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Original Investigation |

Effect of Metformin on Left Ventricular Function After Acute Myocardial Infarction in Patients Without Diabetes:  The GIPS-III Randomized Clinical Trial

Chris P. H. Lexis, MD1; Iwan C. C. van der Horst, MD, PhD2; Erik Lipsic, MD, PhD1; Wouter G. Wieringa, MD1; Rudolf A. de Boer, MD, PhD1; Ad F. M. van den Heuvel, MD, PhD1; Hindrik W. van der Werf, MD1; Remco A. J. Schurer, MD1; Gabija Pundziute, MD, PhD1; Eng S. Tan, MD, PhD1; Wybe Nieuwland, MD, PhD1; Hendrik M. Willemsen, MD1; Bernard Dorhout, PhD1; Barbara H. W. Molmans, PharmD3; Anouk N. A. van der Horst-Schrivers, MD, PhD4; Bruce H. R. Wolffenbuttel, MD, PhD4; Gert J. ter Horst, PhD5; Albert C. van Rossum, MD, PhD6; Jan G. P. Tijssen, PhD7; Hans L. Hillege, MD, PhD1,8; Bart J. G. L. de Smet, MD, PhD9; Pim van der Harst, MD, PhD1; Dirk J. van Veldhuisen, MD, PhD1 ; for the GIPS-III Investigators
[+] Author Affiliations
1University of Groningen, University Medical Center Groningen, Department of Cardiology, Groningen, the Netherlands
2University of Groningen, University Medical Center Groningen, Department of Critical Care, Groningen, the Netherlands
3University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, the Netherlands
4University of Groningen, University Medical Center Groningen, Department of Endocrinology, Groningen, the Netherlands
5University of Groningen, University Medical Center Groningen, Department of Neuroscience, Groningen, the Netherlands
6VU University, VU University Medical Center, Department of Cardiology, Amsterdam, the Netherlands
7University of Amsterdam, Academic Medical Center, Department of Cardiology, Amsterdam, the Netherlands
8University of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen, the Netherlands
9Department of Cardiology, Meander Medical Center, Amersfoort, the Netherlands
JAMA. 2014;311(15):1526-1535. doi:10.1001/jama.2014.3315.
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Importance  Metformin treatment is associated with improved outcome after myocardial infarction in patients with diabetes. In animal experimental studies metformin preserves left ventricular function.

Objective  To evaluate the effect of metformin treatment on preservation of left ventricular function in patients without diabetes presenting with ST-segment elevation myocardial infarction (STEMI).

Design, Setting, and Participants  Double-blind, placebo-controlled study conducted among 380 patients who underwent primary percutaneous coronary intervention (PCI) for STEMI at the University Medical Center Groningen, the Netherlands, between January 1, 2011, and May 26, 2013.

Interventions  Metformin hydrochloride (500 mg) (n = 191) or placebo (n = 189) twice daily for 4 months.

Main Outcomes and Measures  The primary efficacy measure was left ventricular ejection fraction (LVEF) after 4 months, assessed by magnetic resonance imaging. A secondary efficacy measure was the N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration after 4 months. The incidence of major adverse cardiac events (MACE; the combined end point of death, reinfarction, or target-lesion revascularization) was recorded until 4 months as a secondary efficacy measure.

Results  At 4 months, all patients were alive and none were lost to follow-up. LVEF was 53.1% (95% CI, 51.6%-54.6%) in the metformin group (n = 135), compared with 54.8% (95% CI, 53.5%-56.1%) (P = .10) in the placebo group (n = 136). NT-proBNP concentration was 167 ng/L in the metformin group (interquartile range [IQR], 65-393 ng/L) and 167 ng/L in the placebo group (IQR, 74-383 ng/L) (P = .66). MACE were observed in 6 patients (3.1%) in the metformin group and in 2 patients (1.1%) in the placebo group (P = .16). Creatinine concentration (79 µmol/L [IQR, 70-87 µmol/L] vs 79 µmol/L [IQR, 72-89 µmol/L], P = .61) and glycated hemoglobin (5.9% [IQR, 5.6%-6.1%] vs 5.9% [IQR, 5.7%-6.1%], P = .15) were not significantly different between both groups. No cases of lactic acidosis were observed.

Conclusions and Relevance  Among patients without diabetes presenting with STEMI and undergoing primary PCI, the use of metformin compared with placebo did not result in improved LVEF after 4 months. The present findings do not support the use of metformin in this setting.

Trial Registration  clinicaltrials.gov Identifier: NCT01217307.

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Figure 1.
Flow of Patients Through the Glycometabolic Intervention as Adjunct to Primary Coronary Intervention in the ST-Segment Elevation Myocardial Infarction (GIPS-III) Trial

Patients could be excluded for more than 1 reason; the primary reason for exclusion in each case is shown. CABG indicates coronary artery bypass graft; ICD, implantable cardioverter-defibrillator; LVEF, left ventricular ejection fraction; MRI, magnetic resonance imaging; STEMI, ST-segment elevation myocardial infarction; TIMI, Thrombolysis in Myocardial Infarction; PCI, percutaneous coronary intervention.

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Figure 2.
Estimated Effect of Metformin Compared With Placebo on Left Ventricular Ejection Fraction (LVEF) According to Prespecified Subgroups

Estimation of the effect of metformin compared with placebo on LVEF according to prespecified subgroups. The estimated LVEF for the effect of metformin in the prespecified subgroups, as well as the absolute difference in LVEF for the effect of metformin per prespecified subgroup compared with the LVEF in the placebo group is displayed. BMI indicates body mass index; HbA1c, glycated hemoglobin; MI, myocardial infarction; NT-proBNP, N-terminal pro-brain natriuretic peptide; PCI, percutaneous coronary intervention; TIMI, Thrombolysis in Myocardial Infarction.

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