ADVANCE: Perindopril plus indapamide reduces vascular events in patients with type 2 diabetes

In a multicenter, multinational, randomized controlled study, a fixed-dose combination of perindopril/ indapamide was associated with a reduced risk of death and vascular events in patients with type 2 diabetes, many of whom were already taking antihypertensive drugs.

Key Points

The results of the Action in Diabetes and Vascular Disease (ADVANCE) study were presented at the European Society of Cardiology Congress 2007 in Vienna, Austria.

Treatment with the combination therapy reduced the risk of all-cause mortality by 14% (P=.025) compared with placebo, according to Stephen MacMahon, PhD, MPH, principal director, The George Institute for International Health, and professor of cardiovascular medicine and epidemiology at the University of Sydney, Australia.












The primary end point was the combined incidence of macrovascular and microvascular events. The relative risk of these events was reduced by 9% (HR=0.91; 95% CI, 0.83–1.00; P=.041) among patients randomized to perindopril/indapamide compared with those who received placebo. Treatment with perindopril/indapamide was associated with an 18% relative risk reduction in cardiovascular death (P=.027) and a 21% relative risk reduction for renal events (P<.0001) compared with placebo.

"These benefits were achieved in a situation in which risk factors were well controlled," Dr MacMahon said.

The reduction in risk with the study agent was observed regardless of whether patients were hypertensive and regardless of whether they were taking an ACE inhibitor as background therapy. "We added treatment to everybody irrespective of blood pressure and with no blood pressure goals," Dr MacMahon said. The results offer support for current treatment guidelines, which recommend a blood pressure target of <130/80 mmHg in patients with diabetes, and for which no prior evidence existed, he said.

According to Dr MacMahon, the ADVANCE study results demonstrate the favorable effect of adding antihypertensive therapy to the treatment regimens of all patients with diabetes, whether the patients have hypertension or not.

"The benefits are impressive, particularly the 18% reduction in cardiovascular events," said Sidney Smith, MD, professor of medicine and director of the Center for Cardiovascular Science and Medicine at the University of North Carolina, Chapel Hill.

However, Dr Smith challenged the investigators' conclusion that the treatment was equally beneficial in patients with or without hypertension, citing their definition of hypertension as blood pressures >140/90 mmHg. "Recall that the current target level for diabetics is 130/80 mmHg," he said.

Treatment with perindopril/indapamide did not result in a reduction in cerebrovascular events or diabetic ocular events. Dr Smith said the lack of the treatment's effect on cerebrovascular events was surprising.

The results of the ADVANCE study sparked debate about whether some antihypertensive agents are superior to others for reducing the risk of vascular events.

Dr Smith said that more evidence is necessary before it can be said with certainty that ACE inhibitors have vascular protective properties independent of blood-pressure lowering in patients with diabetes.

In an editorial that accompanied the online publication of the ADVANCE study results in The Lancet (editorial, 2007;370:804–805; study results, 2007;370:829–840), Norman M. Kaplan, MD, professor of internal medicine, University of Texas Southwestern Medical Center, Dallas, expressed doubt about the importance of the study drug. "I believe that other drugs-if they lower blood pressure as much and do not have metabolic side effects-would be as protective as this combination treatment. Lowering blood pressure is what counts, not the way by which it is lowered," he stated.

According to Dr MacMahon, treatment with perindopril/indapamide could prevent 1 major vascular event over 5 years for every 66 patients and 1 death over 5 years for every 79 patients treated with the combination.