ACE Inhibitor as One of Several Possible First-Line Agents Is Reasonable for Diabetic Patients With Hypertension

We appreciate the overall constructive criticisms given by Dr. Egger (1) and we respond as follows: The Captopril Prevention Project (CAPPP) Study was the first intervention trial in hypertensive patients to compare an ACE inhibitor–based therapy with conventional antihypertensive therapy, based on diuretics and/or β-blockers, regarding the effects on cardiovascular morbidity and mortality (2). As correctly pointed out by Dr. Egger, in the whole CAPPP study population, both diabetic and nondiabetic subjects combined, no difference was found between regimens in preventing the primary end point (i.e., the combination of fatal as well as nonfatal myocardial infarction and stroke and other cardiovascular deaths). In the whole CAPPP population, the risk of stroke was lower with conventional therapy than with captopril therapy, but this was not the case in the diabetic patients. We are just as puzzled by the result in the full cohort as are others, since this result is not supported by other studies. The contributory factors may have been a higher frequency of history of strokes and transient ischemic attacks at baseline in the captopril group, and this group also had an achieved blood pressure that was 2 mmHg higher as compared with the conventionally treated group (2). The development of diabetes was one of the predefined secondary end points of this study. Contrary to what Dr. Egger states, the captopril group (n = 337) had lower incidences of new-onset diabetes than the conventionally treated group (n = 380) (relative risk 0.86, P = 0.039), and this was especially marked in those who were previously untreated (relative risk 0.67, P = 0.030) (2).

We do appreciate Dr. Egger’s overall concern about the power of the study. The results in the diabetic patient cohort are, like most other studies in this field, derived from a subanalysis from the larger CAPPP project with all its caveats. This aspect was evident in the title of our article. We fully agree with Dr. Egger that the results of this and any other single subanalysis should be interpreted with caution.

Regarding insulin sensitivity, we agree that the studies on ACE inhibition and whole-body glucose uptake during euglycemic clamp technique measurements have been contradictory. Due to space constraints, detailed speculations about the potential mechanisms were beyond the scope of our article. There are also a number of other possible metabolic disturbances in diabetic patients that are influenced beneficially by ACE inhibitior treatment, as we briefly mentioned in our article. However, regarding the effects of renin-angiotensin-aldosterone system inhibition on glucose and insulin metabolism, one should acknowledge that in the CAPPP Study (3), like in the HOPE Study (4) and the just recently published Losartan Intervention Study For End Point Reduction (LIFE) (5,6), drugs affecting renin-angiotensin-aldosterone system have shown significant long-term reduction in the incidence of new-onset diabetes, although the detailed mechanisms remain obscure.

As to treatment combinations, it is important to emphasize that we are actually comparing regimens based on various drugs, and this also holds for the design of other studies like the U.K. Prospective Diabetes Study (UKPDS) (7,8). In the conventional group of the CAPPP Study, the choice of starting treatment with either a diuretic or β-blocker was left to the investigator, since this was the accepted first-line antihypertensive therapy at the time when the CAPPP Study was initiated.

It is true that to some extent the findings may be at deviance with those found in the UKPDS (7), which showed no advantage for captopril over atenolol in reducing the risk of macrovascular and microvascular diabetic complications. As discussed above, these divergent findings may partly be explained by the fact that the blood pressure treatment goal was lower in the UKPDS (<150/<85 mmHg) than in the CAPPP Study (diastolic blood pressure <90 mmHg). Thus, blood pressure lowering may be more important than the choice of antihypertensive agent, although captopril was better tolerated (8).

Further, the diabetic patients recruited in the UKPDS had generally milder disturbances in glucose metabolism, and patients with symptomatic cardiovascular disease were not included in the UKPDS; therefore, these patients were likely to be at lower risk than the diabetic patients in the CAPPP Study. The LIFE Study (5) as well as the subanalysis of the LIFE diabetic population (6) (n = 1,195) showed that an angiotensin II receptor antagonist–based (losartan) regimen was markedly superior in preventing cardiovascular end points in diabetic patients than a β-blocker–based (atenolol) regimen. Even total mortality was reduced ∼40% in the losartan group as compared with the atenolol group. However, the diabetic substudy in LIFE was not powered to be a mortality study, but the results were striking. The results of the LIFE Study are in line with the results of the CAPPP diabetic subpopulation analysis.

As to the concluding remarks by Dr. Egger, we totally agree. Multiple drugs are required in diabetic patients and choosing an ACE inhibitor as one of several possible first-line agents is reasonable, especially in those with renal impairment. Further and more importantly, all five classes of agents, diuretics, β-blockers, calcium antagonists, ACE inhibitors, and AT1-receptor antagonists, have presently been shown to reduce cardiovascular events in diabetic patients.