Benjamin EJ, Virani SS, Callaway CW, Chamberlain AM, Chang AR, Cheng S, Chiuve SE, Cushman M, Delling FN, Deo R, et al. Heart disease and stroke statistics-2018 update: a report from the American Heart Association. Circulation. 2018;137(12):e67–492.
Article
PubMed
Google Scholar
Lloyd-Jones DM, Braun LT, Ndumele CE, Smith SC Jr, Sperling LS, Virani SS, Blumenthal RS. Use of risk assessment tools to guide decision-making in the primary prevention of atherosclerotic cardiovascular disease: a special report from the American Heart Association and American College of Cardiology. J Am Coll Cardiol. 2018. https://doi.org/10.1016/j.jacc.2018.11.005.
Article
PubMed
PubMed Central
Google Scholar
Webster MW, Scott RS. What cardiologists need to know about diabetes. Lancet. 1997;350(Suppl 1):SI23–8.
Article
PubMed
Google Scholar
Matheus AS, Tannus LR, Cobas RA, Palma CC, Negrato CA, Gomes MB. Impact of diabetes on cardiovascular disease: an update. Int J Hypertens. 2013;2013:653789.
Article
PubMed
PubMed Central
CAS
Google Scholar
Livingstone SJ, Levin D, Looker HC, Lindsay RS, Wild SH, Joss N, Leese G, Leslie P, McCrimmon RJ, Metcalfe W, et al. Estimated life expectancy in a Scottish cohort with type 1 diabetes, 2008–2010. JAMA. 2015;313(1):37–44.
Article
CAS
PubMed
PubMed Central
Google Scholar
Kosiborod M, Gomes MB, Nicolucci A, Pocock S, Rathmann W, Shestakova MV, Watada H, Shimomura I, Chen H, Cid-Ruzafa J, et al. Vascular complications in patients with type 2 diabetes: prevalence and associated factors in 38 countries (the DISCOVER study program). Cardiovasc Diabetol. 2018;17(1):150.
Article
PubMed
PubMed Central
CAS
Google Scholar
Rena G, Hardie DG, Pearson ER. The mechanisms of action of metformin. Diabetologia. 2017;60(9):1577–85.
Article
CAS
PubMed
PubMed Central
Google Scholar
Davies MJ, D’Alessio DA, Fradkin J, Kernan WN, Mathieu C, Mingrone G, Rossing P, Tsapas A, Wexler DJ, Buse JB. Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2018;41(12):2669–701.
Article
PubMed
Google Scholar
Maruthur NM, Tseng E, Hutfless S, Wilson LM, Suarez-Cuervo C, Berger Z, Chu Y, Iyoha E, Segal JB, Bolen S. Diabetes medications as monotherapy or metformin-based combination therapy for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med. 2016;164(11):740–51.
Article
PubMed
Google Scholar
Avogaro A, Giorda C, Maggini M, Mannucci E, Raschetti R, Lombardo F, Spila-Alegiani S, Turco S, Velussi M, Ferrannini E, et al. Incidence of coronary heart disease in type 2 diabetic men and women: impact of microvascular complications, treatment, and geographic location. Diabetes Care. 2007;30(5):1241–7.
Article
PubMed
Google Scholar
UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998;352(9131):854–65.
Article
Google Scholar
Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359(15):1577–89.
Article
CAS
PubMed
Google Scholar
Kooy A, de Jager J, Lehert P, Bets D, Wulffele MG, Donker AJ, Stehouwer CD. 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):616–25.
Article
CAS
PubMed
Google Scholar
Katakami N, Yamasaki Y, Hayaishi-Okano R, Ohtoshi K, Kaneto H, Matsuhisa M, Kosugi K, Hori M. Metformin or gliclazide, rather than glibenclamide, attenuate progression of carotid intima-media thickness in subjects with type 2 diabetes. Diabetologia. 2004;47(11):1906–13.
Article
CAS
PubMed
Google Scholar
Lamanna C, Monami M, Marchionni N, Mannucci E. Effect of metformin on cardiovascular events and mortality: a meta-analysis of randomized clinical trials. Diabetes Obes Metab. 2011;13(3):221–8.
Article
CAS
PubMed
Google Scholar
Hong J, Zhang Y, Lai S, Lv A, Su Q, Dong Y, Zhou Z, Tang W, Zhao J, Cui L, 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):1304–11.
Article
CAS
PubMed
PubMed Central
Google Scholar
Petrie JR, Chaturvedi N, Ford I, Hramiak I, Hughes AD, Jenkins AJ, Klein BE, Klein R, Ooi TC, Rossing P, et al. Metformin in adults with type 1 diabetes: design and methods of REducing with MetfOrmin Vascular Adverse Lesions (REMOVAL): an international multicentre trial. Diabetes Obes Metab. 2017;19(4):509–16.
Article
CAS
PubMed
PubMed Central
Google Scholar
Petrie JR, Chaturvedi N, Ford I, Brouwers M, Greenlaw N, Tillin T, Hramiak I, Hughes AD, Jenkins AJ, Klein BEK, 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.
Article
CAS
PubMed
PubMed Central
Google Scholar
Lunder M, Janic M, Japelj M, Juretic A, Janez A, Sabovic M. Empagliflozin on top of metformin treatment improves arterial function in patients with type 1 diabetes mellitus. Cardiovasc Diabetol. 2018;17(1):153.
Article
PubMed
PubMed Central
CAS
Google Scholar
Chan CW, Yu CL, Lin JC, Hsieh YC, Lin CC, Hung CY, Li CH, Liao YC, Lo CP, Huang JL, et al. Glitazones and alpha-glucosidase inhibitors as the second-line oral anti-diabetic agents added to metformin reduce cardiovascular risk in type 2 diabetes patients: a nationwide cohort observational study. Cardiovasc Diabetol. 2018;17(1):20.
Article
PubMed
PubMed Central
CAS
Google Scholar
Dore FJ, Domingues CC, Ahmadi N, Kundu N, Kropotova Y, Houston S, Rouphael C, Mammadova A, Witkin L, Khiyami A, et al. The synergistic effects of saxagliptin and metformin on CD34+ endothelial progenitor cells in early type 2 diabetes patients: a randomized clinical trial. Cardiovasc Diabetol. 2018;17(1):65.
Article
PubMed
PubMed Central
CAS
Google Scholar
Younis A, Eskenazi D, Goldkorn R, Leor J, Naftali-Shani N, Fisman EZ, Tenenbaum A, Goldenberg I, Klempfner R. 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.
Article
PubMed
PubMed Central
CAS
Google Scholar
Gillani SW, Sulaiman SAS, Abdul MIM, Baig MR. Combined effect of metformin with ascorbic acid versus acetyl salicylic acid on diabetes-related cardiovascular complication; a 12-month single blind multicenter randomized control trial. Cardiovasc Diabetol. 2017;16(1):103.
Article
PubMed
PubMed Central
CAS
Google Scholar
Hanem LGE, Salvesen O, Juliusson PB, Carlsen SM, Nossum MCF, Vaage MO, Odegard R, Vanky E. Intrauterine metformin exposure and offspring cardiometabolic risk factors (PedMet study): a 5–10 year follow-up of the PregMet randomised controlled trial. Lancet Child Adolesc Health. 2019;3(3):166–74.
Article
PubMed
Google Scholar
Chen XM, Zhang WQ, Tian Y, Wang LF, Chen CC, Qiu CM. Liraglutide suppresses non-esterified free fatty acids and soluble vascular cell adhesion molecule-1 compared with metformin in patients with recent-onset type 2 diabetes. Cardiovasc Diabetol. 2018;17(1):53.
Article
PubMed
PubMed Central
CAS
Google Scholar
Jadhav S, Ferrell W, Greer IA, Petrie JR, 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.
Article
CAS
PubMed
Google Scholar
Meaney E, Vela A, Samaniego V, Meaney A, Asbun J, Zempoalteca JC, Elisa ZN, Emma MN, Guzman M, Hicks J, et al. Metformin, arterial function, intima-media thickness and nitroxidation in metabolic syndrome: the mefisto study. Clin Exp Pharmacol Physiol. 2008;35(8):895–903.
Article
CAS
PubMed
Google Scholar
Preiss D, Lloyd SM, Ford I, McMurray JJ, Holman RR, Welsh P, Fisher M, Packard CJ, Sattar N. Metformin for non-diabetic patients with coronary heart disease (the CAMERA study): a randomised controlled trial. Lancet Diabetes Endocrinol. 2014;2(2):116–24.
Article
CAS
PubMed
Google Scholar
Sirtori CR, Catapano A, Ghiselli GC, Innocenti AL, Rodriguez J. Metaformin: an antiatherosclerotic agent modifying very low density lipoproteins in rabbits. Atherosclerosis. 1977;26(1):79–89.
Article
CAS
PubMed
Google Scholar
Li SN, Wang X, Zeng QT, Feng YB, Cheng X, Mao XB, Wang TH, Deng HP. Metformin inhibits nuclear factor kappaB activation and decreases serum high-sensitivity C-reactive protein level in experimental atherogenesis of rabbits. Heart Vessels. 2009;24(6):446–53.
Article
PubMed
Google Scholar
Forouzandeh F, Salazar G, Patrushev N, Xiong S, Hilenski L, Fei B, Alexander RW. Metformin beyond diabetes: pleiotropic benefits of metformin in attenuation of atherosclerosis. J Am Heart Assoc. 2014;3(6):e001202.
Article
PubMed
PubMed Central
CAS
Google Scholar
Cai Z, Ding Y, Zhang M, Lu Q, Wu S, Zhu H, Song P, Zou MH. Ablation of adenosine monophosphate-activated protein kinase alpha1 in vascular smooth muscle cells promotes diet-induced atherosclerotic calcification in vivo. Circ Res. 2016;119(3):422–33.
Article
CAS
PubMed
Google Scholar
Luo F, Guo Y, Ruan GY, Long JK, Zheng XL, Xia Q, Zhao SP, Peng DQ, Fang ZF, Li XP. Combined use of metformin and atorvastatin attenuates atherosclerosis in rabbits fed a high-cholesterol diet. Sci Rep. 2017;7(1):2169.
Article
PubMed
PubMed Central
CAS
Google Scholar
de Aguiar LG, Bahia LR, Villela N, Laflor C, Sicuro F, Wiernsperger N, Bottino D, Bouskela E. Metformin improves endothelial vascular reactivity in first-degree relatives of type 2 diabetic patients with metabolic syndrome and normal glucose tolerance. Diabetes Care. 2006;29(5):1083–9.
Article
PubMed
CAS
Google Scholar
Jensterle M, Sebestjen M, Janez A, Prezelj J, Kocjan T, Keber I, Pfeifer M. Improvement of endothelial function with metformin and rosiglitazone treatment in women with polycystic ovary syndrome. Eur J Endocrinol. 2008;159(4):399–406.
Article
CAS
PubMed
Google Scholar
O’Hora TR, Markos F, Wiernsperger NF, Noble MI. Metformin causes nitric oxide-mediated dilatation in a shorter time than insulin in the iliac artery of the anesthetized pig. J Cardiovasc Pharmacol. 2012;59(2):182–7.
Article
PubMed
CAS
Google Scholar
Davis BJ, Xie Z, Viollet B, Zou MH. Activation of the AMP-activated kinase by antidiabetes drug metformin stimulates nitric oxide synthesis in vivo by promoting the association of heat shock protein 90 and endothelial nitric oxide synthase. Diabetes. 2006;55(2):496–505.
Article
CAS
PubMed
Google Scholar
Dong Y, Zhang M, Liang B, Xie Z, Zhao Z, Asfa S, Choi HC, Zou MH. Reduction of AMP-activated protein kinase alpha2 increases endoplasmic reticulum stress and atherosclerosis in vivo. Circulation. 2010;121(6):792–803.
Article
CAS
PubMed
PubMed Central
Google Scholar
Eriksson L, Nystrom T. Activation of AMP-activated protein kinase by metformin protects human coronary artery endothelial cells against diabetic lipoapoptosis. Cardiovasc Diabetol. 2014;13:152.
Article
PubMed
PubMed Central
CAS
Google Scholar
Faxon DP, Fuster V, Libby P, Beckman JA, Hiatt WR, Thompson RW, Topper JN, Annex BH, Rundback JH, Fabunmi RP, et al. Atherosclerotic vascular disease conference: writing group III: pathophysiology. Circulation. 2004;109(21):2617–25.
Article
PubMed
Google Scholar
Bentzon JF, Otsuka F, Virmani R, Falk E. Mechanisms of plaque formation and rupture. Circ Res. 2014;114(12):1852–66.
Article
CAS
PubMed
Google Scholar
Song P, Zhou Y, Coughlan KA, Dai X, Xu H, Viollet B, Zou MH. Adenosine monophosphate-activated protein kinase-alpha2 deficiency promotes vascular smooth muscle cell migration via S-phase kinase-associated protein 2 upregulation and E-cadherin downregulation. Arterioscler Thromb Vasc Biol. 2013;33(12):2800–9.
Article
CAS
PubMed
PubMed Central
Google Scholar
Ding Y, Zhang M, Zhang W, Lu Q, Cai Z, Song P, Okon IS, Xiao L, Zou MH. AMP-Activated protein kinase alpha 2 deletion induces VSMC phenotypic switching and reduces features of atherosclerotic plaque stability. Circ Res. 2016;119(6):718–30.
Article
CAS
PubMed
PubMed Central
Google Scholar
Cholesterol Treatment Trialists C, Mihaylova B, Emberson J, Blackwell L, Keech A, Simes J, Barnes EH, Voysey M, Gray A, Collins R, et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet. 2012;380(9841):581–90.
Article
CAS
Google Scholar
Xu T, Brandmaier S, Messias AC, Herder C, Draisma HH, Demirkan A, Yu Z, Ried JS, Haller T, Heier M, et al. Effects of metformin on metabolite profiles and LDL cholesterol in patients with type 2 diabetes. Diabetes Care. 2015;38(10):1858–67.
Article
CAS
PubMed
Google Scholar
Rosenson RS, Brewer HB Jr, Ansell BJ, Barter P, Chapman MJ, Heinecke JW, Kontush A, Tall AR, Webb NR. Dysfunctional HDL and atherosclerotic cardiovascular disease. Nat Rev Cardiol. 2016;13(1):48–60.
Article
CAS
PubMed
Google Scholar
Rohatgi A, Khera A, Berry JD, Givens EG, Ayers CR, Wedin KE, Neeland IJ, Yuhanna IS, Rader DR, de Lemos JA, et al. HDL cholesterol efflux capacity and incident cardiovascular events. N Engl J Med. 2014;371(25):2383–93.
Article
CAS
PubMed
PubMed Central
Google Scholar
Fadini GP, Iori E, Marescotti MC, de Kreutzenberg SV, Avogaro A. Insulin-induced glucose control improves HDL cholesterol levels but not reverse cholesterol transport in type 2 diabetic patients. Atherosclerosis. 2014;235(2):415–7.
Article
CAS
PubMed
Google Scholar
Kubota M, Nakanishi S, Hirano M, Maeda S, Yoneda M, Awaya T, Yamane K, Kohno N. Relationship between serum cholesterol efflux capacity and glucose intolerance in Japanese-Americans. J Atheroscler Thromb. 2014;21(10):1087–97.
Article
PubMed
Google Scholar
Goldberg RB, Temprosa M, Mele L, Orchard T, Mather K, Bray G, Horton E, Kitabchi A, Krakoff J, Marcovina S, 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):764–75.
Article
CAS
PubMed
Google Scholar
Matsuki K, Tamasawa N, Yamashita M, Tanabe J, Murakami H, Matsui J, Imaizumi T, Satoh K, Suda T. Metformin restores impaired HDL-mediated cholesterol efflux due to glycation. Atherosclerosis. 2009;206(2):434–8.
Article
CAS
PubMed
Google Scholar
Chapman MJ, Ginsberg HN, Amarenco P, Andreotti F, Boren J, Catapano AL, Descamps OS, Fisher E, Kovanen PT, Kuivenhoven JA, et al. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. Eur Heart J. 2011;32(11):1345–61.
Article
CAS
PubMed
PubMed Central
Google Scholar
Group AS, Ginsberg HN, Elam MB, Lovato LC, Crouse JR 3rd, Leiter LA, Linz P, Friedewald WT, Buse JB, Gerstein HC, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010;362(17):1563–74.
Article
Google Scholar
Dewey FE, Gusarova V, O’Dushlaine C, Gottesman O, Trejos J, Hunt C, Van Hout CV, Habegger L, Buckler D, Lai KM, et al. Inactivating variants in ANGPTL4 and risk of coronary artery disease. N Engl J Med. 2016;374(12):1123–33.
Article
CAS
PubMed
PubMed Central
Google Scholar
Peng J, Luo F, Ruan G, Peng R, Li X. Hypertriglyceridemia and atherosclerosis. Lipids Health Dis. 2017;16(1):233.
Article
PubMed
PubMed Central
CAS
Google Scholar
Geerling JJ, Boon MR, van der Zon GC, van den Berg SA, van den Hoek AM, Lombes M, Princen HM, Havekes LM, Rensen PC, Guigas B. Metformin lowers plasma triglycerides by promoting VLDL-triglyceride clearance by brown adipose tissue in mice. Diabetes. 2014;63(3):880–91.
Article
CAS
PubMed
Google Scholar
Li R, Chen LZ, Zhao W, Zhao SP, Huang XS. Metformin ameliorates obesity-associated hypertriglyceridemia in mice partly through the apolipoprotein A5 pathway. Biochem Biophys Res Commun. 2016;478(3):1173–8.
Article
CAS
PubMed
Google Scholar
Luo F, Guo Y, Ruan GY, Peng R, Li XP. Estrogen lowers triglyceride via regulating hepatic APOA5 expression. Lipids Health Dis. 2017;16(1):72.
Article
PubMed
PubMed Central
CAS
Google Scholar
Wulffele MG, Kooy A, de Zeeuw D, Stehouwer CD, Gansevoort RT. The effect of metformin on blood pressure, plasma cholesterol and triglycerides in type 2 diabetes mellitus: a systematic review. J Intern Med. 2004;256(1):1–14.
Article
CAS
PubMed
Google Scholar
Legein B, Temmerman L, Biessen EA, Lutgens E. Inflammation and immune system interactions in atherosclerosis. Cell Mol Life Sci. 2013;70(20):3847–69.
Article
CAS
PubMed
Google Scholar
Isoda K, Young JL, Zirlik A, MacFarlane LA, Tsuboi N, Gerdes N, Schonbeck U, Libby P. Metformin inhibits proinflammatory responses and nuclear factor-kappaB in human vascular wall cells. Arterioscler Thromb Vasc Biol. 2006;26(3):611–7.
Article
CAS
PubMed
Google Scholar
Kim J, Kwak HJ, Cha JY, Jeong YS, Rhee SD, Kim KR, Cheon HG. Metformin suppresses lipopolysaccharide (LPS)-induced inflammatory response in murine macrophages via activating transcription factor-3 (ATF-3) induction. J Biol Chem. 2014;289(33):23246–55.
Article
CAS
PubMed
PubMed Central
Google Scholar
Hattori Y, Suzuki K, Hattori S, Kasai K. Metformin inhibits cytokine-induced nuclear factor kappaB activation via AMP-activated protein kinase activation in vascular endothelial cells. Hypertension. 2006;47(6):1183–8.
Article
CAS
PubMed
Google Scholar
Yu XH, Fu YC, Zhang DW, Yin K, Tang CK. Foam cells in atherosclerosis. Clin Chim Acta. 2013;424:245–52.
Article
CAS
PubMed
Google Scholar
Moore KJ, Tabas I. Macrophages in the pathogenesis of atherosclerosis. Cell. 2011;145(3):341–55.
Article
CAS
PubMed
PubMed Central
Google Scholar
Yang Q, Yuan H, Chen M, Qu J, Wang H, Yu B, Chen J, Sun S, Tang X, Ren W. Metformin ameliorates the progression of atherosclerosis via suppressing macrophage infiltration and inflammatory responses in rabbits. Life Sci. 2018;198:56–64.
Article
CAS
PubMed
Google Scholar
Vasamsetti SB, Karnewar S, Kanugula AK, Thatipalli AR, Kumar JM, Kotamraju S. Metformin inhibits monocyte-to-macrophage differentiation via AMPK-mediated inhibition of STAT3 activation: potential role in atherosclerosis. Diabetes. 2015;64(6):2028–41.
Article
CAS
PubMed
Google Scholar
Li D, Wang D, Wang Y, Ling W, Feng X, Xia M. Adenosine monophosphate-activated protein kinase induces cholesterol efflux from macrophage-derived foam cells and alleviates atherosclerosis in apolipoprotein E-deficient mice. J Biol Chem. 2010;285(43):33499–509.
Article
CAS
PubMed
PubMed Central
Google Scholar
Luo F, Guo Y, Ruan G, Li X. Metformin promotes cholesterol efflux in macrophages by up-regulating FGF21 expression: a novel anti-atherosclerotic mechanism. Lipids Health Dis. 2016;15:109.
Article
PubMed
PubMed Central
CAS
Google Scholar
Wilmanns JC, Pandey R, Hon O, Chandran A, Schilling JM, Forte E, Wu Q, Cagnone G, Bais P, Philip V, et al. Metformin intervention prevents cardiac dysfunction in a murine model of adult congenital heart disease. Mol Metab. 2019;20:102–14.
Article
CAS
PubMed
Google Scholar
Slater RE, Strom JG, Methawasin M, Liss M, Gotthardt M, Sweitzer N, Granzier HL. Metformin improves diastolic function in an HFpEF-like mouse model by increasing titin compliance. J Gen Physiol. 2019;151(1):42–52.
Article
PubMed
PubMed Central
CAS
Google Scholar
Khan SZ, Rivero M, Nader ND, Cherr GS, Harris LM, Dryjski ML, Dosluoglu HH. 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.
Article
PubMed
Google Scholar
Mary A, Hartemann A, Liabeuf S, Aubert CE, Kemel S, Salem JE, Cluzel P, Lenglet A, Massy ZA, Lalau JD, et al. Association between metformin use and below-the-knee arterial calcification score in type 2 diabetic patients. Cardiovasc Diabetol. 2017;16(1):24.
Article
PubMed
PubMed Central
CAS
Google Scholar