Intensive treatment with glucose-lowering therapy can reduce the complications of type 2 diabetes, according to the results of the 11,140-patient ADVANCE study, although the strategy does not seem to impact major cardiovascular events such as heart attack or stroke.

And in contrast to the results of another large-scale study of glucose-lowering in diabetes – the ACCORD trial – the treatment did not appear to have an adverse effect on survival. Both ADVANCE and ACCORD are published in the online edition of the New England Journal of Medicine (June 6).

In ADVANCE the intensive treatment group – treated initially with Servier’s modified-release sulfonylurea drug Diamicron MR (gliclazide) - showed significantly better glucose control over the course of the five-year trial compared to a comparator group treated with a standard glucose-lowering regimen based on other sulfonylureas, said study director Anushka Patel of The George Institute in Sydney, Australia. In the intensive group additional drugs could be added in to help the patients meet the glucose control target.

Levels of haemoglobin A1c (a biomarker for glucose control) were 7.5% for both groups at the start of the study, and fell to 7.3% on standard therapy and 6.5% with the intensive therapy. The latter is close to the normal range, according to David Matthews, professor of diabetes at Oxford University in the UK, who chaired a press conference on the results at the American Diabetes Association conference in San Francisco.

International guidelines recommend low target blood pressure and haemoglobin A1c levels in diabetes, but there is little clinical data to back up that stance.

Critically, the treatment strategy used in ADVANCE was not particularly aggressive and is likely not dissimilar to approaches used in clinical practice around the world, said Stephen MacMahon of The George Institute, one of the principal investigators in ADVANCE. That means the approach should be fairly easy to adopt in clinical practice.

Kidney benefit
Most of the benefit in ADVANCE, which compared standard glucose-lowering therapy with an intensive regimen based on over five years of follow-up, came from a 21% reduction in diabetic nephropathy.

Overall there was a 10% reduction in major vascular complications (heart attack, stroke, kidney disease and eye complications (p=0.013. There was little effect on retinopathy, the other main microvascular complication of type 2 diabetes, or macrovascular events (heart attack or stroke).

“The rate of [retinopathy] was fairly low, certainly lower than previous studies, and therefore the ability to detect the effects of glucose control was reduced. While there was no clear benefit, the results are not inconsistent with an effect,” said Dr Patel.

The effect on nephropathy is significant, however, as prior studies indicate that renal impairment are closely linked to the development of “major vascular events, end-stage renal disease and death,” according to the study authors. And there were also suggestions that a greater benefit might have been observed with the intensive treatment if the study had gone on for longer.

“We hope to follow patients long-term, particularly with regards to survival, to see if the benefits of treatment persist,” commented Prof MacMahon. “There is evidence from other studies of continuing effects of interventions for as long as 10 years or more.”

Last year, the results of the first portion of the study looked at the effects of blood pressure lowering with Servier’s Preterax (ramipril and indapamide), and found that in this case there was a significant 18% reduction in ‘macrovascular’ events such as heart attack and stroke.

Meanwhile, the results of the 10,251-patient ACCORD study, suspended in February after a little over three years of follow-up, found a slight statistical increase in mortality in patients treated with intensive glucose-lowering therapy compared to standard therapy.

This suggests that there is still a lot of discussion to come about the benefits of intensive therapy, but there are some differences between the studies worth nothing. For example, in ACCORD patients had poorer glucose control at enrolment, were treated with a much more aggressive regimen and put on a fair amount of weight. In advance no such weight gain was observed, according to Dr Patel. By Phil Taylor