Trials That Matter: The Effect of a Fixed-Dose Combination of an Angiotensin-Converting Enzyme Inhibitor and a Diuretic on the Complications of Type 2 Diabetes

Providers who care for patients with type 2 diabetes often focus on lowering levels of glucose and hemoglobin A_1c. Strict control of these glycemic measures reduces the incidence of microvascular complications of the disease, such as retinopathy and nephropathy, but has little effect on macrovascular complications, such as myocardial infarction and stroke, from which most patients with type 2 diabetes ultimately die. Prevention of these macrovascular complications requires equal attention to lowering blood pressure and lipid levels. Diabetes care would be simplified enormously if physicians had a treatment that could safely reduce both kinds of complications.

The ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicon-MR Controlled Evaluation) trial was designed to see whether a fixed, low-dose combination of perindopril, 2 mg/d, and indapamide, 0.625 mg/d, added to standard background antihypertensive treatment could safely reduce both microvascular and macrovascular complications of type 2 diabetes (1). Several lines of reasoning motivated study of this intervention. Aggressive control of blood pressure reduces both microvascular and macrovascular complications in patients with diabetes and hypertension (2–7). Angiotensin-converting enzyme (ACE) inhibitors and thiazide diuretics have complementary mechanisms of antihypertensive action. And although a fixed, low-dose combination of antihypertensives might produce only small decreases in blood pressure, it could shift down the population distribution of high blood pressure in patients with type 2 diabetes. In theory, this could result in population-level reductions in outcomes with a minimum of adverse drug effects. The ADVANCE trial was, in essence, an empirical test of principle for the blood pressure–lowering component of a future combination polypill in this population (8).

Finally, the choice of perindopril and indapamide may seem unconventional, but both are widely prescribed in many countries, where they are available in a fixed, low-dose combination pill appropriate for add-on therapy. Also, they …