Diabetes Care Volume 40, July 2017
`
`813
`
`PERSPECTIVES IN CARE
`
`Cardiovascular Disease and Type 2
`Diabetes: Has the Dawn of a New
`Era Arrived?
`
`Diabetes Care 2017;40:813–820 | https://doi.org/10.2337/dc16-2736
`
`Muhammad Abdul-Ghani,1,2
`Ralph A. DeFronzo,1 Stefano Del Prato,3
`Robert Chilton,4 Rajvir Singh,2 and
`Robert E.J. Ryder 5
`
`Hyperglycemia is the major risk factor for microvascular complications in
`patients with type 2 diabetes (T2D). However, cardiovascular disease (CVD) is
`the principal cause of death, and lowering HbA1c has only a modest effect on
`reducing CVD risk and mortality. The recently published LEADER and SUSTAIN-6 trials
`demonstrate that, in T2D patients with high CVD risk, the glucagon-like peptide 1
`receptor agonists liraglutide and semaglutide reduce the primary major adverse
`cardiac events (MACE) end point (cardiovascular death, nonfatal myocardial infarc-
`tion, nonfatal stroke) by 13% and 24%, respectively. The EMPA-REG OUTCOME, IRIS
`(subjects without diabetes), and PROactive (second principal end point) studies
`also demonstrated a significant reduction in cardiovascular events in T2D pa-
`tients treated with empagliflozin and pioglitazone. However, the benefit of
`these four antidiabetes agents (liraglutide, semaglutide, empagliflozin, and
`pioglitazone) on the three individual MACE end points differed, suggesting that
`different underlying mechanisms were responsible for the reduction in cardio-
`vascular events. Since liraglutide, semaglutide, pioglitazone, and empagliflozin
`similarly lower the plasma glucose concentration but appear to reduce CVD risk
`by different mechanisms, there emerges the intriguing possibility that, if used
`in combination, the effects of these antidiabetes agents may be additive or
`even multiplicative with regard to cardiovascular benefit.
`
`Individuals with type 2 diabetes (T2D) have a twofold increased risk for cardio-
`vascular disease (CVD) (myocardial infarction, stroke, peripheral vascular dis-
`ease), and CVD is the principal cause of death in T2D patients (1). Clinical trials
`(2–5) consistently have demonstrated that lowering HbA1c in T2D patients has no (2,3)
`or only a modest (4,5) effect on reducing cardiovascular (CV) risk. In contrast, correction
`of traditional CVD risk factors, e.g., blood pressure and cholesterol, markedly reduces
`CVD risk and mortality in patients with T2D. The recently published LEADER
`(Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome
`Results) (6) and SUSTAIN-6 (Trial to Evaluate Cardiovascular and Other Long-term
`Outcomes with Semaglutide in Subjects with Type 2 Diabetes) (7) trials provide evidence
`that glucagon-like peptide 1 receptor agonists (GLP-1 RAs) (liraglutide and semaglutide)
`reduce CVD risk beyond their glucose-lowering effect and improvement in other
`CVD risk factors in T2D patients with established CVD. Together with EMPA-REG
`OUTCOME (BI 10773 [Empagliflozin] Cardiovascular Outcome Event Trial in Type 2
`Diabetes Mellitus Patients) (8), IRIS (Insulin Resistance Intervention After Stroke
`Trial) (9), and PROactive (PROspective pioglitAzone Clinical Trial In macroVascular
`Events) (10)dwhich showed reduction in major adverse cardiac events (MACE) end
`points of 14%, 24%, and 16% (main secondary end point), respectivelydthese
`studies make it clear that we are entering a new era in T2D management, where the
`
`1Division of Diabetes, University of Texas Health
`Science Center at San Antonio, and South Texas
`Veterans Health Care System, San Antonio, TX
`2Diabetes Clinical Research Center, Academic
`Health System, Hamad General Hospital, Doha,
`Qatar
`3Department of Clinical and Experimental Med-
`icine, University of Pisa School of Medicine, Pisa,
`Italy
`4Division of Cardiology, University of Texas
`Health Science Center at San Antonio, and
`South Texas Veterans Health Care System, San
`Antonio, TX
`5Sandwell and West Birmingham Hospitals Na-
`tional Health Service Trust, Birmingham, U.K.
`
`Corresponding author: Ralph A. DeFronzo,
`albarado@uthscsa.edu.
`
`Received 3 January 2017 and accepted 5 April
`2017.
`
`This article contains Supplementary Data online
`at http://care.diabetesjournals.org/lookup/
`suppl/doi:10.2337/dc16-2736/-/DC1.
`
`M.A.-G. and R.A.D. contributed equally to the
`development of this Perspective.
`
`© 2017 by the American Diabetes Association.
`Readers may use this article as long as the work
`is properly cited, the use is educational and not
`for profit, and the work is not altered. More infor-
`mation is available at http://www.diabetesjournals
`.org/content/license.
`See accompanying article, p. 821.
`
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`
`newer antidiabetes medications, in addi-
`tion to lowering plasma glucose, also
`exert a CV protective effect that is inde-
`pendent of reduction in plasma glucose
`concentration and traditional CVD risk
`factors.
`
`CV RISK IN T2D
`The major benefit of reducing plasma glu-
`cose levels in T2D is prevention of long-
`term microvascular complications and,
`to lesser extent, macrovascular complica-
`tions. Individuals with T2D have two- to
`threefold greater risk of CV events com-
`pared with subjects without diabetes, and
`CVD is responsible for ;80% of the mor-
`tality in T2D (1). Hyperglycemia is a weak
`risk factor for CVD (5,11), and interven-
`tions (2–4) focused on reducing plasma
`glucose have failed to significantly reduce
`CV risk and mortality, particularly in sec-
`ondary prevention trials. Moreover, in
`the United Kingdom Prospective Diabetes
`Study (UKPDS) (11) and Veterans Affairs
`Diabetes Trial (VADT) (12), it took 10 years
`to observe the CV benefit associated
`with improved glycemic control. Most in-
`dividuals with T2D manifest moderate
`to severe insulin resistance, which is as-
`sociated with multiple CV risk factors
`(obesity, dyslipidemia, hypertension,
`endothelial dysfunction, procoagulant
`state). This cluster of CV/metabolic dis-
`turbances is known as insulin resistance
`(metabolic) syndrome and is a principal
`factor responsible for increased CV risk
`in T2D (13,14). A multifactorial interven-
`tion that improves CV risk factors has
`been shown to reduce CV events and
`mortality in T2D (15). Further, the molec-
`ular mechanisms responsible for insulin
`resistance directly contribute to patho-
`genesis of atherosclerosis, independent
`of associated metabolic abnormalities
`(13,14). Thus, obese individuals without
`diabetes but with insulin resistance syn-
`drome manifest a similarly increased risk
`for CVD compared with T2D patients, sup-
`porting the concept that hyperglycemia is
`not the major risk factor for CVD (16).
`Consequently, it is not surprising that
`lowering blood pressure and improving
`the lipid profile lead to greater reduc-
`tion in CVD risk than lowering plasma
`glucose in T2D. Consistent with this, anti-
`diabetes agents like insulin (17), sulfonyl-
`ureas (18,19), and dipeptidyl peptidase
`4 (DPP-4) inhibitors (20–22), which
`lower plasma glucose without affecting
`insulin resistance or other metabolic
`
`abnormalities associated with insulin re-
`sistance syndrome, do not lower CVD risk
`and mortality in T2D. Conversely, piogli-
`tazone, which improves insulin sensitivity
`and multiple components of insulin resis-
`tance syndrome, i.e., blood pressure, lip-
`ids, and endothelial dysfunction (23),
`exerts a favorable effect on CVD risk in
`T2D, independent of its glucose-lowering
`action (9,10). In PROactive (9) pioglita-
`zone lowered MACE (CV death, nonfatal
`myocardial
`infarction [MI], nonfatal
`stroke), which was the main secondary
`end point, by 16% (P 5 0.027), and in
`IRIS (9) pioglitazone reduced the inci-
`dence of recurrent stroke and MI by
`24% in insulin-resistant individuals
`without diabetes who had suffered a
`recent transient ischemic attack or
`stroke.
`
`LEADER AND SUSTAIN-6
`LEADER (6) and SUSTAIN-6 (7) examined
`the effect of once-daily liraglutide and
`once-weekly semaglutide on CV risk
`(Supplementary Table 1). In LEADER (6),
`9,340 T2D patients at high CVD risk (82%
`with prior CV event) were randomized
`to liraglutide, 1.8 mg/day, or placebo for a
`mean of 3.8 years. Investigators were
`blinded to the study intervention and in-
`structed to maintain HbA1c ,7.0% with
`any antidiabetes medication except a
`GLP-1 RA or DPP-4 inhibitor. The primary
`outcome was 3-point MACE. Liraglutide-
`treated patients experienced a 13% re-
`duction in MACE, which was driven by a
`22% reduction in CV mortality (P 5
`0.007). Nonfatal MI was decreased by
`12% (P 5 0.11), while nonfatal stroke
`was reduced by 11% (P 5 0.30).
`In SUSTAIN-6 (phase 3 trial) (7), 3,297
`T2D patients at high risk for CVD were
`randomized to semaglutide, 0.5 and
`1 mg/week, or placebo and followed for
`104 weeks. This study was designed to
`demonstrate noninferiority, which
`accounts for the smaller number of sub-
`jects. The primary outcome was 3-point
`MACE. Most participants (83%) had es-
`tablished CVD and the remaining 17%
`were .60 years of age with multiple CV
`risk factors that were well controlled. In-
`vestigators were instructed to lower
`HbA1c to ,7.0% according to local guide-
`lines without using incretin-based thera-
`pies. Subjects receiving semaglutide
`experienced greater HbA1c reduction
`than those on placebo (1.4% vs. 0.4%).
`This difference (1.0%) in HbA1c was
`
`considerably greater than in LEADER
`(0.4%). Weight loss (4 kg) and systolic
`blood pressure reduction (3 mmHg)
`were twice as great in SUSTAIN-6 versus
`LEADER. In SUSTAIN-6, the primary out-
`come (3-point MACE) was reduced by
`26%, and that decrease was driven pri-
`marily by a 39% reduction in nonfatal
`stroke (P 5 0.04) and a 26% reduction
`in nonfatal MI (P 5 0.12); CV mortality
`was not decreased (hazard ratio [HR] 5
`0.98). Of note, the placebo group had
`significantly more revascularization pro-
`cedures than the semaglutide group,
`which could have reduced future deaths;
`it may be that the similar overall CV
`death rate between the two groups re-
`sulted from the increased number of re-
`vascularization procedures in the control
`group.
`Two aspects of LEADER and SUSTAIN-6
`deserve emphasis: 1) patients at higher
`CVD risk benefited more from GLP-1 RA
`treatment, and 2) the benefit of liraglu-
`tide and semaglutide was evident on top
`of optimal control of traditional CV risk
`factors. In a meta-analysis of the two
`long-acting GLP-1 RAs (Fig. 1), 3-point
`MACE was decreased by 15%, with similar
`and significant benefit for all three com-
`ponents: nonfatal stroke, nonfatal MI,
`and mortality by 18%, 16%, and 13%,
`respectively.
`However, there are some concerns
`about the generalizability of findings in
`LEADER. In the 23% of participants
`without a prior CV event, there was no
`reduction in MACE (HR 5 1.20, P not sig-
`nificant). There was more sulfonylurea
`and insulin use in the placebo group. In
`SUSTAIN-6, the number of participants
`was one-third of that in LEADER, the
`follow-up was short (two years), the
`decrement in HbA1c (1.0%) was much
`
`Figure 1—Effect of long-acting GLP-1 RAs on
`CVD outcome. Data are combined from
`LEADER (6) and SUSTAIN (7).
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`greater in the treatment group than the
`placebo group (although hyperglycemia
`is not considered to be a major risk fac-
`tor for CVD), and the incidence of serious
`eye complications (vitreous hemorrhage,
`blindness, and photocoagulation) was
`significantly increased.
`
`PIOGLITAZONE AND CVD
`In PROactive, 5,238 patients with T2D
`with established CVD (population similar
`to EMPA-REG OUTCOME) were random-
`ized to pioglitazone or placebo plus
`standard of care for CV risk factors and
`glycemic control (10). The 3-point MACE,
`the “main secondary end point,” was sig-
`nificantly reduced (HR 5 0.84, P 5 0.027).
`The primary end point (3-point MACE
`plus coronary and leg revascularization)
`did not reach statistical significance
`(HR 5 0.90, P 5 0.09); however, it is
`now well recognized that peripheral
`vascular disease is refractory to antihy-
`pertensive, lipid-lowering, and glucose-
`lowering therapy (24,25). Further, by
`preserving people from death, MI, and
`stroke, pioglitazone would make more peo-
`ple available for leg revascularization (26).
`In IRIS (9), 3,876 insulin resistant
`(HOMA-IR .3.0) nondiabetic individuals
`with a recent (within 6 months) ischemic
`stroke or transient ischemic attack were
`randomized to pioglitazone or placebo for
`4.8 years. Subjects receiving pioglitazone
`experienced a 24% reduction in fatal/
`nonfatal stroke plus MI (HR 0.76, P 5
`0.007); mortality was reduced slightly
`(by 7%) but not significantly.
`Meta-analysis was performed to exam-
`ine the combined effect of the treatments
`compared with the placebo-treated con-
`trol group. Outcomes were expressed as
`risk ratios and combined risk difference
`(with 95% CI) and were calculated using
`a fixed effect model. To examine the ap-
`propriateness of the model, Cochran’s Q
`was calculated to measure inconsistency
`between studies and I2 was calculated to
`describe the percentage of variation.
`CMA statistical package was used for
`the analysis. Differences were consid-
`ered significant at P , 0.05 (Fig. 2 and
`Supplementary Table 1).
`In a meta-analysis of PROactive plus
`IRIS (Fig. 2), pioglitazone reduced 3-point
`MACE by 18%, with the main effect being
`driven by an 18% reduction in stroke
`and a 26% reduction in MI, while total
`mortality decreased, but not significantly,
`by 8%.
`
`subjects treated with the active drug ex-
`perienced significantly lower HbA1c than
`patients receiving placebo (0.3% in
`EMPA-REG OUTCOME, 1.0% in SUSTAIN-
`6, 0.4% in LEADER, 0.5% in PROactive).
`However, it is unlikely that such HbA1c
`differences over 2–4 years can explain
`the difference in primary outcome
`(MACE). First, hyperglycemia is a weak
`risk factor for CV disease. Intensive gly-
`cemic control failed to decrease CV
`events in the Action to Control Cardio-
`vascular Risk in Diabetes (ACCORD) (2),
`Action in Diabetes and Vascular Disease:
`Preterax and Diamicron MR Controlled
`Evaluation (ADVANCE) (3), and VADT (4)
`studies in T2D patients with long-standing
`diabetes duration, and in UKPDS (5,11)
`and VADT (12) it took 10 years to demon-
`strate a small (;10%), though significant,
`reduction in CV events in newly diag-
`nosed individuals. The beneficial CV ef-
`fects of empagliflozin, liraglutide, and
`pioglitazone were evident after 3, 18,
`and 24 months, respectively. More
`conclusively, IRIS participants were nor-
`moglycemic, making it unlikely that
`improved glucose control was a contribu-
`tory factor to the reduction in MI and
`stroke. The HbA1c difference between
`semaglutide and placebo in SUSTAIN-6
`was clinically meaningful (1.0%), but sim-
`ilar HbA1c reductions in ACCORD and
`ADVANCE had no benefit on MACE. Of
`note, in both LEADER and SUSTAIN-6
`the majority of treatment intensification
`in the placebo group was done with in-
`sulin and sulfonylureas, which have
`been associated with increased ath-
`erosclerotic CV events in some studies
`(14,18,19), although no randomized con-
`trol trials have demonstrated such an ad-
`verse effect.
`
`Prevention of Atherosclerosis
`Reduction in CV events in LEADER,
`SUSTAIN-6, IRIS, and PROactive started
`at 1–2 years after initiation of therapy
`and widened thereafter. This time course
`is reminiscent of interventions that slow
`atherosclerosis, e.g., statins and blood
`pressure–lowering therapy. Similar to re-
`sults with statins and antihypertensive
`medications, MI and stroke were reduced
`in SUSTAIN-6, LEADER, and PROactive, al-
`though the magnitude of reduction var-
`ied (Figs. 1 and 2); the effect on mortality
`varied most among the three studies.
`Pioglitazone improves multiple CV risk
`factors (blood pressure, triglycerides,
`
`Figure 2—Effect of pioglitazone on CVD out-
`comes. Data are combined from PROactive
`(10) and IRIS (9).
`
`EMPA-REG OUTCOME STUDY
`In EMPA-REG OUTCOME, empagliflozin
`caused a 14% reduction (P 5 0.04 for
`superiority) in 3-point MACE in 7,020
`patients with T2D with established CVD
`over 3.1 years (Supplementary Table 1).
`Several outcomes were surprising
`and different from LEADER, SUSTAIN-6,
`PROactive, and IRIS. First, the primary
`outcome was driven by a robust 38% re-
`duction in CV mortality. Second, there
`was a striking disconnect between the
`three MACE components (Fig. 3): 1) for
`nonfatal MI, HR (0.87) decreased slightly
`but not significantly (P 5 0.22); 2) for non-
`fatal stroke, HR (1.24) increased slightly
`but not significantly (P 5 0.22); 3) for
`CV death, HR (0.62) decreased markedly
`and significantly by 38% (P 5 0.001).
`Third, unlike in LEADER, SUSTAIN-6, and
`PROactive, separation between the em-
`pagliflozin and placebo curves occurred
`very early, such that reduction in the pri-
`mary outcome was evident at 3 months
`after starting treatment.
`
`POTENTIAL MECHANISMS TO
`EXPLAIN CV BENEFIT
`Glucose Control
`Although investigators were instructed
`to maintain HbA1c ,7.0% in all trials,
`
`Figure 3—Effect of empagliflozin on CVD out-
`comes in the EMPA-REG OUTCOME trial (8).
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`plasminogen activator inhibitor 1, endo-
`thelial dysfunction, insulin resistance, vis-
`ceral fat) (23) and has documented
`antiatherogenic effects in preclinical
`and clinical studies (9,10,23,27,28). Thus,
`the beneficial effect of pioglitazone in
`PROactive and IRIS is likely the result of
`this thiazolidinedione’s antiatherogenic
`effect.
`GLP-1 RAs also improve many CVD risk
`factors (obesity, hypertension, dyslipide-
`mia, inflammation, visceral fat) in T2D
`patients. However, the magnitude of im-
`provement in CV risk factors in SUSTAIN-6
`and LEADER was modest (2.3 kg weight
`loss and 1.2 mmHg decrease in systolic
`blood pressure in LEADER; 3.6–4.9 kg
`3.4–5.4 mmHg
`weight
`loss
`and
`decrease in systolic blood pressure in
`SUSTAIN-6). LDL cholesterol was not re-
`ported in either study. It is unlikely that
`these changes in CV risk factors can ex-
`plain the 13% (LEADER) and 26% (SUS-
`TAIN-6) reduction in primary outcome.
`In ADVANCE, a greater reduction in sys-
`tolic blood pressure (5.6/2.2 mmHg) was
`associated with a nonsignificant 8% re-
`duction in MI, stroke, and CV death. Sim-
`ilarly, it is unlikely that weight loss was the
`principal factor responsible for reduction
`in the primary outcome. In Look AHEAD:
`Action for Health in Diabetes, a mean
`weight loss of 4 kg in patients with T2D
`(twice that in liraglutide-treated patients
`in LEADER), as well as modest reductions
`in HbA1c, blood pressure, and triglycer-
`ides, was associated with a nonsignificant
`(5%) reduction in MI, stroke, and CV
`death.
`
`Insulin Sensitization
`Insulin resistance is a core defect in T2D
`and is associated with multiple metabolic
`and CV risk factors, which collectively are
`known as insulin resistance (metabolic)
`syndrome (14,16). Furthermore, the
`molecular etiology of insulin resistance
`promotes the development of atheroscle-
`rosis (14). It follows that interventions
`which improve insulin sensitivity might
`reduce CV events in T2D patients. Al-
`though neither insulin resistance nor sur-
`rogate markers of insulin resistance were
`measured in any of the CV outcome trials
`except IRIS, all active interventions (GLP-1
`RAs, sodium–glucose cotransporter 2 in-
`hibitors [SGLT2i], thiazolidinediones) are
`known to improve insulin sensitivity in
`T2D. Pioglitazone is a powerful insulin
`sensitizer in skeletal muscle, liver, and
`
`adipocytes (23), and in IRIS (9) HOMA-IR
`decreased by 24% (P , 0.001). GLP-1 RAs
`do not have a direct insulin-sensitizing ef-
`fect, but they promote weight loss, which
`is associated with enhanced insulin ac-
`tion. Lastly, treatment with dapagliflozin
`for as little as 2 weeks modestly increases
`insulin-mediated glucose disposal sec-
`ondary to reversal of glucotoxicity (29).
`Thus, improved insulin sensitivity could
`have contributed to the reduction in
`MACE in LEADER, SUSTAIN-6, EMPA-REG
`OUTCOME, PROactive, and IRIS.
`
`Direct Action on CV System
`GLP-1 receptors are expressed in the
`myocardium and vasculature (30), and
`GLP-1 and GLP-1 RAs can directly affect
`CV function via multiple mechanisms: 1)
`direct action on the myocardium; 2) di-
`rect effect on blood vessels to increase
`nitric oxide production, cause vasodila-
`tion, and increase blood flow; 3) direct
`effect on atherosclerotic plaque forma-
`tion; and 4) change in autonomic nervous
`system balance (31–33). With respect to
`the latter, GLP-1 RAs have been shown to
`stimulate the parasympathetic nervous
`system (34). This could explain the in-
`crease in heart rate, as well as the cardi-
`oprotective effect, seen with this class of
`antidiabetes drugs. Each of these GLP-1
`actions potentially could have contrib-
`uted to decreased CV events in SUS-
`TAIN-6 and LEADER.
`If GLP-1 RAs
`increase coronary blood flow, especially
`in patients with existing heart disease,
`this effect could reduce ischemia, infarct
`size, and risk of arrhythmias. A recent
`study in subjects with normal glucose tol-
`erance demonstrated that GLP-1 infusion
`augments blood flow in small vessels in
`skeletal muscle and heart (35), and in-
`creased blood flow in small coronary ves-
`sels after myocardial ischemia has been
`shown to predict increased survival and
`reduced infarct size after MI (36).
`Multiple studies in animals and hu-
`mans (37) have demonstrated a cardio-
`protective effect of GLP-1 and GLP-1 RAs
`on myocardial function after ischemic
`injury. These benefits include decreased
`infarct size, increased coronary blood
`flow, improved left ventricular (LV) func-
`tion, decreased LV filling pressure, and
`increased survival. Although the cellular/
`molecular mechanisms of these GLP-1 ac-
`tions are not fully understood, similar ef-
`fects of liraglutide and semaglutide on the
`heart in LEADER and SUSTAIN-6 could
`
`have contributed to the decrease in CV
`events and death. Studies in animals
`have demonstrated that the postischemic
`beneficial effects of GLP-1 on the heart
`are preserved in animals lacking the GLP-1
`receptor, suggesting a GLP-1 receptor–
`independent mechanism (38). In humans,
`beneficial effects of GLP-1 RAs on LV func-
`tion and filling pressure have been ob-
`served with exenatide (37), liraglutide
`(39), and native GLP-1 (40).
`Lastly, GLP-1 RAs can reduce CV events
`by slowing the atherosclerotic process.
`Studies in experimental animals have
`demonstrated that liraglutide accelerates
`endothelial recovery after injury (41),
`retards atheroma formation in apolipo-
`protein E knockout mice (42), exerts
`anti-inflammatory effects on the vascula-
`ture, and inhibits reactive oxygen species
`formation and platelet aggregation (43).
`Collectively, these actions of GLP-1 RAs
`could slow the atherosclerotic process.
`
`Hemodynamic Action of Empagliflozin
`to Reduce CVD
`The beneficial effect of empagliflozin on
`CV events differs from that of pioglita-
`zone and GLP-1 RAs with respect to
`both the time course and the individual
`components benefited (i.e., MI vs. stroke
`vs. mortality). The beneficial effect of em-
`pagliflozin on MACE was driven by a ro-
`bust reduction in CV mortality, was rapid
`in onset, and was associated with a
`marked decrease in hospitalization for
`heart failure. Empagliflozin did not signif-
`icantly reduce the risk of MI, while stroke
`risk increased slightly. As previously re-
`viewed (44), the impressive reductions
`in mortality and heart failure most likely
`are explained by the rapid and simulta-
`neous reductions in blood pressure
`(afterload reduction), intravascular vol-
`ume (preload reduction), and arterial
`stiffnessdi.e., hemodynamic effectsd
`and not by slowing of the atherosclerotic
`process. Consistent with this, a recent pre-
`liminary study demonstrated that empagli-
`flozin treatment for 3 months reduced LV
`mass index and improved diastolic dys-
`function (45). Other factors suggested to
`account for the beneficial CV effects in
`EMPA-REG OUTCOME have been re-
`viewed and include increased circulating
`ketone levels, reduced uric acid, and in-
`creased angiotensin (1–7) and angioten-
`sin type 2 receptor activity, among others
`(44). All of these proposed mechanisms
`focus on nonatherosclerotic processes.
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`IS THERE ADDITIVE
`CARDIOVASCULAR BENEFIT FROM
`COMBINATION THERAPY WITH
`MULTIPLE AGENTS?
`Because the beneficial CV effects of em-
`pagliflozin most likely are hemodynami-
`cally mediated, while those of GLP-1 RAs
`and pioglitazone represent a direct action
`on the vasculature (plus improved CV risk
`factors) to retard atherogenesis, it is plau-
`sible that combination therapy with em-
`pagliflozin plus pioglitazone and/or a
`GLP-1 RA will exert an additive, even syn-
`ergistic, CV benefit (Fig. 4). Empagliflo-
`zin profoundly reduced CV mortality,
`whereas pioglitazone and GLP-1 RAs pri-
`marily reduced the risk of nonfatal MI and
`nonfatal stroke, so addition of empagliflo-
`zin to pioglitazone or a GLP-1 RA may pro-
`duce a robust reduction in all three MACE
`components. Well-designed large, ran-
`domized, placebo-controlled studies
`should be performed to examine whether
`combination therapy with an SGLT2i,
`GLP-1 RA, and/or pioglitazone can pro-
`duce an additive effect to further reduce
`CV events compared with monotherapy
`with these agents.
`Combination therapy with an SGLT2i or
`GLP-1 RA with pioglitazone has other po-
`tential benefits. Pioglitazone improves di-
`astolic dysfunction, enhances myocardial
`insulin sensitivity and reduces myocardial
`fat content (46), and decreases blood
`pressure (23). However, these CV benefits
`can be offset by the drug’s sodium reten-
`tive effect on the kidney. Because SGLT2i
`(47) and, to lesser extent, GLP-1 RAs (31)
`exert a natriuretic effect, the renal salt
`retentive effect of pioglitazone will be
`negated. On the other hand, it is possible
`that the renal sodium retentive effect of
`pioglitazone could reduce some of the
`hemodynamic benefits produced by the
`
`Figure 4—Cardiovascular risk profile of anti-
`diabetes medications.
`
`volume-depleting effect of the SGLT2i.
`Since the side effects (fluid retention
`and weight gain) of pioglitazone are
`dose related (48), we do not recommend
`doses in excess of 30 mg/day. Pioglita-
`zone also promotes fat weight gain by
`stimulation of hypothalamic appetite
`centers (49). However, the fat weight
`gain primarily represents a cosmetic con-
`cern because the greater the weight gain,
`the more the decrement in HbA1c and the
`greater the improvements in b-cell func-
`tion and insulin sensitivity (50,51). Fur-
`thermore, pioglitazone reduces CV
`events (9,10,28). The weight gain can be
`negated by combining pioglitazone with
`an SGLTi or GLP-1 RA or both (52). Com-
`bination therapy with an SGLT2i and GLP-1
`RA is especially effective in reducing
`body weight (53). The only drug shown
`to conclusively reduce liver fat and re-
`verse biopsy-proven nonalcoholic steato-
`hepatitis (NASH) is pioglitazone (54). Both
`GLP-1 RAs (55) and SGLT2i (56) reduce
`visceral (hepatic) fat, making combination
`therapy with any two or three of these
`drugs an attractive option for prevent-
`ing/treating NASH and nonalcoholic fatty
`liver disease (NAFLD), and we recom-
`mend that such a study be carried out.
`In EMPA-REG OUTCOME, empagliflozin
`reduced the composite end point of renal
`disease by 39% (57). Although less well
`appreciated, thiazolidinediones also pre-
`vent diabetic nephropathy in diabetic
`animal models (58), and liraglutide in
`LEADER significantly reduced the com-
`posite renal outcome, although this was
`primarily due to its effect to decrease pro-
`teinuria (6). Thus, combination therapy
`with any of these three classes of antidia-
`betes medications may provide an addi-
`tive renal protective effect. Pioglitazone
`is a potent insulin-sensitizing agent (23)
`and markedly enhances and preserves
`b-cell function (50,51,59). SGLT2i cause
`a modest improvement in insulin sensitiv-
`ity (by 33%) and major improvement in
`b-cell function (by 217%) (29,60). GLP-1
`RAs exert a powerful effect to increase
`b-cell function (52,61–63) and indi-
`rectly improve insulin sensitivity by pro-
`moting weight loss (62). Thus, SGLT2i,
`GLP-1 RAs, and pioglitazone represent a
`triad of antidiabetes medications that,
`when used in combination, may provide
`additive effects in preventing CV compli-
`cations, promoting weight loss, preserv-
`ing renal function, preventing NASH/
`NAFLD, and improving b-cell function
`
`and insulin sensitivity. Patients treated
`with GLP-1 RAs plus pioglitazone should
`have an eye exam before initiating com-
`bination therapy with these two agents
`because of an increased incidence of
`eye complications in SUSTAIN-6 and rare
`cases of macular edema with pioglitazone
`use.
`Although the increase in stroke in
`EMPA-REG OUTCOME did not achieve
`statistical significance, it nevertheless
`presents a worry. The mechanisms respon-
`sible for any such increased stroke risk,
`despite decreased blood pressure, are un-
`clear. Since both pioglitazone (9,10) and
`GLP-1 RAs (6,7) significantly reduce the
`incidence of stroke in T2D patients, it is
`possible that addition of a GLP-1 RA or
`pioglitazone to empagliflozin will pre-
`vent any increase in stroke risk. Al-
`though results of the Dapagliflozin Effect
`on Cardiovascular Events (DECLARE)
`study (due in 2019) and the CANagliflo-
`zin cardioVascular Assessment Study
`(CANVAS)/Study of the Effects of Canagli-
`flozin on Renal Endpoints in Adult Sub-
`jects With Type 2 Diabetes Mellitus
`(CANVAS-R) (due in 2017) are not avail-
`able, a recent meta-analysis (64) suggests
`that all three SGLT2i will exert similar ef-
`fects on CV end points and congestive
`heart failure.
`
`DO THE CARDIOPROTECTIVE
`EFFECTS OF GLP-1 RAs AND SGLT2i
`REPRESENT A CLASS EFFECT?
`It is not possible at this time to deter-
`mine whether the CV risk reduction with
`liraglutide (LEADER) and semaglutide
`(SUSTAIN-6) is a class effect or a specific
`effect inherent to each individual agent.
`It also is difficult to determine whether
`other SGLT2i will exert a similar benefit
`on CV mortality as empagliflozin, al-
`though published data with dapagliflozin
`and canagliflozin suggest that this will be
`the case (64). Ongoing CV outcome stud-
`ies with other GLP-1 RAs (exenatide, du-
`laglutide) and other SGLT2i (dapagliflozin,
`canagliflozin) will provide an answer to
`this question. Previous CV outcome stud-
`ies reported a neutral effect on MACE of
`other antidiabetes agents that act via the
`incretin axis (lixisenatide, alogliptin, saxa-
`gliptin, and sitagliptin) (20–22). However,
`the ability of DPP-4 inhibitors to raise cir-
`culating GLP-1 levels is modest, whereas
`GLP-1 RAs achieve much higher plasma
`GLP-1 levels (.100 pmol/L) than DPP-4
`inhibitors (;30 pmol/L). Lixisenatide
`
`Novo Nordisk Exhibit 2086
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00005
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`818
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`Treating T2D or Blood Glucose
`
`Diabetes Care Volume 40, July 2017
`
`has a short half-life (;4 h). Thus, patients
`are uncovered during most of the day,
`and this could explain its lack of CV ben-
`efit. Consistent with this, the reductions
`in body weight and blood pressure were
`smaller in ELIXA (Evaluation of Cardiovas-
`cular Outcomes in Patients With Type 2
`Diabetes After Acute Coronary Syn-
`drome During Treatment With AVE0010
`[Lixisenatide]) compared with LEADER
`(0.6 vs. 2.4 kg and 0.8 vs. 1.4 mmHg).
`Studies in experimental animals have
`demonstrated that some of the cardio-
`protective effect afforded by GLP-1 is in-
`dependent of the GLP-1 receptor (38). It is
`possible, therefore, that the cardiopro-
`tective action of GLP-1 RAs is structure
`dependent, and lixisenatide has only
`;50% sequence homology with native
`GLP-1. Lastly, the study design and pa-
`tient population in ELIXA differed signifi-
`cantly from LEADER. Patients in ELIXA
`were recruited because they had acute
`coronary syndrome and the primary end
`point was the composite of CV death, MI,
`stroke, and unstable angina (MACE-4).
`
`GENERALIZABILITY OF CV BENEFIT
`Participants in LEADER, SUSTAIN-6,
`EMPA-REG OUTCOME, and PROactive
`had T2D and .80% had a previous CV
`event. It is not possible to determine
`whether T2D patients without estab-
`lished CVD and who are earlier in the nat-
`ural history of their disease will similarly
`benefit from treatment with GLP-1 RAs,
`SGLT2i, or pioglitazone. It can be argued
`that, because pioglitazone and GLP-1 RAs
`slow atherosclerosis and because T2D pa-
`tients are at high risk for atherosclerotic
`complications, these agents are likely to
`reduce CV events in individuals with T2D
`without, as well as with, established CVD.
`Previous studies have demonstrated that
`pioglitazone improves surrogate (ana-
`tomical) markers of CVD (carotid intima-
`media thickness and coronary atheroma
`volume) in T2D patients wi