Eplerenone and New-Onset Diabetes in Mild Heart Failure
Eplerenone and New-Onset Diabetes in Mild Heart Failure
Aims No studies have examined the effect of mineralocorticoid receptor antagonist therapy on new-onset diabetes. In addition, though the combination of diabetes and chronic heart failure (CHF) carries a poor prognosis, few studies have examined predictors of new-onset diabetes in those with CHF.
Methods and results In patients with symptomatically mild CHF who participated in the placebo-controlled Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure, we examined the effect of the aldosterone antagonist, eplerenone, on physician-diagnosed diabetes using univariate Cox proportional hazard analysis. To identify predictors of new-onset diabetes (measures of glycaemia were not available), data from trial arms were combined and multivariate Cox proportional hazard analyses and receiver operating characteristic curve analyses were conducted. At baseline, the mean age of 1846 initially non-diabetic patients was 69 years and mean left ventricular ejection fraction was 26%. Over 21 months, 69 (3.7%) developed diabetes (33 on eplerenone, 36 on placebo). Eplerenone had no effect on new-onset diabetes [hazard ratio (HR) 0.94, 95% confidence interval (CI) 0.59–1.52] and no effect on the composite of new-onset diabetes or mortality (HR 0.80, 95% CI 0.64–1.01). Independent predictors of new-onset diabetes included digoxin therapy, higher serum alanine aminotransferase, longer duration of heart failure, current or previous smoker, higher waist circumference, lower age, and higher systolic blood pressure with a combined c-statistic of 0.74.
Conclusions Eplerenone had no effect on new-onset diabetes in patients with CHF, but further large-scale studies are required to address this question comprehensively. Commonly recorded parameters provided useful information for predicting new-onset diabetes.
Patients with heart failure are at increased risk of developing new-onset diabetes mellitus, and co-existent diabetes is associated with worse heart failure symptoms, higher rates of hospitalization, and reduced survival. Why the risk of incident diabetes is increased in heart failure is uncertain, and relatively little is known about the variables predicting this risk. To date, only the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) and Carvedilol Or Metoprolol European Trial (COMET) trials have examined this question. It is known, however, that angiotensin II receptor blockers (ARBs), and possibly angiotensin-converting enzyme (ACE) inhibitors, reduce the risk of developing diabetes in patients with heart failure (and also in those with hypertension and impaired glucose tolerance). It is therefore of interest to know whether the other type of renin–angiotensin–aldosterone blockers used in heart failure, mineralocorticoid receptor (MR) antagonists, affect the risk of incident diabetes. Data on the effect of MR antagonists on glycaemic indices are conflicting. Treatment with the non-selective MR antagonist, spironolactone, has consistently been associated with elevations in haemoglobin A1c (HbA1c) in patients with and without diabetes, suggesting that spironolactone may increase the risk of new-onset diabetes. In contrast, spironolactone has been shown to improve insulin sensitivity in patients with non-alcoholic fatty liver disease (NAFLD), a condition closely associated with insulin resistance. Even less is known about the actions of the more selective MR antagonist eplerenone. However, in one trial comparing the effects of spironolactone and eplerenone in patients with chronic heart failure, spironolactone recipients showed increases in both HbA1c and cortisol levels, plus a fall in adiponectin, whereas no changes occurred in eplerenone recipients.
New-onset diabetes was a pre-defined secondary endpoint in the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF). In this report we describe the effect of eplerenone, compared with placebo, on new-onset diabetes and the baseline predictors of incident diabetes.
Abstract and Introduction
Abstract
Aims No studies have examined the effect of mineralocorticoid receptor antagonist therapy on new-onset diabetes. In addition, though the combination of diabetes and chronic heart failure (CHF) carries a poor prognosis, few studies have examined predictors of new-onset diabetes in those with CHF.
Methods and results In patients with symptomatically mild CHF who participated in the placebo-controlled Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure, we examined the effect of the aldosterone antagonist, eplerenone, on physician-diagnosed diabetes using univariate Cox proportional hazard analysis. To identify predictors of new-onset diabetes (measures of glycaemia were not available), data from trial arms were combined and multivariate Cox proportional hazard analyses and receiver operating characteristic curve analyses were conducted. At baseline, the mean age of 1846 initially non-diabetic patients was 69 years and mean left ventricular ejection fraction was 26%. Over 21 months, 69 (3.7%) developed diabetes (33 on eplerenone, 36 on placebo). Eplerenone had no effect on new-onset diabetes [hazard ratio (HR) 0.94, 95% confidence interval (CI) 0.59–1.52] and no effect on the composite of new-onset diabetes or mortality (HR 0.80, 95% CI 0.64–1.01). Independent predictors of new-onset diabetes included digoxin therapy, higher serum alanine aminotransferase, longer duration of heart failure, current or previous smoker, higher waist circumference, lower age, and higher systolic blood pressure with a combined c-statistic of 0.74.
Conclusions Eplerenone had no effect on new-onset diabetes in patients with CHF, but further large-scale studies are required to address this question comprehensively. Commonly recorded parameters provided useful information for predicting new-onset diabetes.
Introduction
Patients with heart failure are at increased risk of developing new-onset diabetes mellitus, and co-existent diabetes is associated with worse heart failure symptoms, higher rates of hospitalization, and reduced survival. Why the risk of incident diabetes is increased in heart failure is uncertain, and relatively little is known about the variables predicting this risk. To date, only the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) and Carvedilol Or Metoprolol European Trial (COMET) trials have examined this question. It is known, however, that angiotensin II receptor blockers (ARBs), and possibly angiotensin-converting enzyme (ACE) inhibitors, reduce the risk of developing diabetes in patients with heart failure (and also in those with hypertension and impaired glucose tolerance). It is therefore of interest to know whether the other type of renin–angiotensin–aldosterone blockers used in heart failure, mineralocorticoid receptor (MR) antagonists, affect the risk of incident diabetes. Data on the effect of MR antagonists on glycaemic indices are conflicting. Treatment with the non-selective MR antagonist, spironolactone, has consistently been associated with elevations in haemoglobin A1c (HbA1c) in patients with and without diabetes, suggesting that spironolactone may increase the risk of new-onset diabetes. In contrast, spironolactone has been shown to improve insulin sensitivity in patients with non-alcoholic fatty liver disease (NAFLD), a condition closely associated with insulin resistance. Even less is known about the actions of the more selective MR antagonist eplerenone. However, in one trial comparing the effects of spironolactone and eplerenone in patients with chronic heart failure, spironolactone recipients showed increases in both HbA1c and cortisol levels, plus a fall in adiponectin, whereas no changes occurred in eplerenone recipients.
New-onset diabetes was a pre-defined secondary endpoint in the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF). In this report we describe the effect of eplerenone, compared with placebo, on new-onset diabetes and the baseline predictors of incident diabetes.
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