The Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication trial (DREAM)

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Effect of ramipril on the incidence of diabetes
Authors	Bosch J, Yusuf S, Gerstein HC, Pogue J, Sheridan P, et al.
Journal	New England Journal of Medicine
Year/Volume(Issue)/Pages	2006;355(15):1551-1562
Original Article Abstract
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Contents 1 Quick Summary 2 Hypothesis/Objectives 3 Methods/Design 3.1 Inclusion criteria 3.2 Exclusion criteria 3.3 Design 4 Results 4.1 Baseline characteristics 4.2 Primary endpoint results 4.3 Other 5 Limitations

Quick Summary

• Diabetics is a known major risk factor for cardiovascular and renal disorders, so there is a need for strategies which can prevent diabetes.
• The primary aim of this study was to evaluate the effects of ramipril on the outcomes of newly diagnosed diabetes or death in patients with impaired fasting glucose levels or impaired glucose tolerance.
• After a median 3 year follow up period, there were no significant effects of ramipril on newly diagnosed diabetes or death, but significantly more patients in the ramipril group experienced regression to normoglycemia than placebo.

Hypothesis/Objectives

At this point, previous studies have shown that ACE-inhibitors could slow the progression to or prevent diabetes in patients with hypertension or cardiovascular disease. The objective of this study was to determine if ramipril could reduce the risk of diabetes in patients who have impaired fasting glucose levels or impaired glucose tolerance, but who are at low risk for cardiovascular events.

Methods/Design

		Y	Randomized?
		Y	Controlled?
		Y	Placebo-controlled?
		Y	Prospective?
		U	Double-blind?
		*U = not reported

Inclusion criteria

• Men and women 30 years and older
• Impaired fasting plasma glucose levels: between 110-126 mg/dL OR
• Impaired glucose tolerance: glucose between 140-200 mg/dL 2 hours after an oral glucose load
• No history of diabetes (not including gestational diabetes)
• No history of cardiovascular disease
• No intolerance to ACE inhibitors or thiazolidinediones (TZDs)
• (In 2003, patients with isolated impaired fasting glucose levels were included)

Exclusion criteria

• Current use of ACE inhibitors and/or TZDs and inability to discontinue these medications
• Prior use of oral hypoglycaemic medications except during pregnancy
• Use of systemic glucocorticoids or niacin
• Uncontrolled hypertension requiring ACE inhibitors or angiotensin-2 receptor blockers
• Renal or hepatic disease:
  • renal artery stenosis
  • creatinine clearance <0.6 ml/s or serum creatinine ≥ 2.2 mg/dL (200 μmol/l)
  • clinical proteinuria (≥1 proteinuria on dipstick or ≥300 mg of albuminuria/day)
  • measured alanine transferase ≥2.5 times the upper limit of normal
  • active liver disease
• Major illness with life expectancy of <5 years or that may interfere with participation
• Use of another experimental drug
• Pregnant or unwilling to use reliable contraception
• Major psychiatric disorder
• Diseases and medications that affect glucose tolerance
• Unwillingness to be randomised or to sign informed consent
• Known uncontrolled substance abuse
• Inability to communicate with clinic staff

(from Rationale, design and recruitment characteristics of a large, simple international trial of diabetes prevention: the DREAM trial.)

Design

The 5269 included participants completed a 17-day placebo run-in period to assess adherence, and were then randomized to receive ramipril (n=2623) at 5mg daily for 2 months, increased to 10mg, then 15mg after 1 year, matching placebo (and rosiglitazone (4mg daliy for 2 months then 8mg daily), or matching placebo) (n=2646). Patients were seen at 2 and 6 months, then every 6 months thereafter, for a median follow up time of 3 years. Alanine aminotransferase levels were measured every 2 months for the first year, and at 2 years and the final visit oral glucose tolerance tests (OGTT) were perfomed on patients who had not developed diabetes. If a patient developed diabetes during the study, they were treated with antihyperglycemic medications, except TZDs. Diabetes was diagnosed as fasting plasma glucose (FPG) >126 mg/dL, or a 2-hour post-glucose load level was >200 mg/dL and confirmed by a test on a second day.

Results

Baseline characteristics

Of the included participants, 739 had impaired fasting glucose levels and 4530 had impaired glucose tolerance with or without impaired fasting glucose levels at baseline. The mean age of participants was 54.7 years, and 59.7% were female in the ramipril group, with 58.7% female in the placebo group. There were no statistically significant differences in baseline characteristics between the ramipril and placebo groups.

Primary endpoint results

The primary endpoint was newly diagnosed diabetes or death. There was no significant difference found between the two groups for the primary endpoint (hazard ratio (HR) 0.91 [95% CI 0.81-1.03], p=0.15).

Other

Secondary endpoints were the composite of cardiac (clinical or silent myocardial infarction, stroke, death from cardiovascular events, revascularization procedures, heart failure, newly diagnosed angina with objective evidence of ischemia, or ventricular arrhythmia requiring resuscitation) and renal events (on the basis of measurements in urine and blood at a central laboratory). There was no significant difference found between the two groups for cardiovascular events or hospitalizations (p=0.68 and p=0.67, respectively) compared to placebo. At this point, renal outcomes are still being measured. The effect of rosiglitazone treatment was associated with a significantly lower incidence of diabetes or death (HR 0.40 [95% CI 0.35-0.46], p<0.001). Other endpoints included measurement of glucose levels and regression of glucose levels to normal. There was a significant increase in regression to normal glucose levels for patients in the ramipril group compared to placebo (HR 1.16 [95% CI 1.07-1.27], p=0.001), but no significant difference in median FPG levels (p=0.07). However, median 2-hour post-load glucose levels were significantly lower in the ramipril group compared to placebo (p=0.01).

Limitations

• The trial was sponsored by GlaxoSmithKline, the manufacturer of rosiglitazone (Avandia) and by King Pharmaceuticals and Sanofi-Aventis, the manufacturers of ramipril (Altace).
• The authors did not have follow-up data for glucose levels on all participants, but did have it for 92.6% of them.
• The nonsignificant findings for the outcome of cardiovascular events could be biased by the inclusion of patients without any history of cardiovascular disease.