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

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

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.

Study Overview

• Status: Terminated
• Conditions: Type 2 Diabetes Mellitus
• Intervention / Treatment: Drug: Sitagliptin; Drug: Atorvastatin; Other: Placebo to atorvastatin; Drug: Metformin (open-label); Drug: Glimepiride (open-label); Drug: Placebo to glimepiride; Other: Placebo to sitagliptin; Drug: Glimepiride (double-blind)

• Study Type: Interventional
• Enrollment (Actual): 166
• Phase: Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 79 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sitagliptin/Sitagliptin + Atorvastatin; 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; Sitagliptin 100 mg tablet orally daily; Other Names: Januvia; Drug: Atorvastatin; Atorvastatin 80 mg tablet orally daily; Other Names: Lipitor; Other: Placebo to atorvastatin; Placebo to atorvastatin tablet orally daily.; Drug: Metformin (open-label); Participant will remain on prestudy dose of metformin tablets (at least 1500 mg daily) throughout entire study.; Other Names: Glucophage; Drug: Glimepiride (open-label); 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.; Other Names: Amaryl; Drug: Placebo to glimepiride; Phase B: placebo to glimepiride tablet orally daily.
Active Comparator: Atorvastatin/Atorvastatin + Glimepiride; 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; Atorvastatin 80 mg tablet orally daily; Other Names: Lipitor; Drug: Metformin (open-label); Participant will remain on prestudy dose of metformin tablets (at least 1500 mg daily) throughout entire study.; Other Names: Glucophage; Other: Placebo to sitagliptin; Placebo to sitagliptin tablet orally daily; Drug: Glimepiride (double-blind); Phase B: glimepiride up to 6 mg daily for participants not rescued with open-label glimepiride during Phase A.
Experimental: Sitagliptin + Atorvastatin/Sitagliptin + Atorvastatin; 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; Sitagliptin 100 mg tablet orally daily; Other Names: Januvia; Drug: Atorvastatin; Atorvastatin 80 mg tablet orally daily; Other Names: Lipitor; Drug: Metformin (open-label); Participant will remain on prestudy dose of metformin tablets (at least 1500 mg daily) throughout entire study.; Other Names: Glucophage; Drug: Glimepiride (open-label); 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.; Other Names: Amaryl; Drug: Placebo to glimepiride; Phase B: placebo to glimepiride tablet orally daily.

What is the study measuring?

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 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 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 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 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 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

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC

Study record dates

Study Major Dates

• Study Start (Actual): October 24, 2011
• Primary Completion (Actual): December 4, 2012
• Study Completion (Actual): December 4, 2012

Study Registration Dates

• First Submitted: November 19, 2011
• First Submitted That Met QC Criteria: November 19, 2011
• First Posted (Estimate): November 23, 2011

Study Record Updates

• Last Update Posted (Actual): July 26, 2018
• Last Update Submitted That Met QC Criteria: July 25, 2018
• Last Verified: July 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Enzyme Inhibitors; Antimetabolites; Immunosuppressive Agents; Immunologic Factors; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protease Inhibitors; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Incretins; Dipeptidyl-Peptidase IV Inhibitors; Atorvastatin; Metformin; Sitagliptin Phosphate; Glimepiride
• Other Study ID Numbers: 0431E-211; 2011-003600-20 (EudraCT Number)

Plan for Individual participant data (IPD)

Study Data/Documents

1. CSR Synopsis