An analysis of data from the ACCORD study into intensive therapy of blood glucose has shown that the benefits of such therapy need to be balanced against the increase in total and cardiovascular disease-related mortality, increased weight gain, and high risk for severe hypoglycaemia.

ACCORD was a randomised trial done in 77 clinical sites in North America. People with type 2 diabetes for an average of 10 years, high HbA1c concentrations ( greater than 7•5% ), and cardiovascular disease ( or greater than or equal to 2 cardiovascular risk factors ) were randomly assigned by central randomisation to intensive ( target HbA1c of less than 6%, normal ) or standard ( 7-9% ) glycaemic therapy.

In this new analysis, the prespecified microvascular composite outcomes were: dialysis or renal transplantation, high serum creatinine ( greater than 291•7 micromol/L ), or retinal photocoagulation or vitrectomy, all signifying advanced kidney disease and eye disease ( first composite outcome ); or peripheral neuropathy plus the first composite outcome ( second composite outcome ). 13 prespecified ( less severe ) microvascular secondary measures of diabetes-related kidney, eye, and peripheral nerve complications were also assessed.

10 251 patients were randomly assigned, 5128 to the intensive glycaemia control group and 5123 to standard group. Intensive therapy was stopped before study end because of 22% higher mortality in that group compared with the standard therapy group, and patients were transitioned to standard therapy. At the time of transition of the intensively-treated patients to standard treatment, and at the end of the study, patients from both groups were statistically as likely to reach either composite endpoint. Hence, intensive therapy did not reduce the risk of advanced measures of microvascular outcomes ( such as the need for dialysis or eye surgery for diabetes complications ). However, intensive glucose treatment delayed the onset of albuminuria and some measures of eye complications and neuropathy. Seven secondary measures at study end favoured intensive therapy, including signs of protein leakage into the urine, deterioration of vision, and evidence of nerve damage.

The 22% relative and 0•27% per year absolute increase in all-cause mortality recorded with intensive glycaemia therapy in ACCORD prompted the discontinuation of intensive glycaemia control and transition of patients to standard glycaemia therapy. Additionally, intensive therapy led to increased body-mass index and a three-fold increase in frequency of severe hypoglycaemia. Furthermore, no overall cardiovascular disease benefit had accrued.

The observed benefits associated with intensive glycaemia management should be weighed against higher total and cardiovascular-related mortality, weight gain, and severe hypoglycaemia in patients at high risk of cardiovascular disease. Hence, caution should be exercised in pursuit of a strategy of intensive glycaemic control for prevention of microvascular complications in patients with established type 2 diabetes and characteristics similar to those in the ACCORD trial. An HbA1c target of 6% or less with present strategies seems imprudent. Long-term assessment of benefits versus risks should be done through follow-up of the ACCORD participants.

In an accompanying Comment, Ronald Klein, University of Wisconsin School of Medicine and Public Health, Madison ( USA ) says the ACCORD study was too short and did not have enough statistical power to observe a protective effect for the severe microvascular endpoints, which usually evolve over a longer period. He says it took the UK Prospective Diabetes Study ( UKPDS ) about 10 years to show efficacy of intensive glycaemic control for the same advanced endpoints.

According to Klein, the ACCORD experience will ( or should ) cause clinicians to doubt the importance of glycaemic control in preventing microvascular complications of diabetes. Long-term follow-up of the UKPDS and the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications studies showed that intensive glycaemic control reduced both microvascular and macrovascular complications of diabetes. It might be that the regimen used in ACCORD was perhaps more aggressive than is prudent in patients with type 2 diabetes at high risk for cardiovascular disease. However, with the expected doubling or tripling in the number of people worldwide who will develop type 2 diabetes over the next 20 years, it is important that ACCORD's findings not be misinterpreted as a justification for a return to poor glycaemic control that was common before UKPDS reported.

Source: The Lancet, 2010

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