Metformin associates with improved myocardial perfusion reserve and survival in patients with Type 2 Diabetes Mellitus

Background Metformin is an antihyperglycemic agent frequently used in the treatment of Type 2 Diabetes Mellitus (T2DM). Patients with T2DM are at increased risk of cardiovascular diseases, including coronary artery disease (CAD), silent myocardial infarction (MI) and coronary microvascular dysfunction (CMD), all of which can be detected and quantified using Cardiovascular Magnetic Resonance (CMR). We explored the association between metformin use, stress Myocardial Blood Flow (MBF), Myocardial Perfusion Reserve (MPR), survival and major adverse cardiovascular and cerbrovasular events (MACCE; a composite of all-cause death, MI, stroke, heart failure hospitalisation and coronary revascularisation) in patients with T2DM. Methods A multi-centre study of patients with T2DM, and a cohort of healthy controls underwent quantitative myocardial perfusion CMR. Global MBF and MPR were derived using an automatic artificial intelligence-supported process. Multivariable regression analysis and cox proportional hazard models quantified associations between metformin use, MBF, MPR, all-cause death and MACCE. Results Analysis included 572 patients with T2DM (68% prescribed metformin) with median follow-up 851 days (interquartile range 935-765). Metformin use was associated with an increase in MPR of 0.12 [0.08-0.40], P=0.004. There was a total of 82 (14.3%) first MACCE in all T2DM patients including a total of 25 (4.4%) deaths. Although the number of first MACCE events was similar for patients prescribed metformin (53 (14%)) compared to those who were not (29 (15.8%) (P=0.73)), there was a total of 9 deaths (2.3%) in patients prescribed metformin compred to 16 (8.7%) in patients who were not, adjusted hazard ratio 0.29 [95% CI 0.12-0.73] P=0.009). Conclusion In patients with T2DM, metformin use is associated with higher MPR and improved survival. Clinical Perspective Patients with Type 2 Diabetes Mellitus (T2DM) are at increased risk of cardiovascular disease. Cardiovascular Magnetic Resonane (CMR) can be used to detect and quantify absolute stress myocardial blood flow (MBF) and myocardial perfusion reserve (MPR), both of which are objective measures of coronary microvascular function. Metformin is frequently used in the treatment of T2DM. We investigated the association between metformin use, CMR-derived stress MBF, MPR and clinical outcomes in patients with T2DM. In a longitudinal cohort study of patients with T2DM, metformin use was associated with higher MPR as a marker of microvascular function, and improved survival after adjusting for certain confounding parameters. Further prospective studies are needed to confirm the association between metformin use and improved MPR and reduced mortality, as well as to clarify the mechanisms responsible and quantify the dose these associated outcomes are observed. ![Figure][1] ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was supported directly and indirectly from the National Institute for Health Research Biomedical Research Centres at University College London Hospitals and Barts Health National Health Service Trusts. Recruitment in Leicester was funded through BHF Clinical Research Training Fellowship (G. Gulsin; FS/16/47/32190) and a NIHR Research Professorship (G. McCann; RP-2017-08-ST2-007). Leeds studies were funded by British Heart Foundation with ethical approval from 17/YH/0300, 18/YH/0168 and 18/YH/01900. This research is supported by the National Institute for Health Research (NIHR), through the Local Clinical Research Networks and the NIHR Leeds and Leiciester Clinical Research Facilities. SP is supported by a British Heart Foundation Chair (CH/16/2/32089). EL acknowledges support from the Welcome Trust (221690/Z/20/Z). RDA received funding from the Romanian Society of Cardiology (Research Grant No. 95/01.09.2020). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: All the patients provided written informed consent for their inclusion and approval was provided by the respective ethics committees from each site as described below and conducted in accordance with the Declaration of Helsinki. Leeds data was obtained with ethical approval obtained by Leeds Research Ethics Committee (REC), Leeds, United Kingdom, reference 17/YH/0300, 18/YH/0168 and 18/YH/01900. Barts data used ethical approval from East of England, Cambridge Central Research Ethics Committee, United Kingdom, REC 14/EE/0007. Royal Free data was provided by the University College London/University College London Hospital Joint Committees on the Ethics of Human Research for recruitment at Royal Free Hospital (REC reference 07/H0715/101), United Kingdom. Leicester data ethical approval was provided by the UK Health Research Authority Research Ethics Committee (reference 17/WM/0192). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The datasets used and analysed during the current study are available from the corresponding author on reasonable request. * CAD : Coronary Artery Disease CMD : Coronary Microvascular Dysfunction CMR : Cardiovascular Magnetic Resonance T2DM : Type 2 Diabetes Mellitus LV : Left Ventricle LVEF : Left Ventricular Ejection Fraction MI : Myocardial Infarction MACCE : Major Adverse Cardiovascular and Cerebrovascular Events MBF : Myocardial Blood Flow MPR : Myocardial Perfusion Reserve [1]: pending:yes