Level 1: Likely reliable evidence

A fixed combination of perindopril (an ACE inhibitor) plus indapamide (a diuretic), available under the brand name Preterax, was evaluated in a randomized trial (Lancet. 2007;370:829-840). Patients older than 55 years with type 2 diabetes diagnosed after age 30 and a history of or risk factor for cardiovascular disease were included; 12,877 patients entered a six-week run-in period with a fixed-dose combination tablet of perindopril 2 mg plus indapamide 0.625 mg. Those who adhered to and tolerated the study drug during the run-in period (N=11,140, 86.5%) were randomized to the combination tablet vs. placebo; the dose was doubled after three months.

Mean follow-up was 4.3 years (range one month to 5.6 years). Major macrovascular events were defined as cardiovascular death, nonfatal MI, or nonfatal stroke. Major microvascular events were defined as new or worsening nephropathy (macroalbuminuria, doubling of serum creatinine to ≥200 µmol/L [2.26 mg/dL], renal replacement therapy, or death from renal disease) or retinopathy (proliferative retinopathy, diabetes-related blindness, macular edema, or retinal photocoagulation therapy).

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There were no significant differences in 83% perindopril/indapamide vs. 87% placebo patients who continued treatment during follow-up; 73% vs. 74% were adherent to treatment at the end of follow-up. Perindopril/indapamide was associated with more patients’ discontinuing treatment due to cough (3.3% vs. 1.3%, NNH 50) or hypotension or dizziness (1.2% vs. 0.4%, NNH 125).Perindopril/indapamide was associated with decreased all-cause mortality (7.3% vs. 8.5%, P=.025, NNT 79 over five years), cardiovascular mortality (3.8% vs. 4.6%, P=.027, NNT 125), and total coronary events (major macrovascular events plus hospitalization for unstable angina, coronary revascularization, or silent MI) (8.4% vs. 9.6%, P=.02, NNT 75 over five years). There were no significant differences in major macrovascular events or total cerebrovascular events.

Comparing perindopril/indapamide vs. placebo for microvascular outcomes, 3.3% vs. 3.9% had new or worsening nephropathy (P=.055), 19.6% vs. 23.6% had new microalbuminuria (P<.0001, NNT 25), 43.9% vs. 45.1% had visual deterioration (P=.1), and 15.5% vs. 16.8% had major macrovascular or major microvascular event (P=.041, NNT 66 over five years). Differences in major microvascular events and new or worsening nephropathy were not significant.