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Pleiotropic Effects of Metformin To Be Studied

Evidence shows cardio-protective ability beyond glucose-lowering mechanism of action.

Metformin is a pharmaceutical with considerable pre-clinical evidence for cardio-protective utility beyond its glucose-lowering effect. With increasing diabetes prevalence, metformin is being used more and more throughout the world. Current evidence suggest that metformin use results in benefits to cardiovascular health, but few studies have attempted to show this. Researchers have called for prospective cohort studies that will show just how cardio-protective metformin is. Currently, metformin remains unlabeled for cardiovascular use and does not see wide clinical use to take advantage of its cardio-protective effects. Specifically, it could help improve outcomes post-STEMI.

Currently, it is thought that metformin’s benefits to cardiovascular health are actually not related to its glucose-lowering mechanism of action. Theorized pathways for cardiovascular benefits all relate to inhibition of MPTP at reperfusion. Evidence suggests that metformin can reduce the size of a myocardial infarct when administered prior to the ischemia. The landmark UK Prospective Diabetes Study (UKPDS) showed that metformin reduced acute myocardial infarction risk, when compared to diet modification alone, in diabetes patients. It also showed favorable reductions in all-cause and cardiovascular mortality versus insulin and sulfonylureas, even though all three therapies resulted in similar levels of glycemic control. These results also suggest a separate, non-glucose related mechanism of cardio-protection for metformin.

The lack of good quality direct clinical trials evaluating metformin for this use can be attributed to several barriers, according to the authors. First of all, funding for an off-patent generic drug may be difficult to garner. Second of all, metformin sees very widespread use in current myocardial infarction patients due to diabetes and cardiovascular disease being very common comorbidities.

Many of the clinical studies to date have been observational and/or use a placebo/no therapy comparator, with risks confounding by complex and poorly understood metabolic heterogeneity among patients with diabetes, including significant disparity in cardiovascular risk.  Furthermore, as mentioned, none have specifically examined the effect on mortality of metformin in the context of IRI, either among patients on metformin therapy at the time of STEMI or by administering metformin intravenously at the time of reperfusion (and therefore mPTP opening). This is likely due to the good availability and widespread uptake of metformin, at least in high-income countries, precluding a control group. Moreover, the potential randomized investigation of metformin in STEMI is hampered by the absence of licensed intravenous preparations and a lack of funding for investigation of a drug that is available off-patent. With this in mind, level 2 evidence may be the best that is realistically possible and as such there is a need for well-designed prospective cohort studies of the potential benefit of peri-STEMI metformin. Any such study should be adequately powered to account for the high number of confounding variables inherent in such a study. Finally, it is important to acknowledge the potential deleterious effects of nephrotoxicity and lactic acidosis attendant in the use of metformin in the context of PPCI for STEMI. It is hoped that prospective level 2 studies would clarify the risk–benefit balance of metformin use in this regard, however prior to any prospective randomized study a safety profile for this particular application would be essential.

Type 2 diabetes and its cardiovascular sequelae represent a major global public health challenge. IRI is a major target for intervention in patients suffering STEMI, and may be of particular benefit in diabetic patients who have inflated cardiovascular mortality compared to non-diabetic patients. There is convincing pre-clinical evidence that metformin, given at the time of IRI, may have a cardio-protective role beyond its glucose-lowering effect. However, despite its availability and safety profile, there is a paucity of clinical studies addressing this hypothesis. To repurpose this potentially beneficial therapy to a global population in need of new treatments for STEMI, especially in regions where PPCI is unavailable, well-designed prospective cohort studies of the potential pleiotropic benefits of metformin on cardiovascular disease, and particularly its benefit in ischemia–reperfusion injury, are essential.

Therefore, the authors suggest prospective cohort studies that evaluate peri-STEMI use of metformin. They also suggest that these studies should have high enough power to contend with the large amount of confounding variables that will be present in such a study.

Practice Pearls:

  • Current evidence suggests that metformin is cardio-protective via mechanisms independent of its glucose-lowering ability.
  • Metformin has not seen widespread, high-quality use in studies for its potential role in STEMI therapy.
  • The authors of this paper suggest well-designed prospective cohort studies to evaluate metformin’s role in STEMI therapy.

Bromage DI, Yellon DM. “The pleiotropic effects of metformin: time for prospective studies.” Cardiovasc Diabetol. 2015;14:109.