Have we really demonstrated the cardiovascular safety of anti‐hyperglycaemic 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 associated with cardiovascular disease; however, anti-hyperglycaemic 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 to 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 anti-natriuretic actions, and possibly, adverse effects on the myocardium. In addition, certain anti-hyperglycaemic 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 people with diabetes 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.

Higher mortality rate in patients with heart failure who are taking commonly prescribed antidiabetic medications and achieve recommended levels of glycaemic control

“…It is therefore noteworthy that, in the one study in which patients receiving antihyperglycaemic drugs and achieving an HbA1c concentration <7.0% had higher survival rates, most patients were treated with metformin (Table ). Similarly, sodium‐glucose co‐transporter‐2 inhibitors reduce the likelihood of new‐onset heart failure . Ongoing studies will determine whether these two classes of drugs may allow patients with both diabetes and heart failure to achieve recommended levels of glycaemic control without an increased risk of death.…”

“…In clinical trials and observational studies, treatments with these three classes of drugs have been individually associated with an increased risk of heart failure. 17 If their actions were combined to achieve aggressive glycaemic targets, the summation of risk could explain why patients with both heart failure and diabetes do poorly when they reach HbA1c levels <7.0% with the use of these medications.…”

“…17 Furthermore, in trials in patients with left ventricular systolic dysfunction, the glucagon-like peptide-1 receptor agonist liraglutide worsened the clinical course of heart failure. 17 These findings may explain why intensification of glycaemic control with incretin-based agents has been associated with a high risk of death as well as of heart failure. 18 In contrast to these experiences, certain antidiabetic medications may have favourable effects on heart failure.…”

“…Metformin has been associated with a reduced risk of heart failure. 17 It is therefore noteworthy that, in the one study 4 in which patients receiving antihyperglycaemic drugs and achieving an HbA1c concentration <7.0% had higher survival rates, most patients were treated with metformin (Table 1). Similarly, sodium-glucose co-transporter-2 inhibitors reduce the likelihood of new-onset heart failure.…”

“…Similarly, sodium-glucose co-transporter-2 inhibitors reduce the likelihood of new-onset heart failure. 17 Ongoing studies will determine whether these two classes of drugs may allow patients with both diabetes and heart failure to achieve recommended levels of glycaemic control without an increased risk of death.…”