Additional BP lowering in diabetes is major ADVANCE

3 September 2007

MedWire News: Lowering blood pressure (BP) with a fixed combination of perindopril and indapamide can significantly reduce cardiovascular disease events and death in a range of Type 2 diabetes patients, ADVANCE study findings show.

ADVANCE investigator Stephen McMahon (George Institute for International Health, University of Sydney, New South Wales, Australia) said that such an approach of simply adding a fixed-dose combination therapy irrespective of starting BP, and without aiming for specific BP goals, would provide a simple and effective way to greatly reduce the burden of diabetes-related cardiovascular disease.

Presenting the results at the European Society of Cardiology Annual Congress in Vienna, Austria, McMahon noted: “While much attention has been placed on achieving glucose control in diabetes patients, it is less well recognized that high blood pressure is one of the critical determinants of vascular complications.”

Many diabetes patients do not have hypertension, he explained, but data from the UK Prospective Diabetes Study (UKPDS) suggested that they would also benefit from blood-pressure lowering. In that study, the associations between systolic blood press (SBP) lowering and reductions in myocardial infarction and microvascular endpoints persisted well below the average SBP level of 145 mmHg achieved with intervention.

The ADVANCE (Action in Diabetes and Vascular Disease: preterax and diamicron-MR Controlled Evaluation) trial enrolled 11,140 Type 2 diabetes patients with either a history of major cardiovascular disease or at least one other risk factor for cardiovascular disease.

All patients received the fixed combination tablet containing perindopril 2 mg and indapamide 0.625 mg daily for the 6-week pre-randomization run-in period. The patients continued to take their usual background treatment, except for any angiotensin converting enzyme (ACE) inhibitor other than perindopril, and any other thiazide diuretic. Any ACE inhibitor was substituted for perindopril.

Patients were then randomly assigned to receive the same fixed-dose combination or placebo and at 3 months the combination dose was doubled to perindopril 4 mg and indapamide 1.25 mg.

Over 4.3 years of follow-up, combination-treated patients’ average SBP and DBP levels were 5.6 mmHg and 2.2 mmHg lower, respectively, than placebo-treated patients’ levels. BP levels, at an average of 135 mHg in combination-treated patients and 140 mmHg in placebo-treated patients, were lower than the corresponding 145 mmHg and 155 mmHg in the intervention and placebo arms of UKPDS, McMahon noted. The current study therefore included patients with a lower BP range than has previously been examined.

The results, simultaneously published advance online by The Lancet, show that the ACE-inhibitor plus diuretic combination reduced the risk for all-cause mortality by 14% relative to placebo (p=0.025).

This was driven by a reduction in cardiovascular deaths, at a relative risk reduction of 18% (p=0.027).

The combination was also associated with a 9% relative risk reduction for the combined outcome of any major macro- or microvascular event (p=0.041). However, separate reductions in macrovascular and microvascular events were not independently significant.

Other outcomes significantly reduced with the perindopril plus indapamide combination were coronary heart disease, by 14%, and renal disease, by 21%.

McMahon commented that the lack of independent effect on macrovascular events despite a significant reduction in coronary heart disease could be attributed in part to a low cerebrovascular event rate, and to the relatively modest degree of BP reduction.

He stressed that similar benefits were seen in patients with and without hypertension at baseline, as well as in the presence or absence of treatment with: ACE inhibitors and other BP lowering drugs; statins and other lipid-lowering drugs; and aspirin and other antiplatelet drugs.

The ADVANCE investigators say that, in absolute terms, the results mean one death could be avoided for every 79 patients treated with the fixed combination of perindopril and indapamide for 5 years.

McMahon said that this has important global implications because even if half of diabetes sufferers worldwide were treated it would mean the prevention of 1.5 million deaths.

European Society of Cardiology Annual Congress 2007; Vienna, Austria: 1-5 Sept