New-Onset Diabetes, Antihypertensive Treatment, and Outcome

P. Verdecchia, F. Angeli, G. Reboldi
2007 Hypertension  
N ew-onset diabetes (NOD) confers increased risk for cardiovascular disease and all-cause mortality in different clinical settings. 1,2 In the specific context of hypertensive subjects exposed to the long-term effects of antihypertensive drugs, a study from our group 3 and a recent 28-year follow-up study from Sweden 4 showed a greater risk of major cardiovascular disease in hypertensive subjects who developed NOD than in those who did not. Notably, the yearly incidence of NOD ranged from 1.0%
more » ... D ranged from 1.0% in the Swedish study 4 to 1.9% in our study. 3 This issue of Hypertension hosts a posthoc analysis of the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) database, which tested the hypothesis that NOD is a predictor of cardiac morbidity and cardiac and all-cause mortality. 5 The hypertensive subjects who developed NOD showed a 43% higher risk of cardiac morbidity (ie, a composite of sudden death, myocardial infarction, death associated with revascularization, and congestive heart failure requiring hospitalization) when compared with those who did not develop diabetes. When the determinants of the composite pool of cardiovascular events were examined separately, NOD was associated with a marginally higher risk of myocardial infarction (hazard ratio [HR]: 1.30; 95% CI: 0.99 to 1.70; Pϭ0.057) and a significantly higher risk of congestive heart failure (HR: 1.41; 95% CI: 1.06 to 1.87; Pϭ0.017). These findings are in full agreement with a recent report from the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET), in which NOD was associated with a 74% excess risk of congestive heart failure requiring hospitalization. 6 In the analysis of the VALUE database, all-cause mortality (HR: 0.61; 95% CI: 0.48 to 0.77) and cardiac mortality (HR: 0.44; 95% CI: 0.28 to 0.70) were lower, not higher, in the subjects with NOD than in their nondiabetic counterparts. Despite some obvious caveats, including the relatively small number of fatal events and the shorter follow-up time in the subjects with NOD than in those without NOD, an interesting potential explanation of these results might be the more aggressive treatment reserved by the VALUE trialists to the subjects with NOD. Statins, aspirin, ␤-blockers, and diuretics were given more frequently to subjects who developed NOD than to those who did not, and all of the differences between the 2 groups were statistically significant. 5 This analysis of the VALUE Study confirms that NOD predicts an excess risk of cardiac morbidity and brings in the hypothesis that intensive treatment of cardiovascular risk factors in these subjects might be a rewarding strategy to reduce mortality. Prognostic Value of Drug-Induced Diabetes A recent network meta-analysis of 22 clinical trials showed that angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, calcium channel blockers, and placebo are associated with a significantly lesser risk of NOD as compared with diuretics. 7 The risk of NOD was similar with diuretics and ␤-blockers. 7 This and other reports are feeding a controversy over the prognostic impact of NOD in randomized trials of "old" (ie, diuretics and ␤-blockers) versus "new" (angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and calcium channel blockers) antihypertensive drugs. The essence of the controversy is the apparently innocent nature of NOD, supported by a pretended weakness of the association between the incidence of NOD and the excess risk of hard end points in most trials. The crucial issue is to understand why many trials failed to detect an excess risk of hard events in people treated with diuretics and ␤-blockers if the premise is correct that NOD is an adverse prognostic marker more frequently associated with these drugs. Indeed, different risks of NOD do not necessarily translate into different risks of hard end points in available trials. Based on previous data on the number of subjects needed to treat to prevent 1 new case of diabetes and the estimated incidence of cardiovascular events, we calculated that 1 cardiovascular event specifically associated with NOD may be prevented for every 385 to 449 subjects treated with new, rather than old antihypertensive drugs for Ϸ4 years. 8 It follows that any attempt to draw solid implications on the prognostic value of NOD from randomized studies may be limited by the inadequacy of sample size of available studies, not by the lack of adverse prognostic value by NOD itself. 8
doi:10.1161/hypertensionaha.107.096966 pmid:17679646 fatcat:7rtjqyrtjzewxow6dhwpvhsaby