SCORED And SOLOIST: The Next Scores For SGLT2 Inhibitors

Patients with diabetes (or pre-diabetes) are at high cardiovascular (CV) risk. Most anti-diabetic drugs were approved based on their ability to reduce blood glucose, but only a few of them have been unequivocally shown to reduce CV risk and improve survival. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a newer class of glucose- (and weight-) lowering drugs that inhibit glucose reabsorption in the proximal tubules of the kidney, leading to loss of glucose via the urine. SGLT2 inhibitors were investigated in patients with type 2 diabetes mellitus (T2DM) against placebo in several large CV outcome studies, e.g. the EMPA-REG Outcome, CANVAS Program, and DECLARE-TIMI 58 trials. These SGLT2 inhibitors reduced major adverse CV events, especially in patients with established atherosclerotic CV disease.1 In addition, they displayed a much stronger reduction of hospitalizations for heart failure and progression of kidney disease. These unexpectedly large effects occurred also in patients without previously known atherosclerotic CV disease or heart failure.1 Based on these very favorable results the 2019 European Society of Cardiology (ESC) Guideline on diabetes, pre-diabetes, and CV diseases recommend empagliflozin, canagliflozin, or dapagliflozin (Class IA) to reduce CV events in patients with T2DM and CV disease, or at high CV risk, whereas the former first-line anti-diabetic drug metformin receives a somewhat weaker recommendation.2

Click to Cistanche benefits and side effects for diabetes

Two large outcome trials with the SGLT2 inhibitors dapagliflozin (DAPA-HF) and empagliflozin (EMPEROR-Reduced) in patients with heart failure with reduced ejection fraction (HFrEF) demonstrated a highly significant reduction in CV mortality and heart failure hospitalizations and improvement of quality of life.3,4 All outcomes were ameliorated to the same extent in patients with and without T2DM suggesting that the beneficial effects are independent from anti-diabetic properties of the drugs.

In a late-breaking session at the American Heart Association (AHA) scientific sessions, recently D. Bhatt presented two trials with another SGLT2 inhibitor, sotagliflozin, in patients with T2DM.5,6 The first study, SCORED, randomized patients with T2DM and chronic kidney disease (defined as glomerular filtration rate of 25–60 mL/min/1.73 m2 ) and elevated CV risk to receive sotagliflozin or placebo. The primary endpoint, a composite of total CV deaths, and both total hospitalizations and urgent visits for heart failure, was highly significantly reduced [hazard ratio (HR) 0.74; 95% confidence interval (CI) 0.63–0.88; P< 0.001], whereas for CV deaths only a nonsignificant trend was observed.6 The second trial, SOLOIST-WHF, randomized patients with T2DM after a recent hospitalization for worsening heart failure.5 The same primary endpoint of CV deaths, and total hospitalizations and urgent visits for heart failure, was substantially reduced in the sotagliflozin-treated patients as compared to placebo (HR 0.67; 95% CI 0.52–0.85, P< 0.001). This reduction was observed to a similar extent in patients with HFrEF and patients with HFrEF (ejection fraction > 50%).5 This observation is of major importance as to date there is no evidence-based drug treatment for heart failure with preserved ejection fraction (HFpEF). In a pooled analysis combining HFpEF patients from both SOLOIST-WHF and SCORED, sotagliflozin treatment was associated with a substantial decrease in the primary outcome (HR 0.63, 95% CI 0.45–0.89, P= 0.009) (Figure 1). The absolute risk reduction was 11.6 events per 100 patient-years with an estimated number of patients who needed to treat for one year of only nine to avoid one event. It has to be mentioned that due to the loss of the sponsor, both trials were stopped earlier than planned and the primary endpoints had been changed during the trial.

Nevertheless, the results from these large randomized, controlled, double-blind studies are impressive. In contrast to DAPA-HF and EMPEROR-Reduced, the SOLOIST study did not include patients without T2DM, thus there is no evidence that sotagliflozin also improves heart failure outcomes in non-diabetic patients. Furthermore, the side-effect profile of sotagliflozin appears to be less favorable than that of other SGLT2 inhibitors. The increase in diarrhoea reported with sotagliflozin may be related to additional SGLT1 inhibition in the intestinal tract, as sotagliflozin is much less selective for SGLT2 over SGLT1 than empagliflozin and dapagliflozin. 

In concordance with the other heart failure studies, however, is the profound and early beneficial effect on outcomes the curves between SGLT2 inhibitor and placebo groups diverge as early as within one month in all three heart failure trials.3–5 This raises the question of which mechanisms SGLT2 inhibitors elicit their beneficial effect. The anti-diabetic properties are less important, as also non-diabetic patients profit to a similar extent, and anti-diabetic effects clearly would require a much longer follow-up time to translate into a reduction of hard clinical endpoints. 

The mechanisms by which SGLT2 inhibitors exert their beneficial CV effects are far from clear and have evoked heated discussions, as SGLT2 is not expressed in the myocardium. As the cardioprotective benefit was not related to glucose-lowering, promotion of ketone body utilization, or enhanced natriuresis, but linked to an increased hematocrit, it was assumed that SGLT2 inhibitors may induce hypoxia- and fasting-like state associated with erythrocytosis and amelioration of cardiomyocyte inflammation and stress.7

Small animal models of (diabetic) heart failure 8,9 have been used to unravel potential mechanisms: In a mouse model of ischemia/reperfusion injury, empagliflozin delayed the time to onset of contracture during ischemia by inhibiting the sodium–hydrogen exchanger during ischaemia10. In an HFpEF model, dapagliflozin treatment enhanced glucose handling, but only slightly improved the HFpEF phenotype.11 Given the substantial effects of SGLT2 inhibitors on numerous meaningful hard CV outcomes such as death, atherosclerotic CV events, heart failure, and kidney events, we need to further augment our understanding of the underlying molecular and cellular mechanism underlying this unexpectedly large clinical benefit.

From a clinical point of view, patients with HFrEF should be treated early with a combination of the ‘fantastic four’ drugs (angiotensin receptor/neprilysin inhibitor, beta-blocker, mineralocorticoid receptor antagonist, and SGLT2 inhibitor) to benefit from substantial and sustained reductions of mortality, heart failure hospitalizations, and symptoms.12 More and more data suggest that also HFpEF patients may profit from SGLT2 inhibition, however, for firm evidence we have to await the results of the ongoing EMPEROR-Preserved and DELIVER trials with empagliflozin and dapagliflozin.

Funding 

J.B. is supported by the Deutsche Forschungsgemeinschaft, KFO 311, ‘Advanced cardiac and pulmonary failure: mechanical unloading and repair’.

Conflict of interest:

J.B. reports honoraria for lectures and/or consulting:

Novartis, BMS, Pfizer, Vifor, Bayer, Servier, Daichi Sankyo, CVRx, MSD, Boehringer Ingelheim, Cardior, AstraZeneca, Abiomed, Abbott, Medtronic; research support: Zoll, CVRx, Vifor, Abiomed.

References

1 Zelniker TA, Wiviott SD, Raz I, I'm K, Goodrich EL, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Furtado RHM, Bhatt DL, Leiter LA, McGuire DK, Wilding JPH, Sabatine MS. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet 2019;393:31–39. 

2. Cosentino F, Grant PJ, Aboyans V, Bailey CJ, Ceriello A, Delgado V, Federici M, Filippatos G, Grobbee DE, Hansen TB, Huikuri HV, Johansson I, Ju¨ni P, Lettino M, Marx N, Mellbin LG, O¨ screen CJ, Rocca B, Roffi M, Sattar N, Seferovic PM, SousaUva M, Valensi P, Wheeler DC; ESC Scientific Document Group. 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J 2020;41:255–323. 

3. McMurray JJV, Solomon SD, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, Ponikowski P, Sabatine MS, Anand IS, Belohla´vek J, Bo¨hm M, Chiang C-E, Chopra VK, de Boer RA, Desai AS, Diez M, Drozdz J, Duka´t A, Ge J, Howlett JG, Katova T, Kitakaze M, Ljungman CEA, Merkely B, Nicolau JC, O’Meara E, Petrie MC, Vinh PN, Schou M, Tereshchenko S, Verma S, Held C, DeMets DL, Docherty KF, Jhund PS, Bengtsson O, Sjo¨strand M, Langkilde A-M; DAPA-HF Trial Committees and Investigators.Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019;381:1995–2008. 

4. Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, Januzzi J, Verma S, Tsutsui H, Brueckmann M, Jamal W, Kimura K, Schnee J, Zeller C, Cotton D, Bocchi E, Bo¨hm M, Choi DJ, Chopra V, Chuquiure E, Giannetti N, Janssens S, Zhang J, Gonzalez Juanatey JR, Kaul S, Brunner-La Rocca HP, Merkely B, Nicholls SJ, Perrone S, Pina I, Ponikowski P, Sattar N, Senni M, Seconde MF, Spinar J, Squire I, Taddei S, Wanner C, Zannad F; EMPEROR Reduced Trial Investigators. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med 2020;383:1413–1424. 

5. Bhatt DL, Szarek M, Steg PG, Cannon CP, Leiter LA, McGuire DK, Lewis JB, Riddle MC, Voors AA, Metra M, Lund LH, Komajda M, Testani JM, Wilcox CS, Ponikowski P, Lopes RD, Verma S, Lapuerta P, Pitt B; SOLOIST-WHF Trial Investigators.Sotagliflozin in patients with diabetes and recent worsening heart failure. N Engl J Med 2020;doi:10.1056/NEJMoa2030183. 

6. Bhatt DL, Szarek M, Pitt B, Cannon CP, Leiter LA, McGuire DK, Lewis JB, Riddle MC, Inzucchi SE, Kosiborod MN, Cherney DZI, Dwyer JP, Scirica BM, Bailey CJ, Dı´az R, Ray KK, Udell JA, Lopes RD, Lapuerta P, Steg PG; SCORED Investigators. Sotagliflozin in patients with diabetes and chronic kidney disease. N Engl J Med 2020; doi:10.1056/NEJMoa2030186. 

7. Packer M. Critical examination of mechanisms underlying the reduction in heart failure events with SGLT2 inhibitors: identification of a molecular link between their actions to stimulate erythrocytosis and to alleviate cellular stress. Cardiovasc Res 2020;3:cvaa064. 

8. Riehle C, Bauersachs J. Of mice and men: models and mechanisms of diabetic cardiomyopathy. Basic Res Cardiol 2019;114:2. 

9. Riehle C, Bauersachs J. Small animal models of heart failure. Cardiovasc Res 2019;115: 1838–1849. 

10. Uthman L, Nederlof R, Eerbeek O, Baartscheer A, Schumacher C, Buchholtz N, Hollmann MW, Coronel R, Weber NC, Zuurbier CJ. Delayed ischaemic contracture onset by empagliflozin associates with NHE1 inhibition and is dependent on insulin in isolated mouse hearts. Cardiovasc Res 2019;115:1533–1545. 

11. Withaar C, Meems LMG, Markousis-Mavrogenis G, Boogerd CJ, Sillje´ HHW, Schouten EM, Dokter MM, Voors AA, Westenbrink BD, Lam CSP, de Boer RA. The effects of liraglutide and dapagliflozin on cardiac function and structure in a multi-hit mouse model of Heart Failure with Preserved Ejection Fraction. Cardiovasc Res 2020; doi:10.1093/cvr/cvaa256. 

12. Bauersachs J. Heart failure drug therapy—the fantastic four. Eur Heart J 2021, in press.

Biography: Johann Bauersachs acts as Head of the Department of Cardiology and Angiology at Hannover Medical School (MHH). Since 2010, Johann Bauersachs has been a Full Professor and Director of the MHH-Department of Cardiology and Angiology. Professor Bauersachs is Deputy Editor of the European Heart Journal, Associate Editor of Cardiovascular Research, Fellow of the European Society of Cardiology (ESC), Member of the ESC Congress Program Committee, Member of the ESC Communications Committee, Fellow of the Heart Failure Association (HFA) of the ESC, Chair of the HFA Study Group on Peripartum Cardiomyopathy (PPCM), and Co-Chair of the worldwide EORP Registry on PPCM. Professor Bauersachs is a Board member of the German Cardiac Society (DGK), and Chair of the Committee on Clinical Cardiovascular Medicine of the DGK. He is an Advisory Board member of Cardio Pharmaceuticals. Professor Bauersachs is an interventional cardiologist with special interests in acute coronary syndromes, left ventricular healing and remodeling, acute and chronic heart failure, as well as intensive care.

for more information:Ali.ma@wecistanche.com