Candesartan and Lisinopril Microalbuminuria (CALM) study - CALM

Description:

The CALM trial was a prospective, randomized, parallel group, double blind study designed 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.

Hypothesis:

Candesartan is as effective as lisinopril in reducing blood pressure and microalbuminuria in hypertensive patients with type 2 diabetes and combination treatment is more effective in reducing blood pressure than either drug alone.

Study Design

Study Design:

Patients Enrolled: 199

Patient Populations:

Patients with type 2 diabetes, age 30 to 75 years and with previously diagnosed hypertension and microalbuminuria, with urinary albumin:creatinine ratio 2.5-25 mg/mmol and diastolic blood pressure 90-110 mm Hg after two and four weeks of placebo treatment, respectively.

Exclusions:

Body mass index 40 kg/m2, systolic blood pressure >200 mm Hg, non-diabetic cause of secondary hypertension, cardiovascular event in the past six months, serum creatinine concentration 130 ×6d mol/l in women and 150 ×6d mol/l in men, serum potassium concentration >5.5 mmol/l, glycated haemoglobin concentration (HbA1c) >10%, pregnancy or potential pregnancy, and breast feeding.

Primary Endpoints:

Systolic and diastolic blood pressure and urinary albumin:creatinine ratio.

Secondary Endpoints:

Haemoglobin A1c, creatinine, urea, potassium and urate, creatinine clearance.

Drug/Procedures Used:

After four weeks of placebo treatment, eligible patients were randomized to four treatment groups. Half the patients received candesartan 16 mg once daily and half received lisinopril 20 mg once daily for the first 12 weeks. From 12 to 24 weeks, one third of the patients received candesartan alone, one third lisinopril alone, and one third the combination, unless patients had diastolic blood pressure below 80 mm Hg at 12 weeks. The patients attended the clinic at four and two weeks before randomization, at randomization (week 0), and at 1, 6, 12, 13, 18, and 24 weeks after randomization.

Concomitant Medications:

Eighteen in the candesartan group and 27 in the lisinopril group also received hydrochlorothiazide 12.5 mg once daily. In both groups about 80% of the patients were taking oral antidiabetic drugs and 20% were taking insulin.

Principal Findings:

199 patients with type 2 diabetes and hypertension were enrolled and were randomized as follows: candesartan 16 mg/day for 24 weeks (n=66), lisinopril 20 mg/day for 24 weeks (n=64), candesartan for 12 weeks and then combination (candesartan/lisinopril) for 12 weeks (n=34) or lisinopril for 12 weeks and combination treatment for 12 weeks (n=35). Baseline variables were well matched among the groups. Results are reported as a comparison between the candesartan or lisinopril groups compared to baseline at 12 weeks, between the candesartan, lisinopril or combination treatment groups compared to baseline at 24 weeks as well as a comparison between the treatment groups. 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, compared to baseline. 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. There were no changes in mean values for hemoglobin A1c or any routine laboratory variables from baseline to 12 or 24 weeks in any of the treatment groups. Slight increases were observed at 24 weeks in serum concentrations of creatinine, urea, potassium and urate in the combination treatment group. Creatinine clearance was slightly decreased over 24 weeks in the lisinopril group (adjusted mean decrease 0.0835 ml/sec, P=0.04) and the combination treatment group (0.0735 ml/sec, P=0.05).

Interpretation:

Among patients with microalbuminuria, hypertension, and type 2 diabetes, treatment with combination therapy with candesartan and lisinopril was associated with a reduction in blood pressure as well as having a beneficial effect on albuminuria and was associated with an good safety profile.

References:

Mogensen CE, et al. 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. BMJ 2000;321:1440-1444.

Clinical Topics: Prevention, Novel Agents, Hypertension

Keywords: Diabetes Mellitus, Type 2, Blood Pressure, Creatinine, Tetrazoles, Uric Acid, Hemoglobin A, Glycosylated, Lisinopril, Potassium, Angiotensin II Type 1 Receptor Blockers, Benzimidazoles, Hypertension, Urea


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