MONTREAL — The largest-ever clinical trial in patients with type 2 diabetes continues to yield data that are expected to lead to improved prediction of cardiovascular risk as well as a better understanding of the relationship between intensive metabolic control and cardiovascular outcomes.
In a symposium lecture at the World Diabetes Congress, Dr. John P. Chalmers summarized data from published and unpublished substudies of the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) study, a randomized, placebo-controlled trial that examined the effect of both intensive blood glucose and blood pressure control on micro- and macrovascular complications. The trial involved a multiethnic cohort of 11,140 patients with type 2 diabetes from 215 centers in 20 countries.
The glucose-lowering arm of ADVANCE, funded by grants from the French pharmaceutical company Servier and the National Health and Medical Research Council of Australia, used modified-release gliclazide along with other glucose-lowering drugs to target a hemoglobin A1c of 6.5%.
The intensive-treatment group achieved a mean HbA1c of 6.5%, vs. 7.3% in the standard-treatment group. At a median of 5 years, the intensive group had a 10% relative reduction in the combined outcome of major macro- and microvascular events vs. standard care, primarily as a consequence of a 21% relative reduction in nephropathy. There was a positive trend toward reduction of major cardiovascular (CV) events (N. Engl. J. Med. 2008;358:2560-72). There was no excess mortality, weight gain, or severe hypoglycemic episodes in the intensive group, said Dr. Chalmers, coprincipal investigator for ADVANCE.
In the blood pressure control arm, routine administration of a fixed combination of perindopril and indapamide was associated with a 9% reduction in the relative risk of a major macro- or microvascular event (Lancet 2007;370:829-40).
In a new, not-yet published subgroup analysis of the glucose-lowering arm, the results held true regardless of age, duration of diabetes, sex, body mass index, HbA1c at study entry, urinary albumin excretion, glomerular filtration rate, or initial glucose-lowering treatment, said Dr. Chalmers, senior director of the George Institute for International Health, Sydney.
Cognitive function, however, was an independent predictor of cardiovascular risk. Mild and severe cognitive dysfunction increased the risk for major CV events. with hazard ratios of 1.27 and 1.42, respectively. Cardiovascular death was increased by hazard ratios of 1.41 and 1.56 for mild and severe cognitive dysfunction, respectively, and all-cause death by 1.33 and 1.50 (Diabetologia 2009;52:2328-36).
Another new and unpublished analysis showed that the risk for microvascular complications had a strong linear relationship with HbA1c values down to 6.0%. Each percentage point reduction reduced the risk by 22%. For macrovascular events, CV death, and all-cause death, the risk reduction was linear down to an HbA1c of 7.0%, then leveled off between 7% and 6%.
A substudy of 647 participants showed no significant associations between CV risk and body mass index, but there was a relationship with waist-hip ratio, a better index of visceral fat. Urinary albumin excretion also predicted risk: For every tenfold increase, there was a twofold increase in macrovascular events. Similarly, a halving of glomerular filtration rate was associated with a twofold increased risk for CV events, Dr. Chalmers said.
With ADVANCE data on CV risk predictors, the investigators are developing a risk engine specific for people with diabetes. Data from two other studies presented at the congress showed that neither Framingham score nor the risk engine derived from the 1998 United Kingdom Prospective Diabetes Study (UKPDS) is an accurate risk predictor for patients receiving modern treatments for glucose, blood pressure, and lipid levels.
Dr. Andre Pascal Kengne, also of the George Institute, presented one of these studies, which found that major cardiovascular risk among 7,502 ADVANCE participants was overestimated by 170% and 202% with use of two different Framingham equations.
Disclosures: Dr. Chalmers is on the advisory board for Servier. Dr. Kengne stated that he had no conflicts of interest.