Diabetes and CV Disease: An Uneasy Truce
Abstract & Commentary
By Jonathan Abrams, MD, Professor of Medicine, Division of Cardiology, University of New Mexico, Albuquerque. Dr. Abrams serves on the speaker's bureau for Merck, Pfizer, and Parke-Davis. This article originally appeared in the August issue of Clinical Cardiology Alert. At that time it was reviewed by Rakesh Mishra, MD, FACC, Berkeley Cardiovascular Medical Group, Berkeley, CA. Dr. Mishra reports no financial relationship to this field of study.
Synopsis: The authors of this meta-analysis conclude that their results support the use of aggressive insulin-lowering therapy to reduce major CV outcomes but not all-cause mortality; further, they recommend vigilance in avoiding hypoglycemia while steadily reducing HbA1c.
Source: Ray, K, et al. Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: A meta-analysis of randomized controlled trials. Lancet 2009;373:1765-1772.
The recent literature is filled with trials of type 2 diabetes (DM) treatment and cardiovascular (CV) disease, with conflicting conclusions. While intuitively reasonable, not all trials of intensive glucose management in diabetes have been found to reduce CV events or decrease CV mortality. This report is an analysis of pooled trials, each with a goal of seeing whether aggressive diabetic therapy would decrease major CV outcomes compared to usual diabetic care. After a comprehensive literature search, Ray et al chose 5 randomized, controlled trials meeting stringent criteria for inclusion in this meta-analysis: UKPDS, PROactive, ADVANCE, VADT, and ACCORD.
Diabetic subjects were randomly assigned to placebo (standard regimen) or intensive glucose lowering, with glycemic control monitoring, to achieve decreased hemoglobin A1c (HbA1c) levels. Endpoints included fatal and non-fatal myocardial infarction (MI), coronary artery disease (CAD, fatal or non-fatal), stroke, and all-cause mortality in stable patients not hospitalized. The 5 trials that met selection criteria were culled from 2400 articles selected by search engines (Medline, Cochrane Central, EMBASE) for articles published in English from 1970 to 2009. Various drugs and insulin regimens were used, including intensive insulin and metformin. Participants were mostly male and aged 53-60 years.
The aggressive insulin-treated group experienced a mean reduction of HbA1c by 0.9% lower than usual care subjects. In addition, there were 2.3 fewer MI events and 2.9 fewer CAD events for every 200 patients on intensive treatment for 5 years. However, the event rates for stroke and all-cause mortality were not statistically different from the conventional treatment. Intensive glucose control significantly reduced non-fatal MI events by 17% (odds ratio [OR], 0.83) and CAD events by 15% (OR, 0.85). Heart failure was not different between groups, but there was pronounced heterogeneity between studies, indicating that glitazone use was associated with an excess risk of heart failure. Hypoglycemia and weight gain were more common in the intensive group (38% vs 28%). Severe hypoglycemia was much less common than moderate hypoglycemia and more common in the intensive insulin therapy subjects, who also had a weight gain of 2.5 kg compared to the standard treatment group. The authors conclude that the intensive glucose-lowering treatment has cardiovascular benefit compared with standard treatment in patients with DM. The UKPDS extension group cohort showed a reduction in MI and all-cause mortality with both metformin and sulphonylurea-insulin regimens.
Commentary
This report provides an excellent database and discussion regarding the meta-analysis of 5 major studies. They assess the risk and benefits of high-dose insulin vs usual care. The 5 trials in this meta-analysis provided an assessment of 1500 events of MI, 230 CAD events, 1100 strokes, and 2900 all-cause mortality. Intensive glycemic control in the aggregate of these trials resulted in a 0.9% lower HbA1c and, importantly, a 17% decrease in non-fatal MI and a 15% reduction in CAD events. Other large studies have not been successful in lowering adverse outcomes with aggressive insulin therapy, and even suggest possible harm with intensive HbA1c lowering (ACCORD), warning that intensive glucose control may have adverse outcomes. Nevertheless, the investigators state that this meta-analysis supports the use of intensive insulin therapy with a consistent beneficial effect of intensive insulin treatment on non-fatal MI and CAD without an increase in death.
The ACCORD data demonstrated increased mortality with aggressive insulin treatment over 10 years; ACCORD also demonstrated an increased risk of CV and non-coronary death. The authors suggest a practical clinical approach might be to reduce HbA1c with measures taken to avoid moderate to moderately severe hypoglycemia. Clearly, optimum medication regimens to achieve glycemic control need to be established. However, recent data suggest that insulin itself may not be hazardous. A recent commentary regarding ACCORD suggests that the speed of insulin provision is more important than the degree of intensive insulin therapy. More interest and research in this important area are, and will be, forthcoming. At present, "optimal" diabetic therapy should provide careful insulin provision.
The authors suggest that a practical clinical approach should be to reduce HbA1c concentrations steadily while being careful to avoid severe hypoglycemia. While they acknowledge a large difference in study design among the 5 trials, they believe that intensive glucose-lowering is safe and effective for reduction of macrovascular events compared to standard treatment. The investigators suggest that their findings provide reassurance about the effectiveness of glycemic control for CV risk reduction but not a clear benefit for all-cause mortality. Also, the optimum methods to achieve glycemic control need to be established, and guidelines drawn up, with specific recommendations for reduction of HbA1c in a range of patient populations.
The authors of this meta-analysis conclude that their results support the use of aggressive insulin-lowering therapy to reduce major CV outcomes but not all-cause mortality; further, they recommend vigilance in avoiding hypoglycemia while steadily reducing HbA1c.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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