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.2020.254
EMPA-REG OUTCOME was an FDA-mandated cardiovascular outcome trial with empagliflozin and was the first completed trial with a sodium-glucose co-transporter-2 (SGLT2) inhibitor. EMPA-REG OUTCOME compared empagliflozin and placebo in 7,020 subjects with type 2 diabetes and established atherosclerotic cardiovascular disease. The results were astounding as EMPA-REG OUTCOME demonstrated superiority for major cardiovascular events (cardiovascular death, myocardial infarction, stroke) and cardiovascular deaths were significantly reduced, as was all-cause mortality. Hospitalisation for heart failure, which was a secondary outcome, was also significantly reduced. Later trials with SGLT2 inhibitors have demonstrated reductions in major adverse cardiovascular events (MACE) and hospitalisation for heart failure, and trials with glucagon-like peptide 1 receptor agonists have demonstrated reductions in MACE. Collectively, these trials could transform the management of people with type 2 diabetes.
Br J Diabetes 2020;20:138-141
Key words: diabetes, cardiovascular outcome trial, empagliflozin
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 series describes and summarises the results of each of these CVOTs in the order in which they were published, describing the primary endpoint and important secondary outcomes from the principal publication, and directs attention to important subsequent publications of data from subgroups and post hoc analyses. EMPA-REG OUTCOME was the first published FDA-mandated cardiovascular outcome trial using a sodium-glucose co-transporter-2 (SGLT2) inhibitor.3 It came after three trials with dipeptidyl peptidase 4 (DPP-4) inhibitors4–6 and one trial with the glucagon-like peptide 1 (GLP-1) receptor agonist lixisenatide had demonstrated safety but not cardiovascular benefit,7 and at a time when some commentators were raising questions as to whether the large cost of these trials was justified.8,9
Empagliflozin was approved in 2014 by the Food and Drug Administration (FDA) for use in the USA and by the European Medicines Agency (EMA) for use in Europe. Interim data from EMPA-REG OUTCOME were included in the new drug application to the FDA. The FDA initially rejected the new drug application for empagliflozin based on deficiencies at its main manufacturing facility. Empagliflozin was the third SGLT2 inhibitor to be approved by the FDA and EMA after dapagliflozin and canagliflozin, but was the first to complete a CVOT. At the time of publication of EMPA-REG OUTCOME in 2015 there were no published data on the cardiovascular safety of empagliflozin. In 2016 a meta-analysis of prospectively adjudicated cardiovascular outcomes from eight trials of empagliflozin, including EMPA-REG OUTCOME, demonstrated a significant reduction in major adverse cardiovascular events (MACE) plus (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, hospitalisation for unstable angina).10 The results were still significant when the analysis was performed excluding EMPA-REG OUTCOME.
A paper describing the rationale, design and baseline characteristics of EMPA-REG OUTCOME was published in 2014.11 The principal EMPA-REG OUTCOME results were presented in 2015 at the meeting of the European Association for the Study of Diabetes (EASD), where it received a standing ovation, and published simultaneously in the New England Journal of Medicine.3 The design of the study and key baseline characteristics are described in Box 1. Two doses of empagliflozin were included (10 mg and 25 mg) and the results were pooled for analysis.
In EMPA-REG OUTCOME there was a significant reduction in MACE with empagliflozin, demonstrating superiority versus placebo (Figure 1, Box 2). In the pooled empagliflozin group there were statistically significant reductions in cardiovascular death, hospitalisation for heart failure and death from any cause. There were no significant differences in the rates of myocardial infarction or stroke, although a non-significant increase in strokes was observed. The rate of genital infection was increased with empagliflozin and there was no increase in other adverse events including urinary tract infection. There were four episodes of diabetic ketoacidosis in the pooled empagliflozin group and one in the placebo group.
Other results from EMPA-REG OUTCOME
Further publications from EMPA-REG OUTCOME are detailed in Box 2. 10% of subjects in EMPA-REG OUTCOME had investigator- reported heart failure at baseline.3 Further analysis of heart failure data demonstrated significant reductions in hospitalisation for heart failure in patients with and without baseline heart failure, and across categories of medications to treat diabetes or heart failure.12 Death from heart failure was also significantly reduced with empagliflozin.
Further analysis of renal outcomes showed a reduction in incident or worsening nephropathy, a reduction in doubling of serum creatinine, and a reduction in renal replacement therapy with empagliflozin.13
Based on the pleiotropic effects of SGLT2 inhibitors on cardiovascular risk markers, including reductions in HbA1c, body weight and blood pressure, the EMPA-REG OUTCOME investigators hypothesised that empagliflozin might reduce cardiovascular risk in patients with type 2 diabetes.11 The strongly positive results of EMPA-REG OUTCOME, however, were not predicted and the significant reductions in cardiovascular deaths and hospitalisation for heart failure were particularly unexpected. The reduction in the risk of hospitalisation for heart failure and of cardiovascular death was observed early in EMPA-REG OUTCOME, and since the publication of EMPA-REG OUTCOME there have been many reviews speculating on the possible mechanisms of benefit, as these were not studied in EMPA-REG OUTCOME. Similar reductions in hospitalisation for heart failure were subsequently observed in CANVAS and DECLARE-TIMI 58.14,15 Meta-analysis of EMPA-REG OUTCOME, CANVAS and DECLARE-TIMI 58 has confirmed reductions in heart failure, cardiovascular deaths and renal composites.16 Significant reductions in MACE have been seen in patients with existing atherosclerotic cardiovascular disease, as was included in EMPA-REG OUTCOME, but MACE benefit does not appear to occur in patients without atherosclerotic disease.16 Following analysis of EMPA-REG OUTCOME, the DAPA-HF trial was initiated in patients with severe heart failure and well-characterised baseline ejection fractions, including a majority of subjects who did not have diabetes. This confirmed significant reductions in hospitalisation for heart failure, cardiovascular deaths and total mortality in this different patient group.17
The FDA has recently withdrawn the guidance from 20081 and are consulting on new draft guidance for evaluating the safety of new drugs for improving glycaemic control.18 The FDA comment that none of the CVOTs has identified an increased risk of ischaemic events, and that some have instead identified a reduced risk for cardiovascular events. The draft recommendations for new drugs include a safety database of at least 4,000 patient-years of exposure to the new drug in phase 3 clinical trials, 500 patients with chronic kidney disease, 600 patients with established cardiovascular disease and 600 patients aged >65 years. They recommend that sponsors should use rigorous methods for the collection of adverse cardiovascular events and assess them for adjudication. The need for a dedicated cardiovascular safety trial is removed from the draft, which would mean that, in the future, landmark trials like EMPA-REG OUTCOME may be performed at the discretion of the sponsors and clinical investigators but would not be obligatory.
Conflict of interest The author has received personal fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Lexicon, MSD, NAPP, Novo Nordisk and Sanofi, outside the submitted work.
Funding None.
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.
2. European Medicines Agency (EMA). 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 1 March 2020).
3. 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
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
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10. Salsali A, Kim G, Woerle HJ, et al. Cardiovascular safety of empagliflozin in patients with type 2 diabetes: a meta-analysis of data from randomized placebo-controlled trials. Diabetes Obes Metab 2016;18:1034–40. https://doi.org/10.1111/dom.12734
11. Zinman B, Inzucchi SE, Lachin JM, et al. Rationale, design, and baseline characteristics of a randomized, placebo-controlled cardiovascular outcome trial of empagliflozin (EMPA-REG OUTCMETM). Cardiovasc Diabetol 2014;13:102. https://doi.org/10.1186/1475-2840-13-102
12. Fitchett D, Zinman B, Wanner C, et al, on behalf of the EMPA-REG OUTCOME Trial Investigators. Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME TRIAL®. Eur Heart J 2016;37:1526–34. https://doi.org/10.1093/eurheartj/ehv728
13. Wanner C, Inzucchi SE, Lachin JM, et al, for the EMPA-REG OUTCOME Investigators. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 2016;375:323–34. https://doi.org/10.1056/NEJMoa1515920
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. 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
17. McMurray JJV, Solomon SD, Inzucchi SE, et al, for the DAPA-HF Trial Committees and Investigators. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019;381:1995–2008. https://doi.org/10.1056/NEJMoa1911303
18. Food and Drug Administration. Type 2 diabetes mellitus: evaluating the safety of new drugs for improving glycemic control. Guidance for industry. Silver Spring, MD: US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), 2020. Available from https://www.federalregister.gov/documents/2020/03/10/2020-04877/type-2-diabetes-mellitus-evaluating-the-safety-of-new-drugs-for-improving-glycemic-control-draft (accessed 10 June 2020).
19. Zinman B, Inzucchi SE, Lachin JM, et al, on behalf of the EMPA-REG OUTCOME Investigators (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients). Empagliflozin and cerebro-vascular events in patients with type 2 diabetes mellitus at high cardiovascular risk. Stroke 2017;48:1218–25. https://doi.org/10.1161/STROKEAHA.116.015756
20. Inzucchi SE, Zinman B, Fitchett D, et al. How does empagliflozin reduce cardiovascular mortality? Insights from a mediation analysis of the EMPA-REG OUTCOME Trial. Diabetes Care 2018;41:356–63. https://doi.org/10.2337/dc17-1096
21. Verma S, Mazer CD, Al-Omran M, et al. Cardiovascular outcomes and safety of empagliflozin in patients with type 2 diabetes mellitus and peripheral artery disease: a subanalysis of EMPA-REG OUTCOME. Circulation 2017;136:405–7. https://doi.org/10.1161/CIRCULATIONAHA.117.032031
22. Claggett B, Lachin JM, Hantel S, et al. Long-term benefit of empagliflozin on life expectancy in patients with type 2 diabetes mellitus and established cardiovascular disease. Survival estimates from the EMPA-REG OUTCOME Trial. Circulation 2018;138:1599–1601. https://doi.org/10.1161/CIRCULATIONAHA.118.033810
23. Fitchett D, Inzucchi SE, Wanner C, et al. Relationship between hypoglycaemia, cardiovascular outcomes, and empagliflozin treatment in the EMPA-REG OUTCOME® trial. Eur Heart J 2020;41:209–17. https://doi.org/10.1093/eurheartj/ehz621
24. Sattar N, Fitchett D, Hantel S, George JT, Zinman B. Empagliflozin is associated with improvements in liver enzymes potentially consistent with reductions in liver fat: results from randomised trials including the EMPA-REG OUTCOME® trial. Diabetologia 2018;61:2155–63. https://doi.org/10.1007/s00125-018-4702-3