Diabetes Care 23:888 892, 2000

Clinical Care/Education/Nutrition O R I G I N A L A R T I C L E Therapeutic Benefits of ACE Inhibitors and Other Antihypertensive Drugs in Patients With Type 2 Diabetes MARCO PAHOR, MD BRUCE M. PSATY, MD, PHD MICHAEL H. ALDERMAN, MD WILLIAM B. APPLEGATE, MD, MPH JEFF D. WILLIAMSON, MD, MHS CURT D. FURBERG, MD, PHD OBJECTIVE To assess whether ACE inhibitors are superior to alternative agents for the prevention of cardiovascular events in patients with hypertension and type 2 diabetes. RESEARCH DESIGN AND METHODS This study is a review and meta-analysis of randomized controlled trials that included patients with type 2 diabetes and hypertension who were randomized to an ACE inhibitor or an alternative drug, were followed for 2 years, and had adjudicated cardiovascular events. RESULTS A total of 4 trials were eligible. The Appropriate Blood Pressure Control in Diabetes (ABCD) trial (n = 470) compared enalapril with nisoldipine, the Captopril Prevention Project (CAPPP) (n = 572) compared captopril with diuretics or -blockers, the Fosinopril Versus Amlodipine Cardiovascular Events Trial (FACET) (n = 380) compared fosinopril with amlodipine, and the U.K. Prospective Diabetes Study (UKPDS) (n = 758) compared captopril with atenolol. The cumulative results of the first 3 trials showed a significant benefit of ACE inhibitors compared with alternative treatments on the outcomes of acute myocardial infarction (63% reduction, P 0.001), cardiovascular events (51% reduction, P 0.001), and allcause mortality (62% reduction, P = 0.010). These findings were not observed in the UKPDS. The ACE inhibitors did not appear to be superior to other agents for the outcome of stroke in any of the trials. None of the findings were explained by differences in blood pressure control. CONCLUSIONS Compared with the alternative agents tested, ACE inhibitors may provide a special advantage in addition to blood pressure control. The question of whether atenolol is equivalent to captopril remains open. Conclusive evidence on the comparative effects of antihypertensive treatments will come from large prospective randomized trials. Diabetes Care 23:888 892, 2000 The primary goal of antihypertensive treatment is to prevent clinical complications and not simply to lower elevated blood pressure. Evidence from the Systolic Hypertension in the Elderly Program and the Systolic Hypertension in Europe Trial showed that, compared with placebo, treatment of hypertension in patients with type 2 diabetes prevents major clinical complications (1,2). Data from the From the Sticht Center on Aging (M.P., W.B.A., J.D.W.), Department of Internal Medicine, and the Department of Public Health Sciences (C.D.F.), Wake Forest University, Winston-Salem, North Carolina; the Cardiovascular Health Research Unit (B.M.P.), Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, Washington; and the Department of Epidemiology and Social Medicine (M.H.A.), Albert Einstein College of Medicine, Bronx, New York. Address correspondence and reprint requests to Marco Pahor, MD, Sticht Center on Aging, Department of Internal Medicine, Wake Forest University Baptist Medical Center, Medical Center Boulevard, Winston- Salem, NC 27157. E-mail: mpahor@wfubmc.edu. Received for publication 21 October 1999 and accepted in revised form 1 February 2000. Abbreviations: ABCD, Appropriate Blood Pressure Control in Diabetes; CAPPP, Captopril Prevention Project; FACET, Fosinopril Versus Amlodipine Cardiovascular Events Trial; HOPE, Heart Outcomes Prevention Evaluation; RR, relative risk; UKPDS, U.K. Prospective Diabetes Study. A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances. Hypertension Optimal Treatment trial and the U.K. Prospective Diabetes Study (UKPDS) suggest that, in patients with diabetes, greater blood pressure reduction results in greater clinical benefits (3,4). Although these studies document that treatment of high blood pressure is beneficial in hypertensive patients with type 2 diabetes, none of these trials provides information on the relative therapeutic benefit of individual antihypertensive agents. Recent comparative trials and observational studies in diabetes have suggested that, for the prevention of cardiovascular events, ACE inhibitors may be superior to alternative antihypertensive agents (5,6). That the greater benefit of ACE inhibitors was not explained by better blood pressure control indicates that other mechanisms linked to ACE inhibition may have played an additional role in the prevention of major clinical events. The purpose of the present review and meta-analysis is to summarize the current evidence from randomized clinical trials with clinical outcomes that directly compared ACE inhibitors to alternative antihypertensive agents in patients with hypertension and type 2 diabetes. RESEARCH DESIGN AND METHODS To be included in the meta-analysis, a study had to be a randomized controlled trial published in a peerreviewed journal that included patients with type 2 diabetes and hypertension, evaluated an ACE inhibitor versus an active treatment, followed the participants for 2 years to allow the occurrence of a sufficient number of clinical events, and used predefined criteria to adjudicate the cardiovascular events. Studies were identified through PubMed searches using the following key words: ACE inhibitors, diabetes, hypertension, and clinical trial. The searches were extended through January 2000. Letters to the editor, commentaries, review articles, editorials, and observational studies were not included. Bibliographies of the retrieved articles were searched to identify other eligible studies, and information from colleagues was used to identify more recently published articles. 888 DIABETES CARE, VOLUME 23, NUMBER 7, JULY 2000

Pahor and Associates Table 1 Baseline characteristics according to treatment Age Men BMI Macroalbuminuria Duration of Systolic blood Diastolic blood Trial Agent n (years) (%) (kg/m 2 ) (%) diabetes (years) pressure (mmhg) pressure (mmhg) ABCD (7) Enalapril 235 57.7 ± 8.4 67 31.9 ± 5.9 19 8.5 ± 6.8 156 ± 17 98 ± 7 Nisoldipine 235 57.2 ± 8.2 68 31.3 ± 5.9 18 8.7 ± 6.6 155 ± 19 98 ± 7 CAPPP (8) Captopril 309 55.0 ± 7.6 63 30.9 164 ± 19 97 ± 10 Diuretic/ -blockers 263 55.7 ± 7.4 60 30.3 163 ± 21 97 ± 10 FACET (9) Fosinopril 189 62.8 ± 7.0 64 30.7 ± 4.6 0 10.7 ± 9.1 170 ± 16 95 ± 10 Amlodipine 191 63.3 ± 6.1 56 30.5 ± 5.4 0 10.5 ± 8.6 171 ± 18 94 ± 8 UKPDS (10) Captopril 400 56.3 ± 8.1 51 29.8 ± 5.6 2 2.6 159 ± 20 94 ± 10 Atenolol 358 56.0 ± 8.2 57 29.7 ± 5.3 3 2.7 159 ± 19 93 ± 10 Data are means ± SEM, unless otherwise indicated. The following elements were abstracted: design, sample size, randomized treatments, follow-up time, average age, sex distribution, average BMI, proportion of participants with macroalbuminuria, duration of diabetes, baseline systolic and diastolic arterial pressures, and the number of events (including acute myocardial infarction, stroke, combined cardiovascular events, and all-cause mortality) occurring in each treatment group. The initial search identified 195 articles. Of those, 4 trials met all of the inclusion criteria. Those trials were the Appropriate Blood Pressure Control in Diabetes (ABCD) trial (7), the diabetic group of the Captopril Prevention Project (CAPPP) (8), the Fosinopril Versus Amlodipine Cardiovascular Events Trial (FACET) (9), and the UKPDS (Table 1) (10). The recently published Swedish Trial in Old Patients with Hypertension-2 compared the use of -blockers or diuretics with the use of ACE inhibitors or Ca antagonists and was not included because outcome data in the subgroup of patients with diabetes in that study were not published and were not available from the authors (B. Dalhof, personal communication) (11). For the combined outcome of cardiovascular events, we adopted the definition used in each trial. In the ABCD trial, the cardiovascular events included cardiovascular death, fatal and nonfatal acute myocardial infarction, congestive heart failure requiring hospitalization, fatal or nonfatal stroke, and pulmonary infarction. Because the number of events in patients with diabetes was not reported in the CAPPP, we estimated these numbers by using the sample size, the relative risk (RR) (95% CI), and the P value of the difference between the 2 treatment groups. In the CAPPP, the cardiovascular events included cardiovascular deaths, fatal and nonfatal acute myocardial infarction, and fatal or nonfatal stroke. In the FACET, the cardiovascular events included fatal and nonfatal acute myocardial infarction, fatal and nonfatal stroke, and angina requiring hospitalization. In the UKPDS, the combined end point of cardiovascular events was not reported. We calculated the total number of cardiovascular events by adding the number of fatal and nonfatal acute myocardial infarctions and strokes, the number of congestive heart failure events, and the number of sudden deaths. Because more than 1 event may have occurred in a single patient, this method is likely to have slightly overestimated the number of patients with cardiovascular events in the UKPDS. The overall relative risk (85% CI) of each outcome was calculated with Peto s method (12). Cochran s test for heterogeneity was used to assess the extent to which the differences among the trial results were because of random fluctuations (13). RESULTS In the 4 eligible trials (the ABCD trial, the CAPPP, the FACET, and the UKPDS), the total number of participants was 2,180 (1,133 randomized to an ACE inhibitor and 1,047 randomized to an alternative active agent) with a total follow-up experience of 13,300 personyears. The participants characteristics according to treatment are shown in Table 1. In the ABCD trial, the medication daily dose was 10 60 mg for nisoldipine and 5 40 mg for enalapril. In the CAPPP, 50 mg captopril was given once or twice a day, and 50 100 mg atenolol or metoprolol, 25 mg hydrochlorothiazide, or 2.5 mg bendrofluazide was given once a day. In the FACET, 20 mg fosinopril or 10 mg amlodipine was given once a day. In the UKPDS, the dose of captopril was 25 50 mg twice a day, and the dose of atenolol was 50 100 mg once a day. In the ABCD trial, the FACET, and the UKPDS, systolic (Fig. 1) and diastolic blood pressure decreased significantly with both treatments. In the ABCD trial and the UKPDS, no significant differences were evident in blood pressure control among the randomized treatment groups. In the FACET, the patients randomized to amlodipine achieved a significantly lower systolic blood pressure level than patients randomized to fosinopril. Data on blood pressure control in the diabetic patients of the CAPPP have not been reported. The number of events by treatment group in each trial is shown in Table 2, and the relative risks (95% CIs) of outcomes for ACE inhibitors versus other agents are depicted in Fig. 2. In the ACE inhibitor group, the risk of acute myocardial infarction was significantly decreased in the ABCD trial and the CAPPP, was nonsignificantly lower in the FACET, and was nonsignificantly higher in the UKPDS compared with the alternative treatment. For the outcome of stroke, no significant differences were evident among treatments in any of the trials. In the ACE inhibitor group, the risk of combined cardiovascular events was significantly decreased in the ABCD trial, the CAPPP, and the FACET, and was nonsignificantly increased in the UKPDS compared with the alternative treatment; the risk of all-cause mortality was significantly decreased in the CAPPP, was nonsignificantly lower in the ABCD trial and the FACET, and was nonsignificantly higher in the UKPDS. In initial analyses, the data of the 4 trials were combined. For ACE inhibitors versus other treatments, the RRs (95% CIs) of acute myocardial infarction, stroke, cardiovascular events, and all-cause mortality DIABETES CARE, VOLUME 23, NUMBER 7, JULY 2000 889

Therapeutic benefits of ACE inhibitors Figure 1 Systolic blood pressure changes during follow-up according to treatment in the ABCD trial, the FACET, and the UKPDS. The data of the CAPPP have not been reported. were 0.73 (0.54 0.99), 0.86 (0.59 1.26), 0.77 (0.61 0.91), and 0.85 (0.64 1.12), respectively. To identify potential outliers, we tested the heterogeneity of the results of the trials for individual outcomes of interest through iterative analyses. The test for heterogeneity was significant for the outcomes of acute myocardial infarction and cardiovascular events when the data of the UKPDS were combined with the other 3 trials (P 0.001 for both outcomes) but not when the UKPDS was excluded from the meta-analysis. Thus, only the data for the ABCD trial, the CAPPP, and the FACET were used in the formal meta-analytic calculations. When the data of the ABCD trial, the CAPPP, and the FACET were combined, the patients randomized to an ACE inhibitor had a significantly lower risk of acute myocardial infarction, cardiovascular events, and all-cause mortality than those randomized to an alternative treatment (P 0.001, P 0.001, and P = 0.010, respectively) (Fig. 2). Moreover, no heterogeneity was found with the reduced dataset. No such differences were evident for the outcome of stroke. CONCLUSIONS This review identified 4 trials in which patients with type 2 diabetes and hypertension were randomized to either an ACE inhibitor or to an alternative antihypertensive treatment and were followed for 2 years. The results of these trials have been previously reviewed (5), but to our knowledge, this is the first quantitative meta-analysis of their outcome data. The cumulative results of 3 trials (the ABCD trial, the CAPPP, and the FACET) showed a significant benefit of ACE inhibitors compared with alternative treatments on the outcomes of acute myocardial infarction (63% reduction, P 0.001), cardiovascular events (51% reduction, P 0.001), and all-cause mortality (62% reduction, P = 0.010). These findings were not observed in the UKPDS, which compared captopril with atenolol. The ACE inhibitors did not appear to be superior to other agents for the outcome of stroke in any of the trials. Why do the results of the UKPDS differ from those of the other trials? One possible explanation may be because of differences in population characteristics. In the UKPDS, diabetes was newly diagnosed compared with the other studies (Table 1). The duration of follow-up in the UKPDS is another difference from the other trials. Another explanation is the selective dropout from the trial. Patients randomized to atenolol were more likely to drop out of the randomized treatment (10), and they possibly received an ACE inhibitor if they had a compelling indication such as albuminuria or left ventricular dysfunction. The net effect of such a selective dropout would be to diminish any differences between atenolol and captopril. The potential frequent crossover between groups renders many aspects of the UKPDS difficult to interpret (14). Another plausible hypothesis is that the selective -blocker atenolol is equivalent to captopril. Recent reports indicate in both normotensive and hypertensive individuals that the suppression of angiotensin II levels achieved with -blockade is similar to that obtained with an ACE inhibitor (15). To confirm the hypothesis of equivalence of captopril and atenolol, one must assess the relative risk of events in the CAPPP by using diuretics and individual -blockers. The divergent effects found in the UKPDS compared with the other 3 trials indicate that the overall evidence of the comparative effects of ACE inhibitors is not yet conclusive. If ACE inhibitors are truly more beneficial than other agents for the treatment of hypertension in patients with diabetes, then what are the potential mechanisms? Blood pressure control did not differ significantly between treatments in the ABCD trial. In the FACET, the amlodipine group achieved a significantly lower systolic blood pressure level than the ACE inhibitor group. Total cholesterol levels were similar in both treatment groups in the ABCD trial and the FACET. Microal- Table 2 Number of clinical events according to treatment Mean follow-up ACE inhibitors Other therapies Trial (years) Agent n AMI Stroke CV Death Agent n AMI Stroke CV Death ABCD (7) 5 Enalapril 235 5 7 20 13 Nisoldipine 235 25 11 43 17 CAPPP (8) 6.1 Captopril 309 10 24 30 17 Diuretic/ -blocker 263 25 20 43 27 FACET (9) 2.8 Fosinopril 189 10 4 14 4 Amlodipine 191 13 10 27 5 UKPDS (10) 8.4 Captopril 400 61 21 102 75 Atenolol 358 46 17 75 59 Data are n. AMI, acute myocardial infarction; CV, cardiovascular events. 890 DIABETES CARE, VOLUME 23, NUMBER 7, JULY 2000

Pahor and Associates Acknowledgments The results of this study were presented at the 59th Annual Meeting of the American Diabetes Association, San Diego, CA, 19 June 1999. Figure 2 RR (95% CI) of outcomes for ACE inhibitors compared with other agents in the ABCD trial, the CAPPP, the FACET, the UKPDS, and in combined analyses. buminuria and serum creatinine levels during follow-up were similar in both treatment groups in the FACET. Metabolic control is another important factor that may affect cardiovascular outcomes. In the ABCD trial, the participants had poor metabolic control at baseline and during the 5 years of follow-up, but metabolic control was not significantly different between the ACE inhibitor and the Ca antagonist treated group. In the FACET, the patients randomized to the ACE inhibitor or the Ca antagonist achieved similar HbA 1c and fasting glucose levels during follow-up. Changes in blood pressure, metabolic control, or other risk factors during follow-up were not reported for diabetic patients enrolled in the CAPPP. Thus, from the published data, differences in blood pressure control, metabolic control, or other measured risk factors likely explain the substantial difference in major cardiovascular events. Several other mechanisms not measured in the reviewed trials may account for a greater therapeutic benefit of ACE inhibitors. ACE inhibitors may reduce cardiovascular risk by improving endothelial dysfunction (16), by reducing inflammation (17), and by promoting fibrinolysis through inhibition of plasminogen activator inhibitor 1 (18,19). The recently published Heart Outcomes Prevention Evaluation (HOPE) trial showed that the reduction in cardiovascular events with an ACE inhibitor was much greater than that expected from blood pressure reduction alone compared with placebo, which supports the view that additional mechanisms contribute to the prevention of cardiovascular events with ACE inhibition (20). The main findings of the HOPE trial were confirmed in patients with and without diabetes. The HOPE trial was not included in the present meta-analysis because the comparison group was treated with a placebo and not with an active agent as required by the inclusion criteria. In summary, blood pressure reduction per se is necessary to prevent clinical complications in hypertensive patients (21), but additional clinical benefits can be achieved by non blood pressure mechanisms. The evidence from the present review and meta-analysis of comparative trials in patients with hypertension and diabetes should not be considered conclusive. The available data support the view that, compared with the alternative agents tested, ACE inhibitors appear to provide a special advantage in addition to blood pressure control. The question of whether atenolol is equivalent to captopril remains open. Based on available data from comparative trials, using ACE inhibitors may be prudent as a first-line agent for the treatment of hypertension in patients with type 2 diabetes. Conclusive evidence on the comparative effects of antihypertensive treatments will come from large prospective randomized trials such as the Antihypertensive and Lipid Lowering Treatment To Prevent Heart Attack Trial (22). References 1. Curb JD, Pressel SL, Cutler JA, Savage PJ, Applegate WB, Black H, Camel G, Davis BR, Frost PH, Gonzalez N, Guthrie G, Oberman A, Rutan GH, Stamler J: Effect of diuretic-based antihypertensive treatment on cardiovascular disease risk in older diabetic patients with isolated systolic hypertension: Systolic Hypertension in the Elderly Program Cooperative Research Group. JAMA 276:1886 1892, 1996 2. Tuomilehto J, Rastenyte D, Birkenhager WH, Thijs L, Antikainen R, Bulpitt CJ, Fletcher AE, Forette F, Goldhaber A, Palatini P, Sarti C, Fagard R, Staessen JA: Effects of calcium-channel blockade in older patients with diabetes and systolic hypertension. N Engl J Med 340:677 684, 1999 3. Hansson L, Zanchetti A, Carruthers SG, Dahlof B, Elmfeldt D, Julius S, Menard J, Rahn KH, Wedel H, Westerling S: Effects of intensive blood-pressure lowering and lowdose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial: HOT Study Group. Lancet 351:1755 1762, 1998 4. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 317:703 713, 1998 5. Pahor M, Psaty BM, Furberg CD: Treatment of hypertensive patients with diabetes. Lancet 351:689 690, 1998 6. Pahor M, Psaty BM, Furberg CD: New evidence on the prevention of cardiovascular events in hypertensive patients with type 2 diabetes. J Cardiovasc Pharmacol 32 (Suppl. 2): S18 S23, 1998 7. Estacio RO, Jeffers BW, Hiatt WR, Biggi SL, Gifford N, Schrier RW: The effect of nisoldipine as compared with enalapril on cardiovascular events in patients with non-insulin-dependent diabetes and hypertension. N Engl J Med 338:645 652, 1998 8. Hansson L, Lindholm LH, Niskanen L, Lanke J, Hedner T, Niklason A, Luomanmaki K, Dahlof B, de Faire U, Morlin C, Karlberg BE, Wester PO, Bjorck JE: Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial. Lancet 353:611 616, 1999 9. Tatti P, Pahor M, Byington RP, DiMauro P, Guarisco R, Strollo G, Strollo F: Outcome results of the Fosinopril Versus Amlodipine Cardiovascular Events Randomized Trial in patients with hypertension and NIDDM. DIABETES CARE, VOLUME 23, NUMBER 7, JULY 2000 891

Therapeutic benefits of ACE inhibitors Diabetes Care 21:597 603, 1998 10. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. BMJ 317:713 720, 1998 11. Hansson L, Lindholm LH, Ekbom T, Dahlof B, Lanke J, Schersten B, Wester PO, Hedner T, de Faire U: Randomised trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity: the Swedish Trial in Old Patients With Hypertension-2 study. Lancet 354:1751 1756, 1999 12. Yusuf S, Peto R, Lewis J, Collins R, Sleight P: Beta blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiovasc Dis 27:335 371, 1985 13. Cochran WG: Some methods for strengthening the common chi-square tests. Biometrics 10:417 451, 1954 14. Nathan DM: Some answers, more controversy, from UKPDS: United Kingdom Prospective Diabetes Study. Lancet 352:832 833, 1998 15. Blumenfeld JD, Sealey JE, Mann SJ, Bragat A, Marion R, Pecker MS, Sotelo J, August P, Pickering TG, Laragh JH: Beta-adrenergic receptor blockade as a therapeutic approach for suppressing the reninangiotensin-aldosterone system in normotensive and hypertensive subjects. Am J Hypertens 12:451 459, 1999 16. Bridges AB, McLaren M, Belch JJ: A comparative study of captopril and enalapril on endothelial cell function in congestive heart failure patients. Angiology 46:811 817, 1995 17. Schindler R, Dinarello CA, Koch KM: Angiotensin-converting-enzyme inhibitors suppress synthesis of tumour necrosis factor and interleukin 1 by human peripheral blood mononuclear cells. Cytokine 7:526 533, 1995 18. Oshima S, Ogawa H, Mizuno Y, Yamashita S, Noda K, Saito T, Sumida H, Suefuji H, Kaikita K, Soejima H, Yasue H: The effects of the angiotensin-converting enzyme inhibitor imidapril on plasma plasminogen activator inhibitor activity in patients with acute myocardial infarction. Am Heart J 134:961 966, 1997 19. Vaughan DE, Rouleau JL, Ridker PM, Arnold JM, Menapace FJ, Pfeffer MA: Effects of ramipril on plasma fibrinolytic balance in patients with acute anterior myocardial infarction: HEART Study Investigators. Circulation 96:442 447, 1997 20. Heart Outcomes Prevention Evaluation Study Investigators: Effects of an angiotensinconverting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 324:145 153, 2000 21. 1997 Joint National Committee: The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 157:2413 2446, 1997 22. Davis BR, Cutler JA, Gordon DJ, Furberg CD, Wright JT, Cushman WC, Grimm RH, LaRosa J, Whelton PK, Perry HM, Alderman MH, Ford CE, Oparil S, Francis C, Proschan M, Pressel S, Black HR, Hawkins CM: Rationale and design for the Antihypertensive and Lipid Lowering Treatment To Prevent Heart Attack Trial (ALLHAT). Am J Hypertens 9:342 360, 1996 892 DIABETES CARE, VOLUME 23, NUMBER 7, JULY 2000