Series: Cardiovascular outcome trials for diabetes drugs Sitagliptin and TECOS
Keywords:diabetes, cardiovascular outcome trial, sitagliptin
TECOS (Trial Evaluating Cardiovascular Outcomes with Sitagliptin) was an investigator-initiated cardiovascular outcome trial with sitagliptin. It compared sitagliptin and placebo in 14,671 subjects with type 2 diabetes and demonstrated non-inferiority for major cardiovascular events plus hospitalisation for unstable angina (cardiovascular death, myocardial infarction, stroke, unstable angina) but not superiority. Rates of hospitalisation for heart failure did not differ between the sitagliptin and placebo groups, and there were no significant between-group differences in rates of acute pancreatitis or pancreatic cancer. The clinical role for dipeptidyl peptidase-4 (DPP-4) inhibitors is diminishing as they have not been demonstrated to reduce cardiovascular events and are not associated with weight reduction, but if a DPP-4 inhibitor is indicated, the results of TECOS show that sitagliptin appears safer than saxagliptin or alogliptin.
Food and Drug Administration. Guidance for industry. Diabetes mellitus – evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. Silver Spring, MD: US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), 2008. Available from: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/diabetes-mellitus-evaluating-cardiovascular-risk-new-antidiabetic-therapies-treat-type-2-diabetes (accessed 23 Jan 2020).
European Medicines Agency. Guideline on clinical investigation of medicinal products in the treatment or prevention of diabetes mellitus. London: EMA, 2012. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129256.pdf (accessed 9 Feb 2019).
Scirica BM, Bhatt DL, Braunwald E, et al, for the SAVOR-TIMI 53 Steering Committee and Investigators. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013;369:1317–26. https://doi.org/10.1056/NEJMoa1307684
Zannad F, Cannon CP, Cushman WC, et al, for the EXAMINE Investigators. 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. https://doi.org/10.1016/S0140-6736(14)62225-X
Engel SS, Golm GT, Shapiro D, et al. Cardiovascular safety of sitagliptin in patients with type 2 diabetes mellitus: a pooled analysis. Cardiovasc Diabetol 2013;12:3. https://doi.org/10.1186/1475-2840-12-3
Green JB, Bethel MA, Paul SK, et al. Rationale, design, and organization of a randomized, controlled Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) in patients with type 2 diabetes and established cardiovascular disease. Am Heart J 2013;166:983–9.e7. https://doi.org/10.1016/j.ahj.2013.09.003
Bethel MA, Green JB, Milton J, et al, on behalf of the TECOS Executive Committee. Regional, age and sex differences in baseline characteristics of patients enrolled in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS). Diabetes Obes Metab 2015;17:395–402. https://doi.org/10.1111/dom.12441
Green JB, Bethel MA, Armstrong PW, et al, for the TECOS Study Group. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2015;373:232–42. https://doi.org/10.1056/NEJMoa1501352
McGuire DK, Van de Werf F, Armstrong PW, et al, for the TECOS Study Group. 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. https://doi.org/10.1001/jamacardio.2016.0103
Rosenstock J, Perkovic V, Johansen OE, et al, for the CARMELINA Investigators. Effects of linagliptin vs placebo on major cardiovascular events in adults with type 2 diabetes and high cardiovascular and high renal risk. The CARMELINA randomized clinical trial. JAMA 2019;321:69–79. https://doi.org/10.1001/jama.2018.18269
Rosenstock J, Kahn SE, Johansen OE, et al, for the CAROLINA Investigators. Effect of linagliptin vs glimepiride on major adverse cardiovascular outcomes in patients with type 2 diabetes. The CAROLINA randomized clinical trial. JAMA 2019;322:1155–66. https://doi.org/10.1001/jama.2019.13772
Zelniker TA, Wiviott SD, Raz I, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet 2019;393:31–9. https://doi.org/10.1016/S0140-6736(18)32590-X
Pfeffer MA, Claggett B, Diaz R, et al, for the ELIXA Investigators. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med 2015;373:2247–57. https://doi.org/10.1056/NEJMoa1509225
Hirshberg B, Katz A. Insights from cardiovascular outcome trials with novel antidiabetes agents: what have we learned? An industry perspective. Curr Diab Rep 2015;15:87. https://doi.org/10.1007/s11892-015-0663-9
Steg PG, Roussel R. Randomized trials to evaluate cardiovascular safety of antihyperglycemic medications. A worthwhile effort? Circulation 2016; 134:571–3. https://doi.org/10.1161/CIRCULATIONAHA.116.021914
Zinman B, Wanner C, Lachin JM, et al, for the EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117–28. https://doi.org/10.1056/NEJMoa1504720
Buse JB, Bethel MA, Green JB, et al, for the TECOS Study Group. Pancreatic safety of sitagliptin in the TECOS study. Diabetes Care 2017;40:164–70. https://doi.org/10.2337/dc15-2780
Cornel JH, Bakris GL, Stevens SR, et al, on behalf of the TECOS Study Group. Effect of sitagliptin on kidney function and respective cardiovascular outcomes in type 2 diabetes: outcomes from TECOS. Diabetes Care 2016;39:2304–10. https://doi.org/10.2337/dc16-1415
Standl E, Stevens SR, Armstrong PW, et al, for the TECOS Study Group. Increased risk of severe hypoglycemic events before and after cardiovascular outcomes in TECOS suggests an at-risk type 2 diabetes frail patient phenotype. Diabetes Care 2018;41:593–603. https://doi.org/10.2337/dc17-1778
Shavadia JS, Zheng Y, Green JB, et al. Associations between β-blocker therapy and cardiovascular outcomes in patients with diabetes and established cardiovascular disease. Am Heart J 2019;218:92–9. https://doi.org/10.1016/j.ahj.2019.09.013
Alfredsson J, Green JB, Stevens SR, et al, for the TECOS Study Group. Sex differences in management and outcomes of patients with type 2 diabetes and cardiovascular disease: a report from TECOS. Diabetes Obes Metab 2018;20:2379–88. https://doi.org/10.1111/dom.13377
Pagidipati NJ, Navar AM, Pieper KS, et al, on behalf of the TECOS Study Group. Secondary prevention of cardiovascular disease in patients with type 2 diabetes mellitus: international insights from the TECOS trial (Trial Evaluating Cardiovascular Outcomes with Sitagliptin). Circulation 2017; 136:1193–203. https://doi.org/10.1161/CIRCULATIONAHA.117.027252
Publish & Transfer of Copyright Agreement
For the mutual benefit and protection of the Author and the Journal Owner/Publisher it is necessary that the Author provides formal written Consent to Publish and Transfer of Copyright before publication of the Work.