Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

68th Scientific Sessions of the American Diabetes Association

San Francisco, California / June 6-10, 2008

The results of a trial called ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) confirm the importance of targeting multiple vascular risk factors simultaneously. In the first of the two-part study, significant event reductions were achieved in patients randomized to a fixed combination of perindopril and indapamide relative to placebo. In the newly completed second part, known as the blood glucose-lowering arm, significant event reductions were achieved in patients randomized to modified-release gliclazide with a treatment goal of an HbA1c of <u><</u>6.5% relative to standard control.

“The ADVANCE results go beyond existing evidence, as we have now shown that reducing the HbA1c levels to 6.5% is a safe and effective way to reduce serious complications,” stated Dr. Stephen MacMahon, Co-principal Director, The George Institute for International Health, University of Sydney, Australia. He reported that the results of the second part of ADVANCE are particularly relevant to reducing the risk of kidney disease, which he noted is “one of the most serious and disabling consequences of diabetes, leading to death in one in five diabetics.”

Part II of ADVANCE

The results of the blood glucose-lowering arm were presented at the ADA and published in the New England Journal of Medicine (ADVANCE Collaborative Group. N Engl J Med 2008;358:2560-71). The 11,140 patients were randomized to achieve a mean HbA1c of 6.5% or less on a regimen of modified-release gliclazide plus other drugs as needed to reach the goal or usual care. For entry, patients were required to have been diagnosed with DM2 at 30 years of age or older and to be at least age 55 at enrolment. They were also required to have a history of major macrovascular or microvascular disease or at least one other risk factor for vascular disease. Other than a contraindication to the study treatments, there were no other restrictions including those related to baseline HbA1c.

After a median of five years of follow-up, the mean HbA1c was 6.5% in the intensive treatment group and 7.3% in the standard control group. For the primary outcome of a composite of macrovascular events (death from cardiovascular [CV] causes, nonfatal myocardial infarction, or non-fatal stroke) and major microvascular events (new or worsening nephropathy or retinopathy), there was a relative reduction of 10% (hazard ratio [HR] 0.90; 95% CI, 0.82- 0.98; P=0.01). The largest reduction was in major microvascular events, including a 21% relative reduction (HR 0.79; 95% CI, 0.66-0.93; P=0.006) in the incidence of nephropathy.

“Our first conclusion is that intensive glucose control reduces some of the serious complications of diabetes, primarily new or worsening kidney disease,” reported Dr. Anushka A. Patel, Director of the Cardiovascular Division, The George Institute for International Health, who presented the results at the ADA. She emphasized that the benefits of the regimen used in the tight blood glucose control arm were achieved with a relatively low risk of severe hypoglycemia. Although such events were higher in the intensive treatment arm (2.7% vs. 1.5%; P<0.001), they were uncommon in both groups.

When CV events were assessed separately, the advance of the modified release gliclazide arm trended towards an advantage for several specific outcomes, such as a 12% relative reduction in death from CV causes, but did not show a statistical advantage on any specific macrovascular outcome.

ACCORD Study not Comparable

Although the failure to reach statistical significance was disappointing, the rate of macrovascular events in the ADVANCE trial was lower than anticipated, possibly due to the exceptionally aggressive use of statins, antihypertensive therapies, and antiplatelet agents in both arms. However, the authors stressed that there was no evidence of an increased risk of macrovascular events with intensive treatment, an important point to make in the context of the simultaneously released results of the ACCORD (Action to Control Cardiovascular Risk in Diabetes) study, which was another intensive blood glucose-lowering study stopped early due to an increased CV mortality.

“There are several important differences between the ACCORD and ADVANCE studies, including the degree and pace of glucose lowering and the treatments employed,” Dr. Patel noted. A careful analysis of the ADVANCE data “was unable to identify any subgroup in which there was evidence of an adverse effect from intensive glucose lowering on major vascular outcomes.” Among the notable distinguishing characteristics of ACCORD—which, unlike ADVANCE, was not designed to test a specific antidiabetic drug strategy—was a rate of hypoglycemia requiring medical assistance that was three times greater (10.5% vs. 3.5%; P<0.001) in the intensive treatment arm. In addition, the rate of weight gain greater than 10 kg was almost twice as great (27.8% vs. 14.1%; P<0.001) in the intensive treatment arm, and there were significant differences in fluid retention and non-hypoglycemic adverse events.

In contrast, there was a 7% reduction in all-cause mortality for patients randomized to modified-release gliclazide relative to standard care in the ADVANCE study. Although this reduction was not significant, the confidence intervals of the reduction are consistent within a range of an anticipated mortality benefit associated with a 0.7% reduction in the HbA1c based on observational data, according to ADVANCE investigators. While they concluded that such data reinforce the overall results of the blood glucose-lowering arm of ADVANCE, they linked both arms of the study to conclude that optimal benefits are achieved from simultaneous control of multiple risk factors. In fact, both arms of ADVANCE were positive.

New Antihypertensive Data from Part I of ADVANCE

Specifically, an antihypertensive strategy based on the single pill combination of perindopril and indapamide was associated with a 9% reduction (HR 0.91, 95% CI, 0.83-1.00; P=0.04) in the primary composite end point of microvascular and macrovascular end points relative to placebo in the previously reported results of the blood pressure (BP)-lowering arm of ADVANCE. The relative reductions in microvascular and macrovascular end points were of similar magnitude when assessed separately. In addition, the patients randomized to perindopril/indapamide, which reduced BP on average by 5.6/2.2 mm Hg relative to placebo, had an 18% relative reduction in death from CV disease (HR 0.82, 95% CI, 0.68-0.98; P=0.03) and a 14% reduction in death from any cause (HR 0.86, 95% CI, 0.75-0.98; P=0.03).

In new data from the BP-lowering arm of ADVANCE, the rate of albuminuria in those randomized to perindopril/indapamide was reduced by 21% (95% CI, 15%-27%; P<0.0001) relative to placebo. When a log-linear analysis was conducted to evaluate the relationship of BP and incidence of renal events, a benefit from treatment was observed down to a median of 106/62 mm Hg (P<0.0001 for the trend). This suggests benefit can still be achieved by reducing BP to levels lower than currently recommended targets. More data are needed to evaluate the independent contribution of inhibition of the renin-angiotensin-aldosterone system with perindopril, which has been shown to improve endothelial function independent of BP control when combined with indapamide.

Summary

The results of both arms of the ADVANCE trial, although consistent with expectations, provide evidence-based guidance for risk management in DM2. Intensive blood glucose control anchored with modified-release gliclazide does produce significant reductions in a composite end point of microvascular and macrovascular events when employed to reach an HbA1c of <u><</u>6.5% relative to less rigorous treatment. Similarly, a single-pill combination of perindopril/indapamide has been associated with improvement in the same end points relative to placebo. The study is considered to have direct implications for the day-to-day care of DM2 patients.