Evidence Table 5Key Question 1: Studies of fixed-dose combination products and dual therapy

Study Characteristics
Author, Year
Trial Name (if app.)
Inclusion and Exclusion CriteriaOverall Sample Size
Group Sizes
Baseline Population Characteristics
Mean Age, years
% Female
Background MedicationsIntermediate Outcomes
Health and Utilization Outcomes
Microvascular Disease
Macrovascular Disease
Lower Extremity Ulcers
All-Cause Mortality
Quality of Life
Medical Visits (diabetes)
Active-control studies
Derosa, 2009
The 60’s study
12 months
Funding NR
Inclusion: >18yrs, T2DM, treatment naïve, HbA1c> 6.5, BMI 25-30

Exclusion: ketoacidosis; unstable or rapidly progressive retinopathy, nephropathy or neuropathy; impared liver function; impaired kidney function; anemia; New York Heart Association class I–IV congestive heart failure, history of myocardial infarction or stroke; cerebrovascular conditions within 6 months; women who were pregnant or childbearing potential not taking adequate contraceptive precautions
N=271 randomized

G1 (pioglitazone 15mg/day): n=69

G2 (metformin 1000mg/day): n=67

G3 (pioglitazone 15mg/day + metformin 850mg/day):

G4 (glimepiride 2mg/day + metformin 850mg/day):
G1: Age: 54; White 100%; Female 53.6%

G2: Age: 55; White 100%; Female 49.3%

G3: Age: 57; White 100%; Female 50.7%

G4: Age: 57.7; White 100%; Female 51.5%
NRHbA1c mean change at 15 months:
G1: −1.0 (SD NR)
G2: −1.2 (SD NR)
G3: −2.1 (SD NR)
G4: −1.2 (SD NR)

P <0.01, all groups vs. baseline
(P <0.001 for G3)
P <0.05, G3 vs. G2
P <0.01, G3 vs. G1
McCluskey, 2004
20 weeks
Funding NR
Inclusion: T2DM ≥ 1 year; age 18–80; managed on rosiglitazone 4 or 8mg for at least 2 months; HbA1c 7.5–9.5; BMI 26–42; fasting C-peptide ≥ 0.27 nmol/L; fasing plasma glucose 126–235 mg/dl

Exclusion: require insulin therapy; receiving other sulfonylureas; history of sulfonylurea hypersensitivity; rosiglitazone dose increased within 2 months; body weight increases >2% (for patients weighing ≤ 250 lbs. or >3% (for patients weighing > 250 lbs.) during the stabilization period; clinically abnormal baseline values
N=40 patients randomized

G1 (Glimeperide 8mg/day + rosiglitazone 4 or 8mg/day): n=25

G2 (placebo + rosiglitazone 4 or 8mg/day): n=15
G1: Age: 60.2; White 96%, Other 4%; Female 56%

G2: Age: 50.8; White 80%, Other 20%; Female 60%
NRmean change at 20 weeks:
G1: −1.2 (SD 0.1)
G2: −0.3 (SD 0.2)

P <0.001, G1 vs. G2
Stewart, 2006
32 weeks
Inclusion: 18–70 years old; T2DM; drug naïve subjects with fasting plasma glucose 7–9 mmol/l and HbA1c 7.0–9.0 mmol/l or treated with monotherapy with fasting plasma glucose 6–8mmol/l and HbA1c 6.5–8.0. Prior to visit 2 all subjects must have had fasting plasma glucose 7.0–9.0 mmol/l

Exclusion: prior exposure to TZDs within 6 months; use of insulin; unstable or severe angina; coronary insufficiency; New York Heart Association class I–IV congestive heart failure; blood pressure > 170/100 while on anti-hypertensive treatment
N=526 patients randomized, 509 in ITT population

G1 (rosiglitazone titrated up to 8mg day/ metformin titrated to 2000mg day):
G2 (Metformin titrated up to 3000mg): n=272
G1: Age 58.9; White 98%, Asian 1%, Hispanic <1%, African American 0%, Native Hawaiian/other Pacific Islander 0%; Female 45%

G2: Age: 59.0; White 99%, Asian <1%, Hispanic <1%, African American <1%, Native Hawaiian/other Pacific Islander <1%; Female 44%
Nonechange at 32 weeks:
G1: −0.51% (SD NR)
G2: −0.38% (SD NR)

P =0.0357, G1 vs. G2
Macrovascular disease
Myocardial Infarction:
G1: 1
G2: 0

Angina Pectoris
G1: 2
G2: 0

Myocardial ischaemia:
G1: 1
G2: 0
Weissman, 2005
24 weeks
Inclusion: age 18–75; T2DM; HbA1c 6.5–8.5 for subjects with prior treatment, 7–10 for drug naïve subjects; fasting plasma glucose 7.0–15.0mmol/l; BMI ≥ 27; previous therapy could include diet, exercise or oral therapy (acarbose, sulfonylurea, metformin or metformin + sulfonylurea); metformin dose must have been ≤ 1000mg/day for at least 3 months prior to study; subjects must have stopped TZD at least 3 months prior to screening

Exclusion: uncontrolled hypertension; congestive heart failure requiring treatment; severe angina; anemia or severe edema associated with TZDs; active or chronic metabolic acidosis; clinically significant renal or hepatic disease; prior insulin use within 3 months; subjects non-compliant with metformin up-titration
N=766 randomized, 709 in ITT population

G1 (rosiglitazone titrated to 8mg/day + metformin 1000mg/day): n=358 ITT

G2 (metformin titrated to 2000mg/day): n=351 ITT
G1: Age: 55.5
Race/Female: NR

G2: Age: 55.7
Race/Female: NR
NRmean change from baseline (95% CI):
G1: −0.93 (−1.06, −0.80)
G2: −0.71 (−0.83, −0.60)
non-inferior, G1 vs. G2
Macrovascular disease
Myocardial Infarction (withdrew):
G1: 2
G2: 0

Coronary artery disease (withdrew):
G1: 0
G2: 1

Cardiac Ischemia:
G1: 5 (1.3%)
G2: 3(0.8%)
Goldstein, 2006
24 weeks
Inclusion: Age 18–75; HbA1c of 6.5–8.5% for subjects having received prior combination treatment and 7–10% for drug-naive or monotherapy subjects; fasting plasma glucose 126–270mg/dL; BMI >=27kg/m2; previous treatment with either diet & exercise or with oral therapy with metformin (<=1,000mg/day for at least 3 months prior to study), either as monotherapy or in combination with a sulfonylurea.

Exclusion: Uncontrolled hypertension; congestive heart failure requiring treatment, severe angina, clinically significant renal or hepatic disease; active or chronic metabolic acidosis; receipt of insulin or TZD in 3 months prior to study; history of anemia or severe edema associatyed with TZD therapy; non-compliance with metformin during run-in period.

G1: (rosiglitazone 4mg/day up-titrated to 8mg/day at week 8 + metformin 1,000mg day) n=71

G2: (metformin 1,500mg/day up-titrated to 2,000mg/day at week 8)
G1 = 54.6
G2 = 56.0

Race (%):
G1 = 71.8
G2 = 66.7

G1 = 7.0
G2 = 5.9

G1 = 16.9
G2 = 25.5

G1 = 4.2
G2 = 2.0

% Female:
G1 = 49.3
G2 = 35.3
NRAt 24 weeks:

G1 = −0.61% (1.16)
G2 = −0.65% (1.18)

From: Evidence Tables

Cover of Drug Class Review: Newer Diabetes Medications, TZDs, and Combinations
Drug Class Review: Newer Diabetes Medications, TZDs, and Combinations: Final Original Report [Internet].
Jonas D, Van Scoyoc E, Gerrald K, et al.
Portland (OR): Oregon Health & Science University; 2011 Feb.
Copyright © 2011, Oregon Health & Science University.

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