Intensive glycemic control decreased nonfatal MIs by 17% and coronary heart disease events by 15% in a meta-analysis of five major trials in patients with type 2 diabetes.
Still, intensive treatment did not reduce rates of all-cause mortality, stroke, or heart failure significantly; it doubled the rate of severe hypoglycemic episodes, and it was associated with weight gain, wrote Dr. Kausik K. Ray of the University of Cambridge (U.K.) and his associates.
The investigators performed the meta-analysis because clinical trials “have failed to show consistent beneficial effects on cardiovascular events” with intensive glycemic control, but that may be because individually the trials might have been underpowered to do so.
From an initial review of 2,439 articles in the medical literature, Dr. Ray and his colleagues culled five randomized, controlled trials that fit their strict criteria for inclusion in the meta-analysis: the combined United Kingdom Prospective Diabetes Studies (UKPDS); the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROACTIVE); the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE); the Veterans Affairs Diabetes Trial (VADT); and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.
These studies all were randomized trials of intensive glycemic control vs. either standard care or less intense intensive control; showed significantly different hemoglobin A1c levels between groups during follow-up; and used cardiovascular events as a primary end point. They included 33,040 subjects with longstanding diabetes.
The meta-analysis showed that intensive glycemic control, as evidenced by a 0.9% reduction in HbA1c, significantly decreased nonfatal MI by 17% and CHD events by 15%. It also decreased stroke by a nonsignificant 7%.
Intensive glycemic control did not affect heart failure rates or all-cause mortality, however.
“The absence of convincing data and concerns about possible harm [have] led consensus groups to provide a conservative endorsement for the cardiovascular benefits of intensive glycemic control.
“Our quantitative analysis of randomized controlled trials provides reliable large-scale evidence of a consistent beneficial effect of intensive treatment on nonfatal MI and CHD, without increased risk in all-cause mortality,” Dr. Ray wrote (Lancet 2009;373:1765–72).
Dr. David Kendall, medical director at the International Diabetes Center in Minneapolis concurred, noting that another meta-analysis of the same data, published online last month, came to similar conclusions (Nutr. Metab. Cardiovasc. Dis. 2009 May 8 [doi:10.1016/j.numecd.2009.03.021]).
These findings should help clarify a series of apparently contradictory or inconclusive reports for clinicians. This analysis is particularly important given that the ACCORD trial showed a 22% increase in mortality in patients on intensive glucose control and was halted early. “This meta-analysis allows us to look at the entire data set, which indicates that with a preponderance of evidence, there is evidence of a benefit of intensive glucose control—without undue mortality risk,” Dr. Kendall said in an interview.
He stressed that the findings on this apparently small effect of glucose on macrovascular complications “should not steer us away from the importance of glucose control and its proven benefit for prevention of eye disease, kidney disease, and other serious microvascular complications.” Dr. Kendall was an investigator in ACCORD and has received research support from and is a consultant for several manufacturers of diabetes drugs.
Intensive glycemic control was associated with adverse effects, including greater weight gain (a mean of 2.5 kg) and nearly double the number of patients with severe hypoglycemic episodes as found with less intensive control (2.3% vs. 1.2%).
Dr. Ray reports receiving honoraria from Novartis.
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