ESC: Big Benefits in Diabetes for Small Blood Pressure Drops to Below Normal

September 4, 2007

VIENNA, Sept. 4 -- Even normotensive patients with diabetes can reduce their risk of heart attack, stroke, and renal failure by lowering of blood pressure, researchers reported here.

VIENNA, Sept. 4 -- Even normotensive patients with diabetes can reduce their risk of heart attack, stroke, and renal failure by lowering of blood pressure, researchers reported here.

In a trial of more than 11,000 patients with type 2 diabetes, a fixed combination of an ACE inhibitor and a diuretic (perindopril and indapamide [Preterax]) reduced the risk of major microvascular or macrovascular event by 9% (P=0.04), said Stephan MacMahon, M.D., of the George Institute for International Health in Sydney, Australia.

The relative risk of death from cardiovascular disease was reduced by 18% (211 cardiovascular deaths versus 257, P=0.03) and the relative risk of death from any cause was reduced by 14% (408 versus 471 P=0.03).

The results of the ADVANCE (Action in Diabetes and Vascular Disease) trial were reported at the European Society of Cardiology meeting and simultaneously published online by The Lancet.

The international trial enrolled 11,140 patients with type 2 diabetes at 215 collaborating centers in 20 countries. The average age of patients was 66 and 43% were women.

During a six-week run-in all patients were given a fixed dose combination 2 mg perindopril/0.625 mg indapamide, followed by randomization to the study drug, at the same fixed dose, or placebo. Patients were followed for mean of 4.3 years.

Irrespective of baseline blood pressure, the mean reduction in systolic pressure was 5.6 mm Hg and mean diastolic reduction was 2.2 mm Hg for patients randomized to active therapy. The average systolic pressure during follow-up was 134.7 mm Hg versus 140.3 mm Hg, while the average diastolic pressure was 74.8 mm Hg versus 77.0 mm Hg (P

With the exception of ACE inhibitor use, patients were allowed to remain on all baseline antihypertensive medications. Patients taking an ACE inhibitor had the drug withdrawn and were offered open-label peridopril at 2 mg or 4 mg a day.

After three months the study drug was dose was increased to 4 mg of peridopril/1.25 mg indapamide.

That study design drew criticism from Norman M. Kaplan, M.D., of the University of Texas Southwestern in Dallas, who wrote an accompanying editorial and noted several issues with the methods.

He pointed out that only 3.3% of the patients randomized to the peridopril combination reported cough versus 1.3% of placebo patients, a number that is much lower than the 10% to 15% usually reported with ACE inhibitors.

"Such infrequency of cough would not be seen if ACE inhibitors were started in ACE-inhibitor-nave patients," he wrote.

He also pointed out that 55% of those assigned to placebo were also taking perindopril at the end of follow-up. By the end of the trial, more participants assigned to placebo were taking an angiotensin-receptor blocker or a beta blocker, a calcium antagonist, a thiazide or other diuretic, or other blood-pressure-lowering drug than were those in the intervention group.

"That the physicians giving all of these extra drugs did not reduce the blood pressure of patients allocated placebo (not known to the physician) as much as they lowered the blood pressure of those allocated to the intervention in ADVANCE is strange," he wrote.

Moreover, with physicians permitted so much latitude in use of antihypertensive drugs, Dr. Kaplan questioned the ADVANCE investigators conclusion that "better outcomes could be attributed solely to the intake of perindopril and indapamide."

"As has been said many times before by many experts in most circumstances, lowering blood pressure is what counts, not the way by which it is lowered," Dr. Kaplan concluded.