Two-year follow-up of 4 months metformin treatment vs. placebo in ST-elevation myocardial infarction: data from the GIPS-III RCT

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Abstract

Objectives

Preclinical and clinical studies suggested cardioprotective effects of metformin treatment. In the GIPS-III trial, 4 months of metformin treatment did not improve left ventricular ejection fraction in patients presenting with ST-elevation myocardial infarction (STEMI). Here, we report the 2-year follow-up results.

Methods

Between January 2011 and May 2013, 379 STEMI patients without diabetes undergoing primary percutaneous coronary intervention were randomized to a 4-month treatment with metformin (500 mg twice daily) ( N = 191) or placebo ( N = 188) in the University Medical Center Groningen. Two-year follow-up data was collected to determine its effect on predefined secondary endpoints: the incidence of major adverse cardiac events (MACE), its individual components, all-cause mortality, and new-onset diabetes.

Results

For all 379 patients all-cause mortality data were available. For seven patients (2%) follow-up data on MACE was limited, ranging from 129 to 577 days. All others completed the 2-year follow-up visit. Incidence of MACE was 11 (5.8%) in metformin and 6 (3.2%) in placebo treated patients [hazard ratio (HR) 1.84, confidence interval (CI) 0.68–4.97, P = 0.22]. Three patients died in the metformin group and one in the placebo treatment group. Individual components of MACE were also comparable between both groups. New-onset diabetes mellitus was 34 (17.8%) in metformin and 32 (17.0%) in placebo treated patients (odds ratio 1.15, CI 0.66–1.98, P = 0.84). After multivariable adjustment the incidence of MACE was comparable between the treatment groups (HR 1.02, CI 0.10–10.78, P = 0.99).

Conclusions

Four months metformin treatment initiated at the time of hospitalization in STEMI patients without diabetes did not exert beneficial long-term effects.

Trial registration

clinicaltrials.gov Identifier: NCT01217307.

Electronic supplementary material

The online version of this article (doi:10.1007/s00392-017-1140-z) contains supplementary material, which is available to authorized users.

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Most cited references 23

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The effect of metformin and intensive lifestyle intervention on the metabolic syndrome: the Diabetes Prevention Program randomized trial.

Trevor J. Orchard, Marinella Temprosa, Ronald Goldberg … (2005)

The metabolic syndrome is a high-risk state for diabetes and cardiovascular disease. Little is known about its prevalence and prevention in those with impaired glucose tolerance. To determine the prevalence of the metabolic syndrome at baseline in the Diabetes Prevention Program and the effect of intensive lifestyle intervention and metformin therapy on the syndrome's incidence and resolution. Randomized, controlled clinical trial. Research and community-based centers. Participants had impaired glucose tolerance (World Health Organization criteria plus fasting plasma glucose level >or=5.3 mmol/L [>or=95 mg/dL]) and were followed for a mean of 3.2 years after random assignment to intensive lifestyle intervention, metformin therapy, or placebo. Metformin, 850 mg twice daily, or intensive lifestyle intervention designed to achieve and maintain a 7% weight loss and 150 minutes of exercise per week. The metabolic syndrome was defined as having 3 or more characteristics (waist circumference; blood pressure; and levels of high-density lipoprotein cholesterol, triglycerides, and fasting plasma glucose) that met criteria from the National Cholesterol Education Program Adult Treatment Panel III. Fifty-three percent of participants (n = 1711) had the metabolic syndrome at baseline; incidence did not vary substantially by age. However, low levels of high-density lipoprotein cholesterol predominated in younger participants (age 25 to 44 years), and high blood pressure predominated in older participants (age 60 to 82 years). In life-table analyses (log-rank test), incidence of the metabolic syndrome was reduced by 41% in the lifestyle group (P < 0.001) and by 17% in the metformin group (P = 0.03) compared with placebo. Three-year cumulative incidences were 51%, 45%, and 34% in the placebo, metformin, and lifestyle groups, respectively. There was no significant heterogeneity by ethnic group. The study involved a volunteer group with impaired glucose tolerance, which limits generalizability. The metabolic syndrome affected approximately half of the participants in the Diabetes Prevention Program at baseline. Both lifestyle intervention and metformin therapy reduced the development of the syndrome in the remaining participants.

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Activation of AMP-activated protein kinase by metformin improves left ventricular function and survival in heart failure.

Susheel Gundewar, John Calvert, David J. Lefer … (2009)

Clinical studies have reported that the widely used antihyperglycemic drug metformin significantly reduces cardiac risk factors and improves clinical outcomes in patients with heart failure. The mechanisms by which metformin exerts these cardioprotective effects remain unclear and may be independent of antihyperglycemic effects. We tested the hypothesis that chronic activation of AMP-activated protein kinase (AMPK) with low-dose metformin exerts beneficial effects on cardiac function and survival in in vivo murine models of heart failure. Mice were subjected to permanent left coronary artery occlusion or to 60 minutes left coronary artery occlusion followed by reperfusion for 4 weeks. High-resolution, 2D echocardiography was performed at baseline and 4 weeks after myocardial infarction to assess left ventricular dimensions and function. Metformin (125 microg/kg) administered to mice at ischemia and then daily improved survival by 47% (P<0.05 versus vehicle) at 4 weeks following permanent left coronary artery occlusion. Additionally, metformin given at reperfusion and then daily preserved left ventricular dimensions and left ventricular ejection fraction (P<0.01 versus vehicle) at 4 weeks. The improvement in cardiac structure and function was associated with increases in AMPK and endothelial nitric oxide synthase (eNOS) phosphorylation, as well as increased peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1alpha expression in cardiac myocytes. Furthermore, metformin significantly improved myocardial cell mitochondrial respiration and ATP synthesis compared to vehicle. The cardioprotective effects of metformin were ablated in mice lacking functional AMPK or eNOS. This study demonstrates that metformin significantly improves left ventricular function and survival via activation of AMPK and its downstream mediators, eNOS and PGC-1alpha, in a murine model of heart failure.

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Acute metformin therapy confers cardioprotection against myocardial infarction via AMPK-eNOS-mediated signaling.

Susheel Gundewar, William H Bestermann, John Calvert … (2008)

Clinical studies have reported that metformin reduces cardiovascular end points of type 2 diabetic subjects by actions that cannot solely be attributed to glucose-lowering effects. The therapeutic effects of metformin have been reported to be mediated by its activation of AMP-activated protein kinase (AMPK), a metabolite sensing protein kinase whose activation following myocardial ischemia has been suggested to be an endogenous protective signaling mechanism. We investigated the potential cardioprotective effects of a single, low-dose metformin treatment (i.e., 286-fold less than the maximum antihyperglycemic dose) in a murine model of myocardial ischemia-reperfusion (I/R) injury. Nondiabetic and diabetic (db/db) mice were subjected to transient myocardial ischemia for a period of 30 min followed by reperfusion. Metformin (125 microg/kg) or vehicle (saline) was administered either before ischemia or at the time of reperfusion. Administration of metformin before ischemia or at reperfusion decreased myocardial injury in both nondiabetic and diabetic mice. Importantly, metformin did not alter blood glucose levels. During early reperfusion, treatment with metformin augmented I/R-induced AMPK activation and significantly increased endothelial nitric oxide (eNOS) phosphorylation at residue serine 1177. These findings provide important information that myocardial AMPK activation by metformin following I/R sets into motion events, including eNOS activation, which ultimately lead to cardioprotection.

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Author and article information

Contributors

Pim van der Harst: +31 5036 12355 , p.van.der.harst@umcg.nl

Journal

Journal ID (nlm-ta): Clin Res Cardiol

Journal ID (iso-abbrev): Clin Res Cardiol

Title: Clinical Research in Cardiology

Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )

ISSN (Print): 1861-0684

ISSN (Electronic): 1861-0692

Publication date (Electronic): 28 July 2017

Publication date PMC-release: 28 July 2017

Publication date (Print): 2017

Volume: 106

Issue: 12

Pages: 939-946

Affiliations

[1 ]Department of Cardiology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, The Netherlands

[2 ]Department of Endocrinology and Metabolism, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

[3 ]Department of Critical Care, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

Article

Publisher ID: 1140

DOI: 10.1007/s00392-017-1140-z

PMC ID: 5696505

PubMed ID: 28755285

SO-VID: cc337e35-f290-4b43-882b-904bc69a7cb7

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

History

Date received : 3 April 2017

Date accepted : 20 July 2017

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001826, ZonMw;

Award ID: 95103007

Award Recipient : Iwan C. C. van der Horst

Custom metadata

ScienceOpen disciplines: Cardiovascular Medicine

Keywords: acute myocardial infarction,diabetes,heart failure,percutaneous coronary intervention,metformin

Data availability:

ScienceOpen disciplines: Cardiovascular Medicine

Keywords: acute myocardial infarction, diabetes, heart failure, percutaneous coronary intervention, metformin

Two-year follow-up of 4 months metformin treatment vs. placebo in ST-elevation myocardial infarction: data from the GIPS-III RCT

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Cardiovascular Innovations and Applications

Most cited references 23

The effect of metformin and intensive lifestyle intervention on the metabolic syndrome: the Diabetes Prevention Program randomized trial.

Activation of AMP-activated protein kinase by metformin improves left ventricular function and survival in heart failure.

Acute metformin therapy confers cardioprotection against myocardial infarction via AMPK-eNOS-mediated signaling.

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