BJD

Series: Cardiovascular outcome trials for diabetes drugs Sitagliptin and TECOS

Miles Fisher

Address for correspondence: Professor Miles Fisher
Department of Diabetes, Endocrinology & Clinical Pharmacology, Glasgow Royal Infirmary, 84 Castle Street, Glasgow G4 0SF, UK
E-mail: miles.fisher@ggc.scot.nhs.uk

https://doi.org/10.15277/bjd.2020.242

Abstract

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.

Br J Diabetes 2020;20:55-57

Key words: diabetes, cardiovascular outcome trial, sitagliptin

Introduction

Licensing requirements for new anti-diabetes drugs changed in the USA and Europe in 2008 and 2012, and a dedicated randomised controlled cardiovascular outcome trial (CVOT) was usually required either before or after licensing.1,2 This is the third article in a series which describes and summarises 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 directs attention to important subsequent publications of data from subgroups and post hoc analyses. The first published trial with saxagliptin, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53), showed an increase in hospitalisation for heart failure,3 and there was a similar effect in a subgroup in the Examination of Cardiovascular Outcomes with Alogliptin vs Standard of Care (EXAMINE) trial with alogliptin,4 so the heart failure results with sitagliptin in the TECOS (Trial Evaluating Cardiovascular Outcomes with Sitagliptin) trial were awaited with interest.

Background

The dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin was the first DPP-4 inhibitor to receive a licence in the USA and Europe and was licensed in 2006 by the Food and Drug Administration (FDA) for use in the USA and in 2007 by the European Medicines Agency (EMA) for use in Europe (ie, prior to the 2008 FDA announcement). A post hoc assessment of cardiovascular safety in 14,611 patients was published in 2013 using patient-level data from 25 double-blind studies of duration 12 weeks to 2 years.5 No difference was observed in the incidence rate ratio of major adverse cardiovascular events (MACE), which was defined by a wide range of Medical Dictionary for Regulatory Activities (MedRA) cardiovascular events. Seventy-eight patients had at least one reported MACE event, 40 in the sitagliptin group and 38 in the non-exposed group.

TECOS

A paper describing the design, rationale and organisation of TECOS was published in 2013,6 with a paper in early 2015 describing the baseline characteristics.7 The design of the study and key baseline characteristics are shown in Box 1. Although TECOS was planned prior to the new FDA/EMA guidance, its conduct and planned analyses were consistent with the agencies' recommendations.6 The primary endpoint was major adverse cardiovascular events (MACE) plus hospitalisation for unstable angina (sometimes called ‘MACE plus’) comprising cardiovascular death, non-fatal myocardial infarction, non-fatal stoke, plus hospitalisation for unstable angina. Hospitalisation for heart failure was included as a secondary endpoint. The principal TECOS results were presented in 2015 at the meeting of the American Diabetes Association (ADA) and published simultaneously in the New England Journal of Medicine.8 In TECOS there was no significant difference in ‘MACE plus’, so non-inferiority was established but not superiority (Figure 1, Box 2). Rates of unstable angina were very low at 1.5% in the sitagliptin group and 1.6% in the placebo group, and the frequency of hospitalisation for heart failure was similar at 3.1% in both study groups. There were no significant between-group differences in rates of acute pancreatitis or pancreatic cancer.

547 Fisher Box 1

547 Fisher Figure 1

547 Fisher Box 2

Other results from TECOS

Further publications from TECOS are detailed in Box 2. The most important of these was a further detailed analysis of the heart failure results.9 There was no difference between sitagliptin and placebo for prespecified secondary analyses comparing the effects of sitagliptin and various composites including hospitalisation for heart failure, cardiovascular death and all-cause mortality or in defined subgroups. Total hospitalisation for heart failure events and death following hospitalisation for heart failure also were similar in the two groups. The analysis included a meta-analysis of TECOS, SAVOR-TIMI 53 and EXAMINE, which revealed moderate heterogeneity and suggested that statistical differences were unlikely to account for the discordance in the heart failure findings.

Discussion

TECOS was the third published CVOT with a new diabetes drug and, like the two previous DPP-4 inhibitor trials with saxagliptin and alogliptin, it showed that sitagliptin had no effect on atherosclerotic endpoints. No increase in hospitalisation for heart failure was seen in TECOS or the later Cardiovascular and Renal Microvascular Outcome Study with Linagliptin (CARMELINA) and Cardiovascular Outcome Study of Linagliptin vs Glimepiride in Type 2 Diabetes (CAROLINA) trials with linagliptin.10,11 For patients with existing heart failure or those who are at a high risk of developing heart failure, including following an acute coronary syndrome, other alternatives are available, including sodium-glucose cotransporter 2 inhibitors which significantly reduce heart failure outcomes in people with diabetes.12

In the Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) trial with lixisenatide, which was presented at the same time as TECOS and published later in 2015, lixisenatide had no effect on atherosclerotic endpoints or hospitalisation for heart failure.13 As the four completed CVOTs (SAVOR-TIMI 53, EXAMINE, TECOS, ELIXA) had been non-inferior but not superior, some commentators raised questions as to whether the large cost of these trails was justified14 and whether population-based observational studies or registry-based trials would be more externally valid and cost effective.15 Later in 2015 the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) was the first of many diabetes CVOTs to show positive results,16 and there are now few doubts expressed about the value of these trials.

547 Fisher Key Messages

Conflict of interest The author has received payment for advisory boards and/or lectures from Astra Zeneca, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Janssen, MSD, NAPP, Novartis, Novo Nordisk, Sanofi, Takeda.

Funding None.

References

1.    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).

2.    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).

3.    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

4.    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

5.    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

6.    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

7.    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

8.    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

9.    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

10.  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

11.  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

12.  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

13.  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

14.  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

15.  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

16.  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

17.  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

18.  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

19.  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

20.  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

21.  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

22.  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

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