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

Study Characteristics
Author, Year
Trial Name (if app.)
Duration
Country
Funding
Quality
Inclusion and Exclusion CriteriaOverall Sample Size
Interventions
Group Sizes
Baseline Population Characteristics
Mean Age, years
Race/Ethnicity
% Female
Background MedicationsIntermediate Outcomes
HbA1c
Health and Utilization Outcomes
Microvascular Disease
Macrovascular Disease
Lower Extremity Ulcers
All-Cause Mortality
Quality of Life
Hospitalization
Medical Visits (diabetes)
Other
Active-control studies
Derosa, 2009
The 60’s study
12 months
Italy
Funding NR
Fair
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):
n=69

G4 (glimepiride 2mg/day + metformin 850mg/day):
n=66
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
NR
McCluskey, 2004
20 weeks
US
Funding NR
Fair
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
Multinational
GlaxoSmithKline
Fair
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):
n=254
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
P =NR

Angina Pectoris
G1: 2
G2: 0
P =NR

Myocardial ischaemia:
G1: 1
G2: 0
P =NR
Weissman, 2005
EMPIRE
24 weeks
US
GlaxoSmithKline
Fair
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
EMPIRE
24 weeks
US
GlaxoSmithKline
Fair
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.
N=122

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)
n=51
Age:
G1 = 54.6
G2 = 56.0

Race (%):
Caucasian:
G1 = 71.8
G2 = 66.7

Black:
G1 = 7.0
G2 = 5.9

Hispanic:
G1 = 16.9
G2 = 25.5

Other:
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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