How can three landmark trials of intensive vs standard glucose-lowering strategies — ADVANCE, ACCORD, and VADT — raise more questions than they answer?…
All three studies did not meet their primary objective of reducing cardiovascular events, despite achieving significant lower HbA1c levels, and, in the ACCORD study, the data-monitoring committee prematurely stopped the intensive strategy arm due an excess rate of cardiovascular death. These results flew squarely in the face of conventional wisdom that lowering HbA1c to "normal" levels would improve cardiovascular outcomes, similar to the clearly proven benefit of reducing microvascular complications. Each trial has subsequently published numerous analyses that have tried, mostly unsuccessfully, to explain why mortality, in particular, did not decrease, or in the case of ACCORD even increased, with a more intensive glycemic strategy.
What is interesting is that across these studies, there does appear to be a consistent signal that improved glycemic management may reduce coronary artery events. This observation was first noted over a decade ago in the UKPDS study, in which more intense glycemic control reduced the rate of MI. The ACCORD investigators now report a consistent reduction of about 15% to 20% in non-fatal MI, unstable angina, and coronary revascularization in the intensive therapy arm. The benefit became more apparent during the longer follow-up period, suggesting a legacy effect. Interestingly, when controlling for achieved HbA1c, the benefit was attenuated, which implies that better glycemic control may be causal in reducing ischemic events.
It is important to remember that this is a post-hoc analysis and still cannot reconcile the higher rates of death in the intensive strategy arm. But it raises the possibility that there may be strategies that can both safely lower glucose and reduce cardiovascular events. How you improve glycemic control may be as important as the actual HbA1c target. The score of ongoing cardiovascular outcome trials of novel antihyperglycemic agents will likely provide further insight into this clinical dilemma.
The researchers assessed 10,251 adults aged 40-79 years with established type 2 diabetes, mean glycated hemoglobin A1c (HbA1c) concentration of 67 mmol/mol (8.3%) and risk factors for ischemic heart disease enrolled in the ACCORD trial. Participants were assigned to intensive or standard therapy (target HbA1c less than 42 or 53-63 mmol/mol [less than 6.0% or 7.0-7.9%], respectively). We assessed fatal or non-fatal myocardial infarction, coronary revascularization, unstable angina, and new angina during active treatment (mean 3.7 years) plus a further mean 1.2 years.
Myocardial infarction was less frequent in the intensive than in the standard therapy group during active treatment (hazard ratio [HR] 0.80, 95% CI 0.67–0.96; p=0.015) and overall (0.84, 0.72-0.97; p=0.02). Findings were similar for combined myocardial infarction, coronary revascularization, and unstable angina (active treatment HR 0.89, 95% CI 0.79-0.99, overall 0.87 0.79-0.96) and for coronary revascularization alone (0.84, 0.75-0.94) and unstable angina alone (0.81, 0.67-0.97) during full follow-up. With lowest achieved HbA1C concentrations included as a time-dependent covariate, all hazards became non-significant.
- Raised glucose concentration is a modifiable risk factor for ischemic heart disease in middle-aged people with type 2 diabetes and other cardiovascular risk factors
- Myocardial infarction was less frequent in the intensive than in the standard therapy group
The Lancet, Early Online Publication, 1 August 2014, doi:10.1016/S0140-6736(14)60611-5