Cambridge, UK - A new meta-analysis suggests that intensively controlling blood glucose levels significantly reduces the risk of MI and coronary heart disease (CHD) events and has no effect on all-cause mortality [1]. The findings, which include five of the pivotal diabetes studies that have caused a stir regarding glucose control, support continued therapy that lowers elevated glycated hemoglobin A1c (HbA1c) to less than 7.0%, say researchers.
"There has been a huge amount of controversy and concern that the treatments we had been advocating because we believed they were important, even though there wasn't as much evidence as in other areas like cholesterol and blood pressure, might actually be flawed," lead investigator Dr Kausik Ray (University of Cambridge, UK) told heartwire. "The danger is that our patients and physicians start to slip up in control of sugars because they're not actually sure that it's beneficial and might actually be harmful."
Those concerns stemmed particularly from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) and Action in Diabetes and Vascular Disease (ADVANCE) studies. While ADVANCE showed a reduction in the progression of albuminuria with intensive glucose control, there was no effect on cardiovascular-event rates. ACCORD, on the other hand, was stopped early because of an increased risk of death in patients who underwent intensive blood glucose lowering.
The meta-analysis, however, should help clinicians feel more comfortable adhering to the clinical guideline target of HbA1c.
"We do need more information about who shouldn't get to aggressive targets, and that we'll only get with further research," added Ray. "What this study does do is help those individuals out there with diabetes and their caregivers and lets them know that what they've been doing is likely safe and is justified."
In an editorial appearing in the May 23, 2009 issue of Lancet alongside the study by Ray and colleagues, Dr Thomas Mazzone (University of Illinois, Chicago) also stresses that clinicians should not undervalue the potential benefits of managing hyperglycemia, especially given the effects on microvascular disease, the observational data linking indices of glycemia control to cardiovascular risk, and pathophysiological studies in type 1 diabetics showing reduced cardiovascular events with tight glycemic control [2].
"A glycosylated hemoglobin of 7% for most patients seems reasonable and safe," writes Mazzone.
Intensive glucose control questioned
In addition to ACCORD and ADVANCE, the Veterans Affairs Diabetes Trial (VADT), a long-term study of US veterans with type 2 diabetes receiving intensive blood glucose control, recently showed that intensive blood glucose lowering in patients had no significant effect on the rates of cardiovascular events, death, or microvascular complications. Long-term follow-up of the United Kingdom Prospective Diabetes Study (UKPDS), however, did show that a strategy of early intensive glucose lowering, either with a sulfonylurea or metformin, had lasting, significant effects not only on major diabetes end points but also on risk of MI or all-cause mortality.
Against this backdrop of differing results, Ray and colleagues performed a meta-analysis of randomized clinical trials, including UKPDS, ADVANCE, VADT, ACCORD, and the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROACTIVE). The five trials enrolled 33 040 patients, and all compared the effects of an intensive glucose-lowering regimen on death and cardiovascular outcomes with standard treatment.
Compared with standard therapy, mean HbA1c levels were 0.9% lower among those treated with intensive treatment.
During follow-up of approximately 163 000 person-years, which included 1497 MIs, 2318 CHD events, and 2892 all-cause deaths, investigators report that intensive glycemic control resulted in a 17% reduction in MI and a 15% reduction in the risk of CHD events. There was no effect on stroke and no effect on all-cause mortality.
To heartwire, Ray said the meta-analysis shows the importance of large numbers when assessing risk and benefit. He suspects that these earlier studies, such as ADVANCE and VADT, were underpowered and didn't have sufficient follow-up to show an impact on cardiovascular events. The study also showed that glucose control is slightly less effective than blood-pressure and cholesterol reductions for preventing cardiovascular events and that clinicians should first target hypertension and elevated LDL cholesterol and then go after elevated HbA1c levels, he said.
"Diabetics, as we know, die mostly of vascular disease, and they die about seven years earlier than their nondiabetic counterparts, even though we've made strides in terms of improving outcomes with better blood-pressure control and the use of statins for LDL reduction," said Ray. "There is still residual risk, and this is a further method to reduce that residual risk. If you do all these things together, we know that this is beneficial."
In terms of adverse effects, patients treated with intensive glucose lowering gained more weight, 5.5 pounds, on average, and had almost twice as many severe hypoglycemic events, compared with conventional treatment.
For clinicians, Ray said the study reinforces the recommendations of the American Diabetes Association, American Heart Association, and American College of Cardiology, which state that clinicians should aim to get HbA1c levels to less than 7.0%. Like these organizations, Ray stressed that treatment should be individualized, however, and agents that avoid weight gain and hypoglycemia should be used.
In his editorial, Mazzone echoed a similar sentiment, noting that the 7% target can be adjusted for patients with lower risks associated with hypoglycemia, such as younger patients with no CHD, and those with higher risks, such as elderly patients with heart disease. Like Ray, Mazzone noted that blood-pressure control and LDL-cholesterol reductions will provide greater benefit toward cardiovascular-disease risk, but it is "premature to conclude that glucose control has no part to play."
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