Cardiovascular Protective Properties of GLP-1 Receptor Agonists: More than Just Diabetic and Weight Loss Drugs
Abstract
:1. Introduction
2. Pharmacology
2.1. GLP-1 Physiology
2.2. Pharmacodynamics of GLP-1 Receptor Agonists
2.2.1. Insulin Secretion
2.2.2. Weight Loss and Appetite Suppression
2.2.3. Other Extra-Pancreatic Sites of GLP-1R Expression
2.3. Pharmacokinetics of GLP-1 Receptor Agonists
3. Cardiovascular Benefits of GLP-1 RAs
3.1. Cardiovascular Outcome Trials Data
3.1.1. Composite Adverse Cardiovascular Endpoints
3.1.2. Specific Endpoints of Interest
Ischaemic Heart Disease
Stroke
Heart Failure
Peripheral Artery Disease
3.2. Observational Cardiovascular Data and Real-World Experience
4. Does Risk Factor Modulation Explain the Cardiovascular Benefit of GLP-1 RAs?
4.1. Glycaemic Control
4.2. Weight Loss
4.3. Blood Pressure
4.4. Lipids
5. Evidence of GLP-1 RAs’ Direct Impact on Atherosclerotic Plaques
6. Putative Anti-Atherosclerotic Mechanisms
6.1. Correcting Vascular Dysfunction
6.2. Targeting Diabetic Dyslipidaemia
6.3. Dampening Inflammation
6.4. Reduction in Endoplasmic Reticulum Stress
6.5. Regulating Adiponectin and Other Adipokines
6.6. Modification of Epicardial Adipose Tissue
6.7. Remodeling Plaque towards Stability
6.8. Inhibition of Platelet Aggregation and Thrombosis
7. Future Directions
8. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Agent Name | Brand Name | Molecular Structure | Molecular Weight (g/mol) | Administration | Dosing | Half-Life (t1/2) | Tmax |
---|---|---|---|---|---|---|---|
Exenatide | Byetta® | Modelled on exendin-4 from lizard Heloderma suspectum 39 a.a. peptide amide | 4186.6 | S/C twice daily. 1 h before meals, >6 h apart Uptitration recommended | 5 µg 10 µg | 3–4 h | 2 h |
Exenatide Extended-Release | Bydureon Bcise® | Modelled on exendin-4 39 a.a. synthetic peptide, suspension of microspheres in a MCT vehicle | 4186.6 | S/C once weekly Independent of meals | 2 mg | 3–4 h § | 6 w |
Lixisenatide † | Adlyxinc® | Modelled on exendin-4 44 a.a., amidated at the C-terminal a.a. Contains poly-lysine tail | 4858.6 | S/C once daily 1 h before first meal of day Uptitration recommended | 10 µg 20 µg | 2–4 h | 1–2 h |
Liraglutide | Victoza® | Modelled on mammalian GLP-1 Substitution of arginine for lysine at position 34. Attachment of a C-16 fatty acid (palmitic acid) at position 26 | 3751.3 | S/C once daily Independent of meals Uptitration recommended | 0.6 mg 1.2 mg 1.8 mg | 10–15 h | 9–12 h |
Semaglutide (S/C) | Ozempic® | Modelled on mammalian GLP-1 Albumin binding, with a hydrophilic spacer and a C18 fatty di-acid | 4113.6 | S/C once weekly Independent of meals Uptitration recommended | 0.5 mg 1 mg 2 mg | 1 w | 1–3 d |
Semaglutide (Oral) | Rybelsus® | Modelled on mammalian GLP-1 Albumin binding, with a hydrophilic spacer and a C18 fatty di-acid SNAC for enhanced stomach absorption | 4113.6 | Oral once daily >30 min before first meal of day Uptitration recommended | 7 mg 14 mg | 1 w | 1 h |
Dulaglutide | Trulicity® | Modelled on mammalian GLP-1. Fusion of 2 disulfide-linked GLP-1 chains to the Fc region of human IgG4 | 59,669.8 | S/C once weekly Independent of meals | 0.75 mg 1.5 mg | 4 d | 12–72 h |
Albiglutide | Tanzeum® | Modelled on mammalian GLP-1 2 chains of GLP-1 bound to albumin | 72,070.4 | S/C once weekly Independent of meals Uptitration recommended | 30 mg 50 mg | 6–7 d | 3–5 d |
Efpeglenatide †† | FDA approval pending | Exendin-based Conjugation of exendin chain to IgG4 Fc fragment | NA | S/C once weekly Dosing time/regime not yet standardised | 4 mg 6 mg | 135–180 h | 72–144 h |
Trial | ELIXA | LEADER | SUSTAIN-6 | EXSCEL | Harmony Outcomes | REWIND | PIONEER 6 | AMPLITUDE-O |
---|---|---|---|---|---|---|---|---|
Reference | Pfeffer et al. (2015) [53] | Marso et al. (2016) [54] | Marso et al. (2016) [50] | Holman et al. (2017) [55] | Hernandez et al. (2018) [56] | Gerstein et al. (2019) [57] | Husain et al. (2019) [58] | Gerstein et al. (2021) [59] |
Agent Name | Lixisenatide | Liraglutide | Semaglutide (S/C) | Exenatide | Albiglutide | Dulaglutide | Semaglutide (Oral) | Efpeglenatide |
Active Intervention | Daily S/C lixisenatide (10–20 μg) | Daily S/C liraglutide (1.8 mg) | Weekly semaglutide S/C (0.5 or 1.0 mg) | Weekly S/C ER exenatide (2 mg) | Weekly S/C albiglutide (30–50 mg) | Weekly S/C dulaglutide (1.5 mg) | Daily oral semaglutide (14 mg) | Weekly S/C efpeglenatide (4 or 6 mg) |
Participant Number | 6068 | 9340 | 3297 | 14,752 | 9463 | 9901 | 3183 | 4076 |
Patient Cohort Characteristics | T2DM + ACS in last 180 d Age ≥ 30 | T2DM + high CV risk (age ≥ 50 with prior CAD, stroke, PVD, HF, CKD; or age ≥ 60 with CV RFs) | T2DM + high CV risk (prior CAD, stroke, PVD, HF, CKD; or age ≥ 60 with CV RFs) | T2DM +/− prior CVD (70% had prior CVD) | T2DM + age ≥ 40 + prior CVD, stroke, PAD | T2DM + age ≥ 50 + CVD or CV RFs | High CV risk (with established CVD or CKD; or age ≥ 60 with CV RFs) | T2DM + age ≥ 18 + CVD; or T2DM + age ≥ 50 + CV RFs + CKD |
Median Follow-Up | 2.1 years | 3.8 years | 2 years | 3.2 years | 1.5 years | 5.4 years | 1.3 years | 1.8 years |
Changes in HbA1c | −0.27% | −0.40% | −1.1% (0.5 mg) −1.4% (1.0 mg) | −0.7% | −0.63% (8 m) −0.52% (16 m) | −0.61% | −0.7% | −1.24% |
Definition of Primary Endpoint | CV death, MI, stroke or hospitalisation for unstable angina | First occurrence CV death, nonfatal MI or stroke | First occurrence CV death, nonfatal MI or stroke | First occurrence CV death, nonfatal MI or stroke | First occurrence CV death, nonfatal MI or stroke | First occurrence CV death, nonfatal MI or stroke | First occurrence CV death, nonfatal MI or stroke | First occurrence death from CV or undetermined causes, nonfatal MI or stroke |
MACE Result (HR) | 1.02 (95% CI [0.89, 1.17], p = 0.81) | 0.87 (95% CI [0.78, 0.97], p = 0.01) | 0.74 (95% CI [0.58, 0.95], p = 0.02) | 0.91 (95% CI [0.83, 1.00], p = 0.06) | 0.78 (95% CI [0.68–0.90], p = 0.0006) | 0.88 (95% CI [0.79–0.99], p = 0.026) | 0.79 (95% CI [0.57, 1.11], p = 0.001) | 0.73 (95% CI [0.58–0.92], p = 0.007) |
All-Cause Death (HR) | 0.94 (95% CI [0.78–1.13]) | 0.85 (95% CI [0.74–0.97]) | 1.05 (95% CI [0.74–1.50]) | 0.86 (95% CI [0.77–0.97]) | 0.95 (95% CI [0.79–1.16]) | 0.90 (95% CI [0.80–1.01]) | 0.51 (95% CI [0.31–0.84]) | 0.78 (95% CI [0.58–1.06]) |
Cardiovascular Death (HR) | 0.98 (95% CI [0.78–1.22]) | 0.78 (95% CI [0.66–0.93]) | 0.98 (95% CI [0.65–1.48]) | 0.88 (95% CI [0.76–1.02]) | 0.93 (95% CI [0.73–1.19]) | 0.91 (95% CI [0.78–1.06]) | 0.49 (95% CI [0.27–0.92]) | 0.72 (95% CI [0.50–1.03]) |
Nonfatal Myocardial Infarction (HR) | 1.03 (95% CI [0.87–1.22]) * | 0.88 (95% CI [0.75–1.03]) | 0.74 (95% CI [0.51–1.08]) | 0.97 (95% CI [0.85–1.10]) * | 0.75 (95% CI [0.61–0.90]) * | 0.96 (95% CI [0.79–1.16]) | 1.18 (95% CI [0.73–1.90]) | 0.78 (95% CI [0.55–1.10]) |
Nonfatal Stroke (HR) | 1.12 (95% CI [0.79–1.58]) ** | 0.89 (95% CI [0.72–1.11]) | 0.61 (95% CI [0.38–0.99]) | 0.85 (95% CI [0.70–1.03]) ** | 0.86 (95% CI [0.66–1.14]) ** | 0.76 (95% CI [0.61–0.95]) | 0.74 (95% CI [0.35–1.57]) | 0.80 (95% CI [0.48–1.31]) |
Hospitalisation for Heart Failure (HR) | 0.96 (95% CI [0.75–1.23]) | 0.87 (95% CI [0.73–1.05]) | 1.11 (95% CI [0.77–1.61]) | 0.94 (95% CI [0.78–1.13]) | 0.85 (95% CI [0.70–1.04]) *** | 0.93 (95% CI [0.77–1.12]) | 0.86 (95% CI [0.49–1.55]) | 0.61 (95% CI [0.38–0.98]) |
Effect on Heart Rate | +0.4 bpm | +3.0 bpm | +2.1 bpm (0.5 mg) +2.4 bpm (1.0 mg) | +2.51 bpm | +1.3 bpm | +1.87 bpm | +4 bpm | +3.9 bpm |
Effect on Weight from Baseline | −0.6 kg | −2.3 kg | −3.6 kg (0.5 mg) −4.9 kg (1.0 mg) | −1.27kg | −0.66 kg (8 m) −0.83 kg (16 m) | −1.46 kg | −4.2kg | −2.6 kg |
Effect on Systolic Blood Pressure | −0.8 mmHg | −1.2 mmHg | −3.4 mmHg (0.5 mg) −5.4 mmHg (1.0 mg) | −1.57 mmHg | −0.65 mmHg (8 m) −0.67 mmHg (16 m) | −1.70 mmHg | −2.6 mmHg | −1.5 mmHg |
Overall Effect on CVD | No benefit | MACE benefit + reduced all-cause and CV mortality | MACE benefit + reduced stroke | No MACE benefit but reduced all-cause mortality | MACE benefit + reduced MI | MACE benefit + reduced stroke | No MACE benefit but reduced all-cause and CV mortality | MACE benefit + reduced HF hospitalisation |
Trial Name | ClinicalTrials.gov ID | Purpose | Phase | Trial Status | Estimated Completion | Expected Sample Size | Inclusion Criteria | Active Intervention | Primary Outcome Measures |
---|---|---|---|---|---|---|---|---|---|
LEADPACE | NCT04146155 | Liraglutide in diabetic patients with PAD | Phase 4 | Unknown | December 2021 | 200 | Age > 40; T2DM; HbA1c: 7.5–14%; PAD | Liraglutide | Initial and absolute claudication distance and assessment of limb ischaemia |
STARDUST | NCT04881110 | Liraglutide on peripheral arterial perfusion | Phase 4 | Unknown | June 2022 | 50 | T2DM; HbA1c 6.5–8%; PAD | Liraglutide | Transcutaneous oxygen pressure (mmHg) on anterior and posterior tibial arteries |
STOP | NCT03985384 | Semaglutide on coronary plaque progression and composition using serial CTCA | Phase 4 | Completed, awaiting publication | December 2022 | 140 | Age ≥ 40; T2DM; HbA1c ≥ 7.0%; prior ASCVD or ≥1 CV RF | Semaglutide S/C | Change in noncalcified plaque volume on CTCA |
SAMAS | NCT05147896 | Anti-atherosclerotic mechanisms of oral semaglutide | Phase 4 | Active, recruiting | December 2023 | 100 | T2DM; HbA1c ≤ 8.5% BMI ≥ 30 | Semaglutide oral | cIMT; endothelial function; arterial stiffness |
Effects of Liraglutide on Epicardial Fat Pro-Inflammatory Genes in Type 2 Diabetes and Coronary Artery Disease | NCT03260881 | Liraglutide on the inflammatory environment of EAT | Phase 4 | Active, recruiting | December 2023 | 40 | T2DM; HbA1c ≤ 9%; BMI ≥ 27 and/or WC ≥ 102 cm (men) or 88 cm (women); stable CAD requiring CABG | Liraglutide for minimum of 4–12 w prior to CABG | EAT inflammation as measured by mRNA and protein expression of tumour necrosis factor (TNF)-alpha and interleukin (IL)-6 from blood sample |
STRIDE | NCT04560998 | Semaglutide on walking distance in PAD + T2DM | Phase 3 | Active, not recruiting | July 2024 | 800 | T2DM; PAD | Semaglutide S/C | Change in maximum walking distance |
SOUL | NCT03914326 | Oral semaglutide in T2DM with ASCVD and/or CKD | Phase 3 | Active, not recruiting | July 2024 | 9642 | Age ≥ 50; T2DM; HbA1c 6.5–10.0%; CAD, CeVD, PAD or CKD | Semaglutide oral | Time to first CV death, nonfatal MI or stroke |
SURPASS-CVOT | NCT04255433 | Tirzepatide vs. dulaglutide in T2DM and high CV risk | Phase 3 | Active, not recruiting | October 2024 | 13,299 | T2DM; HbA1c 7.0–10.5%; ASCVD; BMI ≥ 25 | Tirzepatide S/C | Time to first CV death, MI or stroke |
SURMOUNT-MMO | NCT05556512 | Tirzepatide vs. placebo in nondiabetic overweight/obesity with high ASCVD risk | Phase 3 | Active, recruiting | October 2027 | 15,000 | Age ≥ 40; BMI ≥ 27; prior ASCVD or high CV risk | Tirzepatide S/C | Time to first all-cause death, nonfatal MI, nonfatal stroke, coronary revascularisation or heart failure events |
TRIUMPH-3 | NCT05882045 | Retatrutide vs. placebo in obesity with prior CVD | Phase 3 | Active, recruiting | February 2026 | 1800 | BMI ≥ 35.0; prior MI, stroke or PAD | Retatrutide S/C | Percent change from baseline in body weight |
ACHIEVE-4 | NCT05803421 | Orforglipron vs. insulin glargine in T2DM and overweight/obesity and high CV risk | Phase 3 | Active, recruiting | December 2025 | 2620 | T2DM; HbA1c 7.0–10.5%; BMI ≥ 25; high CV risk | Orforglipron oral | Time to first CV death, MI, stroke or hospitalisation for unstable angina |
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Le, R.; Nguyen, M.T.; Allahwala, M.A.; Psaltis, J.P.; Marathe, C.S.; Marathe, J.A.; Psaltis, P.J. Cardiovascular Protective Properties of GLP-1 Receptor Agonists: More than Just Diabetic and Weight Loss Drugs. J. Clin. Med. 2024, 13, 4674. https://doi.org/10.3390/jcm13164674
Le R, Nguyen MT, Allahwala MA, Psaltis JP, Marathe CS, Marathe JA, Psaltis PJ. Cardiovascular Protective Properties of GLP-1 Receptor Agonists: More than Just Diabetic and Weight Loss Drugs. Journal of Clinical Medicine. 2024; 13(16):4674. https://doi.org/10.3390/jcm13164674
Chicago/Turabian StyleLe, Richard, Mau T. Nguyen, Momina A. Allahwala, James P. Psaltis, Chinmay S. Marathe, Jessica A. Marathe, and Peter J. Psaltis. 2024. "Cardiovascular Protective Properties of GLP-1 Receptor Agonists: More than Just Diabetic and Weight Loss Drugs" Journal of Clinical Medicine 13, no. 16: 4674. https://doi.org/10.3390/jcm13164674