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How Does Empagliflozin Reduce Cardiovascular Mortality In Type 2 Patients, Including Those With PAD?

Jan 13, 2018
 

The answer comes from a mediation analysis of the EMPA-REG OUTCOME Trial.

The EMPA-REG OUTCOME trial involved over 7,000 patients with type 2 diabetes (hemoglobin A1c, 7%–10%), established cardiovascular disease, and estimated glomerular filtration rate ≥30 mL·min−1·1.73 m−2 at baseline. PAD at inclusion was defined as the presence of any of the following: limb angioplasty, stenting, or bypass surgery; limb or foot amputation resulting from circulatory insufficiency; evidence of significant peripheral artery stenosis (>50% on angiography, or >50% or hemodynamically significant via noninvasive methods) in ≥1 limb; and ankle brachial index. They were given empagliflozin in addition to standard of care. The study results showed the risk of CV death was 38% less when compared to placebo.

The study through exploratory mediation analysis assessed the extent to which the treatment group showed differences in covariates contributes to CV death risk reduction with empagliflozin.

Of 7,020 patients treated, 1,461 (20.8%) had PAD at baseline (982 treated with empagliflozin, 479 treated with placebo). In this group, baseline mean ±SD age was 64.0±8.5 years; body mass index was 30.7±5.3 kg/m2; hemoglobin A1c was 8.12±0.86%; 69% were male; 10% had a history of HF(heart failure); 67% were current or ex-smokers; 30% had estimated glomerular filtration rate <60 mL·min−1·1.73 m−2; 92% were on antihypertensive therapy; 75% were on lipid-lowering therapy; and 85% were on antiplatelet/anticoagulant therapy. In patients without PAD, the mean ±SD age was 62.9±8.7 years; body mass index was 30.6±5.3 kg/m2; hemoglobin A1c was 8.06±0.84%; 72% were male; 10% had a history of HF; 57% were current or ex-smokers; 25% had estimated glomerular filtration rate <60 mL·min−1·1.73 m−2, 96% were on antihypertensive therapy; 83% were on lipid-lowering therapy; and 90% were on antiplatelet/anticoagulant therapy.

In patients with PAD at baseline, empagliflozin reduced cardiovascular death by 43% all-cause mortality by 38%, 3-point MACE by 16%, 4-point MACE by 7%, HHF(hospitalization for heart failure) by 44%, and the reduction of  incident or worsening nephropathy by 46% versus placebo, consistent with findings in patients without PAD. The reductions in cardiovascular death appeared early and persisted for the duration of the trial. In general, overall AEs (Adverse event) and serious AEs were balanced between the empagliflozin and placebo groups in patients with and without PAD. In patients with PAD, LLA (Lower lib amputation) occurred in 54 of 982 (5.5%) treated with empagliflozin and 30 of 479 (6.3%) treated with placebo. In patients without PAD, LLA occurred in 34 of 3,704 (0.9%) treated with empagliflozin and 13/1853 (0.7%) treated with placebo. In patients with PAD, major LLA occurred in 13 of 982 (1.3%) and 16 of 479 (3.3%) patients in the empagliflozin and placebo groups, respectively, and in patients without PAD, major LLA occurred in 5 of 3704 (0.1%) and 2 of 1853 (0.1%) in the empagliflozin and placebo groups, respectively. In patients with PAD, minor LLA occurred in 41 of 982 (4.2%) and 14 of 479 (2.9%) patients in the empagliflozin and placebo groups, respectively, and in patients without PAD, minor LLA occurred in 29 of 3704 (0.8%) and 11 of 1853 (0.6%) in the empagliflozin and placebo groups, respectively.

Changes in hematocrit and hemoglobin mediated 51.8% and 48.9%, respectively, of the effect of empagliflozin versus placebo on the risk of CV death on the basis of changes from baseline, with similar results in analyses on the basis of updated means. Smaller mediation effects (maximum 29.3%) were observed for uric acid, fasting plasma glucose, and HbA1c. In multivariable models, which incorporated effects of empagliflozin on hematocrit, fasting glucose, uric acid, and urine albumin/creatinine ratio, the combined changes from baseline provided 85.2% mediation, whereas updated mean analyses provided 94.6% mediation of the effect of empagliflozin on CV death.

In the vulnerable subgroup of patients with T2DM and PAD, empagliflozin reduced mortality, HHF, and progression of renal disease with no observed increase in the risk of LLA. The reduction in cardiovascular death with empagliflozin in patients with T2DM and PAD translates to a number needed to treat 29 patients over 3.1 years to prevent 1 event. These data have important translational implications for risk reduction approaches in patients with T2DM and PAD.

In summary, from the results in this analysis from the EMPS-REG OUTCOME trial, changes in markers of plasma volume were the most important mediators of the reduction in risk of CV death with empagliflozin versus placebo.

Practice Pearls:

  • In the subgroup of patients with T2DM and PAD, empagliflozin reduced mortality, HHF, and progression of renal disease with no observed increase in the risk of LLA.
  • Changes in hematocrit and hemoglobin mediated 51.8% and 48.9%, respectively, of the effect of empagliflozin versus placebo on the risk of CV death on the basis of changes from baseline.
  • The use of empagliflozin reduced the risk of CV death by 38% less when compared to placebo.

References:

Silvio E. Inzucchi, Bernard Zinman, Diabetes Care 2017 Dec; dc171096. https://doi.org/10.2337/dc17-1096
Circulation. 2017;136:00–00. DOI: 10.1161/CIRCULATIONAHA.117.032031.

Shah AD, Langenberg C, Type 2 diabetes and incidence of cardiovascular diseases, Lancet Diabetes Endocrinol. 2015;3:105–113. doi: 10.1016/S2213-8587(14)70219-0.

Norman PE, Davis WA,. Peripheral arterial disease and risk of cardiac death in type 2 diabetes:. Diabetes Care. 2006;29:575–580. N Engl J Med. 2015;373:2117–2128. doi: 10.1056/NEJMoa1504720.