Have We Really Demonstrated the Cardiovascular Safety of Antihyperglycemic Drugs?

Rethinking the Concepts of Macrovascular and Microvascular Disease in Type 2 Diabetes

Abstract

A primary goal of the treatment of type 2 mellitus is the prevention of morbidity and mortality due to cardiovascular disease. However, antihyperglycemic drugs have the capacity to cause deleterious effects on the circulation, a risk that is not adequately reflected by the endpoints selected for emphasis in large-scale clinical trials that are designed to evaluate cardiovascular safety. The primary endpoint of the large-scale studies mandated by regulatory authorities focuses only on 3-4 events that depict only a limited view of the circulatory system.

One of the most serious adverse effects of many glucose-lowering drugs is new-onset or worsening heart failure. Most antidiabetic drugs can aggravate heart failure because they exert antinatriuretic actions, and possibly, adverse effects on the myocardium. In addition, certain antihyperglycemic agents may worsen peripheral vascular disease and trigger cardiac arrhythmias that may lead to sudden death. Initiation of treatment with antidiabetic medications may also cause deterioration of the function of the kidneys, retina and peripheral nerves, which are typically regarded as reflecting microvascular disease.

The current confusion about the cardiovascular effects of glucose-lowering drugs may be exacerbated by conceptual uncertainties about the classification of large and small vessel disease in determining the clinical course of diabetes. Physicians should not be falsely reassured by claims that a new treatment appears to have passed a narrowly-defined regulatory test. The management of diabetic patients often carries with it the risk of important cardiovascular consequences, even for drugs that do not overtly increase the risk of myocardial infarction or stroke.

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Graham