Type 2 Diabetes Mellitus
Conditions
Keywords
Type 2 diabetes, beta-cell function, sitagliptin, intensive insulin therapy
Brief summary
Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by progressive deterioration in the function of the pancreatic beta-cells, which are the cells that produce and secrete insulin (the hormone primarily responsible for the handling of glucose in the body). The investigators propose a double-blind, randomized controlled pilot study comparing the effect of sitagliptin (a novel anti-diabetic drug with beta-cell protective potential) versus placebo, on the preservation of beta-cell function over one year in patients with T2DM on metformin, the first-line agent for the treatment of T2DM (ie. the study groups will be (i) sitagliptin and metformin versus (ii) placebo and metformin). This study may demonstrate an important beta-cell protective capacity of sitagliptin. Hypothesis: In patients with T2DM on metformin, treatment with the DPP-IV inhibitor sitagliptin will preserve pancreatic beta-cell function.
Detailed description
Medications currently used in the treatment of T2DM have not been shown to modify the progressive decline in beta-cell function that occurs over time. Recent evidence, however, suggests that a new class of anti-diabetic medications, called dipeptidyl peptidase-IV (DPP-IV) inhibitors, may be able to protect beta cells and hence alter the natural history of T2DM. We thus wish to study the effect of sitagliptin (a DPP-IV inhibitor) on the preservation of beta-cell function in patients with T2DM randomized to either (i) sitagliptin and metformin or (ii) placebo and metformin.
Interventions
DRUGSitagliptin
sitagliptin 100 mg once a day
DRUGPlacebo
placebo once a day
DRUGmetformin
metformin 1000 mg twice a day (bid) by mouth (po)
Sponsors
Merck Sharp & Dohme LLC
Samuel Lunenfeld Research Institute, Mount Sinai Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
30 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Men and women between the ages of 30 and 75 inclusive 2. Physician-diagnosed type 2 diabetes on 0-2 oral hypoglycemic agents 3. Negative for anti-glutamic acid decarboxylase (anti-GAD\_ antibodies (to rule out Latent Autoimmune Diabetes of Adults (LADA) 4. A1c at screening between 6.5% and 9% inclusive if on no oral hypoglycemic agents or 6.0% and 9.0% inclusive if on 1-2 oral hypoglycemic agents
Exclusion criteria
1. Current insulin therapy 2. Type 1 diabetes or secondary forms of diabetes 3. Any major illness with a life expectancy of \< 5 years or that may interfere with the patient's participation in the study 4. Involvement in any other study requiring drug therapy 5. Renal dysfunction as evidenced by serum creatinine \>/= 136 umol/L for males or \>/= 124 umol/L for females or abnormal creatinine clearance (\< 60 ml/min by Modification of Diet in Renal Disease (MDRD) formula) 6. Hepatic disease considered to be clinically significant (includes jaundice, chronic hepatitis, or previous liver transplant) or transaminases \> 2.5 times the upper limit of normal 7. Excessive alcohol consumption, defined as \> 14 alcoholic drinks per week for males and \> 9 alcoholic drinks per week for females 8. Pregnancy or unwillingness to use reliable contraception. Women should not be planning pregnancy for the duration of the study. Reliable contraception includes: birth control pill, intra-uterine device, abstinence, tubal ligation, partner vasectomy, or condoms with spermicide. Any women who miss a menstrual period or think that they may be pregnant must have a pregnancy test as soon as possible 9. History of serious arrhythmia or atrioventricular block on baseline electrocardiogram 10. Uncontrolled hypertension (systolic blood pressure \> 180 mm Hg or diastolic blood pressure \> 110 mm Hg) 11. Unwillingness to undergo multiple daily insulin injection therapy for 4 weeks 12. Unwillingness to perform capillary blood glucose monitoring at least 4 times per day during intensive insulin therapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Preservation of Beta-cell Function Measured by Area-under-the-curve (C-peptide/Glucose)/HOMA-IR | 48 weeks | Area-under-the-C-peptide-curve (AUCCpep) and area-under-the-glucose-curve (AUCgluc) from 0 to 240 minutes during meal tests were calculated using the trapezoidal rule. Insulin resistance was assessed using the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR). Beta-cell function was assessed using the ratio of total AUCCpep to AUCgluc divided by HOMA-IR (AUCCpep/gluc/HOMA-IR), a measure of insulin secretion in the context of ambient insulin sensitivity, analogous to the disposition index and adaptation index. Higher AUCCpep/gluc/HOMA-IR is indicative of better beta-cell function. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Insulinogenic Index Divided by HOMA-IR at 48 Weeks | 48 weeks | Insulinogenic index was calculated as the incremental change in insulin from 0 to 30 minutes divided by the incremental change in glucose over the same period of time. Insulinogenic index divided by HOMA-IR provides an additional measure of beta-cell function. A higher value indicates better beta-cell function |
| Fasting Blood Glucose at 48 Weeks | 48 weeks | — |
| Area-under-the-glucose-curve (AUCglucose) on Meal Test at 1 Year | 1 year | — |
| Time to Loss of Glycemic Control | 1 year | — |
| Proportion of Patients Achieving Sustained Normoglycemia Off Medication at 1-week Post-insulin Therapy | 1 year | — |
Countries
Canada
Participant flow
Recruitment details
Participants were recruited from outpatient clinics at the Leadership Sinai Centre for Diabetes between February 2007 and October 2008.
Pre-assignment details
Participants underwent prerandomization phase of 4-8 weeks of intensive insulin therapy (IIT) consisting of basal detemir and premeal insulin aspart. Only participants who achieved fasting glucose \<7.0 mmol/L 1 day after completing IIT were randomized to either sitagliptin 100 mg once daily or matching placebo.
Participants by arm
| Arm | Count |
|---|---|
| Sitagliptin Sitagliptin 100 mg once daily and metformin 1000 mg twice a day (bid) by mouth po | 10 |
| Placebo Matching placebo once daily and metformin 1000 mg twice a day (bid) by mouth (po) | 11 |
| Total | 21 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
| Overall Study | Lost to Follow-up | 1 | 0 |
Baseline characteristics
| Characteristic | Sitagliptin | Placebo | Total |
|---|---|---|---|
| Age Continuous | 61.3 years | 60.8 years | 60.9 years |
| Area-Under-The-Curve (C-peptide/glucose) / HOMA-IR | 114.8 index of beta-cell function | 126.0 index of beta-cell function | 120.0 index of beta-cell function |
| Body Mass Index | 34.3 kg/m^2 | 32.7 kg/m^2 | 32.7 kg/m^2 |
| Duration of diabetes | 2.8 years | 3.5 years | 3.0 years |
| HbA1c | 6.2 percent glycosylated hemoglobin | 6.1 percent glycosylated hemoglobin | 6.1 percent glycosylated hemoglobin |
| Race/Ethnicity, Customized Other | 6 participants | 2 participants | 8 participants |
| Race/Ethnicity, Customized White | 4 participants | 9 participants | 13 participants |
| Sex: Female, Male Female | 4 Participants | 3 Participants | 7 Participants |
| Sex: Female, Male Male | 6 Participants | 8 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 10 | 0 / 11 |
| serious Total, serious adverse events | 1 / 10 | 1 / 11 |
Outcome results
Primary
Preservation of Beta-cell Function Measured by Area-under-the-curve (C-peptide/Glucose)/HOMA-IR
Area-under-the-C-peptide-curve (AUCCpep) and area-under-the-glucose-curve (AUCgluc) from 0 to 240 minutes during meal tests were calculated using the trapezoidal rule. Insulin resistance was assessed using the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR). Beta-cell function was assessed using the ratio of total AUCCpep to AUCgluc divided by HOMA-IR (AUCCpep/gluc/HOMA-IR), a measure of insulin secretion in the context of ambient insulin sensitivity, analogous to the disposition index and adaptation index. Higher AUCCpep/gluc/HOMA-IR is indicative of better beta-cell function.
Time frame: 48 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sitagliptin | Preservation of Beta-cell Function Measured by Area-under-the-curve (C-peptide/Glucose)/HOMA-IR | 80.4 index of beta-cell function |
| Placebo | Preservation of Beta-cell Function Measured by Area-under-the-curve (C-peptide/Glucose)/HOMA-IR | 71.2 index of beta-cell function |
Secondary
Area-under-the-glucose-curve (AUCglucose) on Meal Test at 1 Year
Time frame: 1 year
Secondary
Fasting Blood Glucose at 48 Weeks
Time frame: 48 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sitagliptin | Fasting Blood Glucose at 48 Weeks | 6.9 mmol/l |
| Placebo | Fasting Blood Glucose at 48 Weeks | 6.7 mmol/l |
Secondary
Insulinogenic Index Divided by HOMA-IR at 48 Weeks
Insulinogenic index was calculated as the incremental change in insulin from 0 to 30 minutes divided by the incremental change in glucose over the same period of time. Insulinogenic index divided by HOMA-IR provides an additional measure of beta-cell function. A higher value indicates better beta-cell function
Time frame: 48 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sitagliptin | Insulinogenic Index Divided by HOMA-IR at 48 Weeks | 3.9 index of beta-cell function |
| Placebo | Insulinogenic Index Divided by HOMA-IR at 48 Weeks | 1.8 index of beta-cell function |
Secondary
Proportion of Patients Achieving Sustained Normoglycemia Off Medication at 1-week Post-insulin Therapy
Time frame: 1 year
Secondary
Time to Loss of Glycemic Control
Time frame: 1 year