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Pharmacological Prevention of Cardiovascular Outcomes in Diabetes Mellitus: Established and Emerging Agents

Review Article
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Abstract

Cardiovascular disease is a major cause of morbidity and mortality in patients with type 2 diabetes. For this reason, there is a great deal of interest in determining how therapies commonly used to treat patients with diabetes impact cardiovascular outcomes. Results from recently completed cardiovascular outcomes trials of diabetes agents from several medication classes are leading to a sea change in how we think about diabetes treatment. The primary focus of this paper is to review recently completed and ongoing diabetes medication cardiovascular outcomes trials. We also review cardiovascular outcome evidence for other classes of medications commonly used in patients with diabetes (i.e., aspirin, anti-hypertensive agents, lipid-lowering agents, and weight loss medications).

Notes

Compliance with Ethical Standards

Funding

No external funds were used in the preparation of this manuscript.

Conflicts of interest

David R. Saxon has no disclosures to report. Neda Rasouli has served as the site principal investigator for medication trials for Novo Nordisk, Bristol-Meyers Squibb, Intarcia Therapeutics, Inc., Calibra Medical, GlaxoSmithKline, Amylin, Boehringer Ingelheim, Ionis Pharmaceuticals, and Regeneron. Robert H. Eckel has served as a consultant for Novo Nordisk and Merck.

References

  1. 1.
    Gregg EW, Li Y, Wang J, et al. Changes in diabetes-related complications in the United States, 1990–2010. N Engl J Med. 2014;370:1514–23.CrossRefPubMedGoogle Scholar
  2. 2.
    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.CrossRefPubMedGoogle Scholar
  3. 3.
    Diamond GA, Bax L, Kaul S. Uncertain effects of rosiglitazone on the risk for myocardial infarction and cardiovascular death. Ann Intern Med. 2007;147:578–81.CrossRefPubMedGoogle Scholar
  4. 4.
    Kaul S, Bolger AF, Herrington D, et al. Thiazolidinedione drugs and cardiovascular risks: a science advisory from the American Heart Association and American College of Cardiology Foundation. Circulation. 2010;121:1868–77.CrossRefPubMedGoogle Scholar
  5. 5.
    Center for Drug Evaluation and Research. Guidance for industry diabetes mellitus: evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes [internet]. 2008. https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf. Accessed 6 July 2017.
  6. 6.
    Hirshberg B, Raz I. Impact of the US Food and Drug Administration cardiovascular assessment requirements on the development of novel antidiabetes drugs. Diabetes Care. 2011;34(Suppl 2):S101–6.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Lipska KJ, Krumholz HM. Is hemoglobin A1c the right outcome for studies of diabetes? JAMA. 2017;317:1017–8.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Control Group, Turnbull FM, Abraira C, et al. Intensive glucose control and macrovascular outcomes in type 2 diabetes. Diabetologia. 2009;52:2288–98.CrossRefGoogle Scholar
  9. 9.
    Kelly TN, Bazzano LA, Fonseca VA, et al. Systematic review: glucose control and cardiovascular disease in type 2 diabetes. Ann Intern Med. 2009;151:394–403.CrossRefPubMedGoogle Scholar
  10. 10.
    Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545–59.CrossRefGoogle Scholar
  11. 11.
    ORIGIN Trial Investigators, Gerstein HC, Bosch J, et al. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med. 2012;367:319–28.CrossRefGoogle Scholar
  12. 12.
    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(8):723–32.  https://doi.org/10.1056/nejmoa1615692 (Epub ahead of print 12 June 2017).Google Scholar
  13. 13.
    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. 1998;352:837–53.Google Scholar
  14. 14.
    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;352:854–65.Google Scholar
  15. 15.
    Schwartz TB, Meinert CL. The UGDP controversy: 34 years of contentious ambiguity laid to rest. Perspect Biol Med. 2004;47:564–74.CrossRefPubMedGoogle Scholar
  16. 16.
    Azoulay L, Suissa S. Sulfonylureas and the risks of cardiovascular events and death: a methodological meta-regression analysis of the observational studies. Diabetes Care. 2017;40:706–14.CrossRefPubMedGoogle Scholar
  17. 17.
    Riddle MC. Modern sulfonylureas: dangerous or wrongly accused? Diabetes Care. 2017;40:629–31.CrossRefPubMedGoogle Scholar
  18. 18.
    Vaccaro O, Masulli M, Nicolucci A, et al. Effects on the incidence of cardiovascular events of the addition of pioglitazone versus sulfonylureas in patients with type 2 diabetes inadequately controlled with metformin (TOSCA.IT): a randomised, multicentre trial. Lancet Diabetes Endocrinol. 2017;5:887–97.CrossRefPubMedGoogle Scholar
  19. 19.
    Bach RG, Brooks MM, Lombardero M, et al. Rosiglitazone and outcomes for patients with diabetes mellitus and coronary artery disease in the bypass angioplasty revascularization investigation 2 diabetes (BARI 2D) trial. Circulation. 2013;128:785–94.CrossRefPubMedGoogle Scholar
  20. 20.
    Home PD, Pocock SJ, Beck-Nielsen H, et al. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet Lond Engl. 2009;373:2125–35.CrossRefGoogle Scholar
  21. 21.
    US Food and Drug Administration. Rosiglitazone-containing diabetes medicines: drug safety communication—FDA eliminates the Risk Evaluation and Mitigation Strategy (REMS) [internet]. 2015. https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm477601.htm. Accessed 7 July 2017.
  22. 22.
    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.CrossRefGoogle Scholar
  23. 23.
    Kernan WN, Viscoli CM, Furie KL, et al. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med. 2016;374:1321–31.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    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.CrossRefPubMedGoogle Scholar
  25. 25.
    Scirica BM, Braunwald E, Raz I, et al. Heart failure, saxagliptin, and diabetes mellitus: observations from the SAVOR-TIMI 53 randomized trial. Circulation. 2014;130:1579–88.CrossRefPubMedGoogle Scholar
  26. 26.
    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.CrossRefPubMedGoogle Scholar
  27. 27.
    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.CrossRefPubMedGoogle Scholar
  28. 28.
    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.CrossRefPubMedGoogle Scholar
  29. 29.
    Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375:311–22.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375:1834–44.Google Scholar
  31. 31.
    Bydureon EXSCEL trial meets primary safety objective in type-2 diabetes patients at wide range of cardiovascular risk [internet]. 2017. https://www.astrazeneca.com/media-centre/press-releases/2017/bydureon-exscel-trial-meets-primary-safety-objective-in-type-2-diabetes-patients-at-wide-range-of-cardiovascular-risk-23052017.html. Accessed 7 July 2017.
  32. 32.
    Intarcia announces successful cardiovascular safety results in phase 3 FREEDOM-CVO trial for ITCA 650, an investigational therapy for type 2 diabetes [internet]. 2016. https://www.intarcia.com/media/press-releases/2016-may-6-cardiovascular-safety.html. Accessed 7 July 2017.
  33. 33.
    Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117–28.CrossRefPubMedGoogle Scholar
  34. 34.
    Ingelfinger JR, Rosen CJ. Cardiac and renovascular complications in type 2 diabetes–is there hope? N Engl J Med. 2016;375:380–2.CrossRefPubMedGoogle Scholar
  35. 35.
    Mudaliar S, Alloju S, Henry RR. Can a shift in fuel energetics explain the beneficial cardiorenal outcomes in the EMPA-REG OUTCOME study? A unifying hypothesis. Diabetes Care. 2016;39:1115–22.CrossRefPubMedGoogle Scholar
  36. 36.
    US Food and Drug Administration. FDA approves Jardiance to reduce cardiovascular death in adults with type 2 diabetes [internet]. 2016. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm531517.htm. Accessed 7 July 2017.
  37. 37.
    Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644–657.  https://doi.org/10.1056/nejmoa1611925 (Epub ahead of print 12 June 2017).Google Scholar
  38. 38.
    Chiasson J-L, Josse RG, Gomis R, et al. Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the STOP-NIDDM trial. JAMA. 2003;290:486–94.CrossRefPubMedGoogle Scholar
  39. 39.
    Hanefeld M, Cagatay M, Petrowitsch T, et al. Acarbose reduces the risk for myocardial infarction in type 2 diabetic patients: meta-analysis of seven long-term studies. Eur Heart J. 2004;25:10–6.CrossRefPubMedGoogle Scholar
  40. 40.
    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.CrossRefPubMedGoogle Scholar
  41. 41.
    Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002;324:71–86.CrossRefGoogle Scholar
  42. 42.
    Smith SC, Benjamin EJ, Bonow RO, et al. AHA/ACCF secondary prevention and risk reduction therapy for patients with coronary and other atherosclerotic vascular disease: 2011 update: a guideline from the American Heart Association and American College of Cardiology Foundation endorsed by the World Heart Federation and the Preventive Cardiovascular Nurses Association. J Am Coll Cardiol. 2011;58:2432–46.CrossRefPubMedGoogle Scholar
  43. 43.
    Capodanno D, Angiolillo DJ. Aspirin for primary cardiovascular risk prevention and beyond in diabetes mellitus. Circulation. 2016;134:1579–94.CrossRefPubMedGoogle Scholar
  44. 44.
    ETDRS Investigators. Aspirin effects on mortality and morbidity in patients with diabetes mellitus. Early treatment diabetic retinopathy study report 14. JAMA. 1992;268:1292–1300.Google Scholar
  45. 45.
    Ogawa H, Nakayama M, Morimoto T, et al. Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: a randomized controlled trial. JAMA. 2008;300:2134–41.CrossRefPubMedGoogle Scholar
  46. 46.
    Belch J, MacCuish A, Campbell I, et al. The prevention of progression of arterial disease and diabetes (POPADAD) trial: factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease. BMJ. 2008;337:a1840.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Hebert PR, Schneider WR, Hennekens CH. Use of aspirin among diabetics in the primary prevention of cardiovascular disease: need for reliable randomized evidence and astute clinical judgment. J Gen Intern Med. 2009;24:1248–50.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Saito Y, Okada S, Ogawa H, et al. Low-dose aspirin for primary prevention of cardiovascular events in patients with type 2 diabetes: 10-year follow-up of a randomized controlled trial. Circulation. 2016;135:659–70.CrossRefPubMedGoogle Scholar
  49. 49.
    Pignone M, Alberts MJ, Colwell JA, et al. Aspirin for primary prevention of cardiovascular events in people with diabetes. Diabetes Care. 2010;33:1395–402.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    American Diabetes Association. 9. Cardiovascular disease and risk management. Diabetes Care. 2017;40:S75–87.CrossRefGoogle Scholar
  51. 51.
    ASCEND: a study of cardiovascular events iN Diabetes [internet]. 2015. https://clinicaltrials.gov/ct2/show/NCT00135226. Accessed 7 July 2017.
  52. 52.
    A study to assess the efficacy and safety of enteric-coated acetylsalicylic acid in patients at moderate risk of cardiovascular disease (ARRIVE) [internet]. 2017. https://clinicaltrials.gov/ct2/show/NCT00501059. Accessed 7 July 2017.
  53. 53.
    De Berardis G, Sacco M, Evangelista V, et al. Aspirin and simvastatin combination for cardiovascular events prevention trial in diabetes (ACCEPT-D): design of a randomized study of the efficacy of low-dose aspirin in the prevention of cardiovascular events in subjects with diabetes mellitus treated with statins. Trials. 2007;8:21.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    ASPREE Investigator Group. Study design of ASPirin in Reducing Events in the Elderly (ASPREE): a randomized, controlled trial. Contemp Clin Trials. 2013;36:555–64.Google Scholar
  55. 55.
    Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129:S1–45.CrossRefPubMedGoogle Scholar
  56. 56.
    Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet Lond Engl. 2004;364:685–96.CrossRefGoogle Scholar
  57. 57.
    Cholesterol Treatment Trialists’ (CTT) Collaborators, Kearney PM, Blackwell L, et al. Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet Lond Engl. 2008;371:117–25.CrossRefGoogle Scholar
  58. 58.
    Cholesterol Treatment Trialists’ (CTT) Collaboration, Baigent C, Blackwell L, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet Lond Engl. 2010;376:1670–81.CrossRefGoogle Scholar
  59. 59.
    Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet Lond Engl. 2002;360:7–22.CrossRefGoogle Scholar
  60. 60.
    Collins R, Armitage J, Parish S, et al. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet Lond Engl. 2003;361:2005–16.CrossRefGoogle Scholar
  61. 61.
    Chou R, Dana T, Blazina I, et al. Statins for prevention of cardiovascular disease in adults: evidence report and systematic review for the US Preventive Services Task Force. JAMA. 2016;316:2008–24.CrossRefPubMedGoogle Scholar
  62. 62.
    Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372:2387–97.CrossRefPubMedGoogle Scholar
  63. 63.
    Lally S, Tan CY, Owens D, et al. Messenger RNA levels of genes involved in dysregulation of postprandial lipoproteins in type 2 diabetes: the role of Niemann-Pick C1-like 1, ATP-binding cassette, transporters G5 and G8, and of microsomal triglyceride transfer protein. Diabetologia. 2006;49:1008–16.CrossRefPubMedGoogle Scholar
  64. 64.
    Leiter LA, Zamorano JL, Bujas-Bobanovic M, et al. Lipid-lowering efficacy and safety of alirocumab in patients with or without diabetes: a sub-analysis of ODYSSEY COMBO II. Diabetes Obes Metab. 2017;19:989–96.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Sattar N, Preiss D, Robinson JG, et al. Lipid-lowering efficacy of the PCSK9 inhibitor evolocumab (AMG 145) in patients with type 2 diabetes: a meta-analysis of individual patient data. Lancet Diabetes Endocrinol. 2016;4:403–10.CrossRefPubMedGoogle Scholar
  66. 66.
    Bangalore S, Kumar S, Lobach I, et al. Blood pressure targets in subjects with type 2 diabetes mellitus/impaired fasting glucose: observations from traditional and Bayesian random-effects meta-analyses of randomized trials. Circulation. 2011;123:2799–810.CrossRefPubMedGoogle Scholar
  67. 67.
    Emdin CA, Rahimi K, Neal B, et al. Blood pressure lowering in type 2 diabetes: a systematic review and meta-analysis. JAMA. 2015;313:603–15.CrossRefPubMedGoogle Scholar
  68. 68.
    Ettehad D, Emdin CA, Kiran A, et al. Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis. Lancet Lond Engl. 2016;387:957–67.CrossRefGoogle Scholar
  69. 69.
    Thomopoulos C, Parati G, Zanchetti A. Effects of blood-pressure-lowering treatment on outcome incidence in hypertension: 10—should blood pressure management differ in hypertensive patients with and without diabetes mellitus? Overview and meta-analyses of randomized trials. J Hypertens. 2017;35:922–44.CrossRefPubMedGoogle Scholar
  70. 70.
    Wharton S, Serodio KJ. Next generation of weight management medications: implications for diabetes and CVD risk. Curr Cardiol Rep. 2015;17:35.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Osborne S. Orexigen pulls the plug on post-marketing cardiovascular trial [internet]. 2016. http://seekingalpha.com/article/3965636-orexigen-pulls-plug-post-marketing-cardiovascular-trial. Accessed 7 July 2017.
  72. 72.
    A study to evaluate the effect of long-term treatment with BELVIQ (lorcaserin HCl) on the incidence of major adverse cardiovascular events and conversion to type 2 diabetes mellitus in obese and overweight subjects with cardiovascular disease or multiple cardiovascular risk factors [internet]. 2017. https://www.clinicaltrials.gov/show/NCT02019264. Accessed 7 July 2017.
  73. 73.
    Vivus announces operational update [internet]. 2017. http://ir.vivus.com/releasedetail.cfm?ReleaseID=904060. Accessed 7 July 2017.
  74. 74.
    Nissen SE, Wolski KE, Prcela L, et al. Effect of naltrexone-bupropion on major adverse cardiovascular events in overweight and obese patients with cardiovascular risk factors: a randomized clinical trial. JAMA. 2016;315:990–1004.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • David R. Saxon
    • 1
    • 2
  • Neda Rasouli
    • 1
    • 3
  • Robert H. Eckel
    • 1
  1. 1.Division of Endocrinology, Metabolism and Diabetes, Department of MedicineUniversity of Colorado School of MedicineAuroraUSA
  2. 2.Research ServiceVeterans Affairs Medical CenterDenverUSA
  3. 3.Division of EndocrinologyVeterans Affairs Medical CenterDenverUSA

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