Physicians' Academy for Cardiovascular Education

First glucose-lowering agent to show CV benefit in outcome trial

Zinman B et al., NEJM 2015

Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes

Zinman B., Wanner C., Lachin JM et al.,
N Eng J Med. September 17, 2015. DOI: 10. 1056/NEJMoa1504720


While type 2 diabetes (T2DM) is a major risk factor for cardiovascular (CV) disease, it is not entirely clear whether glucose lowering reduces CV event rates [1-3]. Although modest CV benefits may be seen after a prolonged follow-up period [4], concerns have been raised that intensive glucose lowering, or the use of specific glucose-lowering agents may be associated with adverse CV outcomes [5].
Inhibitors of sodium-glucose cotransporter 2 (SGLT2) decrease renal glucose re-absorption, thereby increasing urinary glucose excretion and lowering the rate of hyperglycaemia in patients with T2DM [6]. Empagliflozin is a selective SGLT2 inhibitor that has been approved for T2DM [11,12]. As monotherapy or add-on therapy, empagliflozin lowers glycated haemoglobin levels in T2DM, and is associated with weight loss and reductions in blood pressure, without increases in heart rate. Empagliflozin also seems to beneficially affect markers of arterial stiffness and vascular resistance, among other effects. Its use has been associated with an increase in LDL and HDL-c [9-12].
The EMPA-REG OUTCOME trial [13] evaluates the effect of empagliflozin, as compared with placebo, on CV morbidity and mortality in patients with T2DM at high risk for CV events, who are receiving standard care. 7020 patients were randomised (1:1:1 for empagliflozin 10 mg or 25 mg or placebo once daily) and treated for a median of 2.6 years (median observation time: 3.1 years).

Main results

  • The primary outcome of a composite of death from CV causes, nonfatal myocardial infarction (MI, excluding silent MI), or nonfatal stroke occurred in a significantly lower percentage of patients on empagliflozin (490 of 4687, 10.5%) than in the placebo group (282 of 2333, 12.1%, HR: 0.86, 95%CI: 0.74-0.99, P<0.001 for non-inferiority and P=0.04 for superiority).
  • The key secondary outcome of the primary outcome plus hospitalisation for unstable angina also occurred less often in the empagliflozin group (599 of 4687, 12.8%) than in the placebo group (333 of 2333, 14.3%, HR: 0.89, 95%CI: 0.78-1.01, P<0.001 for non-inferiority and P=0.08 for superiority).
  • Risk of CV death was lower with empagliflozin (HR: 0.62, 95%CI: 0.49-0.77, P<0.001), as was all-cause death (HR 0.68, 95%CI: 0.57-0.82, P<0.001) and the risk of hospitalisation for heart failure (HR: 0.65, 95%CI: 0.50-0.85, P=0.002).
  • The occurrence of MI or stroke did not differ significantly between treatments (MI: 4.8% vs. 5.4% with placebo, stroke: 3.5% vs. 3.0%).
  • Separate analyses of each of the doses yielded very similar but not statistically significant hazard ratios as compared with placebo (primary outcome: 10 mg: HR: 0.85, 95%CI: 0.72-1.01, P=0.07, and 25 mg: HR: 0.86, 95%CI: 0.73-1.02, P=0.009).
  • The difference in the glycated haemoglobin level between patients receiving empagliflozin and those on placebo changed from -0.54 % for 10 mg (95%CI: -0.58 to -0.49) and -0.60% for 25 mg, 95%CI: -0.64 to -0.55) at week 12, to -0.24 % for 10 mg (95%CI: -0.40 to -0.08) and -0.36% for 25 mg, 95%CI: -0.51 to -0.20) at week 206.
  • The proportions of patients with adverse events (AEs), serious AEs and AEs leading to study drug discontinuation were similar in the treatment groups. Genital infections were more common in the pooled empagliflozin group. While urosepsis was more often reported (0.4 vs. 0.1%) in the empagliflozin-treated patients, there was no imbalance in overall rates of urinary tract infections, complicated urinary tract infection, or pyelonephritis.
 Download Zinman EMPA REG OUTCOME PACE.pptx


Patients with T2DM and at high CV risk receiving empagliflozin experienced fewer events of death from CV causes, nonfatal MI or nonfatal stroke than patients receiving placebo in addition to standard care. This difference was driven by a significant reduction of CV mortality. With regard to clinical outcomes, the two tested doses of empagliflozin yielded similar results.
Find this article online at NEJM


1. Green JB, Bethel MA, Armstrong PW, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2015; 373: 232-42
2. White WB, Cannon CP, Heller SR, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013; 369: 1327-35.
3 Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013; 369: 1317-26.
4. Holman RR, Paul SK, Bethel MA, et al. 10-Year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008; 359: 1577-89.
5 Udell JA, Cavender MA, Bhatt DL, et al. Glucose-lowering drugs or strategies and cardiovascular outcomes in patients with or at risk for type 2 diabetes: a meta-analysis of randomised controlled trials. Lancet Diabetes Endocrinol 2015; 3: 356-66.
6. Gallo LA, Wright EM, Vallon V. Probing SGLT2 as a therapeutic target for diabetes: basic physiology and consequences. Diab Vasc Dis Res 2015; 12: 78-89.
7. Grempler R, Thomas L, Eckhardt M, et al. Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: characterisation and comparison with other SGLT-2 inhibitors. Diabetes Obes Metab 2012; 14: 83-90.
8. Boehringer Ingelheim Pharmaceuticals. Jardiance (empagliflozin) tablets; prescribing information (http://bidocs .boehringer-ingelheim .com/ BIWebAccess/ViewServlet .ser?docBase=renetnt&folderPath=/ Prescribing+Information/PIs/ Jardiance/ jardiance .pdf) .
9. Haring HU, Merker L, Seewaldt-Becker E, et al. Empagliflozin as add-on to metformin plus sulfonylurea in patients with type 2 diabetes: a 24-week, randomized, double-blind, placebo-controlled trial. Diabetes Care 2013; 36: 3396-404.
10. Haring HU, Merker L, Seewaldt-Becker E, et al. Empagliflozin as add-on to metformin in patients with type 2 diabetes:a 24-week, randomized, double-blind, placebo-controlled trial. Diabetes Care 2014; 37: 1650-9.
11. Kovacs CS, Seshiah V, Swallow R, et al. Empagliflozin improves glycaemic and weight control as add-on therapy to pioglitazone or pioglitazone plus metformin in patients with type 2 diabetes: a 24-week, randomized, placebo-controlled trial. Diabetes Obes Metab 2014; 16: 147-58.
12. Roden M, Weng J, Eilbracht J, et al. Empagliflozin monotherapy with sitagliptin as an active comparator in patients with type 2 diabetes: a randomised, doubleblind, placebo-controlled, phase 3 trial. Lancet Diabetes Endocrinol 2013; 1: 208-19.
13. 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 OUTCOME). Cardiovasc Diabetol 2014; 13: 102.