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New studies provide conflicting evidence on mortality and intensive diabetes treatment
By Rhonda Siddall

28th February, 2008

INTERIM results from the ADVANCE Study, involving 11,140 high-risk patients with Type 2 diabetes provide no evidence of an increased risk of death among those patients receiving intensive treatment to lower blood glucose.


These findings contrast with those reported recently by the US National Heart Lung and Blood Institute (NHLBI), suggesting that intensive glucose lowering had increased the death rate among patients with diabetes recruited to the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. The ACCORD trial has been stopped prematurely because of a higher rate of mortality in the patients in the intensive arm. ACCORD is an NHLBI-sponsored study of around 10,000 patients with Type 2 diabetes and either heart disease or two risk factors for heart disease. The glycaemic control part of the trial was testing whether an intensive strategy that targets an HbA1c level of <6.0% reduces the rate of cardiovascular events more than a standard strategy that targets an HbA1c of 7.0% to 7.9%. Patients were then assigned to two other parts of the trial depending on their blood pressure and cholesterol levels, testing the combination of a fibrate and a statin or statin monotherapy, and these arms will continue.
A separate study, Steno-2, reported this month showing that in high-risk Type 2 diabetes patients, early intensive intervention with multiple drug combinations and behaviour modification leads to reduced rates of death and cardiovascular disorders. 1

ADVANCE was designed to answer two questions in patients with Type 2 diabetes: first, does intensive treatment to lower blood pressure improve outcome; and second, does intensive treatment to reduce blood glucose improve outcome.

In September 2007, the ADVANCE Collaborative Group published evidence in The Lancet showing that the blood pressure-lowering treatment had reduced the death rate among participants. In January 2008, the part of the study designed to assess the effects of the intensive treatment to reduce blood glucose was completed. As in ACCORD, this intensive treatment programme was designed to lower blood glucose to levels below those usually recommended by clinical guidelines. 2

Chairman of the ADVANCE Data Monitoring and Safety Committee, Professor Rory Collins from the University of Oxford, said: “The interim results from ADVANCE provide no confirmation of the adverse mortality trend reported from the ACCORD study.” He also noted that the ADVANCE interim results were based on more than twice as much data and similar levels of glucose control as in ACCORD.

The members of the Data Monitoring and Safety Committee are the only members of ADVANCE study team with access to the study results.

In ADVANCE, the intensive blood glucose lowering programme aimed to reduce levels of HbA1c to below 6.5%. This treatment regimen included a sulphonylurea drug for all patients and a range of other drugs for those not reaching target blood glucose levels. ADVANCE began in July 2001 and patients were treated and followed-up for an average of five years. The Data Monitoring and Safety Committee, made up of a panel of independent experts in the field, met every six months to review the study data for any safety issues or other concerns. Blood pressure treatment included the ACE inhibitor, perindopril, and the diuretic, indapamide. This treatment was shown to reduce mortality in patients with diabetes. 2

Steno-2 reported a 20% absolute risk reduction in the primary end point — all-cause mortality — after a total of 13.3 years of follow-up. Similarly, the absolute risk reduction for cardiovascular death was 13.0% in high-risk Type 2 diabetes patients. 1

Professor Anthony Barnett, Professor of Medicine/Honorary Consultant Physician at the University of Birmingham, told the NOF that these new trials may have provided conflicting evidence by chance or may in time illuminate new mechanisms that explain the findings. Furthermore, says Professor Barnett, Steno-2 and ACCORD studied very different patient populations and this may explain the different outcomes.  

Patients in Steno-2 were younger, had had diabetes on average six years, and were deemed high risk by the presence of microalbuminuria rather than having heart disease or two known risk factors for heart disease as in ACCORD.

1. Gaede P, Lund-Anderson H, Parving HH, et al. Effect of a multifactorial intervention on mortality in type 2 diabetes. NEJM. 2008;358:580-591 http://content.nejm.org/cgi/content/abstract/358/6/580

2. ADVANCE Collaborative Group; Patel A, MacMahon S, Chalmers J, Neal B, et al. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet 2007;370:829-40 http://www.thelancet.com/journals/lancet/article/PIIS0140673607613038/abstract