J A C C : B A S I C T O T R A N S L A T I O N A L S C I E N C E V O L . 5 , N O . 6 , 2 0 2 0

ª 2 0 2 0 T H E A U T H O R S . P U B L I S H E D B Y E L S E V I E R O N B E H A L F O F T H E AM 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 UN DA T I O N . T H I S I S A N O P E N A C C E S S A R T I C L E U N D E R

T H E C C B Y - N C - N D L I C E N S E ( h t t p : / / c r e a t i v e c o mm o n s . o r g / l i c e n s e s / b y - n c - n d / 4 . 0 / ) .

STATE-OF-THE-ART REVIEW

Mechanisms of Cardiovascular Benefits ofSodium Glucose Co-Transporter 2(SGLT2) InhibitorsA State-of-the-Art Review

Gary D. Lopaschuk, PHD,a Subodh Verma, MD, PHDb

HIGHLIGHTS

� Treatment with SGLT2 inhibitors reduces the incidence of cardiovascular death and heart failure hospitalization in patients

with and without diabetes.

� This review discusses the potential mechanisms by which SGLT2 inhibitors exert their beneficial effects, including

beneficial effects on cardiac energy metabolism, reducing inflammation, improving kidney function, and increasing

erythropoiesis.

� Future studies are required to clarify how SGLT2 inhibitors exert their impressive cardiovascular effects, which will allow

for a more specific targeting of heart failure therapy.

SUMMARY

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Recent clinical trials have shown that sodium glucose co-transport 2 (SGLT2) inhibitors have dramatic beneficial car-

diovascular outcomes. These include a reduced incidence of cardiovascular death and heart failure hospitalization in

people with and without diabetes, and those with and without prevalent heart failure. The actual mechanism(s)

responsible for these beneficial effects are not completely clear. Several potential theses have been proposed to explain

the cardioprotective effects of SGLT2 inhibition, which include diuresis/natriuresis, blood pressure reduction, erythro-

poiesis, improved cardiac energy metabolism, inflammation reduction, inhibition of the sympathetic nervous system,

prevention of adverse cardiac remodeling, prevention of ischemia/reperfusion injury, inhibition of the Naþ/Hþ-exchanger,

inhibition of SGLT1, reduction in hyperuricemia, increasing autophagy and lysosomal degradation, decreasing epicardial

fat mass, increasing erythropoietin levels, increasing circulating pro-vascular progenitor cells, decreasing oxidative stress,

and improving vascular function. The strengths and weaknesses of these proposed mechanisms are reviewed in an effort

to try to synthesize and prioritize the mechanisms as they relate to clinical event reduction.

(J Am Coll Cardiol Basic Trans Science 2020;5:632–44) © 2020 The Authors. Published by Elsevier on behalf of

the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license

(http://creativecommons.org/licenses/by-nc-nd/4.0/).

N 2452-302X https://doi.org/10.1016/j.jacbts.2020.02.004

m the aCardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada; and the bDivision of Cardiac Sur-

ry, Li Ka Shing Knowledge Institute of St. Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada. Dr. Lopaschuk

s received speaking honoraria from AstraZeneca; has served as a consultant for Boehringer Ingelheim and Servier; and is a

areholder in Metabolic Modulators Research Ltd. Dr. Verma has received research grants and/or speaking honoraria from

gen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, EOCI Pharmacomm Ltd., Janssen, Merck,

vartis, Novo Nordisk, Sanofi, Sun Pharmaceuticals, and the Toronto Knowledge Translation Working Group; is a Tier 1 Canada

search Chair in cardiovascular surgery; and is the president of the Canadian Medical and Surgical Knowledge Translation

search Group, a federally incorporated not-for-profit physician organization.

e authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ in-

tutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit

JACC: Basic to Translational Science author instructions page.

nuscript received January 22, 2020; revised manuscript received February 5, 2020, accepted February 5, 2020.

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AB BR E V I A T I O N S

AND ACRONYM S

EPO = erythropoietin

LV = left ventricular

NLRP3 = nucleotide-binding

oligomerization domain,

leucine-rich repeat, and pyrin

domain-containing 3

ROS = reactive oxygen species

SGLT = sodium glucose co-

transporter

SNS = sympathetic nervous

system

T2DM = type 2 diabetes

mellitus

O ne of the most serious health concerns inthe world is heart failure, with over 50million people worldwide being afflicted

with this disease (1). Despite the advances made inthe treatment of heart failure, patients diagnosedwith heart failure still have a very poor prognosisand quality of life. It also remains the most commonreason for hospitalization in older individuals (1). Pa-tients with type 2 diabetes mellitus (T2DM) are particu-larly susceptible to developing heart failure, which isthe major cause of morbidity and mortality in these indi-viduals (2–4). It is therefore critical to develop new ther-apies and approaches to prevent and treat heart failure.

A number of sodium glucose co-transporter 2(SGLT2) inhibitors have been developed to treat hy-perglycemia in T2DM, which act by inhibiting glucosereabsorption in the proximal tubule of the kidney (5).A number of large clinical trials have been conductedto evaluate the safety and efficacy of SGLT2 inhibitorsin patients with diabetes (with established vasculardisease, multiple cardiovascular risk factors, or renalinsufficiency) and in those with established heartfailure and reduced ejection fraction (with andwithout type 2 diabetes) (6–12). The remarkable re-sults from the EMPA-REG OUTCOME (EmpagliflozinCardiovascular Outcomes Event Trial in Type 2 Dia-betes Mellitus Patients—Removing Excess Glucose)demonstrated that T2DM patients who were at highrisk of cardiovascular disease had an early reductionin major cardiovascular and renal outcomes (8). Thisincluded a marked reduction in cardiovascular deathand hospitalization for heart failure in patientstreated with empagliflozin. Subsequent large trialswith other SGLT2 inhibitors, such as canagliflozin(CANVAS [Canagliflozin Cardiovascular AssessmentStudy] [9] and CREDENCE [Canagliflozin and RenalOutcomes in Type 2 Diabetes and Nephropathy] trials[10]) and dapagliflozin (DECLARE-TIMI 58 [Dapagli-flozin and Cardiovascular Outcomes in Type 2 Dia-betes] trial (11), confirmed these observations in abroader population of primary and secondary pre-vention patients (see Zelniker et al. [12] and Vermaet al. [13] for discussions of trials).

Whereas the aforementioned trials provided robustevidence to suggest that SGLT2 inhibitors can preventincident heart failure, 2 important questions remainedunanswered. First, could these therapies also be usedin the treatment of prevalent heart failure, and sec-ond, is the benefit seen in people without type 2 dia-betes? Importantly, in this regard, the recentlycompleted DAPA-HF (Dapagliflozin and Prevention ofAdverse Outcomes in Heart Failure) trial, whichenrolled 4,744 patients with heart failure and reducedejection fraction demonstrated a marked reduction on

worsening heart failure or cardiovasculardeath on top of excellent heart failurestandard-of-care therapy (6). Furthermore,this benefit was similar in those with andwithout type 2 diabetes and was consistentacross the spectrum of A1c evaluated eithercategorically or continuously.

POTENTIAL MECHANISMS BY WHICH

SGLT2 INHIBITION IS

CARDIOPROTECTIVE

A substantial number of theories have beenproposed to explain the beneficial effects ofSGLT2 inhibitors (14–18). These includebeneficial effects of SGLT2 inhibition on the

following: 1) blood pressure lowering; 2) increasingdiuresis/natriuresis; 3) improving cardiac energymetabolism; 4) preventing inflammation; 5) weightloss; 6) improving glucose control; 7) inhibiting thesympathetic nervous system; 8) preventing adversecardiac remodeling; 9) preventing ischemia/reperfu-sion injury; 10) inhibiting the cardiac Naþ/Hþ

exchanger; 11) inhibiting SGLT1; 12) reducing hyper-uricemia; 13) increasing autophagy and lysosomaldegradation; 14) decreasing epicardial fat mass; 15)increasing erythropoietin (EPO) levels; 16) increasingcirculating provascular progenitor cells; 17) decreasingoxidative stress; and 18) improving vascular function(Figure 1). In the sections that follow, we provide asummary of these proposed mechanisms and a syn-thesis of what mechanism(s) are likely most importantin terms of the observed clinical results observed.

BLOOD PRESSURE LOWERING. Hypertension is aprevalent modifiable risk factor for the developmentof heart failure. Because SGLT2 inhibitors lower bloodpressure (19), some of the beneficial effects of SGLT2inhibitors in the setting of heart failure have beensuggested to be related to this blood pressureimproved cardiac energetics with SGLT2 inhibitionlowering effect. Although the exact mechanism(s) forthe antihypertensive effects of SGLT2 inhibition arenot fully understood, they are probably mediated bythe osmotic and diuresis effects of SGLT2 inhibitors asa result of an inhibition of sodium reabsorption in theproximal tubules of the kidney. SGLT2 inhibition canresult in a 30% to 60% increase in urinary sodiumexcretion (20). The antihypertensive effect of SGLT2inhibition is greater than that of the thiazide diureticswhen used in combination with ß-blockers or calciumantagonists (21,22). By lowering blood pressure,SGLT2 inhibitors may lower cardiac afterload, withresultant improvement in ventricular arterialcoupling and cardiac efficiency. This would be

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expected to benefit the failing heart. However, theblood pressure–lowering effects of SGLT2 inhibitionare modest and are unlikely to completely explain thebeneficial cardiovascular and kidney effects of thesedrugs. In addition, blood pressure lowering would beanticipated to have a greater effect on stroke ratescompared with other cardiovascular outcomes, whichwas not observed in the EMPA-REG OUTCOME trial(8). Finally, in the DAPA-HF trial, the reductions inblood pressure were quite modest and unlikely to berelated to the large reduction in failure events (6).

DIURESIS AND NATRIURESIS. SGLT2 inhibitors havebeen shown to promote natriuresis and glucosuria,and it has been suggested that the resultant osmoticdiuresis may improve heart failure outcomes. In fact,mediation analyses from the EMPA-REG OUTCOMEtrial suggested that hemoconcentration (presumed tobe secondary to volume contraction) accounted forabout 50% of the cardiovascular benefit observed (8).It is difficult to explain the benefits of SGLT2 in-hibitors purely based on diuresis, because otherdiuretic strategies per se have not been associatedwith an improved event reduction in heart failurestudies. It has been suggested that SGLT2 inhibitorsmay differ somewhat from classical diuretics. In astudy comparing dapagliflozin and hydrochlorothia-zide, for example, a reduction in plasma volume andincrease in erythrocyte mass was observed withdapagliflozin but not with hydrochlorothiazide (23).When compared with a loop diuretic (bumetanide),dapagliflozin was associated with more reduction ininterstitial versus intravascular volume (24). It hastherefore been speculated that SGLT2 inhibition mayafford a differential effect in regulating interstitialfluid (vs. intravascular volume), which may limit thereflex neurohumoral stimulation that occurs inresponse to intravascular volume contraction withtraditional diuretics.

IMPROVED CARDIAC ENERGY METABOLISM. Dra-matic changes in energy metabolism occur in thefailing heart. As heart failure progresses, a continualdecline in mitochondrial oxidative metabolism oc-curs, and the heart becomes more reliant on glycol-ysis as a source of energy (25). Mitochondrial glucoseoxidation decreases in the failing heart (26–28),leading to a decrease in energy production and a fuel-starved heart (29). The uncoupling between glycolysisand glucose oxidation in the failing heart also leads toincreased proton production that leads to a decreasein cardiac efficiency (cardiac work / O2 consumed)(25–28). This decrease in cardiac efficiency is notconfined to patients with heart failure and reducedejection fraction, but also occurs in patients with

heart failure and preserved ejection fraction with leftventricular (LV) hypertrophy who also have a reducedLV mechanical efficiency (30).

It has been proposed that the beneficial effects ofSGLT2 inhibitors in heart failure can occur byimproving cardiac energetics and improving cardiacefficiency. SGLT2 inhibitors increase circulating ke-tone levels, secondary to mobilizing adipose tissuefatty acids, which are then used by the liver forketogenesis (31–33). Circulating ketone levels can in-crease following SGLT2 inhibitor treatment even inthe absence of diabetes (33). These ketones have beenproposed to improve cardiac energetics and cardiacefficiency by being a “thrifty” fuel for the heart(34,35). However, we have shown that ketones are nota more efficient source of fuel for the heart, but theyare an additional source of fuel for the failing heart(36,37). The failing heart is “energy starved,” dueprimarily to a decrease in mitochondrial oxidativemetabolism (25,29). Ketone oxidation is increased inthe failing heart, which has been proposed to be anadaptive metabolic process (37–40). Increasingplasma ketone levels in the blood due to SGLT2 in-hibition does increase cardiac ketone oxidation ratesand therefore improves energy supply to the “starv-ing” failing heart (41). In diabetic cardiomyopathicmice, empagliflozin-induced increases in cardiac ke-tone oxidation provide an additional source of fuelfor the heart, which is associated with an improve-ment in cardiac performance (Figure 2) (41). In sup-port of this, Santos-Gallego et al. (42) have shown thatempagliflozin can decrease adverse remodeling andheart failure in a porcine model of heart failure, byimproving cardiac energetics. It has also been shownthat SGLT2 inhibitors can improve mitochondrialrespiratory function in diabetic rats (43), which alsomay contribute to improving energy production inthe heart. These changes in mitochondrial respirationhave been proposed to be partially mediated due tofavorable alterations in energy supply to the heart.Ketone infusions into patients with heart failure isalso associated with an improvement in contractileperformance (44). Of interest, this ketone-inducedimprovement in contractile performance is also notassociated with an increase in cardiac efficiency. Thismakes sense, as the oxidation of ketones, comparedwith the oxidation of glucose, are not a more efficientsource of energy. As a result, some of the beneficialeffects of SGLT2 inhibition in heart failure may occursecondary to increasing fuel supply to the failingheart, as opposed to supplying the heart with a moreefficient source of fuel. Additionally, the increase incardiac ketone oxidation in the failing heart is notassociated with a decrease in either glucose or fatty

FIGURE 1 Possible Mechanisms by Which SGLT2 Inhibitors Decrease the Severity of Heart Failure

Improved cardiac energetics with SGLT2 inhibition. NLRP3 ¼ nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin

domain-containing 3; SGLT2 ¼ sodium glucose co-transporter 2.

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acid oxidation, resulting in an overall increase inadenosine triphosphate production (37,41). There-fore, whereas SGLT2 inhibitors may not increasecardiac efficiency in the failing heart, they may sup-ply the heart with an extra source of fuel, which maybe particularly beneficial for the energy-compromisedfailing heart.

REDUCTION IN INFLAMMATION. Inflammation is animportant contributor to heart failure severity, and

proinflammatory biomarkers are elevated in patientswith heart failure and correlate with the severity ofthe disease (45,46). This association between heartfailure and markers of inflammation is evident inpatients both with reduced and with preserved ejec-tion fraction (47). Inflammatory cytokines notonly cause endothelial dysfunction, they also canincrease extracellular matrix turnover and increasefibrosis. The SGLT2 inhibitors, empagliflozin (48),

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canagliflozin (49), and dapagliflozin (50) have beenshown to attenuate or ameliorate the inflammatoryprofile in patients with diabetes. This decrease inanti-inflammatory properties of SGLT2 inhibitors hasthe potential to decrease molecular processes relatedto inflammation, such as extracellular matrix turn-over and fibrosis (51). In support of this, dapagliflozinhas been shown to have marked antifibrotic effects inthe post-infarct rat heart by suppressing collagensynthesis (51). Empagliflozin also significantly atten-uates cell-mediated extracellular matrix collagenremodeling (52).

How SGLT2 inhibitors modify the inflammatoryprocess is not exactly clear. Decreasing glucose levelswith SGLT2 inhibitors may decrease macrophage in-flammatory response, as macrophages preferentiallyutilize glucose from glycolysis as an energy source(53). Alternatively, SGLT2 inhibitors may directlytarget the inflammatory pathways independent ofglucose lowering per se. The nucleotide-bindingdomain-like receptor protein (specifically,nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing 3 [NLRP3])inflammasome plays an important role in mediatinginflammation. The NLRP3 inflammasome also con-tributes to chronic inflammation in heart failure,thereby increasing heart failure severity (54). Recentevidence in the kidney (55), liver (56), macrophages(57), vasculature (58), and heart (59,60) suggests thatempagliflozin can inhibit the NLRP3 inflammasomeand that this can occur independent of glucoselowering per se. Whether this is a direct or indirecteffect of SGLT2 inhibitors on NLRP3 is not clear. Theketone ß-hydroxybutyrate is an effective blocker ofthe NLRP3 inflammasome-mediated inflammatoryprocess (61). Because SGLT2 inhibitors increasecirculating ß-hydroxybutyrate levels, it is possiblethat some of the beneficial effects of SLT2 inhibitioncould occur secondary to ketone inhibition of theNLRP3 inflammasome.WEIGHT LOSS. The excretion of glucose by the kid-ney with SGLT2 inhibitor treatment results in a loss ofcalories. As a result of this, there is a subsequentdecrease in body weight as fatty acids are mobilizedfrom adipose tissue stores. Clinical studies haveconsistently shown body weight reduction in patientstreated with SGLT2 inhibitors (62). Whereas thisweight loss may contribute to the beneficial effects ofSGLT2 inhibition, other mechanisms must also beinvolved, as weight loss strategies have been muchless effective in decreasing heart failure severitycompared with SGLT2 inhibition, therefore this isunlikely to be an important mechanism of the heartfailure benefit observed. For example, in the

DAPA-HF trial, whereas there was a modest numericreduction in weight observed, the magnitude ofwhich appeared to be greater in those with diabetes(63). Furthermore, the effects of SGLT2 inhibition onweight loss are moderate and diminish with time, duein part to counter-regulatory mechanisms (such asincreased energy intake) being activated to attempt tomaintain weight (64).

IMPROVING GLUCOSE CONTROL. Whereas SGLT2inhibitors are effective glucose-lowering agents, theefficacy on heart failure is unlikely related to im-provements in glucose lowering per se. Hyperglyce-mia itself has been shown to be a weak risk factor forcardiovascular disease (65). In addition, the rapidefficacy noted (within days of treatment initiation) isdifficult to reconcile with a glucose-lowering effect.Furthermore, the differences in glycemic control inthe cardiovascular outcome trials were small (in aneffort to fulfill the glycemic equipoise principle of thetrials), and post hoc analyses from trials suggestedthat baseline A1c or changes in A1c were not associatedwith any treatment modification with SGLT2 in-hibitors (65). Definitive proof of this concept emergedfrom the DAPA-HF trial wherein the efficacy ofdapagliflozin was entirely consistent in those withand without diabetes. Even in those without diabetes,efficacy was similar in those with pre-diabetes orimpaired glucose tolerance compared with in thosewho were truly euglycemic. When studied continu-ously, using fractional polynomial analyses, baselineA1c was unrelated to the efficacy of dapagliflozin toreduce heart failure and mortality in DAPA-HF. Inaddition, in experimental models of heart failure, thebenefit of SGLT2 inhibition has been observed inde-pendent of diabetes or hyperglycemia (60,66,67).

INHIBITING THE SNS. The observation that SGLT2inhibitors reduce blood pressure in the absence ofincreasing heart rate suggests, indirectly, that theseagents may be associated with a reduction in sym-pathetic nervous system (SNS) activity. In fact,accumulating data indicate that SGLT2 inhibition maylead to a reduction in sympathetic nerve activity,inhibit norepinephrine turnover in brown adiposetissue, and reduce tyrosine hydroxylase production(68–72). These sympathoinhibitory effects appear tobe observed in both animal models of diabetes as wellas those with obesity (without diabetes) (68–72). Ithas also been postulated that the effects of SGLT2inhibition to reduce SNS activity may be secondary toa reduction in renal stress with resultant inhibition ofrenal afferent sympathetic activation (73).

PREVENTING ADVERSE CARDIAC REMODELING.

Adverse cardiac remodeling is an important

FIGURE 2 SGLT2 Inhibition Increases Cardiac Energy Production

SGLT2 inhibitors can increase cardiac energy metabolism. Reproduced with permission from Verma et al. (41). ATP ¼ adenosine triphosphate;

SGLT2 ¼ sodium glucose co-transporter 2.

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contributor to heart failure severity. This includes thedevelopment of cardiac hypertrophy, fibrosis,inflammation, and cardiomyocyte cell death. Severalexperimental and human studies have demonstratedbeneficial effects of SGLT2 inhibition on cardiacremodeling (23,67,74–77). In a randomized trial, peo-ple with type 2 diabetes and a history of coronary

artery disease were treated with empagliflozin versusplacebo for 6 months (76). The primary outcome—change in LV mass index (evaluated by cardiac mag-netic resonance imaging) was significantly lower inthose treated with empagliflozin versus in those whoreceived placebo. Although these data do not provideinsight about the exact mechanism of action, they do

FIGURE 3 Multiple Sites for the Beneficial Effects of SGLT2 Inhibition

Proposed renal mechanisms for increased erythropoietin (EPO) with sodium glucose co-transporter 2 (SGLT2) inhibitors. Reproduced with

permission from Mazer et al. (95).

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suggest that even short-term exposure to SGLT2 in-hibitors can promote cardiac reverse remodeling(Figure 3). Inhibition of the mammalian target ofrapamycin pathway, a major pathway involved incardiac hypertrophy, by SGLT2 inhibition may also beinvolved (76). Prevention of adverse remodeling withSGLT2 inhibition is also associated with a decreasedfibrosis (52,78), which may in part be mediated by theanti-inflammatory actions of SGLT2 inhibition (seereduction in inflammation discussion). As a result,SGLT2 inhibition may reverse the cardiac remodelingseen in heart failure, thereby reducing LV wall stressand improving cardiac function.

PREVENTING ISCHEMIA/REPERFUSION INJURY.

Ischemia/reperfusion injury can promote car-diomyocyte cell death and heart failure. Recentexperimental evidence suggests that SGLT2

inhibition has a cardioprotective effect againstischemia/reperfusion injury in both diabetic andnondiabetic rats (79). This beneficial effect of SGLT2inhibition on ischemia/reperfusion injury is associ-ated with a decrease in calmodulin kinase II activity,resulting in improved sarcoplasmic reticulum Ca2þ

flux and increased contractility. However, whetherthis effect occurs in humans remains unclear.

INHIBITING THE CARDIAC NAD/HD EXCHANGER.

The Naþ/Hþ exchanger is increased in the failing heartand can lead to Naþ and Ca2þ overload in the heart(reviewed by Wakabayashi et al. [80]). Inhibition ofthe Naþ/Hþ exchanger has also been demonstrated toprotect the heart in several experimental models ofheart failure (see Wakabayashi et al. [80] for review).Inhibition of the Naþ/Hþ exchanger has been pro-posed to explain the beneficial effects of SGLT2

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inhibitors in heart failure (81–85). The cardiac Naþ/Hþ

exchanger is inhibited by SGLT2 inhibitors, which canlower myocardial Naþ levels (81). However, it is notclear whether direct inhibition of the cardiac Naþ/Hþ

exchanger occurs at clinically relevant concentrationsof SGLT2 inhibitors. In addition, the development ofNaþ/Hþ exchanger inhibitors has not been shown tobe beneficial in the clinical setting of heart failure(85). Therefore, it is not clear whether some of thebeneficial effects of SGLT2 inhibition in the setting ofheart failure may occur secondary to direct inhibitionof the cardiac Naþ/Hþ exchanger.

INHIBITING SGLT1. Although the heart does not ex-press SGLT2, it does express some SGLT1. Inhibitionof SGLT1 in the heart has the potential to decreasemyocardial Naþ and glucose uptake and decreasehyperglycemia-induced generation of reactive oxy-gen species (ROS) (86). However, whereas some of theSGLT2 inhibitors will decrease SGLT1, such as cana-gliflozin, the concentration necessary to inhibit SGLT1is much higher than the plasma concentrations seenwith the clinical use of SGLT2 inhibitors. In addition,the use of dual inhibitors of SGLT2 and SGLT1 canexacerbate cardiac dysfunction post-myocardialinfarction in rats (87). As a result, it is unlikelythat the beneficial effects of SGLT2 inhibitorscan be explained by any secondary effect onSGLT1 inhibition.

REDUCING HYPERURICEMIA. SGLT2 inhibitorsdecrease plasma uric acid, which adversely affects theprognosis of heart failure (88). Small reductions inuric acid levels have been seen with SGLT2 inhibitortreatment (89). This may be attributed to theincreased glycosuria in the proximal tubules due toSGLT2 inhibition, which stimulates uric acid secretion(90). However, whether a reduction in hyperuricemiaby SGLT2 inhibition is a marker or plays a causal roleremains unknown.

INCREASING AUTOPHAGY AND LYSOSOMAL

DEGRADATION. Cardiac autophagy and lysosomaldegradation can be impaired in diabetes and heartfailure (77,91). By driving catabolic rates due to con-stant glycosuria, it has been proposed that SGLT2inhibition can promote autophagy and lysosomaldegradation, thereby improving mitochondrialmorphology and function (77). An SGLT2-mediatedinhibition of mammalian target of rapamycin mayalso stimulate autophagy and lysosomal degradation,leading to the enhanced degradation of dysfunctionalorganelles. It therefore cannot be ruled out that someof the benefit of SGLT2 inhibition in heart failuremay be secondary to their effects on stimu-lating autophagy.

DECREASING EPICARDIAL FAT MASS. High epicar-dial adipose tissue attenuation on computed tomog-raphy is associated with an increased risk ofcardiovascular events (92). Epicardial adipose tissuecan produce a number of bioactive molecules that cannegatively affect heart function and contribute tocoronary artery disease. In addition, SGLT2 inhibitorsreduce the accumulation and inflammation of peri-vascular adipose tissue, thus minimizing the secre-tion of leptin and its paracrine actions on the heart topromote fibrosis (84). In patients with diabetes whoalso have coronary artery disease, SGLT2 inhibitionreduces epicardial adipose tissue mass, as well as thelevels of bioactive molecules such as tumor necrosisfactor-a and plasminogen activator inhibitor-1 (93).This may contribute to a decreased adverse remod-eling of the failing heart.

INCREASING EPO LEVELS. The fact that SGLT2 in-hibitors raise the hematocrit (94), even in thosewithout diabetes (as seen in DAPA-HF), has led to thesuggestion that these agents may promote erythro-poiesis via enhanced EPO secretion by the kidney(95). Such an increase in EPO may serve to favorablyinfluence cardiomyocyte mitochondrial function,angiogenesis, cell proliferation, and inflammation, inaddition to directly enhancing myocardial tissue ox-ygen delivery (95). Mazer et al. (95) recently evalu-ated this in the EMPA-Heart CardioLink-6randomized clinical trial and demonstrated that EPOlevels increased significantly after 1 month of empa-gliflozin treatment in people with type 2 diabetes andcoronary artery disease accompanied by an increasein hematocrit, reduced ferritin and red blood cellhemoglobin concentration (Figure 3). Whether EPOlevels go up in people without type 2 diabetes re-mains unknown.

INCREASING CIRCULATING PROVASCULAR PROGENITOR

CELLS. Preliminary evidence in humans points to-ward an effect of SGLT2 inhibitors on the restorationof provascular progenitor cells in people with type 2diabetes. In one such completed study, Hess et al.(96) observed that empagliflozin treatment wasassociated with a reduction in the number proin-flammatory M1 cells while increasing the number ofM2 polarized, anti-inflammatory cells. By using theAldeflour assay (STEMCELL Technologies, Cam-bridge, Massachusetts), the investigators found thatSGLT2 inhibition reduced systemic granulocyteburden in individuals with T2DM, increased circu-lating ALDHhiSSCmid monocytes and induced a tran-sition from M1 to M2 polarization—all of which isconsistent with maturation of collateral vessels dur-ing arteriogenesis. The investigators concluded that

CENTRAL ILLUSTRATION Potential Direct Myocardial and Indirect � Systemic Effects of SGLT2i

Lopaschuk, G.D. et al. J Am Coll Cardiol Basic Trans Science. 2020;5(6):632–44.

CAMKII ¼ calmodulin-dependent protein kinase II; EPO ¼ erythropoietin; NHE ¼ sodium/hydrogen exchanger; NLRP3 ¼ nucleotide-binding

oligomerization domain, leucine-rich repeat, and pyrin domain-containing 3; SGLT2i ¼ sodium glucose co-transporter 1(2) inhibitor; SNS ¼sympathetic nervous system.

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SGLT2 inhibition may uniquely serve as a strategy topromote the recovery of circulating provascular cellsin T2DM. Whether this occurs in people withoutT2DM is unknown.

DECREASING OXIDATIVE STRESS. Excessive cardiacmitochondrial ROS production is an importantcontributor to contractile dysfunction in human heartfailure and in animal models of heart failure (for re-view see Zhou and Tian [97]). During the develop-ment of heart failure, increased oxidative stress canresult in mitochondrial dysfunction. This increase inROS production may occur due to a stimulation of

mitochondrial respiration for adenosine triphosphateproduction and an increased electron transport chainactivity. In diabetic mice, increasing glycemic controlwith SGLT2 inhibition can decrease myocardial ROSproduction and cardiac fibrosis (97). In human coro-nary arterial endothelial cells, SGLT2 inhibition canalso decrease ROS generation (98). How SGLT2 inhi-bition decreases ROS production is not clear,although this may occur secondary to favorable ef-fects on the inflammatory process (see reduction ininflammation discussion), cardiac mitochondrialoxidative metabolism (see improved cardiac energy

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metabolism discussion), or decreasing the potentialfor cardiac glucotoxicity (which can promote ROSproduction). Furthermore, there is a paucity of dataon SGLT2 inhibition on ROS production in theabsence of type 2 diabetes.

IMPROVING VASCULAR FUNCTION. Vascular smoothmuscle and endothelial dysfunction contributes tothe pathophysiology of heart failure (99,100). Its ex-istence in patients with heart failure increasesmorbidity and mortality. SGLT2 inhibition has beenshown to improve vascular function by attenuatingendothelial cell activation, inducing direct vaso-relaxation, reducing endothelial cell dysfunction andmolecular changes associated with early atherogen-esis decreasing arterial wall stiffness, and decreasingvascular resistance (101–104). A number of underlyingmechanisms for the beneficial actions of SGLT2 inhi-bition may occur, including beneficial effects ofSGLT2 inhibition on inhibiting the inflammatorypathways and improving mitochondrial function(101). Induction of vasodilation via activation of pro-tein kinase G and voltage-gated potassium channelsby SGLT2 inhibitors has also been proposed (105). Thedirect effects of SGLT2 inhibition on the vascular,combined with the natriuresis effects of SGLT2 inhi-bition, may contribute to the desirable hemodynamiceffects seen with SGLT2 inhibition.

FROM A LIST TO SYNTHESIS:

WHAT MECHANISMS MOST LIKELY

EXPLAIN THE BENEFITS OBSERVED?

A number of clinical trials have demonstrated thatSGLT2 inhibitors have impressive beneficial cardio-vascular effects in both patients with diabetes andpatients who do not have diabetes, but do have heartfailure. As a result, SGLT2 inhibitors are a new weaponthat can be added to the arsenal of weapons used totreat heart failure. However, it remains unclear exactlyhow SGLT2 inhibitors produce their impressive clinicalbenefits in patients with heart failure (CentralIllustration). It is clear that its classical actions oflowering blood glucose cannot fully explain thesebenefits. The early onset of the beneficial effects ofSGLT2 inhibitors in clinical trials suggests that thesebenefits are not occurring as a result of slowing theatherosclerotic process. Whereas the published re-ports are replete with numerous proposed mecha-nisms linking SGLT2 inhibition to cardiovascularprotection, how do we synthesize and prioritize these

to help explain the observed clinical benefits? Taking abedside-to-bench approach, the clinical data wouldsuggest that the mechanism(s) involved must accountfor the following key elements: 1) efficacy in thetreatment and prevention of heart failure; 2) efficacyon top of excellent background therapy, includingneprilysin inhibition; 3) rapid onset of the benefit; 4)efficacy independent of glycemic status; and 5) asso-ciation with renal protection. We opine that the renaleffects of SGLT2 inhibitors are an important mecha-nism of action and that some of the cardiovascularbenefits are secondary to this. According to this the-ory, SGLT2 inhibition result in an early hemodynamiceffect at the level of the proximal renal tubule. This inturn promotes sodium and water loss while also,through tubule-glomerular feedback, promotingafferent arteriolar constriction. The ensuring reduc-tion in intraglomerular pressure leads to renal pro-tection. Improving renal function and/or reducingrenal stress can indirectly improve cardiac functionthrough various pathways, including a reduction inafferent SNS activation, reduction in inflammation,and ROS generation. We propose that future studiesare required to examine these possibilities. We alsoargue that the renal hemodynamic effects areobserved independent of glycemia, because in theDAPA-HF trial an initial drop in estimated glomerularfiltration rate was observed in people both with andwithout diabetes. The increase in EPO production mayalso be secondary to an improvement in renal healthand may explain why the hematocrit is increased to asimilar extent in people both with and without dia-betes in DAPA-HF. Additional intriguing mechanismsfor the benefits of SGLT2 inhibition in heart failureinclude improving cardiac energy metabolism anddecreasing cardiac inflammation. Further studies areneeded to examine SGLT2 inhibition impacts on thesepathways in the setting of heart failure, as well as thepotential inter-relationship between these 2 pathways(because ketones can inhibit the inflammatorypathway). Further studies should help elucidateexactly how SGLT2 inhibitors exert these impressivecardiovascular effects.

ADDRESS FOR CORRESPONDENCE: Dr. Gary D.Lopaschuk, Cardiovascular Research Centre, 423Heritage Medical Research Centre, University ofAlberta, Edmonton, Alberta T6G 2S2, Canada. E-mail:gary.lopaschuk@ualberta.ca.

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KEY WORDS erythropoetin, inflammation,ketones, renal function, sympathetic nervoussystem