A Study of the Co-administration of Sitagliptin and Atorvastatin in Inadequately Controlled Type 2 Diabetes Mellitus (MK-0431E-211)

Study Overview
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Brief Summary
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This two-phase study was to examine if 16 weeks of treatment with sitagliptin in combination with atorvastatin reduces hemoglobin A1C (A1C) and low density lipoprotein cholesterol (LDL-C) from baseline more than atorvastatin alone and sitagliptin alone, respectively. Following a single-blind placebo run-in period, participants were to be randomized to one of three treatment arms (sitagliptin monotherapy, atorvastatin monotherapy, or sitagliptin plus atorvastatin) for 16 weeks (Phase A). During Phase B of the study (Weeks 16 through 54), participants were to receive either sitagliptin plus atorvastatin or glimepiride plus atorvastatin. The primary hypotheses were that after 16 weeks of treatment, sitagliptin in combination with atorvastatin reduces A1C from baseline more than atorvastatin alone, and that atorvastatin in combination with sitagliptin lowers LDL-C from baseline more than sitagliptin alone.

Official Title
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A Phase III Randomized Clinical Trial to Study the Efficacy and Safety of the Co-administration of Sitagliptin and Atorvastatin in Patients With Type 2 Diabetes Mellitus With Inadequate Glycemic Control on Metformin Monotherapy

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Sitagliptin
* Drug: Atorvastatin
* Other: Placebo to sitagliptin
* Other: Placebo to atorvastatin
* Drug: Metformin (open-label)
* Drug: Glimepiride (open-label)
* Drug: Glimepiride (double-blind)
* Drug: Placebo to glimepiride


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: has type 2 diabetes mellitus is a male, or a female who is highly unlikely to conceive is currently on monotherapy with metformin (at least 1500 mg/day) for at least 8 weeks is not on statin therapy or other lipid-lowering agents for at least 6 weeks Exclusion Criteria: has a history of type 1 diabetes mellitus, ketoacidosis or possibly has type 1 diabetes has ever taken a dipeptidyl peptidase IV inhibitor (such as sitagliptin, vildagliptin, alogliptin, or saxagliptin) or a glucagon-like peptide-1 mimetic (such as exenatide or liraglutide), or has required insulin therapy within 12 weeks prior to signing informed consent has been on a peroxisome proliferator-activated receptor gamma agonist within the prior 12 weeks has been treated with a statin or other lipid-lowering agents, including over the counter supplements of fish oils within 6 weeks intends to consume at least 1.2 liters of grapefruit juice per day during the course of the study is on or is likely to require treatment with 14 consecutive days or more, or repeated courses of corticosteroids is on a weight loss program and not in the maintenance phase or has started a weight loss medication (such as orlistat or sibutramine) within the prior 8 weeks has undergone a surgical procedure within the prior 4 weeks has a history of myopathy or rhabdomyolysis with any statin. has cardiovascular disease has New York Heart Association (NYHA) Class III or IV congestive heart failure, inadequately controlled hypertension, a medical history of active liver disease, chronic progressive neuromuscular disorder, is human immunodeficiency virus (HIV) positive, has a clinically significant hematological disorder, uncontrolled endocrine or metabolic disease known to influence glycemic control or serum lipids/lipoproteins, untreated hyperthyroidism or is currently under treatment for hyperthyroidism has a history of malignancy within 5 years, except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer is pregnant or breastfeeding, or is intending to become pregnant or donate eggs within the projected duration of the study and post-study follow-up period uses recreational or illicit drugs or has had a recent history (within the last year) of drug abuse or increased alcohol consumption

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 79 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sitagliptin/Sitagliptin + Atorvastatin<br>In Phase A, participants received sitagliptin 100 mg plus matching placebo to atorvastatin daily for 16 weeks. Participants continuing to Phase B received sitagliptin 100 mg plus atorvastatin 80 mg plus matching placebo to glimepiride daily for an additional 38 weeks. | Drug: Sitagliptin<br>* Sitagliptin 100 mg tablet orally daily<br>* Other names: Januvia;Drug: Atorvastatin<br>* Atorvastatin 80 mg tablet orally daily<br>* Other names: Lipitor;Other: Placebo to atorvastatin<br>* Placebo to atorvastatin tablet orally daily.<br>Drug: Metformin (open-label)<br>* Participant will remain on prestudy dose of metformin tablets (at least 1500 mg daily) throughout entire study.<br>* Other names: Glucophage;Drug: Glimepiride (open-label)<br>* Phase A: Glimepiride 1 or 2 mg tablet once daily with breakfast or the first main meal of the day (titrated up to 6 mg/day) for 16 weeks as rescue therapy for randomized participants not meeting specific glycemic goals.<br>* Other names: Amaryl;Drug: Placebo to glimepiride<br>* Phase B: placebo to glimepiride tablet orally daily.<br>|
| Active Comparator: Atorvastatin/Atorvastatin + Glimepiride<br>In Phase A, participants received atorvastatin 80 mg plus matching placebo to sitagliptin daily for 16 weeks. Participants continuing to Phase B received atorvastatin 80 mg plus matching placebo to sitagliptin plus glimepiride daily for an additional 38 weeks. | Drug: Atorvastatin<br>* Atorvastatin 80 mg tablet orally daily<br>* Other names: Lipitor;Other: Placebo to sitagliptin<br>* Placebo to sitagliptin tablet orally daily<br>Drug: Metformin (open-label)<br>* Participant will remain on prestudy dose of metformin tablets (at least 1500 mg daily) throughout entire study.<br>* Other names: Glucophage;Drug: Glimepiride (double-blind)<br>* Phase B: glimepiride up to 6 mg daily for participants not rescued with open-label glimepiride during Phase A.<br>|
| Experimental: Sitagliptin + Atorvastatin/Sitagliptin + Atorvastatin<br>In Phase A, participants sitagliptin 100 mg plus atorvastatin 80 mg daily for 16 weeks. Participants continuing to Phase B received sitagliptin 100 mg plus atorvastatin 80 mg plus matching placebo to glimepiride daily for an additional 38 weeks. | Drug: Sitagliptin<br>* Sitagliptin 100 mg tablet orally daily<br>* Other names: Januvia;Drug: Atorvastatin<br>* Atorvastatin 80 mg tablet orally daily<br>* Other names: Lipitor;Drug: Metformin (open-label)<br>* Participant will remain on prestudy dose of metformin tablets (at least 1500 mg daily) throughout entire study.<br>* Other names: Glucophage;Drug: Glimepiride (open-label)<br>* Phase A: Glimepiride 1 or 2 mg tablet once daily with breakfast or the first main meal of the day (titrated up to 6 mg/day) for 16 weeks as rescue therapy for randomized participants not meeting specific glycemic goals.<br>* Other names: Amaryl;Drug: Placebo to glimepiride<br>* Phase B: placebo to glimepiride tablet orally daily.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Hemoglobin A1C (A1C) at Week 16 | A1C is measured as percent. Thus, this change from baseline reflects the Week 16 A1C percent minus the Week 0 A1C percent. | Baseline and Week 16 | 
| Percent Change From Baseline in Low Density Lipoprotein Cholesterol (LDL-C) at Week 16 | Percent change from baseline was calculated as the Week 16 value minus the Week 0 value, divided by the Week 0 value ×100%. | Baseline and Week 16 | 
| Number of Participants Who Experienced at Least One Adverse Event | An adverse event is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the investigational product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the investigational product, is also an adverse event. Data presented exclude data following the initiation of glycemic rescue therapy. | Up to 56 weeks (including 2-week follow-up) | 
| Number of Participants Who Discontinued Study Drug Due to an Adverse Event | An adverse event is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the investigational product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the investigational product, is also an adverse event. Data presented exclude data following the initiation of glycemic rescue therapy. | Up to 54 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Fasting Plasma Glucose (FPG) at Week 16 | Change from baseline reflects the Week 16 value minus the Week 0 value. | Baseline and Week 16 | 
| Percent Change From Baseline in Total Cholesterol at Week 16 | Percent change from baseline was calculated as the Week 16 value minus the Week 0 value, divided by the Week 0 value ×100%. | Baseline and Week 16 | 
| Percent Change From Baseline in Apolipoprotein B (Apo B) at Week 16 | Percent change from baseline was calculated as the Week 16 value minus the Week 0 value, divided by the Week 0 value ×100%. | Baseline and Week 16 | 
| Percent Change From Baseline in Non-high Density Lipoprotein Cholesterol (Non-HDL-C) at Week 16 | Percent change from baseline was calculated as the Week 16 value minus the Week 0 value, divided by the Week 0 value ×100%. | Baseline and Week 16 | 
| Percent Change From Baseline in Triglycerides at Week 16 | Percent change from baseline was calculated as the Week 16 value minus the Week 0 value, divided by the Week 0 value ×100%. | Baseline and Week 16 | 
| Percent Change From Baseline in Very Low-density Lipoprotein Cholesterol (VLDL-C) at Week 16 | Percent change from baseline was calculated as the Week 16 value minus the Week 0 value, divided by the Week 0 value ×100%. | Baseline and Week 16 | 
| Percent Change From Baseline in High Density Lipoprotein Cholesterol (HDL-C) at Week 16 | Percent change from baseline was calculated as the Week 16 value minus the Week 0 value, divided by the Week 0 value ×100%. | Baseline and Week 16 |