Diabetes Mellitus, Type 2
Conditions
Keywords
Type 2 Diabetes Mellitus
Brief summary
LY2409021 is being evaluated for possible treatment in type 2 diabetes. This study is designed to compare LY2409021 given alone or given in combination with metformin against placebo the change in hemoglobin A1c after a 24-week treatment period.
Interventions
DRUGLY2409021
Administered Orally
DRUGPlacebo
Administered Orally
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Have a diagnosis of Type 2 diabetes mellitus according to the World Health Organization (WHO) diagnostic criteria * Are women not of child-bearing potential due to surgical sterilization (hysterectomy or bilateral oophorectomy or tubal ligation) or menopause. * Are male patients using a reliable method of birth control during the study and until 3 months after the last dose of study medication. * Are being treated with either diet and exercise alone, or with diet and exercise in combination with metformin. Metformin therapy must have been stable and unchanged for at least 3 months prior to screening and at a dose of at least 1000 milligram per day (mg/day). * Have a hemoglobin A1c (HbA1c) value of 7.0% to 10.5%, inclusive. * Have a body mass index (BMI) between 25 to 45 kilogram per meter squared (kg/m\^2), inclusive. In the opinion of the investigator, are capable and willing to: * Perform self-monitoring of blood glucose * Complete a study diary as required for this protocol * Maintain consistent dietary, physical activity, and sleeping patterns throughout the duration of the study * Comply with treatment regimens * Have given written informed consent to participate in this study in accordance with local regulations and the Ethical Review Board (ERB) governing the study site.
Exclusion criteria
* Have more than 1 episode of severe hypoglycemia (defined as an event during which the patient requires the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions) within 6 months prior to screening, or have a current diagnosis of hypoglycemia unawareness. * Have had two or more emergency room visits or hospitalizations due to poor glucose control in the 6 months prior to screening. * Have gastrointestinal disease that may significantly impact gastric emptying or motility or have undergone gastric bypass or gastric banding surgery. * Have had a previous diagnosis of pancreatitis. * Have New York Heart Association (NYHA) class II, III, or IV symptoms of heart failure * Have a history of myocardial infarction, unstable angina, or a coronary revascularization procedure within 6 months of screening. * Have a history of supraventricular tachycardia, ventricular tachycardia, or other cardiac arrhythmia. * Have a history of transient ischemic attack (TIA) or stroke within 6 months of screening. * Have poorly controlled hypertension (systolic blood pressure greater than or equal to 150 mm Hg or diastolic blood pressure greater than or equal to 90 mm Hg) as determined by the mean of three separate measurements. * Show evidence of labile blood pressure, including symptomatic postural hypotension. * Have any abnormality of the ECG that would impact patient safety or data interpretation. * Show clinical signs or symptoms of liver disease, or liver function tests (LFTs; aspartate aminotransferase \[AST\] or alanine aminotransferase \[ALT\]) greater than 2.5 times upper limit of normal (ULN) as determined by the central laboratory at screening. * Have a current or previous diagnosis of Gilbert's disease. * Have previous or current diagnosis of Hepatitis B or C * Have a serum creatinine \>2 milligrams per deciliter (mg/dL) or, in patients being treated with metformin, a serum creatinine above (or creatinine clearance below) what is approved in the metformin product labeling in the respective country. * Show evidence of uncorrected hypothyroidism or hyperthyroidism based on clinical evaluation and/or an abnormal thyroid stimulating hormone result as determined by the central laboratory at screening; patients receiving dose-stable thyroid replacement therapy for at least 3 months prior to screening will be allowed to participate in the study. * Have any other abnormal laboratory value that, in the opinion of the investigator, precludes the patient from participation in the study. Laboratory abnormalities consistent with type 2 diabetes mellitus and all other eligibility criteria are acceptable: for example, abnormalities of blood glucose, hemoglobin A1c (HbA1c), urinary glucose, and urinary protein (with a range of trace to 1+ on dipstick). * Have a currently suspected or treated malignancy, or are in remission from a clinically significant malignancy (other than basal or squamous cell skin cancer, in situ carcinomas of the cervix, or in situ prostate cancer) for less than 5 years. * Have a personal or family history of pancreatic neoplasia. * Have non-fasting triglycerides \>600 mg/dL. * Use or have used insulin or GLP-1 agonists (for more than 1 week within the 3-month period prior to screening), or any oral antihyperglycemic medication (OAM) other than metformin within the 3-month period prior to screening. * Currently use or intend to use prescription or over-the-counter medications, including herbal supplements, to promote weight loss or to regulate blood glucose. * Have current chronic (\>2 weeks) systemic glucocorticoid therapy (excluding ocular topical, other topical, inhaled preparations) or have received such therapy within 8 weeks prior to screening. * Currently use hyperglycemia-causing agents, hypoglycemia-causing agents (other than metformin), class II and III antiarrythmic agents, agents that reduce gastrointestinal motility, central nervous system stimulants (with the exception of caffeinated beverages), fibrates, and niacin greater than or equal to 1 grams per day (gm/day). * Have an average weekly alcohol intake that exceeds 2 units per day for males and 1 unit per day for females (1 unit = 12 ounces (oz) or 360 mL of beer; 5 oz or 150 milliliters (mL) of wine; 1.5 oz or 45 milliliter (mL) of distilled spirits). * Currently use drugs with a narrow therapeutic index (for example, digoxin, lithium, phenytoin, theophylline, and warfarin). * Currently use drugs that are known to prolong the QT interval. * Currently use or intend to use potent inhibitors of CYP3A, which include but are not limited to atazanavir, indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole, ketoconazole, nefazodone, saquinavir, and telithromycin. * Have previously completed or withdrawn from this study or any other study investigating LY2409021. * Have known allergies to LY2409021 or related compounds. * Are currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an investigational product or unapproved use of a drug or device, or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study * Have any other condition such as alcohol abuse, drug abuse, or psychiatric disorder that may affect the ability to participate in the trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to 24 Week Endpoint in Hemoglobin A1c (HbA1c) | Baseline, 24 weeks | Least squares means of the change from baseline is from a mixed-model repeated measures analysis (MMRM). The model included terms for treatment group, baseline HbA1c, metformin use, visit, and visit-by-treatment interaction. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to 24 Week Endpoint in 7-point Self Monitored Glucose (SMBG) Profile | Baseline, 24 weeks | SMBG profiles consisted of blood glucose values collected before and 2 hours after the 3 main meals and at 0300 hours (3:00 AM). Values represent mean of values collected same time on 3 separate days within a week prior to visit. Least squares (LS) mean of the change from baseline is from a mixed-model repeated measures analysis (MMRM). The model included terms for treatment group, baseline value, metformin use, visit, and visit-by-treatment interaction. |
| Change From Baseline to 24 Week Endpoint in Plasma Glucose | Baseline, 24 weeks | Least squares means of the change from baseline is from a mixed-model repeated measures analysis (MMRM). The model included terms for treatment group, baseline value, metformin use, visit, and visit-by-treatment interaction. |
| Change From Baseline to 24 Week Endpoint in Fasting Insulin | Baseline, 24 weeks | Least squares (LS) mean of the change from baseline is from a mixed-model repeated measures analysis (MMRM). The model included terms for treatment group, baseline value, metformin use, visit, and visit-by-treatment interaction. |
| Change From Baseline to 24 Week Endpoint in Fasting Glucagon-like Peptide 1 (GLP-1) Active and Total | Baseline, 24 weeks | GLP-1 is cleaved from proglucagon to form the active peptide GLP-1. The active form promotes suppression of glucagon secretion. Total GLP-1 is the active GLP-1 and the Dipeptidyl Peptidase IV cleaved GLP-1 form. Least squares (LS) mean of the change from baseline is from a mixed-model repeated measures analysis (MMRM). The model included terms for treatment group, baseline value, metformin use, visit, and visit-by-treatment interaction. |
| Change From Baseline to 24 Week Endpoint in Fasting Lipid Profile | Baseline, 24 weeks | Fasting Lipid Profile included: Triglycerides, Low Density Lipoprotein Cholesterol (LDL-C), High Density Lipoprotein Cholesterol (HDL-C) and Total Cholesterol. Least squares (LS) mean of the change from baseline is from a mixed-model repeated measures analysis (MMRM). The model included terms for treatment group, baseline value, visit, and visit-by-treatment interaction. |
| Change From Baseline to 24 Week Endpoint in Lipoprotein Subfractions-Particles (Total) | Baseline, 24 weeks | Subfraction included: Very Low Density Lipoprotein (VLDL) Total. Least squares mean use an analysis of covariance model. The model included baseline lipoprotein subfractions, metformin use and treatment. |
| Change From Baseline to 24 Week Endpoint in Free Fatty Acids | Baseline, 24 weeks | Least squares mean use an analysis of covariance model. The model included baseline free fatty acid, metformin use and treatment. |
| Change From Baseline to 24 Week Endpoint in Fasting Blood Glucose (FBG) | Baseline, 24 weeks | Least squares means of the change from baseline is from a mixed-model repeated measures analysis (MMRM). The model included terms for treatment group, baseline value, metformin use, visit, and visit-by-treatment interaction. |
| Change From Baseline to 24 Week Endpoint Indices in Beta-cell Function Using HOMA-B | Baseline, 24 week | HOMA-B is a computer model (based on HOMA-2) that uses fasting plasma insulin and glucose concentrations to estimate steady state pancreatic beta cell function (%B) as a percentage of a normal reference population (normal young adults). The normal reference population was set at 100%. Higher values indicate greater beta cell function. Least squares (LS) mean of the change from baseline is from a mixed-model repeated measures analysis (MMRM). The model included terms for treatment group, baseline value, metformin use, visit, and visit-by-treatment interaction. |
| Change From Baseline to 24 Week Endpoint in Weight | Baseline, 24 weeks | Least squares means were adjusted for baseline weight, metformin use, visit, treatment and visit by treatment interaction. |
| Population Pharmacokinetics: Apparent Clearance (CL/F) of LY2409021 | Baseline up to 26 weeks | Population pharmacokinetic parameter apparent clearance (CL/F) is the apparent volume of the body fluid cleared of the drug per unit of time and was estimated by modeling of LY2409021 plasma concentration data from all LY2409021 groups. |
| Population Pharmacokinetics: Apparent Volume of Distribution of LY2409021 | Baseline up to 26 weeks | Population pharmacokinetic parameter, apparent volume of distribution (V/F) is a theoretical volume that a drug would have to occupy (if it were uniformly distributed), to provide the same concentration as it currently is in blood plasma. Apparent volume of distribution (V/F) was estimated by modeling of LY2409021 plasma concentration data from all LY2409021 groups. |
| The Percentage of Participants Experiencing a Hypoglycemic Episode | Baseline through 24 weeks | A hypoglycemic episode is any event during which typical symptoms of hypoglycemia are observed or when the measured plasma glucose concentration is less than or equal to 70 milligrams per deciliter (mg/dL) \[3.9 millimoles per liter (mmol/L)\]. |
| The 30-Day Adjusted Rate of Hypoglycemic Episodes | Baseline through 24 weeks | A hypoglycemic episode is any event during which typical symptoms of hypoglycemia are observed or when the measured plasma glucose concentration is less than or equal to 70 milligrams per deciliter (mg/dL) \[3.9 millimoles per liter (mmol/L)\]. 30-day adjusted rate=(total number of episodes between 2 time intervals/number of days between intervals) X 30 days. Outcome measure was not analyzed due to the limited number of hypoglycemic events observed. |
| Change From Baseline to 24 Week Endpoint Indices in Insulin Sensitivity Using Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) | Baseline, 24 weeks | HOMA-IR is a computer model (based on HOMA2) which uses fasting plasma insulin and glucose concentrations to estimate insulin resistance (HOMA-IR) as a proportion reference population (normal young adults). The normal reference population with normal function was indexed to 1.0. Higher values indicate increased insulin resistance. Least squares means of the change from baseline is from a mixed-model repeated measures analysis (MMRM). The model included terms for treatment group, baseline value, metformin use, visit, and visit-by-treatment interaction. |
Countries
Germany, Italy, Puerto Rico, Romania, Slovakia, Spain, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician. | 63 |
| 2.5 mg LY2409021 2.5 mg LY2409021 orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician. | 63 |
| 10 mg LY2409021 10 mg LY2409021 orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician. | 64 |
| 20 mg LY2409021 20 mg LY2409021 orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician. | 64 |
| Total | 254 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 2 | 2 |
| Overall Study | Excluded due to data integrity issues | 3 | 2 | 2 | 2 |
| Overall Study | Lost to Follow-up | 2 | 1 | 1 | 1 |
| Overall Study | Physician Decision | 0 | 2 | 0 | 0 |
| Overall Study | Protocol Violation | 10 | 5 | 3 | 6 |
| Overall Study | Sponsor Decision | 17 | 14 | 12 | 6 |
| Overall Study | Withdrawal by Subject | 4 | 5 | 3 | 6 |
Baseline characteristics
| Characteristic | Placebo | Total | 20 mg LY2409021 | 10 mg LY2409021 | 2.5 mg LY2409021 |
|---|---|---|---|---|---|
| Age, Continuous | 55.0 years STANDARD_DEVIATION 8.79 | 55.7 years STANDARD_DEVIATION 8.49 | 55.9 years STANDARD_DEVIATION 8.82 | 54.6 years STANDARD_DEVIATION 8.05 | 57.3 years STANDARD_DEVIATION 8.23 |
| Body Mass Index (BMI) | 32.1 kilograms per meter squared (kg/m^2) STANDARD_DEVIATION 4.63 | 32.2 kilograms per meter squared (kg/m^2) STANDARD_DEVIATION 4.9 | 32.6 kilograms per meter squared (kg/m^2) STANDARD_DEVIATION 5.27 | 32.3 kilograms per meter squared (kg/m^2) STANDARD_DEVIATION 4.91 | 31.9 kilograms per meter squared (kg/m^2) STANDARD_DEVIATION 4.86 |
| Diabetes Duration | 5.8 years STANDARD_DEVIATION 5.29 | 6.0 years STANDARD_DEVIATION 5.81 | 5.8 years STANDARD_DEVIATION 6.13 | 5.5 years STANDARD_DEVIATION 4.21 | 6.9 years STANDARD_DEVIATION 7.23 |
| Ethnicity Hispanic or Latino | 16 Participants | 56 Participants | 13 Participants | 13 Participants | 14 Participants |
| Ethnicity Not Hispanic or Latino | 36 Participants | 139 Participants | 37 Participants | 35 Participants | 31 Participants |
| Ethnicity Not Reported | 11 Participants | 59 Participants | 14 Participants | 16 Participants | 18 Participants |
| Hemoglobin A1c (HbA1c) | 8.1 percentage of Hemoglobin A1c (HbA1c) STANDARD_DEVIATION 1 | 8.0 percentage of Hemoglobin A1c (HbA1c) STANDARD_DEVIATION 0.92 | 8.0 percentage of Hemoglobin A1c (HbA1c) STANDARD_DEVIATION 0.92 | 8.1 percentage of Hemoglobin A1c (HbA1c) STANDARD_DEVIATION 0.87 | 8.1 percentage of Hemoglobin A1c (HbA1c) STANDARD_DEVIATION 0.93 |
| Race Asian | 1 Participants | 5 Participants | 0 Participants | 1 Participants | 3 Participants |
| Race Black or African American | 4 Participants | 18 Participants | 6 Participants | 2 Participants | 6 Participants |
| Race White | 58 Participants | 231 Participants | 58 Participants | 61 Participants | 54 Participants |
| Region of Enrollment Germany | 7 Participants | 29 Participants | 6 Participants | 9 Participants | 7 Participants |
| Region of Enrollment Italy | 1 Participants | 5 Participants | 2 Participants | 1 Participants | 1 Participants |
| Region of Enrollment Puerto Rico | 3 Participants | 15 Participants | 5 Participants | 3 Participants | 4 Participants |
| Region of Enrollment Romania | 10 Participants | 44 Participants | 10 Participants | 12 Participants | 12 Participants |
| Region of Enrollment Slovakia | 7 Participants | 26 Participants | 6 Participants | 6 Participants | 7 Participants |
| Region of Enrollment Spain | 6 Participants | 27 Participants | 7 Participants | 7 Participants | 7 Participants |
| Region of Enrollment United States | 29 Participants | 108 Participants | 28 Participants | 26 Participants | 25 Participants |
| Sex: Female, Male Female | 23 Participants | 83 Participants | 19 Participants | 17 Participants | 24 Participants |
| Sex: Female, Male Male | 40 Participants | 171 Participants | 45 Participants | 47 Participants | 39 Participants |
| Waist Circumference | 106.7 centimeters (cm) STANDARD_DEVIATION 12.41 | 107.1 centimeters (cm) STANDARD_DEVIATION 11.97 | 106.8 centimeters (cm) STANDARD_DEVIATION 12.28 | 107.2 centimeters (cm) STANDARD_DEVIATION 12.24 | 107.5 centimeters (cm) STANDARD_DEVIATION 11.16 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 23 / 66 | 31 / 65 | 34 / 66 | 29 / 66 |
| serious Total, serious adverse events | 3 / 66 | 0 / 65 | 2 / 66 | 2 / 66 |
Outcome results
Primary
Change From Baseline to 24 Week Endpoint in Hemoglobin A1c (HbA1c)
Least squares means of the change from baseline is from a mixed-model repeated measures analysis (MMRM). The model included terms for treatment group, baseline HbA1c, metformin use, visit, and visit-by-treatment interaction.
Time frame: Baseline, 24 weeks
Population: All participants randomly assigned to treatment with at least 1 post-baseline HbA1c measurement (excluding participant data from the excluded site); analyzed according to the treatment to which the participants were randomly assigned.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Change From Baseline to 24 Week Endpoint in Hemoglobin A1c (HbA1c) | -0.15 percentage of Hemoglobin A1c (HbA1c) |
| 2.5 mg LY2409021 | Change From Baseline to 24 Week Endpoint in Hemoglobin A1c (HbA1c) | -0.45 percentage of Hemoglobin A1c (HbA1c) |
| 10 mg LY2409021 | Change From Baseline to 24 Week Endpoint in Hemoglobin A1c (HbA1c) | -0.78 percentage of Hemoglobin A1c (HbA1c) |
| 20 mg LY2409021 | Change From Baseline to 24 Week Endpoint in Hemoglobin A1c (HbA1c) | -0.92 percentage of Hemoglobin A1c (HbA1c) |
Comparison: Sixty-five randomized patients (45 completers) per arm were expected to provide at least 90% power to detect 0.8% HbA1c difference with placebo assuming a SD for change in HbA1c of 1.2% (0.05 1-sided type I error).p-value: 0.09490% CI: [-0.58, -0.01]Mixed Models Analysis
Comparison: Sixty-five randomized patients (45 completers) per arm were expected to provide at least 90% power to detect 0.8% HbA1c difference with placebo assuming a SD for change in HbA1c of 1.2% (0.05 1-sided type I error).p-value: <0.00190% CI: [-0.9, -0.34]Mixed Models Analysis
Comparison: Sixty-five randomized patients (45 completers) per arm were expected to provide at least 90% power to detect 0.8% HbA1c difference with placebo assuming a SD for change in HbA1c of 1.2% (0.05 1-sided type I error).p-value: <0.0190% CI: [-1.05, -0.48]Mixed Models Analysis
Secondary
Change From Baseline to 24 Week Endpoint in 7-point Self Monitored Glucose (SMBG) Profile
SMBG profiles consisted of blood glucose values collected before and 2 hours after the 3 main meals and at 0300 hours (3:00 AM). Values represent mean of values collected same time on 3 separate days within a week prior to visit. Least squares (LS) mean of the change from baseline is from a mixed-model repeated measures analysis (MMRM). The model included terms for treatment group, baseline value, metformin use, visit, and visit-by-treatment interaction.
Time frame: Baseline, 24 weeks
Population: All randomized patients with at least 1 post-baseline self-monitored glucose measurement (excluding participant data from the excluded site); analyzed according to the treatment to which the patients were randomized.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Placebo | Change From Baseline to 24 Week Endpoint in 7-point Self Monitored Glucose (SMBG) Profile | Pre-morning meal (fasting) | -14.45 milligrams per deciliter (mg/dL) |
| Placebo | Change From Baseline to 24 Week Endpoint in 7-point Self Monitored Glucose (SMBG) Profile | 2 hours after evening meal | -19.48 milligrams per deciliter (mg/dL) |
| Placebo | Change From Baseline to 24 Week Endpoint in 7-point Self Monitored Glucose (SMBG) Profile | Pre-evening meal | -7.45 milligrams per deciliter (mg/dL) |
| Placebo | Change From Baseline to 24 Week Endpoint in 7-point Self Monitored Glucose (SMBG) Profile | 2 hours after morning meal | -28.75 milligrams per deciliter (mg/dL) |
| Placebo | Change From Baseline to 24 Week Endpoint in 7-point Self Monitored Glucose (SMBG) Profile | 0300 hours (3:00 AM) | -5.13 milligrams per deciliter (mg/dL) |
| Placebo | Change From Baseline to 24 Week Endpoint in 7-point Self Monitored Glucose (SMBG) Profile | Pre-mid-day meal | -17.83 milligrams per deciliter (mg/dL) |
| Placebo | Change From Baseline to 24 Week Endpoint in 7-point Self Monitored Glucose (SMBG) Profile | 2 hours after mid-day meal | -23.75 milligrams per deciliter (mg/dL) |
| 2.5 mg LY2409021 | Change From Baseline to 24 Week Endpoint in 7-point Self Monitored Glucose (SMBG) Profile | 2 hours after evening meal | -21.74 milligrams per deciliter (mg/dL) |
| 2.5 mg LY2409021 | Change From Baseline to 24 Week Endpoint in 7-point Self Monitored Glucose (SMBG) Profile | 2 hours after mid-day meal | -21.17 milligrams per deciliter (mg/dL) |
| 2.5 mg LY2409021 | Change From Baseline to 24 Week Endpoint in 7-point Self Monitored Glucose (SMBG) Profile | Pre-mid-day meal | -16.13 milligrams per deciliter (mg/dL) |
| 2.5 mg LY2409021 | Change From Baseline to 24 Week Endpoint in 7-point Self Monitored Glucose (SMBG) Profile | Pre-evening meal | -11.77 milligrams per deciliter (mg/dL) |
| 2.5 mg LY2409021 | Change From Baseline to 24 Week Endpoint in 7-point Self Monitored Glucose (SMBG) Profile | 0300 hours (3:00 AM) | -9.52 milligrams per deciliter (mg/dL) |
| 2.5 mg LY2409021 | Change From Baseline to 24 Week Endpoint in 7-point Self Monitored Glucose (SMBG) Profile | 2 hours after morning meal | -23.01 milligrams per deciliter (mg/dL) |
| 2.5 mg LY2409021 | Change From Baseline to 24 Week Endpoint in 7-point Self Monitored Glucose (SMBG) Profile | Pre-morning meal (fasting) | -15.76 milligrams per deciliter (mg/dL) |
| 10 mg LY2409021 | Change From Baseline to 24 Week Endpoint in 7-point Self Monitored Glucose (SMBG) Profile | 2 hours after mid-day meal | -31.42 milligrams per deciliter (mg/dL) |
| 10 mg LY2409021 | Change From Baseline to 24 Week Endpoint in 7-point Self Monitored Glucose (SMBG) Profile | Pre-morning meal (fasting) | -29.65 milligrams per deciliter (mg/dL) |
| 10 mg LY2409021 | Change From Baseline to 24 Week Endpoint in 7-point Self Monitored Glucose (SMBG) Profile | 2 hours after morning meal | -48.12 milligrams per deciliter (mg/dL) |
| 10 mg LY2409021 | Change From Baseline to 24 Week Endpoint in 7-point Self Monitored Glucose (SMBG) Profile | Pre-mid-day meal | -27.35 milligrams per deciliter (mg/dL) |
| 10 mg LY2409021 | Change From Baseline to 24 Week Endpoint in 7-point Self Monitored Glucose (SMBG) Profile | Pre-evening meal | -14.15 milligrams per deciliter (mg/dL) |
| 10 mg LY2409021 | Change From Baseline to 24 Week Endpoint in 7-point Self Monitored Glucose (SMBG) Profile | 2 hours after evening meal | -33.93 milligrams per deciliter (mg/dL) |
| 10 mg LY2409021 | Change From Baseline to 24 Week Endpoint in 7-point Self Monitored Glucose (SMBG) Profile | 0300 hours (3:00 AM) | -23.33 milligrams per deciliter (mg/dL) |
| 20 mg LY2409021 | Change From Baseline to 24 Week Endpoint in 7-point Self Monitored Glucose (SMBG) Profile | Pre-mid-day meal | -25.45 milligrams per deciliter (mg/dL) |
| 20 mg LY2409021 | Change From Baseline to 24 Week Endpoint in 7-point Self Monitored Glucose (SMBG) Profile | 0300 hours (3:00 AM) | -25.67 milligrams per deciliter (mg/dL) |
| 20 mg LY2409021 | Change From Baseline to 24 Week Endpoint in 7-point Self Monitored Glucose (SMBG) Profile | 2 hours after evening meal | -32.01 milligrams per deciliter (mg/dL) |
| 20 mg LY2409021 | Change From Baseline to 24 Week Endpoint in 7-point Self Monitored Glucose (SMBG) Profile | 2 hours after morning meal | -45.76 milligrams per deciliter (mg/dL) |
| 20 mg LY2409021 | Change From Baseline to 24 Week Endpoint in 7-point Self Monitored Glucose (SMBG) Profile | Pre-morning meal (fasting) | -32.55 milligrams per deciliter (mg/dL) |
| 20 mg LY2409021 | Change From Baseline to 24 Week Endpoint in 7-point Self Monitored Glucose (SMBG) Profile | Pre-evening meal | -25.02 milligrams per deciliter (mg/dL) |
| 20 mg LY2409021 | Change From Baseline to 24 Week Endpoint in 7-point Self Monitored Glucose (SMBG) Profile | 2 hours after mid-day meal | -39.60 milligrams per deciliter (mg/dL) |
Secondary
Change From Baseline to 24 Week Endpoint Indices in Beta-cell Function Using HOMA-B
HOMA-B is a computer model (based on HOMA-2) that uses fasting plasma insulin and glucose concentrations to estimate steady state pancreatic beta cell function (%B) as a percentage of a normal reference population (normal young adults). The normal reference population was set at 100%. Higher values indicate greater beta cell function. Least squares (LS) mean of the change from baseline is from a mixed-model repeated measures analysis (MMRM). The model included terms for treatment group, baseline value, metformin use, visit, and visit-by-treatment interaction.
Time frame: Baseline, 24 week
Population: All randomized patients with at least 1 post-baseline HOMA-B measurement (excluding participant data from the excluded site); analyzed according to the treatment to which the patients were randomized.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Change From Baseline to 24 Week Endpoint Indices in Beta-cell Function Using HOMA-B | 4.88 percent of normal reference population |
| 2.5 mg LY2409021 | Change From Baseline to 24 Week Endpoint Indices in Beta-cell Function Using HOMA-B | 7.90 percent of normal reference population |
| 10 mg LY2409021 | Change From Baseline to 24 Week Endpoint Indices in Beta-cell Function Using HOMA-B | 17.69 percent of normal reference population |
| 20 mg LY2409021 | Change From Baseline to 24 Week Endpoint Indices in Beta-cell Function Using HOMA-B | 16.39 percent of normal reference population |
Secondary
Change From Baseline to 24 Week Endpoint Indices in Insulin Sensitivity Using Homeostasis Model Assessment of Insulin Resistance (HOMA-IR)
HOMA-IR is a computer model (based on HOMA2) which uses fasting plasma insulin and glucose concentrations to estimate insulin resistance (HOMA-IR) as a proportion reference population (normal young adults). The normal reference population with normal function was indexed to 1.0. Higher values indicate increased insulin resistance. Least squares means of the change from baseline is from a mixed-model repeated measures analysis (MMRM). The model included terms for treatment group, baseline value, metformin use, visit, and visit-by-treatment interaction.
Time frame: Baseline, 24 weeks
Population: All randomized patients with at least 1 post-baseline HOMA-IR measurement (excluding participant data from the excluded site); analyzed according to the treatment to which the patients were randomized.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Change From Baseline to 24 Week Endpoint Indices in Insulin Sensitivity Using Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) | 0.19 proportion of normal reference populatio |
| 2.5 mg LY2409021 | Change From Baseline to 24 Week Endpoint Indices in Insulin Sensitivity Using Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) | 0.02 proportion of normal reference populatio |
| 10 mg LY2409021 | Change From Baseline to 24 Week Endpoint Indices in Insulin Sensitivity Using Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) | 0.26 proportion of normal reference populatio |
| 20 mg LY2409021 | Change From Baseline to 24 Week Endpoint Indices in Insulin Sensitivity Using Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) | 0.19 proportion of normal reference populatio |
Secondary
Change From Baseline to 24 Week Endpoint in Fasting Blood Glucose (FBG)
Least squares means of the change from baseline is from a mixed-model repeated measures analysis (MMRM). The model included terms for treatment group, baseline value, metformin use, visit, and visit-by-treatment interaction.
Time frame: Baseline, 24 weeks
Population: All participants randomly assigned to treatment with at least 1 post-baseline laboratory FBG measurement (excluding participant data from the excluded site); analyzed according to the treatment to which the patients were randomly assigned.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Change From Baseline to 24 Week Endpoint in Fasting Blood Glucose (FBG) | -0.36 millimoles per liter (mmol/L) |
| 2.5 mg LY2409021 | Change From Baseline to 24 Week Endpoint in Fasting Blood Glucose (FBG) | -0.46 millimoles per liter (mmol/L) |
| 10 mg LY2409021 | Change From Baseline to 24 Week Endpoint in Fasting Blood Glucose (FBG) | -1.07 millimoles per liter (mmol/L) |
| 20 mg LY2409021 | Change From Baseline to 24 Week Endpoint in Fasting Blood Glucose (FBG) | -1.14 millimoles per liter (mmol/L) |
Secondary
Change From Baseline to 24 Week Endpoint in Fasting Glucagon-like Peptide 1 (GLP-1) Active and Total
GLP-1 is cleaved from proglucagon to form the active peptide GLP-1. The active form promotes suppression of glucagon secretion. Total GLP-1 is the active GLP-1 and the Dipeptidyl Peptidase IV cleaved GLP-1 form. Least squares (LS) mean of the change from baseline is from a mixed-model repeated measures analysis (MMRM). The model included terms for treatment group, baseline value, metformin use, visit, and visit-by-treatment interaction.
Time frame: Baseline, 24 weeks
Population: All randomized patients with at least 1 post-baseline GLP-1 active and total measurements (excluding participant data from the excluded site); analyzed according to the treatment to which the patients were randomized.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Placebo | Change From Baseline to 24 Week Endpoint in Fasting Glucagon-like Peptide 1 (GLP-1) Active and Total | Active GLP-1 | -0.30 picomoles per liter (pmol/L) |
| Placebo | Change From Baseline to 24 Week Endpoint in Fasting Glucagon-like Peptide 1 (GLP-1) Active and Total | Total GLP-1 | -0.12 picomoles per liter (pmol/L) |
| 2.5 mg LY2409021 | Change From Baseline to 24 Week Endpoint in Fasting Glucagon-like Peptide 1 (GLP-1) Active and Total | Total GLP-1 | 1.84 picomoles per liter (pmol/L) |
| 2.5 mg LY2409021 | Change From Baseline to 24 Week Endpoint in Fasting Glucagon-like Peptide 1 (GLP-1) Active and Total | Active GLP-1 | 0.13 picomoles per liter (pmol/L) |
| 10 mg LY2409021 | Change From Baseline to 24 Week Endpoint in Fasting Glucagon-like Peptide 1 (GLP-1) Active and Total | Active GLP-1 | 0.38 picomoles per liter (pmol/L) |
| 10 mg LY2409021 | Change From Baseline to 24 Week Endpoint in Fasting Glucagon-like Peptide 1 (GLP-1) Active and Total | Total GLP-1 | 4.63 picomoles per liter (pmol/L) |
| 20 mg LY2409021 | Change From Baseline to 24 Week Endpoint in Fasting Glucagon-like Peptide 1 (GLP-1) Active and Total | Active GLP-1 | 0.31 picomoles per liter (pmol/L) |
| 20 mg LY2409021 | Change From Baseline to 24 Week Endpoint in Fasting Glucagon-like Peptide 1 (GLP-1) Active and Total | Total GLP-1 | 8.23 picomoles per liter (pmol/L) |
Secondary
Change From Baseline to 24 Week Endpoint in Fasting Insulin
Least squares (LS) mean of the change from baseline is from a mixed-model repeated measures analysis (MMRM). The model included terms for treatment group, baseline value, metformin use, visit, and visit-by-treatment interaction.
Time frame: Baseline, 24 weeks
Population: All randomized patients with at least 1 post-baseline fasting insulin measurement (excluding participant data from the excluded site); analyzed according to the treatment to which the patients were randomized.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Change From Baseline to 24 Week Endpoint in Fasting Insulin | 10.62 picomoles per liter (pmol/L) |
| 2.5 mg LY2409021 | Change From Baseline to 24 Week Endpoint in Fasting Insulin | 2.61 picomoles per liter (pmol/L) |
| 10 mg LY2409021 | Change From Baseline to 24 Week Endpoint in Fasting Insulin | 14.95 picomoles per liter (pmol/L) |
| 20 mg LY2409021 | Change From Baseline to 24 Week Endpoint in Fasting Insulin | 9.65 picomoles per liter (pmol/L) |
Secondary
Change From Baseline to 24 Week Endpoint in Fasting Lipid Profile
Fasting Lipid Profile included: Triglycerides, Low Density Lipoprotein Cholesterol (LDL-C), High Density Lipoprotein Cholesterol (HDL-C) and Total Cholesterol. Least squares (LS) mean of the change from baseline is from a mixed-model repeated measures analysis (MMRM). The model included terms for treatment group, baseline value, visit, and visit-by-treatment interaction.
Time frame: Baseline, 24 weeks
Population: All randomized patients with at least 1 post-baseline fasting lipid measurement (excluding participant data from the excluded site); analyzed according to the treatment to which the patients were randomized.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Placebo | Change From Baseline to 24 Week Endpoint in Fasting Lipid Profile | Triglycerides | -0.11 millimoles per liter (mmol/L) |
| Placebo | Change From Baseline to 24 Week Endpoint in Fasting Lipid Profile | LDL-C | 0.20 millimoles per liter (mmol/L) |
| Placebo | Change From Baseline to 24 Week Endpoint in Fasting Lipid Profile | HDL-C | 0.03 millimoles per liter (mmol/L) |
| Placebo | Change From Baseline to 24 Week Endpoint in Fasting Lipid Profile | Total Cholesterol | 0.15 millimoles per liter (mmol/L) |
| 2.5 mg LY2409021 | Change From Baseline to 24 Week Endpoint in Fasting Lipid Profile | LDL-C | 0.05 millimoles per liter (mmol/L) |
| 2.5 mg LY2409021 | Change From Baseline to 24 Week Endpoint in Fasting Lipid Profile | HDL-C | 0.02 millimoles per liter (mmol/L) |
| 2.5 mg LY2409021 | Change From Baseline to 24 Week Endpoint in Fasting Lipid Profile | Total Cholesterol | 0.10 millimoles per liter (mmol/L) |
| 2.5 mg LY2409021 | Change From Baseline to 24 Week Endpoint in Fasting Lipid Profile | Triglycerides | 0.07 millimoles per liter (mmol/L) |
| 10 mg LY2409021 | Change From Baseline to 24 Week Endpoint in Fasting Lipid Profile | HDL-C | 0.05 millimoles per liter (mmol/L) |
| 10 mg LY2409021 | Change From Baseline to 24 Week Endpoint in Fasting Lipid Profile | LDL-C | 0.02 millimoles per liter (mmol/L) |
| 10 mg LY2409021 | Change From Baseline to 24 Week Endpoint in Fasting Lipid Profile | Total Cholesterol | 0.10 millimoles per liter (mmol/L) |
| 10 mg LY2409021 | Change From Baseline to 24 Week Endpoint in Fasting Lipid Profile | Triglycerides | 0.06 millimoles per liter (mmol/L) |
| 20 mg LY2409021 | Change From Baseline to 24 Week Endpoint in Fasting Lipid Profile | Total Cholesterol | 0.19 millimoles per liter (mmol/L) |
| 20 mg LY2409021 | Change From Baseline to 24 Week Endpoint in Fasting Lipid Profile | LDL-C | 0.10 millimoles per liter (mmol/L) |
| 20 mg LY2409021 | Change From Baseline to 24 Week Endpoint in Fasting Lipid Profile | Triglycerides | 0.08 millimoles per liter (mmol/L) |
| 20 mg LY2409021 | Change From Baseline to 24 Week Endpoint in Fasting Lipid Profile | HDL-C | 0.04 millimoles per liter (mmol/L) |
Secondary
Change From Baseline to 24 Week Endpoint in Free Fatty Acids
Least squares mean use an analysis of covariance model. The model included baseline free fatty acid, metformin use and treatment.
Time frame: Baseline, 24 weeks
Population: All randomized patients with at least 1 post-baseline free fatty acid measurement (excluding participant data from the excluded site); analyzed according to the treatment to which the patients were randomized.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to 24 Week Endpoint in Free Fatty Acids | -0.04 picomoles per liter (pmol/L) | Standard Error 0.043 |
| 2.5 mg LY2409021 | Change From Baseline to 24 Week Endpoint in Free Fatty Acids | -0.02 picomoles per liter (pmol/L) | Standard Error 0.04 |
| 10 mg LY2409021 | Change From Baseline to 24 Week Endpoint in Free Fatty Acids | -0.15 picomoles per liter (pmol/L) | Standard Error 0.037 |
| 20 mg LY2409021 | Change From Baseline to 24 Week Endpoint in Free Fatty Acids | -0.07 picomoles per liter (pmol/L) | Standard Error 0.04 |
Secondary
Change From Baseline to 24 Week Endpoint in Lipoprotein Subfractions-Particles (Total)
Subfraction included: Very Low Density Lipoprotein (VLDL) Total. Least squares mean use an analysis of covariance model. The model included baseline lipoprotein subfractions, metformin use and treatment.
Time frame: Baseline, 24 weeks
Population: All randomized patients with at least 1 post-baseline lipoprotein subfractions measurement (excluding participant data from the excluded site); analyzed according to the treatment to which the patients were randomized, last observation carried forward (LOCF) principle was applied.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to 24 Week Endpoint in Lipoprotein Subfractions-Particles (Total) | 1.90 nanomoles per liter (nmol/L) | Standard Error 4.296 |
| 2.5 mg LY2409021 | Change From Baseline to 24 Week Endpoint in Lipoprotein Subfractions-Particles (Total) | 6.48 nanomoles per liter (nmol/L) | Standard Error 4.048 |
| 10 mg LY2409021 | Change From Baseline to 24 Week Endpoint in Lipoprotein Subfractions-Particles (Total) | 0.07 nanomoles per liter (nmol/L) | Standard Error 4.099 |
| 20 mg LY2409021 | Change From Baseline to 24 Week Endpoint in Lipoprotein Subfractions-Particles (Total) | 2.04 nanomoles per liter (nmol/L) | Standard Error 4.328 |
Secondary
Change From Baseline to 24 Week Endpoint in Plasma Glucose
Least squares means of the change from baseline is from a mixed-model repeated measures analysis (MMRM). The model included terms for treatment group, baseline value, metformin use, visit, and visit-by-treatment interaction.
Time frame: Baseline, 24 weeks
Population: All randomized patients with at least 1 post-baseline plasma glucose measurement (excluding participant data from the excluded site); analyzed according to the treatment to which the patients were randomized.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Change From Baseline to 24 Week Endpoint in Plasma Glucose | -0.36 millimoles per liter (mmol/L) |
| 2.5 mg LY2409021 | Change From Baseline to 24 Week Endpoint in Plasma Glucose | -0.46 millimoles per liter (mmol/L) |
| 10 mg LY2409021 | Change From Baseline to 24 Week Endpoint in Plasma Glucose | -1.07 millimoles per liter (mmol/L) |
| 20 mg LY2409021 | Change From Baseline to 24 Week Endpoint in Plasma Glucose | -1.14 millimoles per liter (mmol/L) |
Secondary
Change From Baseline to 24 Week Endpoint in Weight
Least squares means were adjusted for baseline weight, metformin use, visit, treatment and visit by treatment interaction.
Time frame: Baseline, 24 weeks
Population: All randomized patients with at least 1 post-baseline weight measurement (excluding participant data from the excluded site); analyzed according to the treatment to which the patients were randomized.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Change From Baseline to 24 Week Endpoint in Weight | -1.07 kilograms (kg) |
| 2.5 mg LY2409021 | Change From Baseline to 24 Week Endpoint in Weight | -0.33 kilograms (kg) |
| 10 mg LY2409021 | Change From Baseline to 24 Week Endpoint in Weight | 0.55 kilograms (kg) |
| 20 mg LY2409021 | Change From Baseline to 24 Week Endpoint in Weight | 0.07 kilograms (kg) |
Secondary
Population Pharmacokinetics: Apparent Clearance (CL/F) of LY2409021
Population pharmacokinetic parameter apparent clearance (CL/F) is the apparent volume of the body fluid cleared of the drug per unit of time and was estimated by modeling of LY2409021 plasma concentration data from all LY2409021 groups.
Time frame: Baseline up to 26 weeks
Population: All randomized patients who received at least 1 one dose of study drug (excluding participant data from the excluded site); analyzed according to the treatment to which the patients were randomized.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Population Pharmacokinetics: Apparent Clearance (CL/F) of LY2409021 | 0.486 liters per hour (L/hr) | Geometric Coefficient of Variation 31 |
Secondary
Population Pharmacokinetics: Apparent Volume of Distribution of LY2409021
Population pharmacokinetic parameter, apparent volume of distribution (V/F) is a theoretical volume that a drug would have to occupy (if it were uniformly distributed), to provide the same concentration as it currently is in blood plasma. Apparent volume of distribution (V/F) was estimated by modeling of LY2409021 plasma concentration data from all LY2409021 groups.
Time frame: Baseline up to 26 weeks
Population: All randomized patients who received at least 1 one dose of study drug (excluding participant data from the excluded site); analyzed according to the treatment to which the patients were randomized.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Population Pharmacokinetics: Apparent Volume of Distribution of LY2409021 | 33.4 liters (L) | Geometric Coefficient of Variation 23.9 |
Secondary
The 30-Day Adjusted Rate of Hypoglycemic Episodes
A hypoglycemic episode is any event during which typical symptoms of hypoglycemia are observed or when the measured plasma glucose concentration is less than or equal to 70 milligrams per deciliter (mg/dL) \[3.9 millimoles per liter (mmol/L)\]. 30-day adjusted rate=(total number of episodes between 2 time intervals/number of days between intervals) X 30 days. Outcome measure was not analyzed due to the limited number of hypoglycemic events observed.
Time frame: Baseline through 24 weeks
Population: Outcome measure was not analyzed due to the limited number of hypoglycemic events observed; therefore zero participants were analyzed.
Secondary
The Percentage of Participants Experiencing a Hypoglycemic Episode
A hypoglycemic episode is any event during which typical symptoms of hypoglycemia are observed or when the measured plasma glucose concentration is less than or equal to 70 milligrams per deciliter (mg/dL) \[3.9 millimoles per liter (mmol/L)\].
Time frame: Baseline through 24 weeks
Population: All randomized participants who received at least 1 dose of study drug (excluding participant data from the excluded site).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | The Percentage of Participants Experiencing a Hypoglycemic Episode | 3.2 percentage of participants |
| 2.5 mg LY2409021 | The Percentage of Participants Experiencing a Hypoglycemic Episode | 6.3 percentage of participants |
| 10 mg LY2409021 | The Percentage of Participants Experiencing a Hypoglycemic Episode | 9.4 percentage of participants |
| 20 mg LY2409021 | The Percentage of Participants Experiencing a Hypoglycemic Episode | 7.8 percentage of participants |