Preventing and Treating Heart Failure with Sodium-Glucose Co-Transporter 2 Inhibitors
2019; Elsevier BV; Volume: 124; Linguagem: Inglês
10.1016/j.amjcard.2019.10.026
ISSN1879-1913
AutoresMuthiah Vaduganathan, James L. Januzzi,
Tópico(s)Metabolism, Diabetes, and Cancer
ResumoHeart failure is a common complication among patients with type 2 diabetes mellitus and is associated with significantly increased risks of subsequent morbidity and mortality. Until recently, therapies and strategies were lacking to attenuate this excess risk of heart failure in this population. Sodium-glucose co-transporter 2 (SGLT2) inhibitors represent a unique class of glucose-lowering therapies that have multisystem health benefits. Three large cardiovascular outcomes trials have demonstrated consistent reductions in heart failure events among patients with type 2 diabetes mellitus with, or at risk for, atherosclerotic cardiovascular disease. Another trial recently showed that an SGLT2 inhibitor, canagliflozin, also significantly reduced heart failure events among patients with type 2 diabetes mellitus and albuminuric chronic kidney disease. The SGLT2 inhibitor class represents an important new therapeutic approach for the prevention of heart failure in at-risk patients with type 2 diabetes mellitus, and is actively being studied for use in treating patients with heart failure (with or without type 2 diabetes mellitus).(Supplementary video “Preventing and Treating Heart Failure with Sodium-Glucose Co-Transporter 2 Inhibitors” is available online.) Heart failure is a common complication among patients with type 2 diabetes mellitus and is associated with significantly increased risks of subsequent morbidity and mortality. Until recently, therapies and strategies were lacking to attenuate this excess risk of heart failure in this population. Sodium-glucose co-transporter 2 (SGLT2) inhibitors represent a unique class of glucose-lowering therapies that have multisystem health benefits. Three large cardiovascular outcomes trials have demonstrated consistent reductions in heart failure events among patients with type 2 diabetes mellitus with, or at risk for, atherosclerotic cardiovascular disease. Another trial recently showed that an SGLT2 inhibitor, canagliflozin, also significantly reduced heart failure events among patients with type 2 diabetes mellitus and albuminuric chronic kidney disease. The SGLT2 inhibitor class represents an important new therapeutic approach for the prevention of heart failure in at-risk patients with type 2 diabetes mellitus, and is actively being studied for use in treating patients with heart failure (with or without type 2 diabetes mellitus). (Supplementary video “Preventing and Treating Heart Failure with Sodium-Glucose Co-Transporter 2 Inhibitors” is available online.) The burden of type 2 diabetes mellitus is rising rapidly worldwide, related to increasing rates and suboptimal control of cardiometabolic risk factors, including obesity.1NCD Risk Factor Collaboration (NCD-RisC)Worldwide trends in diabetes since 1980: a pooled analysis of 751 population-based studies with 4.4 million participants.Lancet. 2016; 387: 1513-1530Google Scholar An expanding and aging global population has led to quadrupling of the prevalence of diabetes.1NCD Risk Factor Collaboration (NCD-RisC)Worldwide trends in diabetes since 1980: a pooled analysis of 751 population-based studies with 4.4 million participants.Lancet. 2016; 387: 1513-1530Google Scholar The associated global economic costs required in the care of type 2 diabetes mellitus are substantial and projected to increase over the next decade.2Bommer C. Sagalova V. Heesemann E. et al.Global economic burden of diabetes in adults: projections from 2015 to 2030.Diabetes Care. 2018; 41: 963-970Google Scholar Glycemic control and prevention of microvascular complications (eg, nephropathy, neuropathy, retinopathy) have been traditional goals of glucose-lowering therapy in patients with type 2 diabetes mellitus, and the predominant focus of clinical practice guidelines.3American Diabetes Association 8. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes-2018.Diabetes Care. 2018; 41: S73-S85Google Scholar Tight glycemic control has not previously translated to early improvement in macrovascular outcomes (eg, acute myocardial infarction, stroke, or cardiovascular death), and until recently, no therapy for type 2 diabetes mellitus has clearly improved heart failure outcomes. In 2008, following concerns of potential excess cardiovascular risk with thiazolidinediones, the US Food and Drug Administration (FDA) issued a guidance to industry requiring that dedicated cardiovascular outcomes trials (CVOTs) be performed to exclude significant cardiovascular risk of established and emerging glucose-lowering therapies.5Greene S.J. Vaduganathan M. Khan M.S. et al.Prevalent and incident heart failure in cardiovascular outcome trials of patients with type 2 diabetes.J Am Coll Cardiol. 2018; 71: 1379-1390Google Scholar In the last decade, more than 20 large-scale CVOTs enrolling more than 150,000 randomized patients have been conducted (Figure 1).4Vijayakumar S. Vaduganathan M. Butler J. Glucose-lowering therapies and heart failure in type 2 diabetes mellitus: mechanistic links, clinical data, and future directions.Circulation. 2018; 137: 1060-1073Google Scholar Nearly all these clinical trial programs have studied a primary endpoint of major adverse cardiovascular events (MACE), namely nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death; heart failure has infrequently been included as a primary or secondary clinical endpoint in CVOTs.4Vijayakumar S. Vaduganathan M. Butler J. Glucose-lowering therapies and heart failure in type 2 diabetes mellitus: mechanistic links, clinical data, and future directions.Circulation. 2018; 137: 1060-1073Google Scholar In this review, we discuss the central importance of heart failure as a therapeutic endpoint in type 2 diabetes mellitus care, particularly in the context of the sodium-glucose co-transporter 2 (SGLT2) inhibitor class of glucose-lowering therapies. The diagnoses of type 2 diabetes mellitus and heart failure are inextricably linked in a number of ways, and several converging lines of data suggest that dedicated therapeutic approaches are needed in the prevention and treatment of heart failure in type 2 diabetes mellitus.6Greene S.J. Butler J. Primary prevention of heart failure in patients with type 2 diabetes mellitus.Circulation. 2019; 139: 152-154Google Scholar Patients with type 2 diabetes mellitus have a heightened risk for development of heart failure; this may be a consequence of pathogenic inputs that contribute to development of diabetic cardiomyopathy with dysregulated oxidative metabolism,7Taylor M. Wallhaus T.R. Degrado T.R. et al.An evaluation of myocardial fatty acid and glucose uptake using PET with [18F]fluoro-6-thia-heptadecanoic acid and [18F]FDG in patients with congestive heart failure.J Nucl Med. 2001; 42: 55-62Google Scholar independent of traditional atherosclerotic cardiovascular disease (ASCVD). Even beyond this, however, patients with type 2 diabetes mellitus experience residual risks of heart failure despite adequate control of traditional risk factors; the population-attributable risk for heart failure related to type 2 diabetes mellitus is substantial, even beyond the presence of hypertension, coronary artery disease, or other cardiometabolic risk factors.8Avery C.L. Loehr L.R. Baggett C. et al.The population burden of heart failure attributable to modifiable risk factors: the ARIC (Atherosclerosis Risk in Communities) study.J Am Coll Cardiol. 2012; 60: 1640-1646Google Scholar Given these considerations, heart failure has become increasingly recognized as a frequent and clinically relevant event; in fact, heart failure may represent the index cardiovascular event for many patients.9McAllister D.A. Read S. Kerssens J. et al.Incidence of hospitalisation for heart failure and case-fatality among 3.25 million people with and without diabetes.Circulation. 2018; 138: 2774-2786Google Scholar When heart failure develops in patients with type 2 diabetes mellitus, it represents a perturbational event. Patients with type 2 diabetes mellitus complicated by heart failure experience markedly higher rates of mortality after disease onset and progression.10Rawshani A. Rawshani A. Franzen S. et al.Mortality and cardiovascular disease in type 1 and type 2 diabetes.N Engl J Med. 2017; 376: 1407-1418Google Scholar In contrast, patients with type 2 diabetes mellitus with optimal control of risk factors experience risk of ASCVD comparable with the general population.11Rawshani A. Rawshani A. Franzen S. et al.Risk factors, mortality, and cardiovascular outcomes in patients with type 2 diabetes.N Engl J Med. 2018; 379: 633-644Google Scholar As reviewed separately, previous clinical trial programs have identified potentially important safety signals for heart failure events with other glucose-lowering therapies.12Kramer C.K. Ye C. Campbell S. Retnakaran R. Comparison of new glucose-lowering drugs on risk of heart failure in type 2 diabetes: a network meta-analysis.JACC Heart Fail. 2018; 6: 823-830Google Scholar Certain therapies, including the dipeptidyl peptidase-4 inhibitor saxagliptin13Scirica B.M. Braunwald E. Raz I. SAVOR-TIMI Steering Committee Investigators et al.Heart failure, saxagliptin, and diabetes mellitus: observations from the SAVOR-TIMI 53 randomized trial.Circulation. 2014; 130: 1579-1588Google Scholar and the thiazolidinedione class, appear to increase risk of heart failure events. Although there was an imbalance in heart failure events observed in a CVOT of alogliptin compared with placebo, this effect did not reach statistical significance.14Zannad F. Cannon C.P. Cushman W.C. EXAMINE Investigators et al.Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: a multicentre, randomised, double-blind trial.Lancet. 2015; 385: 2067-2076Google Scholar Other dipeptidyl peptidase-4 inhibitors have not similarly demonstrated heightened risk of heart failure, reinforcing the importance of rigorous evaluation of risks and benefits related to heart failure across therapeutic classes and drugs within classes. The glucagon-like peptide-1 receptor agonists do not appear to influence, or only modestly reduce, risk of heart failure, despite relatively consistent therapeutic benefits on atherosclerotic cardiovascular events.15Zelniker T.A. Wiviott S.D. Raz I. et al.Comparison of the effects of glucagon-like peptide receptor agonists and sodium-glucose co-transporter 2 inhibitors for prevention of major adverse cardiovascular and renal outcomes in type 2 diabetes mellitus: a systematic review and meta-analysis of cardiovascular outcomes trials.Circulation. 2019; 139: 2022-2031Google Scholar SGLT2 inhibitors are a class of glucose-lowering therapies that inhibit proximal renal tubular sodium and glucose reabsorption. Four SGLT2 inhibitors (canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin) have been approved for use in the United States for their modest glycemic control potential. In addition, this class of therapy has been recognized to have multisystem health benefits.16Nassif M. Kosiborod M. Effect of glucose-lowering therapies on heart failure.Nat Rev Cardiol. 2018; 15: 282-291Google Scholar, 17Vallon V. Thomson S.C. Targeting renal glucose reabsorption to treat hyperglycaemia: the pleiotropic effects of SGLT2 inhibition.Diabetologia. 2017; 60: 215-225Google Scholar Posited mechanisms of observed heart failure–related benefits may be associated with natriuretic, glucoretic, and hemodynamic properties (via inhibition of sodium-hydrogen exchanger [NHE] 3); attenuation of renal function progression; and favorable effects on adverse myocardial remodeling (via inhibition of NHE1) (Figure 2).18Packer M. Anker S.D. Butler J. Filippatos G. Zannad F. Effects of sodium-glucose cotransporter 2 inhibitors for the treatment of patients with heart failure: proposal of a novel mechanism of action.JAMA Cardiol. 2017; 2: 1025-1029Google Scholar, 19Verma S. McMurray J.J.V. Cherney D.Z.I. The metabolodiuretic promise of sodium-dependent glucose cotransporter 2 inhibition: the search for the sweet spot in heart failure.JAMA Cardiol. 2017; 2: 939-940Google Scholar The modest incremental improvement in glycemic control afforded by SGLT2 inhibitors is believed unlikely to account for their robust therapeutic benefits in reducing heart failure events. A prior meta-analysis of more than 37,000 patients found that intensive glycemic control was not associated with lower risk of heart failure events compared with a standard glycemic control strategy.20Castagno D. Baird-Gunning J. Jhund P.S. et al.Intensive glycemic control has no impact on the risk of heart failure in type 2 diabetic patients: evidence from a 37,229 patient meta-analysis.Am Heart J. 2011; 162: 938-948Google Scholar In an exploratory analysis of the Empagliflozin Removal of Excess Glucose: Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME), metrics of glycemic status were demonstrated to mediate only a small portion of observed benefits of empagliflozin on cardiovascular death.21Inzucchi S.E. Zinman B. Fitchett D. et al.How does empagliflozin reduce cardiovascular mortality? Insights from a mediation analysis of the EMPA-REG OUTCOME trial.Diabetes Care. 2018; 41: 356-363Google Scholar Notably, therapy with SGLT2 inhibitors among patients without established cardiovascular disease seemed to result in lower concentrations of natriuretic peptides and troponin at 6 months, 1 year, and 2 years compared with placebo, implying direct or indirect cardiovascular benefits.22Januzzi Jr., J.L. Butler J. Jarolim P. et al.Effects of canagliflozin on cardiovascular biomarkers in older adults with type 2 diabetes.J Am Coll Cardiol. 2017; 70: 704-712Google Scholar Following several large CVOTs, 3 SGLT2 inhibitors have been shown to reduce the risk of cardiovascular events, including heart failure, in patients with type 2 diabetes mellitus with established cardiovascular disease or cardiovascular risk factors.23Zinman B. Wanner C. Lachin J.M. EMPA-REG OUTCOME Investigators et al.Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.N Engl J Med. 2015; 373: 2117-2128Google Scholar, 24Neal B. Perkovic V. Mahaffey K.W. et al.CANVAS Program Collaborative GroupCanagliflozin and cardiovascular and renal events in type 2 diabetes.N Engl J Med. 2017; 377: 644-657Google Scholar, 25Wiviott S.D. Raz I. Bonaca M.P. DECLARE-TIMI Investigators et al.Dapagliflozin and cardiovascular outcomes in type 2 diabetes.N Engl J Med. 2019; 380: 347-357Google Scholar Based on these composite data, the SGLT2 inhibitor class is now recommended as preferred add-on therapy to metformin in patients with type 2 diabetes mellitus and cardiovascular disease.26Davies M.J. D'Alessio D.A. Fradkin J. et al.Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).Diabetes Care. 2018; 41: 2669-2701Google Scholar, 27Das S.R. Everett B.M. Birtcher K.K. et al.2018 ACC expert consensus decision pathway on novel therapies for cardiovascular risk reduction in patients with type 2 diabetes and atherosclerotic cardiovascular disease: a report of the American College of Cardiology task force on expert consensus decision pathways.J Am Coll Cardiol. 2018; 72: 3200-3223Google Scholar The FDA has also broadened the regulatory labels for empagliflozin (in reducing cardiovascular death) and canagliflozin (in reducing MACE). These data from the cardiovascular safety programs have generated intense and broad interest among clinicians, clinical trialists, industry sponsors, and regulators in exploring SGLT2 inhibitors as a therapeutic strategy in heart failure prevention and, potentially, heart failure treatment. The marked and consistent reduction in heart failure events with SGLT2 inhibitors across each of the large phase 3 CVOTs was unexpected by the endocrinology and cardiology communities. As these trials were all initially designed to exclude significant risk of ASCVD, the aforementioned 3-point MACE (3P-MACE) was the initial primary endpoint designated in all 4 large-scale safety programs. Hospitalization for heart failure (HHF) was a secondary or exploratory endpoint in each of these trials; none of the earlier studies were designed to gather rigorous data about prevalent heart failure at the time of enrollment, and to date, no biomarker data about frequency of elevated natriuretic peptide concentrations at baseline are available from any CVOT. Given the apparent signal for efficacy in the parallel CVOT programs of empagliflozin and canagliflozin, the Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58 study (DECLARE-TIMI 58)25Wiviott S.D. Raz I. Bonaca M.P. DECLARE-TIMI Investigators et al.Dapagliflozin and cardiovascular outcomes in type 2 diabetes.N Engl J Med. 2019; 380: 347-357Google Scholar adapted their primary objective during the course of the trial to test a co-primary endpoint of MACE and composite cardiovascular death or HHF. As such, DECLARE-TIMI 58 was the first CVOT of SGLT2 inhibitors to evaluate a primary endpoint inclusive of a heart failure event.25Wiviott S.D. Raz I. Bonaca M.P. DECLARE-TIMI Investigators et al.Dapagliflozin and cardiovascular outcomes in type 2 diabetes.N Engl J Med. 2019; 380: 347-357Google Scholar The overall design and capture of heart failure events in the 4 large CVOTs of SGLT2 inhibitors are outlined in Table 1. The CVOT evaluating ertugliflozin, Evaluation of Ertugliflozin Efficacy and Safety–Cardiovascular Outcomes (VERTIS-CV; NCT01986881) in patients with type 2 diabetes mellitus and established cardiovascular disease, is underway.28Cannon C.P. McGuire D.K. Pratley R. VERTIS-CV Investigators et al.Design and baseline characteristics of the eValuation of ERTugliflozin effIcacy and Safety CardioVascular outcomes trial (VERTIS-CV).Am Heart J. 2018; 206: 11-23Google ScholarTable 1CVOTs Testing Therapeutic Effects of SGLT2 Inhibitors Among Patients with T2DM at High CV RiskHHF Events per 1000 Patient-Years*HHF was variably included as a component of a primary, secondary, or exploratory endpoint across the SGLT2 inhibitor trial programs.HR (95% CI) for HHFTrialRefPublication YearSGLT2 InhibitorNHistory of HF (%)Primary EndpointMedian Follow-Up (Years)SGLT2 Inhibitor ArmPlacebo ArmSGLT2 Inhibitor vs PlaceboEMPA-REG OUTCOME232015Empagliflozin702010.1MACE3.19.414.50.65 (0.50-0.85)CANVAS/CANVAS-R242017Canagliflozin10,14214.4MACE2.45.58.70.67 (0.52-0.87)DECLARE-TIMI 58252019Dapagliflozin17,16010MACE†Co-primary efficacy endpoints adapted during the course of DECLARE-TIMI 58.CV death or HHF†Co-primary efficacy endpoints adapted during the course of DECLARE-TIMI 58.4.26.28.50.73 (0.61-0.88)VERTIS-CV28OngoingErtugliflozin823823.1MACEOngoingCANVAS = Canagliflozin Cardiovascular Assessment Study; CANVAS-R = CANVAS-Renal; CI = confidence interval; CV = cardiovascular; CVOT = CV outcomes trial; DECLARE-TIMI 58 = Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58; HF = heart failure; HHF = hospitalization for HF; HR = hazard ratio; MACE = major adverse CV events; SGLT2 = sodium-glucose co-transporter 2; T2DM = type 2 diabetes mellitus; VERTIS-CV = Evaluation of Ertugliflozin Efficacy and Safety–Cardiovascular Outcomes. HHF was variably included as a component of a primary, secondary, or exploratory endpoint across the SGLT2 inhibitor trial programs.† Co-primary efficacy endpoints adapted during the course of DECLARE-TIMI 58. Open table in a new tab CANVAS = Canagliflozin Cardiovascular Assessment Study; CANVAS-R = CANVAS-Renal; CI = confidence interval; CV = cardiovascular; CVOT = CV outcomes trial; DECLARE-TIMI 58 = Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58; HF = heart failure; HHF = hospitalization for HF; HR = hazard ratio; MACE = major adverse CV events; SGLT2 = sodium-glucose co-transporter 2; T2DM = type 2 diabetes mellitus; VERTIS-CV = Evaluation of Ertugliflozin Efficacy and Safety–Cardiovascular Outcomes. EMPA-REG OUTCOME23Zinman B. Wanner C. Lachin J.M. EMPA-REG OUTCOME Investigators et al.Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.N Engl J Med. 2015; 373: 2117-2128Google Scholar was the first of the SGLT2 inhibitor CVOTs to report, and tested 2 doses of empagliflozin (10 mg or 25 mg administered once daily) compared with placebo among patients with type 2 diabetes mellitus and established cardiovascular disease. Given limited dose-related heterogeneity in therapeutic effects, the dosing arms were pooled for analytic purposes. Empagliflozin significantly reduced risk of 3P-MACE (the primary endpoint), cardiovascular death, all-cause mortality, and HHF compared with placebo.23Zinman B. Wanner C. Lachin J.M. EMPA-REG OUTCOME Investigators et al.Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.N Engl J Med. 2015; 373: 2117-2128Google Scholar The definition of the heart failure event was broadened to include initiation or up-titration of diuretics (either oral or intravenous) during overnight stays, emergency department visits, or inpatient hospitalizations. Subsequent analyses from EMPA-REG OUTCOME showed consistent effects of empagliflozin on heart failure events in patients with or without a baseline history of heart failure.29Fitchett D. Zinman B. Wanner C. EMPA-REG OUTCOME Trial Investigators et al.Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME® trial.Eur Heart J. 2016; 37: 1526-1534Google Scholar, 30Januzzi J. Ferreira J.P. Bohm M. et al.Empagliflozin reduces the risk of a broad spectrum of heart failure outcomes regardless of heart failure status at baseline.Eur J Heart Fail. 2019; 21: 386-388Google Scholar Additionally, the treatment benefits of empagliflozin among patients without a history of heart failure were apparent across a broad range of risk of incident heart failure, estimated based on the 9-variable Health, Aging and Body Composition (Health ABC) Risk Score.31Fitchett D. Butler J. van de Borne P. EMPA-REG OUTCOME Trial Investigators 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® trial.Eur Heart J. 2018; 39: 363-370Google Scholar The initial Canagliflozin Cardiovascular Assessment Study (CANVAS) evaluating canagliflozin was initiated in 2009, and like EMPA-REG OUTCOME, used interim data to support its initial FDA approval in 2013.24Neal B. Perkovic V. Mahaffey K.W. et al.CANVAS Program Collaborative GroupCanagliflozin and cardiovascular and renal events in type 2 diabetes.N Engl J Med. 2017; 377: 644-657Google Scholar However, the trial was not powered to test superiority of canagliflozin; thus, the second CANVAS-Renal CVOT was designed and carried out in 2014 to be analyzed in integrated fashion with the original trial. The paired CANVAS trials evaluated patients with type 2 diabetes mellitus with established cardiovascular disease (~65%) or at high cardiovascular risk due to multiple risk factors (~35%). Canagliflozin was shown to reduce the risk of the primary endpoint of 3P-MACE compared with placebo, but identified a safety signal of increased risk of lower-limb amputation with canagliflozin; this risk has not been seen in other SGLT2 inhibitor CVOTs, and was typically seen in those with preexisting peripheral artery disease, with amputations typically at the level of the toe or forefoot. Composite of cardiovascular death and HHF (an adjudicated secondary endpoint) was lower with canagliflozin, compared with placebo.24Neal B. Perkovic V. Mahaffey K.W. et al.CANVAS Program Collaborative GroupCanagliflozin and cardiovascular and renal events in type 2 diabetes.N Engl J Med. 2017; 377: 644-657Google Scholar Subsequent analyses demonstrated that canagliflozin decreased a number of heart failure outcomes, including HHF alone and composite heart failure–related deaths or hospitalizations. These treatment effects on the secondary endpoint of cardiovascular death or HHF appeared to be significantly greater among patients with a history of heart failure compared with those free from heart failure (P = .021 for interaction).32Radholm K. Figtree G. Perkovic V. et al.Canagliflozin and heart failure in type 2 diabetes mellitus.Circulation. 2018; 138: 458-468Google Scholar DECLARE-TIMI 5825Wiviott S.D. Raz I. Bonaca M.P. DECLARE-TIMI Investigators et al.Dapagliflozin and cardiovascular outcomes in type 2 diabetes.N Engl J Med. 2019; 380: 347-357Google Scholar is one of the largest CVOTs in type 2 diabetes mellitus conducted to date (N = 17,160). The trial also uniquely included a large primary prevention cohort of patients without established cardiovascular disease, but with cardiovascular risk factors (n = 10,186), increasing the generalizability of the study findings. Given the relatively lower baseline cardiovascular risk compared with other trials, DECLARE-TIMI 58 followed patients for a longer period of time (median follow-up 4.2 years). Although dapagliflozin showed no obvious decrease in risk of 3P-MACE (the initially defined primary endpoint) compared with placebo, it did reduce the co-primary endpoint of cardiovascular death or HHF (driven by reductions in HHF). Importantly, amputation risk, which was evaluated in a dedicated core laboratory in the trial, was not observed to increase with dapagliflozin compared with placebo. The treatment benefits of dapagliflozin on cardiovascular death or HHF appeared consistent across a number of tested subgroups, including baseline history of heart failure.25Wiviott S.D. Raz I. Bonaca M.P. DECLARE-TIMI Investigators et al.Dapagliflozin and cardiovascular outcomes in type 2 diabetes.N Engl J Med. 2019; 380: 347-357Google Scholar A recent meta-analysis33Zelniker T.A. Wiviott S.D. Raz I. et al.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: 31-39Google Scholar was performed based on data from these 3 reported CVOTs of SGLT2 inhibitors, encompassing 34,322 patients (60% with established cardiovascular disease) (Figure 3). During the course of the trials, 3342 MACE events and 2028 cardiovascular deaths or HHF events were identified. Interestingly, although the 3 SGLT2 inhibitors reduced MACE by 11%, this benefit was observed only in patients with established cardiovascular disease. In contrast, SGLT2 inhibitors reduced the risk of composite cardiovascular death or HHF by 23%, similarly in patients with or without baseline cardiovascular disease or heart failure. Treatment effects of SGLT2 inhibitors on HHF appeared greatest in patients with chronic kidney disease (CKD) at baseline.33Zelniker T.A. Wiviott S.D. Raz I. et al.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: 31-39Google Scholar VERTIS-CV28Cannon C.P. McGuire D.K. Pratley R. VERTIS-CV Investigators et al.Design and baseline characteristics of the eValuation of ERTugliflozin effIcacy and Safety CardioVascular outcomes trial (VERTIS-CV).Am Heart J. 2018; 206: 11-23Google Scholar is currently underway evaluating the cardiovascular safety of ertugliflozin with respect to 3P-MACE. The trial includes 3 dedicated glycemic substudies that will evaluate the effects of ertugliflozin on glycemic endpoints in the background of other glucose-lowering therapies (insulin ± metformin, sulfonylurea monotherapy, metformin ± sulfonylurea) and prespecified evaluation in patients with stage 3A CKD. Dedicated CVOTs are underway or have recently completed evaluating SGLT2 inhibitors in patients with CKD with or without albuminuria. The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial was the first to report and was recently terminated early due to overwhelming efficacy.34Perkovic V. Jardine M.J. Neal B. CREDENCE Trial Investigators et al.Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.N Engl J Med. 2019; 380: 2295-2306Google Scholar CREDENCE randomized 4401 patients with type 2 diabetes mellitus and CKD (estimated glomerular filtration rate [eGFR] of 30 to <90 mL/min/1.73 m2) with albuminuria being treated with renin-angiotensin-aldosterone system–blocking therapies to receive canagliflozin or placebo. After 2.6 years of median follow-up, canagliflozin reduced the primary composite endpoint (end-stage kidney disease, doubling of serum creatinine level, or death related to renal or cardiovascular causes) by 30% compared with placebo. HHF, an adjudicated secondary endpoint, was reduced by 39% with canagliflozin, compared with placebo. During the trial, after the amputation signal was identified in the CANVAS Program, the CREDENCE protocol was amended in May 2016 to request site investigators to conduct foot examinations during each visit and interrupt therapy in cases of active conditions that may predispose to amputation. Reassuringly, CREDENCE did not demonstrate any between-arm differences in amputation or fracture risk. Despite the tremendous advancement of science and the establishment of new therapeutic targets in type 2 diabetes mellitus care, the capture of heart failure–specific information in completed CVOTs has been limited.5Greene S.J. Vaduganathan M. Khan M.S. et al.Prevalent and incident heart failure in cardiovascular outcome trials of patients with type 2 diabetes.J Am Coll Cardiol. 2018; 71: 1379-1390Google Scholar In a recent systematic review5Greene S.J. Vaduganathan M. Khan M.S. et al.Prevalent and incident heart failure in cardiovascular outcome trials of patients with type 2 diabetes.J Am Coll Cardiol. 2018; 71: 1379-1390Google Scholar of large CVOTs of major therapeutic programs in type 2 diabetes mellitus, heart failure at baseline and during follow-up was infrequently defined. When provided, only a subset of patients enrolled carried a baseline history of heart failure, ranging from 1% to 28% across trials. Similarly, only 3 trials disclosed baseline ejection fraction data among enrolled patients. Diagnoses of heart failure were based on case report identification by investigators, but the types (based on standard ejection fraction classification), etiologies, or functional classes of heart failure could not be further defined. None of the trials collected specific detailed information at the time of incident heart failure diagnosis.5Greene S.J. Vaduganathan M. Khan M.S. et al.Prevalent and incident heart failure in cardiovascular outcome trials of patients with type 2 diabetes.J Am Coll Cardiol. 2018; 71: 1379-1390Google Scholar Furthermore, no data are yet available about how SGLT2 inhibitor therapy affected ability to deliver guideline-directed medical therapy for heart failure, whether it reduced the need for loop diuretic use, or how therapy with SGLT2 inhibitors will affect cardiac structure and function (however, emerging data have suggested that SGLT2 inhibitors contribute to regression of left ventricular mass).35Natali A. Nesti L. Fabiani I. Calogero E. Di Bello V. Impact of empagliflozin on subclinical left ventricular dysfunctions and on the mechanisms involved in myocardial disease progression in type 2 diabetes: rationale and design of the EMPA-HEART trial.Cardiovasc Diabetol. 2017; 16: 130Google Scholar As background rates of heart failure in the 3 reported trials ranged from ~10% to 14%, therapeutic reductions in heart failure events observed across trials primarily reflect prevention of incident heart failure events among patients free from heart failure at baseline, rather than lowering of worsening heart failure events among patients with prevalent heart failure, though ambiguity about prevalence of unrecognized heart failure at baseline continues to be an issue. Notably, SGLT2 inhibitors do not lower blood glucose significantly in those with normal glycemic control, as seen in patients without type 2 diabetes mellitus. In addition, posited multisystem mechanisms of therapeutic benefit of SGLT2 inhibitors, including effects on natriuresis, blood pressure lowering, the renin-angiotensin-aldosterone system axis, maintenance of renal function, erythropoiesis, inflammation and oxidative stress, and myocardial metabolism and energetics, all would be expected to be operative among heart failure patients across the glycemic spectrum.36Butler J. Hamo C.E. Filippatos G. EMPEROR Trials Program et al.The potential role and rationale for treatment of heart failure with sodium-glucose co-transporter 2 inhibitors.Eur J Heart Fail. 2017; 19: 1390-1400Google Scholar This leads to the question of whether SGLT2 inhibitors might be viewed as a heart failure therapy, to be given to all with the diagnosis regardless of presence of type 2 diabetes mellitus. Much more data are needed before such a move could be supported. Dedicated clinical trial programs have been recently completed or are actively underway to explore the potential for SGLT2 inhibitors as a therapeutic option in the treatment of heart failure, including among patients with and without type 2 diabetes mellitus (Table 2). These trials are separately evaluating the efficacy and safety of SGLT2 inhibitors in patients with heart failure with reduced and preserved ejection fraction regardless of baseline type 2 diabetes mellitus status. Furthermore, the Effect of Sotagliflozin on Cardiovascular Events in Patients with Type 2 Diabetes Post Worsening Heart Failure study (SOLOIST-WHF; NCT03521934) is evaluating the effects of sotagliflozin, an oral inhibitor of SGLT1 and SGLT2 yet to receive regulatory approval for use in type 2 diabetes mellitus, among patients hospitalized for worsening heart failure. Although the trial does not require any specific ejection fraction for eligibility, a prespecified primary objective is to understand the therapeutic effects of sotagliflozin among patients with heart failure and ejection fraction 40%Outpatient + inpatient (off IV therapies for 24 h)±T2DM<254700CV death, HHF, or urgent HF visitJun 2021DAPA-HFNCT03036124DapagliflozinHFrEF≤40%Outpatient±T2DM<304744CV death, HHF, or urgent HF visitJul 2019SOLOIST-WHFNCT03521934SotagliflozinWorsening HFNoneInpatient (hemodynamically stable, within 3 days of discharge)+T2DM<304000CV death or HHFJan 2021EMPEROR-ReducedNCT03057977EmpagliflozinHFrEF≤40%Outpatient±T2DM 40%Outpatient±T2DM<205750CV death or HHFNov 2020CV = cardiovascular; CVOT = CV outcomes trial; DAPA-HF = Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure; DELIVER = Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure; EF = ejection fraction; eGFR = estimated glomerular filtration rate; EMPEROR = Empagliflozin Outcome Trial in Patients with Chronic Heart Failure; HF = heart failure; HFpEF = HF with preserved EF; HFrEF = HF with reduced EF; HHF = hospitalization for HF; IV = intravenous; SGLT2 = sodium-glucose co-transporter 2; SOLOIST-WHF = Effect of Sotagliflozin on Cardiovascular Events in Patients with Type 2 Diabetes Post Worsening Heart Failure; T2DM = type 2 diabetes mellitus. Open table in a new tab CV = cardiovascular; CVOT = CV outcomes trial; DAPA-HF = Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure; DELIVER = Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure; EF = ejection fraction; eGFR = estimated glomerular filtration rate; EMPEROR = Empagliflozin Outcome Trial in Patients with Chronic Heart Failure; HF = heart failure; HFpEF = HF with preserved EF; HFrEF = HF with reduced EF; HHF = hospitalization for HF; IV = intravenous; SGLT2 = sodium-glucose co-transporter 2; SOLOIST-WHF = Effect of Sotagliflozin on Cardiovascular Events in Patients with Type 2 Diabetes Post Worsening Heart Failure; T2DM = type 2 diabetes mellitus. Regardless of agent studied, each trial of SGLT2 inhibitors in heart failure will evaluate the same primary endpoint, composite cardiovascular death, or heart failure event (either hospitalization or urgent visit). These trials will also evaluate a broader range of patients with respect to acceptable kidney function, with eGFR down to 20 mL/min/1.73 m2 allowed. The first of these heart failure outcomes trials, Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF; NCT03036124), was recently announced to show marked reductions in the primary composite endpoint (cardiovascular death or hospitalization for heart failure or urgent heart failure visit) and all-cause mortality with dapagliflozin compared with placebo in 4744 patients with heart failure with reduced ejection fraction. Importantly, the treatment benefits were apparent irrespective of baseline diabetes mellitus status. More details and secondary analyses are eagerly anticipated. Parallel trials such as the Effect of Empagliflozin on Exercise Ability and Heart Failure Symptoms in Patients with Chronic Heart Failure with Reduced Ejection Fraction study (EMPERIAL-Reduced; NCT03448419) and EMPERIAL with Preserved Ejection Fraction study (EMPERIAL-Preserved; NCT03448406) trials are exploring the effects of SGLT2 inhibitors on other clinically important endpoints, namely quality of life and 6-minute walking distance among patients with chronic heart failure with or without type 2 diabetes mellitus. These trials are of smaller size (sample size ~300 patients each) and shorter duration (~12 weeks) than the primary trials evaluating SGLT2 inhibitor effects on clinical endpoints in acute and chronic heart failure. Practical considerations about the optimal application of SGLT2 inhibitors in patients with heart failure will hopefully be addressed with these ongoing clinical trial programs. Given the natriuretic properties of SGLT2 inhibitors, the degree of preemptive diuretic dose adjustment is currently uncertain. Similarly, given the modest hemodynamic effects of SGLT2 inhibitors, their use and clinical tolerability along with other therapies in the heart failure armamentarium will need to be studied carefully. As the number of potential therapies for patients with heart failure with reduced ejection fraction increases, the relative staging and sequencing of these agents requires further clarity. Regulatory requirements surrounding CVOTs for established and novel glucose-lowering therapies have raised the global bar for type 2 diabetes mellitus care, introduced a wealth of clinical outcomes data, and uncovered important therapeutic benefits of certain classes of therapies. These trials require enormous resources and global collaborations, and are expensive to conduct; of concern, the trial costs may ultimately translate to increased downstream prices of glucose-lowering therapies. A decade after the initial FDA guidance in 2008, the Endocrinologic and Metabolic Drugs Advisory Committee re-evaluated the initial regulatory requirements. The committee believed these trials remained important in the evaluation paradigm of novel therapies, but streamlined designs may improve cost efficiency of their conduct. The ongoing collection and evaluation of therapeutic approaches to limit the transition between cardiometabolic disease and heart failure are needed. The SGLT2 inhibitor class represents an important new therapeutic approach for the prevention of heart failure in at-risk patients with type 2 diabetes mellitus, and is actively being studied for use in treating patients with heart failure (with or without type 2 diabetes mellitus). MV is supported by the KL2/Catalyst Medical Research Investigator Training award from Harvard Catalyst (NIH/NCATS Award UL 1TR002541); serves on advisory boards for Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, and Boehringer Ingelheim; and participates on clinical endpoint committees for studies supported by Novartis and the NIH. JLJ has received grant support from Roche Diagnostics, Abbott Diagnostics, Singulex, Prevencio, and Cleveland Heart Labs; consulting income from Roche Diagnostics, Novartis, Janssen, and Abbott Diagnostics; and participates on clinical endpoint committees/data safety monitoring boards for Siemens Diagnostics, Janssen, Boehringer Ingelheim, Bayer, and AbbVie. eyJraWQiOiI4ZjUxYWNhY2IzYjhiNjNlNzFlYmIzYWFmYTU5NmZmYyIsImFsZyI6IlJTMjU2In0.eyJzdWIiOiJlZjNkYTRmNWQyZTc5MmQwODQ2ZTBhMmZjYjQ2N2QzOSIsImtpZCI6IjhmNTFhY2FjYjNiOGI2M2U3MWViYjNhYWZhNTk2ZmZjIiwiZXhwIjoxNjc4ODAwNDAxfQ.YINqwEVrnoHuPC6B3BtepyA0LyCxiC7CtR2_5n2oN-hv2TsGV3o7JZ3PHjDMWX7LdMZWdXi8sdfZycgqtpwHkC-xHKFW2PHTvXbOfzlPEOpetnVdI7tMsTxbqN-rzneny60MhWtf47KwnfBBD-8FtE8dNrooics6DK2muVzZo3qXxecA_aVWUyUEweyepFh7yxHw1bERBiT-SIbnJMMpOY9t1WNRe_kB618vDvXhd9ycL0zN-moEJKkCquEyRU_NK1K9UCaeuYzc6SWwJOuieB0i2VU5AkPZ3wlYINoG7l-KgsUI6QDnidH0UpM9cN14w2xGeXDkuZKxFpoSMsoCKA Download .mp4 (6.04 MB) Help with .mp4 files
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