Should metformin remain first-line medical therapy for patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease? An alternative approach | diabetes.medicinematters.com

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07-14-2018 | Metformin | Review | Article

Should Metformin Remain First-Line Medical Therapy for Patients with Type 2 Diabetes Mellitus and Atherosclerotic Cardiovascular Disease? An Alternative Approach

Journal: Current Diabetes Reports

Authors: Josephine L. Harrington, Natalia de Albuquerque Rocha, Kershaw V. Patel, Subodh Verma, Darren K. McGuire

Publisher: Springer US

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Abstract

Purpose of Review

With recent cardiovascular outcome trial (CVOT) results for antihyperglycemic medications, the treatment algorithm for patients with type 2 diabetes (T2DM) and atherosclerotic vascular disease (ASCVD) requires revision.

Recent Findings

All completed CVOTs have demonstrated CV safety of the tested medications, with some trials demonstrating CV efficacy. While metformin remains the first-line recommended medication for T2DM, 18–37% of the patients enrolled in the completed CVOTs were not treated with metformin, providing substantial power to assess CV outcomes independent of metformin. The safety and tolerability of metformin are indisputable, but there are no robust data proving its efficacy for either macro or microvascular disease outcomes. We should reconsider the primacy of metformin in the management of T2DM in patients with ASCVD.

Summary

This article will review the evidence for CV effects of antihyperglycemic agents (AHAs), and propose an evidence-based treatment algorithm for patients with T2DM and ASCVD.

1.

American Diabetes Association. Economic costs of diabetes in the U.S. in 2007. Diabetes Care. 2008;31:596–615.CrossRef

2.

National Diabetes Statistics Report. | Data & Statistics | Diabetes | CDC. https://www.cdc.gov/diabetes/data/statistics/statistics-report.html. Accessed 24 Mar 2018.

3.

Roglic G, World Health Organization Global report on diabetes. World Health Organization, Geneva, Switzerland. http://www.who.int/diabetes/global-report/en/. Accessed 24 Mar 3018.

4.

Patel A, MacMahon S, on behalf of the ADVANCE Collaborative Group, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 358:2560–72.

5.

Bertoni AG, Krop JS, Anderson GF, Brancati FL. Diabetes-related morbidity and mortality in a national sample of U.S. elders. Diabetes Care. 2002;25:471–5.CrossRefPubMed

6.

Gæde P, Lund-Andersen H, Parving H-H, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med. 2008;358:580–91.CrossRefPubMed

7.

Gu K, Cowie CC, Harris MI. Mortality in adults with and without diabetes in a national cohort of the U.S. population, 1971–1993. Diabetes Care. 1998;21:1138–45.CrossRefPubMed

8.

Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HAW. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359:1577–89.CrossRefPubMed

9.

UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 352:837–53.

10.

Rawshani A, Rawshani A, Franzén S, Eliasson B, Svensson A-M, Miftaraj M, et al. Mortality and cardiovascular disease in type 1 and type 2 diabetes. N Engl J Med. 2017;376:1407–18.CrossRefPubMed

11.

Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356:2457–71.CrossRefPubMed

12.

Lago RM, Singh PP, Nesto RW. Congestive heart failure and cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones: a meta-analysis of randomised clinical trials. Lancet. 2007;370:1129–36.CrossRefPubMed

13.

Gore MO, McGuire DK. Resolving drug effects from class effects among drugs for type 2 diabetes mellitus: more support for cardiovascular outcome assessments. Eur Heart J. 2011;32:1832–4.CrossRefPubMed

14.

Meinert CL, Knatterud GL, Prout TE, Klimt CR. A study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. II. Mortality results. Diabetes. 19:Suppl:789–830.

15.

Schramm TK, Gislason GH, Vaag A, et al. Mortality and cardiovascular risk associated with different insulin secretagogues compared with metformin in type 2 diabetes, with or without a previous myocardial infarction: a nationwide study. Eur Heart J. 2011;32:1900–8.CrossRefPubMed

16.

Nissen SE, Wolski K, Topol EJ. Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus. JAMA. 2005;294:2581–6.CrossRefPubMed

17.

Nathan DM. Finding new treatments for diabetes—how many, how fast . . . how good? N Engl J Med. 2007;356:437–40.CrossRefPubMed

18.

Fleming A. FDA approach to the regulation of drugs for diabetes. Am Heart J. 1999;138:S338–45.CrossRefPubMed

19.

Gore MO, McGuire DK. Cardiovascular disease and type 2 diabetes mellitus: regulating glucose and regulating drugs. Curr Cardiol Rep. 2009;11:258–63.CrossRefPubMed

20.

•• Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 373:2117–28. CVOT showing CV superiority for empagliflozin, an SGLT2i

21.

•• Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 377:644–57. CVOT showing CV superiority for canagliflozin, an SGLT2i

22.

•• Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 375:311–22. CVOT showing CV superiority for liraglutide, a GLP-1RA

23.

•• Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 375:1834–44. CVOT showing CV superiority for semaglutide, a GLP-1RA.

24.

Gerstein HC, Miller ME, Byington RP, Goff DC Jr, Bigger JT, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 358:2545–59.

25.

Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360:129–39.CrossRefPubMed

26.

• Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. Management of hyperglycemia in type 2 Diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 38:140–9. Current Guidelines on T2DM management by the American Diabetes Association and European Association for the Study of Diabetes

27.

• AACE/ACE Comprehensive Type 2 Diabetes Management Algorithm 2018. In: Am. Assoc. Clin. Endocrinol. https://www.aace.com/publications/algorithm. Accessed 2 Apr 2018 Current Guidelines on T2DM management by the American Association of Endocrinologists and American College of Endocrinology.

28.

• International Diabetes Federation. Global Guideline for Type 2 Diabetes. https://www.idf.org/e-library/guidelines/79-global-guideline-for-type-2-diabetes. Accessed 6 Apr 2018 Current Guidelines on T2DM management by the International Diabetes Federation.

29.

American Diabetes Association 8. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes—2018. Diabetes Care. 2017;41:S73–85.CrossRef

30.

• 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 Lond Engl. 1998;352:854–65. Study that suggested that there was a decrease in MI and CV mortality rate in patients randomized to metformin. This study played a large role in metformin’s ubiquity CrossRef

31.

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;60:1620–9.CrossRefPubMedPubMedCentral

32.

McCall AL. Insulin therapy and hypoglycemia. Endocrinol Metab Clin N Am. 2012;41:57–87.CrossRef

33.

Klein-Schwartz W, Stassinos GL, Isbister GK. Treatment of sulfonylurea and insulin overdose. Br J Clin Pharmacol. 2016;81:496–504.CrossRefPubMedPubMedCentral

34.

Bailey CJ. Metformin: historical overview. Diabetologia. 2017;60:1566–76.CrossRefPubMed

35.

Seltzer HS. A summary of criticisms of the findings and conclusions of the University Group Diabetes Program (UGDP). Diabetes. 1972;21:976–9.CrossRefPubMed

36.

Salpeter SR, Greyber E, Pasternak GA, Salpeter Posthumous EE. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev CD002967.

37.

Inzucchi SE, Lipska KJ, Mayo H, Bailey CJ, McGuire DK. Metformin in patients with type 2 diabetes and kidney disease: a systematic review. JAMA. 2014;312:2668–75.CrossRefPubMedPubMedCentral

38.

• Diabetes Canada | Clinical Practice Guidelines - 2018 Full Guidelines. http://guidelines.diabetes.ca/fullguidelines. Accessed 9 May 2018. Current guidelines on T2DM management by Diabetes Canada.

39.

Inzucchi SE, Masoudi FA, McGuire DK. Metformin in heart failure. Diabetes Care. 2007;30:e129.CrossRefPubMed

40.

Lipska KJ, Bailey CJ, Inzucchi SE. Use of metformin in the setting of mild-to moderate renal insufficiency. Diabetes Care. 2011;34(6):1431–7.CrossRefPubMedPubMedCentral

41.

U.S. Food and Drug Administration. FDA Drug Safety Communication: FDA revises warnings regarding use of the diabetes medicine metformin in certain patients with reduced kidney function. https://www.fda.gov/Drugs/DrugSafety/ucm493244.htm. Accessed 26 Apr 2018.

42.

WHO | WHO Model Lists of Essential Medicines. In: WHO. http://www.who.int/medicines/publications/essentialmedicines/en/. Accessed 27 Apr 2018.

43.

Boussageon R, Gueyffier F, Cornu C. Metformin as firstline treatment for type 2 diabetes: are we sure? BMJ. 2016;352:h6748.CrossRefPubMed

44.

• Boussageon R, Supper I, Bejan-Angoulvant T, Kellou N, Cucherat M, Boissel J-P, et al. Reappraisal of metformin efficacy in the treatment of type 2 diabetes: a meta-analysis of randomised controlled trials. PLoS Med. 2012;9:e1001204. A meta-analysis of metformin trials (including UKPDS 34) that was unable to exclude reductions or increases in all-cause mortality or CV mortality associated with metformin use.CrossRefPubMedPubMedCentral

45.

Maruthur NM, Tseng E, Hutfless S, Wilson LM, Suarez-Cuervo C, Berger Z, et al. Diabetes medications as monotherapy or metformin-based combination therapy for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med. 2016;164:740–51.CrossRefPubMed

46.

Chiasson JL, Naditch L, Miglitol Canadian University Investigator Group. The synergistic effect of miglitol plus metformin combination therapy in the treatment of type 2 diabetes. Diabetes Care. 2001;24:989–94.CrossRefPubMed

47.

DeFronzo RA, Goodman AM. Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. The multicenter Metformin Study Group. N Engl J Med. 1995;333:541–9.CrossRefPubMed

48.

Hällsten K, Virtanen KA, Lönnqvist F, Sipilä H, Oksanen A, Viljanen T, et al. Rosiglitazone but not metformin enhances insulin- and exercise-stimulated skeletal muscle glucose uptake in patients with newly diagnosed type 2 diabetes. Diabetes. 2002;51:3479–85.CrossRefPubMed

49.

Horton ES, Clinkingbeard C, Gatlin M, Foley J, Mallows S, Shen S. Nateglinide alone and in combination with metformin improves glycemic control by reducing mealtime glucose levels in type 2 diabetes. Diabetes Care. 2000;23:1660–5.CrossRefPubMed

50.

White WB, Cannon CP, Heller SR, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369:1327–35.CrossRefPubMed

51.

Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369:1317–26.CrossRefPubMed

52.

Green JB, Bethel MA, Armstrong PW, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;373:232–42.CrossRefPubMed

53.

Pfeffer MA, Claggett B, Diaz R, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med. 2015;373:2247–57.CrossRefPubMed

54.

Marso SP, McGuire DK, Zinman B, et al. Efficacy and safety of degludec versus glargine in type 2 diabetes. N Engl J Med. 2017;377:723–32.CrossRefPubMedPubMedCentral

55.

Holman RR, Bethel MA, Mentz RJ, et al. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2017;377:1228–39.CrossRefPubMed

56.

Standards of Medical Care in Diabetes | American Diabetes Association. https://professional.diabetes.org/content-page/standards-medical-care-diabetes. Accessed 9 May 2018.

57.

Bergmark BA, Bhatt DL, McGuire D, et al. Abstract 16764: metformin use and clinical outcomes among patients with diabetes mellitus and heart failure or kidney dysfunction—observations from the SAVOR-TIMI 53 trial. Circulation. 2016;134:A16764.

58.

Crowley MJ, Williams JW, Kosinski AS, D’Alessio DA, Buse JB. Metformin use may moderate the effect of DPP-4 inhibitors on cardiovascular outcomes. Diabetes Care. 2017; https://doi.org/10.2337/dc17-1528.

59.

U.S. Food and Drug Administration. FDA approves Jardiance to reduce cardiovascular death in adults with type 2 diabetes. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm531517.htm. Accessed 31 Mar 2018.

60.

U.S. Food and Drug Administration. Victoza (liraglutide [rDNA origin] injection. Package Insert.

61.

Dormandy JA, Charbonnel B, Eckland DJA, 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 Lond Engl. 2005;366:1279–89.CrossRef

62.

Rydén L, Thráinsdóttir I, Swedberg K. Adjudication of serious heart failure in patients from PROactive. Lancet. 2007;369:189–90.CrossRefPubMed

63.

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;298:1180–8.CrossRefPubMed

64.

McGuire DK, de Werf FV, Armstrong PW, 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;1:126–35.CrossRefPubMed

65.

Scirica BM, Braunwald E, Raz I et al. Heart failure, saxagliptin and diabetes mellitus: observations from the SAVOR - TIMI 53 Randomized Trial. Circulation CIRCULATIONAHA.114.010389.

66.

Zannad F, Cannon CP, Cushman WC, 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;385:2067–76.CrossRefPubMed

67.

Holman RR, Coleman RL, Chan JCN, et al. Effects of acarbose on cardiovascular and diabetes outcomes in patients with coronary heart disease and impaired glucose tolerance (ACE): a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2017;5:877–86.CrossRefPubMed

68.

Gerstein HC, Bosch J, Dagenais GR, et al. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med. 2012;367:319–28.CrossRefPubMed

69.

Rosenstock J, Perkovic V, Alexander JH, et al. Rationale, design, and baseline characteristics of the CArdiovascular safety and renal microvascular outcomE study with LINAgliptin (CARMELINA®): a randomized, double-blind, placebo-controlled clinical trial in patients with type 2 diabetes and high cardio-renal risk. Cardiovasc Diabetol. 2018;17:39.CrossRefPubMedPubMedCentral

70.

Forst T, Hanefeld M, Jacob S, Moeser G, Schwenk G, Pfützner A, et al. Association of sulphonylurea treatment with all-cause and cardiovascular mortality: a systematic review and meta-analysis of observational studies. Diab Vasc Dis Res. 2013;10:302–14.CrossRefPubMed

71.

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;36:1304–11.CrossRefPubMedPubMedCentral

72.

Roumie CL, Hung AM, Greevy RA, Grijalva CG, Liu X, Murff HJ, et al. Comparative effectiveness of sulfonylurea and metformin monotherapy on cardiovascular events in type 2 diabetes mellitus: a cohort study. Ann Intern Med. 2012;157:601–10.CrossRefPubMedPubMedCentral

73.

Monami M, Genovese S, Mannucci E. Cardiovascular safety of sulfonylureas: a meta-analysis of randomized clinical trials. Diabetes Obes Metab. 2013;15:938–53.CrossRefPubMed

74.

Schnell O, Standl E, Catrinoiu D, Genovese S, Lalic N, Skra J, et al. Report from the 1st cardiovascular outcome trial (CVOT) summit of the Diabetes & Cardiovascular Disease (D&CVD) EASD Study Group. Cardiovasc Diabetol. 2016; https://doi.org/10.1186/s12933-016-0357-x.

75.

Patel KV, de Albuquerque Rocha N, McGuire DK. Diabetes medications and cardiovascular outcome trials: lessons learned. Cleve Clin J Med. 2017;84:759–67.CrossRefPubMed

76.

Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. The task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016;37:2129–200.CrossRefPubMed

77.

Jorsal A, Kistorp C, Holmager P, et al. Effect of liraglutide, a glucagon-like peptide-1 analogue, on left ventricular function in stable chronic heart failure patients with and without diabetes (LIVE)—a multicentre, double-blind, randomised, placebo-controlled trial. Eur J Heart Fail. 2017;19:69–77.CrossRefPubMed

78.

Margulies KB, Hernandez AF, Redfield MM, et al. Effects of liraglutide on clinical stability among patients with advanced heart failure and reduced ejection fraction: a randomized clinical trial. JAMA. 2016;316:500–8.CrossRefPubMedPubMedCentral

79.

Sano M. A new class of drugs for heart failure: SGLT2 inhibitors reduce sympathetic overactivity. J Cardiol. 2018;71:471–6. https://doi.org/10.1016/j.jjcc.2017.12.004.CrossRefPubMed

80.

Study to evaluate the effect of dapagliflozin on the incidence of worsening heart failure or cardiovascular death in patients with chronic heart failure - full text view - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03036124. Accessed 10 May 2018.

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