Clinical studies on renin angiotensin aldosterone system inhibition and outcomes of new onset diabetes

ACE inhibitors and ARBs have been studied extensively in hypertension, congestive heart failure, coronary artery disease, and renal disease (Table 6). Both drugs consistently reduce risk of coronary events (particularly ACE inhibitors), stroke, and diabetic complications of microvascu-lar disease. In addition, secondary endpoints of some of these studies have suggested reduced incidence of new-onset diabetes. In the Heart Outcomes Prevention Evaluation (HOPE), the incidence of diabetes was 34% lower in the ramipril-treated group than in the group receiving

Table 6

Tissue angiotensin-converting enzyme inhibition and endothelial function

Study

ACE inhibitor

Characteristics of study subject

Outcome

Hornig et al [73]

Prasad et al [74]

Anderson et al (BANFF) [76]

Oosterga et al

enalapril quinapril, enalapril

Padmanabhan et al [72] enalaprilat enalaprilat quinapril quinapril, enalapril, losartan, amlodipine quinapril, captopril

Normotensive male volunteers

Normotensive male volunteers

Normotensive male volunteers quinaprilat, CHF patients enalaprilat

CAD patients

CAD patients with preserved LVF

CAD patients with preserved LVF

CAD patients with preserved LVF

inhibition of contractile effects of AI; reduction in fractional conversion of AI to AII quinapril, but not enalapril, significantly inhibited AII-induced vasoconstriction enalaprilat failed to inhibit the contractile response to AI endothelial-dependent dilation was improved with quinaprilat, but not with enalaprilat enalaprilat significantly potentiated bradykinin-mediated femoral vasodilation increased coronary artery dilation; increased endothelial function in smokers and those with elevated LDL cholesterol only quinapril significantly improved endothelial function quinapril, but not captopril, blocks AI conversion to AII in vascular preparations

Definitions: AI, angiotensin I; AII, antiotensin II; CAD, coronary artery disease; CHF, congestive heart failure; LVF, left ventricular function.

Adapted from Vascular Biology Working Group website. Available at: VBWG.org. Accessed November 12, 2004.

placebo [29,96]. In the LIFE study comparing losartan with atenolol for treating hypertension with left ventricular hypertrophy, losartan was associated with a 25% reduction in new-onset diabetes compared with atenolol [33,98]. Even in the more recent Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, the incidence of new-onset diabetes was significantly lower in the lisinopril arm than in the chlorthalidone arm [97]. The chlorthalidone arm had 302 cases of new-onset diabetes out of 9733 subjects, whereas the lisinopril arm had only 119 patients with new-onset diabetes out of 5840 participants, providing a relative risk of 0.66 (confidence interval [CI], 0.53-0.81). In the CHARM study, candesartan reduced the onset of diabetes by 19% (RR, 0.81; CI, 0.66-0.97) compared with placebo when used in patients with chronic heart failure [42]. The Antihypertensive Treatment and Lipid Profile in a North of Sweden Efficacy Evaluation (ALLHAT) study, which compared can-desartan with hydrochlorothiazide, found that candesartan decreased the incidence of new-onset diabetes significantly (RR, 0.13; CI, 0.02-0.97; P = 0.03) [99]. The SOLVD study recently analyzed data on new-onset diabetes in the enalapril group that was compared with placebo for treatment of chronic heart failure. There was a significant reduction (RR, 0.26; CI, 0.13-0.53) of new-onset of diabetes with use of enalapril [22,23]. The results of the more recent VALUE trial indicate a 23% reduction (RR, 0.77; CI, 0.69-0.86;

P < 0.001) in new-onset of diabetes in hypertensive patients treated with valsartan, as compared with amlodipine [34]. The Study on Cognition and Prognosis in the Elderly by the Captopril Prevention Project (CAPP) and the Cardiovascular Events in Elderly Patients with Isolated Systolic Hypertension (STOP-HTN) study, on the other hand, showed no difference between use of ACE inhibitors or ARBs and control in new-onset of diabetes (Table 7) [100-102]. Possible mechanisms responsible for the reduced incidence of diabetes in these trials include improvement in insulinmediated glucose uptake, enhanced endothelial function, increased nitric oxide activation, reduced inflammatory response, and increased bra-dykinin levels [103-106].

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