Series: Cardiovascular outcome trials for diabetes drugs Alogliptin and EXAMINE

Authors

  • Miles Fisher

DOI:

https://doi.org/10.15277/bjd.2019.230

Keywords:

diabetes, cardiovascular outcome trial, alogliptin

Abstract

EXAMINE was an FDA mandated cardiovascular outcome trial with alogliptin. In contrast to other cardiovascular outcome trials with DPP-4 inhibitors, it was performed in subjects with a recent acute coronary syndrome. EXAMINE compared alogliptin and placebo in 5,380 subjects with type 2 diabetes and demonstrated non-inferiority for major cardiovascular events (cardiovascular death, myocardial infarction, stroke) but not superiority. Data on hospitalisation for heart failure were not included in the principal publication. A subsequent publication showed no overall increase in hospitalisation for heart failure with alogliptin, but when subjects with and without baseline heart failure were separated there was a significant increase in the group without heart failure at baseline. No clear clinical benefit has been established for alogliptin, and there are alternatives such as sitagliptin and linagliptin that are not associated with an increase in hospitalisation for heart failure.

References

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 8th Nov 2019).

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).

White WB, Pratley R, Fleck P, et al. Cardiovascular safety of the dipeptidyl peptidase-4 inhibitor alogliptin in type 2 diabetes mellitus. Diabetes Obes Metab 2013;15:668–73. https://doi.org/10.1111/dom.12093

White WB, Bakris GL, Bergenstal R, et al. EXamination of cArdiovascular outcoMes with AlogliptIN versus Standard of CarE in patients with type 2 diabetes mellitus and acute coronary syndrome (EXAMINE): a cardiovascular safety study of the dipeptidyl peptidase 4 inhibitor alogliptin in patients with type 2 diabetes with acute coronary syndrome. Am Heart J 2011;162:620–6. https://doi.org/10.1016/j.ahj.2011.08.004

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;369:1327–35. https://doi.org/10.1056/NEJMoa1305889

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

Heller SR, Bergenstal RM, White WB, et al, for the EXAMINE Investigators. Relationship of glycated haemoglobin and reported hypoglycaemia to cardiovascular outcomes in patients with type 2 diabetes and recent acute coronary syndrome events: the EXAMINE trial. Diabetes Obes Metab 2017;19:664–71. https://doi.org/10.1111/dom.12871

Zoungas Z, Patel A, Chalmers J, et al, for the ADVANCE Collaborative Group. Severe hypoglycaemia and risks of vascular events and death. N Engl J Med 2010;363:1410–18. https://doi.org/10.1056/NEJMoa1003795

Green JB, Bethel A, 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

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 Sep 19 [Epub ahead of print]. 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

White WB, Heller SR, Cannon CP, et al, for the EXAMINE Investigators. Alogliptin in patients with type 2 diabetes receiving metformin and sulfonylurea therapies in the EXAMINE trial. Am J Med 2018;131:813–19.e5. https://doi.org/10.1016/j.amjmed.2018.02.023

Bergmark BA, Cannon CP, White WB, et al. Baseline adiponectin concentration and clinical outcomes among patients with diabetes and recent acute coronary syndrome in the EXAMINE trial. Diabetes Obes Metab 2017;19:962–9. https://doi.org/10.1111/dom.12905

Whang Y-C, Morrow DA, Cannon CP, et al. High-sensitivity C-reactive protein, low-density lipoprotein cholesterol and cardiovascular outcomes in patients with type 2 diabetes in the EXAMINE (Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care) trial. Diabetes Obes Metab 2018;20:654–9. https://doi.org/10.1111/dom.13136

Garlo KG, White WB, Bakris GL, et al. Kidney biomarkers and decline in eGFR in patients with type 2 diabetes. Clin J Am Soc Nephrol 2018;13:398–405. https://doi.org/10.2215/CJN.05280517

Jarolim P, White WB, Cannon CP, et al. Serial measurement of natriuretic peptides and cardiovascular outcomes in patients with type 2 diabetes in the EXAMINE trial. Diabetes Care 2018;41:1510–15. https://doi.org/ 10.2337/dc18-0109

Cavender MA, White WB, Jarolim P, et al. Serial measurement of high-sensitivity troponin I and cardiovascular outcomes in patients with type 2 diabetes mellitus in the EXAMINE trial (Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care). Circulation 2017; 135:1911–21. https://doi.org/10.1161/CIRCULATIONAHA.116.024632

White WB, Jalil F, Cushman WC, et al. Average clinician-measured blood pressures and cardiovascular outcomes in patients with type 2 diabetes mellitus and ischemic heart disease in the EXAMINE Trial.

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Published

2019-12-17

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