The latest findings from the ADVANCE (Action in Diabetes and Vascular Disease) study have been presented at this week’s meeting of the European Association for the Study of Diabetes congress held in Rome.

The results show that lowering blood pressure and intensive glucose control are additive in reducing the risk of cardiovascular mortality and all-cause mortality in type 2 diabetes.

In the study – the largest-ever performed in patients with type 2 diabetes – combining intensive blood sugar control based on gliclazide modified release (Diamicron MR, Servier) with intensive blood pressure lowering based on a fixed combination of perindopril and indapamide (Preterax, Servier) reduced the risk of death from heart disease by nearly one-quarter (24%) and risk of kidney complications by one-third (33%) in patients with type 2 diabetes. The benefits of tight blood glucose control and blood pressure lowering were both independent and fully additive.

There has been great interest in ADVANCE following surprising results from the ACCORD (Action to Control Cardiovascular Risk in Diabetes) study which was terminated prematurely earlier this year due to a 22% increase in all cause mortality in patients whose blood glucose was aggressively controlled using regimens which included thiazolidinediones.

At an EASD press conference, results from ADVANCE, ACCORD and a third trial VADT (Veterans Affairs Diabetes Trial), were discussed by three leading diabetes researchers: John Chalmers of The George Institute for International Health, Sydney, Australia and head of ADVANCE; David Matthews (Oxford Centre for Diabetes, Endocrinology and Metabolism) and Cliff Bailey, Head of Diabetes Research and Professor of Clinical Science at Aston University in Birmingham.

They addressed the question of why there was no increase in all cause mortality in ADVANCE, despite blood glucose (HBa1c) being lowered to around the same level as that achieved in the intensive arm of ACCORD.

They broadly agreed that the drug strategy used in ACCORD may have been too aggressive for frail elderly patients. Two speakers also stated that although specific effects of drugs used in ACCORD could not be blamed for the excess mortality observed, neither could such effects be ruled out.

Professor Bailey drew attention to the increased number of hypoglycaemic episodes observed in ACCORD, compared with ADVANCE and speculated that these may be linked to the increased mortality observed in ACCORD.

He said that over-intensive efforts to achieve ‘near-normal’ glucose control in ACCORD may have increased risk of mortality in ‘vulnerable’ patients. “The intensity of glucose control must be adapted to the circumstances of the individual. Hypoglycaemia and abnormalities of the diabetic heart may combine to increase susceptibility to fatal heart attack.”

He added that existing treatment guidelines remained appropriate, but they need to be applied flexibly to fit the circumstances of the individual patient.

Prof Chalmers said that ADVANCE had used a more gradual approach and fewer drugs to get patients to target HbA1c levels than the regimens used in ACCORD. Prof Matthews agreed that the strategy used in ACCORD had been too aggressive and that the gradual approach to glucose control used in ADVANCE made more sense biologically.

He added that although results from the two trials could not be used directly to compare the drugs employed in each, some drugs used in ACCORD may have had a downside: “We don’t yet know,” he said. The new ADVANCE findings will be published early next year. By Ian Mason in Rome

– Meantime, an editorial in this week's New England Journal of Medicine calls for tighter control of new diabetes therapies, following cardiovascular safety fears.

Allison Goldfine says that the US Food and Drug Administration’s Endocrinologic and Metabolic Drugs Advisory Committee has discussed a new two-step process for evaluating the cardiovascular safety of new diabetes agents. It would consist of a randomised cardiovascular-event–driven trial, before approval with a longer, larger post-approval trial to establish the safety margin more clearly.

Dr Goldfine adds that the FDA could require manufacturers to submit a design for a cardiovascular-safety trial and ongoing progress reports to obtain and maintain a drug's approved status; failure to achieve milestones might lead to restrictions or withdrawal of approval.