Miles Fisher
Address for correspondence: Miles Fisher
Department of Diabetes, Endocrinology & Clinical Pharmacology, Glasgow Royal Infirmary, 84 Castle St, Glasgow G4 0SF, UK
E-mail: miles.fisher@ggc.scot.nhs.uk
Br J Diabetes 2019;19:34-36
https://doi.org/10.15277/bjd.2019.213
SAVOR-TIMI 53 was the first FDA-mandated cardiovascular outcome trial to be presented and published. It compared saxagliptin and placebo in 16,492 patients with type 2 diabetes. SAVOR-TIMI 53 demonstrated non-inferiority for major cardiovascular events (cardiovascular death, myocardial infarction, stroke) but not superiority. An unexpected statistically significant increase in adjudicated hospitalisation for heart failure was seen in the saxagliptin group. Post hoc analysis demonstrated that subjects at greatest risk for hospitalisation for heart failure had previous heart failure, an estimated glomerular filtration rate <60 mL/min, or elevated baseline levels of N-terminal pro-B type natriuretic peptide. As other dipeptidyl peptidase 4 (DPP-4) inhibitors are available which have not been associated with an increased risk of hospitalisation for heart failure, saxagliptin should be avoided in patients with heart failure or a reduced estimated glomerular filtration rate.
Key words: diabetes, cardiovascular outcome trial, saxagliptin
A controversial meta-analysis of the rosiglitazone development programme showed an increase in non-fatal myocardial infarctions in participants who had received rosiglitazone compared with placebo and active comparators.1 Following this, the licensing requirements for new anti-diabetes drugs changed dramatically in the USA and Europe.2,3 The phase III development programme was required to include participants who were more representative of the wider diabetes population, including older subjects, patients with existing cardiovascular disease and patients with chronic kidney disease. Any cardiovascular event occurring in the phase III development programme was to be blindly adjudicated to provide information on cardiovascular safety. A dedicated randomised controlled cardiovascular outcome trial (CVOT) was usually required either before or after licensing.
We now have published the results of four cardiovascular outcomes trials with dipeptidyl peptidase 4 (DPP-4) inhibitors (saxagliptin, alogliptin, sitagliptin, linagliptin),4-7 five trials with glucagon-like peptide 1 (GLP-1) receptor agonists (lixisenatide, liraglutide, semaglutide, once weekly exenatide, albiglutide),8-12 three trials with sodium-glucose cotransporter-2 (SGLT2) inhibitors (empagliflozin, canagliflozin, dapagliflozin)13-15 and one trial with insulin (degludec).16
In this series I will describe and summarise the results of each of these CVOTs in the chronological order in which they were published, describing the primary endpoint and important secondary outcomes from the principal publication, but also direct attention to important subsequent publications of data from subgroups and post hoc analyses.
The DPP-4 inhibitor saxagliptin was licensed by the FDA in the summer of 2009 for use in the USA and by the EMA in late 2009 for use in Europe. A systematic assessment of cardiovascular outcomes in the phase II and phase III trials in the development programme was published in 2010.17 Atherosclerotic cardiovascular events (death, myocardial infarction, stroke, revascularisation procedures, cardiac ischaemia) were systematically identified. Deaths, myocardial infarction and strokes were blindly adjudicated, and no increase in MACE (major adverse cardiovascular events, a composite of cardiovascular death/myocardial infarction/stroke) was observed. Hospitalisation for heart failure was not described in that publication.
Papers describing the design and rationale and the baseline characteristics of SAVOR-TIMI 53 were published in 2011 and early 2013, respectively.18,19 The principal results were presented later that year at the meeting of the European Society of Cardiology and published simultaneously in the New England Journal of Medicine.4 The design of the study and key baseline characteristics are described in Box 1. In SAVOR-TIMI 53 there was no significant difference in MACE, so non-inferiority was established but not superiority (Figure 1, Box 2). An unexpected significant increase in hospitalisation for heart failure was observed, which was a pre- defined adjudicated endpoint. The criteria to define hospitalisation for heart failure were similar to those used in heart failure studies (see Appendix at www.bjd-abcd.com). The investigators indicated that the findings merited further investigation, needed to be confirmed in other ongoing studies and that a class effect should not be presumed.4
N-terminal pro-B type natriuretic peptide (NT-proBNP), a biomarker for heart failure, was measured in three-quarters of subjects at baseline and a randomly selected subset of subjects at 2 years. Further analysis of heart failure outcomes showed that people at the highest risk for hospitalisation for heart failure with saxagliptin had elevated baseline NT-proBNP, previous heart failure or an estimated glomerular filtration rate (eGFR) ≤60 mL/min.20 The authors stated that there were no known mechanisms by which DPP-4 inhibition could precipitate heart failure and that the cardiovascular consequences of DPP-4 inhibition on other peptide substrates such as natriuretic peptides or bradykinins were unknown. A review of DPP-4 inhibitors and heart failure published shortly after the SAVOR-TIMI 53 heart failure analysis listed several further peptides with cardiovascular effects that are split by DPP-4, suggested that this might be the link between DPP-4 inhibitors and heart failure, and that this area requires further scientific attention.21
It is expensive to run these large CVOTs, so it is understandable that the study steering committee, investigators and sponsors would wish to maximise the impact of the trial by publishing multiple further analyses in subgroups and of specific endpoints (at last count there were nearly 90 publications from UKPDS!). The key further publications from SAVOR-TIMI are detailed in Box 2. Probably the most important of these is the paper looking at the effect of saxagliptin on renal outcomes in SAVOR-TIMI 53.22 Treatment with saxagliptin improved the albumin creatinine ratio, including in the normoalbuminuric range, but had no effect on eGFR. The beneficial effect was independent of an effect on glucose control, and the authors suggested that DPP-4 inhibitors might protect against renal oxidative stress. Improvements in endothelial function and reductions in inflammation are other possible mechanisms of benefit.23
SAVOR-TIMI 53 was the first completed FDA-mandated cardiovascular outcome trial with a new diabetes drug. It showed that saxagliptin had no effect on atherosclerotic endpoints. The increase in hospitalisation for heart failure was unexpected and the mechanisms remain unclear. A possible increase in hospitalisation for heart failure was seen in a subgroup of the EXAMINE trial with alogliptin,5 but not in the TECOS trial with sitagliptin6 or the CARMELINA trial with linagliptin.7 For patients with diagnosed heart failure or a reduced eGFR, sitagliptin or linagliptin are safer alternatives to saxagliptin.
Conflict of interest: I have received payment for advisory boards and/or lectures from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, MSD, Napp, Novo Nordisk, Sanofi, Takeda.
Funding: None.
1. 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. https://doi.org/10.1056/NEJMoa072761
2. 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: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm071627.pdf (accessed 9 Feb 2019).
3. 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).
4. 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
5. 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
6. 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
7. Rosenstock J, Perkovic V, Johansen OE, et al for the CARMELINA Investigators. Effects of linagliptin versus 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.
8. 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.
9. Marso SP, Daniels GH, Brown-Frandsen K, et al for the LEADER Steering Committee on behalf of the LEADER Trial Investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016; 375:311–22. https://doi.org/10.1056/NEJMoa1603827
10. Marso SP, Bain SC, Consoli A, et al for the SUSTAIN-6 Investigators. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2016;375:1834–44. https://doi.org/10.1056/NEJMoa1607141
11. Holman RR, Bethel MA, Mentz RJ, et al for the EXSCEL Study Group. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2017;377:1228–39. https://doi.org/10.1056/NEJMoa1612917
12. Hernandez AF, Green JB, Janmohamed S, et al for the Harmony Outcomes Committees and Investigators. Albiglutide and cardiovascular outcomes in people with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised, placebo-controlled trial. Lancet 2018;392:1519–29. https://doi.org/10.1016/S0140-6736(18)32261-X
13. 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
14. Neal B, Perkovic V, Mahaffey KW, et al for the CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017;377:644–57. https://doi.org/10.1056/NEJMoa1611925
15. Wiviott SD, Bonaca MP, Mosenzon O, et al for the DECLARE-TIMI 58 Investigators. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2019;380:347–57. https://doi.org/10.1056/NEJMoa1812389
16. Marso SP, McGuire DK, Zinman B, et al for the DEVOTE Study Group. Efficacy and safety of degludec versus glargine in type 2 diabetes. N Engl J Med 2017;377:723–32. https://doi.org/10.1056/NEJMoa1615692
17. Frederich R, Alexander JH, Fiedorek FT, et al. A systematic assessment of cardiovascular outcomes in the saxagliptin drug development program for type 2 diabetes. Postgrad Med 2010;122:16–27. https://doi.org/10.3810/pgm.2010.05.2138
18. Scirica BM, Bhaat DL, Braunwald E, et al. The design and rationale of the Saxglitin Assessment of Vascualr Outcomes Recorded in patients with diabetes-mellitus-Thrombolysis in Myocardial Infarction (SAVOR-TIMI) 53 study. Am Heart J 2011;162:818–25. https://doi.org/10.1016/j.ahj.2011.08.006
19. Mosenzon O, Raz I, Scirica BM, et al. Baseline characteristics of the patient population in the Saxaglitin Assessment of Vascualr Outcomes Recorded in patients with diabetes mellitus (SAVOR)-TIMI 53 trial. Diabetes Metab Res Rev 2013;29:417–26. https://doi.org/10.1002/dmrr.2413
20. 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. https://doi.org/10.1161/CIRCULATIONAHA.114.010389
21. Standl E, Erbach M, Schnell O. Dipeptidyl-peptidase-4 Inhibitors and heart failure: class effect, substance-specific effect, or chance effect? Curr Treat Options Cardiovasc Med 2014;16:353. https://doi.org/10.1007/s11936-014-0353-y
22. Mosenzon O, Leibowitz G, Bhatt DL, et al. Effect of saxagliptin on renal outcomes in the SAVOR-TIMI 53 trial. Diabetes Care 2017;40:69–76. https://doi.org/10.2337/dc16-0621
23. Haluzik M, Frolik J, Rychlik I. Renal effects of DPP-4 inhibitors: a focus on microalbuminuria. Int J Endocrinol 2013;2013:895102. https://doi.org/10.1155/2013/895102 [Epub 2013 Sep 5]
24. Udell JA, 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 and moderate or severe renal impairment: observations from the SAVOR-TIMI 53 trial. Diabetes Care 2015;38:696–705. https://doi.org/10.2337/dc14-1850
25. Leiter LA, Teoh H, Braunwald E, et al for the SAVOR-TIMI 53 Steering Committee and Investigators. Efficacy and safety of saxagliptin in older participants in the SAVOR-TIMI 53 trial. Diabetes Care 2015;38:1145–53. https://doi.org/10.2337/dc14-2868
26. Cavender MA, Scirica BM, Raz I, et al. Cardiovascular outcomes of patients in SAVOR-TIMI 53 by baseline hemoglobin A1c. Am J Med 2016;129:340e1–8. https://doi.org/10.1016/j.amjmed.2015.09.022
27. Raz I, Bhatt DL, Hirshberg B, et al. Incidence of pancreatitis and pancreatic cancer in a randomized controlled multicentre trial (SAVOR-TIMI 53) of the dipeptidyl peptidase-4 inhibitor saxagliptin. Diabetes Care 2014;37:2435–41. https://doi.org/10.2337/dc13-2546
28. Leiter LA, Teoh H, Mosenzon O, et al for the SAVOR-TIMI 53 Steering Committee and Investigators. Frequency of cancer events in the SAVOR-TIMI 53 trial. Diabetes Obes Metab 2015;18:186–90. https://doi.org/10.1111/dom.12582
29. Cahn A, Raz I, Mosenzon O, et al. Predisposing factors for any and major hypoglycaemia with saxagliptin versus placebo and overall: analysis from the SAVOR-TIMI 53 trial. Diabetes Care 2016;39:1329–37. https://doi.org/10.2337/dc15-2763