Empagliflozin reduces cardiovascular events, mortality and renal events in participants with type 2 diabetes after coronary artery bypass graft surgery: subanalysis of the EMPA-REG OUTCOME® randomised trial

Abstract

Aims/hypothesisAfter coronary artery bypass graft (CABG) surgery in individuals with type 2 diabetes, there remains a considerable residual cardiovascular risk. In the EMPA-REG OUTCOME® trial in participants with type 2 diabetes and established cardiovascular disease, empagliflozin reduced the risk of cardiovascular death by 38%, all-cause mortality by 32%, hospitalisation for heart failure by 35% and incident or worsening nephropathy by 39% vs placebo when given in addition to standard of care. The aim of this post hoc analysis of the EMPA-REG OUTCOME® trial was to determine the effects of the sodium glucose cotransporter 2 inhibitor empagliflozin on cardiovascular events and mortality in participants with type 2 diabetes and a self-reported history of CABG surgery.MethodsThe EMPA-REG OUTCOME® trial was a randomised, double-blind, placebo-controlled trial. Participants with type 2 diabetes and established cardiovascular disease were randomised 1:1:1 to receive placebo, empagliflozin 10 mg or empagliflozin 25 mg, once daily, in addition to standard of care. In subgroups by self-reported history of CABG (yes/no) at baseline, we assessed: cardiovascular death; all-cause mortality; hospitalisation for heart failure; and incident or worsening nephropathy (progression to macroalbuminuria, doubling of serum creatinine, initiation of renal replacement therapy or death due to renal disease). Differences in risk between empagliflozin and placebo were assessed using a Cox proportional hazards model.ResultsAt baseline, 25% (1175/4687) of participants who received empagliflozin and 24% (563/2333) of participants who received placebo had a history of CABG surgery. In participants with a history of CABG surgery, HRs (95% CI) with empagliflozin vs placebo were 0.52 (0.32, 0.84) for cardiovascular mortality, 0.57 (0.39, 0.83) for all-cause mortality, 0.50 (0.32, 0.77) for hospitalisation for heart failure and 0.65 (0.50, 0.84) for incident or worsening nephropathy. Results were consistent between participants with and without a history of CABG surgery (p > 0.05 for treatment by subgroup interactions).Conclusions/interpretationIn participants with type 2 diabetes and a self-reported history of CABG surgery, treatment with empagliflozin was associated with profound reductions in cardiovascular and all-cause mortality, hospitalisation for heart failure, and incident or worsening nephropathy. These data have important implications for the secondary prevention of cardiovascular events after CABG in individuals with type 2 diabetes.Trial registration:ClinicalTrials.gov NCT01131676Electronic supplementary materialThe online version of this article (10.1007/s00125-018-4644-9) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Highly Selective and Potent Human β‐Secretase 2 (BACE2) Inhibitors against Type 2 Diabetes: Design, Synthesis, X‐ray Structure and Structure–Activity Relationship Studies

“…All test inhibitors showed purity > 95 %byH PLC analysis. 171.3, 167.7, 160.1, 140.9, 138.2, 137.1, 129.8, 130.0, 128.8, 128.1, 127.8, 127.0, 125.9, 121.1 13 CNMR, LRMS, and HRMS data are identical to those reported previously. [36] N 1 -((2S,3R)-3-Hydroxy-1-phenyl-4-((3-(trifluoromethyl)benzyl)amino)butan-2-yl)-N 3 -methyl-N 3 -((R)-1-phenylethyl)isophthalamide (3 k):T itle compound was obtained from acid 4a and isosteric amine 18 a following the procedure described for compound 2f.…”

“…Column chromatography was performed using 230-400 mesh, 60 pore diameter silica gel. 1 Ha nd 13 CNMR spectra were recorded at room temperature on aB ruker AV800, DRX-500 and ARX-400 or aV arian INOVA300. Chemical shifts (d values) are reported in parts per million and are referenced to the deuterated residual solvent peak.…”

“…Despite these currently available options for lowering blood glucose, there are severe liabilities associated with these existing antidiabetic drugs, especially related to cardiovascular complications . Although examples of recent drugs with reduced risk of cardiovascular death have been reported (e.g., the SGLT2 inhibitor empagliflozin), new therapies based on innovative mechanisms are still urgently needed to address improvement of treatment and current unmet needs.…”

“…ples of recent drugs with reducedr isk of cardiovascular death have been reported (e.g.,t he SGLT2 inhibitor empagliflozin), [13] new therapies based on innovative mechanisms are still urgently neededt oa ddress improvement of treatment and current unmet needs.…”

Dysplastic urothelial changes accompany empagliflozin administration in urinary bladder of experimental diabetes

“…Empagliflozin (EMPA) is one of the sodium-glucose cotransporter 2 inhibitors (SGLT2is) that have the advantage of not causing hypoglycaemia as they act distinctively by increasing urinary glucose excretion. 1,2 EMPA has pleiotropic effects in type 2 diabetes (T2D) including a reduction of major adverse cardiovascular events 3,4 and an improvement in the renal outcomes, 5 yet uncommon but serious safety issues were reported with SGLT2is use, such as urinary tract infection (UTI). 6 Another important safety concern is the increased incidence of renal and testicular tumours associated with highdose EMPA in male mice.…”