Cardiovascular effects of metformin

Metformin has been used to control blood sugar in type 2 diabetes for more than 50 years. Its protective properties on the heart have been recognised in recent years, including in our own work and collaborations. We are now conducting clinical trials to see whether metformin’s beneficial effects extend to other conditions.

Metformin is widely regarded to have cardioprotective effects in type 2 diabetes which may be mediated via a number of mechanisms including activation of endothelial AMP kinase (see Vascular, Pathophysiology and Therapy – Coordinated regulation of metabolism and vascular health).

Our recent studies indicate that metformin:

(a) improves endothelial function in women with chest pain and normal coronary arteries [1];

(b) is associated with reduced mortality in chronic heart failure [2,3],

(c) has an insulin-sparing effect in type 1 diabetes (T1DM) – systematic review [4].

We are now conducting two double-blind randomised placebo-controlled trials (RCTs) examining the cardiovascular effects of metformin in two other conditions:

1) Stable coronary artery disease

The CAMERA trial (Principal Investigator: Prof N Sattar, http://www.clinicaltrials.gov/ct2/show/NCT00723307) is a single-centre randomised controlled trial (RCT) of metformin vs. placebo over 1.5 years in men and women with stable coronary artery disease (funded by the Chief Scientist Office of the Scottish Government). The primary endpoint is change in common carotid artery intima-media thickness (cIMT): results are due in late 2012.

2) Type 1 diabetes

The REMOVAL trial (Chief Investigator: Prof JR Petrie, http://www.clinicaltrials.gov/ct2/show/NCT01483560) is an international multi-centre RCT of metformin vs. placebo over three years in men and women with type 1 diabetes (T1DM) aged 40 years and over. The primary endpoint is change in cIMT and secondary endpoints include changes in numerous important biomarkers and clinical outcomes such as HbA1c, LDL-cholesterol, albuminuria, endothelial function and retinopathy staging. It has major funding from the Juvenile Diabetes Research Foundation, New York, USA over the next five years. The project involves collaboration with Imperial College London (carotid artery reading centre), the University of Wisconsin-Madison, USA (retinal image reading centre), the Robarts Research Institute (London, Ontario, Canada) and the NHMRC Clinical Trials Unit (Sydney, Australia) and is recruiting in the UK, Australia, Canada, Denmark and Holland: completion due in early 2016.

These RCTs are examples of our capacity to initiate and execute world-leading clinical trials in partnership with the Robertson Centre for Biostatistics (Professor Ian Ford)/ Glasgow Clinical Trials Unit (see Clinical Trials and Implementation Research Theme). The group also has experience in conducting trials of metformin in polycystic ovarian syndrome[5-7].

Selected Publications:

1. Jadhav ST, Ferrell WR, Petrie JR, Greer I, Cobbe SM, Sattar N. Effects of metformin on microvascular function and exercise tolerance in women with angina and normal coronary arteries: a randomized, double-blind, placebo-controlled study.  J Am Coll Cardiol 2006;48(5): 956-63.
2. MacDonald MR, Eurich DT, Majumdar SR, Lewsey JD, Bhagra S, Jhund PS, Petrie MC, McMurray JJ, Petrie JR, McAlister FA. Treatment of type 2 diabetes and outcomes in patients with heart failure: a nested case-control study from the U.K. General Practice Research Database. Diabetes Care 2010; 33(6):1213-8.
3. Evans JM, Doney AS, AlZadjali MA, Ogston SA, Petrie JR, Morris AD, Struthers AD, Wong AK, Lang CC. Effect of Metformin on mortality in patients with heart failure and type 2 diabetes mellitus. Am J Cardiol 2010;106(7): 1006-10.
4. Vella S, Buetow L, Royle P, Livingstone S, Colhoun H, Petrie JR. The use of metformin in type 1 diabetes: a systematic review of efficacy. Diabetologia 2010;53(5):809-20.
5. Fleming R, Hopkinson ZE, Wallace AM, Greer IA, Sattar N. Ovarian function and metabolic factors in women with oligomenorrhea treated with metformin in a randomized double blind placebo-controlled trial. J Clin Endocrinol Metab. 2002;87(2):569-74.
6. Harborne L, Fleming R, Lyall H, Sattar N, Norman J. Metformin or antiandrogen in the treatment of hirsutism in polycystic ovary syndrome. J Clin Endocrinol Metab. 2003;88(9):4116-23.
7. Preiss D, Sattar N, Harborne L, Norman J, Fleming R. The effects of 8 months of metformin on circulating GGT and ALT levels in obese women with polycystic ovarian syndrome. Int J Clin Pract. 2008;62(9):1337-43.