GIPS-III: Diabetes Drug Metformin Not Cardioprotective in Nondiabetic STEMI Patients After Primary PCI

WASHINGTON, DC—The biguanide drug metformin, commonly prescribed to treat diabetes, fails to preserve left ventricular (LV) function or provide any other cardioprotective benefits in nondiabetic patients undergoing percutaneous coronary intervention (PCI) after ST-segment elevation myocardial infarction (STEMI). Results of the GIPS-III randomized trial were presented March 30, 2014,at the annual American College of Cardiology/i2 Scientific Session and published simultaneously in the Journal of the American Medical Association.

In observational studies of patients with acute MI, concurrent treatment with metformin was associated with lower peak CK-MB and troponin values and with improved survival after STEMI in patients with type 2 diabetes compared with other antihyperglycemic strategies.

Based on these and other experimental data, Iwan C.C. van der Horst, MD, PhD, of University Medical Center Groningen (Groningen, the Netherlands), and colleagues randomized 380 nondiabetic STEMI patients at their institution undergoing primary PCI between January 1, 2011, and May 26, 2013, to metformin (500 mg, n = 191) or placebo (n = 189) twice daily for 4 months.

At the end of 4 months, there were no deaths in GIPS-III (Glycometabolic Intervention As Adjunct To Primary Coronary Intervention In ST-Segment Elevation Myocardial Infarction). However, LVEF, the primary endpoint, was no different between the metformin and placebo groups. Neither were other outcomes such as reinfarction, stent thrombosis, and TLR different (table 1).

Table 1. GIPS-III: Four-Month Outcomes


(n = 191)

(n = 188)

P Value













Stent Thrombosis








MACE = death, reinfarction, or TLR.

Metformin’s lack of effect on LVEF was maintained across all prespecified subgroups. Concentrations of creatinine, glucose, and HBA1c were also similar between the groups.

The study authors note that the research failed to confirm the effects of metformin observed in experimental studies. “Because [LVEF] is currently regarded as the most important predictor of morbidity and mortality after STEMI, it is unlikely that metformin will have a significant effect on long-term outcome after STEMI in patients without diabetes,” they conclude.

Dr. van der Horst and colleagues did note that a reason for metformin’s lack of efficacy may have been the time window between coronary occlusion and achieving effective plasma levels of the drug. “On average,” they observe, “the administration of the first dose of study medication took place 101 minutes after coronary intervention. Considering a time to peak plasma concentration of metformin after oral administration of approximately 180 minutes, the average time between PCI and the achievement of effective plasma levels was approximately 4 hours. Therefore, our study does not exclude a potential beneficial effect of effective plasma metformin levels during reperfusion or earlier.”

Nevertheless, “A role for metformin in preventing heart failure after [MI] remains unproven,” the authors conclude.

Panel co-chair Steven E. Nissen, MD, of the Cleveland Clinic Foundation (Cleveland, OH), commented that “this study among other things shows the extraordinary progress we’ve made over the last couple of decades in acute myocardial infarction. Here you have a group of fairly sick STEMI patients who at the end of the day have 54% ejection fraction, so it’s a little difficult for those patients to do better.”


Lexis CPH, van der Horst ICC, Lipsic E, et al. Effect of metformin on left ventricular function after myocardial infarction in patients without diabetes. GIPS-III randomized clinical trial. JAMA. 2014;Epub ahead of print.




  • GIPS-III was supported by ZonMw, the Netherlands Organization for Health Research and Development.
  • Dr. van der Horst reports no relevant conflicts of interest.


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