MD Conference Express ADA 2011 - (Page 26)

n S E L E C T E D U P D A T E S I N D Y S G LY C E M I A Figure 1. Risk of Hyperglycemia with the Use of Antihypertensives. Thiazide Central antiadrenergic agents Peripheral antiadrenergic agents ACE inhibitors ß-Blockers Calcium channel blockers Vasodilators >1 Agent without thiazide >1 Agent with thiazide 0.5 Decreased Risk 1 1.5 2 Increased Risk 2.5 3 1.40 [1.26-1.58] other cardiovascular risk factors, particularly in patients who are at risk for the development of diabetes. Dr. Ernst emphasized, “Diuretics remain valuable agents for blood pressure control and preventing cardiovascular disease-related events. Fear of their dysglycemic effects should not be reason to avoid them.” Statins Early data on the association of statins with new-onset diabetes is conflicted. In a study that compared pravastatin with placebo for primary prevention (WOSCOPS), the statin was associated with a 30% decrease in the incidence of new-onset diabetes (p=0.042), but the number of people developing diabetes were small [Freeman DJ et al. Circulation 2001]. Three of four subsequent major statin trials (ASCOT-LLA, CORONA, HPS) that included data on new-onset diabetes suggested a possible increased risk (about 14% to 15%), while the fourth showed no difference (LIPID). The “game changer” was the JUPITER trial, said David Preiss, FRCPath, MRCP, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Scotland, United Kingdom. New-onset diabetes was a specified secondary endpoint in this large trial (n=17,802) of rosuvastatin versus placebo for primary prevention, and the statin was associated with a 25% increase in diabetes (270 cases vs 216 cases in the control group; p=0.01) [Ridker PM et al. N Engl J Med 2008]. The data from these studies led Dr. Preiss and colleagues to conduct a collaborative meta-analysis on 13 randomized placebo- and standard care-controlled trials, in which they combined published and unpublished data. The results demonstrated a 9% increased relative risk of diabetes that was associated with statins, with a modest absolute risk of only 1 extra case of diabetes per 1000 patient-years [Sattar N et al. Lancet 2010]. The important point, said Dr. Preiss, was the clear benefit of the statins in reducing cardiovascular disease-related events (Table 2). Table 2. Risk-Benefit Considerations with Statins. Diabetes Relative Risk or Benefit Absolute Risk or Benefit (per 1020 patient-years) 9% increase 1 excess case CHD and CVD Benefit* • 23% decrease in CHD cases • 21% decrease in CVD cases • 5.4 fewer CHD cases • 9 fewer CVD cases Adjusted ORs and 95%CI Reproduced with permission from the American College of Physicians, from Antihypertensive Drug Therapy and the Initiation of Treatment for Diabetes Mellitus, Gurwitz JH et al Annals Internal Medicine; vol. 118, no. 4, 273-278, 1993; permission conveyed through Copyright Clearance Center, Inc. In some subsequent hypertension trials, there was a 20% to 50% increase in new-onset diabetes that was associated with thiazide, although the development of diabetes was not a defined endpoint. One exception was the Atherosclerosis Risk in Communities (ARIC) study, in which thiazide was not associated with an increased risk of diabetes (HR=0.95), but β-blockers were (HR=1.26) [Gress TW et al. N Engl J Med 2000]. Since diuretics were often used with β-blockers in the earlier studies, exactly how much of the risk of diabetes to attribute specifically to thiazides is uncertain. Many questions remain about how the various antihypertensive agents work, and a better understanding of the side effects of these agents could help clarify their association with hyperglycemia. Small, short-term studies have shown that thiazide appears to worsen glycemic control in a dosedependent manner by reducing insulin secretion and peripheral insulin sensitivity. In addition, long-term observational studies in patients who are treated with antihypertensives have shown an inverse relationship between potassium and glucose levels. Taken together, the data suggest that thiazide impairs the potassiummediated release of insulin. However, potassium probably does not account for all of the risk, and there has not been adequate study to determine if managing potassium levels will prevent dysglycemia. No increased harm has been found with diabetes that develops during treatment of hypertension with thiazide. In addition, the time to the development of diabetes has been shorter among subjects with uncontrolled hypertension than those with controlled hypertension [Izzo R et al. Diabetes Care 2009]. These findings indicate that clinicians should control blood pressure in their patients with hypertension while aggressively controlling *Per mmol/L reduction in low-density lipoprotein; CVD=cardiovascular disease; CHD=coronary heart disease. From Baigent C et al. Lancet 2005. Trial data suggested the possibility that intensive statin regimens may be associated with a somewhat greater risk. For example, in the JUPITER trial, the risk of incident 26 August 2011 www.mdconferencexpress.com  http://www.mdconferencexpress.com http://www.mdconferencexpress.com

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