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SGLT2i improves LV structure and function in nondiabetic patients with HFrEF

sciencedirect.com
Literature - Santos-Gallego CG, Vargas-Delgado AP, Requena-Ibanez JA, et al. - J Am Coll Cardiol. 2021;77:243-255. doi: 10.1016/j.jacc.2020.11.008.

Introduction and methods

Large clinical trials have demonstrated improved HF outcomes by SGLT2 inhibitors in patients with T2DM as well as patients with HFrEF [1-6]. The early benefits of SGLT2i in clinical outcomes, however, cannot be explained solely by the glucose-lowering effects of SGLT2 inhibitors, since the hypoglycemic activity of the compound is comparable to other glucose-lowering drugs that do not improve HF [7].

In nondiabetic porcine models of HF, empagliflozin significantly improved adverse left ventricular (LV) remodeling, decreased LV volumes and LV hypertrophy, reduced neurohormonal activation, and improved cardiac diastolic and systolic function compared to control group [8,9]. Based upon these results, the EMPA-TROPISM (are the “Cardiac Benefits” of Empagliflozin Independent of Its Hypoglycemic Activity) trial was designed to translate the preclinical data from the HF porcine models to human nondiabetic patients with HFrEF [10].

This study assessed the effects of empagliflozin on LV function and volumes, functional capacity, and quality of life (QoL) in HFrEF patients without T2DM.

The EMPA-TROPISM trial is a single-site, double-blind, randomized, placebo-controlled trial that included nondiabetic patients (>18 years) with HF (New York Heart Association [NYHA] functional class II and III), LVEF<50%, and stable symptoms and medical therapy within the last 3 months. Patients (n=84) were randomized (1:1) to receive empagliflozin 10 mg daily or matching placebo. The primary endpoint was between-groups change in left ventricular end-diastolic volume (LVEDV) and left ventricular end-systolic volume (LVESV). Secondary endpoints include the between-groups changes in peak oxygen consumption (VO₂) and cardiac pulmonary adaptation. Other endpoints were LV mass, LVEF, LV sphericity index, oxygen uptake efficiency slope (OUES), minute ventilation per carbon dioxide production (VCO₂), distance in the 6-min walk test, and QoL. Follow-up was 6 months after randomization.

Main results

  • There was, from baseline to 6 months, a significant reduction in LVEDV in patients treated with empagliflozin compared to patients with placebo (-25.1±26.0 mL vs. -1.5±25.4 mL, respectively, P<0.001).
  • LVESV was reduced in the empagliflozin (-26.6±20.5 mL) group compared to placebo (-0.5±21.9 mL, P<0.001).
  • Empagliflozin significantly reduced LV mass compared to patients on placebo (-17.8±31.9 g vs. 4.1±13.4 g, respectively, P<0.001).
  • There was an 6.0±4.2% increase in LVEF in patients receiving empagliflozin compared to those treated with placebo (-0.1±3.9%, P<0.001).
  • LV sphericity was reduced by empagliflozin compared to placebo (Δsphericity index: -0.10±0.08 g vs. 0.01±0.08 g, respectively, P<0.001).
  • Plasma concentrations of NT-proBNP were decreased by 11.5% in the empagliflozin group compared to an 8.5% increase in placebo (P=0.01).
  • Patients treated with empagliflozin had an improved peak VO₂ compared to those on placebo (1.1±2.6 vs. -0.5±1.9 ml/min/kg, respectively, P=0.017).
  • OUES was increased in patients on empagliflozin (111±267) compared to patients using placebo (-145±318, P<0.01).
  • There was a significant improvement in the 6-min walk test in the empagliflozin group compared to those in the placebo group (81±64 m vs. -35±68 m, respectively, P<0.001).
  • The QoL was significantly improved in patients using empagliflozin compared to patients on placebo (KCCQ-12 Δfrom baseline: 21±18 vs. 1.9±15, respectively, P<0.001).

Conclusion

The EMPA-TROPISM trial showed that a 6-month daily administration of empagliflozin benefits nondiabetic patients with HFrEF by reducing LV volume, decreasing LV hypertrophy, improving LVEF, and a less spherical LV with less pronounced architectural remodeling, compared to placebo. In addition, empagliflozin improved functional capacity and QoL in these patients.

References

1. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373: 2117–28.

2. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017;377: 644–57.

3. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2019;380:347–57.

4. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019;381: 1995–2008.

5. Packer M, Anker SD, Butler J, et al., for the EMPEROR-Reduced Trial Investigators. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med 2020;383:1413–24.

6. Petrie MC, Verma S, Docherty KF, et al. Effect of dapagliflozin on worsening heart failure and cardiovascular death in patients with heart failure with and without diabetes. JAMA 2020;323: 1353–68.

7. Flores E, Santos-Gallego CG, Diaz-Mejia N, Badimon JJ. Do the SGLT-2 inhibitors offer more than hypoglycemic activity? Cardiovasc Drugs Ther 2018;32:213–22.

8. Santos-Gallego CG, Requena-Ibanez JA, San Antonio R, et al. Empagliflozin ameliorates adverse left ventricular remodeling in nondiabetic heart failure by enhancing myocardial energetics. J Am Coll Cardiol 2019;73:1931–44.

9. Santos-Gallego CG, Requena-Ibanez JA, San Antonio R, et al. Empagliflozin ameliorates diastolic dysfunction and left ventricular fibrosis/stiffness in non-diabetic heart failure: a multimodality study. JACC Cardiovasc Imaging 2020:S1936-878X(20)30799-3. doi: 10.1016/j.jcmg.2020.07.042.

10. Santos-Gallego CG, Garcia-Ropero A, Mancini D, et al. Rationale and design of the EMPA-TROPISM Trial (ATRU-4): are the “cardiac benefits” of empagliflozin independent of its hypoglycemic activity? Cardiovasc Drugs Ther 2019;33:87–95.

Find this article online at J Am Coll Cardiol Watch a video by Carlos Santos-Gallego on this study

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