamet	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk80 % change + SE, premenopausal females n=18, 9	10.9 percent change
Avandamet	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk80 % change, premenopausal females n=18, 9	-4.7 percent change
Avandamet	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk80 % change - SE, premenopausal females n=18, 9	-18.1 percent change
Avandamet	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk56 % change + SE, premenopausal females n=18, 9	12.6 percent change
Avandamet	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk56 % change, premenopausal females n=18, 9	0.8 percent change
Avandamet	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk56 % change - SE, premenopausal females n=18, 9	-9.8 percent change
Avandamet	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk20 % change + SE, premenopausal females n=16, 9	-7.8 percent change
Avandamet	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk20 % change, premenopausal females n=16, 9	-18.9 percent change
Avandamet	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk20 % change - SE, premenopausal females n=16, 9	-28.8 percent change
Avandamet	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk80 % change+ SE, postmenopausal females n=23, 21	-14.3 percent change
Avandamet	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk80 % change, postmenopausal females n=23, 21	-24.4 percent change
Avandamet	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk80% change - SE, postmenopausal females n=23, 21	-33.4 percent change
Avandamet	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Wk56 % change+ SE, postmenopausal females n=22, 21	5.1 percent change

p-value: 0.48695% CI: [-9.6, 23.6]ANCOVA

p-value: 0.379195% CI: [-13.7, 46.1]ANCOVA

p-value: 0.706595% CI: [-15.3, 27.6]ANCOVA

p-value: 0.138195% CI: [-9.5, 92.7]ANCOVA

p-value: 0.719595% CI: [-25.4, 22.7]ANCOVA

Secondary

Percent Change From Baseline in Distal Radius BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)

BMD was measured by dual X-ray absorptiometry (DXA). The percent change from baseline in BMD at a given timepoint was defined at the participant level by the following formula: percent change = (BMD at given week minus BMD at baseline)/BMD at baseline x 100. This outcome measure was analyzed for a subset of participants in the bone study only.

Time frame: Baseline and Weeks 20, 56, and 80

Population: Week 20 Evaluable for the Bone Sub-study Population. This is a subset of the bone sub-study with LOCF from Week 20. Only participants with BMD assessment(s) at Week 20 or later were included.

Arm	Measure	Group	Value (MEAN)	Dispersion
Metformin	Percent Change From Baseline in Distal Radius BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Male population, Week 56, n=38, 43	0.7 percent change	Standard Error 0.73
Metformin	Percent Change From Baseline in Distal Radius BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Female population, Week 20, n=49, 44	0.6 percent change	Standard Error 0.94
Metformin	Percent Change From Baseline in Distal Radius BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Overall population, Week 56, n=87, 87	0.5 percent change	Standard Error 0.55
Metformin	Percent Change From Baseline in Distal Radius BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Premenopausal population, Week 80, n=21, 14	1.1 percent change	Standard Error 1.51
Metformin	Percent Change From Baseline in Distal Radius BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Male population, Week 20, n=38, 43	1.5 percent change	Standard Error 0.75
Metformin	Percent Change From Baseline in Distal Radius BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Premenopausal population, Week 56, n=21, 14	2.2 percent change	Standard Error 1.37
Metformin	Percent Change From Baseline in Distal Radius BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Male population, Week 80, n=38, 43	0.4 percent change	Standard Error 0.84
Metformin	Percent Change From Baseline in Distal Radius BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Premenopausal population, Week 20, n=21, 14	2.6 percent change	Standard Error 1.51
Metformin	Percent Change From Baseline in Distal Radius BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Female population, Week 80, n=49, 44	0.1 percent change	Standard Error 1
Metformin	Percent Change From Baseline in Distal Radius BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Postmenopausal population, Week 80, n=28, 30	-0.5 percent change	Standard Error 1.61
Metformin	Percent Change From Baseline in Distal Radius BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Overall population, Week 20, n=87, 87	1.2 percent change	Standard Error 0.58
Metformin	Percent Change From Baseline in Distal Radius BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Postmenopausal population, Week 56, n=28, 30	-0.3 percent change	Standard Error 1.34
Metformin	Percent Change From Baseline in Distal Radius BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Female population, Week 56, n=49, 44	0.6 percent change	Standard Error 0.87
Metformin	Percent Change From Baseline in Distal Radius BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Postmenopausal population, Week 20, n=28, 30	0.5 percent change	Standard Error 1.36
Metformin	Percent Change From Baseline in Distal Radius BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Overall population, Week 80, n=87, 87	0.3 percent change	Standard Error 0.63
Avandamet	Percent Change From Baseline in Distal Radius BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Postmenopausal population, Week 20, n=28, 30	1.3 percent change	Standard Error 1.49
Avandamet	Percent Change From Baseline in Distal Radius BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Overall population, Week 80, n=87, 87	-0.1 percent change	Standard Error 0.66
Avandamet	Percent Change From Baseline in Distal Radius BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Overall population, Week 56, n=87, 87	0.5 percent change	Standard Error 0.58
Avandamet	Percent Change From Baseline in Distal Radius BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Overall population, Week 20, n=87, 87	0.9 percent change	Standard Error 0.61
Avandamet	Percent Change From Baseline in Distal Radius BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Male population, Week 80, n=38, 43	-0.6 percent change	Standard Error 0.82
Avandamet	Percent Change From Baseline in Distal Radius BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Male population, Week 56, n=38, 43	0.4 percent change	Standard Error 0.71
Avandamet	Percent Change From Baseline in Distal Radius BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Male population, Week 20, n=38, 43	0.2 percent change	Standard Error 0.73
Avandamet	Percent Change From Baseline in Distal Radius BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Female population, Week 80, n=49, 44	0.1 percent change	Standard Error 1.07
Avandamet	Percent Change From Baseline in Distal Radius BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Female population, Week 56, n=49, 44	0.7 percent change	Standard Error 0.93
Avandamet	Percent Change From Baseline in Distal Radius BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Female population, Week 20, n=49, 44	1.1 percent change	Standard Error 0.99
Avandamet	Percent Change From Baseline in Distal Radius BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Premenopausal population, Week 80, n=21, 14	-0.3 percent change	Standard Error 1.44
Avandamet	Percent Change From Baseline in Distal Radius BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Premenopausal population, Week 56, n=21, 14	-0.6 percent change	Standard Error 1.3
Avandamet	Percent Change From Baseline in Distal Radius BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Premenopausal population, Week 20, n=21, 14	0.7 percent change	Standard Error 1.4
Avandamet	Percent Change From Baseline in Distal Radius BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Postmenopausal population, Week 80, n=28, 30	-0.2 percent change	Standard Error 1.76
Avandamet	Percent Change From Baseline in Distal Radius BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Postmenopausal population, Week 56, n=28, 30	0.8 percent change	Standard Error 1.46

p-value: 0.610295% CI: [-1.9, 1.1]ANCOVA

p-value: 0.344595% CI: [-2.9, 1]ANCOVA

p-value: 0.973595% CI: [-2.4, 2.3]ANCOVA

p-value: 0.486195% CI: [-5.8, 2.9]ANCOVA

p-value: 0.87795% CI: [-3.5, 4]ANCOVA

Secondary

Percent Change From Baseline in Estradiol at Weeks 20, 56, and 80

Blood was taken for measurement of estradiol. Percent change from baseline was based on log transformed data. Standard error, SE; Wk, Week; %, percent. This outcome measure was analyzed for a subset of female participants in the bone study only. n is the number of evaluable participants, which is the number of female participants with a value at baseline and at the specified visit for the parameter of interest.

Time frame: Baseline and Weeks 20, 56, and 80

Population: Week 20 Evaluable for the Bone Sub-study Population. This is a subset of the bone sub-study with LOCF from Week 20. Only participants with estradiol measurements at Week 20 or later were included.

Arm	Measure	Group	Value (NUMBER)
Metformin	Percent Change From Baseline in Estradiol at Weeks 20, 56, and 80	Wk20 % change, females n=36, 25	-5.097 percent change
Metformin	Percent Change From Baseline in Estradiol at Weeks 20, 56, and 80	Wk56 % change - SE, premenopausal females n=12, 8	-23.820 percent change
Metformin	Percent Change From Baseline in Estradiol at Weeks 20, 56, and 80	Wk56 % change, females n=27, 21	-0.815 percent change
Metformin	Percent Change From Baseline in Estradiol at Weeks 20, 56, and 80	Wk20 % change + SE, premenopausal females n=15, 10	5.738 percent change
Metformin	Percent Change From Baseline in Estradiol at Weeks 20, 56, and 80	Wk 20 % change - SE, females n= 36, 25	-16.500 percent change
Metformin	Percent Change From Baseline in Estradiol at Weeks 20, 56, and 80	Wk20 % change, premenopausal females n=15, 10	-3.721 percent change
Metformin	Percent Change From Baseline in Estradiol at Weeks 20, 56, and 80	Wk80 % change, females n=30, 22	-21.360 percent change
Metformin	Percent Change From Baseline in Estradiol at Weeks 20, 56, and 80	Wk20 % change - SE, premenopausal females n=15, 10	-12.334 percent change
Metformin	Percent Change From Baseline in Estradiol at Weeks 20, 56, and 80	Wk80 % change + SE, premenopausal females n=13, 9	25.386 percent change
Metformin	Percent Change From Baseline in Estradiol at Weeks 20, 56, and 80	Wk80 % change+ SE, postmenopausal females n=17, 13	-27.303 percent change
Metformin	Percent Change From Baseline in Estradiol at Weeks 20, 56, and 80	Wk 56 % change - SE, females n= 27, 21	-12.175 percent change
Metformin	Percent Change From Baseline in Estradiol at Weeks 20, 56, and 80	Wk80 % change, postmenopausal females n=17, 13	-33.045 percent change
Metformin	Percent Change From Baseline in Estradiol at Weeks 20, 56, and 80	Wk80 % change, premenopausal females n= 13, 9	-17.314 percent change
Metformin	Percent Change From Baseline in Estradiol at Weeks 20, 56, and 80	Wk80% change - SE, postmenopausal females n=17, 13	-38.334 percent change
Metformin	Percent Change From Baseline in Estradiol at Weeks 20, 56, and 80	Wk56 % change + SE, females n= 27, 21	12.015 percent change
Metformin	Percent Change From Baseline in Estradiol at Weeks 20, 56, and 80	Wk56 % change+ SE, postmenopausal females n=15, 13	-25.758 percent change
Metformin	Percent Change From Baseline in Estradiol at Weeks 20, 56, and 80	Wk80 % change - SE, premenopausal females n=13, 9	-45.472 percent change
Metformin	Percent Change From Baseline in Estradiol at Weeks 20, 56, and 80	Wk56 % change, postmenopausal females n=15, 13	-32.766 percent change
Metformin	Percent Change From Baseline in Estradiol at Weeks 20, 56, and 80	Wk20 % change + SE, females n= 36, 25	7.863 percent change
Metformin	Percent Change From Baseline in Estradiol at Weeks 20, 56, and 80	Wk56% change - SE, postmenopausal females n=15, 13	-39.113 percent change
Metformin	Percent Change From Baseline in Estradiol at Weeks 20, 56, and 80	Wk56 % change + SE, premenopausal females n=12, 8	35.708 percent change
Metformin	Percent Change From Baseline in Estradiol at Weeks 20, 56, and 80	Wk20 % change+ SE, postmenopausal females n=21, 15	3.432 percent change
Metformin	Percent Change From Baseline in Estradiol at Weeks 20, 56, and 80	Wk 80 % change - SE, females n= 30, 22	-32.268 percent change
Metformin	Percent Change From Baseline in Estradiol at Weeks 20, 56, and 80	Wk20 % change, postmenopausal females n=21, 15	-12.870 percent change
Metformin	Percent Change From Baseline in Estradiol at Weeks 20, 56, and 80	Wk56 % change, premenopausal females n= 12, 8	1.677 percent change
Metformin	Percent Change From Baseline in Estradiol at Weeks 20, 56, and 80	Wk20% change - SE, postmenopausal females n=21, 15	-26.603 percent change
Metformin	Percent Change From Baseline in Estradiol at Weeks 20, 56, and 80	Wk80 % change + SE, females n= 30, 22	-8.695 percent change
Avandamet	Percent Change From Baseline in Estradiol at Weeks 20, 56, and 80	Wk20% change - SE, postmenopausal females n=21, 15	-22.391 percent change
Avandamet	Percent Change From Baseline in Estradiol at Weeks 20, 56, and 80	Wk80 % change + SE, females n= 30, 22	0.097 percent change
Avandamet	Percent Change From Baseline in Estradiol at Weeks 20, 56, and 80	Wk80 % change, females n=30, 22	-15.441 percent change
Avandamet	Percent Change From Baseline in Estradiol at Weeks 20, 56, and 80	Wk 80 % change - SE, females n= 30, 22	-28.567 percent change
Avandamet	Percent Change From Baseline in Estradiol at Weeks 20, 56, and 80	Wk56 % change + SE, females n= 27, 21	10.268 percent change
Avandamet	Percent Change From Baseline in Estradiol at Weeks 20, 56, and 80	Wk56 % change, females n=27, 21	-2.439 percent change
Avandamet	Percent Change From Baseline in Estradiol at Weeks 20, 56, and 80	Wk 56 % change - SE, females n= 27, 21	-13.682 percent change
Avandamet	Percent Change From Baseline in Estradiol at Weeks 20, 56, and 80	Wk20 % change + SE, females n= 36, 25	14.875 percent change
Avandamet	Percent Change From Baseline in Estradiol at Weeks 20, 56, and 80	Wk20 % change, females n=36, 25	-0.646 percent change
Avandamet	Percent Change From Baseline in Estradiol at Weeks 20, 56, and 80	Wk 20 % change - SE, females n= 36, 25	-14.875 percent change
Avandamet	Percent Change From Baseline in Estradiol at Weeks 20, 56, and 80	Wk80 % change + SE, premenopausal females n=13, 9	67.328 percent change
Avandamet	Percent Change From Baseline in Estradiol at Weeks 20, 56, and 80	Wk80 % change, premenopausal females n= 13, 9	7.667 percent change
Avandamet	Percent Change From Baseline in Estradiol at Weeks 20, 56, and 80	Wk80 % change - SE, premenopausal females n=13, 9	-30.722 percent change
Avandamet	Percent Change From Baseline in Estradiol at Weeks 20, 56, and 80	Wk56 % change + SE, premenopausal females n=12, 8	19.557 percent change
Avandamet	Percent Change From Baseline in Estradiol at Weeks 20, 56, and 80	Wk56 % change, premenopausal females n= 12, 8	-11.431 percent change
Avandamet	Percent Change From Baseline in Estradiol at Weeks 20, 56, and 80	Wk56 % change - SE, premenopausal females n=12, 8	-34.386 percent change
Avandamet	Percent Change From Baseline in Estradiol at Weeks 20, 56, and 80	Wk20 % change + SE, premenopausal females n=15, 10	8.866 percent change
Avandamet	Percent Change From Baseline in Estradiol at Weeks 20, 56, and 80	Wk20 % change, premenopausal females n=15, 10	-3.005 percent change
Avandamet	Percent Change From Baseline in Estradiol at Weeks 20, 56, and 80	Wk20 % change - SE, premenopausal females n=15, 10	-13.581 percent change
Avandamet	Percent Change From Baseline in Estradiol at Weeks 20, 56, and 80	Wk80 % change+ SE, postmenopausal females n=17, 13	-25.501 percent change
Avandamet	Percent Change From Baseline in Estradiol at Weeks 20, 56, and 80	Wk80 % change, postmenopausal females n=17, 13	-31.754 percent change
Avandamet	Percent Change From Baseline in Estradiol at Weeks 20, 56, and 80	Wk80% change - SE, postmenopausal females n=17, 13	-37.482 percent change
Avandamet	Percent Change From Baseline in Estradiol at Weeks 20, 56, and 80	Wk56 % change+ SE, postmenopausal females n=15, 13	-18.475 percent change
Avandamet	Percent Change From Baseline in Estradiol at Weeks 20, 56, and 80	Wk56 % change, postmenopausal females n=15, 13	-25.372 percent change
Avandamet	Percent Change From Baseline in Estradiol at Weeks 20, 56, and 80	Wk56% change - SE, postmenopausal females n=15, 13	-31.686 percent change
Avandamet	Percent Change From Baseline in Estradiol at Weeks 20, 56, and 80	Wk20 % change+ SE, postmenopausal females n=21, 15	16.140 percent change
Avandamet	Percent Change From Baseline in Estradiol at Weeks 20, 56, and 80	Wk20 % change, postmenopausal females n=21, 15	-5.061 percent change

p-value: 0.704195% CI: [-26.773, 57.892]ANCOVA

p-value: 0.640395% CI: [-61.586, 341.371]ANCOVA

p-value: 0.847495% CI: [-17.015, 25.198]ANCOVA

Secondary

Percent Change From Baseline in Femoral Neck BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)

Time frame: Baseline and Weeks 20, 56, and 80

Arm	Measure	Group	Value (MEAN)	Dispersion
Metformin	Percent Change From Baseline in Femoral Neck BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Male population, Week 56, n=38, 43	-0.7 percent change	Standard Error 0.64
Metformin	Percent Change From Baseline in Femoral Neck BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Female population, Week 20, n=49, 44	-0.4 percent change	Standard Error 0.49
Metformin	Percent Change From Baseline in Femoral Neck BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Overall population, Week 56, n=87, 87	-0.7 percent change	Standard Error 0.39
Metformin	Percent Change From Baseline in Femoral Neck BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Premenopausal population, Week 80, n=21, 14	0.9 percent change	Standard Error 0.73
Metformin	Percent Change From Baseline in Femoral Neck BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Male population, Week 20, n=38, 43	-0.4 percent change	Standard Error 0.6
Metformin	Percent Change From Baseline in Femoral Neck BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Premenopausal population, Week 56, n=21, 14	-0.1 percent change	Standard Error 0.96
Metformin	Percent Change From Baseline in Femoral Neck BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Male population, Week 80, n=38, 43	-1.4 percent change	Standard Error 0.66
Metformin	Percent Change From Baseline in Femoral Neck BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Premenopausal population, Week 20, n=21, 14	0.9 percent change	Standard Error 0.83
Metformin	Percent Change From Baseline in Femoral Neck BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Female population, Week 80, n=49, 44	-0.3 percent change	Standard Error 0.56
Metformin	Percent Change From Baseline in Femoral Neck BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Postmenopausal population, Week 80, n=28, 30	-1.3 percent change	Standard Error 0.87
Metformin	Percent Change From Baseline in Femoral Neck BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Overall population, Week 20, n=87, 87	-0.1 percent change	Standard Error 0.36
Metformin	Percent Change From Baseline in Femoral Neck BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Postmenopausal population, Week 56, n=28, 30	-1.2 percent change	Standard Error 0.81
Metformin	Percent Change From Baseline in Femoral Neck BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Female population, Week 56, n=49, 44	-0.6 percent change	Standard Error 0.55
Metformin	Percent Change From Baseline in Femoral Neck BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Postmenopausal population, Week 20, n=28, 30	-1.1 percent change	Standard Error 0.71
Metformin	Percent Change From Baseline in Femoral Neck BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Overall population, Week 80, n=87, 87	-0.7 percent change	Standard Error 0.39
Avandamet	Percent Change From Baseline in Femoral Neck BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Postmenopausal population, Week 20, n=28, 30	-0.4 percent change	Standard Error 0.74
Avandamet	Percent Change From Baseline in Femoral Neck BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Overall population, Week 80, n=87, 87	-1.4 percent change	Standard Error 0.39
Avandamet	Percent Change From Baseline in Femoral Neck BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Overall population, Week 56, n=87, 87	-0.8 percent change	Standard Error 0.39
Avandamet	Percent Change From Baseline in Femoral Neck BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Overall population, Week 20, n=87, 87	-0.2 percent change	Standard Error 0.36
Avandamet	Percent Change From Baseline in Femoral Neck BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Male population, Week 80, n=38, 43	-2.2 percent change	Standard Error 0.59
Avandamet	Percent Change From Baseline in Femoral Neck BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Male population, Week 56, n=38, 43	-1.3 percent change	Standard Error 0.57
Avandamet	Percent Change From Baseline in Femoral Neck BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Male population, Week 20, n=38, 43	-0.7 percent change	Standard Error 0.53
Avandamet	Percent Change From Baseline in Femoral Neck BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Female population, Week 80, n=49, 44	-1.2 percent change	Standard Error 0.57
Avandamet	Percent Change From Baseline in Femoral Neck BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Female population, Week 56, n=49, 44	-0.5 percent change	Standard Error 0.56
Avandamet	Percent Change From Baseline in Femoral Neck BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Female population, Week 20, n=49, 44	-0.2 percent change	Standard Error 0.5
Avandamet	Percent Change From Baseline in Femoral Neck BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Premenopausal population, Week 80, n=21, 14	-0.3 percent change	Standard Error 0.68
Avandamet	Percent Change From Baseline in Femoral Neck BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Premenopausal population, Week 56, n=21, 14	-0.4 percent change	Standard Error 0.89
Avandamet	Percent Change From Baseline in Femoral Neck BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Premenopausal population, Week 20, n=21, 14	-0.3 percent change	Standard Error 0.77
Avandamet	Percent Change From Baseline in Femoral Neck BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Postmenopausal population, Week 80, n=28, 30	-2.1 percent change	Standard Error 0.91
Avandamet	Percent Change From Baseline in Femoral Neck BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Postmenopausal population, Week 56, n=28, 30	-0.7 percent change	Standard Error 0.85

p-value: 0.12695% CI: [-1.7, 0.2]ANCOVA

p-value: 0.311795% CI: [-2.2, 0.7]ANCOVA

p-value: 0.177695% CI: [-2.2, 0.4]ANCOVA

p-value: 0.225995% CI: [-3.2, 0.8]ANCOVA

p-value: 0.38495% CI: [-2.8, 1.1]ANCOVA

Secondary

Percent Change From Baseline in in HOMA-S and HOMA-B to Week 80 (US and Mexico Subset of Participants)

Blood was taken for measurement of homeostasis model assessment for insulin sensitivity (HOMA-S) and beta-cell function (HOMA-B). Percent change from baseline at Week 80 was based on log transformed data. This outcome measure was analyzed for a subset of participants in the US and Mexico only. GM, geometric mean; SE, standard error.

Time frame: Baseline and Week 80

Arm	Measure	Group	Value (NUMBER)
Metformin	Percent Change From Baseline in in HOMA-S and HOMA-B to Week 80 (US and Mexico Subset of Participants)	Percent change HOMA-B + SE	88.25 percent change
Metformin	Percent Change From Baseline in in HOMA-S and HOMA-B to Week 80 (US and Mexico Subset of Participants)	Percent change HOMA-B	78.85 percent change
Metformin	Percent Change From Baseline in in HOMA-S and HOMA-B to Week 80 (US and Mexico Subset of Participants)	Percent change HOMA-B - SE	69.92 percent change
Metformin	Percent Change From Baseline in in HOMA-S and HOMA-B to Week 80 (US and Mexico Subset of Participants)	Percent change HOMA-S + SE	25.13 percent change
Metformin	Percent Change From Baseline in in HOMA-S and HOMA-B to Week 80 (US and Mexico Subset of Participants)	Percent change HOMA-S	18.65 percent change
Metformin	Percent Change From Baseline in in HOMA-S and HOMA-B to Week 80 (US and Mexico Subset of Participants)	Percent change HOMA-S - SE	12.49 percent change
Avandamet	Percent Change From Baseline in in HOMA-S and HOMA-B to Week 80 (US and Mexico Subset of Participants)	Percent change HOMA-S	55.58 percent change
Avandamet	Percent Change From Baseline in in HOMA-S and HOMA-B to Week 80 (US and Mexico Subset of Participants)	Percent change HOMA-B + SE	92.32 percent change
Avandamet	Percent Change From Baseline in in HOMA-S and HOMA-B to Week 80 (US and Mexico Subset of Participants)	Percent change HOMA-S + SE	63.67 percent change
Avandamet	Percent Change From Baseline in in HOMA-S and HOMA-B to Week 80 (US and Mexico Subset of Participants)	Percent change HOMA-B	83.14 percent change
Avandamet	Percent Change From Baseline in in HOMA-S and HOMA-B to Week 80 (US and Mexico Subset of Participants)	Percent change HOMA-S - SE	47.91 percent change
Avandamet	Percent Change From Baseline in in HOMA-S and HOMA-B to Week 80 (US and Mexico Subset of Participants)	Percent change HOMA-B - SE	74.39 percent change

p-value: 0.714895% CI: [-9.87, 16.34]ANCOVA

p-value: <0.00195% CI: [14.82, 49.78]ANCOVA

Secondary

Percent Change From Baseline in Intact Parathyroid Hormone at Week 80

Blood was taken for measurement of intact parathyroid hormone. Percent change from baseline was based on log transformed data. Standard error, SE; Wk, Week; %, percent. This outcome measure was analyzed for a subset of participants in the bone study only. n is the number of evaluable participants, which is the number of participants with a value at baseline and at the specified visit for the parameter of interest.

Time frame: Baseline and Week 80

Population: Week 20 Evaluable for the Bone Sub-study Population. This is a subset of the bone sub-study with LOCF from Week 20. Only participants with intact parathyroid hormone measurements at Week 20 or later were included.

Arm	Measure	Group	Value (NUMBER)
Metformin	Percent Change From Baseline in Intact Parathyroid Hormone at Week 80	Wk80 % change, males n= 16, 21	-9.238 percent change
Metformin	Percent Change From Baseline in Intact Parathyroid Hormone at Week 80	Wk 80 % change - SE, females n= 30, 22	-13.056 percent change
Metformin	Percent Change From Baseline in Intact Parathyroid Hormone at Week 80	Wk80 % change, overall n=45, 38	-7.634 percent change
Metformin	Percent Change From Baseline in Intact Parathyroid Hormone at Week 80	Wk80 % change + SE, premenopausal females n=13, 7	14.295 percent change
Metformin	Percent Change From Baseline in Intact Parathyroid Hormone at Week 80	Wk80 % change - SE, males n=16, 21	-16.655 percent change
Metformin	Percent Change From Baseline in Intact Parathyroid Hormone at Week 80	Wk80 % change, premenopausal females n= 13, 7	-7.686 percent change
Metformin	Percent Change From Baseline in Intact Parathyroid Hormone at Week 80	Wk80 % change + SE, males n=16, 21	-1.160 percent change
Metformin	Percent Change From Baseline in Intact Parathyroid Hormone at Week 80	Wk80 % change - SE, premenopausal females n=13, 7	-25.440 percent change
Metformin	Percent Change From Baseline in Intact Parathyroid Hormone at Week 80	Wk80 % change + SE, females n= 30, 22	4.662 percent change
Metformin	Percent Change From Baseline in Intact Parathyroid Hormone at Week 80	Wk80 % change+ SE, postmenopausal females n=16, 10	3.017 percent change
Metformin	Percent Change From Baseline in Intact Parathyroid Hormone at Week 80	Wk80 % change - SE, overall n= 45, 38	-13.565 percent change
Metformin	Percent Change From Baseline in Intact Parathyroid Hormone at Week 80	Wk80 % change, postmenopausal females n=16, 10	-12.109 percent change
Metformin	Percent Change From Baseline in Intact Parathyroid Hormone at Week 80	Wk80 % change, females n=30, 22	-4.608 percent change
Metformin	Percent Change From Baseline in Intact Parathyroid Hormone at Week 80	Wk80% change - SE, postmenopausal females n=16, 10	-25.014 percent change
Metformin	Percent Change From Baseline in Intact Parathyroid Hormone at Week 80	Wk80 % change + SE, overall n= 45, 38	-1.296 percent change
Avandamet	Percent Change From Baseline in Intact Parathyroid Hormone at Week 80	Wk80% change - SE, postmenopausal females n=16, 10	-23.807 percent change
Avandamet	Percent Change From Baseline in Intact Parathyroid Hormone at Week 80	Wk80 % change + SE, overall n= 45, 38	0.843 percent change
Avandamet	Percent Change From Baseline in Intact Parathyroid Hormone at Week 80	Wk80 % change, overall n=45, 38	-6.279 percent change
Avandamet	Percent Change From Baseline in Intact Parathyroid Hormone at Week 80	Wk80 % change - SE, overall n= 45, 38	-12.898 percent change
Avandamet	Percent Change From Baseline in Intact Parathyroid Hormone at Week 80	Wk80 % change + SE, males n=16, 21	-2.619 percent change
Avandamet	Percent Change From Baseline in Intact Parathyroid Hormone at Week 80	Wk80 % change, males n= 16, 21	-8.941 percent change
Avandamet	Percent Change From Baseline in Intact Parathyroid Hormone at Week 80	Wk80 % change - SE, males n=16, 21	-14.852 percent change
Avandamet	Percent Change From Baseline in Intact Parathyroid Hormone at Week 80	Wk80 % change + SE, females n= 30, 22	11.166 percent change
Avandamet	Percent Change From Baseline in Intact Parathyroid Hormone at Week 80	Wk80 % change, females n=30, 22	-1.759 percent change
Avandamet	Percent Change From Baseline in Intact Parathyroid Hormone at Week 80	Wk 80 % change - SE, females n= 30, 22	-13.182 percent change
Avandamet	Percent Change From Baseline in Intact Parathyroid Hormone at Week 80	Wk80 % change + SE, premenopausal females n=13, 7	24.396 percent change
Avandamet	Percent Change From Baseline in Intact Parathyroid Hormone at Week 80	Wk80 % change, premenopausal females n= 13, 7	-0.126 percent change
Avandamet	Percent Change From Baseline in Intact Parathyroid Hormone at Week 80	Wk80 % change - SE, premenopausal females n=13, 7	-20.160 percent change
Avandamet	Percent Change From Baseline in Intact Parathyroid Hormone at Week 80	Wk80 % change+ SE, postmenopausal females n=16, 10	8.297 percent change
Avandamet	Percent Change From Baseline in Intact Parathyroid Hormone at Week 80	Wk80 % change, postmenopausal females n=16, 10	-9.170 percent change

p-value: 0.868295% CI: [-14.785, 20.818]ANCOVA

p-value: 0.97495% CI: [-18.308, 23.214]ANCOVA

p-value: 0.837895% CI: [-22.997, 37.735]ANCOVA

p-value: 0.788995% CI: [-43.839, 108.422]ANCOVA

p-value: 0.8895% CI: [-34.853, 63.935]ANCOVA

Secondary

Percent Change From Baseline in Lumbar Spine Bone Mass Density (BMD) at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)

BMD was measured by dual X-ray absorptiometry (DXA). The percent change from baseline in BMD at a given timepoint was defined at the participant level by the following formula: percent change = (BMD at given week minus BMD at baseline)/BMD at baseline x 100%. This outcome measure was analyzed for a subset of participants in the bone study only.

Time frame: Baseline and Weeks 20, 56, and 80

Arm	Measure	Group	Value (MEAN)	Dispersion
Metformin	Percent Change From Baseline in Lumbar Spine Bone Mass Density (BMD) at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Male population, Week 56, n=38, 43	-0.2 percent change	Standard Error 0.61
Metformin	Percent Change From Baseline in Lumbar Spine Bone Mass Density (BMD) at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Female population, Week 20, n=49, 44	-0.9 percent change	Standard Error 0.52
Metformin	Percent Change From Baseline in Lumbar Spine Bone Mass Density (BMD) at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Overall population, Week 56, n=87, 87	-1.4 percent change	Standard Error 0.45
Metformin	Percent Change From Baseline in Lumbar Spine Bone Mass Density (BMD) at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Premenopausal population, Week 80, n=21, 14	-2.4 percent change	Standard Error 1.01
Metformin	Percent Change From Baseline in Lumbar Spine Bone Mass Density (BMD) at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Male population, Week 20, n=38, 43	-0.1 percent change	Standard Error 0.63
Metformin	Percent Change From Baseline in Lumbar Spine Bone Mass Density (BMD) at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Premenopausal population, Week 56, n=21, 14	-0.8 percent change	Standard Error 0.88
Metformin	Percent Change From Baseline in Lumbar Spine Bone Mass Density (BMD) at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Male population, Week 80, n=38, 43	-0.7 percent change	Standard Error 0.81
Metformin	Percent Change From Baseline in Lumbar Spine Bone Mass Density (BMD) at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Premenopausal population, Week 20, n=21, 14	0.2 percent change	Standard Error 0.75
Metformin	Percent Change From Baseline in Lumbar Spine Bone Mass Density (BMD) at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Female population, Week 80, n=49, 44	-2.7 percent change	Standard Error 0.77
Metformin	Percent Change From Baseline in Lumbar Spine Bone Mass Density (BMD) at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Postmenopausal population, Week 80, n=28, 30	-3.3 percent change	Standard Error 1.22
Metformin	Percent Change From Baseline in Lumbar Spine Bone Mass Density (BMD) at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Overall population, Week 20, n=87, 87	-0.5 percent change	Standard Error 0.41
Metformin	Percent Change From Baseline in Lumbar Spine Bone Mass Density (BMD) at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Postmenopausal population, Week 56, n=28, 30	-2.7 percent change	Standard Error 1.09
Metformin	Percent Change From Baseline in Lumbar Spine Bone Mass Density (BMD) at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Female population, Week 56, n=49, 44	-2.0 percent change	Standard Error 0.7
Metformin	Percent Change From Baseline in Lumbar Spine Bone Mass Density (BMD) at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Postmenopausal population, Week 20, n=28, 30	-1.4 percent change	Standard Error 0.73
Metformin	Percent Change From Baseline in Lumbar Spine Bone Mass Density (BMD) at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Overall population, Week 80, n=87, 87	-2.1 percent change	Standard Error 0.54
Avandamet	Percent Change From Baseline in Lumbar Spine Bone Mass Density (BMD) at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Postmenopausal population, Week 20, n=28, 30	-1.1 percent change	Standard Error 0.69
Avandamet	Percent Change From Baseline in Lumbar Spine Bone Mass Density (BMD) at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Overall population, Week 80, n=87, 87	0.1 percent change	Standard Error 0.54
Avandamet	Percent Change From Baseline in Lumbar Spine Bone Mass Density (BMD) at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Overall population, Week 56, n=87, 87	0.3 percent change	Standard Error 0.44
Avandamet	Percent Change From Baseline in Lumbar Spine Bone Mass Density (BMD) at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Overall population, Week 20, n=87, 87	0.5 percent change	Standard Error 0.4
Avandamet	Percent Change From Baseline in Lumbar Spine Bone Mass Density (BMD) at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Male population, Week 80, n=38, 43	1.0 percent change	Standard Error 0.9
Avandamet	Percent Change From Baseline in Lumbar Spine Bone Mass Density (BMD) at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Male population, Week 56, n=38, 43	0.7 percent change	Standard Error 0.68
Avandamet	Percent Change From Baseline in Lumbar Spine Bone Mass Density (BMD) at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Male population, Week 20, n=38, 43	-0.2 percent change	Standard Error 0.71
Avandamet	Percent Change From Baseline in Lumbar Spine Bone Mass Density (BMD) at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Female population, Week 80, n=49, 44	0.2 percent change	Standard Error 0.75
Avandamet	Percent Change From Baseline in Lumbar Spine Bone Mass Density (BMD) at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Female population, Week 56, n=49, 44	0.3 percent change	Standard Error 0.68
Avandamet	Percent Change From Baseline in Lumbar Spine Bone Mass Density (BMD) at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Female population, Week 20, n=49, 44	1.2 percent change	Standard Error 0.51
Avandamet	Percent Change From Baseline in Lumbar Spine Bone Mass Density (BMD) at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Premenopausal population, Week 80, n=21, 14	-0.7 percent change	Standard Error 1.03
Avandamet	Percent Change From Baseline in Lumbar Spine Bone Mass Density (BMD) at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Premenopausal population, Week 56, n=21, 14	0.2 percent change	Standard Error 0.9
Avandamet	Percent Change From Baseline in Lumbar Spine Bone Mass Density (BMD) at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Premenopausal population, Week 20, n=21, 14	0.5 percent change	Standard Error 0.77
Avandamet	Percent Change From Baseline in Lumbar Spine Bone Mass Density (BMD) at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Postmenopausal population, Week 80, n=28, 30	0 percent change	Standard Error 1.16
Avandamet	Percent Change From Baseline in Lumbar Spine Bone Mass Density (BMD) at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Postmenopausal population, Week 56, n=28, 30	-0.1 percent change	Standard Error 1.04

p-value: 0.000595% CI: [-3.3, -1]ANCOVA

p-value: 0.236395% CI: [-4.6, 1.2]ANCOVA

p-value: 0.016195% CI: [-5.9, -0.6]ANCOVA

p-value: 0.033895% CI: [-4.9, -0.2]ANCOVA

p-value: 0.004595% CI: [-3.9, -0.7]ANCOVA

p-value: 0.001295% CI: [-3.5, -0.9]ANCOVA

p-value: 0.003195% CI: [-2.7, -0.6]ANCOVA

p-value: 0.030895% CI: [-2, -0.1]ANCOVA

p-value: 0.095495% CI: [-3.7, 0.3]ANCOVA

p-value: 0.001595% CI: [-4.7, -1.2]ANCOVA

p-value: 0.00295% CI: [-4.1, -1]ANCOVA

Secondary

Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80

Blood was taken for measurement of P1NP. Percent change from baseline was based on log transformed data. Standard error, SE; Wk, Week; %, percent. This outcome measure was analyzed for a subset of participants in the bone study only. n is the number of evaluable participants, which is the number of participants with a value at baseline and at the specified visit for the parameter of interest.

Time frame: Baseline and Weeks 20, 56, and 80

Population: Week 20 Evaluable for the Bone Sub-study Population. This is a subset of the bone sub-study with LOCF from Week 20. Only participants with P1NP measurements at Week 20 or later were included.

Arm	Measure	Group	Value (NUMBER)
Metformin	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk80 % change + SE, overall n= 72, 64	-18.4 percent change
Metformin	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk80 % change, overall n=72, 64	-22.0 percent change
Metformin	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk80 % change - SE, overall n=72, 64	-25.5 percent change
Metformin	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk56 % change + SE, overall n=72, 64	-23.5 percent change
Metformin	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk56 % change, overall n=72, 64	-26.9 percent change
Metformin	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk56 % change - SE, overall n=72, 64	-30.2 percent change
Metformin	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk20 % change + SE, overall n=66, 59	-24.0 percent change
Metformin	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk20 % change, overall n=66, 59	-27.0 percent change
Metformin	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk20 % change - SE, overall n=66, 59	-30.0 percent change
Metformin	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk80 % change + SE, males n=30, 32	-18.5 percent change
Metformin	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk80 % change, males n=30, 32	-24.1 percent change
Metformin	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk80 % change - SE, males n=30, 32	-29.4 percent change
Metformin	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk56 % change + SE, males n=30, 32	-22.7 percent change
Metformin	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk56 % change, males n=30, 32	-27.7 percent change
Metformin	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk56 % change - SE, males n=30, 32	-32.4 percent change
Metformin	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk20 % change + SE, males n=26, 29	-20.2 percent change
Metformin	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk20 % change, males n=26, 29	-25.4 percent change
Metformin	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk20 % change - SE, males n=26, 29	-30.3 percent change
Metformin	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk80 % change + SE, females n=42, 32	-19.3 percent change
Metformin	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk80 % change, females n=42, 32	-23.8 percent change
Metformin	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk80 % change - SE, females n=42, 32	-28.2 percent change
Metformin	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk56 % change + SE, females n=42, 32	-28.6 percent change
Metformin	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk56 % change, females n=42, 32	-32.8 percent change
Metformin	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk56 % change - SE, females n=42, 32	-36.9 percent change
Metformin	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk20 % change + SE, females n=40, 30	-25.2 percent change
Metformin	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk20 % change, females n=40, 30	-30.0 percent change
Metformin	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk20 % change - SE, females n=40, 30	-34.5 percent change
Metformin	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk80 % change + SE, premenopausal females n=19, 10	-16.9 percent change
Metformin	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk80 % change, premenopausal females n=19, 10	-23.6 percent change
Metformin	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk80 % change - SE, premenopausal females n=19, 10	-29.7 percent change
Metformin	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk56 % change + SE, premenopausal females n=19, 10	-25.3 percent change
Metformin	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk56 % change, premenopausal females n=19, 10	-31.0 percent change
Metformin	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk56 % change - SE, premenopausal females n=19, 10	-36.2 percent change
Metformin	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk20 % change + SE, premenopausal females n=17, 10	-24.6 percent change
Metformin	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk20 % change, premenopausal females n=17, 10	-31.4 percent change
Metformin	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk20 % change - SE, premenopausal females n=17, 10	-37.7 percent change
Metformin	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk80 % change+ SE, postmenopausal females n=23, 22	-22.5 percent change
Metformin	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk80 % change, postmenopausal females n=23, 22	-28.4 percent change
Metformin	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk80% change - SE, postmenopausal females n=23, 22	-33.8 percent change
Metformin	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk56 % change+ SE, postmenopausal females n=23, 22	-32.1 percent change
Metformin	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk56 % change, postmenopausal females n=23, 22	-37.9 percent change
Metformin	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk56% change - SE, postmenopausal females n=22, 22	-43.2 percent change
Metformin	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk20 % change+ SE, postmenopausal females n=23, 20	-25.2 percent change
Metformin	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk20 % change, postmenopausal females n=23, 20	-31.9 percent change
Metformin	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk20% change - SE, postmenopausal females n=23, 20	-38.0 percent change
Avandamet	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk56 % change, females n=42, 32	-32.0 percent change
Avandamet	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk80 % change + SE, overall n= 72, 64	-20.7 percent change
Avandamet	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk56 % change+ SE, postmenopausal females n=23, 22	-35.2 percent change
Avandamet	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk80 % change, overall n=72, 64	-24.3 percent change
Avandamet	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk56 % change - SE, females n=42, 32	-36.6 percent change
Avandamet	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk80 % change - SE, overall n=72, 64	-27.8 percent change
Avandamet	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk20 % change, premenopausal females n=17, 10	-36.5 percent change
Avandamet	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk56 % change + SE, overall n=72, 64	-26.6 percent change
Avandamet	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk20 % change + SE, females n=40, 30	-31.6 percent change
Avandamet	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk56 % change, overall n=72, 64	-30.0 percent change
Avandamet	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk20 % change+ SE, postmenopausal females n=23, 20	-34.0 percent change
Avandamet	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk56 % change - SE, overall n=72, 64	-33.3 percent change
Avandamet	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk20 % change, females n=40, 30	-36.6 percent change
Avandamet	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk20 % change + SE, overall n=66, 59	-31.6 percent change
Avandamet	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk20 % change - SE, premenopausal females n=17, 10	-43.1 percent change
Avandamet	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk20 % change, overall n=66, 59	-34.6 percent change
Avandamet	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk20 % change - SE, females n=40, 30	-41.2 percent change
Avandamet	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk20 % change - SE, overall n=66, 59	-37.5 percent change
Avandamet	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk56 % change, postmenopausal females n=23, 22	-41.4 percent change
Avandamet	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk80 % change + SE, males n=30, 32	-18.2 percent change
Avandamet	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk80 % change + SE, premenopausal females n=19, 10	-11.0 percent change
Avandamet	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk80 % change, males n=30, 32	-23.4 percent change
Avandamet	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk80 % change+ SE, postmenopausal females n=23, 22	-27.6 percent change
Avandamet	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk80 % change - SE, males n=30, 32	-28.2 percent change
Avandamet	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk80 % change, premenopausal females n=19, 10	-20.1 percent change
Avandamet	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk56 % change + SE, males n=30, 32	-23.0 percent change
Avandamet	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk20% change - SE, postmenopausal females n=23, 20	-47.1 percent change
Avandamet	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk56 % change, males n=30, 32	-27.6 percent change
Avandamet	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk80 % change - SE, premenopausal females n=19, 10	-28.3 percent change
Avandamet	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk56 % change - SE, males n=30, 32	-31.9 percent change
Avandamet	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk80 % change, postmenopausal females n=23, 22	-33.8 percent change
Avandamet	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk20 % change + SE, males n=26, 29	-24.7 percent change
Avandamet	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk56 % change + SE, premenopausal females n=19, 10	-23.4 percent change
Avandamet	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk20 % change, males n=26, 29	-29.5 percent change
Avandamet	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk56% change - SE, postmenopausal females n=22, 22	-47.0 percent change
Avandamet	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk20 % change - SE, males n=26, 29	-33.9 percent change
Avandamet	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk56 % change, premenopausal females n=19, 10	-30.9 percent change
Avandamet	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk80 % change + SE, females n=42, 32	-19.2 percent change
Avandamet	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk80% change - SE, postmenopausal females n=23, 22	-39.4 percent change
Avandamet	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk80 % change, females n=42, 32	-24.4 percent change
Avandamet	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk56 % change - SE, premenopausal females n=19, 10	-37.6 percent change
Avandamet	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk80 % change - SE, females n=42, 32	-29.3 percent change
Avandamet	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk20 % change, postmenopausal females n=23, 20	-40.9 percent change
Avandamet	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk56 % change + SE, females n=42, 32	-27.0 percent change
Avandamet	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Wk20 % change + SE, premenopausal females n=17, 10	-29.0 percent change

p-value: 0.559595% CI: [-12.3, 7.4]ANCOVA

p-value: 0.912595% CI: [-15.3, 20.4]ANCOVA

p-value: 0.912295% CI: [-14, 14.5]ANCOVA

p-value: 0.743595% CI: [-21.2, 38.7]ANCOVA

p-value: 0.389795% CI: [-23, 11]ANCOVA

Secondary

Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80

Blood was taken for measurement of serum calcium. Percent change from baseline was based on log transformed data. Geometric mean, GM; standard error, SE. This outcome measure was analyzed for a subset of participants in the bone study only. n is the number of evaluable participants, which is the number of participants with a value at baseline and at the specified visit for the parameter of interest.

Time frame: Baseline and Weeks 12, 32, 56, and 80

Population: Week 20 Evaluable for the Bone Sub-study Population. This is a subset of the bone sub-study with LOCF from Week 20. Only participants with serum calcium measurements at Week 20 or later were included.

Arm	Measure	Group	Value (NUMBER)
Metformin	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk80 % change + SE, overall n= 79, 79	0.929 percent change
Metformin	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk80 % change, overall n=79, 79	0.424 percent change
Metformin	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk80 % change - SE, overall n= 79, 79	-0.079 percent change
Metformin	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk56 % change + SE, overall n= 79, 79	1.098 percent change
Metformin	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk56 % change, overall n= 79, 79	0.527 percent change
Metformin	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk56 % change - SE, overall n 79, 79	-0.040 percent change
Metformin	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk32 % change + SE, overall n=78, 77	0.136 percent change
Metformin	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk32 % change, overall n= 78, 77	-0.316 percent change
Metformin	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk32 % change - SE, overall n 78, 79	-0.766 percent change
Metformin	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk12 % change + SE, overall n=81, 78	0.568 percent change
Metformin	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk12 % change, overall n= 81, 78	0.123 percent change
Metformin	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk12 % change - SE, overall n 81, 78	-0.320 percent change
Metformin	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk80 % change + SE, males n=34, 39	0.8777 percent change
Metformin	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk80 % change, males n= 34, 39	0.071 percent change
Metformin	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk80 % change - SE, males n 34, 39	-0.728 percent change
Metformin	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk56 % change + SE, males n=34, 39	1.304 percent change
Metformin	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk56 % change, males n= 34, 39	0.646 percent change
Metformin	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk56 % change - SE, males n 34, 39	-0.009 percent change
Metformin	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk32 % change + SE, males n=33, 39	-0.538 percent change
Metformin	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk32 % change, males n= 33, 39	-1.281 percent change
Metformin	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk32 % change - SE, males n 33,39	-2.019 percent change
Metformin	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk12 % change + SE, males n=37, 40	1.410 percent change
Metformin	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk12 % change, males n= 37, 40	0.656 percent change
Metformin	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk12 % change - SE, males n 37, 40	-0.091 percent change
Metformin	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk80 % change + SE, females n= 45, 40	1.508 percent change
Metformin	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk80 % change, females n=45, 40	0.735 percent change
Metformin	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk80 % change - SE, females n= 45, 40	-0.033 percent change
Metformin	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk12 % change + SE, premenopausal females n=19, 13	0.420 percent change
Metformin	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk56 % change + SE, females n= 45, 40	1.692 percent change
Metformin	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk56 % change, females n=45, 40	0.720 percent change
Metformin	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk56 % change - SE, females n= 45, 40	-0.242 percent change
Metformin	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk32 % change + SE, females n= 45, 38	0.637 percent change
Metformin	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk32 % change, females n=45, 38	0.038 percent change
Metformin	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk32 % change - SE, females n= 45, 38	-0.557 percent change
Metformin	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk12 % change + SE, females n= 44, 38	0.715 percent change
Metformin	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk12 % change, females n=44, 38	0.055 percent change
Metformin	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk12 % change - SE, females n= 44, 38	-0.600 percent change
Metformin	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk80 % change + SE, premenopausal females n=19, 14	1.429 percent change
Metformin	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk80 % change, premenopausal females n= 19, 14	0.531 percent change
Metformin	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk80 % change - SE, premenopausal females n 19, 14	-0.359 percent change
Metformin	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk56 % change + SE, premenopausal females n=19, 14	2.091 percent change
Metformin	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk56 % change, premenopausal females n= 19, 14	0.960 percent change
Metformin	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk56 % change - SE, premenopausal females n 19, 14	-0.159 percent change
Metformin	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk32 % change + SE, premenopausal females n=19, 13	1.074 percent change
Metformin	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk32 % change, premenopausal females n= 19, 13	0.070 percent change
Metformin	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk32 % change - SE, premenopausal females n 19, 13	-0.923 percent change
Metformin	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk12 % change, premenopausal females n= 19, 13	-0.657 percent change
Metformin	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk12 % change - SE, premenopausal females n 19, 13	-1.722 percent change
Metformin	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk80 % change+ SE, postmenopausal females n=26, 26	2.019 percent change
Metformin	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk80 % change, postmenopausal females n=26, 26	0.760 percent change
Metformin	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk80% change - SE, postmenopausal females n=26, 26	-0.484 percent change
Metformin	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk56 % change+ SE, postmenopausal females n=26, 26	2.181 percent change
Metformin	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk56 % change, postmenopausal females n=26, 26	0.560 percent change
Metformin	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk56% change - SE, postmenopausal females n=26, 26	-1.035 percent change
Metformin	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk32 % change+ SE, postmenopausal females n=26, 25	0.844 percent change
Metformin	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk32 % change, postmenopausal females n=26, 25	0.056 percent change
Metformin	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk32% change - SE, postmenopausal females n=26, 25	-0.726 percent change
Metformin	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk12 % change+ SE, postmenopausal females n=25, 25	0.844 percent change
Metformin	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk12 % change, postmenopausal females n=25, 25	-0.042 percent change
Metformin	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk12% change - SE, postmenopausal females n=25, 25	-0.921 percent change
Avandamet	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk56 % change - SE, females n= 45, 40	-0.053 percent change
Avandamet	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk80 % change + SE, overall n= 79, 79	1.104 percent change
Avandamet	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk12 % change + SE, premenopausal females n=19, 13	-0.218 percent change
Avandamet	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk80 % change, overall n=79, 79	0.592 percent change
Avandamet	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk32 % change + SE, females n= 45, 38	-0.653 percent change
Avandamet	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk80 % change - SE, overall n= 79, 79	0.083 percent change
Avandamet	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk32% change - SE, postmenopausal females n=26, 25	-2.178 percent change
Avandamet	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk56 % change + SE, overall n= 79, 79	1.313 percent change
Avandamet	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk32 % change, females n=45, 38	-1.293 percent change
Avandamet	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk56 % change, overall n= 79, 79	0.735 percent change
Avandamet	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk12 % change, premenopausal females n= 19, 13	-1.280 percent change
Avandamet	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk56 % change - SE, overall n 79, 79	0.160 percent change
Avandamet	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk32 % change - SE, females n= 45, 38	-1.930 percent change
Avandamet	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk32 % change + SE, overall n=78, 77	-0.735 percent change
Avandamet	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk56% change - SE, postmenopausal females n=26, 26	-0.677 percent change
Avandamet	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk32 % change, overall n= 78, 77	-1.204 percent change
Avandamet	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk12 % change + SE, females n= 44, 38	-0.425 percent change
Avandamet	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk32 % change - SE, overall n 78, 79	-1.607 percent change
Avandamet	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk12 % change - SE, premenopausal females n 19, 13	-2.330 percent change
Avandamet	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk12 % change + SE, overall n=81, 78	-0.315 percent change
Avandamet	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk12 % change, females n=44, 38	-1.081 percent change
Avandamet	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk12 % change, overall n= 81, 78	-0.767 percent change
Avandamet	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk12 % change, postmenopausal females n=25, 25	-2.074 percent change
Avandamet	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk12 % change - SE, overall n 81, 78	-1.216 percent change
Avandamet	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk12 % change - SE, females n= 44, 38	-1.733 percent change
Avandamet	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk80 % change + SE, males n=34, 39	1.551 percent change
Avandamet	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk80 % change+ SE, postmenopausal females n=26, 26	1.915 percent change
Avandamet	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk80 % change, males n= 34, 39	0.817 percent change
Avandamet	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk80 % change + SE, premenopausal females n=19, 14	0.704 percent change
Avandamet	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk80 % change - SE, males n 34, 39	0.877 percent change
Avandamet	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk32 % change+ SE, postmenopausal females n=26, 25	-0.535 percent change
Avandamet	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk56 % change + SE, males n=34, 39	1.092 percent change
Avandamet	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk80 % change, premenopausal females n= 19, 14	-0.111 percent change
Avandamet	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk56 % change, males n= 34, 39	0.498 percent change
Avandamet	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk80 % change, postmenopausal females n=26, 26	0.604 percent change
Avandamet	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk56 % change - SE, males n 34, 39	-0.094 percent change
Avandamet	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk80 % change - SE, premenopausal females n 19, 14	-0.918 percent change
Avandamet	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk32 % change + SE, males n=33, 39	-0.585 percent change
Avandamet	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk12 % change+ SE, postmenopausal females n=25, 25	-1.163 percent change
Avandamet	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk32 % change, males n= 33, 39	-1.254 percent change
Avandamet	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk56 % change + SE, premenopausal females n=19, 14	2.334 percent change
Avandamet	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk32 % change - SE, males n 33,39	-1.919 percent change
Avandamet	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk80% change - SE, postmenopausal females n=26, 26	-0.690 percent change
Avandamet	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk12 % change + SE, males n=37, 40	0.543 percent change
Avandamet	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk56 % change, premenopausal females n= 19, 14	1.298 percent change
Avandamet	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk12 % change, males n= 37, 40	-0.147 percent change
Avandamet	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk32 % change, postmenopausal females n=26, 25	-1.360 percent change
Avandamet	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk12 % change - SE, males n 37, 40	-0.833 percent change
Avandamet	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk56 % change - SE, premenopausal females n 19, 14	0.273 percent change
Avandamet	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk80 % change + SE, females n= 45, 40	1.049 percent change
Avandamet	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk56 % change+ SE, postmenopausal females n=26, 26	2.691 percent change
Avandamet	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk80 % change, females n=45, 40	0.279 percent change
Avandamet	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk32 % change + SE, premenopausal females n=19, 13	-0.650 percent change
Avandamet	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk12% change - SE, postmenopausal females n=25, 25	-2.976 percent change
Avandamet	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk80 % change - SE, females n= 45, 40	-0.484 percent change
Avandamet	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk32 % change, premenopausal females n= 19, 13	-1.679 percent change
Avandamet	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk56 % change + SE, females n= 45, 40	1.884 percent change
Avandamet	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk56 % change, postmenopausal females n=26, 26	0.993 percent change
Avandamet	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk56 % change, females n=45, 40	0.911 percent change
Avandamet	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Wk32 % change - SE, premenopausal females n 19, 13	-2.698 percent change

p-value: 0.789595% CI: [-1.066, 1.417]ANCOVA

p-value: 0.415595% CI: [-1.064, 2.587]ANCOVA

p-value: 0.622395% CI: [-2.253, 1.382]ANCOVA

p-value: 0.590895% CI: [-3.043, 1.826]ANCOVA

p-value: 0.915495% CI: [-3.037, 2.814]ANCOVA

Secondary

Percent Change From Baseline in Total Body BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)

Time frame: Baseline and Weeks 20, 56, and 80

Arm	Measure	Group	Value (MEAN)	Dispersion
Metformin	Percent Change From Baseline in Total Body BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Male population, Week 56, n=38, 43	0.5 percent change	Standard Error 0.41
Metformin	Percent Change From Baseline in Total Body BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Female population, Week 20, n=49, 44	-0.2 percent change	Standard Error 0.56
Metformin	Percent Change From Baseline in Total Body BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Overall population, Week 56, n=87, 87	1.3 percent change	Standard Error 0.63
Metformin	Percent Change From Baseline in Total Body BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Premenopausal population, Week 80, n=21, 14	5.3 percent change	Standard Error 2.26
Metformin	Percent Change From Baseline in Total Body BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Male population, Week 20, n=38, 43	0.2 percent change	Standard Error 0.43
Metformin	Percent Change From Baseline in Total Body BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Premenopausal population, Week 56, n=21, 14	5.2 percent change	Standard Error 2.42
Metformin	Percent Change From Baseline in Total Body BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Male population, Week 80, n=38, 43	0.3 percent change	Standard Error 0.43
Metformin	Percent Change From Baseline in Total Body BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Premenopausal population, Week 20, n=21, 14	-0.2 percent change	Standard Error 1.38
Metformin	Percent Change From Baseline in Total Body BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Female population, Week 80, n=49, 44	2.0 percent change	Standard Error 1
Metformin	Percent Change From Baseline in Total Body BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Postmenopausal population, Week 80, n=28, 30	0.2 percent change	Standard Error 0.56
Metformin	Percent Change From Baseline in Total Body BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Overall population, Week 20, n=87, 87	0.0 percent change	Standard Error 0.37
Metformin	Percent Change From Baseline in Total Body BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Postmenopausal population, Week 56, n=28, 30	-0.2 percent change	Standard Error 0.49
Metformin	Percent Change From Baseline in Total Body BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Female population, Week 56, n=49, 44	1.9 percent change	Standard Error 1.03
Metformin	Percent Change From Baseline in Total Body BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Postmenopausal population, Week 20, n=28, 30	-0.2 percent change	Standard Error 0.45
Metformin	Percent Change From Baseline in Total Body BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Overall population, Week 80, n=87, 87	1.1 percent change	Standard Error 0.64
Avandamet	Percent Change From Baseline in Total Body BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Postmenopausal population, Week 20, n=28, 30	0.1 percent change	Standard Error 0.54
Avandamet	Percent Change From Baseline in Total Body BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Overall population, Week 80, n=87, 87	1.1 percent change	Standard Error 0.64
Avandamet	Percent Change From Baseline in Total Body BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Overall population, Week 56, n=87, 87	-0.1 percent change	Standard Error 0.63
Avandamet	Percent Change From Baseline in Total Body BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Overall population, Week 20, n=87, 87	0.5 percent change	Standard Error 0.37
Avandamet	Percent Change From Baseline in Total Body BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Male population, Week 80, n=38, 43	0.5 percent change	Standard Error 0.38
Avandamet	Percent Change From Baseline in Total Body BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Male population, Week 56, n=38, 43	0.5 percent change	Standard Error 0.37
Avandamet	Percent Change From Baseline in Total Body BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Male population, Week 20, n=38, 43	0.5 percent change	Standard Error 0.38
Avandamet	Percent Change From Baseline in Total Body BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Female population, Week 80, n=49, 44	1.0 percent change	Standard Error 1.01
Avandamet	Percent Change From Baseline in Total Body BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Female population, Week 56, n=49, 44	1.2 percent change	Standard Error 1.04
Avandamet	Percent Change From Baseline in Total Body BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Female population, Week 20, n=49, 44	0.5 percent change	Standard Error 0.57
Avandamet	Percent Change From Baseline in Total Body BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Premenopausal population, Week 80, n=21, 14	-0.2 percent change	Standard Error 2.73
Avandamet	Percent Change From Baseline in Total Body BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Premenopausal population, Week 56, n=21, 14	-1.0 percent change	Standard Error 2.94
Avandamet	Percent Change From Baseline in Total Body BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Premenopausal population, Week 20, n=21, 14	0.3 percent change	Standard Error 1.66
Avandamet	Percent Change From Baseline in Total Body BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Postmenopausal population, Week 80, n=28, 30	-0.4 percent change	Standard Error 0.67
Avandamet	Percent Change From Baseline in Total Body BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Postmenopausal population, Week 56, n=28, 30	-0.6 percent change	Standard Error 0.58

p-value: 0.701595% CI: [-1.5, 1]ANCOVA

p-value: 0.676795% CI: [-0.7, 1]ANCOVA

p-value: 0.419995% CI: [-3.4, 1.5]ANCOVA

p-value: 0.252695% CI: [-16.4, 5.4]ANCOVA

p-value: 0.415395% CI: [-1.8, 0.8]ANCOVA

Secondary

Percent Change From Baseline in Total Cholesterol, Low-density Lipoprotein (LDL) Cholesterol, High-density Lipoprotein (HDL) Cholesterol, and Triglycerides at Week 80

Blood was taken for measurement of total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides. Percent change from baseline at Week 80 was based on log transformed data. Geometric mean, GM; standard error, SE. n is the number of evaluable participants, which is the number of participants with a value at baseline and at the specified visit for the parameter of interest.

Time frame: Baseline and Week 80

Population: Week 32 evaluable population with LOCF from Week 32. n is the number of evaluable participants, which is defined as the number of participants with a value at baseline and at the specified visit for the parameter of interest.

Arm	Measure	Group	Value (NUMBER)
Metformin	Percent Change From Baseline in Total Cholesterol, Low-density Lipoprotein (LDL) Cholesterol, High-density Lipoprotein (HDL) Cholesterol, and Triglycerides at Week 80	% change + SE, Total cholesterol, n=258, 265	-1.615 percent change
Metformin	Percent Change From Baseline in Total Cholesterol, Low-density Lipoprotein (LDL) Cholesterol, High-density Lipoprotein (HDL) Cholesterol, and Triglycerides at Week 80	% change, Total cholesterol, n=258, 265	-2.89 percent change
Metformin	Percent Change From Baseline in Total Cholesterol, Low-density Lipoprotein (LDL) Cholesterol, High-density Lipoprotein (HDL) Cholesterol, and Triglycerides at Week 80	% change - SE, Total cholesterol, n=258, 265	-4.140 percent change
Metformin	Percent Change From Baseline in Total Cholesterol, Low-density Lipoprotein (LDL) Cholesterol, High-density Lipoprotein (HDL) Cholesterol, and Triglycerides at Week 80	% change + SE, LDL cholesterol, n=248, 252	-4.933 percent change
Metformin	Percent Change From Baseline in Total Cholesterol, Low-density Lipoprotein (LDL) Cholesterol, High-density Lipoprotein (HDL) Cholesterol, and Triglycerides at Week 80	% change, LDL cholesterol, n=248, 252	-7.11 percent change
Metformin	Percent Change From Baseline in Total Cholesterol, Low-density Lipoprotein (LDL) Cholesterol, High-density Lipoprotein (HDL) Cholesterol, and Triglycerides at Week 80	% change - SE, LDL cholesterol, n=248, 252	-9.228 percent change
Metformin	Percent Change From Baseline in Total Cholesterol, Low-density Lipoprotein (LDL) Cholesterol, High-density Lipoprotein (HDL) Cholesterol, and Triglycerides at Week 80	% change + SE, HDL cholesterol, n=258, 265	6.761 percent change
Metformin	Percent Change From Baseline in Total Cholesterol, Low-density Lipoprotein (LDL) Cholesterol, High-density Lipoprotein (HDL) Cholesterol, and Triglycerides at Week 80	% change, HDL cholesterol, n=258, 265	5.60 percent change
Metformin	Percent Change From Baseline in Total Cholesterol, Low-density Lipoprotein (LDL) Cholesterol, High-density Lipoprotein (HDL) Cholesterol, and Triglycerides at Week 80	% change - SE, HDL cholesterol, n=258, 265	4.453 percent change
Metformin	Percent Change From Baseline in Total Cholesterol, Low-density Lipoprotein (LDL) Cholesterol, High-density Lipoprotein (HDL) Cholesterol, and Triglycerides at Week 80	% change + SE, triglycerides, n=258, 265	-2.696 percent change
Metformin	Percent Change From Baseline in Total Cholesterol, Low-density Lipoprotein (LDL) Cholesterol, High-density Lipoprotein (HDL) Cholesterol, and Triglycerides at Week 80	% change, triglycerides, n=258, 265	-5.330 percent change
Metformin	Percent Change From Baseline in Total Cholesterol, Low-density Lipoprotein (LDL) Cholesterol, High-density Lipoprotein (HDL) Cholesterol, and Triglycerides at Week 80	% change - SE, triglycerides, n=258, 265	-7.893 percent change
Avandamet	Percent Change From Baseline in Total Cholesterol, Low-density Lipoprotein (LDL) Cholesterol, High-density Lipoprotein (HDL) Cholesterol, and Triglycerides at Week 80	% change, triglycerides, n=258, 265	-4.627 percent change
Avandamet	Percent Change From Baseline in Total Cholesterol, Low-density Lipoprotein (LDL) Cholesterol, High-density Lipoprotein (HDL) Cholesterol, and Triglycerides at Week 80	% change + SE, Total cholesterol, n=258, 265	4.218 percent change
Avandamet	Percent Change From Baseline in Total Cholesterol, Low-density Lipoprotein (LDL) Cholesterol, High-density Lipoprotein (HDL) Cholesterol, and Triglycerides at Week 80	% change + SE, HDL cholesterol, n=258, 265	9.483 percent change
Avandamet	Percent Change From Baseline in Total Cholesterol, Low-density Lipoprotein (LDL) Cholesterol, High-density Lipoprotein (HDL) Cholesterol, and Triglycerides at Week 80	% change, Total cholesterol, n=258, 265	2.91 percent change
Avandamet	Percent Change From Baseline in Total Cholesterol, Low-density Lipoprotein (LDL) Cholesterol, High-density Lipoprotein (HDL) Cholesterol, and Triglycerides at Week 80	% change + SE, triglycerides, n=258, 265	-2.042 percent change
Avandamet	Percent Change From Baseline in Total Cholesterol, Low-density Lipoprotein (LDL) Cholesterol, High-density Lipoprotein (HDL) Cholesterol, and Triglycerides at Week 80	% change - SE, Total cholesterol, n=258, 265	1.614 percent change
Avandamet	Percent Change From Baseline in Total Cholesterol, Low-density Lipoprotein (LDL) Cholesterol, High-density Lipoprotein (HDL) Cholesterol, and Triglycerides at Week 80	% change, HDL cholesterol, n=258, 265	8.324 percent change
Avandamet	Percent Change From Baseline in Total Cholesterol, Low-density Lipoprotein (LDL) Cholesterol, High-density Lipoprotein (HDL) Cholesterol, and Triglycerides at Week 80	% change + SE, LDL cholesterol, n=248, 252	3.304 percent change
Avandamet	Percent Change From Baseline in Total Cholesterol, Low-density Lipoprotein (LDL) Cholesterol, High-density Lipoprotein (HDL) Cholesterol, and Triglycerides at Week 80	% change - SE, triglycerides, n=258, 265	-7.143 percent change
Avandamet	Percent Change From Baseline in Total Cholesterol, Low-density Lipoprotein (LDL) Cholesterol, High-density Lipoprotein (HDL) Cholesterol, and Triglycerides at Week 80	% change, LDL cholesterol, n=248, 252	0.98 percent change
Avandamet	Percent Change From Baseline in Total Cholesterol, Low-density Lipoprotein (LDL) Cholesterol, High-density Lipoprotein (HDL) Cholesterol, and Triglycerides at Week 80	% change - SE, HDL cholesterol, n=258, 265	7.179 percent change
Avandamet	Percent Change From Baseline in Total Cholesterol, Low-density Lipoprotein (LDL) Cholesterol, High-density Lipoprotein (HDL) Cholesterol, and Triglycerides at Week 80	% change - SE, LDL cholesterol, n=248, 252	-1.286 percent change

p-value: 0.000695% CI: [2.522, 9.526]ANCOVA

p-value: 0.05695% CI: [2.486, 15.304]ANCOVA

p-value: 0.07295% CI: [-0.232, 5.47]ANCOVA

p-value: 0.83595% CI: [-6.056, 8.035]ANCOVA

Secondary

Percent Change From Baseline in Total Hip BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)

Time frame: Baseline and Weeks 20, 56, and 80

Arm	Measure	Group	Value (MEAN)	Dispersion
Metformin	Percent Change From Baseline in Total Hip BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Male population, Week 56, n=38, 43	0.2 percent change	Standard Error 0.41
Metformin	Percent Change From Baseline in Total Hip BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Female population, Week 20, n=49, 44	-0.3 percent change	Standard Error 0.37
Metformin	Percent Change From Baseline in Total Hip BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Overall population, Week 56, n=87, 87	-0.2 percent change	Standard Error 0.31
Metformin	Percent Change From Baseline in Total Hip BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Premenopausal population, Week 80, n=21, 14	1.3 percent change	Standard Error 0.71
Metformin	Percent Change From Baseline in Total Hip BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Male population, Week 20, n=38, 43	0.5 percent change	Standard Error 0.35
Metformin	Percent Change From Baseline in Total Hip BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Premenopausal population, Week 56, n=21, 14	0.8 percent change	Standard Error 0.69
Metformin	Percent Change From Baseline in Total Hip BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Male population, Week 80, n=38, 43	0.3 percent change	Standard Error 0.46
Metformin	Percent Change From Baseline in Total Hip BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Premenopausal population, Week 20, n=21, 14	0.3 percent change	Standard Error 0.48
Metformin	Percent Change From Baseline in Total Hip BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Female population, Week 80, n=49, 44	0.0 percent change	Standard Error 0.6
Metformin	Percent Change From Baseline in Total Hip BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Postmenopausal population, Week 80, n=28, 30	-0.9 percent change	Standard Error 0.97
Metformin	Percent Change From Baseline in Total Hip BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Overall population, Week 20, n=87, 87	0.2 percent change	Standard Error 0.24
Metformin	Percent Change From Baseline in Total Hip BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Postmenopausal population, Week 56, n=28, 30	-1.1 percent change	Standard Error 0.81
Metformin	Percent Change From Baseline in Total Hip BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Female population, Week 56, n=49, 44	-0.2 percent change	Standard Error 0.52
Metformin	Percent Change From Baseline in Total Hip BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Postmenopausal population, Week 20, n=28, 30	-0.4 percent change	Standard Error 0.57
Metformin	Percent Change From Baseline in Total Hip BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Overall population, Week 80, n=87, 87	0.0 percent change	Standard Error 0.35
Avandamet	Percent Change From Baseline in Total Hip BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Postmenopausal population, Week 20, n=28, 30	-0.6 percent change	Standard Error 0.6
Avandamet	Percent Change From Baseline in Total Hip BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Overall population, Week 80, n=87, 87	-1.5 percent change	Standard Error 0.35
Avandamet	Percent Change From Baseline in Total Hip BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Overall population, Week 56, n=87, 87	-1.2 percent change	Standard Error 0.32
Avandamet	Percent Change From Baseline in Total Hip BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Overall population, Week 20, n=87, 87	-0.4 percent change	Standard Error 0.24
Avandamet	Percent Change From Baseline in Total Hip BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Male population, Week 80, n=38, 43	-1.0 percent change	Standard Error 0.41
Avandamet	Percent Change From Baseline in Total Hip BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Male population, Week 56, n=38, 43	-0.8 percent change	Standard Error 0.37
Avandamet	Percent Change From Baseline in Total Hip BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Male population, Week 20, n=38, 43	-0.3 percent change	Standard Error 0.31
Avandamet	Percent Change From Baseline in Total Hip BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Female population, Week 80, n=49, 44	-1.8 percent change	Standard Error 0.61
Avandamet	Percent Change From Baseline in Total Hip BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Female population, Week 56, n=49, 44	-1.4 percent change	Standard Error 0.54
Avandamet	Percent Change From Baseline in Total Hip BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Female population, Week 20, n=49, 44	-0.6 percent change	Standard Error 0.38
Avandamet	Percent Change From Baseline in Total Hip BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Premenopausal population, Week 80, n=21, 14	-0.9 percent change	Standard Error 0.69
Avandamet	Percent Change From Baseline in Total Hip BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Premenopausal population, Week 56, n=21, 14	-1.6 percent change	Standard Error 0.67
Avandamet	Percent Change From Baseline in Total Hip BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Premenopausal population, Week 20, n=21, 14	0.0 percent change	Standard Error 0.47
Avandamet	Percent Change From Baseline in Total Hip BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Postmenopausal population, Week 80, n=28, 30	-2.3 percent change	Standard Error 1.02
Avandamet	Percent Change From Baseline in Total Hip BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Postmenopausal population, Week 56, n=28, 30	-1.5 percent change	Standard Error 0.85

p-value: 0.000595% CI: [-2.3, -0.7]ANCOVA

p-value: 0.01195% CI: [-1.7, -0.2]ANCOVA

p-value: 0.061895% CI: [-1.1, 0]ANCOVA

p-value: 0.01195% CI: [-2.3, -0.3]ANCOVA

p-value: 0.027295% CI: [-1.9, -0.1]ANCOVA

p-value: 0.033795% CI: [-1.6, -0.1]ANCOVA

p-value: 0.015295% CI: [-3.1, -0.3]ANCOVA

p-value: 0.05795% CI: [-2.4, 0]ANCOVA

p-value: 0.029695% CI: [-4.3, -0.2]ANCOVA

p-value: 0.015595% CI: [-4.4, -0.5]ANCOVA

p-value: 0.58795% CI: [-1.7, 1]ANCOVA

p-value: 0.185495% CI: [-3.6, 0.7]ANCOVA

Secondary

Percent Change From Baseline in Trochanter BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)

Time frame: Baseline and Weeks 20, 56, and 80

Arm	Measure	Group	Value (MEAN)	Dispersion
Metformin	Percent Change From Baseline in Trochanter BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Male population, Week 56, n=38, 43	0.9 percent change	Standard Error 0.67
Metformin	Percent Change From Baseline in Trochanter BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Female population, Week 20, n=49, 44	-0.2 percent change	Standard Error 0.52
Metformin	Percent Change From Baseline in Trochanter BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Overall population, Week 56, n=87, 87	-0.2 percent change	Standard Error 0.49
Metformin	Percent Change From Baseline in Trochanter BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Premenopausal population, Week 80, n=21, 14	1.7 percent change	Standard Error 1.18
Metformin	Percent Change From Baseline in Trochanter BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Male population, Week 20, n=38, 43	0.7 percent change	Standard Error 0.55
Metformin	Percent Change From Baseline in Trochanter BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Premenopausal population, Week 56, n=21, 14	0.3 percent change	Standard Error 0.94
Metformin	Percent Change From Baseline in Trochanter BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Male population, Week 80, n=38, 43	1.1 percent change	Standard Error 0.69
Metformin	Percent Change From Baseline in Trochanter BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Premenopausal population, Week 20, n=21, 14	0.0 percent change	Standard Error 0.71
Metformin	Percent Change From Baseline in Trochanter BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Female population, Week 80, n=49, 44	-0.2 percent change	Standard Error 0.93
Metformin	Percent Change From Baseline in Trochanter BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Postmenopausal population, Week 80, n=28, 30	-1.1 percent change	Standard Error 1.45
Metformin	Percent Change From Baseline in Trochanter BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Overall population, Week 20, n=87, 87	0.1 percent change	Standard Error 0.35
Metformin	Percent Change From Baseline in Trochanter BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Postmenopausal population, Week 56, n=28, 30	-1.1 percent change	Standard Error 1.25
Metformin	Percent Change From Baseline in Trochanter BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Female population, Week 56, n=49, 44	-0.3 percent change	Standard Error 0.8
Metformin	Percent Change From Baseline in Trochanter BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Postmenopausal population, Week 20, n=28, 30	-0.3 percent change	Standard Error 0.76
Metformin	Percent Change From Baseline in Trochanter BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Overall population, Week 80, n=87, 87	-0.1 percent change	Standard Error 0.54
Avandamet	Percent Change From Baseline in Trochanter BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Postmenopausal population, Week 20, n=28, 30	-1.0 percent change	Standard Error 0.8
Avandamet	Percent Change From Baseline in Trochanter BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Overall population, Week 80, n=87, 87	-2.1 percent change	Standard Error 0.55
Avandamet	Percent Change From Baseline in Trochanter BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Overall population, Week 56, n=87, 87	-1.7 percent change	Standard Error 0.49
Avandamet	Percent Change From Baseline in Trochanter BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Overall population, Week 20, n=87, 87	-0.6 percent change	Standard Error 0.34
Avandamet	Percent Change From Baseline in Trochanter BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Male population, Week 80, n=38, 43	-0.4 percent change	Standard Error 0.61
Avandamet	Percent Change From Baseline in Trochanter BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Male population, Week 56, n=38, 43	-0.5 percent change	Standard Error 0.6
Avandamet	Percent Change From Baseline in Trochanter BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Male population, Week 20, n=38, 43	-0.2 percent change	Standard Error 0.48
Avandamet	Percent Change From Baseline in Trochanter BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Female population, Week 80, n=49, 44	-2.6 percent change	Standard Error 0.96
Avandamet	Percent Change From Baseline in Trochanter BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Female population, Week 56, n=49, 44	-2.1 percent change	Standard Error 0.82
Avandamet	Percent Change From Baseline in Trochanter BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Female population, Week 20, n=49, 44	-0.8 percent change	Standard Error 0.53
Avandamet	Percent Change From Baseline in Trochanter BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Premenopausal population, Week 80, n=21, 14	-1.4 percent change	Standard Error 1.12
Avandamet	Percent Change From Baseline in Trochanter BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Premenopausal population, Week 56, n=21, 14	-2.6 percent change	Standard Error 0.89
Avandamet	Percent Change From Baseline in Trochanter BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Premenopausal population, Week 20, n=21, 14	0.0 percent change	Standard Error 0.67
Avandamet	Percent Change From Baseline in Trochanter BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Postmenopausal population, Week 80, n=28, 30	-3.6 percent change	Standard Error 1.53
Avandamet	Percent Change From Baseline in Trochanter BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	Postmenopausal population, Week 56, n=28, 30	-2.2 percent change	Standard Error 1.31

p-value: 0.003895% CI: [-3.2, -0.6]ANCOVA

p-value: 0.013495% CI: [-2.7, -0.3]ANCOVA

p-value: 0.096795% CI: [-1.5, 0.1]ANCOVA

p-value: 0.051295% CI: [-3, 0]ANCOVA

p-value: 0.03395% CI: [-4.6, -0.2]ANCOVA

p-value: 0.054795% CI: [-3.7, 0]ANCOVA

p-value: 0.061395% CI: [-6.3, 0.2]ANCOVA

p-value: 0.136995% CI: [-3.9, 1.7]ANCOVA

Secondary

Percent Change in Free Fatty Acids (FFA) From Baseline at Week 80 (US and Mexico Subset of Participants).

Blood was taken for measurement of FFA. Percent change from baseline at Week 80 was based on log transformed data. This outcome measure was analyzed for a subset of participants in the US and Mexico only.

Time frame: Baseline and Week 80

Arm	Measure	Group	Value (NUMBER)
Metformin	Percent Change in Free Fatty Acids (FFA) From Baseline at Week 80 (US and Mexico Subset of Participants).	Percent change from baseline + SE	14.353 percent change
Metformin	Percent Change in Free Fatty Acids (FFA) From Baseline at Week 80 (US and Mexico Subset of Participants).	Percent change from baseline	9.40 percent change
Metformin	Percent Change in Free Fatty Acids (FFA) From Baseline at Week 80 (US and Mexico Subset of Participants).	Percent change from baseline - SE	4.657 percent change
Avandamet	Percent Change in Free Fatty Acids (FFA) From Baseline at Week 80 (US and Mexico Subset of Participants).	Percent change from baseline + SE	1.267 percent change
Avandamet	Percent Change in Free Fatty Acids (FFA) From Baseline at Week 80 (US and Mexico Subset of Participants).	Percent change from baseline	-2.97 percent change
Avandamet	Percent Change in Free Fatty Acids (FFA) From Baseline at Week 80 (US and Mexico Subset of Participants).	Percent change from baseline - SE	-7.028 percent change

p-value: 0.034295% CI: [-20.617, -0.899]ANCOVA

Secondary

Slope of Delta-cell Function as Estimated by the Ratio deltaI/deltaG

The ratio Delta I/Delta G is calculated based on the oral glucose tolerance test (OGTT), where Delta I = (30 minute immunoreactive insulin minus 0 minute immunoreactive insulin) and Delta G = (30 minute plasma glucose minus 0 minute plasma glucose). The 0 minute values are fasting insulin and glucose; the 30 minute values are taken 30 minutes after the oral glucose challenge. This outcome measure was analyzed for a subset of participants in the US and Mexico only.

Time frame: Baseline and Week 80

Population: Week 32 Evaluable Population with LOCF. Only evaluable participants, defined as participants from US and Mexico sites with a value at baseline and at the specified visit, were analyzed.

Arm	Measure	Value (MEAN)	Dispersion
Metformin	Slope of Delta-cell Function as Estimated by the Ratio deltaI/deltaG	-86.23 ratio	Standard Error 59.706
Avandamet	Slope of Delta-cell Function as Estimated by the Ratio deltaI/deltaG	-5.38 ratio	Standard Error 55.229

p-value: 0.31995% CI: [-79.035, 240.744]Repeated measures analysis

Source: ClinicalTrials.gov · Data processed: Feb 4, 2026

A Type 2 Diabetes Study of the Longer-Term Glycemic Effect of AVANDAMET vs. Metformin

Conditions

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Brief summary

Detailed description

Related papers

Interventions

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Study design

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Exclusion criteria

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Secondary

Countries

Participant flow

Participants by arm

Withdrawals & dropouts

Baseline characteristics

Adverse events

Outcome results

Change From Baseline in HbA1c at Week 80

Change From Baseline in FPG at Week 80

Change in C-peptide From Baseline at Week 80 (US and Mexico Subset of Participants)

Change in Fasting Insulin From Baseline at Week 80 (US and Mexico Subset of Participants)

Change in Fasting Plasma Glucose (FPG) From Baseline at Week 80

Mean Change From Baseline in HbA1c at Week 80

Number of Participants Achieving FPG <=6 mmol/L (110 mg/dL) and <=7 mmol/L (126 mg/dL) at Week 80

Number of Participants Achieving HbA1c <=6.5% and <7% at Week 80

Number of Participants Achieving Treatment Failure

Number of Participants at Final Dose Level

Percent Change From Baseline in 25-hydroxy Vitamin D at Week 80

Percent Change From Baseline in Adiponectin at Week 80 (United States [US] and Mexico Subset of Participants )

Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80

Percent Change From Baseline in C-reactive Protein (CRP) at Week 80 (US and Mexico Subset of Participants)

Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80

Percent Change From Baseline in Distal Radius BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)

Percent Change From Baseline in Estradiol at Weeks 20, 56, and 80

Percent Change From Baseline in Femoral Neck BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)

Percent Change From Baseline in in HOMA-S and HOMA-B to Week 80 (US and Mexico Subset of Participants)

Percent Change From Baseline in Intact Parathyroid Hormone at Week 80

Percent Change From Baseline in Lumbar Spine Bone Mass Density (BMD) at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)

Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80

Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80

Percent Change From Baseline in Total Body BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)

Percent Change From Baseline in Total Cholesterol, Low-density Lipoprotein (LDL) Cholesterol, High-density Lipoprotein (HDL) Cholesterol, and Triglycerides at Week 80

Percent Change From Baseline in Total Hip BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)

Percent Change From Baseline in Trochanter BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)

Percent Change in Free Fatty Acids (FFA) From Baseline at Week 80 (US and Mexico Subset of Participants).

Slope of Delta-cell Function as Estimated by the Ratio deltaI/deltaG