Correspondence
Effect of Ramipril on the Incidence of Diabetes
N Engl J Med 2007; 356:522-524February 1, 2007
- Article
To the Editor:
The Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) trial investigators (Oct. 12 issue)1 report that there was an increase in the incidence of regression to normoglycemia (a secondary outcome) of 16% among patients receiving ramipril as compared with those receiving placebo but that there was no effect on the incidence of diabetes or death. The authors appear to have overlooked the significant reduction in mean diastolic blood pressure in the ramipril group, as compared with the reduction in the placebo group, at 2 months (4.3 mm Hg vs. 1.6 mm Hg). We wonder whether the effect on the secondary outcome could merely be the result of decreased blood pressure rather than a favorable glycemic effect of ramipril itself.
Previous studies have shown that hypertension itself worsens insulin resistance2 and that insulin resistance can predispose patients to hypertension.3,4 In the International Verapamil Sustained Release–Trandolapril Study (INVEST) cohort of 16,176 patients, the risk of new-onset diabetes was directly and independently associated with blood pressure at follow-up.5 Given this interaction between insulin resistance and impaired glucose tolerance and hypertension, we propose that the effect of ramipril on glycemic control reflects, to a large extent, better blood-pressure control with a metabolically inert medication rather than an effect of the angiotensin-converting–enzyme (ACE) inhibitor itself.
5 ReferencesSripal Bangalore, M.D., M.H.A.
Franz H. Messerli, M.D.
St. Luke's–Roosevelt Hospital, New York, NY 10025
sbangalo@chpnet.org 1
The DREAM Trial Investigators
Full Text | Web of Science | Medline2
Ferrannini E ,Buzzigoli G ,Bonadonna R , et al. Insulin resistance in essential hypertension. N Engl J Med 1987;317:350-357
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Lissner L ,Bengtsson C ,Lapidus L ,Kristjansson K ,Wedel H . Fasting insulin in relation to subsequent blood pressure changes and hypertension in women. Hypertension 1992;20:797-801
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Taittonen L ,Uhari M ,Nuutinen M ,Turtinen J ,Pokka T ,Akerblom HK . Insulin and blood pressure among healthy children: cardiovascular risk in young Finns. Am J Hypertens 1996;9:194-199
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Cooper-Dehoff R ,Cohen JD ,Bakris GL , et al. Predictors of development of diabetes mellitus in patients with coronary artery disease taking antihypertensive medications (findings from the INternational VErapamil SR-Trandolapril STudy [INVEST]). Am J Cardiol 2006;98:890-894
CrossRef | Web of Science | Medline
To the Editor:
Diabetes is an ever-increasing problem in our society, associated with considerable morbidity, mortality, and financial costs. In the DREAM trial, ramipril failed to reduce the incidence of diabetes or death, but it did increase the incidence of regression to normoglycemia.
However, although listed as an exclusion criterion,1 140 participants in the placebo group in the DREAM trial received angiotensin-receptor blockers (ARBs). ARBs and ACE inhibitors probably have a similar metabolic effect,2-4 and it is therefore possible that the inclusion of these patients diminished the effect of ramipril on the primary end point. Similarly — and more important — since the expected metabolic effect of even supranormal doses of ramipril is likely to be much less than that of rosiglitazone, it is conceivable that any effect of ramipril on the primary outcome was masked by the overwhelming benefit of rosiglitazone.
It would be interesting to know the results of a post hoc analysis for the primary outcome excluding participants who received either rosiglitazone or ARBs. Although we recognize the limitations of such an analysis, it might help guide future research on this important topic.
4 ReferencesBrian J. Potter, M.D.
Jacques LeLorier, M.D., Ph.D.
Centre Hospitalier de l'Université de Montréal, Montreal, QC H2W 1T8, Canada
brianjpotter@gmail.com 1
Gerstein HC ,Yusuf S ,Holman R ,Bosch J ,Pogue J . Rationale, design and recruitment characteristics of a large, simple international trial of diabetes prevention: the DREAM trial. Diabetologia 2004;47:1519-1527
CrossRef | Web of Science | Medline2
Yusuf S ,Ostergren JB ,Gerstein HC , et al. Effects of candesartan on the development of a new diagnosis of diabetes mellitus in patients with heart failure. Circulation 2005;112:48-53[Erratum, Circulation 2005;112:e292.]
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Abuissa H ,Jones PG ,Marso SP ,O'Keefe JH Jr . Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers for prevention of type 2 diabetes: a meta-analysis of randomized clinical trials. J Am Coll Cardiol 2005;46:821-826
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Ostergren JB . Angiotensin receptor blockade with candesartan in heart failure: findings from the Candesartan in Heart failure -- Assessment of Reduction in Mortality and morbidity (CHARM) programme. J Hypertens Suppl 2006;24:S3-S7
CrossRef | Medline
To the Editor:
The DREAM trial extends findings from previous studies regarding the effect of inhibiting the renin–angiotensin system on new-onset diabetes, and the accompanying editorial places the implications of the study in perspective. The editorialists postulate that there are many mechanisms that could account for improved glucose metabolism in patients treated with inhibitors of the renin–angiotensin system, and the DREAM authors attempt to explain why, despite these mechanisms, ramipril did not decrease the incidence of new-onset diabetes.1 We believe one element that has been overlooked here and elsewhere is potassium homeostasis.2 It is accepted that thiazide diuretics decrease potassium levels, and a recent analysis of 59 clinical trials using diuretics identified a tight inverse correlation between changes in serum potassium levels and blood glucose levels.3 It thus seems reasonable that a similar, directionally opposite relationship could partially explain the protective effect of inhibitors of the renin–angiotensin system. If this is the case, then it would be valuable for readers to be cognizant of changes in serum potassium in patients treated with ramipril. Such data could help clinicians better understand the DREAM results with regard to the effect of ramipril.
3 ReferencesBenjamin J. Epstein, Pharm.D.
Rhonda M. Cooper-DeHoff, Pharm.D.
University of Florida, Gainesville, FL 32610
epstein@cop.ufl. edu 1
Ingelfinger JR ,Solomon CG . Angiotensin-converting-enzyme inhibitors for impaired glucose tolerance -- is there still hope? N Engl J Med 2006;355:1608-1610
Full Text | Web of Science | Medline2
Kurtz TW ,Pravenec M . Antidiabetic mechanisms of angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists: beyond the renin-angiotensin system. J Hypertens 2004;22:2253-2261
CrossRef | Web of Science | Medline3
Zillich AJ ,Garg J ,Basu S ,Bakris GL ,Carter BL . Thiazide diuretics, potassium, and the development of diabetes: a quantitative review. Hypertension 2006;48:219-224
CrossRef | Web of Science | Medline
Author/Editor Response
Bangalore and Messerli ask whether changes in blood pressure could explain the greater regression to normoglycemia with ramipril than with placebo. After adjustment for the change in blood pressure that occurred during the course of the trial, ramipril significantly increased the likelihood of regression to normoglycemia (adjusted hazard ratio for the ramipril group, 1.12; 95% confidence interval [CI], 1.03 to 1.23; P=0.008), indicating that the effect of ramipril on blood pressure does not explain its effect on regression of dysglycemia.
Potter and LeLorier ask whether the use of ARBs for uncontrolled hypertension could have affected our results. Only 286 of our 5269 patients (5.4%) received ARBs at baseline, with 5.6% receiving them at 2 years and and 7.9% receiving them at the end of the study. Adjustment for this small difference does not affect the primary outcome (adjusted hazard ratio for the ramipril group, 0.90; 95% CI, 0.80 to 1.02). Neither the effect of ramipril on the primary outcome (Figure 1AFigure 1
The Primary Outcome (Panel A) and Regression to Normoglycemia (Panel B) in the Ramipril Group, as Compared with the Placebo Group, According to the Presence or Absence of Rosiglitazone.) nor the effect of ramipril on regression to normoglycemia (Figure 1B) was influenced by the presence or absence of rosiglitazone.Epstein and Cooper-DeHoff ask whether the effect of potassium could have influenced our results. Unfortunately, we did not measure potassium levels after randomization.
Jackie Bosch, M.Sc.
Salim Yusuf, D.Phil., M.D.
Hertzel Gerstein, M.D.
McMaster University, Hamilton, ON L8S 1C7, Canada
dream@cardio.on. ca - Citing Articles (2)
Citing Articles
1
D. P. Macfarlane, K. R. Paterson, M. Fisher. (2008) Cardiovascular drugs as antidiabetic agents: evidence for the prevention of type 2 diabetes. Diabetes, Obesity and Metabolism 10:7, 533-544
CrossRef2
Benjamin Ko, George Bakris. 2008. The Renin–Angiotensin–Aldosterone System and the Kidney. , 167-180.
CrossRef
