Reduced Cardiovascular Morbidity and Mortality in Hypertensive Diabetic Patients on First-Line Therapy With an ACE Inhibitor Compared With a Diuretic/β-Blocker–Based Treatment Regimen: A subanalysis of the Captopril Prevention Project

The CAPPP was conducted at 536 health centers in Sweden and Finland using the PROBE (Prospective Randomized Open Blinded Endpoint) study design (22,24), which has great similarity to routine clinical practice. Patients were treated and followed for an average of 6.1 years (23). Male and female patients with treated or untreated primary hypertension, aged 25–66 years, were included if their untreated diastolic blood pressure was ≥100 mmHg on two different occasions. Patients with secondary hypertension, serum creatinine >150 μmol/l, and indications requiring β-blockade treatment were excluded. Eligible patients were randomized to receive either a captopril-based regimen or conventional antihypertensive treatment (diuretics and/or β-blockers).

The treatment goal was a supine diastolic blood pressure ≤90 mmHg. To reach this goal, the dose could be increased to 100 mg daily (once or twice daily) in the captopril-treated group; if necessary, a diuretic could be added. In the conventionally treated group, an optimal dose of a β-blocker or a diuretic was used. The investigators were free to choose the agents, and in a second step, the diuretic and the β-blocker could be combined. As a last step, a calcium-channel blocker could be added in both treatment groups.

The primary end point was the combination of fatal and nonfatal myocardial infarction and stroke as well as other cardiovascular deaths. Events were evaluated by an independent and blinded end point committee before being accepted. Secondary end points were new or deteriorated ischemic heart disease (IHD) and congestive heart failure (CHF), atrial fibrillation, diabetes, transient ischemic attacks, and noncardiovascular deaths as previously defined (22,23).

The diagnosis of diabetes was made according to WHO criteria (25) and required at least two abnormal fasting glucose values that were unequivocal (i.e., between 5.5 and 6.7 mmol/l). If they were not unequivocal, diagnosis was confirmed by an oral glucose tolerance test.

The diabetic patients were, for the most part, treated with diet and/or oral hypoglycemic agents at baseline (Table 1), and thus they had type 2 diabetes. The CAPPP study was approved by ethics committees at participating centers in Sweden and Finland.

Analysis was by intention to treat. Cox regression analyses were performed, with time since randomization as the nonparametrically modeled time variable; age at randomization was therefore introduced as a covariate. Further covariates used were sex and systolic blood pressure at randomization. Both systolic blood pressure at randomization and previously untreated patients as well as their product were introduced into the model (23). All computations were performed in the commercial software Stata. P < 0.05 (two-sided) was considered statistically significant.

Among the 10,985 patients in the CAPPP, there were 309 patients with diabetes in the captopril group and 263 in the conventional therapy group. These 572 patients provided 3,445 patient-years, and only one of them was lost to follow-up. Blood pressure at baseline was similar in the captopril compared with the conventional therapy group (163.6/97.1 vs. 163.3/97.3 mmHg). The baseline characteristics were comparable between the two study groups (Table 1). Blood pressure levels during the study are shown in Fig. 1. If the in-study blood pressure for every diabetic patient is defined as the average of all blood pressure recordings from 12 months onwards, then these in-study blood pressures were somewhat higher in the captopril than in the conventional group (155.5/89.0 mmHg; P = 0.091 vs. 153.5/88.0 mmHg; P = 0.040).

In diabetic patients, the incidence of the primary end point, fatal and nonfatal myocardial infarction and stroke as well as other cardiovascular deaths, was significantly lower in the captopril than in the conventional therapy group (relative risk [RR] = 0.59; P = 0.018) (Tables 2 and 3 and Fig. 2). When the events comprising the primary end point were analyzed separately, the following results were obtained: 1) cardiovascular mortality, defined as fatal stroke and myocardial infarction, sudden death, and other cardiovascular death, tended to be lower in the captopril group (RR = 0.48; P = 0.084) (Table 2); 2) fatal and nonfatal strokes did not differ between the study groups (RR = 1.02; P = 0.959) (Table 2); and 3) fatal and nonfatal myocardial infarctions were markedly less frequent in the captopril than in the conventional therapy group (RR = 0.34; P = 0.002) (Table 2).

Analyses of secondary events showed that 1) total mortality was lower in the captopril than in the conventional therapy group (RR = 0.54; P = 0.034) (Table 2), and 2) all cardiac events (fatal and nonfatal myocardial infarction, other cardiovascular deaths, and sudden deaths as well as IHD, CHF, and atrial fibrillation) were lower in the captopril than in the conventional therapy group (RR = 0.67; P = 0.029) (Table 2).

In addition, we investigated whether the observed benefits of ACE inhibitor–based therapy in diabetic patients could be related to baseline clinical and metabolic characteristics. Thus, the effects of captopril versus conventional treatment on the RRs of the primary end point were further analyzed in various subgroups. These were sex and dichotomized continuous variables, including BMI, fasting glucose, blood pressure, and serum cholesterol, as well as HDL cholesterol and serum triglycerides which were dichotomized at their median values (Table 3). The benefits of captopril therapy were more evident in male diabetic patients (P = 0.004) and in those with poor glycemic control (P = 0.033) and tended to be more pronounced in those with elevated serum cholesterol (P = 0.052) and lowered HDL cholesterol (P = 0.052). In these analyses, P values were adjusted for the effects of age, sex, previously untreated patients, and systolic blood pressure.

The incidence of new-onset diabetes in an originally nondiabetic study population was 337 in the captopril group and 380 in the conventional group (RR 0.79; P = 0.007) (23).

In regard to the effects on cardiovascular morbidity and mortality, the CAPPP study (23) was the first intervention trial in hypertensive patients to compare an ACE inhibitor–based therapy with conventional antihypertensive therapy that was based on diuretics and/or β-blockers. For the entire study population, diabetic and nondiabetic subjects combined, both regimens were equally effective in preventing the primary end point. However, the effects of the two regimens in the diabetic subpopulation showed a clear difference in the risk of developing a primary end point in favor of a captopril-based regimen. Importantly, captopril treatment in the diabetic subpopulation reduced fatal cardiovascular events by about one-half. However, as a subgroup analysis, the data should be interpreted with caution.

At baseline, blood pressure levels and other characteristics were comparable between the captopril and conventional groups. During the study, the achieved blood pressure levels were, if anything, somewhat higher in the captopril than in the conventional regimen; therefore, the favorable outcomes are evidently not explained by differences in blood pressure reductions.

At first sight, these findings may seem to deviate from those of the UKPDS (7), which showed no advantage for captopril over atenolol in reducing the risk of macro- and microvascular diabetic complications. The divergent findings may be explained to a great extent by the fact that the blood pressure treatment goal was lower in the UKPDS (<150/85 mmHg) than in the CAPPP study (<90 mmHg). These findings from the UKPDS suggest that blood pressure lowering may be more important per se than the choice of antihypertensive agent, although captopril was better tolerated by most patients (7). Because the effective lowering of blood pressure in the UKPDS was highly beneficial in diabetic patients, this confirms the observations in the HOT study in which the excess risk of having diabetes was almost nullified in patients whose diastolic blood pressure was reduced to ∼80 mmHg (8). Furthermore, the diabetic patients recruited in the UKPDS generally had milder disturbances in glucose metabolism (inclusion criteria: UKPDS, fasting plasma glucose >6.0 mmol/l; WHO, plasma glucose ≥7.8 mmol/l corresponding to blood glucose ≥6.7 mmol/l). In addition, patients with symptomatic cardiovascular disease were not included in the UKPDS; therefore, the patients in that study were probably at lower risk than the diabetic patients in the CAPPP study.

The results from the analysis of diabetic patients in the CAPPP study further suggest that the choice of antihypertensive drug regimen may be of importance when there is metabolic decompensation, e.g., in those patients with poor glycemic control and perhaps in those with more unfavorable lipid abnormalities. Thus, these results support those of the Heart Outcomes Prevention Evaluation (HOPE) study (26,27), which showed that subjects with multiple risk factors are likely to benefit from ACE inhibitor–based therapy, because the protective effect is well beyond that obtained by blood pressure reduction per se. The favorable effects of ACE inhibitor–based therapy may be a result of the improvement of whole-body glucose uptake observed with captopril treatment during euglycemic clamp measurements (11). There are also a variety of other disturbances in diabetic patients that are improved by ACE inhibition, e.g., attenuation of sympathetic nerve activity (28), enhancement of nitric oxide formation (29), improvement of endothelial dysfunction (30), improvement in coronary reserve (31), and even the direct inhibition of the atherosclerosis process, as suggested by animal experiments (32).

In conclusion, analysis of the outcome of the diabetic patient group in the CAPPP showed that the ACE inhibitor is an obvious first-choice drug for hypertensive patients with diabetes, especially when there is metabolic decompensation. However, because elevated blood pressure levels should be aggressively treated in diabetic patients, a multiple drug regimen is commonly required to achieve optimal treatment targets.

Steering committee: Lennart Hansson, Jan-Erik Björck, Björn Dahlöf, Ulf de Faire, Thomas Hedner, Bengt E. Karlberg, Jan Lanke, Lars H. Lindholm, Kimmo Luomanmäki, Claes Mörlin, Leo Niskanen, P. O. Wester. End point committee: Gottfried Härtel, Pentti Siltanen, Karl Swedberg, Andreas Terent. End point secretariat, Gothenburg: Anita Holmner. Safety committee: Leif Erhardt, Markku Kupari, Thomas Thulin, Pär-Ola Bendahl (statistician). Data management, Lund: Björn Slaug. Coordinators: Sweden: Per-Olof Andersson, Johan Asplund, Anders Dahlqvist, Björn Fagerberg, Göran Frithz, Bengt-Göran Hansson, Anders Hägg, Svend Aage Jonsen, Thomas Kahan, Bo Carlberg, Bo Erik Kristensson, Jörgen Kuylenstierna, Hans Larsson, Bengt Lindström, Ingrid Mattiasson, Bengt-Hjalmar Möller, Ove R. Nilsson, Håkan Stakeberg, Anders Svensson, Kerstin Tolagen, Leif Weiner, Brage Åström, Jan Östergren; Finland: Aapo Lehtonen, Mauno Lilja, Matti Nikkilä, Juhani Partanen; and all CAPPP investigators (23).

This study was supported by a project grant from Bristol-Myers Squibb.