Skip to main content

Advertisement

SpringerLink
Log in

Outcome studies and safety as guide for decision making in treating patients with type 2 diabetes

  • Published:
Reviews in Endocrine and Metabolic Disorders Aims and scope Submit manuscript

Abstract

Cardiovascular disease is the leading cause of mortality in patients with diabetes. Over the past 20 years multiple CV outcome studies have been conducted assessing the cardiovascular benefits of tight glycemic control or of particular glucose lowering agents. Improved glycemic control per-se failed to significantly reduce the risk of adverse cardiovascular outcomes in the short term, and it is only after >15 years that a reduction in adverse CV outcomes with tight glycemic control was perceived. Moreover tight glycemic control and increased attendant hypoglycemia led to increased mortality observed in the ACCORD trial. These data highlighted the importance of setting individualized glycemic targets and assessing the CV safety of the individual glucose lowering agents. Three DPP-4 inhibitors have presented CV outcome data to date demonstrating overall CV safety yet the question of increased hospitalization for heart failure with saxagliptin remains unexplained. Lixisenatide was the first GLP-1 receptor agonist to publish CV outcome data which demonstrated overall safety. The SGLT-2 inhibitor empagliflozin demonstrated CV superiority and a reduction in all-cause mortality and hospitalization for heart failure vs. placebo via mechanisms which remain to be fully elucidated. The outcome studies, though large and costly, have had a considerable effect on diabetes guidelines, these now emphasizing the importance of individualization of care. The outcome studies will presumably influence the new guidelines and dictate better tailoring of the drug regimen to the individual patient, matching patient comorbidities to the accumulating data regarding the safety and efficacy of each drug and class.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. GBD 2013 Mortality and Causes of Death Collaborators. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–2013: A systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;385(9963):117–71.

    Article  PubMed Central  Google Scholar 

  2. Conway BN, May ME, Fischl A, Frisbee J, Han X, Blot WJ. Cause-specific mortality by race in low-income black and white people with type 2 diabetes. Diabet Med. 2015;32(1):33–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Geiss LS, Herman WH, Smith PJ. Mortality among persons with non-insulin dependent diabetes. Harris MI, Cowie CC, Stern MP, Boyko EJ, Reiber GE, Bennett PH Diabetes in America. 2nd ed. Bethesda, MD: National Institutes of Health; 1995; 233–58.

  4. Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med. 2003;348(5):383–93.

    Article  PubMed  Google Scholar 

  5. Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med. 2008;358(6):580–91.

    Article  CAS  PubMed  Google Scholar 

  6. Stark Casagrande S, Fradkin JE, Saydah SH, Rust KF, Cowie CC. The prevalence of meeting A1C, blood pressure, and LDL goals among people with diabetes, 1988-2010. Diabetes Care. 2013;36(8):2271–9.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Emerging Risk Factors Collaboration, Sarwar N, Gao P, Seshasai SR, Gobin R, Kaptoge S, Di Angelantonio E, Ingelsson E, Lawlor DA, Selvin E, Stampfer M, Stehouwer CD, Lewington S, Pennells L, Thompson A, Sattar N, White IR, Ray KK, Danesh J. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: A collaborative meta-analysis of 102 prospective studies. Lancet. 2010;375(9733):2215–22.

    Article  Google Scholar 

  8. Haffner SM, Lehto S, Rönnemaa T, Pyörälä K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects withand without prior myocardial infarction. N Engl J Med. 1998;339(4):229–34.

    Article  CAS  PubMed  Google Scholar 

  9. Whiteley L, Padmanabhan S, Hole D, Isles C. Should diabetes be considered a coronary heart disease risk equivalent?: Results from 25 years of follow-up in the Renfrew and Paisley survey. Diabetes Care. 2005;28(7):1588–93.

    Article  PubMed  Google Scholar 

  10. Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, Kirby A, Sourjina T, Peto R, Collins R, Simes R, Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: Prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005;366(9493):1267–78.

    Article  CAS  PubMed  Google Scholar 

  11. Pyŏrälä K, Pedersen TR, Kjekshus J, Faergeman O, Olsson AG, Thorgeirsson G. Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. A subgroup analysis of the Scandinavian simvastatin survival study (4S). Diabetes Care. 1997;20(4):614–20.

    Article  PubMed  Google Scholar 

  12. Cholesterol Treatment Trialists’ (CTT) Collaborators, Kearney ,PM, Blackwell L, Collins R, Keech A, Simes J, Peto R, Armitage J, Baigent C. Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: A meta-analysis. Lancet. 2008;371(9607):117–25.

    Article  Google Scholar 

  13. American Diabetes Association. 8. Cardiovascular disease and risk management. Diabetes Care. 2016a;39(Suppl 1):S60–71.

    Google Scholar 

  14. Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, Darius H, Lewis BS, Ophuis TO, Jukema JW, De Ferrari GM, Ruzyllo W, De Lucca P, Im K, Bohula EA, Reist C, Wiviott SD, Tershakovec AM, Musliner TA, Braunwald E, Califf RM, IMPROVE-IT Investigators. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372(25):2387–97.

    Article  CAS  PubMed  Google Scholar 

  15. European Association for Cardiovascular Prevention & Rehabilitation, Reiner Z, Catapano AL, De Backer G, Graham I, Taskinen MR, Wiklund O, Agewall S, Alegria E, Chapman MJ, Durrington P, Erdine S, Halcox J, Hobbs R, Kjekshus J, Filardi PP, Riccardi G, Storey RF, Wood D, ESC Committee for Practice Guidelines (CPG) 2008–2010 and 2010–2012 Committees. ESC/EAS Guidelines for the management of dyslipidaemias: The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J. 2011;32(14):1769–818.

    Article  Google Scholar 

  16. Sabatine MS, Giugliano RP, Wiviott SD, Raal FJ, Blom DJ, Robinson J, Ballantyne CM, Somaratne R, Legg J, Wasserman SM, Scott R, Koren MJ, Stein, EA; Open-Label Study of Long-Term Evaluation against LDL Cholesterol (OSLER) Investigators. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372(16):1500–1509

  17. Robinson JG, Farnier M, Krempf M, Bergeron J, Luc G, Averna M, Stroes ES, Langslet G, Raal FJ, El Shahawy M, Koren MJ, Lepor NE, Lorenzato C, Pordy R, Chaudhari U, Kastelein JJ, ODYSSEY LONG TERM Investigators. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372(16):1489–99.

    Article  CAS  PubMed  Google Scholar 

  18. James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J, Lackland DT, LeFevre ML, MacKenzie TD, Ogedegbe O, Smith Jr SC, Svetkey LP, Taler SJ, Townsend RR, Wright Jr JT, Narva AS, Ortiz E. 2014 evidence-based guideline for the management of high blood pressure in adults: Report from the panel members appointed to the eighth joint National Committee (JNC 8). J Am Med Assoc. 2014;311(5):507–20.

    Article  CAS  Google Scholar 

  19. ACCORD Study Group, Cushman WC, Evans GW, Byington RP, Goff Jr DC, Grimm Jr RH, Cutler JA, Simons-Morton DG, Basile JN, Corson MA, Probstfield JL, Katz L, Peterson KA, Friedewald WT, Buse JB, Bigger JT, Gerstein HC, Ismail-Beigi F. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010;362(17):1575–85.

    Article  Google Scholar 

  20. Patel A, ADVANCE Collaborative Group, MacMahon S, Chalmers J, Neal B, Woodward M, Billot L, Harrap S, Poulter N, Marre M, Cooper M, Glasziou P, Grobbee DE, Hamet P, Heller S, Liu LS, Mancia G, Mogensen CE, Pan CY, Rodgers A, Williams B. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): A randomised controlled trial. Lancet. 2007;370(9590):829–40.

    Article  CAS  PubMed  Google Scholar 

  21. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: Results of the HOPE study and MICRO-HOPE substudy. Heart Outcomes Prevention Evaluation Study Investigators. Lancet. 2000;355(9200):253–9

  22. Lindholm LH, Ibsen H, Dahlöf B, Devereux RB, Beevers G, de Faire U, Fyhrquist F, Julius S, Kjeldsen SE, Kristiansson K, Lederballe-Pedersen O, Nieminen MS, Omvik P, Oparil S, Wedel H, Aurup P, Edelman J, Snapinn S, LIFE Study Group. Cardiovascular morbidity and mortality in patients with diabetes in the losartan intervention for endpoint reduction in hypertension study (LIFE): A randomized trial against atenolol. Lancet. 2002;359(9311):1004–10.

    Article  CAS  PubMed  Google Scholar 

  23. SPRINT Research Group, Wright Jr JT, Williamson JD, Whelton PK, Snyder JK, Sink KM, Rocco MV, Reboussin DM, Rahman M, Oparil S, Lewis CE, Kimmel PL, Johnson KC, Goff Jr DC, Fine LJ, Cutler JA, Cushman WC, Cheung AK, Ambrosius WT. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 2015;373(22):2103–16.

    Article  Google Scholar 

  24. Look AHEAD Research Group, Wing RR, Bolin P, Brancati FL, Bray GA, Clark JM, Coday M, Crow RS, Curtis JM, Egan CM, Espeland MA, Evans M, Foreyt JP, Ghazarian S, Gregg EW, Harrison B, Hazuda HP, Hill JO, Horton ES, Hubbard VS, Jakicic JM, Jeffery RW, Johnson KC, Kahn SE, Kitabchi AE, Knowler WC, Lewis CE, Maschak-Carey BJ, Montez MG, Murillo A, Nathan DM, Patricio J, Peters A, Pi-Sunyer X, Pownall H, Reboussin D, Regensteiner JG, Rickman AD, Ryan DH, Safford M, Wadden TA, Wagenknecht LE, West DS, Williamson DF, Yanovski SZ. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med. 2013;369(2):145–54.

    Article  Google Scholar 

  25. Chang SH, Stoll CR, Song J, Varela JE, Eagon CJ, Colditz GA. The effectiveness and risks of bariatric surgery: An updated systematic review and meta-analysis, 2003-2012. JAMA Surg. 2014;149(3):275–87.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352(9131):837–53

  27. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352(9131):854–65

  28. 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 

  29. Skyler JS, Bergenstal R, Bonow RO, Buse J, Deedwania P, Gale EA, Howard BV, Kirkman MS, Kosiborod M, Reaven P, Sherwin RS, American Diabetes Association, American College of Cardiology Foundation, American Heart Association. Intensive glycemic control and the prevention of cardiovascular events: Implications of the ACCORD, ADVANCE, and VA diabetes trials: A position statement of the American Diabetes Association and a scientific statement of the American College of Cardiology Foundation and the American Heart Association. Diabetes Care. 2009;32(1):187–92.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Ray KK, Seshasai SR, Wijesuriya S, Sivakumaran R, Nethercott S, Preiss D, Erqou S, Sattar N. Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: A meta-analysis of randomised controlled trials. Lancet. 2009;373(9677):1765–72.

    Article  CAS  PubMed  Google Scholar 

  31. Hayward RA, Reaven PD, Wiitala WL, Bahn GD, Reda DJ, Ge L, McCarren M, Duckworth WC, Emanuele NV, VADT Investigators. Follow-up of glycemic control and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;372(23):2197–206.

    Article  CAS  PubMed  Google Scholar 

  32. Pistrosch F, Ganz X, Bornstein SR, Birkenfeld AL, Henkel E, Hanefeld M. Risk of and risk factors for hypoglycemia and associated arrhythmias in patients with type 2 diabetes and cardiovascular disease: A cohort study under real-world conditions. Acta Diabetol. 2015;52(5):889–95.

    Article  CAS  PubMed  Google Scholar 

  33. Paneni F, Beckman JA, Creager MA, Cosentino F. Diabetes and vascular disease: Pathophysiology, clinical consequences, and medical therapy: Part I. Eur Heart J. 2013;34(31):2436–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Miyazawa T, Nakagawa K, Shimasaki S, Nagai R. Lipid glycation and protein glycation in diabetes and atherosclerosis. Amino Acids. 2012;42(4):1163–70.

    Article  CAS  PubMed  Google Scholar 

  35. Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M, STOP-NIDDM Trial Research Group. Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: The STOP-NIDDM trial. J Am Med Assoc. 2003;290(4):486–94.

    Article  CAS  Google Scholar 

  36. Holman RR, Bethel MA, Chan JC, Chiasson JL, Doran Z, Ge J, Gerstein H, Huo Y, McMurray JJ, Ryden L, Liyanage W, Schröder S, Tendera M, Theodorakis MJ, Tuomilehto J, Yang W, Hu D, Pan C, ACE Study Group. Rationale for and design of the Acarbose Cardiovascular Evaluation (ACE) trial. Am Heart J. 2014;168(1):23–9.e2.

    Article  CAS  PubMed  Google Scholar 

  37. Raz I, Wilson PW, Strojek K, Kowalska I, Bozikov V, Gitt AK, Jermendy G, Campaigne BN, Kerr L, Milicevic Z, Jacober SJ. Effects of prandial versus fasting glycemia on cardiovascular outcomes in type 2 diabetes: The HEART2D trial. Diabetes Care. 2009;32(3):381–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Raz I, Ceriello A, Wilson PW, Battioui C, Su EW, Kerr L, Jones CA, Milicevic Z, Jacober SJ. Post hoc subgroup analysis of the HEART2D trial demonstrates lower cardiovascular risk in older patients targeting postprandial versus fasting/premeal glycemia. Diabetes Care. 2011;34(7):1511–3.

    Article  PubMed  PubMed Central  Google Scholar 

  39. NAVIGATOR Study Group, Holman RR, Haffner SM, McMurray JJ, Bethel MA, Holzhauer B, Hua TA, Belenkov Y, Boolell M, Buse JB, Buckley BM, Chacra AR, Chiang FT, Charbonnel B, Chow CC, Davies MJ, Deedwania P, Diem P, Einhorn D, Fonseca V, Fulcher GR, Gaciong Z, Gaztambide S, Giles T, Horton E, Ilkova H, Jenssen T, Kahn SE, Krum H, Laakso M, Leiter LA, Levitt NS, Mareev V, Martinez F, Masson C, Mazzone T, Meaney E, Nesto R, Pan C, Prager R, Raptis SA, Rutten GE, Sandstroem H, Schaper F, Scheen A, Schmitz O, Sinay I, Soska V, Stender S, Tamás G, Tognoni G, Tuomilehto J, Villamil AS, Vozár J, Califf RM. Effect of nateglinide on the incidence of diabetes and cardiovascular events. N Engl J Med. 2010;362(16):1463–76.

    Article  Google Scholar 

  40. ORIGIN Trial Investigators, Gerstein HC, Bosch J, Dagenais GR, Díaz R, Jung H, Maggioni AP, Pogue J, Probstfield J, Ramachandran A, Riddle MC, Rydén LE, Yusuf S. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med. 2012;367(4):319–28.

    Article  Google Scholar 

  41. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356(24):2457–71.

    Article  CAS  PubMed  Google Scholar 

  42. Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, Massi-Benedetti M, Moules IK, Skene AM, Tan MH, Lefèbvre PJ, Murray GD, Standl E, Wilcox RG, Wilhelmsen L, Betteridge J, Birkeland K, Golay A, Heine RJ, Korányi L, Laakso M, Mokán M, Norkus A, Pirags V, Podar T, Scheen A, Scherbaum W, Schernthaner G, Schmitz O, Skrha J, Smith U, Taton J, PROactive Investigators. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): A randomized controlled trial. Lancet. 2005;366(9493):1279–89.

    Article  CAS  PubMed  Google Scholar 

  43. Lewis JD, Habel LA, Quesenberry CP, Strom BL, Peng T, Hedderson MM, Ehrlich SF, Mamtani R, Bilker W, Vaughn DJ, Nessel L, Van Den Eeden SK, Ferrara A. Pioglitazone use and risk of bladder cancer and other common cancers in persons with diabetes. J Am Med Assoc. 2015;314(3):265–77.

    Article  CAS  Google Scholar 

  44. Home PD, Pocock SJ, Beck-Nielsen H, Curtis PS, Gomis R, Hanefeld M, Jones NP, Komajda M, McMurray, JJ; RECORD Study Team. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): A multicentre, randomised, open-label trial. Lancet 2009;373(9681):2125–2135

  45. Tucker ME. FDA panel advises easing restrictions on rosiglitazone. BMJ. 2013;346:f3769.

    Article  PubMed  Google Scholar 

  46. Actos prescribing information available at: http://general.takedapharm.com/content/file.aspx?filetypecode=actospi&cacheRandomizer=7f8180b7-a1c8-4d46-ac32-5be4fad5578a.

  47. Bilik D, McEwen LN, Brown MB, Pomeroy NE, Kim C, Asao K, Crosson JC, Duru OK, Ferrara A, Hsiao VC, Karter AJ, Lee PG, Marrero DG, Selby JV, Subramanian U, Herman WH. Thiazolidinediones and fractures: Evidence from translating research into action for diabetes. J Clin Endocrinol Metab. 2010;95(10):4560–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. 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.

    Article  CAS  PubMed  Google Scholar 

  49. White WB, Cannon CP, Heller SR, et al; for the EXAMINE Investigators. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013; 369: 1327–1335

  50. 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.

    Article  CAS  PubMed  Google Scholar 

  51. 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.

    Article  CAS  PubMed  Google Scholar 

  52. Green JB, Bethel MA, Armstrong PW, Buse JB, Engel SS, Garg J, Josse R, Kaufman KD, Koglin J, Korn S, Lachin JM, McGuire DK, Pencina MJ, Standl E, Stein PP, Suryawanshi S, Van de Werf F, Peterson ED, Holman RR, TECOS Study Group. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;373(3):232–42.

    Article  CAS  PubMed  Google Scholar 

  53. Schernthaner G. Cahn A. Raz I. Is the use of DPP-4 inhibitors associated with an increased risk for heart failure? Lessons from EXAMINE, SAVOR and TECOS. Accepted for publication in Diabetes Care.

  54. Pfeffer MA, Claggett B, Diaz R, Dickstein K, Gerstein HC, Køber LV, Lawson FC, Ping L, Wei X, Lewis EF, Maggioni AP, McMurray JJ, Probstfield JL, Riddle MC, Solomon SD, Tardif JC, ELIXA Investigators. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med. 2015;373(23):2247–57.

    Article  CAS  PubMed  Google Scholar 

  55. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE, EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117–28.

    Article  CAS  PubMed  Google Scholar 

  56. Inzucchi SE, Zinman B, Wanner C, Ferrari R, Fitchett D, Hantel S, Espadero RM, Woerle HJ, Broedl UC, Johansen OE. SGLT-2 inhibitors and cardiovascular risk: Proposed pathways and review of ongoing outcome trials. Diab Vasc Dis Res. 2015;12(2):90–100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. American Diabetes Association. Glycemic targets. Diabetes Care. 2016b;39(Suppl 1):S39–46.

    Google Scholar 

  58. Cahn A, Raz I, Kleinman Y, Balicer R, Hoshen M, Lieberman N, Brenig N, Del Prato S, Cefalu WT. Clinical assessment of individualized glycemic goals in patients with type 2 diabetes: Formulation of an algorithm based on a survey among leading worldwide Diabetologists. Diabetes Care. 2015;38(12):2293–300.

    Article  CAS  PubMed  Google Scholar 

  59. Monami M, Dicembrini I, Martelli D, Mannucci E. Safety of dipeptidyl peptidase-4 inhibitors: A meta-analysis of randomized clinical trials. Curr Med Res Opin. 2011;27(Suppl 3):57–64.

    Article  CAS  PubMed  Google Scholar 

  60. Monami M, Dicembrini I, Nardini C, Fiordelli I, Mannucci E. Effects of glucagon-like peptide-1 receptor agonists on cardiovascular risk: A meta-analysis of randomized clinical trials. Diabetes Obes Metab. 2014;16(1):38–47.

    Article  CAS  PubMed  Google Scholar 

  61. Liakos A, Karagiannis T, Bekiari E, Boura P, Tsapas A. Update on long-term efficacy and safety of dapagliflozin in patients with type 2 diabetes mellitus. Ther Adv Endocrinol Metab. 2015;6(2):61–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Currie CJ, Johnson JA. The safety profile of exogenous insulin in people with type 2 diabetes: Justification for concern. Diabetes Obes Metab. 2012;14(1):1–4.

    Article  CAS  PubMed  Google Scholar 

  63. Fisher M, Petrie MC, Ambery PD, Donaldson J, Ye J, McMurray JJ. Cardiovascular safety of albiglutide in the harmony programme: A meta-analysis. Lancet Diabetes Endocrinol. 2015;3(9):697–703.

    Article  PubMed  Google Scholar 

  64. Gilbert RE, Krum H. Heart failure in diabetes: Effects of anti-hyperglycaemic drug therapy. Lancet. 2015;385(9982):2107–17.

    Article  CAS  PubMed  Google Scholar 

  65. Scheen AJ. Safety of dipeptidyl peptidase-4 inhibitors for treating type 2 diabetes. Expert Opin Drug Saf. 2015;14(4):505–24.

    Article  CAS  PubMed  Google Scholar 

  66. Leiter LA, Teoh H, Mosenzon O, Cahn A, Hirshberg B, Stahre CA, Hoekstra JB, Alvarsson M, Im K, Scirica BM, Bhatt DL, Raz I, SAVOR-TIMI 53 Steering Committee, Investigators. Frequency of Cancer Events with Saxagliptin in the SAVOR-TIMI 53 Trial. Diabetes Obes Metab. 2015. doi:10.1111/dom.12582.

    PubMed  Google Scholar 

  67. Nauck MA, Friedrich N. Do GLP-1-based therapies increase cancer risk? Diabetes Care. 2013;36(Suppl 2):S245–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Currie CJ, Poole CD, Gale EA. The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia. 2009;52(9):1766–77.

    Article  CAS  PubMed  Google Scholar 

  69. Bordeleau L, Yakubovich N, Dagenais GR, Rosenstock J, Probstfield J, Chang Yu P, Ryden LE, Pirags V, Spinas GA, Birkeland KI, Ratner RE, Marin-Neto JA, Keltai M, Riddle MC, Bosch J, Yusuf S. Gerstein HC; ORIGIN trial investigators. The association of basal insulin glargine and/or n-3 fatty acids with incident cancers in patients with dysglycemia. Diabetes Care. 2014;37(5):1360–6.

    Article  CAS  PubMed  Google Scholar 

  70. Thomsen RW, Pedersen L, Møller N, Kahlert J, Beck-Nielsen H, Sørensen HT. Incretin-based therapy and risk of acute pancreatitis: A nationwide population-based case-control study. Diabetes Care. 2015;38(6):1089–98.

    Article  CAS  PubMed  Google Scholar 

  71. Faillie JL, Babai S, Crépin S, Bres V, Laroche ML, Le Louet H, Petit P, Montastruc JL, Hillaire-Buys D, French Pharmacovigilance Centers Network. Pancreatitis associated with the use of GLP-1 analogs and DPP-4 inhibitors: A case/non-case study from the French Pharmacovigilance database. Acta Diabetol. 2014;51(3):491–7.

    CAS  PubMed  Google Scholar 

  72. Raz I, Bhatt DL, Hirshberg B, Mosenzon O, Scirica BM, Umez-Eronini A, Im K, Stahre C, Buskila A, Iqbal N, Greenberger N, Lerch MM. Incidence of pancreatitis and pancreatic cancer in a randomized controlled multicenter trial (SAVOR-TIMI 53) of the dipeptidyl peptidase-4 inhibitor saxagliptin. Diabetes Care. 2014;37(9):2435–41.

    Article  CAS  PubMed  Google Scholar 

  73. 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 

  74. American Diabetes Association. Approaches to glycemic treatment. Diabetes Care. 2016c;39(Suppl. 1):S52–9.

    Google Scholar 

Download references

Conflict of interests

Avivit Cahn reports receipt of consulting fees and payment for lectures from: AstraZeneca, Boehringer Ingelheim, Elli Lilly, MSD, Novartis, Novo Nordisk and Sanofi.

Simona Cernea received payment for lectures from AstraZeneca, Berlin-Chemie Menarini, Eli Lilly, Novo Nordisk, Sanofi-Aventis, Servier Pharma, for clinical trial Steering Committee meetings as National Lead Investigator for DECLARE-TIMI58 from TIMI Study Group and support for travel to meetings from AstraZeneca, Eli Lilly, Sanofi-Aventis.

Itamar Raz reports: Advisory Board: AstraZeneca/Bristol-Meyers Squibb, Eli Lilly and Company, Merck Sharp & Dohme Limited, Novo Nordisk, Inc., Sanofi, Orgenesis, SmartZyme Innovation Ltd., Labstyle Innovations Ltd., Boehringer Ingelheim. Consultant: AstraZeneca/Bristol-Meyers Squibb, Insuline Medical, Gili Medical, Kamada Ltd., FuturRx Ltd., Nephrogenex Inc.,Diabetes Medical Center (Tel Aviv, Israel). Speaker’s Bureau: AstraZeneca/Bristol-Meyers Squibb, Eli Lilly and Company, Johnson & Johnson, Merck Sharp & Dohme Limited, Novartis Pharma AG, Novo Nordisk, Inc., Sanofi, Teva, Boehringer Ingelheim. Stock/Shareholder: Insuline Medical, Labstyle Innovations, SmartZyme Innovation Ltd., Orgenesis, Glucome Ltd.

Author information

Authors and Affiliations

  1. Diabetes Unit, Department of Internal Medicine, Hadassah Hebrew University Hospital, PO Box 12000, 91120, Jerusalem, Israel

    Avivit Cahn & Itamar Raz

  2. Endocrinology and Metabolism Unit, Department of Internal Medicine, Hadassah Hebrew University Hospital, Jerusalem, Israel

    Avivit Cahn

  3. Department M3/Internal Medicine IV, University of Medicine and Pharmacy, Târgu Mureş, Romania

    Simona Cernea

  4. Diabetes, Nutrition and Metabolic Diseases Outpatient Unit, Emergency County Clinical Hospital, Târgu Mureş, Romania

    Simona Cernea

Authors
  1. Avivit Cahn
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Simona Cernea
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Itamar Raz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Itamar Raz.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cahn, A., Cernea, S. & Raz, I. Outcome studies and safety as guide for decision making in treating patients with type 2 diabetes. Rev Endocr Metab Disord 17, 117–127 (2016). https://doi.org/10.1007/s11154-016-9351-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11154-016-9351-6

Keywords

Search

Navigation