Recently, Pahor et al. (1)presented a meta-analysis based on four studies assessing whether ACE inhibitors are superior to alternative agents for the prevention of cardiovascular events in patients with hypertension and type 2 diabetes. The four eligible trials were as follows: 1) the Fosinopril Versus Amlodipine Cardiovascular Events Randomized Trial (FACET), 2) the Appropriate Blood Pressure Control in Diabetes Trial (ABCD), 3) the Captopril Prevention Project (CAPPP), and 4) the U.K. Prospective Diabetes Study (UKPDS)(2,3,4,5). FACET's study lasted only 2.8 years, whereas the other studies lasted 5, 6.1,and 8.4 years, respectively. All of the trials were blind except for FACET. The primary end points of FACET were serum lipids and glucose metabolism,whereas the primary end point of the ABCD trial was the rate of decline in creatinine clearance. Neither of these two studies were powered for cardiovascular end points, only for the primary end points mentioned above. The CAPPP study, based on 10,985 hypertensive patients, showed that captopril and conventional antihypertensive treatments did not differ in efficacy in the prevention of cardiovascular morbidity and mortality. However, the subanalysis of the 572 diabetic patients (5.2%) showed a significantly better cardiovascular outcome for ACE inhibition versus alternative treatments. The UKPDS fulfilled all of the ideal criteria for conducting a cardiovascular end point trial of blood pressure lowering in hypertensive type 2 diabetic patients (n = 758); the study was double-blind, and randomized,powered for cardiovascular end points, included the largest number of patients, had the longest observation period (8.4 years), and consequently had the largest number of cardiovascular events. Actually, the number of events in the UKPDS study was greater than the combined event rate of the three studies mentioned previously, which deal with acute myocardial infarction (MI) and the cardiovascular end point combined and death. Despite these findings, Pahor et al. (1) claim that the UKPDS should be excluded from the meta-analysis because a test of heterogeneity revealed the study as a potential outlier. In other words, the test revealed that the UKPDS results were different from the results of the three studies previously mentioned, which all suffer from various flaws in relation to the study design, as previously discussed.

The ABCD trial originally reported 5 MI cases treated with ACE inhibition and 25 MI cases treated with nisoldipine. However, these figures were corrected by the principal investigator of the ABCD trial, Robert Schrier, in his state-of-the-art lecture at the American Society of Nephrology 6 November 1999 in Miami, FL. The correct figures were presented as 9 MI cases in the ACE inhibitor group and 27 MI cases in the nisoldipine group. The relative risk(95% CI) for MI quoted in the Pahor et al. analysis(1) was 0.73 (0.54-0.99). Applying these corrected values will now give the following numbers of acute MI, stroke, cardiovascular events, and all causes of mortality from ACE-inhibitors versus other antihypertensive drugs: 90 vs. 111, 56 vs. 58, 170 vs. 190, and 109 vs. 108, respectively. Therefore, none of the reported differences in cardiovascular events and mortality are significant; the differences are only borderline significant.

Aggressive blood pressure lowering in hypertensive diabetic patients is recommended. However, a reduction in blood pressure to a level <130/85 mmHg is unlikely to be achieved by monotherapy in most patients, as demonstrated in several recent trials carried out in hypertensive patients, including the four studies mentioned above. Consequently, we suggested that the combination of ACE inhibitors with other first-line drugs, such as calcium channel blockers,diuretics, and β-blockers, is a rational choice for treatment of hypertensive diabetic patients.

H.H.-P. is a member of advisory panels for Merck and Bristol Myers Squibb.

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