Long-Term Safety of Antihypertensive Therapy Ehud Grossman and Franz H. Messerli Lowering blood pressure (BP) in hypertensive patients reduces morbidity and mortality. However the long-term safety of some antihypertensive agents was a matter of concern. Diuretic, the gold standard treatment in hypertension may impair glucose tolerance and thereby accelerate the de- velopment of diabetes mellitus. It was also asso- ciated with increased cardiovascular mortality in diabetic patients. However, recent evidence showed that low-medium dose of thiazide diuretic especially when given in combination with potassi- um sparing agent is effective in reducing BP and cardiovascular morbidity and mortality. Beta block- ers are less effective than other antihypertensive agents in the elderly. Therefore they may be appropriate as a first choice in young and middle- age hypertensives, and in those with fast heart rate, but they should not be considered appropriate as the first-line therapy in the elderly with uncompli- cated hypertension. Several years ago a plethora of publications showed that short-acting calcium antagonists may increase the risk for myocardial infarction and cancer. A few years ago two studies showed that calcium antagonists are less effective than angiotensin converting enzyme inhibitors in preventing cardiovascular events in diabetic hyper- tensive patients. However, recent results from large prospective randomized studies showed that calci- um antagonists reduce cardiovascular morbidity and mortality in diabetic and non-diabetic hyper- tensive patients. Some investigators have sug- gested that angiotensin receptor blockers (ARBs) may increase the risk of myocardial infarction in hypertensive patients. However, recent meta analyses refuted this conclusions and showed that ARBs are probably as effective as other antihyper- tensive agents in prevention of myocardial infarc- tion. Despite the concern that has been raised regarding the long-term safety of some antihyper- tensive agents, it is clear that lowering BP is safe and beneficial. n 2006 Elsevier Inc. All rights reserved. H ypertension is one of the major risk factors for cardiovascular morbidity and mortality. It is clear that lowering blood pressure is ben- eficial 1-5 ; however, there are still some doubts regarding the long-term safety of antihyperten- sive therapy. We will discuss some of the doubts and show what is clearly safe and what is still open to debate. Diuretics Numerous prospective studies attested to the safety and efficacy of thiazide diuretics in reducing morbidity and mortality in hypertensive pa- tients. 1,2 However, the safety of diuretics in diabetic hypertensive patients has been questioned. Fifteen years ago, Warram et al 6 showed that in diabetic hypertensive patients, the risk of cardiovascular mortality was 3.8-fold higher in those treated with diuretics than in those who were not treated. In contrast later, prospective studies showed that diuretics reduced cardiovas- cular morbidity and mortality in elderly diabetic hypertensive patients. 7-9 The old belief that di- uretics may paradoxically increase cardiovascu- lar morbidity and mortality can be put to rest in view of the recent evidence of clear benefit. In the past, a high dose of diuretic was used, which may account for lack of benefit, whereas in more recent studies, a low- to medium-dose diuretic with or without potassium-sparing agents was used. It is well accepted that the low to medium dose of diuretic is effective in lowering blood Progress in Cardiovascular Diseases, Vol. 49, No. 1 (July/August), 2006: pp 16-25 16 From the Internal Medicine D and Hypertension Unit, The Chaim Sheba Medical Center, Tel-Hashomer, Affil- iated to the Sackler School of Medicine Tel-Aviv University, Israel, and Division of Cardiology, St. Luke’s- Roosevelt Hospital, NY. Address reprint requests to Ehud Grossman, Internal Medicine D and Hypertension Unit, The Chaim Sheba Medical Center, Tel-Hashomer, 52621 Israel. E-mail: gross-e@zahav.net.il 0033-0620/$ - see front matter n 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.pcad.2006.06.002