Effects of Metformin Go Beyond the Treatment of Type 2 Diabetes

Metformin proposes therapeutic benefit for HFpEF treatment.

Heart failure with preserved ejection fraction or HFpEF is a type of heart failure when the heart is able to pump in a normal manner, but the heart muscles are too stiff to fill adequately. HFpEF arises after chronic diseases, such as obesity, hypertension, diabetes mellitus, and chronic kidney disease, cause damage to the heart. HFpEF is associated with pulmonary and peripheral edema, which are the results of the accumulation of blood/fluid in the lungs. Additionally, symptoms may be the result of insufficient heart pumps during exercise causing exercise intolerability. It is unfortunate that the prevalence of HFpEF is on the rise; however, there is not a truly effective treatment for this disease as of now.

In spite of the fact that the effect of metformin on diastolic function has not been examined in patients with HFpEF, many clinical studies have explored the relationship between metformin and heart failure, reporting positive association on mortality. Conclusions from an analysis assessing over 20,000 people with diabetes in the REACH (Reduction of Atherothrombosis for Continued Health) registry showed a 31% decrease in heart failure mortality rate in patients who were treated with metformin in comparison with those patients who were not on metformin.

The results from a retrospective nationwide cohort study, published in 2010, showed that the effect of metformin therapy was related to a low risk of mortality in patients with diabetes who have heart failure. Another cohort study, published in 2017, was conducted to compare the safety aspects of sulfonylureas and metformin as monotherapy on the risk of heart failure. Based on the data analysis, this study concluded that there is a higher risk of heart failure and CV death in male patients starting treatment with sulfonylurea as compared to similar patients initiating metformin. Moreover, an ongoing clinical trial, called MET-DIME, is assessing if the addition of metformin to standard treatment for patients with metabolic syndrome shows improvement in diastolic dysfunction.

A new study published in the Journal of General Physiology, December of 2018, was conducted to assess whether metformin might have a beneficial effect on diastolic function in patients with HFpEF. In order to examine this objective, researchers of this study examined metformin treatment in a mouse model with HFpEF-like characteristics including: increased LV stiffness, diastolic dysfunction, concentric hypertrophy, preserved ejection fraction, and exercise intolerance. All HFpEF-like characteristics were induced by transverse aortic constriction surgery and co-administration of mineralocorticoid supplementation.

Investigators examined the effects of metformin on the following: diastolic LV function, LV muscle stiffness, titin expression, and phosphorylation. Echocardiography and pressure-volume analysis were the measuring tools used in this study to examine the objectives. Also, data were analyzed by T-test, two-way ANOVA, or nonlinear regression accordingly.

Results of this study showed that metformin reduces left ventricle stiffness by making titin, which is a heart muscle protein, more compliant. Titin causes recoiling of the heart muscle after it is stretched. Addition of phosphate groups to this protein’s spring-like elements can tweak its stiffness. Researchers found that metformin treatment increased the number of phosphate groups in titin’s spring-like elements in a mouse model with HFpEF-like characteristics.

This study concluded that metformin may be considered as a therapy option for patients with HFpEF. It appears that metformin has the ability to lower titin-based passive stiffness in the left ventricle. Although there are other contributors to diastolic stiffness, it appears that titin is the dominant factor. It was suggested that the results of this study could be used for immediate translation for clinical use because metformin is an FDA-approved treatment in patients with diabetes.

Practice Pearls:

• Titin, a heart muscle protein, seems to be the primary factor causing left ventricle stiffness in HFpEF.
• Addition of phosphate group can increase titin compliance in HFpEF.
• Metformin improves diastolic function in an HFpEF-like mouse model lowering titin-based passive stiffness.

References:

Andersson, C., J.B. Olesen, P.R. Hansen, P. Week, M.L. Norgaard, C.H. Jørgensen, T. Lange, S.Z. Abildstrøm, T.K. Schramm, A. Vaag, et al. 2010. Metformin treatment is associated with a low risk of mortality in diabetic patients with heart failure: A retrospective nationwide cohort study. Diabetologia. 53:2546–2553. https://doi.org/10.1007/s00125-010 -1906-6

Roussel R, Travert F, Pasquet B, et al. Metformin Use and Mortality Among Patients With Diabetes and Atherothrombosis. Arch Intern Med. 2010;170(21):1892–1899. doi:10.1001/archinternmed.2010.409

Ladeiras-Lopes, R., R. Fontes-Carvalho, N. Bettencourt, F. Sampaio, V. Gama, and A.F. Leite-Moreira. 2014. METformin in DIastolic Dysfunction of MEtabolic syndrome (MET-DIME) trial: rationale and study design: MET-DIME trial. Cardiovasc. Drugs Ther. 28:191–196. https://doi.org/10 .1007/s10557-014-6512-2

Roumie, Christianne L et al. “Comparative Safety of Sulfonylurea and Metformin Monotherapy on the Risk of Heart Failure: A Cohort Study” Journal of the American Heart Association vol. 6,4 e005379. 19 Apr. 2017, doi:10.1161/JAHA.116.005379

Rebecca E. Slater, Joshua G. Strom, Mei Methawasin, Martin Liss, Michael Gotthardt, Nancy Sweitzer, Henk L. Granzier. Metformin improves diastolic function in an HFpEF-like mouse model by increasing titin compliance. The Journal of General Physiology, 2018; jgp.201812259 DOI: 10.1085/jgp.201812259

Ghazal Blair, Pharm.D. Candidate 2019, LECOM School of Pharmacy