Dramatic Benefits in Diabetes for Small Blood Pressure Drops to Below Normal

Stephan MacMahon, M.D., of the George Institute for International Health in Sydney, Australia stated that, 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).

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 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<0.001 for both).

Dr. MacMahon said, "The results clearly are specific to this specific treatment, but that is not to say there are not likely to be broader benefits of blood pressure lowering itself, aside from the specific agent," and he noted that, "we did not treat to a specific goal and the actual blood pressure reduction was quite small, but it appears that any lowering of blood pressure is beneficial."

At baseline, more than 40% of participants were using another ACE-inhibitor, while 5% to 6% were taking an angiotensin receptor blocker, about one in four were using beta-blockers, 30% to 32% were taking calcium channel-blockers and about 15% were using a diuretic.

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 Patients taking an ACE inhibitor had the drug withdrawn and were offered open-label peridopril at 2 mg or 4 mg a day.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.

Norman M. Kaplan, M.D., of the University of Texas Southwestern in Dallas, 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-naïve 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.

"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.

Practice Pearl:

• Explain to interested patients that the results of this trial suggest that even modest reductions in blood pressure can reduce mortality for patients with diabetes.

MacMahon S et al "Effects of a fixed combination of peridopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomized controlled trial" Lancet Published online September 2, 2007.