SGLT2 Inhibitors Are Lifesavers in Heart Failure

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Ragavendra R. Baliga, MD, MBA, FACP, FRCP (Edin), FACC, Editor

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Deepak L. Bhatt, MD, MPH, FACC, FAHA, FSCAI, FESC, Editor

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Eduardo Bossone, MD, PhD, FCCP, FESC, FACC, Editor

The first three trials of sodium-glucose cotransporter-2 (SGLT2) inhibitors investigating cardiovascular (CV) safety, as required by the Food and Drug Administration, all revealed an unexpected approximate 30% reduction in heart failure (HF) hospitalizations in patients with type 2 diabetes mellitus (T2DM) with and at risk for CV disease.Zinman B. Wanner C. Lachin J.M. et al.Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.Neal B. Perkovic V. Mahaffey K.W. et al.Canagliflozin and cardiovascular and renal events in type 2 diabetes.Wiviott S.D. Raz I. Bonaca M.P. et al.Dapagliflozin and cardiovascular outcomes in type 2 diabetes. However, these drugs were not associated with decreased stroke risk or reductions in myocardial infarction. These findings piqued the interest of HF specialists and led to clinical trials specifically investigating the effects of SGLT2 inhibitors in patients with HF (Fig. 1).McMurray J.J.V. Solomon S.D. Inzucchi S.E. et al.Dapagliflozin in patients with heart failure and reduced ejection fraction.Zannad F. Ferreira J.P. Pocock S.J. et al.SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-reduced and DAPA-HF trials.Packer M. Butler J. Zannad F. et al.Empagliflozin and major renal outcomes in heart failure.Packer M. Anker S.D. Butler J. et al.Cardiovascular and renal outcomes with empagliflozin in heart failure.Anker S.D. Butler J. Filippatos G. et al.Empagliflozin in heart failure with a preserved ejection fraction.Bhatt D.L. Szarek M. Steg P.G. et al.Sotagliflozin in patients with diabetes and recent worsening heart failure.Bhatt D.L. Szarek M. Pitt B. et al.Sotagliflozin in patients with diabetes and chronic kidney disease.Figure thumbnail gr1

Fig. 1Myocardial direct and indirect effects of SGLT2 inhibitors (SGLT2i).

(Adapted from Lopaschuk GD, Verma S. Mechanisms of Cardiovascular Benefits of Sodium Glucose Co-Transporter 2 (SGLT2) Inhibitors: A State-of-the-Art Review. JACC Basic Transl Sci. 2020 Jun 22;5(6):632-644.)In the DAPA-HF trial reported in the New England Journal of Medicine in November 2019,McMurray J.J.V. Solomon S.D. Inzucchi S.E. et al.Dapagliflozin in patients with heart failure and reduced ejection fraction. the investigators found that in patients with symptomatic heart failure with reduced ejection fraction (HFrEF), dapagliflozin was beneficial in that dapagliflozin versus placebo was associated with a reduction in CV deaths and HF events, recurrent HF events, and ventricular arrhythmias, and also was associated with improvement in symptoms. These benefits were consistent across the age spectrum, risk spectrum, baseline diuretic use, baseline use of sacubitril/valsartan (although only 10% of the study cohort was on this combination), and mineralocorticoid receptor antagonists (MRAs). There was no sign of excess adverse safety events with these combinations of drugs. A subgroup analysis indicated that the benefit seen was independent of the presence or absence of diabetes. Almost all the patients had moderate HF, so the benefit and side-effect profile in patients with more severe HF was not studied.The results of EMPEROR-REDUCED trialPacker M. Anker S.D. Butler J. et al.Cardiovascular and renal outcomes with empagliflozin in heart failure. indicated that empagliflozin was superior to placebo in improving HF outcomes among patients with symptomatic stable HFrEF (EF ≤ 40%) on excellent baseline guideline-directed medical therapy, irrespective of diabetes status. Benefit was primarily driven by a reduction in HF hospitalizations, not mortality. There was an early and sustained benefit on KCCQ-CSS. There was also a benefit in kidney outcomes. The use of MRAs did not influence the effect of empagliflozin on clinical outcomes. Even patients with severe left ventricular dysfunction appeared to benefit; the trial enrolled patients with an average ejection fraction (EF) of 27%, and greater than 70% of patients had an EF ≤30%; patients with EF greater than 30% were only included if they had an HF hospitalization in the prior 12 months and met specific natriuretic peptide benchmarks. A higher rate of genital mycotic infections was observed with SGLT2 inhibition, as had been previously reported with multiple other trials in this class.Of note, the DAPA-HF trial was larger and did show a benefit in CV and all-cause mortality with dapagliflozin use. The subgroup analysis of the EMPEROR-REDUCED trial suggested that this benefit may not necessarily be driven by a diuretic effect alone (as noted among patients with and without recent volume overload), but further studies are needed to clarify this and other potential mechanisms of benefit. The cardiorenal benefits could be due to a combination of several factors, including a decrease in arterial stiffness, increase in hematocrit, decreased glucotoxicity, increase in weight loss, decrease in inflammation, increase in circulating provascular progenitor cells,Hess D.A. Terenzi D.C. Trac J.Z. et al.SGLT2 inhibition with empagliflozin increases circulating provascular progenitor cells in people with type 2 diabetes mellitus. and decrease in circulating plasma volume with lower potential for developing volume depletion.Zelniker T.A. Braunwald E. Mechanisms of cardiorenal effects of sodium-glucose cotransporter 2 inhibitors: JACC state-of-the-art review.SOLOIST-WHF was the first large, randomized controlled trial to show that initiation of SGLT2 inhibition in acute HF in stabilized patients prior to discharge or shortly thereafter is safe and effective. The benefits were consistent in those with not only HFrEF but also heart failure with preserved ejection fraction (HFpEF). Sotagliflozin is an SGLT2 inhibitor, but also inhibits SGLT1, which is expressed in the gut and delays glucose absorption. The goal of the trial was to assess the safety and efficacy of sotagliflozin in reducing CV events among patients with T2DMand recent HF admission. The primary endpoint of total CV death, hospitalization for HF, or urgent visit for HF for sotagliflozin versus placebo was 70 versus 98 events/100 patient-years (hazard ratio, 0.67; 95% confidence interval, 0.52–0.85; P = .0009). This achieved significance by 28 days of follow-up. There was also a significant improvement in the KCCQBhatt D.L. Szarek M. Steg P.G. et al.Sotagliflozin in patients with diabetes and recent worsening heart failure. and in days alive and outside of the hospital.Szarek M. Bhatt D.L. Steg P.G. et al.Effect of sotagliflozin on total hospitalizations in patients with type 2 diabetes and worsening heart failure: a randomized trial. In the pooled analysis of SCORED and SOLOIST-WHF data, benefits were present irrespective of baseline EF (including among patients with HFpEF) and prior history of HF. Empagliflozin has also been found to be beneficial in acute HF.Voors A.A. Angermann C.E. Teerlink J.R. et al.The SGLT2 inhibitor empagliflozin in patients hospitalized for acute heart failure: a multinational randomized trial.The Framingham study reported that 10% of the patients with HF die within the first month and 20% to 30% die within the first year.Levy D. Kenchaiah S. Larson M.G. et al.Long-term trends in the incidence of and survival with heart failure. Similar findings have been reported recently,Conrad N. Judge A. Canoy D. et al.Temporal trends and patterns in mortality after incident heart failure: a longitudinal analysis of 86 000 individuals. and 1 in 4 US patients hospitalized for HF die or are rehospitalized within 30 days of discharge,Wadhera R.K. Joynt Maddox K.E. Wasfy J.H. et al.Association of the hospital readmissions reduction program with mortality among Medicare beneficiaries hospitalized for heart failure, acute myocardial infarction, and pneumonia. making it important that the therapy of acute HF be urgent. Given that mortality in acute HF is high in the first month after diagnosis, the early benefit of SGLT2 inhibitors in HF makes it important that therapy is started early. In DAPA-HF, there was a 49% reduction in events (worsening HF or CV death) by day 28. In the EMPEROR-Reduced trial, the benefit of reduction in combined risk of death, hospitalization for HF, or an emergent/urgent HF visit reached statistical significance at 12 days after randomization. In SOLOIST-WHF, there was a 39% reduction in events (total CV death, HHF, and urgent HF visit) by 28 days. These studies have prompted the call for early initiation of SGLT2 inhibitor therapy in HF.McMurray J.J.V. Packer M. How should we sequence the treatments for heart failure and a reduced ejection fraction?: A redefinition of evidence-based medicine.Greene S.J. Butler J. Fonarow G.C. Simultaneous or rapid sequence initiation of quadruple medical therapy for heart failure-optimizing therapy with the need for speed.

Baliga R. Door-to-GDMT time & door to max-dose GDMT time. Available at: https://youtu.be/HM-bdHScVdE. In: RR B, editor. Dr RR Baliga's 'GOT KNOWLEDGE DOC" Podkast. YouTube: MasterMedfacts.com; 2021. Accessed.

Verma S. Anker S.D. Butler J. et al.Early initiation of SGLT2 inhibitors is important, irrespective of ejection fraction: SOLOIST-WHF in perspective.The pooled analysis of EMPEROR-Reduced and EMPEROR-Preserved suggests that the kidney benefit is primarily among patients with HFrEF,Zannad F. Ferreira J.P. Pocock S.J. et al.SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-reduced and DAPA-HF trials. and eGFR slope analysis may not be predictive of kidney outcomes among patients with HF. The SCORED trial showed that sotagliflozin has beneficial effects on CV outcomes among patients with T2DM and chronic kidney disease. The benefit was primarily in reduction of HF events, but there was also a reduction in CV death/myocardial infarction/stroke, primarily owing to reduction in MI and stroke. A reduction in kidney events was not observed, likely owing to early cessation of the trial because of loss of funding. The significant reduction in kidney disease progression has also been shown in CREDENCEPerkovic V. Jardine M.J. Neal B. et al.Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. and DAPA-CKD,Heerspink H.J.L. Stefánsson B.V. Correa-Rotter R. et al.Dapagliflozin in patients with chronic kidney disease. indicating an expanded role for SGLT2 is in nephrology practice as adjunctive agents to slow the progression of kidney disease.

To discuss these salutary benefits of SGLT2 inhibitors in detail, we have assembled a terrific panel of international experts on this new class of therapeutic agents. We hope these articles will persuade you all to consider, in appropriate patients, early initiation of these lifesavers.

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N Engl J Med. 383 (): 1436-1446https://doi.org/10.1056/NEJMoa2024816Article InfoIdentification

DOI: https://doi.org/10.1016/j.hfc.2022.07.001

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