- Email: [email protected]
Preventing and Treating Heart Failure with Sodium-Glucose Co-Transporter 2 Inhibitors
REVIEW
Preventing and Treating Heart Failure with Sodium-Glucose Co-Transporter 2 Inhibitors Muthiah Vaduganathan, MD, MPH,a James L. Januzzi Jr, MDb a
Brigham and Women’s Hospital Heart & Vascular Center, Harvard Medical School, Boston, Mass; bDivision of Cardiology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Mass.
ABSTRACT 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.) Ó 2019 Elsevier Inc. All rights reserved. The American Journal of Medicine (2019) 132:S21−S29 KEYWORDS: Heart failure; Sodium-glucose co-transporter 2 inhibitors; Type 2 diabetes mellitus
INTRODUCTION The burden of type 2 diabetes mellitus is rising rapidly worldwide, related to increasing rates and suboptimal control of cardiometabolic risk factors, including obesity.1 An expanding and aging global population has led to quadrupling of the prevalence of diabetes.1 The associated global economic costs required in the care of type 2 diabetes
mellitus are substantial and projected to increase over the next decade.2 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.3 Tight glycemic control has not previously translated to early
Funding: This work was supported by Boehringer Ingelheim Pharmaceuticals, Inc. Manuscript and figure formatting support was provided by Linda Merkel, PhD, of Elevate Scientific Solutions, which was contracted and funded by Boehringer Ingelheim Pharmaceuticals, Inc. The authors entirely drafted the manuscript and received no direct or indirect compensation related to the development of the manuscript. Publication of this supplement was supported by the Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance. Conflicts of Interest: 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. Authorship: The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE). The authors were responsible for all content and editorial decisions, were involved at all stages of manuscript development, and approved the final version that reflects the authors’ interpretations and conclusions. Boehringer Ingelheim was given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations. This article is co-published in The American Journal of Medicine (Vol. 132, Issue 10S, October 2019) and The American Journal of Cardiology (Vol. 124, Issue S1, December 2019). Requests for reprints should be addressed to James L. Januzzi, Jr, MD, Cardiology Division, Massachusetts General Hospital, 32 Fruit St, Yawkey 5984, Boston, MA 02114. E-mail address: [email protected]
0002-9343/© 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.amjmed.2019.08.008
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improvement in macrovascular outcomes (eg, acute myoconverging lines of data suggest that dedicated therapeutic cardial infarction, stroke, or cardiovascular death), and approaches are needed in the prevention and treatment of until recently, no therapy for type 2 diabetes mellitus has heart failure in type 2 diabetes mellitus.6 Patients with type clearly improved heart failure outcomes. In 2008, following 2 diabetes mellitus have a heightened risk for development concerns of potential excess cardiovascular risk with thiaof heart failure; this may be a consequence of pathogenic zolidinediones, the US Food and Drug Administration inputs that contribute to development of diabetic cardiomy(FDA) issued a guidance to industry requiring that dediopathy with dysregulated oxidative metabolism,7 indepencated cardiovascular outcomes trident of traditional atherosclerotic als (CVOTs) be performed to CLINICAL SIGNIFICANCE cardiovascular disease (ASCVD). exclude significant cardiovascular Even beyond this, however, patients Heart failure is a common complica- with type 2 diabetes mellitus experirisk of established and emerging glucose-lowering therapies.4 In the tion among patients with type 2 diabe- ence residual risks of heart failure last decade, more than 20 largetes mellitus and is associated with despite adequate control of tradiscale CVOTs enrolling more than significantly increased risks of subse- tional risk factors; the populationattributable risk for heart failure 150,000 randomized patients have quent morbidity and mortality. been conducted (Figure 1).5 Nearly Implementation of sodium-glucose co- related to type 2 diabetes mellitus is all these clinical trial programs transporter 2 inhibitors represents an substantial, even beyond the presence of hypertension, coronary have studied a primary endpoint important new therapeutic approach artery disease, or other cardiometaof major adverse cardiovascular for the prevention of heart failure in bolic risk factors.8 Given these conevents (MACE), namely nonfatal at-risk patients with type 2 diabetes siderations, heart failure has become myocardial infarction, nonfatal mellitus, and is actively being studied increasingly recognized as a frestroke, and cardiovascular death; for use in treating patients with heart quent and clinically relevant event; heart failure has infrequently been failure (with or without diabetes). included as a primary or secondary in fact, heart failure may represent clinical endpoint in CVOTs.5 In the index cardiovascular event for many patients.9 When heart failure this review, we discuss the central importance of heart failure as a therapeutic endpoint in type develops in patients with type 2 diabetes mellitus, it repre2 diabetes mellitus care, particularly in the context of the sents a perturbational event. Patients with type 2 diabetes sodium-glucose co-transporter 2 (SGLT2) inhibitor class of mellitus complicated by heart failure experience markedly glucose-lowering therapies. higher rates of mortality after disease onset and progression.10 In contrast, patients with type 2 diabetes mellitus with optimal control of risk factors experience risk of HEART FAILURE IN TYPE 2 DIABETES MELLITUS: ASCVD comparable with the general population.11 COMMON AND DEADLY As reviewed separately, previous clinical trial programs have identified potentially important safety signals for heart The diagnoses of type 2 diabetes mellitus and heart failure failure events with other glucose-lowering therapies.12 are inextricably linked in a number of ways, and several
Figure 1 Rapid growth of number and size of CVOTs in patients with T2DM since the 2008 FDA guidance to industry. The black data points reflect the cumulative number of CVOTs. The gray data points reflect the cumulative number of patients enrolled across CVOTs, reported in thousands. *Includes CVOTs that have had top-line results released or publicly announced. CVOT = cardiovascular outcomes trial; FDA = Food and Drug Administration; T2DM = type 2 diabetes mellitus.
Vaduganathan and Januzzi SGLT2 Inhibitors and Heart Failure Events
Figure 2 Proposed mechanisms of cardiorenal protection and reduction of HF risk with SGLT2 inhibitors. Figure adapted from Verma S et al.19 Reproduced with permission from JAMA Cardiology. 2017;2(9):939-940. Copyright Ó 2017 American Medical Association. All rights reserved. ATP = adenosine triphosphate; HF = heart failure; LV = left ventricular; SGLT2 = sodium-glucose co-transporter 2.
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S24 Certain therapies, including the dipeptidyl peptidase-4 inhibitor saxagliptin13 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.14 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.15
SGLT2 INHIBITORS: A NEW THERAPEUTIC APPROACH 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.16,17 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).18,19 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.20 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.21 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.22 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.23−25 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.26,27 The FDA has also broadened the regulatory labels for empagliflozin (in reducing cardiovascular death)
The American Journal of Medicine, Vol 132, No 10S, October 2019 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.
REDUCTION IN HEART FAILURE EVENTS: AN UNEXPECTED, BUT WELCOME FINDING 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)25 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.25
PREVENTION OF HEART FAILURE EVENTS WITH SGLT2 INHIBITORS 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.28 EMPA-REG OUTCOME23 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 doserelated 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.23 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
Vaduganathan and Januzzi Table 1
SGLT2 Inhibitors and Heart Failure Events
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CVOTs Testing Therapeutic Effects of SGLT2 Inhibitors Among Patients with T2DM at High CV Risk HHF Events per 1000 HR (95% CI) Patient-Years* for HHF
Trial
Ref Publication Year
SGLT2 Inhibitor
N
History of HF (%)
Primary Endpoint
Median SGLT2 Follow-Up Inhibitor (Years) Arm
Placebo Arm
EMPA-REG OUTCOME 23
2015
Empagliflozin 7020
10.1
MACE
3.1
9.4
14.5
CANVAS/ CANVAS-R DECLARE-TIMI 58
24
2017
Canagliflozin 10,142
14.4
MACE
2.4
5.5
8.7
25
2019
Dapagliflozin 17,160
10
4.2
6.2
8.5
VERTIS-CV
28
Ongoing
Ertugliflozin
8238
23.1
MACEy CV death or HHFy MACE
SGLT2 Inhibitor vs Placebo 0.65 (0.50-0.85) 0.67 (0.52-0.87) 0.73 (0.61-0.88)
Ongoing
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. *HHF was variably included as a component of a primary, secondary, or exploratory endpoint across the SGLT2 inhibitor trial programs. y
Co-primary efficacy endpoints adapted during the course of DECLARE-TIMI 58.
showed consistent effects of empagliflozin on heart failure events in patients with or without a baseline history of heart failure.29,30 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.31 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 2013.24 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 3PMACE 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.24 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).32 DECLARE-TIMI 5825 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.25 A recent meta-analysis33 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.33 VERTIS-CV28 is currently underway evaluating the cardiovascular safety of ertugliflozin with respect to 3PMACE. The trial includes 3 dedicated glycemic substudies that will evaluate the effects of ertugliflozin on glycemic
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Figure 3 Meta-analysis of SGLT2 inhibitor trials on HHF and CV death stratified by the presence of established ASCVD. Figure adapted from Zelniker TA et al.33 Reprinted from The Lancet, 393, Zelniker TA, 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”, 31−39, Copyright 2018, with permission from Elsevier. ASCVD = atherosclerotic CV disease; CANVAS = Canagliflozin Cardiovascular Assessment Study; CI = confidence interval; CV = cardiovascular; DECLARE-TIMI 58 = Dapagliflozin Effect on Cardiovascular Events−Thrombolysis in Myocardial Infarction 58; EMPA-REG OUTCOME = Empagliflozin Removal of Excess Glucose: Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients; HHF = hospitalization for heart failure; HR = hazard ratio; SGLT2 = sodiumglucose co-transporter 2.
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.34 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.
CAVEATS OF COMPLETED CVOTS 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.5 In a recent systematic review5 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.5 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).35
TREATMENT OF HEART FAILURE WITH OR WITHOUT TYPE 2 DIABETES MELLITUS 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.
≤ 40% > 40% HFrEF HFpEF NCT03057977 NCT03057951 EMPEROR-Reduced EMPEROR-Preserved
Empagliflozin Empagliflozin
NCT03521934 SOLOIST-WHF
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.
Jul 2020 Nov 2020 CV death or HHF CV death or HHF 3600 5750 < 20 < 20
4000 < 30 None
NCT03036124 DAPA-HF
Sotagliflozin Worsening HF
≤ 40% HFrEF
NCT03619213
Dapagliflozin
Inpatient (hemodynamically stable, + T2DM within 3 days of discharge) Outpatient §T2DM Outpatient §T2DM
4744 §T2DM
< 30
CV death, HHF, or Jun 2021 urgent HF visit CV death, HHF, or Jul 2019 urgent HF visit CV death or HHF Jan 2021 4700 < 25 §T2DM
Outpatient + inpatient (off IV therapies for 24 h) Outpatient
SGLT2 Inhibitors and Heart Failure Events
DELIVER
Dapagliflozin
HFpEF
> 40%
T2DM eGFR Exclusion Anticipated N Status (mL/min/1.73 m2) Setting EF Eligibility Population SGLT2 Inhibitor ClinicalTrials.gov Identifier Trial
Table 2
Ongoing CVOTs Testing Therapeutic Effects of SGLT2 Inhibitors Among Patients with Acute or Chronic HF with or without T2DM
Primary Endpoint
Expected Completion Date
Vaduganathan and Januzzi
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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.36 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 (SOLOISTWHF; 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 <50%. 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 allcause 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
S28 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.
FDA REGULATORY GUIDANCE TO INDUSTRY: A DECADE LATER 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).
References 1. NCD 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(10027):1513–30. 2. Bommer C, Sagalova V, Heesemann E, et al. Global economic burden of diabetes in adults: projections from 2015 to 2030. Diabetes Care 2018;41(5):963–70. 3. American Diabetes Association. 8. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes-2018. Diabetes Care 2018;41(suppl 1):S73–85.
The American Journal of Medicine, Vol 132, No 10S, October 2019 4. Vijayakumar 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(10):1060– 73. 5. Greene SJ, Vaduganathan M, Khan MS, et al. Prevalent and incident heart failure in cardiovascular outcome trials of patients with type 2 diabetes. J Am Coll Cardiol 2018;71(12):1379–90. 6. Greene SJ, Butler J. Primary prevention of heart failure in patients with type 2 diabetes mellitus. Circulation 2019;139(2):152–4. 7. Taylor M, Wallhaus TR, Degrado TR, et al. An evaluation of myocardial fatty acid and glucose uptake using PET with [18F]fluoro-6-thiaheptadecanoic acid and [18F]FDG in patients with congestive heart failure. J Nucl Med 2001;42(1):55–62. 8. Avery CL, Loehr LR, 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(17): 1640–6. 9. McAllister DA, 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(24):2774–86. 10. Rawshani A, Rawshani A, Franzen S, et al. Mortality and cardiovascular disease in type 1 and type 2 diabetes. N Engl J Med 2017;376(15): 1407–18. 11. Rawshani 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(7):633–44. 12. Kramer CK, 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(10):823–30. 13. Scirica BM, Braunwald E, Raz I, et al. SAVOR-TIMI Steering Committee Investigators. Heart failure, saxagliptin, and diabetes mellitus: observations from the SAVOR-TIMI 53 randomized trial. Circulation 2014;130(18):1579–88. 14. Zannad F, Cannon CP, Cushman WC, et al. EXAMINE Investigators. 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(9982):2067–76. 15. Zelniker TA, Wiviott SD, 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 (17):2022–31. 16. Nassif M, Kosiborod M. Effect of glucose-lowering therapies on heart failure. Nat Rev Cardiol 2018;15(5):282–91. 17. Vallon V, Thomson SC. Targeting renal glucose reabsorption to treat hyperglycaemia: the pleiotropic effects of SGLT2 inhibition. Diabetologia 2017;60(2):215–25. 18. Packer M, Anker SD, 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(9):1025–9. 19. Verma S, McMurray JJV, Cherney DZI. The metabolodiuretic promise of sodium-dependent glucose cotransporter 2 inhibition: the search for the sweet spot in heart failure. JAMA Cardiol 2017;2(9):939–40. 20. Castagno D, Baird-Gunning J, Jhund PS, 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(5):938–48. 21. Inzucchi SE, 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;41:356–63. 22. Januzzi J.L. Jr., 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(6):704–12. 23. Zinman B, Wanner C, Lachin JM, et al. EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373(22):2117–28.
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24. Neal B, Perkovic V, Mahaffey KW, et al. CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017;377(7):644–57. 25. Wiviott SD, Raz I, Bonaca MP, et al. DECLARE-TIMI Investigators. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2019;380(4):347–57. 26. Davies MJ, D’Alessio DA, 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(12):2669– 701. 27. Das SR, Everett BM, Birtcher KK, 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 (24):3200–23. 28. Cannon CP, McGuire DK, Pratley R, et al. VERTIS-CV Investigators. Design and baseline characteristics of the eValuation of ERTugliflozin effIcacy and Safety CardioVascular outcomes trial (VERTIS-CV). Am Heart J 2018;206:11–23. 29. Fitchett D, Zinman B, Wanner C, et al. EMPA-REG OUTCOME Trial Investigators. Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPAREG OUTCOMEÒ trial. Eur Heart J 2016;37(19):1526–34. 30. Januzzi J, Ferreira JP, 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(3):386–8.
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31. Fitchett D, Butler J, van de Borne P, et al. EMPA-REG OUTCOME Trial Investigators. Effects of empagliflozin on risk for cardiovascular death and heart failure hospitalization across the spectrum of heart failure risk in the EMPA-REG OUTCOMEÒ trial. Eur Heart J 2018;39(5):363–70. 32. Radholm K, Figtree G, Perkovic V, et al. Canagliflozin and heart failure in type 2 diabetes mellitus. Circulation 2018;138(5):458–68. 33. Zelniker TA, Wiviott SD, 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(10166):31–9. 34. Perkovic V, Jardine MJ, Neal B, et al. CREDENCE Trial Investigators. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019;380(24):2295–306. 35. Natali 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(1):130. 36. Butler J, Hamo CE, Filippatos G, et al. EMPEROR Trials Program. The potential role and rationale for treatment of heart failure with sodium-glucose co-transporter 2 inhibitors. Eur J Heart Fail 2017; 19(11):1390–400.
SUPPLEMENTARY DATA Supplementary data to this article can be found online at https://doi.org/10.1016/j.amjmed.2019.08.008.
Preventing and Treating Heart Failure with Sodium-Glucose Co-Transporter 2 Inhibitors Muthiah Vaduganathan, MD, MPH,a James L. Januzzi Jr, MDb a
Brigham and Women’s Hospital Heart & Vascular Center, Harvard Medical School, Boston, Mass; bDivision of Cardiology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Mass.
ABSTRACT 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.) Ó 2019 Elsevier Inc. All rights reserved. The American Journal of Medicine (2019) 132:S21−S29 KEYWORDS: Heart failure; Sodium-glucose co-transporter 2 inhibitors; Type 2 diabetes mellitus
INTRODUCTION The burden of type 2 diabetes mellitus is rising rapidly worldwide, related to increasing rates and suboptimal control of cardiometabolic risk factors, including obesity.1 An expanding and aging global population has led to quadrupling of the prevalence of diabetes.1 The associated global economic costs required in the care of type 2 diabetes
mellitus are substantial and projected to increase over the next decade.2 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.3 Tight glycemic control has not previously translated to early
Funding: This work was supported by Boehringer Ingelheim Pharmaceuticals, Inc. Manuscript and figure formatting support was provided by Linda Merkel, PhD, of Elevate Scientific Solutions, which was contracted and funded by Boehringer Ingelheim Pharmaceuticals, Inc. The authors entirely drafted the manuscript and received no direct or indirect compensation related to the development of the manuscript. Publication of this supplement was supported by the Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance. Conflicts of Interest: 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. Authorship: The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE). The authors were responsible for all content and editorial decisions, were involved at all stages of manuscript development, and approved the final version that reflects the authors’ interpretations and conclusions. Boehringer Ingelheim was given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations. This article is co-published in The American Journal of Medicine (Vol. 132, Issue 10S, October 2019) and The American Journal of Cardiology (Vol. 124, Issue S1, December 2019). Requests for reprints should be addressed to James L. Januzzi, Jr, MD, Cardiology Division, Massachusetts General Hospital, 32 Fruit St, Yawkey 5984, Boston, MA 02114. E-mail address: [email protected]
0002-9343/© 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.amjmed.2019.08.008
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improvement in macrovascular outcomes (eg, acute myoconverging lines of data suggest that dedicated therapeutic cardial infarction, stroke, or cardiovascular death), and approaches are needed in the prevention and treatment of until recently, no therapy for type 2 diabetes mellitus has heart failure in type 2 diabetes mellitus.6 Patients with type clearly improved heart failure outcomes. In 2008, following 2 diabetes mellitus have a heightened risk for development concerns of potential excess cardiovascular risk with thiaof heart failure; this may be a consequence of pathogenic zolidinediones, the US Food and Drug Administration inputs that contribute to development of diabetic cardiomy(FDA) issued a guidance to industry requiring that dediopathy with dysregulated oxidative metabolism,7 indepencated cardiovascular outcomes trident of traditional atherosclerotic als (CVOTs) be performed to CLINICAL SIGNIFICANCE cardiovascular disease (ASCVD). exclude significant cardiovascular Even beyond this, however, patients Heart failure is a common complica- with type 2 diabetes mellitus experirisk of established and emerging glucose-lowering therapies.4 In the tion among patients with type 2 diabe- ence residual risks of heart failure last decade, more than 20 largetes mellitus and is associated with despite adequate control of tradiscale CVOTs enrolling more than significantly increased risks of subse- tional risk factors; the populationattributable risk for heart failure 150,000 randomized patients have quent morbidity and mortality. been conducted (Figure 1).5 Nearly Implementation of sodium-glucose co- related to type 2 diabetes mellitus is all these clinical trial programs transporter 2 inhibitors represents an substantial, even beyond the presence of hypertension, coronary have studied a primary endpoint important new therapeutic approach artery disease, or other cardiometaof major adverse cardiovascular for the prevention of heart failure in bolic risk factors.8 Given these conevents (MACE), namely nonfatal at-risk patients with type 2 diabetes siderations, heart failure has become myocardial infarction, nonfatal mellitus, and is actively being studied increasingly recognized as a frestroke, and cardiovascular death; for use in treating patients with heart quent and clinically relevant event; heart failure has infrequently been failure (with or without diabetes). included as a primary or secondary in fact, heart failure may represent clinical endpoint in CVOTs.5 In the index cardiovascular event for many patients.9 When heart failure this review, we discuss the central importance of heart failure as a therapeutic endpoint in type develops in patients with type 2 diabetes mellitus, it repre2 diabetes mellitus care, particularly in the context of the sents a perturbational event. Patients with type 2 diabetes sodium-glucose co-transporter 2 (SGLT2) inhibitor class of mellitus complicated by heart failure experience markedly glucose-lowering therapies. higher rates of mortality after disease onset and progression.10 In contrast, patients with type 2 diabetes mellitus with optimal control of risk factors experience risk of HEART FAILURE IN TYPE 2 DIABETES MELLITUS: ASCVD comparable with the general population.11 COMMON AND DEADLY As reviewed separately, previous clinical trial programs have identified potentially important safety signals for heart The diagnoses of type 2 diabetes mellitus and heart failure failure events with other glucose-lowering therapies.12 are inextricably linked in a number of ways, and several
Figure 1 Rapid growth of number and size of CVOTs in patients with T2DM since the 2008 FDA guidance to industry. The black data points reflect the cumulative number of CVOTs. The gray data points reflect the cumulative number of patients enrolled across CVOTs, reported in thousands. *Includes CVOTs that have had top-line results released or publicly announced. CVOT = cardiovascular outcomes trial; FDA = Food and Drug Administration; T2DM = type 2 diabetes mellitus.
Vaduganathan and Januzzi SGLT2 Inhibitors and Heart Failure Events
Figure 2 Proposed mechanisms of cardiorenal protection and reduction of HF risk with SGLT2 inhibitors. Figure adapted from Verma S et al.19 Reproduced with permission from JAMA Cardiology. 2017;2(9):939-940. Copyright Ó 2017 American Medical Association. All rights reserved. ATP = adenosine triphosphate; HF = heart failure; LV = left ventricular; SGLT2 = sodium-glucose co-transporter 2.
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S24 Certain therapies, including the dipeptidyl peptidase-4 inhibitor saxagliptin13 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.14 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.15
SGLT2 INHIBITORS: A NEW THERAPEUTIC APPROACH 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.16,17 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).18,19 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.20 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.21 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.22 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.23−25 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.26,27 The FDA has also broadened the regulatory labels for empagliflozin (in reducing cardiovascular death)
The American Journal of Medicine, Vol 132, No 10S, October 2019 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.
REDUCTION IN HEART FAILURE EVENTS: AN UNEXPECTED, BUT WELCOME FINDING 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)25 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.25
PREVENTION OF HEART FAILURE EVENTS WITH SGLT2 INHIBITORS 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.28 EMPA-REG OUTCOME23 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 doserelated 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.23 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
Vaduganathan and Januzzi Table 1
SGLT2 Inhibitors and Heart Failure Events
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CVOTs Testing Therapeutic Effects of SGLT2 Inhibitors Among Patients with T2DM at High CV Risk HHF Events per 1000 HR (95% CI) Patient-Years* for HHF
Trial
Ref Publication Year
SGLT2 Inhibitor
N
History of HF (%)
Primary Endpoint
Median SGLT2 Follow-Up Inhibitor (Years) Arm
Placebo Arm
EMPA-REG OUTCOME 23
2015
Empagliflozin 7020
10.1
MACE
3.1
9.4
14.5
CANVAS/ CANVAS-R DECLARE-TIMI 58
24
2017
Canagliflozin 10,142
14.4
MACE
2.4
5.5
8.7
25
2019
Dapagliflozin 17,160
10
4.2
6.2
8.5
VERTIS-CV
28
Ongoing
Ertugliflozin
8238
23.1
MACEy CV death or HHFy MACE
SGLT2 Inhibitor vs Placebo 0.65 (0.50-0.85) 0.67 (0.52-0.87) 0.73 (0.61-0.88)
Ongoing
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. *HHF was variably included as a component of a primary, secondary, or exploratory endpoint across the SGLT2 inhibitor trial programs. y
Co-primary efficacy endpoints adapted during the course of DECLARE-TIMI 58.
showed consistent effects of empagliflozin on heart failure events in patients with or without a baseline history of heart failure.29,30 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.31 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 2013.24 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 3PMACE 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.24 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).32 DECLARE-TIMI 5825 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.25 A recent meta-analysis33 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.33 VERTIS-CV28 is currently underway evaluating the cardiovascular safety of ertugliflozin with respect to 3PMACE. The trial includes 3 dedicated glycemic substudies that will evaluate the effects of ertugliflozin on glycemic
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Figure 3 Meta-analysis of SGLT2 inhibitor trials on HHF and CV death stratified by the presence of established ASCVD. Figure adapted from Zelniker TA et al.33 Reprinted from The Lancet, 393, Zelniker TA, 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”, 31−39, Copyright 2018, with permission from Elsevier. ASCVD = atherosclerotic CV disease; CANVAS = Canagliflozin Cardiovascular Assessment Study; CI = confidence interval; CV = cardiovascular; DECLARE-TIMI 58 = Dapagliflozin Effect on Cardiovascular Events−Thrombolysis in Myocardial Infarction 58; EMPA-REG OUTCOME = Empagliflozin Removal of Excess Glucose: Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients; HHF = hospitalization for heart failure; HR = hazard ratio; SGLT2 = sodiumglucose co-transporter 2.
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.34 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.
CAVEATS OF COMPLETED CVOTS 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.5 In a recent systematic review5 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.5 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).35
TREATMENT OF HEART FAILURE WITH OR WITHOUT TYPE 2 DIABETES MELLITUS 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.
≤ 40% > 40% HFrEF HFpEF NCT03057977 NCT03057951 EMPEROR-Reduced EMPEROR-Preserved
Empagliflozin Empagliflozin
NCT03521934 SOLOIST-WHF
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.
Jul 2020 Nov 2020 CV death or HHF CV death or HHF 3600 5750 < 20 < 20
4000 < 30 None
NCT03036124 DAPA-HF
Sotagliflozin Worsening HF
≤ 40% HFrEF
NCT03619213
Dapagliflozin
Inpatient (hemodynamically stable, + T2DM within 3 days of discharge) Outpatient §T2DM Outpatient §T2DM
4744 §T2DM
< 30
CV death, HHF, or Jun 2021 urgent HF visit CV death, HHF, or Jul 2019 urgent HF visit CV death or HHF Jan 2021 4700 < 25 §T2DM
Outpatient + inpatient (off IV therapies for 24 h) Outpatient
SGLT2 Inhibitors and Heart Failure Events
DELIVER
Dapagliflozin
HFpEF
> 40%
T2DM eGFR Exclusion Anticipated N Status (mL/min/1.73 m2) Setting EF Eligibility Population SGLT2 Inhibitor ClinicalTrials.gov Identifier Trial
Table 2
Ongoing CVOTs Testing Therapeutic Effects of SGLT2 Inhibitors Among Patients with Acute or Chronic HF with or without T2DM
Primary Endpoint
Expected Completion Date
Vaduganathan and Januzzi
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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.36 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 (SOLOISTWHF; 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 <50%. 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 allcause 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
S28 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.
FDA REGULATORY GUIDANCE TO INDUSTRY: A DECADE LATER 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).
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SUPPLEMENTARY DATA Supplementary data to this article can be found online at https://doi.org/10.1016/j.amjmed.2019.08.008.