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Home , ACE inhibitor, Vasodilation

EDITORIAL

Cardiovascular and Metabolic Benefits of ACE Inhibition Moving beyond pressure reduction

CE inhibitors are a class of that This possibility was explored in the low-up of 13,300 person-years. ACE inhibit the activity of ACE, an enzyme Outcome Prevention Evaluation (HOPE) inhibitors were compared with Alocated on endothelial cells (1–4). In Study, in which 3,577 individuals with dia- channel blockers, -blockers, or addition to being bound to endothelial cells, betes received either placebo or in these studies. Comparable blood pres- ACE also circulates freely in an unbound (up to 10 mg daily) and were followed for sure reduction was achieved in both arms. form. This enzyme has 2 key metabolic 4.5 years (15). Ramipril reduced the risk of All of the studies, except for the hyperten- effects: 1) it catalyzes the conversion of the composite outcome of myocardial sion component of the U.K. Prospective I to angiotensin II, in both cir- infarction, stroke, or cardiovascular death Study (UKPDS), had consistent culation and ; and 2) it catalyzes the by 25% and that of overt nephropathy by findings and, when meta-analyzed, demon- breakdown of into inactive 24%. This benefit occurred with a very strated an overall relative-risk reduction of products (5). Inhibition of the activity of modest decrease in and was 51% (95% CI 33–64) for cardiovascular this enzyme, therefore, may decrease tissue shown to be independent of the change in events and 43% (13–62) for all-cause mor- and circulating levels of angiotensin II and blood pressure. Only 56% of the individu- tality. The UKPDS was not combined may increase levels of bradykinin. Lower als with diabetes in the study had a diagno- because it was statistically heterogeneous in levels of angiotensin II result in decreased sis of at randomization. Of comparison with the other 3 studies. , decreased stimulation of these patients, 28% were taking -blockers, Although the authors provide several vascular growth, decreased 20% were taking diuretics and 44% were explanations for this heterogeneity, the rea- sympathetic stimulation, decreased levels taking calcium channel blockers at ran- son remains unclear and is likely to not be of plasminogen activator inhibitor, and domization in addition to either an ACE resolved until further trials are published. decreased aggregation (5). Lower inhibitor or placebo. Thus, the HOPE What conclusions can be drawn, levels of circulating angiotensin II also result Study suggests that ACE inhibitors may therefore, from this systematic overview in less adrenal production of have a cardioprotective effect over and and the related trials of ACE inhibitor and increased urinary potassium loss; this above any antihypertensive effect. The ? First, ACE inhibitors are effec- effect may help maintain optimal -cell study also suggested favorable metabolic tive antihypertensive agents. Second, they function (6). Increased bradykinin levels effects. Levels of glycated were have favorable, or at worst, neutral meta- lead to direct as well as indirect lower in participants on ramipril than in bolic effects. Third, clinical trials have uni- vasodilation through bradykinin-mediated participants on placebo during the first formly shown that they are safe in the and production. In 2 years of the study. It is important to note post– period and, addition, increased production of nitric that the HOPE Study did not compare subsequently, with a very low risk of sig- oxide helps facilitate insulin-mediated glu- ramipril with another active agent and that nificant side effects. Fourth, there is a cose uptake, thereby improving insulin sen- the study was clearly not designed as a trial growing body of evidence to suggest that sitivity (7–10). In addition to all of the to control blood pressure or to be relevant they have cardioprotective benefits over above vascular and metabolic effects, inhi- to people with hypertension only. and above those related to blood pressure bition of ACE also reduces blood pressure. Other large studies have carefully com- lowering. These data support the recom- These mechanisms are active in all indi- pared the benefits of an ACE inhibitor with mended use of ACE inhibitors as first-line viduals taking an ACE inhibitor and are all those of other antihypertensive drugs in agents in people with diabetes who are at possible explanations for the observed ben- people with diabetes and hypertension. a particularly high risk for cardiovascular eficial effect of ACE inhibitors in people at These studies were carefully sought and outcomes, including those individuals risk for cardiovascular . Individuals analyzed in a systematic overview by Pahor who previously experienced myocardial with diabetes are at a particularly high risk et al. (16) in this issue of Diabetes Care. All infarction, , and for ; for example, the randomized controlled trials that included (17). Furthermore, they suggest that ACE presence of diabetes increases the risk of hypertensive patients with inhibitors should be used as first-line anti- cardiovascular mortality multifold in both and compared an ACE inhibitor with hypertensive agents in all people with dia- men and women(11–14). Therefore, if ACE another active therapy for the treatment of betes. The UKPDS results suggest that inhibitors do have particular cardioprotec- hypertension were included in the further research to clarify the relative ben- tive effects, they may be more easily overview if they reported a follow-up dura- efit of selective -blockers versus ACE detectable in this group of high-risk patients tion of 2 years and assessed the develop- inhibitors is clearly needed. However, in than in the general population. Moreover, ment of cardiovascular events. Four clinical light of the fact that 60% of individuals the benefits of any of the metabolic effects trials were identified that studied a com- with diabetes with hypertension require at may be more relevant to this population. bined total of 2,180 individuals for a fol- least 2 agents (18), either a selective -blocker

882 DIABETES CARE, VOLUME 23, NUMBER 7, JULY 2000 Editorial or a low-dose is an appropriate terone system: influence of ACE inhibition. Edelstein SL: Why is diabetes mellitus a additional agent. J Cardiovasc Pharmacol 24 (Suppl. 3):S61– stronger risk factor for fatal ischemic heart S69, 1994 disease in women than in men? The Ran- HERTZEL C. GERSTEIN, MD, MSC, FRCPC 7. Henriksen EJ, Jacob S, Kinnick TR, Young- cho Bernardo Study. JAMA 265:627–631, blood EB, Schmit MB, Dietze GJ: ACE 1991 From the Division of Endocrinology and Metabo- inhibition and transport in insulin- 14. Goldbourt U, Yaari S, Medalie JH: Factors lism, McMaster University and the Hamilton Health resistant muscle: roles of bradykinin and predictive of long-term coronary heart dis- Sciences Corporation, Hamilton, Ontario, Canada. nitric oxide. Am J Physiol 277:R332–R336, ease mortality among 10,059 male Israeli Address correspondence to Hertzel C. Gerstein, 1999 civil servants and municipal employees: a MD, MSc, FRCPC, Department of Medicine, Rm. 8. Henriksen EJ, Jacob S: Effects of 23-year mortality follow-up in the Israeli 3V38, 1200 Main St. West, Hamilton, ON, L8N 3Z5 on glucose transport activity in skeletal Ischemic Heart Disease Study. Cardiology Canada. E-mail: [email protected]. muscle of obese Zucker rats. 44: 82:100–121, 1993 H.C.G. has received consulting fees, honoraria, 267–272, 1995 15. Heart Outcome Prevention Evaluation and research support from Aventis and King Phar- maceuticals. 9. Galletti F, Strazzullo P, Capaldo B, Carretta (HOPE) Study Investigators: Effects of R, Fabris F, Ferrara LA, Glorioso N, Sem- ramipril on cardiovascular and microvas- plicini A, Mancini M: Controlled study of cular outcomes in people with diabetes References the effect of angiotensin converting enzyme mellitus: results of the HOPE study and the 1. Vanhoutte PM: inhibition versus calcium-entry blockade MICRO HOPE substudy. Lancet 255:253– and inhibition of converting enzyme. Eur on insulin sensitivity in overweight hyper- 259, 2000 Heart J 19 (Suppl. J):J7–J15, 1998 tensive patients: Italian Study 16. Pahor M, Psaty BM, Alderman MH, Apple- 2. Campbell DJ: Circulating and tissue (TRIS). J Hypertens 17:439–445, 1999 gate WB, Williamson JD, Furberg CD: angiotensin systems. J Clin Invest 79:1–6, 10. Vuorinen-Markkola H, Yki-Jarvinen H: Therapeutic benefits of ACE inhibitors and 1987 Antihypertensive therapy with other antihypertensive drugs in patients with 3. Dostal DE, Baker KM: The cardiac - improves glucose storage and insulin sen- type 2 diabetes. Diabetes Care 23:888–892, angiotensin system: conceptual, or a regu- sitivity in hypertensive patients with non- 2000 lator of cardiac function? Circ Res 85:643– insulin-dependent diabetes mellitus. 17. The National Committee on Preven- 650, 1999 Metabolism 44:85–89, 1995 tion, Detection, Evaluation, and Treatment 4. Dzau VJ: Mechanism of protective effects of 11. Stamler J, Vaccaro O, Neaton JD, Went- of High Blood Pressure: The sixth report of ACE inhibition on coronary disease. worth D: Diabetes, other risk factors, and the Joint National Committee on Preven- Eur Heart J 19 (Suppl. J):J2–J6, 1998 12-year cardiovascular mortality for men tion, Detection, Evaluation, and Treatment 5. Lonn EM, Yusuf S, Jha P, Montague TJ, Teo screened in the Multiple Risk Factor Inter- of High Blood Pressure. Arch Intern Med KK, Benedict CR, Pitt B: Emerging role of vention Trial. Diabetes Care 16:434–444, 157:2413–2446, 1997 angiotensin-converting enzyme inhibitors 1993 18. U.K. Prospective Diabetes Study (UKPDS) in cardiac and vascular protection. Circula- 12. Kannel WB, McGee DL: Diabetes and car- Group: Tight blood pressure control and tion 90:2056–2069, 1994 diovascular disease: the Framingham study. risk of macrovascular and microvascular 6. Ferrannini E, Seghieri G, Muscelli E: JAMA 241:2035–2038, 1979 complications in type 2 diabetes: UKPDS Insulin and the renin-angiotensin-aldos- 13. Barrett-Connor E, Cohn BA, Wingard DL, 38. Br Med J 317:703–713, 1998

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