Intensive BP and Glucose-Lowering Additive in Diabetic Patients 

Lowering blood pressure and intensive glucose control are additive in reducing the risk of cardiovascular mortality and all-cause mortality in people with type 2 diabetes, new results from the Action in Diabetes and Vascular Disease (ADVANCE) trial show.

Presenting new data here at the European Association for the Study of Diabetes (EASD) 44th Annual Meeting, Dr John Chalmers (George Institute for International Health, Australia) emphasized that the benefits of the two strategies appeared to act independently not only on microvascular events but also macrovascular events.

"The joint effects of these two treatments provide very substantial benefits," Chalmers concluded, "including an almost one-third reduction in nephropathy and renal events, a one-quarter reduction in cardiovascular death, and close to one-fifth reduction in all-cause mortality."

Results for both the blood-pressure lowering and glucose-lowering effects have previously been reported in The Lancet and the New England Journal of Medicine [1,2]. In all, the multicenter, randomized, placebo-controlled study enrolled a total of 11,140 patients with type 2 diabetes from 215 centers in 20 countries worldwide—the largest diabetes study of its kind to date—with a five-year follow-up. Patients were randomized in one arm of the study to treatment with a fixed combination of perindopril and indapamide or matching placebo, and in the other arm of the study to either standard glucose control or intensive glucose control, defined as the use of modified-release gliclazide plus any additional drugs to achieve a glycated hemoglobin level of 6.5% or less. Primary end points were composites of major macrovascular events (nonfatal myocardial infarction [MI], nonfatal stroke, or cardiovascular death) and major microvascular events (new or worsening nephropathy or retinopathy) assessed both together and individually.

As previously reported, the intensive blood-pressure lowering reduced the risk of cardiovascular death by 18%, but the intensive glucose-control had no significant effects on major macrovascular events, cardiovascular death, or death from any cause.

But in new information presented today, Chalmers showed that the relative risk reduction for the combined intensive treatments both for all-cause mortality and for cardiovascular mortality were significantly reduced with combined treatment, beyond that of either treatment independently.

*Standard glucose/placebo blood pressure (BP) vs intensive glucose/intensive BP

Statistical tests confirmed that the effects of the two treatments were independent of each other for all clinical outcomes (p>0.1) and that where only one treatment appeared to have a significant effect, the second treatment "did not undo that effect," Chalmers said.

"Multifactorial treatments, including routine blood-pressure lowering and intensive glucose control, are indicated for all patients with type 2 diabetes," Chalmers concluded.

During discussion following the ADVANCE presentation, Dr Markku Laakso (University of Kuopio, Finland) asked Chalmers to speculate on why intensive glucose lowering has repeatedly failed to show the kind of reduction in cardiovascular events that experts, for years, have anticipated such a strategy could produce.

In response, Chalmers said that the message from ACCORD, ADVANCE, and most recently the Veterans Affairs Diabetes Trial (VADT) is that a trial with follow-up of only five years is not long enough to pick up the slow-acting effects of glucose-lowering on cardiovascular disease.

Dr David Matthews (Oxford University, UK) also emphasized that the "signal goes in the right direction" for reduced cardiovascular events.

"Glucose gives you atherosclerosis over four, five, or six years, so whatever you do in terms of testing therapeutics, you have to think that you’re going to get answers at year six or seven. And that’s true for all these trials."

Instead, he said, over a shorter time period, beneficial effects will be seen in terms of "surrogates" for future cardiovascular disease, including reduced nephropathy—something achieved in both the BP and glucose arms of the trial.

Pearls for your Practice

• Patients randomized to treatment with a fixed combination of perindopril and indapamide and to intensive glucose control to achieve a glycated hemoglobin level of 6.5% or higher had nearly a one-third reduction in nephropathy and renal events vs those who received no antihypertensive treatment and standard glucose control.
• Patients who received aggressive antihypertensive treatment and intensive glycemic control had a one-quarter reduction in cardiovascular death and close to one-fifth reduction in all-cause mortality

ADVANCE Collaborative Group. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): Lancet 2007; 370:829-840.

The ADVANCE collaborative group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008; 358:2560-72.