1. 1 Effect of Ramipril on the Incidence of Diabetes The DREAM Trial Investigators N Engl J Med 2006;355 FM R1 윤나리

2. 2 Introduction Diabetes – –fifth leading cause of death worldwide – –a major risk factor for various cardiovascular and renal disorders – –The prevalence of diabetes is increasing -> increases the risk of premature cardiovascular disease and death. – –Physical activity, weight loss and some glucose-lowering agents Several trials – –HOPE; high risk for cardiovascular events – –->cardiovascular events(22%), diabetes(34%)

3. 3 the Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) study – –prospective trial – –evaluate whether ramipril reduces the risk of diabetes – –in people who have impaired fasting glucose levels (after an 8- hour fast) or impaired glucose tolerance but who are at low risk for cardiovascular event

4. 4 Methods July 2001 and August 2003 5269 persons 30 years of age or older Inclusion criteria – –impaired fasting plasma glucose levels – –impaired glucose tolerance – –who did not have a history of diabetes (not including gestational diabetes) cardiovascular disease intolerance of either angiotensin-converting–enzyme (ACE) inhibitors or thiazolidinediones

5. 5 17-day, single blind, double-placebo run-in period showed adherence to their study medications during that period, participants were randomly assigned ramipril – –5 mg daily for the first 2 months – –with an increase to 10 mg at the 2-month visit – –15 mg after 1 year matching placebo – –rosiglitazone or matching placebo – –4 mg once daily for the first 2 months – –8 mg thereafter

6. 6 Visits – –2 months and 6 months – –every 6 months, February and April 2006 – –Alanine aminotransferase levels ; every 2 months during 1st year – –healthy diet and lifestyle – –Electrocardiogram (baseline) At the 2-year and final visits – –OGTT – –Diabetes had not developed annual visits, – –Fasting plasma levels of glucose and glycated hemoglobin

7. 7 OGTT 1. 1. the fasting plasma glucose level – –126 mg per deciliter (7.0 mmol per liter) or higher 2. 2. fasting plasma glucose level – –exceeded 95 mg per deciliter (5.3 mmol per liter) – –and the glycated hemoglobin value exceeded 93% of the upper limit of the normal range for the assay Diabetes – –medications were continued – –antihyperglycemic agents other than thiazolidinediones Not diabetes – –single-blind placebo washout period – –underwent a glucose-tolerance test (2 hours after an oral glucose load) 2 to 3 months later

8. 8 Outcomes primary outcome – –newly diagnosed diabetes or death DM – –fasting plasma glucose level at least 126 mg per deciliter (7.0 mmol per liter) – –2-hour post-load glucose level at least 200 mg per deciliter (11.1 mmol per liter) – –with confirmation by a second test on a different day key secondary outcomes – –cardiovascular events (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) – –renal events (on the basis of measurements in urine and blood at a central laboratory)

9. 9 RESULTS

10. 10 Baseline and Follow-up SCREENING – –A total of 24,592 participants – –191 centers in 21 countries. 5808 entered the run-in phase of the trial exclusion – –Ineligibility (94.2%) and refusal to participate (3.0%) Of those entering the run-in phase, – –5269 participants were randomly assigned to treatment – –739 had impaired fasting glucose levels alone – –4530 had impaired glucose tolerance with or without impaired fasting glucose levels exclusion during the run-in period – –ineligibility (284 participants) and refusal to participate (159 participants)

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12. 12 TABLE 2

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14. 14 FIGURE 2

15. 15 FIGURE 3

16. 16 TABLE 3

17. 17 DISCUSSION Our study suggests – –the use of up to 15 mg of ramipril daily for 3 years does not significantly prevent diabetes or death in people without cardiovascular disease who have impaired fasting glucose levels or impaired glucose tolerance significantly more participants receiving ramipril – –normal fasting glucose levels – –glucose tolerance – –the distribution of the glucose levels had shifted downward in the ramipril group by the end of the study

18. 18 Results 1. 1.Specifically designed to determine whether ramipril prevents diabetes 2. 2.fasting glucose levels and 2-hour postload glucose levels below the diagnostic threshold for diabetes 3. 3.participants with cardiovascular disease and heart failure were excluded relatively younger (mean age, 55 years, vs. 65 years in other trials) mean blood pressure of 136/83 mm Hg at baseline in our study is substantially lower than that reported in the hypertension trials

19. 19 compared ramipril with placebo – –several other trials – –a beta-blocker or a diuretic – –increase the risk of diabetes ->leading to an overestimation of the effects of ACEi Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) duration of follow-up – –was shorter in our trial (median, 3 years) – –previous studies of ACE inhibitors and angiotensin-receptor blockers (median, about 4.5 years) – –Kaplan–Meier curves

20. 20 most participants had baseline glucose levels that were far from the diagnostic threshold for diabetes and close to the normal threshold – –median fasting plasma glucose (106.3 mg/dl) – –median 2-hour post-load glucose(156.7 mg/dl) ->effect on regression to normal levels than progression to diabetic levels.Limitation – –glucose levels were available for only 92.6% ->not reached primary outcome – –3 years of follow-up

21. 21 CONCLUSION The DREAM trial did not show that ramipril prevents diabetes in this population – –it did demonstrate an effect of ramipril on regression to normal glucose levels. ramipril may have favorable effects on glucose metabolism the routine use of ramipril – –preventing diabetes is not indicated.