Cardiovascular outcome trials in patients with type 2 diabetes mellitus: a major breakthroughThe Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes (EMPA-REG OUTCOME) trial was the landmark trial for this class of drugs: 7020 patients with type 2 diabetes mellitus (T2DM) and a history of a previous cardiovascular event were randomized to either empagliflozin (10 or 25 mg) or placebo on top of standard care (Table 3).14Zinman B. Wanner C. Lachin J.M. et al.Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. Although designed as a noninferiority trial for 3P-MACE, in EMPA-REG OUTCOME empagliflozin reduced the risk of not only this primary outcome (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.74–0.99; P = .0038), but also of all-cause mortality (32% relative risk reduction), cardiovascular mortality (38% relative risk reduction), and HF hospitalizations (HHF; 35% relative risk reduction) over a median follow-up of 3.1 years. The separation of the Kaplan-Meier curves for either HHF or cardiovascular death occurred early in the trial, leading to a number needed to treat to prevent one such event of 35 over 3 years.15Fitchett D. Zinman B. Wanner C. et al.Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME(R) trial. The effect of empagliflozin was consistent in patients with and without HF at baseline and across subgroups with different glucose-lowering drugs and HF treatments.15Fitchett D. Zinman B. Wanner C. et al.Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME(R) trial. Moreover, in patients without HF at baseline, empagliflozin consistently reduced the risk of cardiovascular death and HHF irrespective of their baseline HF risk.16Fitchett D. Butler J. van de Borne P. et al.Effects of empagliflozin on risk for cardiovascular death and heart failure hospitalization across the spectrum of heart failure risk in the EMPA-REG OUTCOME(R) trial. In a post hoc analysis of the 221 patients who experienced at least one HHF after randomization in EMPA-REG OUTCOME, the number of adjudicated clinical events (second events of HF rehospitalization, HF rehospitalization or cardiovascular death, HF rehospitalization or all-cause death) within 30, 45, 60, and 90 days from the admission date of first HHF were compared in the empagliflozin (126 patients) versus placebo (95 patients) groups.17Savarese G. Sattar N. Januzzi J. et al.Empagliflozin is associated with a lower risk of post-acute heart failure rehospitalization and mortality. After 30 days, the rates of readmission were nearly two-fold higher in patients who received placebo compared with empagliflozin.17Savarese G. Sattar N. Januzzi J. et al.Empagliflozin is associated with a lower risk of post-acute heart failure rehospitalization and mortality. Essentially, empagliflozin emerged as a potential treatment of HF, because its effect was in the same magnitude of that of established HF treatment (eg, enalapril and eplerenone).18Zannad F. McMurray J.J. Krum H. et al.Eplerenone in patients with systolic heart failure and mild symptoms.,19Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS).

Table 3Summary results of cardiovascular outcomes in cardiovascular outcome trials on sodium-glucose cotransporter 2 inhibitors

Points estimates are hazard ratio (95% confidence interval).

Abbreviations: 3P-MACE, three-point major adverse cardiovascular events (ie, a composite of myocardial infarction, stroke, or cardiovascular death); CANVAS, CANagliflozin cardioVascular Assessment Study; CREDENCE, canagliflozin and renal events in diabetes with established nephropathy clinical evaluation; CV, cardiovascular; DECLARE-TIMI 58, Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58; EMPA-REG OUTCOME, empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes; HHF, hospitalization for heart failure; VERTIS-CV, eValuation of ERTugliflozin effIcacy and Safety CardioVascular outcomes trial.

In the Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) trial, where 17,160 patients with T2DM and with or at risk of atherosclerotic CVD (ASCVD) were randomized to dapagliflozin or placebo on top of standard therapy, dapagliflozin was not superior to placebo as regards 3P-MACE (HR, 0.93; 95% CI, 0.84–1.03), but the risk of the coprimary outcome of cardiovascular death or HHF was significantly reduced in the dapagliflozin group, driven mainly by a 27% reduction in risk of HHF.20Wiviott S.D. Raz I. Bonaca M.P. et al.Dapagliflozin and cardiovascular outcomes in type 2 diabetes. The effect of dapagliflozin on this composite outcome was greater in patients with a previous myocardial infarction, in patients with higher levels of N-terminal pro–brain natriuretic peptide and high-sensitivity troponin T, but independent of T2DM duration.21Furtado R.H.M. Bonaca M.P. Raz I. et al.Dapagliflozin and cardiovascular outcomes in patients with type 2 diabetes mellitus and previous myocardial infarction., 22Zelniker T.A. Morrow D.A. Mosenzon O. et al.Relationship between baseline cardiac biomarkers and cardiovascular death or hospitalization for heart failure with and without sodium-glucose co-transporter 2 inhibitor therapy in DECLARE-TIMI 58., 23Bajaj H.S. Raz I. Mosenzon O. et al.Cardiovascular and renal benefits of dapagliflozin in patients with short and long-standing type 2 diabetes: analysis from the DECLARE-TIMI 58 trial. As regards baseline HF status, the risk reduction in HHF conferred by dapagliflozin treatment was consistent in patients with and without prior HF, but the risk of cardiovascular death was reduced only in patients with HF with reduced ejection fraction.24Kato E.T. Silverman M.G. Mosenzon O. et al.Effect of dapagliflozin on heart failure and mortality in type 2 diabetes mellitus.Canagliflozin was tested in the CANagliflozin cardioVascular Assessment Study (CANVAS) Programme, a combined analysis of two double-blind placebo-controlled trials enrolling a total of 10,142 patients with T2DM who were randomized to canagliflozin versus placebo on top of optimal medical care.25Neal B. Perkovic V. Mahaffey K.W. et al.Canagliflozin and cardiovascular and renal events in type 2 diabetes. Among them, 66% had established CVD and 34% had high cardiovascular risk.26Mahaffey K.W. Jardine M.J. Bompoint S. et al.Canagliflozin and cardiovascular and renal outcomes in type 2 diabetes mellitus and chronic kidney disease in primary and secondary cardiovascular prevention groups. Canagliflozin was superior to placebo, significantly reducing the risk of 3P-MACE by 14%, and the risk of HHF by 33%.26Mahaffey K.W. Jardine M.J. Bompoint S. et al.Canagliflozin and cardiovascular and renal outcomes in type 2 diabetes mellitus and chronic kidney disease in primary and secondary cardiovascular prevention groups. A post hoc analysis suggested that the benefit of canagliflozin on cardiovascular death or HHF may be greater in patients with a history of HF (HR, 0.61; 95% CI, 0.46–0.80), who constituted 14% of the whole trial population, compared with those without HF at baseline (HR, 0.87; 95% CI, 0.72–1.06; P value for interaction 0.021), with no additional safety concerns.27Radholm K. Figtree G. Perkovic V. et al.Canagliflozin and heart failure in type 2 diabetes mellitus: results from the CANVAS Program. The efficacy of canagliflozin was consistent across different body mass index strata28Ohkuma T. Van Gaal L. Shaw W. et al.Clinical outcomes with canagliflozin according to baseline body mass index: results from post hoc analyses of the CANVAS Program. and renal function.29Neuen B.L. Ohkuma T. Neal B. et al.Cardiovascular and renal outcomes with canagliflozin according to baseline kidney function.In parallel, the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial was conducted in patients with T2DM and chronic kidney disease: 4401 patients with T2DM with an estimated glomerular filtration rate ranging from 30 to 90 mL/min/1.73 m2 were randomized to either canagliflozin or placebo on top of angiotensin-converting enzyme inhibitors.30Perkovic V. Jardine M.J. Neal B. et al.Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. The primary outcome was a composite of sustained (at least 30 days) doubling of serum creatinine, end-stage kidney disease, and death from renal or cardiovascular causes. The relative risk of the primary outcome was reduced by 30% in the canagliflozin group compared with placebo.30Perkovic V. Jardine M.J. Neal B. et al.Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. Patients who received canagliflozin also had a lower risk of cardiovascular death, myocardial infarction, or stroke (HR, 0.80; 95% CI, 0.67–0.95) and HHF (HR, 0.61; 95% CI, 0.47–0.80). Results of the CREDENCE trial were also examined by baseline hemoglobin A1c (HbA1c), reporting that the benefit of canagliflozin on the primary outcome was consistent across HbA1c categories, even in those with levels lower than 7%, with no signals of increased serious adverse events.31Cannon C.P. Perkovic V. Agarwal R. et al.Evaluating the effects of canagliflozin on cardiovascular and renal events in patients with type 2 diabetes mellitus and chronic kidney disease according to baseline HbA1c, including those with HbA1c In the eValuation of ERTugliflozin effIcacy and Safety CardioVascular outcomes trial (VERTIS-CV) trial, where 8246 patients with T2DM and ASCVD were randomized to ertugliflozin versus placebo, ertugliflozin was noninferior, but not superior, to placebo as regards the effect on 3P-MACE (HR, 0.97; 95.6% CI, 0.85–1.11) and on the time to first HHF/cardiovascular death (HR, 0.88; 95.8% CI, 0.75–1.03).32Cannon C.P. Pratley R. Dagogo-Jack S. et al.Cardiovascular outcomes with ertugliflozin in type 2 diabetes. However, a prespecified analysis reported that ertugliflozin significantly reduced total HF-related events (ie, including first and recurrent events), by 30% and total HHF/cardiovascular death by 17%, regardless of presence of HF at baseline and of ejection fraction values.33Cosentino F. Cannon C.P. Cherney D.Z.I. et al.Efficacy of ertugliflozin on heart failure-related events in patients with type 2 diabetes mellitus and established atherosclerotic cardiovascular disease: results of the VERTIS CV Trial. Because VERTIS-CV included a higher proportion of patients with HF history at baseline (24%) compared with the other SGLT2i CVOTs, these results offered a particularly accurate insight of the total HF burden.33Cosentino F. Cannon C.P. Cherney D.Z.I. et al.Efficacy of ertugliflozin on heart failure-related events in patients with type 2 diabetes mellitus and established atherosclerotic cardiovascular disease: results of the VERTIS CV Trial.Finally, a meta-analysis of pooled data from the reported CVOTs showed that SGLT2i reduce the risk of 3P-MACE by a modest 10% (HR, 0.90; 95% CI, 0.85–0.95), being demonstrated within trials for empagliflozin and canagliflozin only.34McGuire D.K. Shih W.J. Cosentino F. et al.Association of SGLT2 inhibitors with cardiovascular and kidney outcomes in patients with type 2 diabetes: a meta-analysis. As regards cardiovascular death, the overall significant reduction offered by SGLT2i in patients with T2DM is of 15%, but only empagliflozin demonstrated significant outcomes for cardiovascular death risk reduction and the heterogeneity was 64%.34McGuire D.K. Shih W.J. Cosentino F. et al.Association of SGLT2 inhibitors with cardiovascular and kidney outcomes in patients with type 2 diabetes: a meta-analysis. However, the most consistent effect of SGLT2i across trials was that on HHF, with a 32% relative risk reduction (HR, 0.68; 95% CI, 0.61–0.76) and no heterogeneity (Fig. 1).34McGuire D.K. Shih W.J. Cosentino F. et al.Association of SGLT2 inhibitors with cardiovascular and kidney outcomes in patients with type 2 diabetes: a meta-analysis. There was no significant interaction between the use of SGLT2i and the presence of ASCVD and/or HF at baseline.34McGuire D.K. Shih W.J. Cosentino F. et al.Association of SGLT2 inhibitors with cardiovascular and kidney outcomes in patients with type 2 diabetes: a meta-analysis.

Fig. 1Incidence rates of heart failure hospitalization in the treatment and placebo groups in each trial. CANVAS, CANagliflozin cardioVascular Assessment Study; CREDENCE, Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation; DECLARE-TIMI 58, Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58; EMPA-REG OUTCOME, Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes; VERTIS-CV, eValuation of ERTugliflozin effIcacy and Safety CardioVascular outcomes trial.

More recently, efficacy and safety of the SGLT2/SGLT1i sotagliflozin was tested against placebo in the Sotagliflozin on Cardiovascular Events in Patients with Type 2 Diabetes Post Worsening Heart Failure (SOLOIST-WHF) trial, including 1222 patients with T2DM and a recent hospitalization for worsening HF.35Bhatt D.L. Szarek M. Steg P.G. et al.Sotagliflozin in patients with diabetes and recent worsening heart failure. Despite the trial being terminated early because of the COVID-19 pandemic, sotagliflozin significantly reduced the occurrence of the primary end point of HHF/urgent visits for HF and cardiovascular death (first and subsequent events) compared with placebo (51.0 vs 76.3 per 100 patient-years; HR, 0.67; 95% CI, 0.52–0.85).35Bhatt D.L. Szarek M. Steg P.G. et al.Sotagliflozin in patients with diabetes and recent worsening heart failure. Importantly, in SOLOIST, the first dose of the trial product was administered before hospital discharge or after a median of 2 days following discharge, supporting the safety of early initiation of SGLT2i in patients with HF.35Bhatt D.L. Szarek M. Steg P.G. et al.Sotagliflozin in patients with diabetes and recent worsening heart failure. The benefit of sotagliflozin was evident for all patients regardless of their ejection fraction, even though the small sample size of the subgroup with heart failure with preserved ejection fraction limits the finding on this subgroup.35Bhatt D.L. Szarek M. Steg P.G. et al.Sotagliflozin in patients with diabetes and recent worsening heart failure. Sotagliflozin was also tested in the Sotagliflozin on Cardiovascular and Renal Events in Patients with Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk (SCORED) trial, enrolling 10,540 patients with T2DM and chronic kidney disease (25–60 mL/min/1.73 m2).36Bhatt D.L. Szarek M. Pitt B. et al.Sotagliflozin in patients with diabetes and chronic kidney disease. Sotagliflozin reduced the primary end point (ie, the composite of the total number of deaths from cardiovascular causes, HHF, and urgent HF visits) by 26% (HR, 0.74; 95% CI, 0.63–0.88); however, in the sotagliflozin group adverse events including diarrhea, genital mycotic infections, volume depletion, and diabetic ketoacidosis were more common.36Bhatt D.L. Szarek M. Pitt B. et al.Sotagliflozin in patients with diabetes and chronic kidney disease.

Taken together, these results paved the way for designing future trials to specifically assess the outcomes in patients with HF, regardless of the presence of T2DM.

The supporting results from real-world observationsThe first large observational study looking into the association between SGLT2i and HF outcomes in patients with T2DM was the Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors (CVD-REAL), collecting data from the United States, Sweden, Denmark, Norway, Germany, and the United Kingdom from 2012 to 2013. In this study, new users of empagliflozin, canagliflozin, and dapagliflozin were compared with other glucose-lowering drugs, for a total of 309,056 patients.37Kosiborod M. Cavender M.A. Fu A.Z. et al.Lower risk of heart failure and death in patients initiated on sodium-glucose cotransporter-2 inhibitors versus other glucose-lowering drugs: the CVD-REAL Study (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors). SGLT2i were associated with a lower risk of HHF (HR, 0.61; 95% CI, 0.51–0.73) and all-cause death (HR, 0.49; 95% CI, 0.41–0.57) compared with other antihyperglycemic medications.37Kosiborod M. Cavender M.A. Fu A.Z. et al.Lower risk of heart failure and death in patients initiated on sodium-glucose cotransporter-2 inhibitors versus other glucose-lowering drugs: the CVD-REAL Study (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors). The relative risks for HHF and death associated with SGLT2i use were similar in the two subgroups with and without established ASCVD, representing 13% and 87% of the study population, respectively.38Cavender M.A. Norhammar A. Birkeland K.I. et al.SGLT-2 inhibitors and cardiovascular risk: an analysis of CVD-REAL. However, the absolute event rates for HHF differed substantially, being higher in patients with established CVD at baseline (2.3/100 patient-years for SGLT2i users vs 3.2/100 patient-years for other glucose-lowering drugs) than in patients without established CVD (0.1/100 patient-years in those on SGLT2 inhibitors vs 0.9/100 patient-years for those on other glucose-lowering drugs).38Cavender M.A. Norhammar A. Birkeland K.I. et al.SGLT-2 inhibitors and cardiovascular risk: an analysis of CVD-REAL. This led to speculate that the number needed to treat in future randomized trials on HF outcomes in high-risk patients would be considerably lower in a patient population with established CVD at baseline, including history of HF; as mentioned, this was subsequently confirmed by the results of EMPA-REG OUTCOME. Moreover, the early divergence of the Kaplan-Meier curves for HHF and cardiovascular death in the previously mentioned CVOTs suggested a short duration of trials designated ad hoc for HF outcomes.In EMPRISE, a large observational study conducted in the United States, empagliflozin was associated with a decreased risk of HHF by 50% (HR, 0.50; 95% CI, 0.28–0.91) compared with sitagliptin.39Ryan P.B. Buse J.B. Schuemie M.J. et al.Comparative effectiveness of canagliflozin, SGLT2 inhibitors and non-SGLT2 inhibitors on the risk of hospitalization for heart failure and amputation in patients with type 2 diabetes mellitus: a real-world meta-analysis of 4 observational databases (OBSERVE-4D). Accordingly, in a real-world meta-analysis of four observational databases from the United States canagliflozin therapy was associated with a lower risk of HHF compared with other glucose-lowering agents, with an HR of 0.39 (95% CI, 0.26–0.60).39Ryan P.B. Buse J.B. Schuemie M.J. et al.Comparative effectiveness of canagliflozin, SGLT2 inhibitors and non-SGLT2 inhibitors on the risk of hospitalization for heart failure and amputation in patients with type 2 diabetes mellitus: a real-world meta-analysis of 4 observational databases (OBSERVE-4D). SGLT2i use in patients with T2DM was associated with a 30% lower risk of first HHF and cardiovascular death in the Swedish HF registry, consistently across ejection fraction and renal function, in patients with and without baseline metformin treatment.40Becher P.M. Schrage B. Ferrannini G. et al.Use of sodium-glucose co-transporter 2 inhibitors in patients with heart failure and type 2 diabetes mellitus: data from the Swedish Heart Failure Registry.From bedside to bench: mechanisms of action of SGLT2iSGLT2i have a simple pharmacodynamic: by blocking sodium-glucose reabsorption in the proximal renal tubule of patients with T2DM, their use leads to increased renal glucose excretion and lower plasma glucose levels, and thus to HbA1c and glucotoxicity reduction.41Cardiovascular effects of new oral glucose-lowering agents: DPP-4 and SGLT-2 inhibitors., 42Monami M. Liistro F. Scatena A. Nreu B. Mannucci E. Short and medium-term efficacy of sodium glucose co-transporter-2 (SGLT-2) inhibitors: a meta-analysis of randomized clinical trials., 43SGLT2 inhibitors: mechanisms of cardiovascular benefit beyond glycaemic control. An overall improvement of the cardiovascular risk factor profile, including weight loss, fat mass reduction, lowering of blood pressure and arterial stiffness, and improvements in endothelial dysfunction, inflammation, and oxidative stress were initially studied.44Sodium-glucose transporter 2 inhibition and cardiovascular events in patients with diabetes: information from clinical trials and observational real-world data., 45SGLT2 inhibition in diabetes mellitus: rationale and clinical prospects., 46Heerspink H.J. Perkins B.A. Fitchett D.H. Husain M. Cherney D.Z. Sodium glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus: cardiovascular and kidney effects, potential mechanisms, and clinical applications., 47Ridderstråle M. Andersen K.R. Zeller C. Kim G. Woerle H.J. Broedl U.C. Comparison of empagliflozin and glimepiride as add-on to metformin in patients with type 2 diabetes: a 104-week randomised, active-controlled, double-blind, phase 3 trial., 48Baker W.L. Smyth L.R. Riche D.M. Bourret E.M. Chamberlin K.W. White W.B. Effects of sodium-glucose co-transporter 2 inhibitors on blood pressure: a systematic review and meta-analysis. As regards the hemodynamic effects induced by SGLT2i, the volume depletion does not activate the renin-angiotensin-aldosterone system or the sympathetic nervous system49Griffin M. Rao V.S. Ivey-Miranda J. et al.Empagliflozin in heart failure: diuretic and cardiorenal effects.; this is probably caused by the absence of change in intravascular volume, which is normally responsible for the deleterious neurohormonal activation.49Griffin M. Rao V.S. Ivey-Miranda J. et al.Empagliflozin in heart failure: diuretic and cardiorenal effects.,50Jensen J. Omar M. Kistorp C. et al.Effects of empagliflozin on estimated extracellular volume, estimated plasma volume, and measured glomerular filtration rate in patients with heart failure (Empire HF Renal): a prespecified substudy of a double-blind, randomised, placebo-controlled trial. As a result, SGLT2i likely exert a diuretic effect while also causing an efficient body fluid redistribution, reducing cardiac preload.51SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review.Hemoconcentration emerged as a principal mechanism of the SGLT2i benefit from the EMPA-REG OUTCOME trial: the relative increase in hematocrit was 12% and changes in hematocrit and hemoglobin explained 52% and 49%, respectively, of the reduction of cardiovascular death seen with empagliflozin compared with placebo, reflecting the hemoconcentration and possibly a direct increase in erythropoietin secretion.52Inzucchi S.E. Zinman B. Wanner C. et al.SGLT-2 inhibitors and cardiovascular risk: proposed pathways and review of ongoing outcome trials., 53Ferrannini E. Baldi S. Frascerra S. et al.Shift to fatty substrate utilization in response to sodium-glucose cotransporter 2 inhibition in subjects without diabetes and patients with type 2 diabetes.,