IN DEPTH
`GLP-1 Receptor Agonists for the Reduction of
`Atherosclerotic Cardiovascular Risk in Patients
`With Type 2 Diabetes
`
`Nikolaus Marx
`Naveed Sattar
`
`, MD; Mansoor Husain , MD; Michael Lehrke , MD; Subodh Verma , MD, PhD;
`, FMedSci, PhD
`
`ABSTRACT: Patients with type 2 diabetes are at high risk for development of cardiovascular disease, including myocardial
`infarction, stroke, heart failure, and cardiovascular death. Multiple large cardiovascular outcome trials with novel glucose-
`lowering agents, namely SGLT2i (SGLT2 inhibitors) and GLP-1 RA (GLP-1 receptor agonists), have demonstrated
`robust and significant reductions of major adverse cardiovascular events and additional cardiovascular outcomes, such as
`hospitalizations for heart failure. This evidence has changed the landscape for treatment of patients with type 2 diabetes.
`Both diabetes and cardiology guidelines and professional societies have responded to this paradigm shift by including strong
`recommendations to use SGLT2i and/or GLP-1 RA, with evidence-based benefits to reduce cardiovascular risk in high-risk
`individuals with type 2 diabetes, independent of the need for additional glucose control. GLP-1 RA were initially developed as
`glucose-lowering drugs because activation of the GLP-1 receptor by these agents leads to a reduction in blood glucose and
`an improvement in postprandial glucose metabolism. By stimulating GLP-1R in hypothalamic neurons, GLP-1 RA additionally
`induce satiety and lead to weight loss. Data from cardiovascular outcome trials demonstrated a robust and consistent
`reduction in atherothrombotic events, particularly in patients with established atherosclerotic cardiovascular disease. Despite
`the consistent evidence of atherosclerotic cardiovascular disease benefit from these trials, the number of patients receiving
`these drugs remains low. This overview summarizes the experimental and clinical evidence of cardiovascular risk reduction
`offered by GLP-1 RA, and provides practical information on how these drugs should be implemented in the treatment of type
`2 diabetes in the cardiology community.
`
`Key Words: cardiovascular risk ◼ diabetes ◼ GLP-1 receptor agonists ◼ incretin hormones ◼ major cardiovascular events ◼ myocardial infarction
`
`People with type 2 diabetes (T2D) have an elevated
`
`to reduce cardiovascular risk in people with T2D. Over
`the past several years, multiple large cardiovascular out-
`come trials (CVOTs) with novel glucose-lowering agents,
`namely SGLT2i (SGLT2 inhibitors) and GLP-1 RA (GLP-1
`receptor agonists), have demonstrated robust and signif-
`icant reductions of major adverse cardiovascular events
`(MACE) and additional cardiovascular outcomes, such as
`hospitalizations for HF (HHF). These beneficial effects
`on cardiovascular outcomes are thought to be largely
`independent of the glucose-lowering properties of these
`agents. The evidence from these CVOTs has changed
`the landscape for treatment of patients with T2D5 with
`
`risk of developing cardiovascular disease, includ-
`ing myocardial infarction (MI), heart failure (HF),
`peripheral artery disease, stroke, and cardiovascular
`death. Intensive glucose-lowering strategies failed to
`convincingly reduce cardiovascular morbidity and mortal-
`ity in patients with diabetes at high cardiovascular risk,1–3
`although a meta-analysis of these trials did suggest a
`modest benefit on nonfatal MI.4 Nevertheless, these data
`led for years to a perception among cardiologists that
`blood pressure control and low-density lipoprotein (LDL)
`cholesterol lowering were the only effective measures
`
`The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
`Correspondence to: Nikolaus Marx, MD, Department of Internal Medicine I (Cardiology), University Hospital Aachen, RWTH Aachen University, Pauwelsstraße 30,
`D-52074 Aachen, Germany. Email nmarx@ukaachen.de
`For Sources of Funding and Disclosures, see page 1891.
`© 2022 The Authors. Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the
`terms of the Creative Commons Attribution Non-Commercial License, which permits use, distribution, and reproduction in any medium, provided that the original work
`is properly cited and is not used for commercial purposes.
`
`1882 December 13, 2022
`
`Circulation. 2022;146:1882–1894. DOI: 10.1161/CIRCULATIONAHA.122.059595
`
`Circulation
`
`Circulation is available at www.ahajournals.org/journal/circ
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`Downloaded from http://ahajournals.org by on January 16, 2024
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`

`

`Nonstandard Abbreviations and Acronyms
`AMPLITUDE-O Effect of Efpeglenatide on Cardio-
`vascular Outcomes
` atherosclerotic cardiovascular
`disease
`C-reactive protein
` cardiovascular outcome trial
`dipeptidyl peptidase-4
` estimated glomerular filtration rate
` Evaluation of Cardiovascular
`Outcomes in Patients With Type
`2 Diabetes After Acute Coronary
`Syndrome During Treatment With
`AVE0010
` end-stage kidney disease
`end-stage renal disease
` glucose-dependent insulinotropic
`polypeptide
`GLP-1 receptor
` GLP-1 receptor agonists
`
`ASCVD
`
`CRP
`CVOT
`DPP4
`eGFR
`ELIXA
`
`ESKD
`ESRD
`GIP
`
`GLP-1R
`GLP-1 RA
`HARMONY
`OUTCOMES
`
` Effect of Albiglutide, When Added
`to Standard Blood Glucose Lower-
`ing Therapies, on Major Cardiovas-
`cular Events in Subjects With Type
`2 Diabetes Mellitus
`hemoglobin A1c
`heart failure
` hospitalizations for heart failure
` Liraglutide Effect and Action in Dia-
`betes: Evaluation of Cardiovascular
`Outcome Results
` major adverse cardiovascular
`events
`myocardial infarction
` Investigating the Cardiovascular
`Safety of Oral Semaglutide in Sub-
`jects With Type 2 Diabetes
` Researching Cardiovascular Events
`With a Weekly Incretin in Diabetes
`SGLT2 inhibitors
` sodium N-(8-(2-hydroxybenzoyl)
`amino) caprylate
` Semaglutide Cardiovascular Out-
`comes Trial
` Long-Term Outcomes With Sema-
`glutide in Subjects With Type 2
`Diabetes
`type 2 diabetes
`
`HbA1c
`HF
`HHF
`LEADER
`
`MACE
`
`MI
`PIONEER-6
`
`REWIND
`
`SGLT2i
`SNAC
`
`SOUL
`
`SUSTAIN 6
`
`T2D
`
`a paradigm shift in both diabetes and cardiology guide-
`lines. Now they include strong recommendations to use
`SGLT2i and GLP-1 RA with proven cardiovascular ben-
`efits to reduce cardiovascular risk in high-risk individu-
`
`als with T2D, independent of baseline hemoglobin A1c
`(HbA1c).6–8 On the basis of data from dedicated HF tri-
`als,9–12 SGLT2i have emerged as an important treatment
`for patients with HF with both reduced and preserved
`ejection fractions. Despite the overwhelming evidence of
`cardiovascular benefit from large CVOTs, the number of
`patients receiving these lifesaving drugs remains low.13–
`15 There may be several reasons for this: clinical inertia, a
`lack of knowledge in the cardiology community about the
`results of CVOTs, uncertainty in prescribing these agents,
`and concerns about potential side effects. To address
`these aspects, this overview summarizes the clinical and
`experimental evidence of cardiovascular risk reduction
`offered by GLP-1 RA and provides practical information
`on how these drugs should be implemented in the treat-
`ment of T2D in the cardiology community.
`
`INCRETIN SYSTEM/BACKGROUND TO
`GLP-1 RA
`Incretin System
`GLP-1 is a small peptide hormone released from gas-
`trointestinal L cells upon nutrient ingestion. It binds to
`the GLP-1R (GLP-1 receptor) and exhibits incretin ef-
`fects that include glucose-dependent insulin secretion
`from pancreatic β cells, inhibition of glucagon release
`from pancreatic α cells, and the prolongation of gastric
`emptying. Together, these actions contribute to a reduc-
`tion in blood glucose and an improvement in postprandial
`glucose metabolism. By stimulating GLP-1R–expressing
`hypothalamic neurons, GLP-1 also induces satiety and
`leads to weight loss. GLP-1 is generated through the
`cleavage of pre-proglucagon by convertase PC1/3, re-
`leasing equipotent peptides GLP-1(7-36 amide) and
`GLP-1(7-37). However, the half-life of GLP-1 is only a
`few minutes because of its cleavage by the ubiquitously
`expressed enzyme DPP4 (dipeptidyl peptidase-4) (see
`review16). Cleavage of the 2 N-terminal amino acids by
`DPP4 generates the metabolites GLP-1(9-36 amide)
`and GLP-1(9-37), which cannot activate GLP-1R. Thus,
`it no longer induces insulin secretion, but may still exhibit
`other GLP-1R–independent effects in the cardiovascu-
`lar system.17,18 In humans, the expression of the GLP-1R
`has been shown in various tissues, including pancreatic
`islet, lung, kidney, stomach, brain, endothelial cells, and
`smooth muscle cells, as well as specific atrial and ven-
`tricular cardiomyocytes.19
`
`Incretin-Based Therapies
`The potent action of the incretin hormone GLP-1 on
`glucose metabolism has led to the development of
`novel antidiabetic agents. Among them, DPP4 inhibi-
`tors prolong the half-life of GLP-1 by reducing DPP4
`activity by about 80%, leading to an ~2-fold increase in
`GLP-1 plasma levels during postprandial periods. These
`
`Circulation. 2022;146:1882–1894. DOI: 10.1161/CIRCULATIONAHA.122.059595
`
`December 13, 2022 1883
`
`STATE OF THE ART
`
`Marx et al
`
`GLP-1 Receptor Agonists to Reduce CV Risk in Diabetes
`
`Downloaded from http://ahajournals.org by on January 16, 2024
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`agents, including sitagliptin, vildagliptin, saxagliptin, and
`linagliptin, typically reduce HbA1c by 0.5% to 0.8%. Re-
`gardless of promising preclinical and mechanistic human
`studies on their antiatherothrombotic effects (see re-
`view20), consistent beneficial cardiovascular effects have
`not been established in large CVOTs.21
`The second class of incretin-based drugs currently
`available for the treatment of patients with T2D is GLP-1
`RA. Initially, exenatide (exendin-4), a GLP-1 mimetic
`found in the saliva of the Gila monster, was discovered.
`This peptide has 53% sequence homology with human
`GLP-1, cannot be cleaved by DPP4 and has been shown
`to be a full agonist of the GLP-1R. Subsequently, vari-
`ous GLP-1 RA were developed based on human GLP-
`1, such as liraglutide, semaglutide, and dulaglutide, etc.
`These GLP-1 RA reduce HbA1c ~0.8-1.5% (at doses
`now prescribed to patients with diabetes) and lead to
`additional weight loss.22 In addition to their effect on
`postprandial glucose excursions, GLP-1 RA also reduce
`fasting plasma glucose.23–25 Originally, these drugs were
`only available as injectable agents to be administered
`subcutaneously. However, recent technology has led
`to the development of an orally available GLP-1 RA
`with the coformulation of semaglutide and the absorp-
`tion enhancer SNAC (sodium N-(8-(2-hydroxybenzoyl)
`amino) caprylate). This small fatty acid derivative, which
`promotes absorption across the gastric epithelium by
`causing a local increase of pH, leading to higher solu-
`bility and protection from proteolytic degradation,26 has
`enabled oral bioavailability of the GLP-1 RA semaglu-
`tide. Table 1 summarizes the characteristics of currently
`approved GLP-1 RA.
`To date, 3 of these drugs (liraglutide, semaglutide, and
`dulaglutide) are widely available with licensed indications
`for the prevention of cardiovascular disease. Although
`GLP-1 RA are more expensive than older glucose-low-
`ering agents, recent cost-effectiveness analyses sug-
`gest that the added costs of treatment with GLP-1 RA in
`patients currently recommended for these drugs are off-
`set by lower inpatient and outpatient care costs, resulting
`in budget neutrality against standard of care.33
`Additional novel incretin-based glucose-lowering
`strategies include “dual” GIP (glucose-dependent insu-
`linotropic polypeptide) and GLP-1 RA, such as once-
`weekly tirzepatide. In people with T2D and elevated
`cardiovascular risk, tirzepatide, compared with insulin
`glargine, demonstrated greater and clinically meaning-
`ful HbA1c reduction with a lower incidence of hypo-
`glycemia.34 In addition, a meta-analysis of randomized
`phase II/III trials with tirzepatide versus placebo or
`GLP-1 RA has demonstrated significantly improved
`glycemic control and body weight,35 whereas another
`predefined meta-analysis of cardiovascular outcomes
`suggested cardiovascular safety with a potential for
`cardiovascular benefit.36 On the basis of these ben-
`eficial data on various risk factors, the combination
`
`of a GIP agonist with a GLP-1 RA is thought to be a
`promising approach to reduce cardiovascular events in
`high-risk patients. In May 2022, the US Food and Drug
`Administration approved tirzepatide injection to improve
`blood sugar control in adults with T2D as an addition
`to diet and exercise. The SURPASS-CVOT, a phase 3,
`randomized, double-blind, cardiovascular outcomes trial
`for tirzepatide assessing both noninferiority and supe-
`riority of tirzepatide versus dulaglutide (1.5 mg weekly),
`is ongoing and will provide data on the effect of tirzepa-
`tide on cardiovascular outcomes.37
`
`CARDIOVASCULAR/KIDNEY EFFECTS
`OF GLP-1 RA IN CARDIOVASCULAR
`OUTCOME TRIALS
`Effects on MACE
`Eight CVOTs testing the benefits of GLP-1 RAs have
`now been published.38–45 They have varying character-
`istics, as shown in Table 2. All but 1 trial used subcu-
`taneously injected GLP-1 RA, with 5 of these being
`once-weekly injections, 2 daily injectables, and the last
`an oral preparation taken once daily (semaglutide 14 mg
`per day). A meta-analysis46 of these 8 CVOTs revealed a
`14% reduction in the primary outcome of the 3-compo-
`nent MACE (cardiovascular death, nonfatal MI, and non-
`fatal stroke; number needed to treat, 65), with moderate
`heterogeneity (Table 3). These results improve to a 15%
`reduction in MACE with low heterogeneity (14.9%) after
`removal of the ELIXA trial (Evaluation of Cardiovascular
`Outcomes in Patients With Type 2 Diabetes After Acute
`Coronary Syndrome During Treatment With AVE0010).
`In this study, the sensitivity analyses supported the re-
`moval of ELIXA, with lixisenatide too short-acting for the
`once daily administration used in its CVOT.38 The ongoing
`SOUL trial (Semaglutide Cardiovascular Outcomes Trial)
`compares the risk of MACE with oral semaglutide versus
`placebo in subjects with T2D at high risk of cardiovascu-
`lar events (REGISTRATION: URL: https://clinical trials.
`gov; Unique Identifier: NCT03914326). This will address
`the current knowledge gap left by the PIONEER-6 safe-
`ty study (Investigating the Cardiovascular Safety of Oral
`Semaglutide in Subjects With Type 2 Diabetes) in which
`oral semaglutide failed reach statistically significant re-
`ductions in MACE compared with placebo (hazard ratio,
`0.79 [95% CI, 0.57–1.11]; P<0.001 for noninferiority;
`P=0.17 for superiority).44
`
`Effects on HF
`The GLP-1 RA CVOTs included only a limited num-
`ber of patients with a history HF, ranging from 12%
`to 24% of the population (New York Heart Associa-
`tion Class I–III, with Class IV patients excluded). Still,
`all GLP-1 RA had a neutral effect on risk of HHF (as
`
`1884
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`December 13, 2022
`
`Circulation. 2022;146:1882–1894. DOI: 10.1161/CIRCULATIONAHA.122.059595
`
`STATE OF THE ART
`
`Marx et al
`
`GLP-1 Receptor Agonists to Reduce CV Risk in Diabetes
`
`Downloaded from http://ahajournals.org by on January 16, 2024
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`Table 1. Characteristics of Approved GLP-1 Receptor Agonists
`
`General aspects
`
`Pharmacokinetics
`
`GLP-1 receptor agonists
`
`Doses*
`
`Administration
`
`TTP
`
`Elimination half-life
`
`Reference
`
`Exenatide BID
`
`Liraglutide QD
`
`Lixisenatide QD
`
`Dulaglutide QW
`
`Exenatide ER
`
`Semaglutide SC
`
`Semaglutide oral
`
`5 µg
`10 µg
`
`0.6 mg
`1.2 mg
`1.8 mg
`
`10 µg
`20 µg
`
`0.75 mg
`1.5 mg
`4.5 mg
`
`2 mg
`
`0.25 mg
`0.5 mg
`1.0 mg
`(2.4 mg)‡
`
`3 mg
`7 mg
`14 mg
`
`Twice daily
`
`2.1–2.2 h
`
`3.3–4.0 h
`
`Once daily
`
`11.0–13.8 h
`
`12.6–14.3 h
`
`Once daily
`
`About 2 h
`
`2.6 h
`
`Once weekly
`
`48 h
`
`4.7–5.5 h
`
`Once weekly
`
`Once weekly
`
`Not formally assessed†
`
`3.3–4.0 h
`
`24 h
`
`5.7–6.7 d
`
`Once daily
`
`About 1–4 h
`
`5.7–6.7 d
`
`27
`
`28
`
`29
`
`30
`
`27
`
`31
`
`32
`
`ER indicates extended release; and TTP, time to peak.
`*For the initiation and up-titration, see Table 2.
`†The onset of exenatide ER does not quickly lead to measurable concentrations; therefore, this has not been formally evaluated.
`‡Semaglutide (2.4 mg once weekly) was approved by the Food and Drug Administration for obesity in patients without diabetes.
`
`a predefined secondary end point) in the placebo-con-
`trolled randomized controlled trials despite increasing
`heart rate by 3 to 5 beats per minute. Two meta-anal-
`yses including the 8 CVOTs including 60 080 patients
`found HHF to be reduced by 10% to 11%.46,47 This
`suggests that GLP-1 RA may also reduce HHF.48 It
`is notable that the 2 trials with the most marked risk
`reductions in HHF, HARMONY OUTCOMES (Effect of
`Albiglutide, When Added to Standard Blood Glucose
`Lowering Therapies, on Major Cardiovascular Events
`in Subjects With Type 2 Diabetes Mellitus), testing al-
`biglutide versus placebo, and AMPLITUDE-O (Effect
`of Efpeglenatide on Cardiovascular Outcomes), testing
`efpeglenatide versus placebo, also showed the great-
`est risk reductions in 3-point MACE, suggesting that
`antiatherosclerotic mechanisms may underlie some of
`the observed benefits on HHF, at least with the cur-
`rent tested doses of GLP-1 RAs. Of note, neither albi-
`glutide nor efpeglenatide are currently available in the
`United States or European Union.
`Dedicated studies on safety and efficacy of GLP-1
`RA in patients with HF are missing. Only 2 small studies
`examined the effect of GLP-1 RA in patients with HF
`with reduced ejection fraction. In the placebo-controlled
`LIVE study in 241 patients with HF with reduced ejection
`fraction with and without diabetes, liraglutide treatment
`during 24 weeks did not change left ventricular ejec-
`tion fraction, quality of life, or HF symptoms. However,
`patients in the liraglutide group exhibited a higher risk
`for cardiovascular events (sustained ventricular tachycar-
`
`dia, atrial fibrillation, or acute coronary syndromes; n=12
`[10%] in the liraglutide group versus n=3 [3%] in the
`placebo group).49 In the FIGHT study, 300 patients with
`HF with reduced ejection fraction and recent hospitaliza-
`tion for HF with and without diabetes were randomized
`to liraglutide or placebo. After 180 days, there was no
`difference in the primary end point of death, HF hospital-
`ization, or change in NT-proBNP (N-terminal pro-B-type
`natriuretic peptide) between groups.50
`
`Effect on Kidney Outcomes
`Various GLP-1 RA have been shown to reduce albumin-
`uria/ progression of albuminuria, an established surrogate
`parameter for worsening kidney function, and a meta-
`analysis of GLP-1 RA CVOTs suggests that a combined
`kidney outcome that includes progression of albuminuria
`was reduced by 21% to 22% (Table 3).46 Only dulaglu-
`tide has been examined in chronic kidney disease (CKD)
`stages 3 to 4 in patients with T2D and demonstrated a
`slower estimated glomerular filtration rate (eGFR) decline
`compared with insulin glargine.51 A recent pooled analy-
`sis of the SUSTAIN 6 trial (Long-Term Outcomes With
`Semaglutide in Subjects With Type 2 Diabetes) and the
`LEADER trial (Liraglutide Effect and Action in Diabetes:
`Evaluation of Cardiovascular Outcome Results) suggests
`that semaglutide/liraglutide may provide kidney-protec-
`tive effects, which seem to be more pronounced in pa-
`tients with pre-existing CKD.52 Still, the benefit of GLP-1
`RA on kidney function and the risk of kidney failure has
`
`Circulation. 2022;146:1882–1894. DOI: 10.1161/CIRCULATIONAHA.122.059595
`
`December 13, 2022 1885
`
`STATE OF THE ART
`
`Marx et al
`
`GLP-1 Receptor Agonists to Reduce CV Risk in Diabetes
`
`Downloaded from http://ahajournals.org by on January 16, 2024
`
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`Page 00004
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`

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`Table 2. Baseline Characteristics and Use of Glucose-Lowering Agents Across Trials
`
`ELIXA
`(n=6068)
`
`LEADER
`(n=9340)
`
`SUSTAIN 6
`(n=3297)
`
`EXSCEL
`(n=14 752)
`
`HARMONY OUT-
`COMES (n=9463)
`
`REWIND
`(n=9903)
`
`PIONEER-6
`(n=3183)
`
`AMPLITUDE-
`O (n=4076)
`
`Drug
`
`Lixisenatide
`
`Liraglutide
`
`Semaglutide
`
`Exenatide
`
`Albiglutide
`
`Dulaglutide
`
`Semaglutide Efpeglenatide
`
`Administration route
`
`Subcutaneous
`
`Subcutaneous Subcutaneous Subcutaneous Subcutaneous
`
`Subcutaneous Oral
`
`Target dose
`
`10 µg/d or 20
`µg/d
`
`1.8 mg/d
`
`0.5 mg/wk or
`1 mg/wk
`
`2 mg/wk
`
`30 mg/wk or 50
`mg/wk
`
`1.5 mg/wk
`
`14 mg/d
`
`Age, y
`
`Sex
`
` Female
`
`Male
`
`60±10
`
`
`
`31%
`
`69%
`
`64±7
`
`
`
`36%
`
`64%
`
`65±7
`
`
`
`39%
`
`61%
`
`62±9
`
`
`
`38%
`
`62%
`
`64±7
`
`
`
`31%
`
`69%
`
`66±7
`
`
`
`46%
`
`54%
`
`66±7
`
`
`
`32%
`
`68%
`
`Subcutaneous
`
`4 mg/wk or 6
`mg/d
`
`65±8
`
`
`
`33%
`
`67%
`
`32.3±6.5
`
`32.7±6.2
`
`BMI kg/m2
`
`30.1±5.6
`
`Diabetes duration, y
`
`9.2±8.2
`
`HbA1c %
`
`Established cardio-
`vascular disease
`
`7.7±1.3
`
`100%
`
`History of heart failure
`
`22%
`
`32.5±6.3
`
`12.8±8.0
`
`8.7±1.6
`
`81%
`
`18%
`
`32.8±6.2
`
`13.9±8.1
`
`8.7±1.5
`
`83%
`
`24%
`
`32.7±6.4
`
`13.1±8.3
`
`8.1±1.0
`
`73%
`
`16%
`
`32.3±5.9
`
`14.2±8.8
`
`8.7±1.5
`
`100%
`
`20%
`
`32.3±5.7
`
`10.5±7.2
`
`7.3±1.1
`
`31%
`
`9%
`
`14.9±8.5
`
`15.4±8.8
`
`8.2±1.6
`
`8.9±1.5
`
`85%
`
`12%
`
`90%
`
`18%
`
`Systolic blood pres-
`sure (mm Hg)
`
`eGFR, mL/min per
`1.73 m2*
`
`129±17
`
`136±18
`
`136±17
`
`135±17
`
`135±17
`
`137±17
`
`136±18
`
`135±16
`
`78±21
`
`80 (NR)
`
`80 (61–92)
`
`77 (61–92)
`
`79±25
`
`77±23
`
`74±21
`
`72±22
`
`Numerical data are mean±SD or percentage, unless otherwise specified.
`AMPLITUDE-O indicates Effect of Efpeglenatide on Cardiovascular Outcomes; BMI, body mass index; CVD, cardiovascular disease; DPP4, dipeptidyl pepti-
`dase-4; eGFR, estimated glomerular filtration rate; ELIXA, Evaluation of Cardiovascular Outcomes in Patients With Type 2 Diabetes After Acute Coronary Syndrome
`During Treatment With AVE001; HARMONY OUTCOMES, Effect of Albiglutide, When Added to Standard Blood Glucose Lowering Therapies, on Major Cardio-
`vascular Events in Subjects With Type 2 Diabetes Mellitus; HbA1c, hemoglobin A1c; LEADER, Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovas-
`cular Outcome Results; NR, not reported; PIONEER-6, Investigating the Cardiovascular Safety of Oral Semaglutide in Subjects With Type 2 Diabetes; REWIND,
`Researching Cardiovascular Events With a Weekly Incretin in Diabetes; SGLT2, sodium-glucose cotransporter-2; and SUSTAIN 6, Long-Term Outcomes With
`Semaglutide in Subjects With Type 2 Diabetes.
`*eGFR data are median (interquartile range) for SUSTAIN 6 and EXSCEL.
`
`yet to be confirmed. The ongoing FLOW trial is directly
`comparing once-weekly semaglutide subcutaneously
`versus placebo in patients with CKD, and its results are
`keenly anticipated (REGISTRATION: URL: https://clini-
`cal trials.gov; Unique Identifier: NCT03819153).
`
`Ongoing Trials
`On the basis of data from STEP-1, in which 2.4 mg of
`once weekly semaglutide subcutaneously plus lifestyle
`intervention was associated with sustained, clinically
`relevant reductions in body weight versus placebo,53
`semaglutide has been approved by the Food and Drug
`Administraton as a medication for chronic weight man-
`agement in adults with obesity or who are overweight.
`The ongoing SELECT-trial randomized overweight par-
`ticipants (body mass index ≥27 kg/m2) without T2D but
`with established CVD to semaglutide versus placebo
`and will assess whether this GLP-1 RA can reduce the
`primary composite cardiovascular end point of 3-point
`MACE54 (REGISTRATION: URL: https://clinical trials.
`gov; Unique Identifier: NCT03574597). The results of
`this trial will extend our understanding of obesity man-
`agement with GLP-1 RA and the effect of this class on
`cardiovascular risk reduction in patients without T2D.
`
`MECHANISMS OF CARDIOVASCULAR
`RISK REDUCTION BY GLP-1 RA
`Clinical data from large CVOTs in patients with T2D
`clearly show a reduction of cardiovascular morbidity and
`mortality by treatment with GLP-1 RA, as summarized in
`Effects on MACE above. A detailed analysis of the event
`curves with a separation of the curves after 12 to 18
`months, as well as the fact that primary and secondary
`outcomes such as MI, stroke, cardiovascular death, and
`revascularization are reduced, suggest that the benefi-
`cial effects of GLP-1 RAs are mediated by a reduction
`of atherosclerosis-related events. Various mechanisms
`have been proposed to contribute to these results.
`GLP-1 itself affects the pancreas, gut, and stomach as
`well as liver, adipose tissue, skeleton muscle, kidney, heart
`and vessels, and the immune system (see review55). Both
`DPP4 inhibitors and GLP-1 RA are GLP-1–based thera-
`pies. However, in contrast with GLP-1 RA, DPP4 inhibi-
`tors did not reduce MACE in large CVOTs. This difference
`may be a result of modest enhancement of DPP4 inhibi-
`tors and prolonged action of endogenous postprandial
`GLP-1 within the physiological range. Because GLP-1
`RA achieve multiple-fold higher and near continuous
`pharmacological activation of the GLP-1R, the beneficial
`
`1886
`
`December 13, 2022
`
`Circulation. 2022;146:1882–1894. DOI: 10.1161/CIRCULATIONAHA.122.059595
`
`STATE OF THE ART
`
`Marx et al
`
`GLP-1 Receptor Agonists to Reduce CV Risk in Diabetes
`
`Downloaded from http://ahajournals.org by on January 16, 2024
`
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`IPR2023-00724
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`Table 3. Summary Eesults of Meta-Analysis for MACE and Its Components as Reported by Sattar
`et al46
`
`
`
`MACE
`
`CV death
`
`MI
`
`All-cause mortality
`
`Incident HHF
`
`Main analysis with all 8
`CVOTs (HR; I2)
`
`Sensitivity analyses minus
`ELIXA (HR; I2)
`
`0.86 (0.80 to 0.93) 45%
`
`0.85 (0.80 to 0.90) 15%
`
`0.87 (0.80 to 0.94) 13%
`
`0.85 (0.78 to 0.93) 12%
`
`0.90 (0.83 to 0.98) 27%
`
`0.88 (0.81 to 0.96) 16%
`
`0.88 (0.82 to 0.94) 10%
`
`0.87 (0.81 to 0.94) 17%
`
`0.89 (0.82 to 0.98) 3%
`
`0.88 (0.79 to 0.98) 12%
`
`Kidney composite (+ albuminuria)
`
`0.79 (0.73 to 0.87) 48%
`
`0.78 (0.71 to 0.87) 57%
`
`Worsening kidney function (eGFR)
`
`0.86 (0.72 to 1.02) 43%
`
`0.82 (0.69 to 0.98) 40%
`
`CV indicates cardiovascular; CVOTs, cardiovascular outcome trials; eGFR, estimated glomerular filtration rate; ELIXA,
`Evaluation of Cardiovascular Outcomes in Patients With Type 2 Diabetes After Acute Coronary Syndrome During Treatment
`With AVE001; HHF, hospitalization for heart failure; HR, hazard ratio; MACE, major adverse cardiovascular events; and MI,
`myocardial infarction.
`
`effects observed in CVOTs may depend on the supra-
`physiological effects only achieved by robust GLP-1 RA.
`
`Effect of GLP-1 RA on Cardiovascular Risk
`Factors
`All available GLP-1 RA have effects on cardiovascular
`risk factors. GLP-1 RA lead to a reduction in systolic
`blood pressure of 2 to 6 mm Hg, and blood pressure
`lowering has been discussed as a mediator of car-
`diovascular event reduction.22 Previous data from tri-
`als in patients with hypertension suggest that blood
`pressure reduction leads to a significant reduction in
`MACE, with meta-analyses showing that a systolic
`blood pressure reduction of 10 mm Hg was associ-
`ated with ~20% reduction of MACE. Therefore, the
`effect of GLP-1 RA on blood pressure in their CVOTs
`was rather modest. For example, the average reduc-
`tions were only 1.2 mm Hg in LEADER and 1.7 mm Hg
`in REWIND (Researching Cardiovascular Events With
`a Weekly Incretin in Diabetes), making it unlikely that
`blood pressure alone can explain the observed car-
`diovascular benefits.56 With respect to lipids, GLP-1
`RA have been shown to modestly reduce total cho-
`lesterol, LDL cholesterol, and triglycerides, suggest-
`ing a potential beneficial effect.57 Depending on the
`study population, GLP-1 RA lead to a reduction of
`HbA1c between 0.8% and 1.5%.58 A meta-analysis of
`large CVOTs in patients with T2D and cardiovascular
`disease, such as ACCORD, ADVANCED, and VADT,
`showed an intensive versus a less stringent glucose-
`lowering strategy modestly reduced only nonfatal MI,
`but not cardiovascular death.4 Thus, the glucose-low-
`ering properties of GLP-1 RA can at best only partially
`explain the cardiovascular benefits observed. In addi-
`tion, the metabolic effects of all currently commonly
`used GLP-1 RA lead to a modest reduction in weight
`between 2.5 and 4 kg, depending on the trial.58,59 Such
`a weight reduction may contribute to the reduction of
`cardiovascular events. Previous data from the Look
`
`AHEAD trial60 suggested a limited efficacy of mod-
`est body weight loss on cardiovascular risk reduction
`in patients with diabetes, but a subsequent post hoc
`reanalysis showed that those who lost >10% weight
`might have lower risk for future cardiovascular out-
`comes.61 Of note, higher approved doses of semaglu-
`tide and tirzepatide demonstrate up to 10% to 20%
`weight loss in persons with and without diabetes, with
`lesser weight loss in people with diabetes.62 Still, fur-
`ther trials are needed to support importance of weight
`loss per se, and we note that the ongoing STEP and
`SURPASS-CVOT trials may help determine to what
`extent weight loss contributes to cardiovascular ben-
`efits. Taken together, even the combination of these
`modest effects on classical cardiovascular risk factors
`may not entirely explain the beneficial results seen in
`the CVOTs of GLP-1 RA.
`
`Additional Effects of GLP-1 RA on
`Atherosclerosis and Inflammation
`Various experimental data in preclinical models of ath-
`erosclerosis have shown that GLP-163 and GLP-1 RA
`reduce atherosclerotic lesion development and pro-
`gression by leading to more stabilized, less vulnerable
`plaques,64,65 most likely by antiatherogenic and anti-in-
`flammatory effects in endothelial cells, monocytes, and
`macrophages as well as vascular smooth muscle cells,
`which express GLP-1R.19,64,66–70
`The hypothesis of anti-inflammatory properties of
`GLP-1 RA has been fostered by clinical data in small
`population of patients with liraglutide showing decreased
`production of TNF-α and interleukin-1 in isolated human
`peripheral blood mononuclear cells.71 In addition, various
`GLP-1 RA have been shown to reduce systemic inflamma-
`tion as measured by levels of CRP (C-reactive protein).72,73
`Overall, the beneficial effects of GLP-1 RA on car-
`diovascular outcomes in high-risk patients with T2D are
`most likely explained by a combination of metabolic, vas-
`cular, antithrombotic and anti-inflammatory effects.
`
`Circulation. 2022;146:1882–1894. DOI: 10.1161/CIRCULATIONAHA.122.059595
`
`December 13, 2022 1887
`
`STATE OF THE ART
`
`Marx et al
`
`GLP-1 Receptor Agonists to Reduce CV Risk in Diabetes
`
`Downloaded from http://ahajournals.org by on January 16, 2024
`
`Novo Nordisk Exhibit 2103
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00006
`
`

`

`GUIDELINE RECOMMENDATIONS
`On the basis of the results of multiple rigorous CVOTs,
`guidelines committees in both diabetes and cardiology
`have developed recommendations for the treatment of
`patients with T2D at high cardiovascular risk with GLP-1
`RAs. The 2019 European Society of Cardiology guide-
`lines on diabetes, prediabetes, and CVD recommend
`treatment with GLP-1 RA (or SGLT2i) in patients with
`T2D and atherosclerotic cardiovascular disease (AS-
`CVD) or high/very high risk (high-risk patients, diabetes
`duration ≥10 years without target organ damage plus
`any other additional risk factor; very high–risk patients,
`diabetes and established CVD, evidence of target organ
`damage [proteinuria, eGFR <30 mL/min/1.73 m2, left
`ventricular hypertrophy, or retinopathy], 3 or more major
`risk factors, or early-onset type 1 diabetes [of long dura-
`tion [>20 years]) to reduce cardiovascular events.
`The 2020 report of the American College of Cardiol-
`ogy Solution Set Oversight Committee on novel thera-
`pies for cardiovascular risk reduction in patients with
`T2D recommends initiating a patient-clinician discussion
`about the use of an SGLT2i and/or a GLP-1 RA with
`demonstrated cardiovascular benefit for patients with
`T2D who have or who are at very high risk for clinical
`atherosclerotic cardiovascular disease, HF, and/or dia-
`betic kidney disease.74
`The 2022 American Diabetes Association “Standards
`of Medical Care in Diabetes” recommend treatment with
`GLP-1 RA or SGLT2i in T2D with ASCVD or high risk
`(such as patients ≥55 years of age with coronary, carotid,
`or lower-extremity artery stenosis >50% or left ventricu-
`lar hypertrophy), independently of baseline HbA1c, indi-
`vidualized HbA1c target, or metformin use.8
`
`PRACTICAL ASPECTS ON THE USE OF
`GLP-1 RA FOR THE CARDIOLOGIST
`Patient Selection
`On the basis of current guideline recommendations,
`SGLT2i and GLP-1 RA with proven cardiovascular ben-
`efit are recommended in patients with T2D and ASCVD
`or those at high risk of cardiovascular e