J O U R N A L O F T H E 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
`ª 2 0 1 8 B Y T H E 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
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`P U B L I S H E D B Y E L S E V I E R
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`V O L . 7 2 , N O .
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`1 5 , 2 0 1 8
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`MINI FOCUS ON DIABETES
`
`THE PRESENT AND FUTURE: JACC STATE-OF-THE-ART REVIEW
`
`The Changing Landscape of
`Diabetes Therapy for
`Cardiovascular Risk Reduction
`JACC State-of-the-Art Review
`
`Jonathan D. Newman, MD, MPH,a Anish K. Vani, MD,a Jose O. Aleman, MD, PHD,b Howard S. Weintraub, MD,a
`Jeffrey S. Berger, MD, MS,a Arthur Z. Schwartzbard, MDa
`
`ABSTRACT
`
`Type 2 diabetes mellitus (T2D) is a major risk factor for cardiovascular disease (CVD), the most common cause of death
`in T2D. Despite improved risk factor control, however, adults with T2D continue to experience substantial excess CVD
`risk. Until recently, however, improved glycemic control has not been associated with robust macrovascular benefit.
`The advent of 2 new classes of antihyperglycemic agents, the sodium-glucose cotransporter-2 inhibitors and the
`glucagon-like peptide-1 receptor agonists, and their respective large cardiovascular outcome trials, has led to a paradigm
`shift in how cardiologists and heath care practitioners conceptualize T2D treatment. Herein, the authors review the
`recent trial evidence, the potential mechanisms of action of the sodium-glucose cotransporter-2 inhibitors and
`the glucagon-like peptide-1 receptor agonists, safety concerns, and their use for the primary prevention of CVD
`as well as in diabetic patients with impaired renal function and heart failure. (J Am Coll Cardiol 2018;72:1856–69)
`© 2018 by the American College of Cardiology Foundation.
`
`T ype 2 diabetes mellitus (T2D) is a major risk
`
`factor for cardiovascular disease (CVD), the
`most common cause of death in T2D (1).
`Traditional CVD risk factor management for patients
`with T2D who have or are at elevated risk for CVD in-
`cludes a multifactorial
`lifestyle intervention along
`with intensive interventions to control blood pres-
`sure, lipids, antiplatelet therapy, and glycemic ther-
`apy,
`as
`reviewed previously (2). A focus on
`traditional risk factor control has led to substantial
`
`reductions in the burden of CVD for adults with T2D
`(3,4). Despite improved risk factor control, however,
`adults with T2D continue to experience substantial
`excess CVD risk. Historically, many physicians have
`dichotomized management of patients with diabetes
`into 2 categories: 1)
`improve glycemic control to
`reduce microvascular complications; and 2) control
`established CVD risk factors, such as tobacco use,
`hyperlipidemia, and hypertension to reduce the risk
`of macrovascular disease,
`the biggest driver of
`
`Listen to this manuscript’s
`audio summary by
`JACC Editor-in-Chief
`Dr. Valentin Fuster.
`
`From the aDivision of Cardiology and Center for the Prevention of Cardiovascular Disease, Department of Medicine, New York
`University Medical Center, New York, New York; and the bDivision of Endocrinology, New York University Medical Center, New
`York, New York. Drs. Newman and Berger have been partially funded by the National Heart, Lung, and Blood Institute of the
`National Institutes of Health (K23HL125991 to Dr. Newman; HL114978 to Dr. Berger). Dr. Aleman has been partially funded by the
`American Heart Association. Funders had no role in the design and conduct of the study; collection, management, analysis, and
`interpretation of the data; and preparation, review, or approval of the paper. Dr. Weintraub has received honoraria from Amgen,
`Sanofi, and Gilead for consulting; has served on the Speakers Bureau for Amgen; and has received research funding from Amarin,
`Sanofi, Akcea, and Ionis. Dr. Berger has received research funding from AstraZeneca and Janssen. Dr. Schwartzbard has received
`research funding to New York University from Merck/Pfizer, Amarin, Sanofi, and Ionis; and has served as a consultant to the
`formulary committee for Optum Rx. Dr. Vani has reported that he has no relationships relevant to the contents of this paper to
`disclose.
`
`Manuscript received May 6, 2018; revised manuscript received July 18, 2018, accepted July 24, 2018.
`
`ISSN 0735-1097/$36.00
`
`https://doi.org/10.1016/j.jacc.2018.07.071
`
`Exhibit #
`
`Exhibit 2602
`
`07/09/24
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`exhibitsticker.com
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`
`1857
`
`morbidity and mortality for patients with T2D. In this
`setting, antidiabetic agents were used primarily for
`glucose lowering, requiring titration and monitoring
`of therapy even though glycemic control had not
`been associated with reduced cardiovascular (CV)
`risk. Cardiologists and other providers caring for the
`diabetic patient deferred diabetes management to ex-
`perts in endocrinology or diabetes care. Over the last
`several years, trials designed first to demonstrate
`safety of newer antidiabetic agents demonstrated su-
`periority for CVD risk reduction among adults with
`T2D with a history of or at high risk for recurrent
`CVD events. These findings have implications for car-
`diologists and health care providers who commonly
`care for adults with T2D and elevated CVD risk.
`Herein, we will review and integrate these recent
`data into updated management pathways for adults
`with T2D who are at high risk for CVD. The focus will
`be upon reviewing recent trial evidence for agents in
`the 2 major new classes with demonstrated efficacy
`for CVD risk reduction: the sodium-glucose cotrans-
`porter 2 inhibitors (SGLT2-i) and the glucagon-like
`peptide-1 receptor agonists (GLP-1 RA). Recent re-
`views have included most (5–7), but not all (8,9)
`recent CV outcome trials with relevance for care of
`adults with T2D and heightened CVD risk. We will add
`to recent reviews by including an examination of the
`use of SGLT2-i and GLP-1 RA for cardiorenal protec-
`tion in the high-risk diabetic patient, and also focus
`on the use of these agents in the setting of comorbid
`heart failure (HF) risk. We will also examine the role
`of background CV and antidiabetic medical therapy in
`these recent trials. Finally, we will examine emerging
`evidence for use of these agents for primary as well as
`secondary CVD prevention. A discussion of other
`agents, such as dipeptidyl peptidase-4 inhibitors,
`with less well-established CVD risk reduction profiles
`is beyond the scope of this review, and we refer the
`interested reader to prior reviews for an examination
`of other antidiabetic drug classes for CVD risk
`reduction in the high-risk adult with T2D (10,11).
`
`THE DEVELOPMENT OF CV SAFETY AND
`OUTCOME TRIALS FOR THE
`HIGH-RISK DIABETIC PATIENT
`
`The rationale for the development of CV outcome
`studies has been reviewed in detail previously (11,12).
`In brief, partly due to signals of adverse CV safety
`with earlier glucose-lowering medications (13), the
`U.S. Food and Drug Administration (FDA) and Euro-
`pean Medicines Agency subsequently required new
`glucose-lowering therapies to demonstrate CV safety
`in prospective, randomized controlled outcome trials
`
`A B B R E V I A T I O N S
`
`A N D A C R O N Y M S
`
`CVD = cardiovascular disease
`
`GLP-1 RA = glucagon-like
`peptide-1 receptor agonists
`
`HbA1c = glycated hemoglobin
`
`HR = hazard ratio
`
`(12). Designed for detection of risk signals,
`some of these CV outcome trials have not
`only demonstrated CV safety, but have also
`shown robust reductions in CV events and all-
`cause mortality (5–8). As recommended (12),
`these CV outcome trials have focused pri-
`marily on high-risk diabetic patients, such as
`patients with pre-existing vascular disease,
`renal impairment, advanced age, or multiple
`risk factors for CVD. These patients are
`commonly referred to cardiology practices,
`and an in-depth review of the results from
`recent major CV outcome trials will assist the
`cardiologist and other health care practitioners in
`caring for the high-risk patient with T2D. We will
`begin by reviewing the mechanism and major trial
`outcomes and safety for the SGLT2-i, followed by a
`discussion of the GLP-1 RA. We will then discuss is-
`sues germane to both classes of agents in recent CV
`outcomes trials, including issues related to concomi-
`tant CV medical therapy and insulin use in these
`recent CV outcomes trials, and the application of
`these newer agents for the primary prevention of CVD
`in adults with T2D. A summary of the major trial re-
`sults is presented in Table 1.
`
`LDL = low-density lipoprotein
`
`MI = myocardial infarction
`
`SGLT2-i = sodium-glucose
`cotransporter-2 inhibitors
`
`T2D = type 2 diabetes mellitus
`
`THE SGLT2 INHIBITORS
`
`The SGLT2-i have demonstrated impressive reductions
`in CV risk in 2 major CV outcomes trials, EMPA-REG
`OUTCOME (Empagliflozin Cardiovascular Outcome
`Event Trial in Type 2 Diabetes Mellitus Patients) and the
`CANVAS Program (Canagliflozin Cardiovascular Assess-
`ment Study) (5,8), with other trials in this drug class
`ongoing (14). The potential mechanisms of effect have
`been described in detail (15), and will be summarized
`here and in the Central Illustration.
`
`POTENTIAL MECHANISMS OF BENEFIT FOR THE
`INHIBITORS. M e t a b o l i c
`e f f e c t s. SGLT2-i
`SGLT2
`work by inhibiting the high-capacity,
`low-affinity
`SGLT2 receptor in the proximal tubule of the kidney,
`which is responsible for reabsorbing approximately
`90% of filtered glucose
`(16). Paradoxically,
`in
`hyperglycemic states such as diabetes, SGLT2 activity
`is increased and leads to greater reabsorption of both
`glucose and salt
`(17).
`Importantly,
`for safety,
`the
`glucose-lowering effects of SGLT2-i decrease at lower
`plasma glucose levels, thereby accounting for the
`reduced risk of hypoglycemia seen with this class of
`antidiabetic agents
`(15). As
`seen in EMPA-REG
`OUTCOME and the CANVAS Program, treatment with
`SGLT2-i improves CV and microvascular endpoints in
`patients with T2D (5,8). Notably, the difference in
`magnitude reduction in glycated hemoglobin (HbA1c)
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`T A B L E 1 Summary of the GLP-1 RA and SGLT2-i Cardiovascular Outcome Trials
`
`EMPA-REG
`
`CANVAS
`
`LEADER
`
`SUSTAIN-6
`
`Agent
`n
`Median follow-up, yrs
`Mean baseline HbA1c, %
`Primary outcome
`
`HR (95% CI)
`
`Adverse events
`
`Empagliflozin
`7,020
`3.1
`8.1
`CV death
`Nonfatal MI
`Nonfatal stroke
`0.86 (0.74–0.99),
`p ¼ 0.04
`Genital infections
`(male and female)
`
`Canagliflozin
`10,142
`2.4
`8.2
`CV death
`Nonfatal MI
`Nonfatal stroke
`0.86 (0.75–0.97),
`p ¼ 0.02
`Amputations, fractures,
`male genital infections,
`female mycotic
`infections, volume
`depletion
`
`Liraglutide
`9,340
`3.8
`8.7
`CV death
`Nonfatal MI
`Nonfatal stroke
`0.87 (0.78–0.97)
`p ¼ 0.01
`Acute gallstone disease, injection
`site reactions, and adverse
`events leading to drug
`discontinuation (nausea,
`vomiting, diarrhea, abdominal
`pain/discomfort, anorexia)
`
`Semaglutide
`3,297
`2.1
`8.7
`CV death
`Nonfatal MI
`Nonfatal stroke
`0.74 (0.58–0.95)
`p ¼ 0.02
`Retinopathy, gastrointestinal
`disorders, any adverse
`leading to drug
`discontinuation (nausea,
`vomiting, diarrhea in a
`dose-dependent response)
`
`Bolded outcome was statistically significant (p < 0.05).
`GLP-1 RA ¼ glucagon-like peptide-1 receptor agonists; HbA1c ¼ hemoglobin A1c; HR ¼ hazard ratio; SGTL2-i ¼ sodium-glucose cotransporter 2 inhibitors.
`
`between the active treatment and placebo arms in these
`trials was modest
`(0.3% and 0.6% in EMPA-REG
`OUTCOME and CANVAS, respectively) and is unlikely
`to account for the reduction in CV events with SGLT2-i
`(5,8). Although still speculative,
`the nonglycemic
`effects of SGLT2-i
`likely drive the observed weight
`loss, reduction in blood pressure, and preservation of
`renal function. Improvements in these pathogenic risk
`factors may reduce CV events, heart
`failure, and
`progression of nephropathy (15). Interestingly, both
`empagliflozin and canagliflozin demonstrated small
`increases (z3 to 4 mg/dl
`increases in low-density
`lipoprotein [LDL] cholesterol) over the trial duration
`(5,8,18). Some SGLT2-I, such as canagliflozin, have also
`been shown to reduce epicardial adipose tissue, which
`may be linked to coronary atherogenesis and impaired
`myocardial function, possibly providing an additional
`mechanism of CV benefit for SGLT2-i (19); a clinical
`trial examining dapagliflozin and epicardial adipose
`tissue is ongoing (NCT02235298).
`SGLT2-i–induced glucosuria can promote uric acid
`excretion, with animal models suggesting a possible
`inhibitory
`effect
`of
`glucosuria
`on uric
`acid
`reabsorption mediated by the GLUT9 isoform 2
`transporter (20). High uric acid levels have been
`associated with increased CV and renal disease (21).
`Glucosuria also leads to ongoing caloric loss, a
`persistent catabolic state, and increased ketogenesis
`(15). The resulting mild ketonemia caused by SGLT2-i
`may be an efficient fuel substrate for the heart,
`and may mitigate some of the metabolic effects
`associated with incipient heart failure (18).
`H e m o d y n a m i c e f f e c t s . The very early reduction in
`CV mortality observed in the EMPA-REG OUTCOME
`trial and early reduction in heart failure in CANVAS,
`
`along with heterogeneity of the hazard ratios (HRs)
`for the atherosclerotic components of the 3-point
`major adverse cardiovascular events (MACE-3), sug-
`gest that the early cardioprotective mechanism of
`benefit from SGLT2-i may be related to improved
`hemodynamic status (5,8,22). This reasoning is sup-
`ported by a recent post hoc mediation analysis of
`EMPA-REG OUTCOME, which demonstrated that
`plasma volume, as measured by hemodynamic
`markers (e.g., hematocrit), appeared to have a larger
`effect on the reduction of CV mortality than measures
`of glycemia (23).
`SGLT2-i may also derive hemodynamic benefit
`through a reduction in blood pressure, but this is
`unlikely to explain the rapid reduction in CV mor-
`tality observed in the SGLT2-i CV outcome trials. A
`meta-analysis of 27 SGLT2-i trials demonstrated a
`systolic blood pressure reduction of approximately
`4 mm Hg among patients with T2D, likely driven by
`natriuresis osmotic diuretic effects (24). Animal
`studies have suggested that SGLT2-i have the poten-
`tial to restore nocturnal dipping and have an additive
`effect when combined with use of
`a
`renin-
`angiotensin-aldosterone system inhibitor, possibly
`due to effects of the renin-angiotensin-aldosterone
`system in the volume-contracted state (15,25). The
`natriuretic and diuretic effects of SGLT2-i may also
`improve arterial stiffness (15), an independent sub-
`clinical predictor of CV risk and mortality (26),
`although the exact mechanism remains unclear.
`Moreover, a reduction in blood pressure can mitigate
`heart failure risk by reducing cardiac afterload and
`improving coronary flow and cardiac contractility. A
`reduction in plasma volume via natriuresis and os-
`motic diuresis can also reduce cardiac pre-load and
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`CENTRAL ILLUSTRATION Potential Pathways of Cardiovascular Benefit From Use of SGLT2 Inhibitors and GLP-1
`Receptor Antagonists for Patients With T2D
`
`SGLT-2 Inhibitors
`
`GLP-1R Agonists
`
`Afterload
`Epicardial Fat
`
`! Preload
`I
`
`f Glycosuria
`
`Natriuresis
`Uricosuria
`
`Hemodynamic
`Effect
`
`\
`
`t Satiety
`
`Nausea
`
`\
`
`j
`
`Anti-Atherogenic
`Effect
`
`1111
`
`Major Adverse
`
`l Cardiovascular
`
`Events
`Nephropathy
`Weight
`Blood Pressure
`
`Newman, J.D. et al. J Am Coll Cardiol. 2018;72(15):1856–69.
`
`♦ Vasodiliation
`
`I Post-prandial
`t GLucose
`
`Potential mechanisms of action of sodium-glucose cotransporter 2 (SGTL2) inhibitors and glucagon-like peptide receptor (GLP-1 R) agonists to mediate glycemic
`control and cardiovascular benefit. The cardiovascular benefit of SGLT2 inhibitors may occur through glycosuria and favorable hemodynamic effects. Conversely, the
`benefit of the GLP-1 R agonists may occur via post-prandial pancreatic insulin secretion and favorable antiatherogenic effects.
`
`myocardial stretch, thus protecting against the pro-
`gression of heart
`failure and arrhythmogenesis,
`respectively (27).
`The effects of SGLT2-i on renal hemodynamics and
`glomerular function may be a primary mechanism
`through which CV benefit from this class of agents is
`derived. The cardiorenal benefits of SGLT2-i include
`lowering intraglomerular pressure and reducing dia-
`betic hyperfiltration (28), a process characterized by
`diminished distal salt delivery and maladaptive
`tubuloglomerular
`feedback,
`resulting in afferent
`
`arteriole vasodilatation and hyperfiltration (29).
`SGLT2-i counteract this process and lower intra-
`glomerular pressure leading to cardiorenal protective
`effects for patients with diabetes. A reduction in
`intraglomerular pressure may also suppress renal
`inflammation and fibrosis, further protecting against
`nephropathy and albuminuria (15). Current evidence
`from CV outcome trials with SGLT2-i supports this
`possibility (Figure 1). The ongoing CREDENCE (Eval-
`uation of the Effects of Canagliflozin on Renal and
`Cardiovascular Outcomes
`in Participants With
`
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`F I G U R E 1 Summary of Renal Benefits in Major Recent Trials of SGTL2-i and GLP-1 RA
`
`Renal Outcomes
`(95% CI)
`
`:
`
`0.61 (0.53-0.7)
`
`I
`
`■
`
`I
`
`1--+-1
`
`0.73 (0.67-0.79)
`
`0.78 (0.67-0.92)
`
`0.64 (0.46-0.88)
`
`EMPA-REG
`
`CANVAS
`PROGRAM
`
`LEADER
`
`SUSTAIN-6
`
`0.6
`0.4
`All trials used a roughly similar composite for
`adverse renal outcomes including progression
`of albuminuria.
`
`0.8
`Favors Therapy
`
`1.0
`
`1.2
`Favors Placebo
`
`1.4
`
`Renal outcomes were all favorably reduced by therapy in EMPA-REG (Empagliflozin
`Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), CANVAS
`PROGRAM (Canagliflozin Cardiovascular Assessment Study), LEADER (Liraglutide Effect
`and Action in Diabetes: Evaluation of Cardiovascular Outcome Results), and SUSTAIN-6
`(Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in
`Subjects With Type 2 Diabetes). All trials used a roughly similar composite for adverse
`renal outcomes including progression of albuminuria. CI ¼ confidence interval; SGLT2-i ¼
`sodium-glucose co-transporter 2 inhibitor.
`
`(NCT02065791) evalu-
`trial
`Diabetic Nephropathy)
`ating primary renal endpoints will further define the
`cardiorenal protective effects of canagliflozin in
`approximately 4,200 adults with T2D and diabetic
`nephropathy (defined as stage 2 or 3 chronic kidney
`disease with macroalbuminuria) on a maximally
`tolerated angiotensin-converting enzyme inhibitor or
`angiotensin receptor blocker
`(30). The primary
`endpoint of this important trial includes a composite
`of end-stage renal disease, doubling of serum creati-
`nine, and renal or CV death.
`CLINICAL TRIAL EVIDENCE SUPPORTING SGLT2-I
`USE FOR THE REDUCTION OF CVD. Major CV
`outcome trials have been completed for 2 agents in
`this class: empagliflozin (EMPA-REG OUTCOME) and
`canagliflozin (CANVAS Program) (5,8), with results
`from trials of other agents expected in 2019 (15,30,31).
`In both EMPA-REG OUTCOME and the CANVAS Pro-
`gram, SGLT2-i led to reductions in MACE-3 (CV death,
`nonfatal myocardial
`infarction [MI]; or nonfatal
`stroke) (Figure 2). Reduced heart failure hospitaliza-
`tions (Figure 2) and renal outcomes (Figure 1) were
`also demonstrated, but were not formally tested in
`the CANVAS Program because of the hierarchical
`testing plan (8). One difference between EMPA-REG
`OUTCOME and the CANVAS Program is the signifi-
`cant reduction in CV and all-cause mortality with
`
`empagliflozin, both of which were not observed in the
`CANVAS Program (5,8).
`The main reason for the difference in study out-
`comes between these 2 trials may be attributable to
`differences in the enrolled study populations and
`differential follow-up duration. Participants in EMPA-
`REG OUTCOME were followed for a median of 3.1
`years and all were required to have a history of CV
`disease (coronary artery disease, stroke, or peripheral
`artery disease). Participants in the CANVAS Program
`were followed for a shorter duration (median of 2.4
`years) and could have either CV risk factors alone
`(34% of participants) or established CVD (66%).
`Reflecting the higher-risk population enrolled in
`EMPA-REG OUTCOME (secondary prevention), the
`MACE-3 composite and all-cause mortality were
`substantially higher in placebo group of EMPA-REG
`OUTCOME compared with the CANVAS Program
`(43.9 per 1,000 patient-years vs. 31.5 per 1,000
`patient-years,
`respectively)
`(5,8,14). The CANVAS
`Program is a combination of 2 separate studies;
`although both had identical entry criteria (8), follow-
`up duration differed substantially: mean follow-up
`duration in CANVAS was 5.7 years, versus 2.1 years
`in the CANVAS-R study (8). As noted previously (14),
`the combination of z one-third primary prevention
`patients in the CANVAS program and shorter-term
`treatment
`in roughly one-half of
`the population
`(CANVAS-R) may partially explain a smaller effect of
`canagliflozin compared with empagliflozin.
`C a r d i o r e n a l p r o t e c t i o n a n d S G L T 2 - i . Type 2 dia-
`betes is a major risk factor for macrovascular and
`microvascular disease (32). Kidney disease develops
`in nearly 35% of patients with T2D and is associated
`with increased mortality (33). Both EMPA-REG
`OUTCOME and the CANVAS Program demonstrated
`cardiorenal protective effects of SGLT2-i with empa-
`respectively (Figure 1).
`gliflozin or canagliflozin,
`The renal benefits of empagliflozin were reported
`as a pre-specified secondary analysis from EMPA-
`REG OUTCOME (34). Participants
`in EMPA-REG
`OUTCOME had an estimated glomerular filtration
`rate $30 ml/min per 1.73 m2 of body surface area (5).
`The pre-specified renal outcomes included incident
`or worsening nephropathy (progression to macro-
`albuminuria, doubling of the serum creatinine level,
`initiation of renal-replacement therapy, or death from
`renal disease) and incident albuminuria (34). Overall,
`there was nearly a 40% reduction (HR: 0.61; 95%
`confidence interval [CI]: 0.53 to 0.70) in the primary
`renal outcome (absolute risk reduction 6.1%)
`for
`participants receiving empagliflozin compared with
`placebo (Figure 1) (34). Although the CANVAS Pro-
`gram analysis plan precluded formal assessments of
`
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`IllllJIJL
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`11
`
`F I G U R E 2 Summary of Reductions in MACE in Recent SGLT2-i Trials
`
`MACE-3
`
`CV Death
`
`Fatal and Nonfatal MI
`
`Fatal and Nonfatal Stroke
`
`Heart Failure Hospitalization
`
`All-Cause Mortality
`
`I
`
`0.5
`Favors SGLT2-i
`
`1.0
`
`1.5
`Favors Placebo
`
`■ ■
`
`EMPA-REG, N = 7020
`CANVAS PROGRAM, N = 10,142
`
`Both empagliflozin and canagliflozin significantly reduced MACE-3 and heart failure
`hospitalization in the EMPA-REG trial and CANVAS Program, respectively. A reduction in
`cardiovascular (CV) death and all-cause mortality was observed with use of empagliflozin.
`MACE ¼ major adverse cardiac events; MI ¼ myocardial infarction; other abbreviations
`as in Figure 1.
`
`outcome trials (5,8). In general, empagliflozin and
`canagliflozin were well tolerated. Approximately 23%
`and 29% of participants in EMPA-REG OUTCOME and
`CANVAS discontinued active study drug, compared
`with 29% and 30% for placebo, respectively (5,8). The
`percent discontinuation of active drug is similar to
`other major placebo-controlled CV outcome trials
`(43). Genital
`infections were more common with
`SGLT2-i versus placebo in both EMPA-REG OUTCOME
`and the CANVAS Program. However, these infections
`infrequently resulted in study drug discontinuation.
`Additionally, there were differences in the definition
`and sex distribution of genital infections between the
`2 trials, but these differences also did not appear to
`influence rates of drug discontinuation (5,8). Impor-
`tantly, there was no difference in the occurrence of
`complicated urinary tract infections between partici-
`pants receiving SGLT2-i compared with placebo in
`these trials. The risk of volume depletion appears
`similar with both empagliflozin and canagliflozin,
`though volume depletion was statistically more
`common only in the CANVAS Program(5,8). The
`CANVAS Program identified new safety concerns for
`amputations and fractures, which were collected as
`interest (Figure 3A).
`an adverse event of special
`Increased risk of fractures or amputations have not
`
`for
`the point estimates
`significance,
`statistical
`reduction in renal events with empagliflozin and
`canagliflozin suggest a consistency of benefit for
`reduction in renal events with SGTL2-i (5,8). A post
`hoc analysis of the CANVAS Program evaluating par-
`ticipants with an estimated glomerular filtration rate
`(eGFR) down to 30 ml/min/1.73 m2 found a similar
`reduction in CV events and progression of kidney
`disease among those with impaired renal function at
`baseline, despite a progressive attenuation of HbA1C
`lowering with SGLT2-i at lower eGFR (35).
`H e a r t f a i l u r e b e n e fi t s a n d S G L T 2 - i . Similar to the
`relationship between diabetes and renal dysfunction,
`heart failure (HF) is also highly prevalent in patients
`with T2D (36). Patients with T2D and comorbid HF
`have an extremely poor prognosis, with a median
`survival of approximately 4 years (37). As shown in
`Figure 2, the magnitude of reduction in the heart
`failure composite endpoint is similar for empagli-
`flozin and canagliflozin (22,38). It has been suggested
`that the rapid benefit observed with SGLT2-i is un-
`likely due to reductions in atherothrombotic events
`via improved control of classical CV risk factors, but
`rather related to the hemodynamic and diuretic ef-
`fects of SGLT2-i given the rapidity of benefit (38–40).
`Limitations of these trials include the absence of
`systematically collected baseline biomarkers of heart
`failure or echocardiography data (22,38). It is also
`important to note that EMPA-REG OUTCOME and the
`CANVAS Program were not designed as heart failure
`trials and had few patients with investigator-reported
`heart failure at baseline. Moreover, the safety and
`efficacy of SGLT2-i in patients with clinical symptoms
`of heart failure is unknown. However, given the
`baseline characteristics of patients included in these
`studies (older, long duration of T2D, comorbid CAD
`and hypertension), and the high usage of drugs to
`treat heart failure, it is reasonable to assume that the
`burden of comorbid left ventricular dysfunction
`and/or HF in this population was substantial (22).
`Recent analyses have also suggested the reduction in
`HF and mortality may be a class effect applicable to a
`broad population of patients with T2D in real-word
`practice settings (41,42). The ongoing heart failure
`trials with empagliflozin (EMPEROR-HF [EMPagli-
`flozin outcomE tRial in patients with chrOnic heaRt
`failure]) and dapagliflozin (DAPA-HF [Dapagliflozin-
`Heart Failure]) will provide further insight into SGLT-
`2i and heart failure in patients with and without
`diabetes, as well as heart failure patients with both
`preserved and reduced ejection fraction.
`REPORTED SIDE EFFECTS OF SGLT2-I USE IN CV
`OUTCOME TRIALS. Figure 3A presents the a summary
`of the side effects observed in the major SGLT2-i CV
`
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`1862
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`Newman et al.
`Glucose Lowering Drugs for CVD in Diabetes
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`J A C C V O L . 7 2 , N O .
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`1 5 , 2 0 1 8
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`O C T O B E R 9 , 2 0 1 8 : 1 8 5 6 – 6 9
`
`F I G U R E 3 Summary of Side Effects in Major Recent Trials of SGLT2-i and GLP-1 RA
`
`THE GLP-1 RECEPTOR AGONISTS
`
`A
`
`Genital Infections
`
`Volume Depletion
`
`All Fractures
`
`All Amputations
`
`+ ji------------t
`
`1-+-1
`~
`
`~
`
`■
`
`0
`Favors SGLT2-i
`
`1
`
`2
`
`EMPA-REG
`■
`
`4
`Favors Placebo
`CANVAS PROGRAM
`■
`
`B
`
`Acute Gallstone
`Disease
`
`Adverse GI Symptoms
`Leading to Drug
`Discontinuation
`
`Retinopathy
`Complications
`
`■
`
`■
`
`1--+-1
`
`■
`
`0
`Favors GLP1-RA
`
`■
`
`: i------------t
`
`1
`
`LEADER
`■
`
`2
`
`3
`Favors Placebo
`SUSTAIN-6
`■
`
`(A) Side effects of SGLT2-i. Genital infections were significantly increased with SGLT-2i
`use in EMPA-REG OUTCOME and the CANVAS Program. Amputation risk was significantly
`increased with canagliflozin use. (B) Side effects of GLP-1 RA. Liraglutide and semaglutide
`were significantly associated with higher drug discontinuation rates due to adverse GI
`symptoms. Acute gallstone disease was significantly increased with liraglutide use, and
`retinopathy complication was significantly increased with semaglutide use.
`GI ¼ gastrointestinal; other abbreviations as in Figures 1 and 2.
`
`been demonstrated with empagliflozin (44,45),
`although lower
`limb amputations were not pre-
`specified
`events
`of
`concern
`in
`EMPA-REG
`OUTCOME. Although increased amputations with
`canagliflozin have also been reported from the FDA’s
`Adverse Event Reporting System (46) and in a
`propensity-matched cohort from the U.S. Department
`of Defense Military Health System (42), a plausible
`mechanism for effects of SGLT2-i on bone or vascular
`biology has not been determined (14).
`
`In comparison to the CV outcomes trials with SGLT2-i,
`trial results with the GLP-1 RA have been more het-
`erogeneous (6,7,9,47);
`there are additional
`trials
`ongoing using albiglutide (HARMONY outcomes [Ef-
`fect of Albiglutide, When Added to Standard Blood
`Glucose Lowering Therapies, on Major Cardiovascular
`Events in Subjects With Type 2 Diabetes Mellitus];
`NCT02465515) and dulaglutide (REWIND [Research-
`ing Cardiovascular Events With a Weekly Incretin in
`Diabetes]; NCT01394952). The potential mechanisms
`of effect have been described in detail (48,49), and
`are summarized here and in the Central Illustration.
`
`POTENTIAL MECHANISMS OF BENEFIT FOR THE
`GLP-1 RECEPTOR AGONISTS. Oral glucose ingestion
`results in higher serum insulin levels than an equiv-
`alent parenteral glucose load, likely mediated by the
`incretin pathway (50). Glucagon-like peptide (GLP)-1,
`a type of incretin polypeptide,
`is secreted by the
`distal intestinal L-cells in response to oral nutrient
`ingestion and has several downstream effects prior
`to its rapid degradation by DPP4. (51). Endogenous
`GLP-1 acts primarily to stimulate pancreatic beta cells
`to release insulin and inhibit glucagon secretion,
`thereby providing a glucose-dependent mechanism
`to reduce post-prandial hyperglycemia without
`resulting in significant hypoglycemia (52). In vivo and
`animal studies have demonstrated a GLP-1–mediated
`increase in pancreatic islet and beta-cell mass, high-
`lighting a potential mechanism to retard T2D pro-
`gression (53). The incretin pathway may be impaired
`in T2D secondary to reduced GLP-1 secretion and
`resistance, providing a target for pharmacological
`intervention (54).
`Synthetic GLP-1 RA are resistant to DPP4 degrada-
`tion and accentuate the pleotropic effects associated
`with GLP-1 polypeptides (55). To date, there are 6
`FDA-approved GLP-1-RA, which differ in structure
`and duration of effect. These include: exenatide (both
`short- and long-acting formulations),
`liraglutide,
`semaglutide, dulaglutide, lixisenatide, and albiglu-
`tide. Both exenatide and lixisenatide are derived
`from exogenous Gila monster venom, whereas the
`others are modifications of endogenous GLP-1 (56).
`The longer-acting formulations are associated with
`dose-dependent reductions in HbA1c and lowering of
`fasting (vs. post-prandial) reductions in glucose. The
`shorter-acting formulations
`are associated with
`greater post-prandial glucose lowering, likely medi-
`ated more by slowing of gastric motility as opposed to
`insulin release, as discussed in detail elsewhere
`(56,57). Large CV outcome trials have been completed
`
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`J A C C V O L . 7 2 , N O .
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`1 5 , 2 0 1 8
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`O C T O B E R 9 , 2 0 1 8 : 1 8 5 6 – 6 9
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`Newman et al.
`Glucose Lowering Drugs for CVD in Diabetes
`
`1863
`
`for 4 of the GLP-1 RA, all of which demonstrated
`noninferiority
`compared with placebo in T2D
`(6,7,9,47). However,
`only
`liraglutide
`(LEADER
`[Liraglutide Effect and Action in Diabetes: Evaluation
`of Cardiovascular Outcome Results]) and semaglutide
`(SUSTAIN-6 [Trial to Evaluate Cardiovascular and
`Other Long-term Outcomes With Semaglutide in
`Subjects With Type 2 Diabetes]) showed superiority in
`reducing MACE (6,7), as summarized in Figure 4. The
`CV benefit