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SGLT2 inhibitor does not improve cardiac energy metabolism in HF

ahajournals.org
Literature - Hundertmark MJ, Adler A, Antoniades C, et al. - Circulation. 2023 May 30;147(22):1654-1669. doi: 10.1161/CIRCULATIONAHA.122.062021

Introduction and methods

Background

Although SGLT2 inhibitors have emerged as a cornerstone of treatment for patients with HFrEF or HFpEF [1,2], their precise cardiac mechanism of action remains unclear. Possibly, SGLT2 inhibition improves myocardial energy metabolism [3-7].

Aim of the study

The study aim was to investigate the effects of treatment with empagliflozin on myocardial energetics, serum metabolomics, and cardiorespiratory fitness in HF patients.

Methods

The EMPA-VISION (Assessment of Cardiac Energy Metabolism, Function and Physiology in Patients With Heart Failure Taking Empagliflozin) trial was a prospective, single-center, double-blind, placebo-controlled, mechanistic RCT conducted in the UK in which 72 symptomatic patients with nonischemic, chronic HFrEF (LVEF ≤40%; n=36) or HFpEF (LVEF ≥50%; n=36) who received appropriate doses of guideline-directed HF medical therapy were enrolled. Patients were stratified into their respective cohorts (HFrEF vs. HFpEF) and randomized to empagliflozin 10 mg (n=35: 17 HFrEF and 18 HFpEF) or placebo (n=37: 19 HFrEF and 18 HFpEF) once daily for 12 weeks.

Outcomes

The primary endpoint was change in the cardiac phosphocreatine:ATP (PCr/ATP) ratio from baseline to 12 weeks as measured by magnetic resonance spectroscopy.

Exploratory endpoints included measures of energy metabolism at rest and during dobutamine stress (65% of age-maximum heart rate), myocardial triglyceride content, cardiac function and volumes at rest and during dobutamine stress, measures of cardiac fibrosis, and blood biomarkers related to drug effects on metabolism or neurohormonal activation.

Main results

Primary endpoint

  • At 12 weeks, there was no significant difference in cardiac energetics, as indicated by the change in PCr/ATP ratio, at rest between the empagliflozin and placebo groups in HFrEF patients (adjusted mean treatment difference: –0.25; 95%CI: –0.58 to 0.09 ; P=0.14) and HFpEF patients (adjusted mean treatment difference: –0.16; 95%CI: –0.60 to 0.29; P=0.47).

Exploratory endpoints

  • Empagliflozin also did not improve cardiac energetics during dobutamine stress in HFrEF patients (adjusted mean treatment difference: –0.13; 95%CI: –0.35 to 0.09 ; P=0.23) and HFpEF patients (adjusted mean treatment difference: –0.22; 95%CI: –0.66 to 0.23; P=0.32).
  • A principal component analysis showed empagliflozin had no significant effect on a set of 19 serum metabolites related to energy metabolism compared with placebo.
  • No significant differences were observed in myocardial triglyceride content, LVEF, circulating ketone bodies, serum-derived biomarkers, cardiorespiratory fitness, or quality of life between the treatment groups in either cohort.
  • In HFrEF patients, empagliflozin treatment did result in a reduction in LV mass (adjusted mean treatment difference: −9.65 g; 95%CI: −17.49 to −1.81; P=0.02) and LV mass index (adjusted mean treatment difference: –4.46 g/m² ; 95%CI: −8.42 to −0.50; P=0.03).
  • Empagliflozin was overall safe and well tolerated, with more adverse events reported in the placebo group (n=19) than the empagliflozin group (n=17).

Conclusion

The EMPA-VISION trial showed that 12-week treatment with empagliflozin did not change cardiac energetics, serum metabolites associated with energy metabolism, LVEF, and cardiorespiratory fitness in patients with HFrEF or HFpEF compared with placebo. The authors conclude that their results do not confirm the “thrifty fuel hypothesis,” which suggests that improved energy provision—by using ketones as substrates—is a central mechanism behind the beneficial clinical effects of SGLT2 inhibition observed in HF patients.

References

1. McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Bohm M, Burri H, Butler J, Celutkiene J, Chioncel O, et al; ESC Scientific Document Group. 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021;42:3599–3726. doi: 10.1093/eurheartj/ehab368

2. Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, Byun JJ, Colvin MM, Deswal A, Drazner MH, Dunlay SM, Evers LR, et al. 2022 AHA/ACC/HFSA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2022;145:e895–e1032. doi: 10.1161/CIR.0000000000001063

3. Byrne NJ, Parajuli N, Levasseur JL, Boisvenue J, Beker DL, Masson G, Fedak PWM, Verma S, Dyck JRB. Empagliflozin prevents worsening of cardiac function in an experimental model of pressure overload-induced heart failure. JACC Basic Transl Sci. 2017;2:347–354. doi: 10.1016/j.jacbts.2017.07.003

4. Santos-Gallego CG, Ibanez JAR, Antonio RS, Ishikawa K, Watanabe S, Botija MBP, Salvo AJS, Hajjar R, Fuster V, Badimon J. Empagliflozin induces a myocardial metabolic shift from glucose consumption to ketone metabolism that mitigates adverse cardiac remodeling and improves myocardial contractility. J Am Coll Cardiol. 2018;71:674–674. doi: 10.1016/S0735-1097(18)31215-4

5. Verma S, Rawat S, Ho KL, Wagg CS, Zhang L, Teoh H, Dyck JE, Uddin GM, Oudit GY, Mayoux E, et al. Empagliflozin increases cardiac energy production in diabetes: novel translational insights into the heart failure benefits of SGLT2 inhibitors. JACC Basic Transl Sci. 2018;3:575–587. doi: 10.1016/j.jacbts.2018.07.006

6. Abdurrachim D, Manders E, Nicolay K, Mayoux E, Prompers JJ. Single dose of empagliflozin increases in vivo cardiac energy status in diabetic db/db mice. Cardiovasc Res. 2018;114:1843–1844. doi: 10.1093/cvr/cvy246

7. Abdurrachim D, Teo XQ, Woo CC, Chan WX, Lalic J, Lam CSP, Lee PTH. Empagliflozin reduces myocardial ketone utilization while preserving glucose utilization in diabetic hypertensive heart disease: A hyperpolarized (13) C magnetic resonance spectroscopy study. Diabetes Obes Metab. 2019;21:357–365. doi: 10.1111/dom.13536

Find this article online at Circulation.

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