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A M E R I C A N C O L L E G E O F C A R D I O L O G Y F O U N D A T I O N

MINI-FOCUS ISSUE: COMORBIDITIES

STATE-OF-THE-ART REVIEW

Antihyperglycemic Therapies toTreat Patients With Heart Failureand Diabetes Mellitus

Abhinav Sharma, MD,a,b,c Lauren B. Cooper, MD,d Mona Fiuzat, PHD,a Robert J. Mentz, MD,a

João Pedro Ferreira, MD, PHD,e,f Javed Butler, MD, MPH, MBA,g David Fitchett, MD,h Alan Charles Moses, MD,i

Christopher O’Connor, MD,a,d Faiez Zannad, MD, PHDe

JACC: HEART FAILURE CME/MOC/ECME

This article has been selected as the month’s JACC: Heart Failure

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Antihyperglycemic Therapies to Treat Patients With Heart Failure and

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To obtain credit for JACC: Heart Failure CME/MOC/ECME, you must:

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ISSN 2213-1779/$36.00

the most common comorbidities seen amongst patients with heart fail-

ure; 2) identify anti-diabetic therapies that are safe or beneficial among

patients with heart failure and type 2 diabetes mellitus; and 3) identify

anti-diabetic therapies that may be associated with an increased risk of

heart failure outcomes among patients with type 2 diabetes mellitus.

CME/MOC/ECME Editor Disclosure: Editor-in-Chief Christopher M. O’Con-

nor,MD,has received consultant fees/honoraria fromAbbVie, Inc., Actelion

Pharmaceuticals Ltd., Bayer, Bristol-Myers Squibb, Cardiorentis, Merck &

Co., Inc., ResMed, and Roche Diagnostics; and ownership interest in Bis-

cardia, LLC. Executive Editor Mona Fiuzat, PharmD, has received research

support from ResMed, Gilead, Critical Diagnostics, Otsuka, and Roche Di-

agnostics. Tariq Ahmad, MD, MPH, has received a travel scholarship from

Thoratec. Abhinav Sharma,MD, has received support fromBayer-Canadian

Cardiovascular Society, Alberta Innovates Health Solution, Roche Di-

agnostics, and Takeda. Mitchell Psotka, MD, PhD, and Kishan Parikh, MD,

have no relationships relevant to the contents of this paper to disclose.

Author Disclosures: Dr. Sharma has received support from Bayer-Canadian

Cardiovascular Society, Alberta Innovates Health Solution, Bristol-Myers

Squibb-Pfizer, Roche Diagnostics, and Takeda. Dr. Mentz has received

support from U.S. National Institutes of Health (NIH) grants U10HL110312

andR01AG045551-01A1 and fromAmgen,AstraZeneca, Bayer, Bristol-Myers

Squibb, GlaxoSmithKline, Gilead, Luitpold, Medtronic, Merck, Novartis,

Otsuka, and ResMed; has received honoraria from HeartWare, Janssen,

LuitpoldPharmaceuticals,Merck,Novartis, ResMed, andThoratec/St. Jude;

and has served as an advisory board member for Amgen, Luitpold, Merck,

and Boehringer Ingelheim. Dr. Butler has received support from NIH,

European Union, and Patient Centered Outcomes Research Initiative

(PCORI); and has consulted for Amgen, AstraZeneca, Bayer, Boehringer

Ingelheim, Bristol-Myers Squibb, CVRx, Janssen, Luitpold, Medtronic,

Novartis, Relypsa, Vifor, and ZS Pharma. Dr. Moses is an employee of Novo

Nordisk; has received continuing medical education from Boehringer; has

consulted for Boehringer, Lilly, Amgen, Merck, Sanofi, Novartis,

AstraZeneca; is a steering committee member for the EMPA REG Outcome

trial; and has been on the datamonitoring and safety board for the SUSTAIN

6 and PIONEER 6 studies. Dr. Zannad has received honoraria from Takeda

Development Center. All other authors have reported that they have no

relationships relevant to the contents of this paper to disclose.

Medium of Participation: Print (article only); online (article and quiz).

CME/MOC/ECME Term of Approval

Issue date: October 2018

Expiration date: September 30, 2019

https://doi.org/10.1016/j.jchf.2018.05.020

Sharma et al. J A C C : H E A R T F A I L U R E V O L . 6 , N O . 1 0 , 2 0 1 8

Antihyperglycemic Therapies in Heart Failure O C T O B E R 2 0 1 8 : 8 1 3 – 2 2

814

Antihyperglycemic Therapies to Treat PatientsWith Heart Failure and Diabetes Mellitus

Abhinav Sharma, MD,a,b,c Lauren B. Cooper, MD,d Mona Fiuzat, PHD,a Robert J. Mentz, MD,a

João Pedro Ferreira, MD, PHD,e,f Javed Butler, MD, MPH, MBA,g David Fitchett, MD,h Alan Charles Moses, MD,i

Christopher O’Connor, MD,a,d Faiez Zannad, MD, PHDe

ABSTRACT

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There is increasing recognition of the relationship between diabetes and heart failure (HF). Comorbid diabetes is associated

withworse outcomes in patientswithHF, and death fromHF forms a large burden ofmortality amongpatientswith diabetes

and atherosclerotic cardiovascular disease. However, there is evidence of harm relating to the risk of HF outcomes from

several antihyperglycemic therapies. The absence ofwell-powered randomized controlled studies has resulted in significant

treatment variations in the glycemic management in patients with coexisting diabetes and HF. However, there is emerging

evidence from recent clinical trials suggesting that sodium-glucose–co-transporter-2 inhibitors may be used as a therapy to

improve HF outcomes. In order to understand the current state of knowledge, we reviewed the evolving evidence of

antihyperglycemic therapies and present strategies to optimize these therapies in patients with diabetes and HF. This

analysis is based on discussions among scientists, clinical trialists, industry sponsors, and regulatory representatives

who attended the 12th Global Cardiovascular Clinical Trialists Forum, Washington, DC, December 1 to 3, 2016.

(JAmCollCardiolHF2018;6:813–22)©2018PublishedbyElsevieronbehalfof theAmericanCollegeofCardiologyFoundation.

D iabetes is now recognized as one of themost common comorbidities among pa-tients with heart failure (HF) (1,2). Death

from HF forms a large burden of mortality amongpatients with diabetes and atherosclerotic cardiovas-cular (CV) disease (3). Diabetes poses a more than 2-fold increased risk of HF development (4). Further-more, comorbid diabetes is associated with worseoutcomes in patients with HF (5,6). Recent advancesin our understanding of the underlying pathophysi-ology in patients with diabetes and HF have resultedin emerging paradigms of disease mechanisms

m the aDuke Clinical Research Institute, Duke University, Durham, No

erta Heart Institute, University of Alberta, Edmonton, Alberta, Canada; cD

lifornia; dInova Heart and Vascular Institute, Falls Church, Virginia; eCen

titut national de la santé et de la recherche médicale, Université de Lorr

nce; fCardiovascular Research and Development Unit, Department of

dicine, University of Porto, Porto, Portugal; gDivision of Cardiology, Stony

Cardiology, St. Michael’s Hospital, University of Toronto, Toronto, On

nmark. Dr. Sharma has received support from Bayer-Canadian Cardiov

istol-Myers Squibb-Pfizer, Roche Diagnostics, and Takeda. Dr. Mentz ha

alth (NIH) grants U10HL110312 and R01AG045551-01A1 and from Amgen

ithKline, Gilead, Luitpold, Medtronic, Merck, Novartis, Otsuka, and ResM

itpold Pharmaceuticals, Merck, Novartis, ResMed, and Thoratec/St. Jude

gen, Luitpold, Merck, and Boehringer Ingelheim. Dr. Butler has receive

ntered Outcomes Research Initiative (PCORI); and has consulted for A

istol-Myers Squibb, CVRx, Janssen, Luitpold, Medtronic, Novartis, Relypsa

vo Nordisk; has received continuing medical education from Boehringer;

nofi, Novartis, and AstraZeneca; is a steering committee member for the

nitoring and safety board for the SUSTAIN 6 and PIONEER 6 studies

velopment Center. All other authors have reported that they have no re

close. John R. Teerlink, MD, served as Guest Editor for this paper.

nuscript received November 27, 2017; revised manuscript received May 6

(Figure 1) (1,7). There are several mechanisms of HFdevelopment in the diabetic population, includingchronic hyperglycemia, insulin resistance, and thenonglucose components of the metabolic syndromethat are prevalent in patients with type 2 diabetes.Of those non–glucose-associated comorbidities, hy-pertension, dyslipidemia, and obesity may allcontribute to the development of HF (8,9).

Despite the major public health consequencesassociated with diabetes and HF, there is conflictingevidence of increased HF hospitalization risk withinand among various classes of antihyperglycemic

rth Carolina; bDivision of Cardiology, Mazankowski

ivision of Cardiology, Stanford University, Palo Alto,

tre d’Investigations Cliniques Plurithématique 1433,

aine, CHRU de Nancy and F-CRIN INI-CRCT, Nancy,

Physiology and Cardiothoracic Surgery, Faculty of

Brook University, Stony Brook, New York; hDivision

tario, Canada; and the iNovo Nordisk A/S, Soborg,

ascular Society, Alberta Innovates Health Solution,

s received support from U.S. National Institutes of

, AstraZeneca, Bayer, Bristol-Myers Squibb, Glaxo-

ed; has received honoraria from HeartWare, Janssen,

; and has served as an advisory board member for

d support from NIH, European Union, and Patient

mgen, AstraZeneca, Bayer, Boehringer Ingelheim,

, Vifor, and ZS Pharma. Dr. Moses is an employee of

has consulted for Boehringer, Lilly, Amgen, Merck,

EMPA REG Outcome trial; and has been on the data

. Dr. Zannad has received honoraria from Takeda

lationships relevant to the contents of this paper to

, 2018, accepted May 6, 2018.

AB BR E V I A T I O N S

AND ACRONYM S

CI = confidence interval

CV = cardiovascular

FDA = U.S. Food and Drug

Administration

HF = heart failure

HR = hazard ratio

MACE = major adverse cardiac

event(s)

NYHA = New York Heart

Association

OR = odds ratio

PPAR = peroxisome

proliferator-activated receptor

J A C C : H E A R T F A I L U R E V O L . 6 , N O . 1 0 , 2 0 1 8 Sharma et al.O C T O B E R 2 0 1 8 : 8 1 3 – 2 2 Antihyperglycemic Therapies in Heart Failure

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therapies (10–12). Evaluation of strategies to optimizeoutcomes have not been adequately explored, as pa-tients with HF are frequently excluded fromantihyperglycemia drug trials (13). However, severalantihyperglycemic therapies may reduce the risk ofHF and CV events. In order to address these knowl-edge gaps, we reviewed the current evidenceregarding the risks and benefits of antihyperglycemictherapies in patients with diabetes and HF, and wehighlighted potential strategies to improve HF out-comes by using antihyperglycemic therapies. Thisanalysis is based on discussions among scientists,clinical trialists, industry sponsors, and regulatoryrepresentatives who attended the 12th Global Car-diovascular Clinical Trialists Forum, Washington, DC,December 1 to 3, 2016.

RECOGNITION OF HF HOSPITALIZATION

AS AN IMPORTANT EVENT IN

ANTIHYPERGLYCEMIC DRUG TRIALS

In December 2008, the U.S. Food and Drug Admin-istration (FDA) issued guidance to pharmaceuticalsponsors setting out updated expectations for on-going development of antihyperglycemic drugs (14).The primary focus of the guidance was to directsponsors to ensure the cardiovascular (CV) safety ofantihyperglycemic therapies. Prior to the guidance,approval for antihyperglycemic therapies focused onglycemic efficacy, namely the reduction of hemo-globin A1c (HbA1c). In addition, safety data werelimited to outcomes derived from short-term, 6- and12-month phase 2 and 3 randomized controlled trials.However, 2 meta-analyses identified concerns for CVsafety for 2 classes of antihyperglycemic therapies:muraglitazar (the investigational dual-peroxisomeproliferator-activated receptor [PPAR]-alpha and-gamma agonist, which was never approved) (15) andthe FDA-approved agent rosiglitazone, a thiazolidi-nedione (TZD) (16). As a result of these controversialstudies, the FDA and, subsequently, the EuropeanMedicines Agency mandated long-term CV safetytrials as a requirement for obtaining approval of newantihyperglycemic therapies. The meta-analysis thatinitially suggested an increased risk of CV outcomesprimarily focused on myocardial infarction (MI) andCV death. FDA guidance mandated that sponsorsconduct CV outcome trials to demonstrate thatantihyperglycemic therapies did not primarily in-crease the risk of CV major adverse cardiac event(s)(MACE), primarily focusing on a composite of CVdeath, MI, or stroke (14). The guidance indicates thatother relevant CV events (hospitalization for acutecoronary syndromes or urgent revascularization)

could be considered. However, HF as a CVsafety event was not suggested in the guid-ance. Furthermore, although the guidancemandated that patients at high risk of CVevents be enrolled (including patients withrelatively advanced disease, elderly patients,and patients with some degree of renalimpairment), there was no requirement toenroll patients with HF. As a result of theguidance, there has been a significant in-crease in the number of CV outcome trialsfor antihyperglycemic therapies, yet nonehas included HF in the primary endpoint. HFis a key outcome of interest because thedemonstration of an increased risk of HFhospitalization associated with TZDs (17). In

more recent trials, the possibility of increased risk ofHF hospitalization associated with some dipeptidylpeptidase (DPP)-4 inhibitors (saxagliptin and alog-liptin but not sitagliptin) has reaffirmed the impor-tance of HF outcomes among antihyperglycemiadrug trials (18). The emergence of antihyperglycemictherapies, namely sodium-glucose co-transporter-2inhibitors, that may reduce the risk of HF outcomeshas resulted in significant interest in how to usethese therapies as a strategy to reduce the risk of HFhospitalizations (8).

RISKS AND BENEFITS OF

ANTIHYPERGLYCEMIC THERAPIES IN

PATIENTS WITH DIABETES AND HF

INCLUSION OF PATIENTS WITH HEART FAILURE IN

ANTIHYPERGLYCEMIA DRUG TRIALS. Clinical trialsof antihyperglycemic therapies often excluded pa-tients with HF, and 33% of anti-hyperglycemic drugtrials did not have a stated definition for HF events(13). Previous trials also frequently excluded allpatients with any symptoms of HF or thosereceiving treatment for HF (Online Table 1) (19–25).Although recent CV safety trials have includedmore precise HF definitions, patients with moresevere HF symptoms, typically those with NewYork Heart Association (NYHA) functional classes IIIto IV, were excluded (26–29). However, more recentantihyperglycemia trials typically did not have anyspecific HF exclusion (except for the EXAMINE[Examination of Cardiovascular Outcomes withAlogliptin versus Standard of Care] trial, whichexcluded patients with NYHA functional class IV)(30). Furthermore, the SUSTAIN-6 (Semaglutide inSubjects with Type 2 Diabetes-6) trial (31) and theLEADER (Liraglutide Effect and Action in Diabetes:Evaluation of Cardiovascular Outcome Results) trial

FIGURE 1 Current Paradigm in Mechanisms Leading to the Development of

Diabetic Cardiomyopathy

FFA ¼ free fatty acid; VEGF ¼ vascular endothelial growth factor; VEGFR ¼ vascular

endothelial growth factor receptor.

FIGURE 2 Risk of

CANVAS ¼ Canaglifl

isenatide in Acute Co

vascular Outcomes,

Cardiovascular Outco

Study of Cardiovascu

Failure Treatment; L

Cardiovascular Outco

Outcomes Recorded

Infarction 53; SUSTA

Trial Evaluating Card

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(32) encouraged inclusion of HF patients by desig-nating NYHA functional classes II to III and sys-tolic/diastolic dysfunction as enrichment criteria.WILL ANTIHYPERGLYCEMIC THERAPIES INCREASE

THE LIKELIHOOD OF NEW-ONSET OR RECURRENT

HEART FAILURE? Clinicians have a broad menu ofantihyperglycemic medications that can be used as

Heart Failure Events Seen in Recent Antihyperglycemic Drug Trials

ozin Cardiovascular Assessment Study; ELIXA ¼ Evaluation of Lix-

ronary Syndrome; EMPA-REG OUTCOME ¼ Empagliflozin, Cardio-

and Mortality in Type 2 Diabetes; EXAMINE ¼ Examination of

mes with Alogliptin versus Standard of Care; EXSCEL ¼ Exenatide

lar Event Lowering; FIGHT ¼ Functional Impact of GLP-1 for Heart

EADER ¼ Liraglutide Effect and Action in Diabetes: Evaluation of

me Results; SAVOR-TIMI 53 ¼ Saxagliptin Assessment of Vascular

in Patients with Diabetes Mellitus-Thrombolysis In Myocardial

IN-6 ¼ Semaglutide in Subjects with Type 2 Diabetes; TECOS ¼iovascular Outcomes with Sitagliptin-6.

first-, second-, or third-line therapies. However,despite the extensive number of drugs available, theoptimal therapies for use in patients with diabetesand HF have not been established due to lack of high-quality randomized trial data and conflicting signalsof risk and benefit among and within classesantihyperglycemic therapies (Figure 2).

METFORMIN AND SULFONYLUREAS. Randomizedclinical trials suggest that metformin may reducemacrovascular events and that it is generally recom-mended as first-line treatment for patients with type2 diabetes (19,33). No prospective randomized trialhas evaluated whether metformin is the optimal first-line agent in patients with diabetes and HF. Cohortand administrative database analyses in patients withdiabetes and HF suggest that metformin alone or incombination is associated with a lower mortality thansulfonylurea therapy (34,35).

Sulfonylureas improve glycemia control byincreasing insulin release and, unlike other classes ofantidiabetic drugs, they do not cause sodium reten-tion. However, as with metformin, there are no ran-domized clinical trials assessing the CV safety of theseagents specifically in patients with HF. In patients withnewly diagnosed diabetes, the UKPDS (UnitedKingdom Prospective Diabetes Study) trial suggestedthat the combination of insulin and sulfonylureaversus diet-based treatment did not increase HF risk(hazard ratio [HR]: 0.91; 95% confidence interval [CI]:0.54 to 1.52) (19). However, population-based studieshave suggested the possibility of increased risk of HFhospitalizations associated with sulfonylureascompared with metformin (36).

THIAZOLIDINEDIONES. TZDs work by improving in-sulin sensitivity, improving blood pressure control,optimizing lipid profiles, and potentially reducing thedevelopment of atherosclerosis. Although a 2007meta-analysis suggested that, compared with pla-cebo, rosiglitazone increased the odds for MI (oddsratio [OR]: 1.43; 95% CI: 1.03 to 1.98) and demon-strated a trend toward increased risk of death (OR:1.64; 95% CI: 0.98 to 2.64), subsequent analyses havesuggested no increased MI risk associated with use ofrosiglitazone (37). With regard to HF outcomes,several studies have suggested that increased HF riskis associated with use of TZD. In a small randomizedcontrolled trial of 224 patients with diabetes and HFwith reduced ejection fraction (HFrEF), comparedwith placebo, rosiglitazone was associated with anincreased risk of new or worsening peripheral edemaand an increased use of HF medications (38). ThePROACTIVE (PROspective pioglitAzone Clinical TrialIn macroVascular Events) trial demonstrated a risk of

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HF hospitalizations associated with pioglitazone thatwas increased compared with placebo (pioglitazone6%, placebo 4%, respectively; p ¼ 0.007) (25). TheRECORD (Rosiglitazone evaluated for cardiovascularoutcomes in oral agent combination therapy for type2 diabetes) trial demonstrated a doubling of fatal andnonfatal HF in patients receiving rosiglitazone (2.7%vs. 1.3%, respectively; HR: 2.1; 95% CI: 1.35 to 3.27)(22). Furthermore, in the RECORD trial, of the 61 HFcases treated with rosiglitazone, 4 patients experi-enced the initial HF event as a fatal event, and 30% ofthe surviving patients died during trial follow-up.These events were significantly increased comparedwith those in the control group in which 29 patientswere hospitalized for HF; none of these cases werefatal initially, but 28% of the patients subsequentlydied. These data demonstrate that TZD-induced HFcarries significant prognostic importance (17). As aresult of these studies, diabetes and HF guidelinesrecommend not using TZD in patients with signs andsymptoms of congestive HF and that initiation ofthese therapies is contraindicated in patients withNYHA functional classes III to IV HF (39,40). Ifcongestive heart failure is newly diagnosed orconsidered likely, even in the absence of prior leftventricular dysfunction, the use of the TZD should bereconsidered (40).

INSULIN. Insulin has a dose-dependent anti-natriuretic effect, and mild fluid retention may beseen with use of insulin, particularly in individualswith poorly controlled glucose levels at the time ofinitiation (Online Ref. 1); however, unlike TZDs, it isunclear whether insulin may actually increase the riskof adverse HF events (Online Refs. 2,3). In the BARI-2D (Bypass Angioplasty Revascularization Investiga-tion 2 Diabetes) study, insulin therapy did not resultin any significant differences in HF outcomescompared with metformin and TZDs therapies (20).The ORIGIN (Outcome Reduction With Initial GlagineIntervention) trial randomized 12,537 patients withdysglycemia (defined as impaired glucose tolerance,impaired fasting glucose, or diabetes) to the basalinsulin glargine or placebo therapy. Overall, insulintherapy was not associated with increased HF risk(HR: 0.9; 95% CI: 0.77 to 1.05) (23). More recent datafrom the ORIGIN trial suggest that insulin does notincrease the risk of recurrent HF events (OnlineRef. 4). Despite the lack of randomized evidencesuggesting harm for HF outcome, guidelines haveencouraged caution in the use of insulin in patientswith HF (Online Ref. 5).

DIPEPTIDYL-PEPTIDASE-4 INHIBITORS. There are 3placebo-controlled randomized controlled clinical

trials that evaluated the safety of DPP-4 inhibitors inpatients with type 2 diabetes (30, Online Refs. 6,7). Inthe SAVOR-TIMI 53 (Saxagliptin Assessment ofVascular Outcomes Recorded in Patients with Dia-betes Mellitus-Thrombolysis In Myocardial Infarction53) trial (Online Ref. 6), 16 of 492 patients with type 2diabetes at high risk of CV events were randomized toreceive saxagliptin or placebo therapy. Saxagliptinwas associated with an increased risk of HF hospi-talization (HR: 1.27; 95% CI: 1.07 to 1.51; p ¼ 0.007)(Online Ref. 8). The EXAMINE study randomized5,380 patients within 15 to 90 days after MI to alog-liptin or placebo therapy. Alogliptin had no impact onthe composite event of CV death and hospitalizationfor HF (HR: 1.00; 95% CI: 0.82 to 1.21) (8,30). Forpatients with no baseline HF history, there was asignificant increase in HF risk associated withalogliptin (2.2% vs. 1.3%, respectively; HR: 1.76; 95%CI: 1.07 to 2.90) (8). In the TECOS (Trial EvaluatingCardiovascular Outcomes with Sitagliptin) study,14,671 subjects with type 2 diabetes and establishedatherosclerotic cardiovascular disease were random-ized to receive sitagliptin or placebo therapy. Sita-gliptin did not increase hospitalization for HF (HR:1.00; 95% CI: 0.83 to 1.20) (9). Recently the FDAreleased a warning for drugs containing saxagliptin oralogliptin for HF risk.

A small mechanistic study of the DPP-4 inhibitorvildagliptin was conducted in patients with diabetesand HF. The VIVIDD (Vildagliptin in VentricularDysfunction Diabetes) study randomized 254 patientsto receive the DPP-4 inhibitor vildagliptin versusplacebo for 52 weeks (Online Ref. 9). The inclusioncriteria included left ventricle ejection fraction(LVEF) of <35% and poorly controlled diabetes. Theprimary outcomes (change in LVEF) were similar be-tween groups. The LV systolic and diastolic volumeswere increased in the vildagliptin arm compared withthose in the placebo groups. Caution is warranted ininterpreting the findings of increased LV chambervolumes as the clinical relevance remains unclear. Intotality, the risk of HF events was balanced betweenthe groups.

Current society consensus statements have sug-gested that DPP-4 inhibitors be used with caution inpatients with diabetes and HF (Online Ref. 10). Theuse of sitagliptin in patients with HF is likelyacceptable given the absence of HF risk seen amongpatients with pre-existing HF (HR: 1.03; 95% CI: 0.72to 1.36) (9).GLUCAGON-LIKE PEPTIDE-1 RECEPTOR AGONISTS.

Glucagon-like peptide (GLP)-1 is secreted by cellslocated in the distal intestine in response to ingestionof food. GLP-1 receptor stimulation in pancreatic

FIGURE 3 Potential Mechanisms of SGLT-2 Inhibitors in the Heart and Kidneys

BP ¼ blood pressure; CV ¼ cardiovascular; HF ¼ heart failure; SGLT ¼ sodium-glucose

co-transporter.

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beta-cells facilitates glucose-dependent insulinsecretion in addition to suppression of glucagonrelease by alpha-cells (Online Ref. 11). The ELIXA(Evaluation of Lixisenatide in Acute Coronary Syn-drome) trial evaluated the GLP-1 receptor agonistlixisenatide in patients with type 2 diabetes who hadhad an MI in the preceding 180 days (Online Ref. 12).Compared with placebo, lixisenatide did not signifi-cantly reduce the risk of the primary MACE (HR: 1.02;95% CI: 0.89 to 1.17) and had no impact on HF hos-pitalizations (HR: 0.96; 95% CI: 0.75 to 1.23). Similarresults were seen in patients with and without HF.The LEADER trial evaluated the CV safety of liraglu-tide in 9,340 subjects with established cardiovasculardisease or CV risk factors (32). Liraglutide reduced therisk of the primary MACE outcome of CV death,nonfatal MI, and nonfatal stroke (HR: 0.87; 95% CI:0.78 to 0.97). CV mortality was significantly reducedby 22% (HR: 0.78; 95% CI: 0.66 to 0.93). Liraglutidewas associated with numerically fewer HF hospitali-zations, but the difference was not statistically sig-nificant (218 [4.7%] vs. 248 [5.3%], respectively; HR:0.87; 95% CI: 0.73 to 1.05). The SUSTAIN-6 trial, ran-domized 3,297 patients with diabetes and establishedCV disease or CV risk factors to semaglutide versusplacebo therapy (31). The trial demonstrated thenoninferiority of semaglutide versus placebo for theprimary MACE outcome (HR: 0.74; 95% CI: 0.58 to

0.95; p for noninferiority: <0.001). Semaglutide didnot statistically increase the risk of HF events (vs.placebo: 3.6% vs. 3.3%, respectively; HR: 1.11; 95% CI:0.77 to 1.61). The EXSCEL (Exenatide Study of Car-diovascular Event Lowering) trial evaluated the CVsafety of exenatide versus placebo in patients withdiabetes at high risk for CV; overall, the studydemonstrated noninferiority for the primary MACEoutcome (HR: 0.91; 95% CI: 0.83 to 1.00). There wasno increased risk of HF seen in patients randomizedto exenatide (HR: 0.94; 95% CI: 0.78 to 1.13) (OnlineRef. 13).

Despite the apparent safety of GLP-1 receptor ag-onists in patients with HF, divergent results arosewhen GLP-1 receptor agonists were evaluated specif-ically among patients with established HF. The FIGHT(Functional Impact of GLP-1 for Heart Failure Treat-ment) study (Online Ref. 14) randomized 300 patientswith and without diabetes with reduced EF(LVEF # 40%) to receive either liraglutide or placebo.Patients were also required to have had a recent HFhospitalization (within 14 days) and a pre-admissionoral dose of diuretic such as furosemide, at least40 mg or an equivalent. The primary endpoint was aglobal rank score across 3 hierarchical tiers: time todeath, time to HF rehospitalization, and time-averaged proportional change in N-terminal pro–B-type natriuretic peptide level from baseline to 180days. Compared with placebo, liraglutide had no sig-nificant effect on the primary endpoint (p¼0.31).However, the point estimates suggested higher risk ofdeath or HF-related events with liraglutide in pa-tients with diabetes (vs. placebo; 47% vs. 34%,respectively; HR: 1.54; 95% CI: 0.97 to 2.46). TheLIraglutide on left LIVE (VEntricular function inchronic heart failure patients) study randomized 241patients with and without diabetes and HFrEF(LVEF #45%) to receive liraglutide or matching pla-cebo for 24 weeks (Online Ref. 15). The primaryoutcome measurement (change in LVEF fromrandomization to end of follow-up) did not differbetween the liraglutide and the placebo group; how-ever, increased adverse cardiac events (death causedby ventricular tachycardia, nonfatal ventriculartachycardia, atrial fibrillation requiring intervention,aggravation of ischemic heart disease, and worseningof HF) were seen in 12 patients (10%) treated withliraglutide compared with 3 patients (3%) in the pla-cebo group (p ¼ 0.04).

Reasons for divergent signals of risk in patientswith HFrEF seen in the FIGHT and LIVE studiescompared with those in the larger LEADER, ELIXA,SUSTAIN-6, and EXSCEL trials remain unclear. Ahigher risk HF patient population might have had

CENTRAL ILLUSTRATION Oral Antihyperglycemic Treatment Strategy in Patients With Diabetesand Heart Failure

Sharma, A. et al. J Am Coll Cardiol HF. 2018;6(10):813–22.

*Saxagliptin and alogliptin may increase the risk for heart failure hospitalization. ASCVD ¼ atherosclerotic cardiovascular disease;

CV ¼ cardiovascular; DPP ¼ dipeptidyl dipeptidase; GLP-1RA ¼ glucagon-like peptide-1 receptor agonists; HbA1c ¼ hemoglobin A1c;

HHF ¼ hospitalization for heart failure; SGLT ¼ Sodium-glucose co-transporter; TZD ¼ thiazolidinediones.

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potentially differential responses to GLP-1 receptoragonist compared with the trial populations enrolledin the CV safety studies. It is unclear whether signalsof risk would emerge for patients with HFpEF.Further research will be needed to ascertain thesafety of liraglutide and other GLP-1 receptor agonistsin patients with established HFrEF. Despite theseresults, caution in interpretations across trials shouldbe considered as these trials enrolled different pa-tient populations and used different trial endpoints.For instance, the SUSTAIN-6 trial had a much smallerpopulation than the LEADER population and had ashorter follow-up.SODIUM-GLUCOSE CO-TRANSPORTER-2 INHIBITOR.

Sodium-glucose co-transporter (SGLT)-2 facilitatesglucose and sodium movement across cell mem-branes in the proximal renal tubule. Inhibition ofSGLT-2 results in insulin-independent improvementsin glycemic control due to glycosuria of approxi-mately 70 to 80 g/day (Online Refs. 16,17). TheEMPA-REG OUTCOME (Empagliflozin, CardiovascularOutcomes, and Mortality in Type 2 Diabetes) trial wasa CV safety trial of the SGLT-2 inhibitor empagliflozin(Online Ref. 18). The trial randomized 7,020 patientswith type 2 diabetes and established CV disease toreceive 10 or 25 mg of empagliflozin or placebo.Empagliflozin reduced the primary MACE endpoint

compared with that with placebo therapy (10.5% vs.12.1%, respectively; HR: 0.86; 95% CI: 0.74 to 0.99).Furthermore, empagliflozin reduced the risk of HFadmissions compared with placebo (4.1% vs. 2.7%,respectively; HR: 0.65; 95% CI: 0.50 to 0.85). Amongthe patients with a baseline history of HF, empagli-flozin therapy was associated with a numericallylower rate of HF hospitalization (10.4% vs. 12.3%,respectively; HR: 0.75; 95% CI: 0.48 to 1.19) and CVmortality (8.2% vs. 11.1%, respectively; HR: 0.71; 95%CI: 0.43 to 1.16) (Online Ref. 19). Adverse eventsconsistent with congestive HF such as edema werereported in a higher proportion of patients treatedwith placebo (216 of 2,333 patients [9.3%]) than withempagliflozin (9.3% vs. 4.5%, respectively).

The CANVAS (Canagliflozin Cardiovascular Assess-ment Study) program integrated 2 clinical trials with atotal of 10,142 patients with type 2 diabetes and highCV risk. Patients were randomized to receive canagli-flozin or placebo, and the trial demonstrated a signif-icant reduction in the risk of CV death, nonfatal MI, ornonfatal stroke (26.9 vs. 31.5, respectively, per 1,000patient-years; HR: 0.86; 95% CI: 0.75 to 0.97). Nointeraction was seen between patients with andwithout a baseline history of HF (interaction p ¼ 0.51).An unexpected finding of an increased risk of toe ormetatarsal amputation was identified (6.3 vs. 3.4,

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respectively, per 1,000 patient-years; HR: 1.97; 95% CI:1.41 to 2.75). Randomization to canagliflozin wasassociated with a reduced risk of HF hospitalization(5.5 vs. 8.7, respectively, per 1,000 patient-years; HR:0.67; 95% CI: 0.52 to 0.87). Furthermore, patients witha history of HF appear to have derived a greatermagnitude of benefit from canagliflozin with regard toreduction in the risk of CV death and HF hospitaliza-tion than patients without a history of HF (OnlineRef. 20). Similar results have been seen inpopulation-level studies (Online Ref. 21). The ability ofSGLT-2 inhibitors to optimize volume status throughglycosuria and also inhibit the sodium-hydrogenexchanger in the kidneys and the heart may result ina cascade of responses including increased natriuresis,decreased myocardial fibrosis, and increased cardiaccontractility (Figure 3) (Online Refs. 22,23).

OPTIMIZING THERAPIES IN PATIENTS WITH

DIABETES AND HF

The STENO-2 (Intensified Multifactorial Interventionin Patients With Type 2 Diabetes and Micro-albuminuria-2) trial demonstrated that aggressiverisk factor modification involving glycemic control,blood pressure, and lipid profile improved clinicaloutcomes among patients with type 2 diabetes mel-litus (Online Ref. 24). Such multifactorial treatmentstrategies may improve outcomes in patients withdiabetes and HF, yet those strategies have never beentested in a well-powered randomized controlled trial.As a result, there is little evidence to guide clinicianswith regard to glycemic targets in patients with dia-betes and HF. Current HF and diabetes guidelinesrecommend lowering HbA1c concentration to <7% inpatients with HF (Class IIa, Level of Evidence: A toreduce microvascular complications, B to reducemacrovascular complications) (39, Online Refs. 5,25).Guidelines also suggest that less stringent glycemictargets goals (such as HbA1c <8% [64 mmol/mol]) maybe appropriate for patients with a history of severehypoglycemia, limited life expectancy, advancedmicrovascular or macrovascular complications, andextensive comorbid conditions (Online Ref. 25). HFmay be considered a significant comorbid condition,given the poor prognosis associated with patientswho have both diabetes and HF. Further research willbe needed to determine optimal strategies to indi-vidualize glycemic control among patients with dia-betes and HF. Recent guidelines have not specificallysuggested treatment strategies beyond avoidance ofTZDs in patients with diabetes and HF (39, OnlineRefs. 5,25). The absence of such recommendationsarises from a lack of robust randomized controlled

trial evidence in this patient population. Metformin isgenerally recommended as the first-line agent due tothe relative safety of these agents in patients withdiabetes and HF. With SGLT-2 inhibitors, given thepossible reduction in the risk of MACE and HF out-comes in patients with established HF, we recom-mend these as the second-line agents (CentralIllustration). The increased risk of toe and metatarsalamputation with canagliflozin should be consideredwhen using this therapy; however, the increased riskhas not been seen with empagliflozin. Liraglutidereduces the risk of CV outcomes in patients withestablished atherosclerotic CV disease, but cautionshould be used with GLP-1 receptor agonists in pa-tients with recent HF hospitalization, given the sig-nals of increased risk of adverse events seen in theFIGHT trial. Other classes of antihyperglycemic ther-apies do not have proven mortality benefit andshould be considered only when SGLT-2 inhibitorsand liraglutide cannot be used. Finally, a team-basedapproach including a diabetologist and the patient’sprimary care provider is essential to ensuring optimalcontinuity of care.

FUTURE DIRECTIONS

Given the results of the EMPA-REG OUTCOMESand the CANVAS trials, there is significant interestin exploring the role of SGLT-2 inhibitors in patientswith HF, regardless of the presence of diabetes (OnlineTable 2). The EMPEROR-Reduced (EMPagliflozinoutcomE tRial in Patients With chrOnic heaRt FailureWith Reduced Ejection Fraction; NCT03057977) andEMPEROR-Preserved (EMPagliflozin outcomE tRialin Patients With chrOnic heaRt Failure With Pre-served Ejection Fraction; NCT03057951) trials are 2examples of CV outcome trials that are evaluating theimpact of SGLT-2 inhibitors in HF patients. For thefirst time, many of these trials are evaluating HFhospitalization as part of the composite of primaryoutcomes. Furthermore, several mechanistic studiesare evaluating the impact of SGLT-2 inhibitor oninvasive hemodynamics, body sodium content, car-diac biomarkers, and even arrhythmia burden amongpatients with HF (Online Table 2). If these trialssuccessfully demonstrate improved HF outcomeswith use of SGLT-2 inhibitor, this would represent asignificant shift in our therapeutic strategies tomanage and treat HF patients.

Although these trials are currently underway, thereare still several additional questions that warrantfurther evaluation. Although metformin is recom-mended as the first-line agent, given the absence of aclear mortality reduction signal, future research

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should evaluate SGLT-2 inhibitors as potential first-line therapy. Pragmatic strategy trials of mono- anddual-therapy antihyperglycemic drug therapies,strategy trials of new antihyperglycemic therapiescompared with therapies that have mortality benefit(Online Ref. 26), and identifying optimal time oftherapy initiation (e.g., during hospitalization vs. inoutpatients) are also needed. Patients with stage D HFoften cannot tolerate HF therapies; therefore, evalu-ation of the safety and efficacy of SGLT-2 inhibitors inthis population is warranted.

CONCLUSIONS

Given the significant public health consequences ofdiabetes and HF, strategies to optimize and treatthese patients are desperately needed. As the

number of antihyperglycemic and HF therapies in-creases, pragmatic trials to help guide clinicians asto which therapies to use and when to initiate themwill be needed. The encouraging results of theSGLT-2 inhibitor trials suggest that these therapiesmay become the cornerstone in the treatment ofpatients with diabetes and HF. The extensiveknowledge gaps that continue to exist can beaddressed through enhanced collaboration amongacademics, industries, and government in order tohelp improve the lives of patients with diabetes andHF.

ADDRESS FOR CORRESPONDENCE: Dr. AbhinavSharma, Duke Clinical Research Institute, 2400Pratt Street, Durham, North Carolina 27705. E-mail:a.sharma@duke.edu.

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KEY WORDS antihyperglycemic therapies,diabetes mellitus, heart failure, outcomes,SGLT-2

APPENDIX For supplemental references andtables, please see the online version of thispaper.

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