GIPS-III shows no benefit of metformin for STEMI

No difference in LVEF, pro-BNP post PCI

Of all anti-diabetic drugs, metformin has been shown to have potential beneficial long-term cardiovascular effects, especially on left ventricular (LV) function. However, a recent study showed that metformin has no benefit when given to patients without diabetes who had just suffered an ST-segment acute MI (STEMI).

Chris P.H. Lexis, MD, of University Medical Center Groningen, the Netherlands presented the results of the Glycometabolic Intervention as Adjunct to Primary Percutaneous Coronary Interventionin ST-Segment Elevation Myocardial Infarction (GIPS-III) study during a latebreaking clinical-trial session at the American College of Cardiology 2014 Scientific Sessions in March of this year. The paper was also published simultaneously in the Journal of the American Medical Association (JAMA).

Dr. Lewis reported that in patients without diabetes, metformin 500 mg twice a day, started directly after percutaneous coronary intervention (PCI) and continued for four months, does not preserve left ventricular ejection fraction [LVEF] after STEMI compared with placebo. Although patients included in the trial were not diabetic, Dr. Lewis said that no adverse effects were reported, and that the findings indicate that use of this hypoglycemic agent “was safe” in this patient population.

Metformin is the most widely used hypoglycemic agent in the world, and several clinical trials such as the United Kingdom Prospective Diabetes Study (UK-PDS) suggested a potential beneficial effect in improving ventricular function independent of its glucose-lowering effects. Metformin also possibly reduced death in the Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction 2 (DIGAMI-2) trial. Hence, heart and diabetes experts entertained the theory that metformin might have independent pleiotropic effects; a theory that was also supported by observations in rats, wherein administration of metformin improved left ventricular function.

Dr. Lexis explained the rationale for the study that although timely reperfusion can reduce myocardial damage andthe risk for LV dysfunction in STEMI, this complication can still occur in up to 50 percent of patients. And the development of heart failure is associated with a three- to four-fold higher mortality risk. One in seven people with acute MI “will die from the consequences,” he noted.

In GIPS-III, 380 patients undergoing primary PCI for STEMI were randomized to metformin 500 mg or placebo twice a day for four months. Major exclusion criteria were previous MI, known diabetes, the need for bypass surgery, severe renal dysfunction, and other standard contraindications for MRI examination.

The primary end point was LVEF after four months, assessed by MRI. The principal secondary outcome was N-terminal probrain natriuretic peptide (NTproBNP) level at four months.

The incidence of major adverse cardiac events (MACE; the combined end point of death, reinfarction, or target lesion revascularization) was also recorded up to four months as a secondary efficacy measure.

There was no significant difference in the primary end point, LVEF on MRI in the metformin and placebo arms: 53.1 percent versus 54.8 percent (P = .10). NTproBNP levels also did not differ between the two arms—167 ng/L in both groups (P = .66). MACE were observed in six patients (3.1percent) in the metformin group and in two patients (1.1 percent) in the placebo group (P = .16). Dr. Lewis further reported that creatinine concentration and HbA1c were not significantly different between arms. No cases of lactic acidosis were reported.

Sotirios Tsimikas, MD, from the vascular medicine program, University of California, San Diego, La Jolla, commented if it would have made a difference if metformin was given before PCI, rather than after PCI.

Dr. Lexis concluded that metformin does not play a role in remodeling the heart and improving LV function after STEMI, despite the encouraging findings in animal models. “In humans, there is interaction with many drugs; metformin is given on top of statins, ACE inhibitors, and other agents,” he noted. And although ejection fraction is affected by the infarct, it is also affected by other variables, he said. With a JAMA and Medscape Internal Medicine report

VitalSigns Issue 63 Vol. 3, May 1-31, 2014