KEY POINTS
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GLP-1RAs lower MACE by around 14% to 15% overall with broadly consistent benefits across its constituents’ outcomes, including CV death.
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Three drugs in the class—liraglutide, semaglutide, and dulaglutide—are available for use and approved by regulatory agents for protection against CV outcomes.
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Most preparations are injectable and given once weekly, but once daily oral semaglutide is also available.
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GLP-1RAs lower glucose, weight, and blood pressure and improve lipids but do not increase hypoglycemia rates.
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On the basis of available evidence, relevant guidelines recommend the use of either GLP-1RA or SGLT2i in people with diabetes and existing cardiovascular disease.
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GLP-1RAs may be prioritized in those with much higher BMIs or post stroke or where atherosclerotic disease dominates.
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GLP-1RAs are also recommended in people with diabetes but without existing cardiovascular disease based either on high measured cardiovascular risk or imaging evidence of atherosclerotic disease.
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Present limited trial data suggest GLP-1RAs improve MACE and other outcomes beyond SGLT2i, a finding that fits with distinct mechanisms of action of these two classes of drugs.
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GLP-1RAs also robustly reduce important kidney outcomes with an impact for kidney guidelines, marking them as additional treatment pillars for preventing CKD.
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Semaglutide at higher doses and tirzepatide have clear symptomatic benefits in patients with heart failure and preserved ejection fraction, with preliminary evidence for harder outcome benefits in such patients.
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Finally, higher-dose semaglutide lowered MACE in people with high BMI and established cardiovascular disease but no diabetes, widening indications to beyond diabetes. Other drugs that also lower weight more, such as the GLP-1RA-GIP agonist, tirzepatide, and several others, are being tested in outcome trials that will report in next 1 to 5 years.
BACKGROUND
Glucagon-like peptide (GLP)-1 is a small peptide hormone released from gastrointestinal L-cells after food intake. It binds to the GLP-1 receptor (GLP-1R), leading to an incretin effect that enhances glucose-dependent insulin secretion from pancreatic beta cells and promotes inhibition of glucagon release from pancreatic alpha cells. It also leads to a slowing of gastric emptying. The result of such actions is a reduction in fasting blood glucose and improved postprandial glucose metabolism. By stimulating GLP-1R in the brain, GLP-1 also induces satiety and, this action together with slowing gastric emptying, leads to weight loss.
GLP-1R agonists (GLP-1RAs) have been developed as novel antidiabetic agents that replicate the actions of incretin hormone GLP-1. Initially, exenatide (exendin-4) was developed. It is a GLP-1 mimetic found in the saliva of the gila monster with 53% sequence homology with human GLP-1. This peptide has been shown to be a full agonist of the GLP-1R. Subsequently, other GLP-1RAs were developed based on human GLP-1, such as liraglutide, semaglutide, and dulaglutide. The vast majority are delivered by subcutaneous injection, but recent technology has allowed the development of an orally available GLP-1 RA with the coformulation of semaglutide and the absorption enhancer Sodium N -(8-[2-hydroxybenzoyl] Amino) Caprylate (SNAC). Other oral nonpeptide GLP-1 RAs are in development and could come to the market within 1–2 years.
All GLP-1RAs improve glucose levels, variably lower body weight, lower blood pressure, and improve lipids. They do, however, increase the heart rate by one to three beats per minute. Up to 2021, several cardiovascular outcome trials had been reported in people with diabetes with different GLP-1RAs. The first to report was the LEADER trial and the last, AMPLITUDE-O. The characteristics of all eight trials are given in Table 13.1 , adapted from a 2022 meta-analysis of all eight trials. Since then, the FLOW and SELECT trials have reported out expanding data. A more recent meta-analysis (2024) including such data has recently reported with a focus on kidney outcomes and included patients with and without diabetes. The key findings from all the available evidence from both a cardiovascular and kidney perspective are summarized below.
Table 13.1
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 OUTCOMES ( n = 9463) |
REWIND
( n = 9903) |
PIONEER 6
( n = 3183) |
AMPLITUDE-O
( n = 4076) |
|
|---|---|---|---|---|---|---|---|---|
| Drug | Lixisenatide | Liraglutide | Semaglutide | Exenatide | Albiglutide | Dulaglutide | Semaglutide | Efpeglenatide |
| Year reported | ||||||||
| Structural basis | Exendin-4 | Human GLP-1 | Human GLP-1 | Exendin-4 | Human GLP-1 | Human GLP-1 | Human GLP-1 | Exendin-4 |
| Administration route | Subcutaneous | Subcutaneous | Subcutaneous | Subcutaneous | Subcutaneous | Subcutaneous | Oral | Subcutaneous |
| Dose | 20 µg/day | 1.8 mg/day | 0.5 or 1 mg/week | 2 mg/week | 30 or 50 mg/week | 1.5 mg/week | 14 mg/day | 4 or 6 mg/day |
| Age, mean, years | 60 ± 10 | 64 ± 7 | 65 ± 7 | 62 ± 9 | 64 ± 7 | 66 ± 7 | 66 ± 7 | 65 ± 8 |
| Female gender, no. (%) | 1861 (31%) | 3337 (36%) | 1295 (39%) | 5603 (38%) | 2894 (31%) | 4589 (46%) | 1007 (32%) | 1344 (33%) |
| BMI (kg/m 2 ) | 30.1 ± 5.6 | 32.5 ± 6.3 | 32.8 ± 6.2 | 32.7 ± 6.4 | 32.3 ± 5.9 | 32.3 ± 5.7 | 32.3 ± 6.5 | 32.7 ± 6.2 |
| Caucasian | 4576 (75%) | 7238 (78%) | 2736 (83%) | 11,175 (76%) | 6583 (70%) | 7498 (76%) | 2300 (72%) | 3534 (87%) |
| Diabetes duration, years | 9.2 ± 8.2 | 12.8 ± 8.0 | 13.9 ± 8.1 | 13.1 ± 8.3 | 14.2 ± 8.8 | 10.6 ± 7.2 | 14.9 ± 8.5 | 15.4 ± 8.8 |
| HbA 1c (%) | 7.7 ± 1.3 | 8.7 ± 1.6 | 8.7 ± 1.5 | 8.1 ± 1.0 | 8.7 ± 1.5 | 7.3 ± 1.1 | 8.2 ± 1.6 | 8.9 ± 1.5 |
| Established CVD | 6068 (100%) | 7598 (81%) | 2735 (83%) | 11,175 (76%) | 6678 (71%) | 3114 (31%) | 2692 (85%) | 3650 (90%) |
| History of heart failure | 1358 (22%) | 1667 (18%) | 777 (24%) | 2389 (16%) | 1922 (20%) | 852 (9%) | 388 (12%) | 737 (18%) |
| Systolic blood pressure (mmHg) | 129 ± 17 | 136 ± 18 | 136 ± 17 | 135 ± 17 | 135 ± 17 | 137 ± 17 | 136 ± 18 | 135 ± 16 |
| eGFR (mL/min per 1.73 m 2 )* | 78 ± 21 | 80 (NR) | 80 (61–92) | 77 (61–92) | 79 ± 25 | 75 ± 24 | 74 ± 21 | 72 ± 22 |
| Glucose-Lowering Drugs Used (%) | ||||||||
| Insulin | 2374 (39%) | 4159 (45%) | 1913 (58%) | 6838 (46%) | 5597 (59%) | 2398 (24%) | 1943 (61%) | 2560 (63%) |
| Biguanide | 4021 (66%) | 7136 (76%) | 2414 (73%) | 11,295 (77%) | 7970 (84%) | 8016 (81%) | 2437 (77%) | 2985 (73%) |
| Sulfonylurea | 2004 (33%) | 4721 (51%) | 1410 (43%) | 5401 (37%) | 2725 (29%) | 5644 (57%) | 1007 (32%) | 1036 (25%) |
| Thiazolidinedione | 95 (2%) | 573 (6%) | 76 (2%) | 579 (4%) | 194 (2%) | 168 (2%) | NR | NR |
| DPP-4 inhibitor | NR | 6 (<1%) | 5 (<1%) | 2203 (15%) | 1437 (15%) | 88 (1%) | 0 | 0 |
| SGLT2 inhibitor | NR | NR | 5 (<1%) | 77 (1%) | 575 (6%) | 12 (0%) | 301 (10%) | 618 (15%) |
CARDIOVASCULAR OUTCOME TRIALS OF GLP-1RA IN TYPE 2 DIABETES AND RELEVANT META-ANALYSES
Baseline Characteristics of Populations Studied in Outcome the First Eight Outcome Trials
Of all the eight trials included in the 2022 meta-analysis, ELIXA was unusual as it enrolled patients with a recent acute coronary syndrome; all other trials included patients with stable cardiovascular disease, cardiovascular risk factors, or both. All trials, except ELIXA, had 3-point MACE as the primary endpoint; in ELIXA the primary endpoint was an expanded 4-point composite, including hospitalization for unstable angina. The mean age at baseline ranged from 60 years in ELIXA to 66 years in PIONEER 6 and REWIND. The proportion of patients with established cardiovascular disease at baseline ranged from 100% in ELIXA and Harmony Outcomes to 31% of those in REWIND ( Table 13.1 ). Kidney function was similar across trials (median/mean estimated glomerular filtration rate ranged from 72–80 mL/min per 1.73 m 2 ), whereas mean HbA1c was lowest in REWIND and ELIXA (7.2% and 7.7%, respectively) and highest in AMPLITUDE-O at 8.9%. REWIND had the lowest proportional use of insulin at baseline (24% compared with 39%–63% in remaining trials). The median length of follow-up ranged from 1.3 years in PIONEER 6 to 5.4 years in REWIND.
MACE Outcomes and Specific Drugs Approved for CV Prevention
In the pooled analysis, treatment with a GLP-1 receptor agonist led to a 14% relative risk reduction in 3-point MACE ( Fig. 13.1 ) with moderate heterogeneity. The following trials showed superiority for MACE: LEADER (liraglutide), SUSTAIN-6 (semaglutide), HARMONY Outcomes (albiglutide), REWIND (dulaglutide), and AMPLITUDE-0 (efpeglenatide). Of these, albiglutide and efpeglenatide are not available for use in practice but the other three agents are now licensed for CV protection, widely available and increasingly used for this purpose.
Risk of MACE.
Three-component MACE consisted of cardiovascular death, myocardial infarction, and stroke. NNTs are calculated over a weighted average median follow-up of 3.0 years. P values for superiority. CVOTs , Cardiovascular outcome trials; CI , confidence interval; GLP-1 , glucagon-like peptide-1; MACE , major adverse cardiovascular events; NNT , number needed to treat.
Taken from Sattar N, Lee MMY, Kristensen SL, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of randomised trials. Lancet Diabetes Endocrinol . 2021;9(10):653–662. https://doi:10.1016/S2213-8587(21)00203-5 .
EXPANDING EVIDENCE BASE: NEW TRIALS IN CHRONIC KIDNEY DISEASE AND IN PATIENTS WITH ASCVD BUT WITHOUT TYPE 2 DIABETES
Two important trials have been reported in the last 2 years, widening the evidence base for GLP-1RAs. Below is a brief description of these trials followed by a new meta-analysis incorporating these new data.
FLOW Trial
The FLOW trial tested the efficacy of 1 mg semaglutide versus placebo in 3533 people living with T2 diabetes and chronic kidney disease (CKD). The primary outcome was major kidney disease events, a composite of the onset of kidney failure (dialysis, transplantation, or an eGFR of <15 mL/min/1.73 m 2 ), at least a 50% reduction in the eGFR from baseline, or death from kidney-related or CV causes. It was stopped early at 3.4 years mean follow-up for overwhelming efficacy with a 24% reduction in the primary endpoint in the placebo group ( Fig. 13.2 ). The results were similar for a composite of the kidney-specific components of the primary outcome. Further, death from CV causes (by 29%), MACE (by 18%), and all-cause mortality (by 20%) were all significantly reduced with semaglutide relative to a placebo. Serious adverse events were reported in a lower percentage of participants in the semaglutide group than in the placebo group (49.6% vs. 53.8%).
Primary outcome plot from FLOW.
Cumulative incidence plot of the primary outcome, major kidney disease events (a composite of the onset of kidney failure [dialysis, transplantation, or an estimated glomerular filtration rate (eGFR) of < 15 mL per minute per 1.73 m 2 of body-surface area], ≥50% reduction in eGFR from baseline, or death from kidney-related or cardiovascular causes). CI , Confidence interval.
Taken from Perkovic V, Tuttle KR, Rossing P, et al.; FLOW Trial Committees and Investigators. Effects of semaglutide on chronic kidney disease in patients with type 2 diabetes. N Engl J Med . 2024;391(2):109–121. https://doi:10.1056/NEJMoa2403347 . Epub 2024 May 24. PMID: 38785209.
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