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on June 27, 2005

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Submitted on December 10, 2004
Revised on March 10, 2005
Accepted on March 24, 2005

Effects of Candesartan on the Development of a New Diagnosis of Diabetes Mellitus in Patients With Heart Failure

Salim Yusuf DPhil, FRCP^*, Jan B. Ostergren MD, PhD, Hertzel C. Gerstein MD, MSc, Marc A. Pfeffer MD, PhD, Karl Swedberg MD, PhD, Christopher B. Granger MD, Bertil Olofsson PhD, Jeffrey Probstfield MD, John V. McMurray MD, on behalf of the Candesartan in Heart Failure--Assessment of Reduction in Mortality and Morbidity Program (CHARM) Investigators

From the Population Health Research Institute (S.Y., H.C.G.), McMaster University, and Hamilton Health Sciences, Hamilton, Canada; Karolinska University Hospital (J.B.O.), Stockholm, Sweden; Brigham and Women’s Hospital (M.A.P.), Boston, Mass; Sahlgrenska University Hospital/Ostra (K.S.), Goteberg, Sweden; Duke University Medical Center (C.B.G.), Durham, NC; AstraZeneca (B.O.), Molndal, Sweden; University of Washington (J.P.), Seattle; and University of Glasgow (J.V.M.), Glasgow, Scotland.

^* To whom correspondence should be addressed. E-mail: yusufs{at}mcmaster.ca.

Background--Diabetes is a risk factor for heart failure, and both conditions are increasing. Identifying treatments that prevent both conditions will be clinically important. We previously reported that candesartan (an angiotensin receptor blocker) reduces cardiovascular mortality and heart failure hospitalizations in heart failure patients (CHARM: Candesartan in Heart Failure--Assessment of Reduction in Mortality and Morbidity Program).

Methods and Results--We assessed the impact of candesartan versus placebo on the development of diabetes, a predefined secondary outcome in a randomized, controlled, double-blind study involving 5436 of the 7601 patients with heart failure, irrespective of ejection fraction, who did not have a diagnosis of diabetes at entry into the trial. Patients received candesartan (target of 32 mg once daily) or matching placebo for 2 to 4 years. One hundred sixty-three (6.0%) individuals in the candesartan group developed diabetes, as compared with 202 (7.4%) in the placebo group (hazard ratio [HR], 0.78 with a 95% confidence interval [CI] of 0.64 to 0.96; P=0.020). The composite end point of death or diabetes occurred in 692 (25.2%) and 779 (28.6%), respectively, in the candesartan and placebo groups (HR, 0.86; 95% CI, 0.78 to 0.95; P=0.004). The results were not statistically heterogeneous in the various subgroups examined, although the apparent magnitude of benefit appeared to be smaller among those treated concomitantly with angiotensin-converting enzyme inhibitors at trial entry (HR, 0.88; 95% CI, 0.65 to 1.20) compared with those not receiving these drugs (HR, 0.71; 95% CI, 0.53 to 0.93; P for heterogeneity, 0.28).

Conclusions--The angiotensin receptor blocker candesartan appears to prevent diabetes in heart failure patients, suggesting that the renin-angiotensin axis is implicated in glucose regulation.

Key words: renin • diabetes mellitus • prevention • heart failure • glucose

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