- Click here for explanation of classification scheme.

To assess prospectively whether rosiglitazone together with lifestyle recommendations can reduce the frequency of diabetes in individuals with impaired fasting glucose or glucose intolerance, or both.

Initial inclusion criteria (in 2001) included:

• either impaired fasting glucose (fasting plasma glucose concentration >6.1 mmol/L and <7.0 mmol/L and two hour plasma glucose concentration <11.1 mmol/L during the oral glucose tolerance test) or impaired glucose tolerance (fasting plasma glucose concentration <7.0 mmol/L and two hour plasma concentration >7.8 mmol/L and <11.1 mmol/L)
• aged 30 years or more

Inclusion criteria expanded in 2003 to also include individuals with isolated impaired fasting glucose (fasting glucose concentration >6.1 mmol/L and <7.0 mmol/L and two hour plasma glucose concentration <7.8 mmol/L to broaden the generalizability of the study

 

• history of diabetes (except gestational diabetes)
• history of cardiovascular disease (including heart failure and low ejection fraction)
• intolerance to either angiotensin-converting enzyme inhibitors or thiazolidinediones

Recruitment recruited from 191 sites in 21 countries; details previously published

Design randomized blinded controlled trial

Blinding used (if applicable)  a 17-day single-blind placebo run-in was utilized for eligibilty; prospective study double blinded  

Intervention (if applicable)

After a 17 day single-blind placebo run-in period for eligibility (consumption of at least 80% of run-in medication required); patients were randomly assigned (stratified by site) to receive either rosiglitazone (four mg once daily for the first two months and then eight mg once daily) or placebo and were followed for a median of three years (range 2.5 to 4.7 years). Participants attended visits two and six months after randomization and every six months thereafter.   

At all visits, all participants were provided with advice by the research staff about healthy diets and lifestyle habits to reduce diabetes.

Statistical Analysis

Analyses were done by intent to treat.

Cox proportional hazards models were used to estimate the effect of rosiglitazone on the primary outcome (incident diabetes or death from any other cause).

Calculation of median fasting and two hour glucose concentrations at every scheduled measurement time was done to assess the effect of study drug on glucose concentrations.

ANOVA (with adjustment for the baseline value) was used to assess differences between groups in the mean change in ALT after one year, in systolic and diastolic blood pressure from the beginning to end of study, and the slope of change in body mass index, weight, waist-to-hip ratio, and waist and hip circumference during the course of the study.

Significance was established as P<0.05.

 

Timing of Measurements

Laboratory

A 75 g oral glucose tolerance test with local fasting and two hour plasma glucose concentration measurement was done after two years and final visit. At other yearly visits, local fasting plasma glucose and glycated hemoglobin concentrations were measured.

If at any visit the fasting plasma glucose concentration was 7.0 mmol/L or greater or the twp hour plasma glucose concentration was 11.1 mmol/L or greater (suggesting possible diabetes), an oral glucose tolerance test was scheduled within the next three months to confirm or refute the diagnosis.

Participants had local measurements of alanine aminotransferase (ALT) concentrations every two months during the first year; subsequent measurements were done at the discretion of the site physician.

Blood pressure was measured at two months, six months, 12 months, and yearly until end of study.

Anthropometrics

Weight, waist and hip circumference measurements (protocol not described) at baseline, after two years, and at the end of the study.

Dependent Variables

Primary:

•  incident diabetes--diagnosed if 1) on a visit the fasting plasma glucose was 7.0 mmol/L or greater or the two hour plasma glucose concentration was 11.1 mmol/L or greater during a 75 g oral glucose tolerance test and confirmed by a second test within the next three months; 2) a single test was consistent with diabetes; or 3) a physician diagnosed diabetes outside the study and the diagnosis was confimed by the prescription of an antidiabetic agent.
• death from any cause

Secondary: 

• cardiovascular events
• regression to normal fasting and two hour post-load glucose concentrations (normoglycemic)

Independent Variables

• Rosiglitazone or placebo group

Control Variables

 

Initial N: Baseline--5269 (59.2 percent women); Rosiglitazone group--N=2335 (58.3 percent women); Placebo--N=2634 (60.1 percent women)

Attrition (final N): 59 dropped out of rosiglitazone group (2.53 percent); 46 (1.75 percent) dropped out of placebo group

Age: Group mean age--54.7±10. years; mean age Rosglitazone group--56.4±10.9 years; mean age Placebo group--56.8±10.9 years

Ethnicity: not specifically discussed; but indicated that various ethnic groups were included in the study

Other relevant demographics:

 Baseline Clinical and Medical history

Variable	Rosiglitazone	Placebo
Isolated IGT	1504 (57.1 percent)	1524 (57.9 percent)
Isolated IFG	369 (14.0 percent)	370 (14.1 percent)
Both IGT and IFG	762 (28.9 percent)	740 (28.1 percent)
Mean fasting glucose (mmol/L)	5.8±0.7	5.8±0.7
Mean two hour plasma glucose (mmol/L)	8.7±1.4	8.7±0.5
Left venticular hypertrophy on ECG	118±4.5	129±4.9
History of hypertension	1159 (44.0 percent)	1132 (43.0 percent)

 Anthropometrics

Measurement	Rosiglitazone	Placebo
Weight (kg)	84.8±19.0	85.0±18.9
Body mass index (BMI)	30.8±5.6	31.0±5.6
waist/hip ratio male	0.96±0.07	0.96±0.07
waist/hip ratio female	0.86±0.07	0.87±0.09
waist male (cm)	101±14	102±13
waist female (cm)	96±14	96±14
Systolic blood pressure	135.9±17.9	136.3±18.8
Diastolic blood pressure	83.3±10.6	83.5±10.9

Location: 191 sites in 21 countries

Geographic Distribution	Rosiglitazone	Placebo
North America	1082 (41.1 percent)	1067 (40.5 percent)
South America	564 (21.4 percent)	571 (21.7 percent)
Europe	549 (20.8 percent)	555 (21.1 percent)
India	330 (12.5 percent)	332 (12.6 percent)
Australia	110 (4.2 percent)	108 (4.1 percent)

 During the trial:

• 992 (18.8 percent) experienced the primary outcome; 63 (1.2 percent) died and 938 (17.8 percent) developed diabetes.
• In surviving participants, adherence to study drug (at least 80 percent adherent) was 71.7 percent (n=1868) in the rosiglitazone group and 75.1 percent (n=1952) in the placebo group. 752 (28.8 percent) and 641 (25.3 percent) stopped taking assigned treatment at any point during study; 602 (23.6 percent) in the rosiglitazone group and 517 (20.2 percent) in the placebo group were not taking allotted drug at their last visit.
• Reasons for stopping rosiglizone and placebo included participant refusal (503 [18.9 percent] in the rosiglitazone group) and 439 [16.7 percent] in the placebo group), edema (439 [4.8 percent] and 41 [1.6 percent]), physician's advice (50 [1.9 percent] and 39 [1.5 percent]), and weight gain (50 [1.5 percent] and 15 [0.6 percent)]. One patient in the rosiglizone and three in the placebo group stopped because of hypoglycemia.

 

Variables	Rosiglitazone group Measures and percent	Placebo group Measures and percent	Statistical Significance of Group Difference
Composite Primary Outcome	306 (11.6 percent)	686 (26.0 percent)	hazard ratio 0.40; P<0.0001
Diabetes	280 (10.6 percent)	658 (25.0 percent)	<0.0001
Death	30 (1.1 percent)	33 (3.3 percent)	0.7
Normoglycemic	1330 (50.5 percent)	798 (30.3 percent)	0.0001
Cardiovascular events composite	75(2.9 percent)	55(2.2 percent)	0.08
Myocardial infarction,  stroke, or cardiovascular death	32(2.2 percent)	33(0.9 percent)	0.3
Heart failure	14(0.5 percent)	2(0.1)	0.01

 

Other Findings

• Mean hepatic ALT concentrations during the first year of therapy were 4.2 U/L lower in patients treated with rosiglitazone than in the placebo group (P<0.0001).
• The effect of rosiglitazone was not significantly different in different areas of the world, in both sexes, and across all ages.

 

This large prospective, blinded international clinical trial showed that the addition of eight mg of rosiglitazone daily to basic lifestyle recommendations, substantially reduced the risk of diabetes or death by about two thirds in individuals at high risk of diabetes. Moreover, rosiglitazone significantly increased the likelihood of regression to normoglycemia by about 70-80 percent compared with placebo.

A consistent reduction in the primary outcome was noted in people with impaired fasting glucose and those with impaired lucose tolerance, in men and women, in all participating regions of the world (consisting of many ethnic groups), in patients of all ages, and in participants of varying weight and fat distribution. Participants with a higher body mass index or abdominal fat distribution who were allocated to receive rosiglatozone all had the same three to four percent per group incidence of the primary outcome, despite progressively higher rates in the corresponding control participants; this finding accounts for the observation of higher risk reduction with higher baseline obesity. Rosiglitaone therefore seems to reduce or eliminate the relation between increasing obesity and a higher risk of diabetes.

Government:	CIHR
Industry:	Sanofi-Aventis, Glaxo Smith Kline, King Pharmaceuticals Pharmaceutical/Dietary Supplement Company:

Strengths of study include:

• Large sample size
• Blinded, randomized trial
• Included men and women of varying ages, ethnic groups and regions of the world

Limitations may include:

• the observation period may have been too short to draw reliable conclusions with regard to the cardiovascular effects of rosiglitazone
• ? generalizability to adults younger than 30 years of age