Type 2 Diabetes Mellitus
Conditions
Brief summary
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.
Interventions
DRUGSitagliptin
Sitagliptin 100 mg tablet orally daily
DRUGAtorvastatin
Atorvastatin 80 mg tablet orally daily
Placebo to sitagliptin tablet orally daily
Placebo to atorvastatin tablet orally daily.
Participant will remain on prestudy dose of metformin tablets (at least 1500 mg daily) throughout entire study.
DRUGGlimepiride (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.
DRUGGlimepiride (double-blind)
Phase B: glimepiride up to 6 mg daily for participants not rescued with open-label glimepiride during Phase A.
Phase B: placebo to glimepiride tablet orally daily.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 79 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Hemoglobin A1C (A1C) at Week 16 | Baseline and Week 16 | A1C is measured as percent. Thus, this change from baseline reflects the Week 16 A1C percent minus the Week 0 A1C percent. |
| Percent Change From Baseline in Low Density Lipoprotein Cholesterol (LDL-C) at Week 16 | Baseline and 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%. |
| Number of Participants Who Experienced at Least One Adverse Event | Up to 56 weeks (including 2-week follow-up) | 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. |
| Number of Participants Who Discontinued Study Drug Due to an Adverse Event | Up to 54 weeks | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Triglycerides at Week 16 | Baseline and 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%. |
| Change From Baseline in Fasting Plasma Glucose (FPG) at Week 16 | Baseline and Week 16 | Change from baseline reflects the Week 16 value minus the Week 0 value. |
| Percent Change From Baseline in High Density Lipoprotein Cholesterol (HDL-C) at Week 16 | Baseline and 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%. |
| Percent Change From Baseline in Very Low-density Lipoprotein Cholesterol (VLDL-C) at Week 16 | Baseline and 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%. |
| Percent Change From Baseline in Total Cholesterol at Week 16 | Baseline and 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%. |
| Percent Change From Baseline in Apolipoprotein B (Apo B) at Week 16 | Baseline and 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%. |
| Percent Change From Baseline in Non-high Density Lipoprotein Cholesterol (Non-HDL-C) at Week 16 | Baseline and 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%. |
Participant flow
Recruitment details
Note: 10 participants were enrolled in the study more than once (at more than 1 study site). Nine participants were enrolled twice and one participant was randomized at 3 different sites. Therefore, data of 10 actual participants (counted as 21 participants due to multiple screening/randomization) were removed from the efficacy analyses.
Participants by arm
| Arm | Count |
|---|---|
| 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 matching placebo to glimepiride plus atorvastatin 80 mg daily for an additional 38 weeks. | 55 |
| 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. | 56 |
| 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. | 55 |
| Total | 166 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Phase A | Adverse Event | 1 | 2 | 2 |
| Phase A | Lost to Follow-up | 4 | 3 | 2 |
| Phase A | Physician Decision | 1 | 0 | 1 |
| Phase A | Study terminated by sponsor | 37 | 40 | 39 |
| Phase B | Lost to Follow-up | 0 | 1 | 0 |
| Phase B | Study terminated by sponsor | 12 | 10 | 11 |
Baseline characteristics
| Characteristic | Sitagliptin/Sitagliptin + Atorvastatin | Atorvastatin/Atorvastatin + Glimepiride | Sitagliptin + Atorvastatin/Sitagliptin + Atorvastatin | Total |
|---|---|---|---|---|
| Age, Continuous | 56.2 Years STANDARD_DEVIATION 9.7 | 56.3 Years STANDARD_DEVIATION 8.2 | 53.7 Years STANDARD_DEVIATION 10 | 55.4 Years STANDARD_DEVIATION 9.4 |
| Sex: Female, Male Female | 24 Participants | 27 Participants | 24 Participants | 75 Participants |
| Sex: Female, Male Male | 31 Participants | 29 Participants | 31 Participants | 91 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 55 | 3 / 56 | 5 / 55 |
| serious Total, serious adverse events | 0 / 55 | 0 / 56 | 1 / 55 |
Outcome results
Primary
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.
Time frame: Baseline and Week 16
Population: Full analysis set (FAS) population included all participants who took at least one dose of study medication and had baseline and at least one post-randomization observation for the analysis endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sitagliptin/Sitagliptin + Atorvastatin | Change From Baseline in Hemoglobin A1C (A1C) at Week 16 | -1.17 Percent | Standard Error 0.2 |
| Atorvastatin/Atorvastatin + Glimepiride | Change From Baseline in Hemoglobin A1C (A1C) at Week 16 | 0.04 Percent | Standard Error 0.31 |
| Sitagliptin + Atorvastatin/Sitagliptin + Atorvastatin | Change From Baseline in Hemoglobin A1C (A1C) at Week 16 | -1.01 Percent | Standard Error 0.22 |
Primary
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.
Time frame: Up to 54 weeks
Population: All participants as treated population included all randomized participants who received at least 1 dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sitagliptin/Sitagliptin + Atorvastatin | Number of Participants Who Discontinued Study Drug Due to an Adverse Event | 1 Participants |
| Atorvastatin/Atorvastatin + Glimepiride | Number of Participants Who Discontinued Study Drug Due to an Adverse Event | 2 Participants |
| Sitagliptin + Atorvastatin/Sitagliptin + Atorvastatin | Number of Participants Who Discontinued Study Drug Due to an Adverse Event | 2 Participants |
Primary
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.
Time frame: Up to 56 weeks (including 2-week follow-up)
Population: All participants as treated population included all randomized participants who received at least 1 dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sitagliptin/Sitagliptin + Atorvastatin | Number of Participants Who Experienced at Least One Adverse Event | 10 Participants |
| Atorvastatin/Atorvastatin + Glimepiride | Number of Participants Who Experienced at Least One Adverse Event | 13 Participants |
| Sitagliptin + Atorvastatin/Sitagliptin + Atorvastatin | Number of Participants Who Experienced at Least One Adverse Event | 13 Participants |
Primary
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%.
Time frame: Baseline and Week 16
Population: FAS population included all participants who took at least one dose of study medication and had baseline and at least one post-randomization observation for the analysis endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sitagliptin/Sitagliptin + Atorvastatin | Percent Change From Baseline in Low Density Lipoprotein Cholesterol (LDL-C) at Week 16 | 4.9 Percent change | Standard Deviation 10.4 |
| Atorvastatin/Atorvastatin + Glimepiride | Percent Change From Baseline in Low Density Lipoprotein Cholesterol (LDL-C) at Week 16 | -35.7 Percent change | Standard Deviation 7.1 |
| Sitagliptin + Atorvastatin/Sitagliptin + Atorvastatin | Percent Change From Baseline in Low Density Lipoprotein Cholesterol (LDL-C) at Week 16 | -38.7 Percent change | Standard Deviation 6.6 |
Secondary
Change From Baseline in Fasting Plasma Glucose (FPG) at Week 16
Change from baseline reflects the Week 16 value minus the Week 0 value.
Time frame: Baseline and Week 16
Population: FAS population included all participants who took at least one dose of study medication and had baseline and at least one post-randomization observation for the analysis endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sitagliptin/Sitagliptin + Atorvastatin | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 16 | -15.7 mg/dL | Standard Error 6.4 |
| Atorvastatin/Atorvastatin + Glimepiride | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 16 | 22.7 mg/dL | Standard Error 10.1 |
| Sitagliptin + Atorvastatin/Sitagliptin + Atorvastatin | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 16 | -26.0 mg/dL | Standard Error 14 |
Secondary
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%.
Time frame: Baseline and Week 16
Population: FAS population included all participants who took at least one dose of study medication and had baseline and at least one post-randomization observation for the analysis endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sitagliptin/Sitagliptin + Atorvastatin | Percent Change From Baseline in Apolipoprotein B (Apo B) at Week 16 | -4.8 Percent change | Standard Error 6.5 |
| Atorvastatin/Atorvastatin + Glimepiride | Percent Change From Baseline in Apolipoprotein B (Apo B) at Week 16 | -32.9 Percent change | Standard Error 5.6 |
| Sitagliptin + Atorvastatin/Sitagliptin + Atorvastatin | Percent Change From Baseline in Apolipoprotein B (Apo B) at Week 16 | -29.0 Percent change | Standard Error 4.6 |
Secondary
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%.
Time frame: Baseline and Week 16
Population: FAS population included all participants who took at least one dose of study medication and had baseline and at least one post-randomization observation for the analysis endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sitagliptin/Sitagliptin + Atorvastatin | Percent Change From Baseline in High Density Lipoprotein Cholesterol (HDL-C) at Week 16 | -0.3 Percent change | Standard Error 3.2 |
| Atorvastatin/Atorvastatin + Glimepiride | Percent Change From Baseline in High Density Lipoprotein Cholesterol (HDL-C) at Week 16 | -5.8 Percent change | Standard Error 3.5 |
| Sitagliptin + Atorvastatin/Sitagliptin + Atorvastatin | Percent Change From Baseline in High Density Lipoprotein Cholesterol (HDL-C) at Week 16 | 1.5 Percent change | Standard Error 6 |
Secondary
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%.
Time frame: Baseline and Week 16
Population: FAS population included all participants who took at least one dose of study medication and had baseline and at least one post-randomization observation for the analysis endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sitagliptin/Sitagliptin + Atorvastatin | Percent Change From Baseline in Non-high Density Lipoprotein Cholesterol (Non-HDL-C) at Week 16 | -1.0 Percent change | Standard Error 8.8 |
| Atorvastatin/Atorvastatin + Glimepiride | Percent Change From Baseline in Non-high Density Lipoprotein Cholesterol (Non-HDL-C) at Week 16 | -34.4 Percent change | Standard Error 6.7 |
| Sitagliptin + Atorvastatin/Sitagliptin + Atorvastatin | Percent Change From Baseline in Non-high Density Lipoprotein Cholesterol (Non-HDL-C) at Week 16 | -34.6 Percent change | Standard Error 6.7 |
Secondary
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%.
Time frame: Baseline and Week 16
Population: FAS population included all participants who took at least one dose of study medication and had baseline and at least one post-randomization observation for the analysis endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sitagliptin/Sitagliptin + Atorvastatin | Percent Change From Baseline in Total Cholesterol at Week 16 | -1.7 Percent change | Standard Error 6.2 |
| Atorvastatin/Atorvastatin + Glimepiride | Percent Change From Baseline in Total Cholesterol at Week 16 | -28.3 Percent change | Standard Error 4.8 |
| Sitagliptin + Atorvastatin/Sitagliptin + Atorvastatin | Percent Change From Baseline in Total Cholesterol at Week 16 | -25.7 Percent change | Standard Error 6 |
Secondary
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%.
Time frame: Baseline and Week 16
Population: FAS population included all participants who took at least one dose of study medication and had baseline and at least one post-randomization observation for the analysis endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sitagliptin/Sitagliptin + Atorvastatin | Percent Change From Baseline in Triglycerides at Week 16 | -9.9 Percent change | Standard Error 8.6 |
| Atorvastatin/Atorvastatin + Glimepiride | Percent Change From Baseline in Triglycerides at Week 16 | -28.7 Percent change | Standard Error 6.5 |
| Sitagliptin + Atorvastatin/Sitagliptin + Atorvastatin | Percent Change From Baseline in Triglycerides at Week 16 | -10.5 Percent change | Standard Error 13.5 |
Secondary
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%.
Time frame: Baseline and Week 16
Population: FAS population included all participants who took at least one dose of study medication and had baseline and at least one post-randomization observation for the analysis endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sitagliptin/Sitagliptin + Atorvastatin | Percent Change From Baseline in Very Low-density Lipoprotein Cholesterol (VLDL-C) at Week 16 | -15.5 Percent change | Standard Error 7.2 |
| Atorvastatin/Atorvastatin + Glimepiride | Percent Change From Baseline in Very Low-density Lipoprotein Cholesterol (VLDL-C) at Week 16 | -28.6 Percent change | Standard Error 6.6 |
| Sitagliptin + Atorvastatin/Sitagliptin + Atorvastatin | Percent Change From Baseline in Very Low-density Lipoprotein Cholesterol (VLDL-C) at Week 16 | -10.4 Percent change | Standard Error 13.5 |