Metformin: evidence from preclinical and clinical studies for potential novel applications in cardiovascular disease

References

• American Diabetes A. 9. pharmacologic approaches to glycemic treatment: standards of medical care in diabetes-2020. Diabetes Care. 2020;43(Suppl 1):S98–110.
   PubMed Web of Science ®Google Scholar
• Marín-Peñalver JJ, Martín-Timón I, Sevillano-Collantes C, et al. Update on the treatment of type 2 diabetes mellitus. World J Diabetes. 2016;7(17):354–395. DOI:10.4239/wjd.v7.i17.354
   PubMed Web of Science ®Google Scholar
• Younis A, Eskenazi D, Goldkorn R, et al. The addition of vildagliptin to metformin prevents the elevation of interleukin 1ss in patients with type 2 diabetes and coronary artery disease: a prospective, randomized, open-label study. Cardiovasc Diabetol. 2017;16(1):69. DOI:10.1186/s12933-017-0551-5
   PubMedGoogle Scholar
• Loi H, Boal F, Tronchere H, et al. Metformin protects the heart against hypertrophic and apoptotic remodeling after myocardial infarction. Front Pharmacol. 2019;10:154.
   PubMed Web of Science ®Google Scholar
• Varjabedian L, Bourji M, Pourafkari L, et al. Cardioprotection by metformin: beneficial effects beyond glucose reduction. Am J Cardiovasc Drugs. 2018;18(3):181–193. DOI:10.1007/s40256-018-0266-3
   PubMed Web of Science ®Google Scholar
• Griffin SJ, Leaver JK, Irving GJ. Impact of metformin on cardiovascular disease: a meta-analysis of randomised trials among people with type 2 diabetes. Diabetologia. 2017;60(9):1620–1629.
   PubMed Web of Science ®Google Scholar
• Rena G, Lang CC. Repurposing metformin for cardiovascular disease. Circulation. 2018;137(5):422–424.
   PubMed Web of Science ®Google Scholar
• Sattar N, Lee MMY, Kristensen SL, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of randomised trials. Lancet Diabetes Endocrinol. 2021;9(10):653–662. DOI:10.1016/S2213-8587(21)00203-5
   PubMed Web of Science ®Google Scholar
• McGuire DK, Shih WJ, Cosentino F, et al. Association of SGLT2 inhibitors with cardiovascular and kidney outcomes in patients with type 2 diabetes: a meta-analysis. JAMA Cardiol. 2021;6(2):148–158. DOI:10.1001/jamacardio.2020.4511
   PubMed Web of Science ®Google Scholar
• Davies MJ, D’alessio DA, Fradkin J, et al. Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia. 2018;61(12):2461–2498. DOI:10.1007/s00125-018-4729-5
   PubMed Web of Science ®Google Scholar
• Cosentino F, Grant PJ, Aboyans V, et al. 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J. 2020;41(2):255–323. DOI:10.1093/eurheartj/ehz486
   PubMed Web of Science ®Google Scholar
• Davies MJ, Aroda VR, Collins BS, et al. Management of hyperglycemia in type 2 diabetes, 2022. a consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2022;45(11):2753–2786. DOI:10.2337/dci22-0034
   PubMed Web of Science ®Google Scholar
• Davies MJ, Aroda VR, Collins BS, et al. Management of hyperglycaemia in type 2 diabetes, 2022. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia. 2022;65(12):1925–1966. DOI:10.1007/s00125-022-05787-2
   PubMed Web of Science ®Google Scholar
• Rena G, Hardie DG, Pearson ER. The mechanisms of action of metformin. Diabetologia. 2017;60(9):1577–1585.
   PubMed Web of Science ®Google Scholar
• Zhang C-S Metformin activates AMPK through the lysosomal pathway.
   Google Scholar
• Zhang CS, Jiang B, Li M, et al. The lysosomal v-ATPase-Ragulator complex is a common activator for AMPK and mTORC1, acting as a switch between catabolism and anabolism. Cell Metab. 2014;20(3):526–540. DOI:10.1016/j.cmet.2014.06.014
   PubMed Web of Science ®Google Scholar
• Van Nostrand JL, Hellberg K, Luo EC, et al. AMPK regulation of Raptor and TSC2 mediate metformin effects on transcriptional control of anabolism and inflammation. Genes Dev. 2020;34(19–20):1330–1344. DOI:10.1101/gad.339895.120
   PubMed Web of Science ®Google Scholar
• Zhang CX, Pan SN, Meng RS, et al. Metformin attenuates ventricular hypertrophy by activating the AMP-activated protein kinase-endothelial nitric oxide synthase pathway in rats. Clin Exp Pharmacol Physiol. 2011;38(1):55–62. DOI:10.1111/j.1440-1681.2010.05461.x
   PubMedGoogle Scholar
• Takashima M, Ogawa W, Hayashi K, et al. Role of KLF15 in regulation of hepatic gluconeogenesis and metformin action. Diabetes. 2010;59(7):1608–1615. DOI:10.2337/db09-1679
   PubMedGoogle Scholar
• Vettor R, Valerio A, Ragni M, et al. Exercise training boosts eNOS-dependent mitochondrial biogenesis in mouse heart: role in adaptation of glucose metabolism. Am J Physiol Endocrinol Metab. 2014;306(5):E519–28. DOI:10.1152/ajpendo.00617.2013
   PubMedGoogle Scholar
• Gundewar S, Calvert JW, Jha S, et al. Activation of AMP-activated protein kinase by metformin improves left ventricular function and survival in heart failure. Circ Res. 2009;104(3):403–411. DOI:10.1161/CIRCRESAHA.108.190918
   PubMed Web of Science ®Google Scholar
• Wang XF, Zhang JY, Li L, et al. Metformin improves cardiac function in rats via activation of AMP-activated protein kinase. Clin Exp Pharmacol Physiol. 2011;38(2):94–101. DOI:10.1111/j.1440-1681.2010.05470.x
   PubMed Web of Science ®Google Scholar
• Gormsen LC, Sundelin EI, Jensen JB, et al. In Vivo imaging of human 11C-Metformin in peripheral organs: dosimetry, biodistribution, and kinetic analyses. J Nucl Med. 2016;57(12):1920–1926. DOI:10.2967/jnumed.116.177774
   PubMed Web of Science ®Google Scholar
• Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017;377(12):1119–1131. DOI:10.1056/NEJMoa1707914
   PubMed Web of Science ®Google Scholar
• Tardif JC, Kouz S, Waters DD, et al. Efficacy and safety of low-dose colchicine after myocardial infarction. N Engl J Med. 2019;381(26):2497–2505. DOI:10.1056/NEJMoa1912388
   PubMed Web of Science ®Google Scholar
• Nidorf SM, Fiolet ATL, Mosterd A, et al. Colchicine in patients with chronic coronary disease. N Engl J Med. 2020;383(19):1838–1847. DOI:10.1056/NEJMoa2021372
   PubMed Web of Science ®Google Scholar
• Cameron AR, Morrison VL, Levin D, et al. Anti-inflammatory effects of metformin irrespective of diabetes status. Circ Res. 2016;119(5):652–665.
   PubMed Web of Science ®Google Scholar
• Vasamsetti SB, Karnewar S, Kanugula AK, et al. Metformin inhibits monocyte-to-macrophage differentiation via AMPK-mediated inhibition of STAT3 activation: potential role in atherosclerosis. Diabetes. 2015;64(6):2028–2041. DOI:10.2337/db14-1225
   PubMed Web of Science ®Google Scholar
• Gopoju R, Panangipalli S, Kotamraju S. Metformin treatment prevents SREBP2-mediated cholesterol uptake and improves lipid homeostasis during oxidative stress-induced atherosclerosis. Free Radical Biology & Medicine. 2018;118:85–97.
   PubMed Web of Science ®Google Scholar
• Yang Q, Yuan H, Chen M, et al. Metformin ameliorates the progression of atherosclerosis via suppressing macrophage infiltration and inflammatory responses in rabbits. Life Sci. 2018;198:56–64.
   PubMedGoogle Scholar
• Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352(9131):854–865.
   PubMed Web of Science ®Google Scholar
• Schernthaner G, Brand K, Bailey CJ. Metformin and the heart: update on mechanisms of cardiovascular protection with special reference to comorbid type 2 diabetes and heart failure. Metabolism. 2022;130:155160.
   PubMed Web of Science ®Google Scholar
• Group C. Intensive glucose control and macrovascular outcomes in type 2 diabetes. reply to Emanuele NV [letter] and Yudkin JS, Richter B [letter]. Diabetologia. 2010;53(1):218.
   PubMedGoogle Scholar
• Giugliano D, Bellastella G, Longo M, et al. Relationship between improvement of glycaemic control and reduction of major cardiovascular events in 15 cardiovascular outcome trials: a meta-analysis with meta-regression. Diab Obes Metab. 2020;22(8):1397–1405. DOI:10.1111/dom.14047
   PubMedGoogle Scholar
• Mohsin AA, Chen Q, Quan N, et al. Mitochondrial complex i inhibition by metformin limits reperfusion injury. J Pharmacol Exp Ther. 2019;369(2):282–290. DOI:10.1124/jpet.118.254300
   PubMedGoogle Scholar
• Weng S, Luo Y, Zhang Z, et al. Effects of metformin on blood lipid profiles in nondiabetic adults: a meta-analysis of randomized controlled trials. Endocrine. 2020;67(2):305–317. DOI:10.1007/s12020-020-02190-y
   PubMedGoogle Scholar
• Golay A. Metformin and body weight. Int J Obes (Lond). 2008;32(1):61–72.
   PubMedGoogle Scholar
• Little PJ, Askew CD, Xu S, et al. Endothelial dysfunction and cardiovascular disease: history and analysis of the clinical utility of the relationship. Biomedicines. 2021;9(6):699. DOI:10.3390/biomedicines9060699
   PubMedGoogle Scholar
• Mone P, Gambardella J, Pansini A, et al. Cognitive impairment in frail hypertensive elderly patients: role of hyperglycemia. Cells. 2021;10(8):2115. DOI:10.3390/cells10082115
   PubMed Web of Science ®Google Scholar
• Sardu C, Paolisso P, Sacra C, et al. Effects of metformin therapy on coronary endothelial dysfunction in patients with prediabetes with stable angina and nonobstructive coronary artery stenosis: the codyce multicenter prospective study. Diabetes Care. 2019;42(10):1946–1955. DOI:10.2337/dc18-2356
   PubMed Web of Science ®Google Scholar
• Kataoka Y, Nicholls SJ, Andrews J, et al. Plaque microstructures during metformin therapy in type 2 diabetic subjects with coronary artery disease: optical coherence tomography analysis. Cardiovasc Diagn Ther. 2022;12(1):77–87. DOI:10.21037/cdt-21-346
   PubMedGoogle Scholar
• Petrie JR, Chaturvedi N, Ford I, et al. Cardiovascular and metabolic effects of metformin in patients with type 1 diabetes (REMOVAL): a double-blind, randomised, placebo-controlled trial. Lancet Diabetes Endocrinol. 2017;5(8):597–609. DOI:10.1016/S2213-8587(17)30194-8
   PubMed Web of Science ®Google Scholar
• Preiss D, Lloyd SM, Ford I, et al. Metformin for non-diabetic patients with coronary heart disease (the CAMERA study): a randomised controlled trial. Lancet Diabetes Endocrinol. 2014;2(2):116–124. DOI:10.1016/S2213-8587(13)70152-9
   PubMed Web of Science ®Google Scholar
• Lexis CP, van der Horst IC, Lipsic E, et al. Effect of metformin on left ventricular function after acute myocardial infarction in patients without diabetes: the GIPS-III randomized clinical trial. JAMA. 2014;311(15):1526–1535. DOI:10.1001/jama.2014.3315
   PubMedGoogle Scholar
• Top WMC, Lehert P, Schalkwijk CG, et al. Metformin and N-terminal pro B-type natriuretic peptide in type 2 diabetes patients, a post-hoc analysis of a randomized controlled trial. PLoS ONE. 2021;16(4):e0247939. DOI:10.1371/journal.pone.0247939
   PubMedGoogle Scholar
• Stultiens JMG, Top WMC, Kimenai DM, et al. Metformin and high-sensitivity cardiac troponin I and T trajectories in type 2 diabetes patients: a post-hoc analysis of a randomized controlled trial. Cardiovasc Diabetol. 2022;21(1):49. DOI:10.1186/s12933-022-01482-z
   PubMedGoogle Scholar
• Lamanna C, Monami M, Marchionni N, et al. Effect of metformin on cardiovascular events and mortality: a meta-analysis of randomized clinical trials. Diab Obes Metab. 2011;13(3):221–228. DOI:10.1111/j.1463-1326.2010.01349.x
   PubMed Web of Science ®Google Scholar
• Goldberg RB, Orchard TJ, Crandall JP, et al. Effects of long-term metformin and lifestyle interventions on cardiovascular events in the diabetes prevention program and its outcome study. Circulation. 2022;145(22):1632–1641. DOI:10.1161/CIRCULATIONAHA.121.056756
   PubMedGoogle Scholar
• Bergmark BA, Bhatt DL, McGuire DK, et al. Metformin use and clinical outcomes among patients with diabetes mellitus with or without heart failure or kidney dysfunction: observations from the SAVOR-TIMI 53 trial. Circulation. 2019;140(12):1004–1014.
   PubMedGoogle Scholar
• Lorell BH, Carabello BA. Left ventricular hypertrophy: pathogenesis, detection, and prognosis. Circulation. 2000;102(4):470–479.
   PubMed Web of Science ®Google Scholar
• Okin PM, Devereux RB, Jern S, et al. Regression of electrocardiographic left ventricular hypertrophy during antihypertensive treatment and the prediction of major cardiovascular events. JAMA. 2004;292(19):2343–2349. DOI:10.1001/jama.292.19.2343
   PubMed Web of Science ®Google Scholar
• Fagard RH, Celis H, Thijs L, et al. Regression of left ventricular mass by antihypertensive treatment: a meta-analysis of randomized comparative studies. Hypertension. 2009;54(5):1084–1091. DOI:10.1161/HYPERTENSIONAHA.109.136655
   PubMed Web of Science ®Google Scholar
• Xiao H, Ma X, Feng W, et al. Metformin attenuates cardiac fibrosis by inhibiting the TGFbeta1-Smad3 signalling pathway. Cardiovasc Res. 2010;87(3):504–513. DOI:10.1093/cvr/cvq066
   PubMedGoogle Scholar
• Bujak M, Ren G, Kweon HJ, et al. Essential role of Smad3 in infarct healing and in the pathogenesis of cardiac remodeling. Circulation. 2007;116(19):2127–2138. DOI:10.1161/CIRCULATIONAHA.107.704197
   PubMed Web of Science ®Google Scholar
• Patel SK, Wai B, Lang CC, et al. Genetic variation in kruppel like factor 15 is associated with left ventricular hypertrophy in patients with type 2 diabetes: discovery and replication cohorts. EBioMedicine. 2017;18:171–178.
   PubMedGoogle Scholar
• Mohan M, Al-Talabany S, McKinnie A, et al. A randomized controlled trial of metformin on left ventricular hypertrophy in patients with coronary artery disease without diabetes: the MET-REMODEL trial. Eur Heart J. 2019;40(41):3409–3417.
   PubMedGoogle Scholar
• Kamel AM, Sabry N, Farid S. Effect of metformin on left ventricular mass and functional parameters in non-diabetic patients: a meta-analysis of randomized clinical trials. BMC Cardiovasc Disord. 2022;22(1):405.
   PubMedGoogle Scholar
• Benes J, Kotrc M, Kroupova K, et al. Metformin treatment is associated with improved outcome in patients with diabetes and advanced heart failure (HFrEF). Sci Rep. 2022;12(1):13038. DOI:10.1038/s41598-022-17327-4
   PubMedGoogle Scholar
• Halabi A, Sen J, Huynh Q, et al. Metformin treatment in heart failure with preserved ejection fraction: a systematic review and meta-regression analysis. Cardiovasc Diabetol. 2020;19(1):124. DOI:10.1186/s12933-020-01100-w
   PubMed Web of Science ®Google Scholar
• Khan MS, Solomon N, DeVore AD, et al. Clinical outcomes with metformin and sulfonylurea therapies among patients with heart failure and diabetes. JACC Heart Fail. 2022;10(3):198–210. DOI:10.1016/j.jchf.2021.11.001
   PubMed Web of Science ®Google Scholar
• Wiggers H, Kober L, Gislason G, et al. The DANish randomized, double-blind, placebo controlled trial in patients with chronic HEART failure (DANHEART): a 2 x 2 factorial trial of hydralazine-isosorbide dinitrate in patients with chronic heart failure (H-Heft) and metformin in patients with chronic heart failure and diabetes or prediabetes (Met-HeFT). Am Heart J. 2021;231:137–146.
   PubMed Web of Science ®Google Scholar
• Docherty KF, Jhund PS, Bengtsson O, et al. Effect of Dapagliflozin in DAPA-HF according to background glucose-lowering therapy. Diabetes Care. 2020;43(11):2878–2881. DOI:10.2337/dc20-1402
   PubMedGoogle Scholar
• Larsen AH, Jessen N, Norrelund H, et al. A randomised, double-blind, placebo-controlled trial of metformin on myocardial efficiency in insulin-resistant chronic heart failure patients without diabetes. Eur J Heart Fail. 2020;22(9):1628–1637. DOI:10.1002/ejhf.1656
   PubMedGoogle Scholar
• Larsen AH, Wiggers H, Dollerup OL, et al. Metformin lowers body weight but fails to increase insulin sensitivity in chronic heart failure patients without diabetes: a randomized, double-blind, placebo-controlled study. Cardiovasc Drugs Ther. 2021;35(3):491–503. DOI:10.1007/s10557-020-07050-5
   PubMedGoogle Scholar
• Wong AK, Symon R, AlZadjali MA, et al. The effect of metformin on insulin resistance and exercise parameters in patients with heart failure. Eur J Heart Fail. 2012;14(11):1303–1310. DOI:10.1093/eurjhf/hfs106
   PubMed Web of Science ®Google Scholar
• Kersten C, Knottnerus ILH, Heijmans E, et al. Effect of metformin on outcome after acute ischemic stroke in patients with type 2 diabetes mellitus. J Stroke Cerebrovasc Dis. 2022;31(9):106648. DOI:10.1016/j.jstrokecerebrovasdis.2022.106648
   PubMedGoogle Scholar
• Mima Y, Kuwashiro T, Yasaka M, et al. Impact of metformin on the severity and outcomes of acute ischemic stroke in patients with type 2 diabetes mellitus. J Stroke Cerebrovasc Dis. 2016;25(2):436–446. DOI:10.1016/j.jstrokecerebrovasdis.2015.10.016
   PubMedGoogle Scholar
• Bellastella G, Maiorino MI, Longo M, et al. Glucagon-like peptide-1 receptor agonists and prevention of stroke systematic review of cardiovascular outcome trials with meta-analysis. Stroke. 2020;51(2):666–669. DOI:10.1161/STROKEAHA.119.027557
   PubMedGoogle Scholar
• Mary A, Hartemann A, Liabeuf S, et al. Association between metformin use and below-the-knee arterial calcification score in type 2 diabetic patients. Cardiovasc Diabetol. 2017;16(1):24. DOI:10.1186/s12933-017-0509-7
   PubMedGoogle Scholar
• Sirtori CR, Franceschini G, Gianfranceschi G, et al. Metformin improves peripheral vascular flow in nonhyperlipidemic patients with arterial disease. J Cardiovasc Pharmacol. 1984;6(5):914–923. DOI:10.1097/00005344-198409000-00027
   PubMedGoogle Scholar
• Khan SZ, Rivero M, Nader ND, et al. Metformin is associated with improved survival and decreased cardiac events with no impact on patency and limb salvage after revascularization for peripheral arterial disease. Ann Vasc Surg. 2019;55:63–77.
   PubMed Web of Science ®Google Scholar
• Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J. 2016;37(38):2893–2962. DOI:10.1093/eurheartj/ehw210
   PubMed Web of Science ®Google Scholar
• Harada M, Tadevosyan A, Qi X, et al. Atrial fibrillation activates AMP-Dependent protein kinase and its regulation of cellular calcium handling: potential role in metabolic adaptation and prevention of progression. J Am Coll Cardiol. 2015;66(1):47–58. DOI:10.1016/j.jacc.2015.04.056
   PubMedGoogle Scholar
• Ostropolets A, Elias PA, Reyes MV, et al. Metformin is associated with a lower risk of atrial fibrillation and ventricular arrhythmias compared with sulfonylureas: an observational study. Circ Arrhythm Electrophysiol. 2021;14(3):e009115. DOI:10.1161/CIRCEP.120.009115
   PubMedGoogle Scholar
• Chang SH, Wu LS, Chiou MJ, et al. Association of metformin with lower atrial fibrillation risk among patients with type 2 diabetes mellitus: a population-based dynamic cohort and in vitro studies. Cardiovasc Diabetol. 2014;13(1):123. DOI:10.1186/s12933-014-0123-x
   PubMed Web of Science ®Google Scholar
• Cheng YY, Leu HB, Chen TJ, et al. Metformin-inclusive therapy reduces the risk of stroke in patients with diabetes: a 4-year follow-up study. J Stroke Cerebrovasc Dis. 2014;23(2):e99–105. DOI:10.1016/j.jstrokecerebrovasdis.2013.09.001
   PubMed Web of Science ®Google Scholar
• Lal JC, Mao C, Zhou Y, et al. Transcriptomics-based network medicine approach identifies metformin as a repurposable drug for atrial fibrillation. Cell Rep Med. 2022;3(10):100749. DOI:10.1016/j.xcrm.2022.100749
   PubMedGoogle Scholar
• Xu T, Brandmaier S, Messias AC, et al. Effects of metformin on metabolite profiles and LDL cholesterol in patients with type 2 diabetes. Diabetes Care. 2015;38(10):1858–1867. DOI:10.2337/dc15-0658
   PubMed Web of Science ®Google Scholar
• Goldberg RB, Temprosa M, Mele L, et al. Change in adiponectin explains most of the change in HDL particles induced by lifestyle intervention but not metformin treatment in the Diabetes Prevention Program. Metabolism. 2016;65(5):764–775. DOI:10.1016/j.metabol.2015.11.011
   PubMedGoogle Scholar
• Kooy A, de Jager J, Lehert P, et al. Long-term effects of metformin on metabolism and microvascular and macrovascular disease in patients with type 2 diabetes mellitus. Arch Intern Med. 2009;169(6):616–625. DOI:10.1001/archinternmed.2009.20
   PubMedGoogle Scholar
• Hong J, Zhang Y, Lai S, et al. Effects of metformin versus glipizide on cardiovascular outcomes in patients with type 2 diabetes and coronary artery disease. Diabetes Care. 2013;36(5):1304–1311. DOI:10.2337/dc12-0719
   PubMed Web of Science ®Google Scholar
• Jadhav S, Ferrell W, Greer IA, et al. 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):956–963. DOI:10.1016/j.jacc.2006.04.088
   PubMed Web of Science ®Google Scholar
• Yu X, Jiang D, Wang J, et al. Metformin prescription and aortic aneurysm: systematic review and meta-analysis. Heart. 2019;105(17):1351–1357. DOI:10.1136/heartjnl-2018-314639
   PubMed Web of Science ®Google Scholar
• Golledge J, Arnott C, Moxon J, et al. Protocol for the Metformin Aneurysm Trial (MAT): a placebo-controlled randomised trial testing whether metformin reduces the risk of serious complications of abdominal aortic aneurysm. Trials. 2021;22(1):962. DOI:10.1186/s13063-021-05915-0
   PubMedGoogle Scholar
• Sundstrom J, Kristofi R, Ostlund O, et al. A registry-based randomised trial comparing an SGLT2 inhibitor and metformin as standard treatment of early stage type 2 diabetes (SMARTEST): rationale, design and protocol. J Diabetes Complications. 2021;35(10):107996. DOI:10.1016/j.jdiacomp.2021.107996
   PubMedGoogle Scholar