Long-term effects of angiotensin-converting enzyme inhibition and metabolic control in hypertensive type 2 diabetic patients

Background. In hypertensive type 2 diabetic patients, treatment with angiot ensin-converting enzyme (ACE) inhibitors is associated with a lower inciden ce of cardiovascular events than those treated with calcium channel-blockin g agents. However, the long-term renal effects of ACE inhibitors in these p atients remain inconclusive. In 1989, we commenced a placebo-controlled, do uble-blind, randomized study to examine the anti-albuminuric effects of ena lapril versus nifedipine (slow release) in 102 hypertensive, type 2 diabeti c patients. These patients have been followed up for a mean trial duration of 5.5 +/- 2.2 years. We examined the determinants, including the effect of ACE inhibition on clinical outcomes in these patients. Methods. After a six-week placebo-controlled, run-in period, 52 patients we re randomized double-blind to receive nifedipine (slow release) and 50 pati ents to receive enalapril, After the one-year analysis, which confirmed the superior anti-albuminuric effects of enalapril (-54%) over nifedipine (+11 %), all patients were continued on their previously assigned treatment with informed consent. They were subdivided into normoalbuminuric (N = 43), mic roalbuminuric (N = 34), and macroalbuminuric (N = 25) groups based on two o f three 24-hour urinary albumin excretion (UAE) measurements during the run -in period. Renal function was shown by the 24-hour UAE, creatinine clearan ce (C-Cr), and the regression coefficient of the yearly plasma creatinine r eciprocal (beta-1/Cr), Clinical endpoints were defined as death, cardiovasc ular events, and/or renal events (need for renal replacement therapy or dou bling of baseline plasma creatinine). Results. In the whole group, patients treated with enalapril were more like ly to revert to being normoalbuminuric (23.8 vs. 15.4%), and fewer of them developed macroalbuminuria (19.1 vs. 30.8%) compared with the nifedipine-tr eated patients (P < 0.05). In the microalbuminuric group, treatment with en alapril (N = 21) was associated with a 13.0% (P < 0.01) reduction in 24-hou r UAE compared with a 17.3% increase in the nifedipine group (N = 13). In t he macroalbuminuric patients, enalapril treatment (N = 11) was associated w ith stabilization compared with a decline in renal function in the nifedipi ne group, as shown by the beta-1/Cr (0.65 +/- 4.29 vs. -1.93 +/- 2.35 1/mu mol X 10(-3), P < 0.05) after adjustment for baseline values. Compared with the normoalbuminuric and microalbuminuric patients, those with macroalbumi nuria had the lowest mean C-Cr (75.5 +/- 24.1 vs. 63.5 +/- 21.3 vs. 41.9 +/ - 18.5 mL/min, P < 0.001) and the highest frequency of clinical events (4.7 vs. 5.9 vs. 52%, P < 0.001). On multivariate analysis, beta-1/Cr (R-2 = 0. 195, P < 0.001) was independently associated with baseline HbA(1c) (beta = -0.285, P = 0.004), whereas clinical outcomes (R-2 = 0.176, P < 0.001) were independently related to the mean low-density lipoprotein cholesterol (bet a = 2.426, P = 0.018), high-density lipoprotein cholesterol (beta = -8.797, P = 0.03), baseline UAE (beta = 0.002, P = 0.04), and mean C-Cr during tre atment (beta = -0.211, P = 0.006). Conclusion. In this prospective cohort analysis involving 102 hypertensive, type 2 diabetic patients with varying degrees of albuminuria followed up f or a mean duration of five years, we observed the importance of good metabo lic and blood pressure control on the progression of albuminuria and renal function. Treatment with enalapril was associated with a greater reduction in albuminuria than with nifedipine in the entire patient group, and especi ally in those with microalbuminuria. In the macroalbuminuric patients, the rate of deterioration in renal function was also attenuated by treatment wi th enalapril.