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The Relationship Between Type 2 Diabetes, NAFLD, and Cardiovascular Risk

  • Macrovascular Complications in Diabetes (VR Aroda and R Shah, Section Editors)
  • Published:
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Abstract

Purpose of Review

Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are strongly associated. Both also associate with an increased risk of cardiovascular disease (CVD).

Recent Findings

Several studies have provided evidence that NAFLD could be an independent CVD risk factor. Given the strong association between NAFLD and T2DM, assessing the independent CV effect of these two conditions remains challenging. However, patients with T2DM and NAFLD exhibit higher risk of CVD compared with T2DM without NAFLD suggesting a potential synergistic increase of CV risk in patients with both T2DM and NAFLD supported by several shared pathophysiological pathways. Several anti-diabetic therapies have shown beneficial effect on both NAFLD and CVD.

Summary

Patients with T2DM and NAFLD should be considered at high risk of CVD and could benefit from more intensive CV prevention. Additional long-term follow-up is needed to demonstrate that the treatment of NAFLD effectively reduces the risk of CVD.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64(1):73–84. https://doi.org/10.1002/hep.28431.

    Article  PubMed  Google Scholar 

  2. Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018;67(1):328–57. https://doi.org/10.1002/hep.29367Most recent practice guideline for the management of NAFLD from AASLD.

    Article  PubMed  Google Scholar 

  3. European Association for the Study of the Liver. Electronic address eee, European Association for the Study of D, European Association for the Study of O. EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol. 2016;64(6):1388–402. https://doi.org/10.1016/j.jhep.2015.11.004Most recent European practice guideline for the management of NAFLD.

    Article  Google Scholar 

  4. Loomba R, Wong R, Fraysse J, Shreay S, Li S, Harrison S, et al. Nonalcoholic fatty liver disease progression rates to cirrhosis and progression of cirrhosis to decompensation and mortality: a real world analysis of Medicare data. Aliment Pharmacol Ther. 2020;51(11):1149–59. https://doi.org/10.1111/apt.15679.

    Article  CAS  PubMed  Google Scholar 

  5. Long MT, Zhang X, Xu H, Liu CT, Corey KE, Chung RT, et al. Hepatic fibrosis associates with multiple cardiometabolic disease risk factors: the Framingham Heart Study. Hepatology. 2020. https://doi.org/10.1002/hep.31608.

  6. Anstee QM, Targher G, Day CP. Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis. Nat Rev Gastroenterol Hepatol. 2013;10(6):330–44. https://doi.org/10.1038/nrgastro.2013.41.

    Article  CAS  PubMed  Google Scholar 

  7. Collaborators GBDCoD. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392(10159):1736–88. https://doi.org/10.1016/S0140-6736(18)32203-7.

    Article  Google Scholar 

  8. Younossi ZM, Golabi P, de Avila L, Paik JM, Srishord M, Fukui N, et al. The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: a systematic review and meta-analysis. J Hepatol. 2019;71(4):793–801. https://doi.org/10.1016/j.jhep.2019.06.021.

    Article  PubMed  Google Scholar 

  9. Doycheva I, Cui J, Nguyen P, Costa EA, Hooker J, Hofflich H, et al. Non-invasive screening of diabetics in primary care for NAFLD and advanced fibrosis by MRI and MRE. Aliment Pharmacol Ther. 2016;43(1):83–95. https://doi.org/10.1111/apt.13405.

    Article  CAS  PubMed  Google Scholar 

  10. Webster MWI, Scott RS. What cardiologists need to know about diabetes. Lancet. 1997;350:S23–S8. https://doi.org/10.1016/S0140-6736(97)90025-8.

    Article  Google Scholar 

  11. Kosiborod M, Gomes MB, Nicolucci A, Pocock S, Rathmann W, Shestakova MV, 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. https://doi.org/10.1186/s12933-018-0787-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Rydén L, Grant PJ, Anker SD, Berne C, Cosentino F, Danchin N, et al. ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J. 2013;34(39):3035–87. https://doi.org/10.1093/eurheartj/eht108.

    Article  PubMed  Google Scholar 

  13. Hayward RA, Reaven PD, Wiitala WL, Bahn GD, Reda DJ, Ge L, et al. Follow-up of glycemic control and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;372(23):2197–206. https://doi.org/10.1056/NEJMoa1414266.

    Article  CAS  PubMed  Google Scholar 

  14. 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. https://doi.org/10.1056/NEJMoa0806470.

    Article  CAS  PubMed  Google Scholar 

  15. McPherson S, Hardy T, Henderson E, Burt AD, Day CP, Anstee QM. Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical management. J Hepatol. 2015;62(5):1148–55. https://doi.org/10.1016/j.jhep.2014.11.034.

    Article  PubMed  Google Scholar 

  16. Wang P, Kang D, Cao W, Wang Y, Liu Z. Diabetes mellitus and risk of hepatocellular carcinoma: a systematic review and meta-analysis. Diabetes Metab Res Rev. 2012;28(2):109–22. https://doi.org/10.1002/dmrr.1291.

    Article  CAS  PubMed  Google Scholar 

  17. Birkenfeld AL, Shulman GI. Nonalcoholic fatty liver disease, hepatic insulin resistance, and type 2 diabetes. Hepatology. 2014;59(2):713–23. https://doi.org/10.1002/hep.26672.

    Article  PubMed  Google Scholar 

  18. Watt GP, De La Cerda I, Pan JJ, Fallon MB, Beretta L, Loomba R, et al. Elevated glycated hemoglobin is associated with liver fibrosis, as assessed by elastography, in a population-based study of Mexican Americans. Hepatol Commun. 2020;4(12):1793–801. https://doi.org/10.1002/hep4.1603.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zhou YY, Zhou XD, Wu SJ, Hu XQ, Tang B, Poucke SV, et al. Synergistic increase in cardiovascular risk in diabetes mellitus with nonalcoholic fatty liver disease: a meta-analysis. Eur J Gastroenterol Hepatol. 2018;30(6):631–6. https://doi.org/10.1097/MEG.0000000000001075.

    Article  PubMed  Google Scholar 

  20. Targher G, Lonardo A, Byrne CD. Nonalcoholic fatty liver disease and chronic vascular complications of diabetes mellitus. Nat Rev Endocrinol. 2018;14(2):99–114. https://doi.org/10.1038/nrendo.2017.173Meta-analysis underlying the increase risk of CVD in T2DM patient with NAFLD compared to T2DM without NAFLD.

    Article  CAS  PubMed  Google Scholar 

  21. Zhou YY, Zhou XD, Wu SJ, Fan DH, Van Poucke S, Chen YP, et al. Nonalcoholic fatty liver disease contributes to subclinical atherosclerosis: a systematic review and meta-analysis. Hepatol Commun. 2018;2(4):376–92. https://doi.org/10.1002/hep4.1155.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Targher G, Byrne CD, Lonardo A, Zoppini G, Barbui C. Non-alcoholic fatty liver disease and risk of incident cardiovascular disease: a meta-analysis. J Hepatol. 2016;65(3):589–600. https://doi.org/10.1016/j.jhep.2016.05.013.

    Article  PubMed  Google Scholar 

  23. Taylor RS, Taylor RJ, Bayliss S, Hagstrom H, Nasr P, Schattenberg JM, et al. Association between fibrosis stage and outcomes of patients with nonalcoholic fatty liver disease: a systematic review and meta-analysis. Gastroenterology. 2020;158(6):1611–25 e12. https://doi.org/10.1053/j.gastro.2020.01.043.

    Article  CAS  PubMed  Google Scholar 

  24. Vilar-Gomez E, Calzadilla-Bertot L, Wai-Sun Wong V, Castellanos M, Aller-de la Fuente R, Metwally M, et al. Fibrosis severity as a determinant of cause-specific mortality in patients with advanced nonalcoholic fatty liver disease: a multi-national cohort study. Gastroenterology. 2018;155(2):443–57 e17. https://doi.org/10.1053/j.gastro.2018.04.034.

    Article  PubMed  Google Scholar 

  25. Henson JB, Simon TG, Kaplan A, Osganian S, Masia R, Corey KE. Advanced fibrosis is associated with incident cardiovascular disease in patients with non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2020;51(7):728–36. https://doi.org/10.1111/apt.15660.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Hagstrom H, Nasr P, Ekstedt M, Hammar U, Stal P, Askling J, et al. Cardiovascular risk factors in non-alcoholic fatty liver disease. Liver Int. 2019;39(1):197–204. https://doi.org/10.1111/liv.13973.

    Article  PubMed  Google Scholar 

  27. Alexander M, Loomis AK, van der Lei J, Duarte-Salles T, Prieto-Alhambra D, Ansell D, et al. Non-alcoholic fatty liver disease and risk of incident acute myocardial infarction and stroke: findings from matched cohort study of 18 million European adults. BMJ. 2019;367:l5367. https://doi.org/10.1136/bmj.l5367.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Henson JB, Roden M, Targher G, Corey KE. Is nonalcoholic fatty liver disease not a risk factor for cardiovascular disease: not yet time for a change of heart. Hepatology. 2020;71(5):1867–9. https://doi.org/10.1002/hep.31156.

    Article  PubMed  Google Scholar 

  29. Paik JM, Golabi P, Biswas R, Alqahtani S, Venkatesan C, Younossi ZM. Nonalcoholic fatty liver disease and alcoholic liver disease are major drivers of liver mortality in the United States. Hepatol Commun. 2020;4(6):890–903. https://doi.org/10.1002/hep4.1510.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Caussy C, Soni M, Cui J, Bettencourt R, Schork N, Chen CH, et al. Nonalcoholic fatty liver disease with cirrhosis increases familial risk for advanced fibrosis. J Clin Invest. 2017;127(7):2697–704. https://doi.org/10.1172/JCI93465.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Bazick J, Donithan M, Neuschwander-Tetri BA, Kleiner D, Brunt EM, Wilson L, et al. Clinical model for NASH and advanced fibrosis in adult patients with diabetes and NAFLD: guidelines for referral in NAFLD. Diabetes Care. 2015;38(7):1347–55. https://doi.org/10.2337/dc14-1239.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Agarwal AK, Jain V, Singla S, Baruah BP, Arya V, Yadav R, et al. Prevalence of non-alcoholic fatty liver disease and its correlation with coronary risk factors in patients with type 2 diabetes. J Assoc Physicians India. 2011;59:351–4.

    CAS  PubMed  Google Scholar 

  33. Chan WK, Tan AT, Vethakkan SR, Tah PC, Vijayananthan A, Goh KL. Ultrasonography-diagnosed non-alcoholic fatty liver disease is not associated with prevalent ischemic heart disease among diabetics in a multiracial Asian hospital clinic population. Clin Res Hepatol Gastroenterol. 2014;38(3):284–91. https://doi.org/10.1016/j.clinre.2014.02.009.

    Article  PubMed  Google Scholar 

  34. Takeuchi Y, Ito H, Komatsu Y, Oshikiri K, Antoku S, Abe M, et al. Non-alcoholic fatty liver disease is an independent predictor for macroangiopathy in Japanese type 2 diabetic patients: a cross-sectional study. Intern Med. 2012;51(13):1667–75. https://doi.org/10.2169/internalmedicine.51.7307.

    Article  PubMed  Google Scholar 

  35. Targher G, Bertolini L, Padovani R, Poli F, Scala L, Tessari R, et al. Increased prevalence of cardiovascular disease in Type 2 diabetic patients with non-alcoholic fatty liver disease. Diabet Med. 2006;23(4):403–9. https://doi.org/10.1111/j.1464-5491.2006.01817.x.

    Article  CAS  PubMed  Google Scholar 

  36. Targher G, Bertolini L, Rodella S, Tessari R, Zenari L, Lippi G, et al. Nonalcoholic fatty liver disease is independently associated with an increased incidence of cardiovascular events in type 2 diabetic patients. Diabetes Care. 2007;30(8):2119–21. https://doi.org/10.2337/dc07-0349.

    Article  CAS  PubMed  Google Scholar 

  37. Idilman IS, Akata D, Hazirolan T, Doganay Erdogan B, Aytemir K, Karcaaltincaba M. Nonalcoholic fatty liver disease is associated with significant coronary artery disease in type 2 diabetic patients: a computed tomography angiography study 2. J Diabetes. 2015;7(2):279–86. https://doi.org/10.1111/1753-0407.12172.

    Article  CAS  PubMed  Google Scholar 

  38. Lu H, Zeng L, Liang B, Shu X, Xie D. High prevalence of coronary heart disease in type 2 diabetic patients with non-alcoholic fatty liver disease. Arch Med Res. 2009;40(7):571–5. https://doi.org/10.1016/j.arcmed.2009.07.009.

    Article  CAS  PubMed  Google Scholar 

  39. Adams LA, Harmsen S, St Sauver JL, Charatcharoenwitthaya P, Enders FB, Therneau T, et al. Nonalcoholic fatty liver disease increases risk of death among patients with diabetes: a community-based cohort study. Am J Gastroenterol. 2010;105(7):1567–73. https://doi.org/10.1038/ajg.2010.18.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Targher G, Bertolini L, Poli F, Rodella S, Scala L, Tessari R, et al. Nonalcoholic fatty liver disease and risk of future cardiovascular events among type 2 diabetic patients. Diabetes. 2005;54(12):3541–6. https://doi.org/10.2337/diabetes.54.12.3541.

    Article  CAS  PubMed  Google Scholar 

  41. Wild SH, Walker JJ, Morling JR, McAllister DA, Colhoun HM, Farran B, et al. Cardiovascular disease, cancer, and mortality among people with type 2 diabetes and alcoholic or nonalcoholic fatty liver disease hospital admission. Diabetes Care. 2018;41(2):341–7. https://doi.org/10.2337/dc17-1590.

    Article  PubMed  Google Scholar 

  42. Mangla N, Ajmera VH, Caussy C, Sirlin C, Brouha S, Bajwa-Dulai S, et al. Liver stiffness severity is associated with increased cardiovascular risk in patients with type 2 diabetes. Clin Gastroenterol Hepatol. 2020;18(3):744–6 e1. https://doi.org/10.1016/j.cgh.2019.05.003.

    Article  PubMed  Google Scholar 

  43. Brouha SS, Nguyen P, Bettencourt R, Sirlin CB, Loomba R. Increased severity of liver fat content and liver fibrosis in non-alcoholic fatty liver disease correlate with epicardial fat volume in type 2 diabetes: a prospective study. Eur Radiol. 2018;28(4):1345–55. https://doi.org/10.1007/s00330-017-5075-6.

    Article  PubMed  Google Scholar 

  44. Brouwers M, Simons N, Stehouwer CDA, Isaacs A. Non-alcoholic fatty liver disease and cardiovascular disease: assessing the evidence for causality. Diabetologia. 2020;63(2):253–60. https://doi.org/10.1007/s00125-019-05024-3Recent review article of the pathophysiological link between NAFLD and CVD.

    Article  CAS  PubMed  Google Scholar 

  45. Adiels M, Olofsson SO, Taskinen MR, Boren J. Overproduction of very low-density lipoproteins is the hallmark of the dyslipidemia in the metabolic syndrome. Arterioscler Thromb Vasc Biol. 2008;28(7):1225–36. https://doi.org/10.1161/ATVBAHA.107.160192.

    Article  CAS  PubMed  Google Scholar 

  46. Chapman MJ, Guerin M, Bruckert E. Atherogenic, dense low-density lipoproteins. Pathophysiology and new therapeutic approaches. Eur Heart J. 1998;19(Suppl A):A24–30.

    CAS  PubMed  Google Scholar 

  47. Do R, Willer CJ, Schmidt EM, Sengupta S, Gao C, Peloso GM, et al. Common variants associated with plasma triglycerides and risk for coronary artery disease. Nat Genet. 2013;45(11):1345–52. https://doi.org/10.1038/ng.2795.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Vaughan DE. PAI-1 and atherothrombosis. J Thromb Haemost. 2005;3(8):1879–83. https://doi.org/10.1111/j.1538-7836.2005.01420.x.

    Article  CAS  PubMed  Google Scholar 

  49. Alessi MC, Bastelica D, Mavri A, Morange P, Berthet B, Grino M, et al. Plasma PAI-1 levels are more strongly related to liver steatosis than to adipose tissue accumulation. Arterioscler Thromb Vasc Biol. 2003;23(7):1262–8. https://doi.org/10.1161/01.ATV.0000077401.36885.BB.

    Article  CAS  PubMed  Google Scholar 

  50. Biondi-Zoccai GG, Abbate A, Liuzzo G, Biasucci LM. Atherothrombosis, inflammation, and diabetes. J Am Coll Cardiol. 2003;41(7):1071–7. https://doi.org/10.1016/s0735-1097(03)00088-3.

    Article  CAS  PubMed  Google Scholar 

  51. Cusi K. Treatment of patients with type 2 diabetes and non-alcoholic fatty liver disease: current approaches and future directions. Diabetologia. 2016;59(6):1112–20. https://doi.org/10.1007/s00125-016-3952-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Gerstein HC, Miller ME, Ismail-Beigi F, Largay J, McDonald C, Lochnan HA, et al. Effects of intensive glycaemic control on ischaemic heart disease: analysis of data from the randomised, controlled ACCORD trial. Lancet. 2014;384(9958):1936–41. https://doi.org/10.1016/S0140-6736(14)60611-5.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Merino J, Leong A, Posner DC, Porneala B, Masana L, Dupuis J, et al. Genetically driven hyperglycemia increases risk of coronary artery disease separately from type 2 diabetes. Diabetes Care. 2017;40(5):687–93. https://doi.org/10.2337/dc16-2625.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Bornfeldt KE, Tabas I. Insulin resistance, hyperglycemia, and atherosclerosis. Cell Metab. 2011;14(5):575–85. https://doi.org/10.1016/j.cmet.2011.07.015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Santos RD, Valenti L, Romeo S. Does nonalcoholic fatty liver disease cause cardiovascular disease? Current knowledge and gaps. Atherosclerosis. 2019;282:110–20. https://doi.org/10.1016/j.atherosclerosis.2019.01.029.

    Article  CAS  PubMed  Google Scholar 

  56. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017;377(12):1119–31. https://doi.org/10.1056/NEJMoa1707914.

    Article  CAS  PubMed  Google Scholar 

  57. Betrapally NS, Gillevet PM, Bajaj JS. Changes in the intestinal microbiome and alcoholic and nonalcoholic liver diseases: causes or effects? Gastroenterology. 2016;150(8):1745–55 e3. https://doi.org/10.1053/j.gastro.2016.02.073.

    Article  PubMed  Google Scholar 

  58. Henao-Mejia J, Elinav E, Jin C, Hao L, Mehal WZ, Strowig T, et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature. 2012;482(7384):179–85. https://doi.org/10.1038/nature10809.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Loomba R, Seguritan V, Li W, Long T, Klitgord N, Bhatt A, et al. Gut microbiome-based metagenomic signature for non-invasive detection of advanced fibrosis in human nonalcoholic fatty liver disease. Cell Metab. 2017;25(5):1054–62 e5. https://doi.org/10.1016/j.cmet.2017.04.001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Aron-Wisnewsky J, Vigliotti C, Witjes J, Le P, Holleboom AG, Verheij J, et al. Gut microbiota and human NAFLD: disentangling microbial signatures from metabolic disorders. Nat Rev Gastroenterol Hepatol. 2020;17(5):279–97. https://doi.org/10.1038/s41575-020-0269-9.

    Article  PubMed  Google Scholar 

  61. Aron-Wisnewsky J, Clement K. The gut microbiome, diet, and links to cardiometabolic and chronic disorders. Nat Rev Nephrol. 2016;12(3):169–81. https://doi.org/10.1038/nrneph.2015.191.

    Article  CAS  PubMed  Google Scholar 

  62. Caussy C, Tripathi A, Humphrey G, Bassirian S, Singh S, Faulkner C, et al. A gut microbiome signature for cirrhosis due to nonalcoholic fatty liver disease. Nat Commun. 2019;10(1):1406. https://doi.org/10.1038/s41467-019-09455-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Oh TG, Kim SM, Caussy C, Fu T, Guo J, Bassirian S, et al. A universal gut-microbiome-derived signature predicts cirrhosis. Cell Metab. 2020;32(5):901. https://doi.org/10.1016/j.cmet.2020.10.015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Tang WHW, Backhed F, Landmesser U, Hazen SL. Intestinal microbiota in cardiovascular health and disease: JACC State-of-the-Art Review. J Am Coll Cardiol. 2019;73(16):2089–105. https://doi.org/10.1016/j.jacc.2019.03.024.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Schiattarella GG, Sannino A, Toscano E, Giugliano G, Gargiulo G, Franzone A, et al. Gut microbe-generated metabolite trimethylamine-N-oxide as cardiovascular risk biomarker: a systematic review and dose-response meta-analysis. Eur Heart J. 2017;38(39):2948–56. https://doi.org/10.1093/eurheartj/ehx342.

    Article  CAS  PubMed  Google Scholar 

  66. Qi J, You T, Li J, Pan T, Xiang L, Han Y, et al. Circulating trimethylamine N-oxide and the risk of cardiovascular diseases: a systematic review and meta-analysis of 11 prospective cohort studies. J Cell Mol Med. 2018;22(1):185–94. https://doi.org/10.1111/jcmm.13307.

    Article  CAS  PubMed  Google Scholar 

  67. Buse JB, Wexler DJ, Tsapas A, Rossing P, Mingrone G, Mathieu C, et al. 2019 Update to: 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. 2020;43(2):487–93. https://doi.org/10.2337/dci19-0066.

    Article  CAS  PubMed  Google Scholar 

  68. Musso G, Cassader M, Rosina F Gambino R. Impact of current treatments on liver disease, glucose metabolism and cardiovascular risk in non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of randomised trials. Diabetologia. 2012;55(4):885–904. https://doi.org/10.1007/s00125-011-2446-4.

  69. Li Y, Liu L, Wang B, Wang J, Chen D. Metformin in non-alcoholic fatty liver disease: a systematic review and meta-analysis. Biomed Rep. 2013;1(1):57–64. https://doi.org/10.3892/br.2012.18.

    Article  CAS  PubMed  Google Scholar 

  70. Uygun A, Kadayifci A, Isik AT, Ozgurtas T, Deveci S, Tuzun A, et al. Metformin in the treatment of patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2004;19(5):537–44. https://doi.org/10.1111/j.1365-2036.2004.01888.x.

    Article  CAS  PubMed  Google Scholar 

  71. Shields WW, Thompson KE, Grice GA, Harrison SA, Coyle WJ. The effect of metformin and standard therapy versus standard therapy alone in nondiabetic patients with insulin resistance and nonalcoholic steatohepatitis (NASH): a pilot trial. Ther Adv Gastroenterol. 2009;2(3):157–63. https://doi.org/10.1177/1756283X09105462.

    Article  Google Scholar 

  72. Haukeland JW, Konopski Z, Eggesbo HB, von Volkmann HL, Raschpichler G, Bjoro K, et al. Metformin in patients with non-alcoholic fatty liver disease: a randomized, controlled trial. Scand J Gastroenterol. 2009;44(7):853–60. https://doi.org/10.1080/00365520902845268.

    Article  CAS  PubMed  Google Scholar 

  73. Lavine JE, Schwimmer JB, Van Natta ML, Molleston JP, Murray KF, Rosenthal P, et al. Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. JAMA. 2011;305(16):1659–68. https://doi.org/10.1001/jama.2011.520.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. 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.

  75. Kooy A, de Jager J, Lehert P, Bets D, Wulffele MG, Donker AJ, 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):616–25. https://doi.org/10.1001/archinternmed.2009.20.

    Article  CAS  PubMed  Google Scholar 

  76. Hong J, Zhang Y, Lai S, Lv A, Su Q, Dong Y, 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. https://doi.org/10.2337/dc12-0719.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Boussageon R, Supper I, Bejan-Angoulvant T, Kellou N, Cucherat M, Boissel JP, et al. Reappraisal of metformin efficacy in the treatment of type 2 diabetes: a meta-analysis of randomised controlled trials. PLoS Med. 2012;9(4):e1001204. https://doi.org/10.1371/journal.pmed.1001204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. 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. https://doi.org/10.1111/j.1463-1326.2010.01349.x.

    Article  CAS  PubMed  Google Scholar 

  79. Cui J, Philo L, Nguyen P, Hofflich H, Hernandez C, Bettencourt R, et al. Sitagliptin vs. placebo for non-alcoholic fatty liver disease: a randomized controlled trial. J Hepatol. 2016;65(2):369–76. https://doi.org/10.1016/j.jhep.2016.04.021.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Macauley M, Hollingsworth KG, Smith FE, Thelwall PE, Al-Mrabeh A, Schweizer A, et al. Effect of vildagliptin on hepatic steatosis. J Clin Endocrinol Metab. 2015;100(4):1578–85. https://doi.org/10.1210/jc.2014-3794.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369(14):1317–26. https://doi.org/10.1056/NEJMoa1307684.

    Article  CAS  PubMed  Google Scholar 

  82. Green JB, Bethel MA, Armstrong PW, Buse JB, Engel SS, Garg J, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;373(3):232–42. https://doi.org/10.1056/NEJMoa1501352.

    Article  CAS  PubMed  Google Scholar 

  83. Zannad F, Cannon CP, Cushman WC, Bakris GL, Menon V, Perez AT, et al. Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: a multicentre, randomised, double-blind trial. Lancet. 2015;385(9982):2067–76. https://doi.org/10.1016/S0140-6736(14)62225-X.

    Article  CAS  PubMed  Google Scholar 

  84. Standl E, Schnell O. DPP-4 inhibitors and risk of heart failure EXAMINEd. Lancet. 2015;385(9982):2022–4. https://doi.org/10.1016/S0140-6736(15)60037-X.

    Article  CAS  PubMed  Google Scholar 

  85. Rosenstock J, Perkovic V, Johansen OE, Cooper ME, Kahn SE, Marx N, et al. Effect of linagliptin vs placebo on major cardiovascular events in adults with type 2 diabetes and high cardiovascular and renal risk: the CARMELINA Randomized Clinical Trial. JAMA. 2019;321(1):69–79. https://doi.org/10.1001/jama.2018.18269.

    Article  CAS  PubMed  Google Scholar 

  86. Rehman MB, Tudrej BV, Soustre J, Buisson M, Archambault P, Pouchain D, et al. Efficacy and safety of DPP-4 inhibitors in patients with type 2 diabetes: meta-analysis of placebo-controlled randomized clinical trials. Diabetes Metab. 2017;43(1):48–58. https://doi.org/10.1016/j.diabet.2016.09.005.

    Article  CAS  PubMed  Google Scholar 

  87. Zhu J, Yu X, Zheng Y, Li J, Wang Y, Lin Y, et al. Association of glucose-lowering medications with cardiovascular outcomes: an umbrella review and evidence map. Lancet Diabetes Endocrinol. 2020;8(3):192–205. https://doi.org/10.1016/S2213-8587(19)30422-XRecent systematic review and meta-analysis of the anti-diabetic drugs and CV outcomes.

    Article  CAS  PubMed  Google Scholar 

  88. Musso G, Cassader M, Paschetta E, Gambino R. Thiazolidinediones and advanced liver fibrosis in nonalcoholic steatohepatitis: a meta-analysis. JAMA Intern Med. 2017;177(5):633–40. https://doi.org/10.1001/jamainternmed.2016.9607Recent meta-analysis of the effect of thiazolidinediones on NASH-related advanced fibrosis.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, Massi-Benedetti M, Moules IK, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet. 2005;366(9493):1279–89. https://doi.org/10.1016/S0140-6736(05)67528-9.

    Article  CAS  PubMed  Google Scholar 

  90. Kernan WN, Viscoli CM, Furie KL, Young LH, Inzucchi SE, Gorman M, et al. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med. 2016;374(14):1321–31. https://doi.org/10.1056/NEJMoa1506930.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Liao HW, Saver JL, Wu YL, Chen TH, Lee M, Ovbiagele B. Pioglitazone and cardiovascular outcomes in patients with insulin resistance, pre-diabetes and type 2 diabetes: a systematic review and meta-analysis. BMJ Open. 2017;7(1):e013927. https://doi.org/10.1136/bmjopen-2016-013927.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Lincoff AM, Wolski K, Nicholls SJ, Nissen SE. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA. 2007;298(10):1180–8. https://doi.org/10.1001/jama.298.10.1180.

    Article  CAS  PubMed  Google Scholar 

  93. Armstrong MJ, Gaunt P, Aithal GP, Barton D, Hull D, Parker R, et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet. 2016;387(10019):679–90. https://doi.org/10.1016/S0140-6736(15)00803-X.

    Article  CAS  PubMed  Google Scholar 

  94. Newsome PN, Buchholtz K, Cusi K, Linder M, Okanoue T, Ratziu V, et al. A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis. N Engl J Med. 2020. https://doi.org/10.1056/NEJMoa2028395.

  95. Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311–22. https://doi.org/10.1056/NEJMoa1603827.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jodar E, Leiter LA, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375(19):1834–44. https://doi.org/10.1056/NEJMoa1607141.

    Article  CAS  PubMed  Google Scholar 

  97. Gerstein HC, Colhoun HM, Dagenais GR, Diaz R, Lakshmanan M, Pais P, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet. 2019;394(10193):121–30. https://doi.org/10.1016/S0140-6736(19)31149-3.

    Article  CAS  PubMed  Google Scholar 

  98. Pfeffer MA, Claggett B, Diaz R, Dickstein K, Gerstein HC, Kober LV, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med. 2015;373(23):2247–57. https://doi.org/10.1056/NEJMoa1509225.

    Article  CAS  PubMed  Google Scholar 

  99. Holman RR, Bethel MA, Hernandez AF. Once-weekly exenatide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2017;377(25):2502. https://doi.org/10.1056/NEJMc1714163.

    Article  PubMed  Google Scholar 

  100. Hernandez AF, Green JB, Janmohamed S, D'Agostino RB Sr, Granger CB, Jones NP, et al. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial. Lancet. 2018;392(10157):1519–29. https://doi.org/10.1016/S0140-6736(18)32261-X.

    Article  CAS  PubMed  Google Scholar 

  101. Zelniker TA, Wiviott SD, Raz I, Im K, Goodrich EL, Furtado RHM, et al. Comparison of the effects of glucagon-like peptide receptor agonists and sodium-glucose cotransporter 2 inhibitors for prevention of major adverse cardiovascular and renal outcomes in type 2 diabetes mellitus. Circulation. 2019;139(17):2022–31. https://doi.org/10.1161/CIRCULATIONAHA.118.038868Recent meta-analysis of the CV outcomes of GLP-1-RA and SGLT2 inhibitors.

    Article  CAS  PubMed  Google Scholar 

  102. Kuchay MS, Krishan S, Mishra SK, Farooqui KJ, Singh MK, Wasir JS, et al. Effect of empagliflozin on liver fat in patients with type 2 diabetes and nonalcoholic fatty liver disease: a randomized controlled trial (E-LIFT Trial). Diabetes Care. 2018;41(8):1801–8. https://doi.org/10.2337/dc18-0165.

    Article  CAS  PubMed  Google Scholar 

  103. Latva-Rasku A, Honka MJ, Kullberg J, Mononen N, Lehtimaki T, Saltevo J, et al. The SGLT2 Inhibitor dapagliflozin reduces liver fat but does not affect tissue insulin sensitivity: a randomized, double-blind, placebo-controlled study with 8-week treatment in type 2 diabetes patients. Diabetes Care. 2019;42(5):931–7. https://doi.org/10.2337/dc18-1569.

    Article  CAS  PubMed  Google Scholar 

  104. Cusi K, Bril F, Barb D, Polidori D, Sha S, Ghosh A, et al. Effect of canagliflozin treatment on hepatic triglyceride content and glucose metabolism in patients with type 2 diabetes. Diabetes Obes Metab. 2019;21(4):812–21. https://doi.org/10.1111/dom.13584.

    Article  CAS  PubMed  Google Scholar 

  105. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117–28. https://doi.org/10.1056/NEJMoa1504720.

    Article  CAS  PubMed  Google Scholar 

  106. Neal B, Perkovic V, Matthews DR. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(21):2099. https://doi.org/10.1056/NEJMc1712572.

    Article  PubMed  Google Scholar 

  107. Wiviott SD, Raz I, Sabatine MS. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. Reply N Engl J Med. 2019;380(19):1881–2. https://doi.org/10.1056/NEJMc1902837.

    Article  PubMed  Google Scholar 

  108. McMurray JJV, Solomon SD, Inzucchi SE, Kober L, Kosiborod MN, Martinez FA, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381(21):1995–2008. https://doi.org/10.1056/NEJMoa1911303.

    Article  CAS  PubMed  Google Scholar 

  109. Saad M, Mahmoud AN, Elgendy IY, Abuzaid A, Barakat AF, Elgendy AY, et al. Cardiovascular outcomes with sodium-glucose cotransporter-2 inhibitors in patients with type II diabetes mellitus: a meta-analysis of placebo-controlled randomized trials. Int J Cardiol. 2017;228:352–8. https://doi.org/10.1016/j.ijcard.2016.11.181.

    Article  PubMed  Google Scholar 

  110. McGuire DK, Van de Werf F, Armstrong PW, Standl E, Koglin J, Green JB, et al. Association between sitagliptin use and heart failure hospitalization and related outcomes in type 2 diabetes mellitus: secondary analysis of a randomized clinical trial. JAMA Cardiol. 2016;1(2):126–35. https://doi.org/10.1001/jamacardio.2016.0103.

    Article  PubMed  Google Scholar 

  111. Boettcher E, Csako G, Pucino F, Wesley R, Loomba R. Meta-analysis: pioglitazone improves liver histology and fibrosis in patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2012;35(1):66–75. https://doi.org/10.1111/j.1365-2036.2011.04912.x.

    Article  CAS  PubMed  Google Scholar 

  112. Mantovani A, Byrne CD, Scorletti E, Mantzoros CS, Targher G. Efficacy and safety of anti-hyperglycaemic drugs in patients with non-alcoholic fatty liver disease with or without diabetes: an updated systematic review of randomized controlled trials. Diabetes Metab. 2020;46(6):427–41. https://doi.org/10.1016/j.diabet.2019.12.007Recent systematic review of the effect of anti-diabetic drug on NAFLD.

    Article  CAS  PubMed  Google Scholar 

  113. Dufour JF, Caussy C, Loomba R. Combination therapy for non-alcoholic steatohepatitis: rationale, opportunities and challenges. Gut. 2020;69(10):1877–84. https://doi.org/10.1136/gutjnl-2019-319104.

    Article  CAS  PubMed  Google Scholar 

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Funding

RL receives funding support from NIEHS (P42ES010337), NCATS (UL1TR001442), NIDDK (U01DK061734, R01DK106419, P30DK120515, R01DK121378, R01DK124318), NHLBI (P01HL147835), NIAAA (U01AA029019), and DOD PRCRP (W81XWH-18-2-0026).

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Authors and Affiliations

  1. Hôpital Lyon Sud, Département Endocrinologie, Diabète et Nutrition, Hospices Civils de Lyon, 69495, Pierre-Bénite, France

    Cyrielle Caussy & Adrien Aubin

  2. Department of Medicine, NAFLD Research Center, University of California at San Diego, La Jolla, CA, USA

    Rohit Loomba

  3. Division of Gastroenterology, Department of Medicine, University of California at San Diego, La Jolla, CA, USA

    Rohit Loomba

  4. Division of Epidemiology, Department of Family and Preventive Medicine, University of California at San Diego, La Jolla, CA, USA

    Rohit Loomba

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  1. Cyrielle Caussy
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Correspondence to Cyrielle Caussy or Rohit Loomba.

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Conflict of Interest

C.C received consultant fees from Gilead, NovoNordisk, AstraZeneca, received grant support from Gilead. A.A declares no conflict of interest. R.L serves as a consultant for Anylam/Regeneron, Amgen, Arrowhead Pharmaceuticals, AstraZeneca, Bristol-Myer Squibb, CohBar, Eli Lilly, Galmed, Gilead, Glympse bio, Inipharm, Intercept, Ionis, Janssen Inc., Madrigal, Metacrine, Inc., NGM Biopharmaceuticals, Novartis, Novo Nordisk, Pfizer, Sagimet, 89 bio, and Viking Therapeutics. In addition, his institution has received grant support from Allergan, Astrazeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, Galectin Therapeutics, Galmed Pharmaceuticals, Genfit, Gilead, Intercept, Inventiva, Janssen, Madrigal Pharmaceuticals, Merck, NGM Biopharmaceuticals, Pfizer and Siemens. He is also co-founder of Liponexus, Inc.

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This article is part of the Topical Collection on Macrovascular Complications in Diabetes

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Caussy, C., Aubin, A. & Loomba, R. The Relationship Between Type 2 Diabetes, NAFLD, and Cardiovascular Risk. Curr Diab Rep 21, 15 (2021). https://doi.org/10.1007/s11892-021-01383-7

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