Randomised controlled trial of dual blockade of renin-angiotensin system in patients with hypertension, microalbuminuria, and non-insulin dependent diabetes: the candesartan and lisinopril microalbuminuria (CALM) study

Abstract

Objectives To assess and compare the effects of candesartan or lisinopril, or both, on blood pressure and urinary albumin excretion in patients with microalbuminuria, hypertension, and type 2 diabetes. Design Prospective, randomised, parallel group, double blind study with four week placebo run in period and 12 weeks' monotherapy with candesartan or lisinopril followed by 12 weeks' monotherapy or combination treatment. Setting Tertiary hospitals and primary care centres in four countries (37 centres). Participants 199 patients aged 30-75 years. Interventions Candesartan 16 mg once daily, lisinopril 20 mg once daily. Main outcome measures Blood pressure and urinary albumin:creatinine ratio. Results At 12 weeks mean (95% confidence interval) reductions in diastolic blood pressure were 9.5 mm Hg (7.7 mm Hg to 11.2 mm Hg, P < 0.001) and 9.7 mm Hg (7.9 mm Hg to 11.5 mm Hg, P < 0.001), respectively, and in urinary albumin:creatinine ratio were 30% (15% to 42%, P < 0.001) and 46% (35% to 56%, P < 0.001) for candesartan and lisinopril, respectively. At 24 weeks the mean reduction in diastolic blood pressure with combination treatment (16.3 mm Hg, 13.6 mm Hg to 18.9 mm Hg, P < 0.001) was significantly greater than that with candesartan (10.4 mm Hg, 7.7 mm Hg to 13.1 mm Hg, P < 0.001) or lisinopril (mean 10.7 mm Hg, 8.0 mm Hg to 13.5 mm Hg, P < 0.001). Furthermore, the reduction in urinary albumin:creatinine ratio with combination treatment (50%, 36% to 61%, P < 0.001) was greater than with candesartan (24%, 0% to 43%, P = 0.05) and lisinopril (39%, 20% to 54%, P < 0.001). All treatments were generally well tolerated. Conclusion Candesartan 16 mg once daily is as effective as lisinopril 20 mg once daily in reducing blood pressure and microalbuminuria in hypertensive patients with type 2 diabetes. Combination treatment is well tolerated and more effective in reducing blood pressure.

Evidence for renoprotection by blockade of the renin–angiotensin–aldosterone system in hypertension and diabetes

“…34,40,[46][47][48][56][57][58][59] Clinical trials, grouped by the degree of albuminuria, demonstrating the beneficial effects of RAAS inhibition on renal end points in patients with diabetes mellitus are summarized in Table 2. 34,40,42,48,49,[57][58][59][60][61][62][63][64][65][66][67][68][69][70][71] Normoalbuminuria The Bergamo Nephrologic Diabetes Complications Trial (BENEDICT) is the only primary prevention study to date to demonstrate that the development of microalbuminuria can be prevented by the use of an ACE inhibitor alone or in combination with a CCB in hypertensive normoalbuminuric patients with type II diabetes. 59 …”

Combination therapy with AT1-receptor blockers

“…29 Both candesartan and lisinopril produced significant reductions in blood pressure, compared with baseline, at 12 weeks; the mean reductions were −12.4/−9.5 mm Hg and −15.7/−9.7 mm Hg, respectively, and there was no significant difference between the two treatments. After 24 weeks, how-ever, the reduction in blood pressure in patients receiving combination therapy was significantly greater than that in patients receiving monotherapy with either agent.…”

New concepts in blood pressure-lowering management in diabetic patients: the case for early ACE inhibitor combination therapy with diuretics

“…[15][16][17] Furthermore, dual blockade using a drug of each class is a possible approach in patients who do not respond to single blockade. 17 Thus, with the latest results from DETAIL in mind, the clinician may choose either an ACE inhibitor or an ARB, or even the two in combination. However, questions remain regarding the longer term in advanced nephropathy.…”