Cardiovascular diseases are the leading cause of death globally, with a disease burden estimated at 626 million cases worldwide.1 Health outcomes of cardiovascular disease are marked by disability and premature mortality. Two significant risk factors for the development of atherosclerotic cardiovascular disease (ASCVD) are diabetes and obesity, which can more than double the risk of ASCVD in adults.2 Glucagon-like peptide-1 receptor agonists (GLP1RAs) are synthetic glucagon-like peptide-1 analogs that can improve insulin sensitivity and increase satiety.3 Initial evidence demonstrated that potentiation of the incretin system with GLP1RAs improved glycemic control in patients with type 2 diabetes (T2D) and promoted weight loss in patients with obesity. Early clinical trial data showed that, in patients with T2D, GLP1RA therapy was not only safe from a cardiovascular perspective, but significantly lowered the risk of major adverse cardiovascular events (MACE) (eg, cardiovascular death, nonfatal myocardial infarction [MI], nonfatal stroke).4 Recent meta-analyses have demonstrated that GLP1RA therapy lowers the relative risk of MACE by approximately 10% to 14% and the relative risk of all-cause death by approximately 12% to 13% in patients with T2D.4-6 Another meta-analysis of patients with obesity but not diabetes showed GLP1RAs lower the risk of MI and all-cause mortality.7 Thus, it was hypothesized that this cardiovascular benefit may extend to other patient populations, such as those with obesity or heart failure (with or without concomitant diabetes).
As data for GLP1RAs are emerging rapidly, it is vital for clinicians to remain informed of the latest clinical trial evidence. The primary purpose of this systematic review was to provide a comprehensive evaluation of the cardiovascular outcome trial data to date for GLP1RAs in various patient populations. This review summarizes key clinical data regarding the benefit of GLP1RAs in reducing ASCVD risk that can be applied by clinicians in practice.
Methods
This systematic review followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) checklist.8 The clinical question “What are the cardiovascular outcomes for adults treated with GLP1RAs compared to placebo?” was determined using the PICO (patient population of interest [P], intervention [I], comparator [C], and outcomes [O]) method. Ovid MEDLINE (which includes PubMed as well as Publisher, In-Data-Review, In-Process, and PubMed-not-MEDLINE records from the National Library of Medicine) was searched from inception (1946) until July 8, 2025, using the following terms: major adverse cardiovascular event or cardiovascular death or myocardial infarction or stroke or unstable angina, and glucagon-like peptide-1 receptor agonist or albiglutide or dulaglutide or efpeglenatide or exenatide or liraglutide or lixisenatide or semaglutide or tirzepatide. The search was limited to randomized controlled trials (RCTs).
The search was limited to MEDLINE, as most RCTs are indexed in this database. No language restrictions were applied. All citations were imported into Covidence software (Covidence, Melbourne, Australia).
The Cochrane RCT classifier was used to tag RCTs and remove references that were tagged as non-RCTs before screening. Eligible studies were double-blind RCTs that compared any GLP1RA (including tirzepatide, which is a combined GLP1RA and glucose-dependent insulinotropic polypeptide receptor agonist) versus placebo and reported a composite MACE outcome (defined as cardiovascular death, nonfatal MI, and nonfatal stroke with or without hospitalization for unstable angina) as the primary endpoint. Trials that evaluated adverse cardiovascular events exclusively as secondary, exploratory, or post hoc analyses were excluded.
The title and abstract of each article were screened by one author (N.B. or A.R.B.), and all articles of potential interest were screened in full by 2 authors (N.B. and A.R.B.). Any disagreements were resolved through discussion. The following data were extracted from each trial by 3 authors (N.B., S.B., and A.R.B.): design, inclusion and exclusion criteria, baseline characteristics, intervention, comparator, duration of follow-up, MACE, the individual components of MACE, adverse heart failure events, all-cause death, serious adverse events, and discontinuation of therapy due to an adverse event.
The quality of each included trial was assessed using the Cochrane Risk of Bias 2 tool.9 As this review aimed to assess cardiovascular outcomes in different patient populations (eg, T2D, obesity, ASCVD, heart failure), no quantitative synthesis of the evidence (ie, meta-analysis) was performed. Data were presented based on the patient population enrolled in the trial. This review was not registered on a systematic review registry.
Results
The PRISMA flow diagram is included as Figure 1. The search returned a total of 134 articles, and 12 randomized, placebo-controlled trials were included, for a total of 92,221 patients (Table 1).10-21 Ten trials were conducted in patients with T2D,10-18,21 while 2 trials included patients with obesity and concurrent ASCVD or heart failure with preserved ejection fraction (HFpEF), respectively.19,20 The GLP1RAs that were studied included albiglutide (1), dulaglutide (1), efpeglenatide (1), exenatide (2), liraglutide (1), lixisenatide (1), semaglutide (4), and tirzepatide (1). In 10 trials10-14,16-20 the GLP1RA was administered subcutaneously, while 2 trials investigated the oral formulation of semaglutide.15,21 Among the trials with subcutaneous injection, the GLP1RA was dosed weekly in 8 trials,10,12-14,16,17,19,20 while lixisenatide was administered daily in the ELIXA11 trial and exenatide was given as a continuous infusion in the trial by Ruff and colleagues.18 All of the trials involved multiple international sites, and 11 were funded by the drug manufacturer.10-17,19-21 At baseline, the mean age of participants ranged from 60 to 65 years, and a majority were White males with an average body mass index (BMI) of 32 kg/m2.
Most patients did not have chronic kidney disease. Many trials excluded patients with an eGFR of <25-30 mL/min/1.73 m2, though 2 trials16,20 included patients with an eGFR as low as 15 mL/min/1.73 m2. One trial19 only excluded patients with end-stage renal disease or who required dialysis, though the mean eGFR was 82 mL/min/1.73 m2.
Baseline medications included renin-angiotensin-aldosterone system inhibitors (approximately 80% of participants), statins (approximately 70%), β-blockers (approximately 60%), antiplatelet agents (approximately 60%), and sodium-glucose cotransporter 2 (SGLT2) inhibitors (<10%). Median follow-up was roughly 2.1 years (range, 1.2-5.4 years). A graphical abstract is included as Figure 2.
Risk of bias
The majority of trials were considered to have a low risk of bias, as they were large-scale, international, randomized, placebo-controlled trials (Table 2). In the SUMMIT20 trial, the authors disclosed their decision to alter their primary endpoints halfway through the trial based on the publication of the STEP-HFpEF trials.22,23 The trial was originally powered to measure a primary composite endpoint including cardiovascular death, worsening heart failure events, and change in Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS). The steering committee chose to split this composite into 2 co-primary endpoints to improve the interpretability of their findings: (1) a composite of cardiovascular death and worsening heart failure events and (2) KCCQ-CSS.
It is therefore possible that this trial was not adequately powered to detect differences in the new co-primary endpoints. Accordingly, the domain of reported results was classified as “some concerns” for this trial.
Patients with diabetes
Ten trials enrolled patients with T2D.10-18,21 On average, patients had a disease duration of 10-15 years with a mean glycated hemoglobin (HbA1c) of 8.0%. All of the RCTs recruited patients at high risk for ASCVD due to either a history of established ASCVD (eg, prior MI or stroke, symptomatic peripheral artery disease, or history of revascularization) or the presence of one or more cardiovascular risk factors (eg, ≥60 years of age, hypertension, albuminuria, left ventricular hypertrophy, or left ventricular dysfunction).
All 10 RCTs reported a composite of MACE as the primary endpoint (Table 3). Eight trials10,12-17,21 utilized a 3-point MACE outcome, defined as cardiovascular death, nonfatal MI, and nonfatal stroke, whereas 2 trials utilized a 4-point MACE outcome that included hospitalization for unstable angina.11,18 The primary MACE endpoint occurred less frequently in patients on GLP1RA therapy versus placebo in all trials, 8 of which met the criteria for noninferiority.10-15,17,18 The REWIND16 (dulaglutide) and SOUL21 (semaglutide) trials were designed as superiority trials and therefore did not assess for noninferiority. Six trials demonstrated the superiority of GLP1RA therapy over placebo with respect to MACE with similar point estimates and an average relative risk reduction of 19%: albiglutide (hazard ratio [HR], 0.78; 95% CI, 0.68-0.90), dulaglutide (HR, 0.88; 95% CI, 0.79-0.99), efpeglenatide (HR, 0.73; 95% CI, 0.58-0.92), liraglutide (HR, 0.87; 95% CI, 0.78-0.97), subcutaneous semaglutide (HR, 0.74; 95% CI, 0.58-0.95), and oral semaglutide (HR, 0.86; 95% CI, 0.77-0.96).10,12,14,16,17,21 Lixisenatide and exenatide, while noninferior, were not demonstrated to be superior to placebo with respect to MACE.11,13,18 With respect to individual components of the composite MACE outcome, a reduction in MI was observed with liraglutide (6.3% vs 7.3%; HR, 0.86; 95% CI, 0.73-1.00), albiglutide (3.8% vs 5.1%; HR, 0.75; 95% CI, 0.61-0.90), and oral semaglutide (4.0% vs 5.2%; HR, 0.74; 95% CI, 0.61-0.89).10,14,21 A lower risk of stroke was demonstrated with subcutaneous semaglutide (1.6% vs 2.7%; HR, 0.61; 95% CI, 0.38-0.99) and dulaglutide (3.2% vs 4.2%; HR, 0.76; 95% CI, 0.62-0.94).12,16 Most trials did not show a statistically significant reduction in the secondary outcomes of cardiovascular or all-cause death with the exception of the LEADER trial, in which liraglutide was associated with a reduction in both cardiovascular death (4.7% vs 6.0%; HR, 0.78; 95% CI, 0.66-0.93) and all-cause death (8.2% vs 9.6%; HR, 0.85; 95% CI, 0.74-0.97).10
Patients with overweight/obesity and ASCVD
The SELECT trial included patients with overweight/obesity (BMI ≥27 kg/m2) and established ASCVD.19 The mean BMI at baseline was 33 kg/m2, though a majority of patients (72%) had a BMI of ≥30 kg/m2. This was the only GLP1RA trial to date that specifically excluded patients with T2D (the mean HbA1c at baseline was 5.8%). Over a mean follow-up of 3.3 years, patients randomized to subcutaneous semaglutide demonstrated superiority over placebo at reducing the primary composite outcome of 3-point MACE (HR, 0.80; 95% CI 0.72-0.90) (Table 3).
This was primarily driven by a reduction in nonfatal MI (2.7% vs 3.7%; HR, 0.72; 95% CI, 0.61-0.85). Mean body weight was approximately 9% lower in the semaglutide group at 2 years. Cardiovascular death was numerically lower in the semaglutide group, but the difference was not statistically significant.
The occurrence of a composite endpoint of adverse heart failure events and all-cause death was lower with semaglutide, but that result was not considered to be statistically significant based on hierarchical testing.
Patients with obesity and HFpEF
The SUMMIT trial is the only trial to date to investigate a GLP1RA in patients with HFpEF and report cardiovascular outcomes.20 Patients were required to have a BMI of ≥30 kg/m2; the mean baseline BMI was 38 kg/m2. Forty-eight percent of patients had T2D, the mean left ventricular ejection fraction (LVEF) at baseline was 61%, and most patients (73%) had New York Heart Association class II symptoms. Over a median follow-up of 2 years, the occurrence of the primary composite outcome of cardiovascular death or any worsening heart failure event (defined as any heart failure hospitalization, intravenous diuresis in an urgent care setting, or intensification of oral diuretic therapy) was significantly lower with tirzepatide compared to placebo (HR, 0.62; 95% CI, 0.41-0.95), which was mostly driven by worsening heart failure events (8.0% vs 14.2%; HR, 0.54; 95% CI, 0.34-0.85), specifically heart failure hospitalizations (3.3% vs 7.1%; HR, 0.44; 95% CI, 0.22-0.87) (Table 3).
Tirzepatide was also associated with an improvement in KCCQ-CSS at 52 weeks (mean increase, 6.9 points; 95% CI, 3.3-10.6 points; P < 0.001). Rates of cardiovascular and all-cause death were similar between the tirzepatide and placebo groups.
Safety
The discontinuation of treatment due to an adverse event was higher with GLP1RA therapy versus placebo in a majority of trials, most commonly due to gastrointestinal-related adverse events (eg, nausea, vomiting, diarrhea, abdominal pain) (Table 3). The difference in rates of discontinuation due to an adverse event were reported to be statistically significantly higher in 6 trials (rates ranged from 1.3- to 2.6-fold higher with GLP1RA use).10,11,17-19,21 In the SUSTAIN-6 trial (subcutaneous semaglutide), the results suggested a dose-dependent effect (a discontinuation rate of 11.5% with 0.5 mg weekly vs 14.5% with 1 mg weekly).12 There were no significant differences in the incidence of serious adverse events between GLP1RA therapy and placebo in the 6 trials, with the exception of the AMPLITUDE-O trial, which showed an increase in serious gastrointestinal events with efpeglenatide (3.3% vs 1.8%).17 In the SELECT and SUMMIT trials, the rate of discontinuation due to gastrointestinal symptoms with higher-dose semaglutide and tirzepatide was up to 5-fold higher than in the placebo groups, with discontinuation rates ranging from 4% to 10%.19,20 In the SELECT trial, the overall number of serious adverse events was lower in the semaglutide group, mostly due to a reduction in cardiac disorders.19
Discussion
This systemic review identified 12 RCTs that investigated the cardioprotective effects of GLP1RAs in patients with T2D and/or obesity, as well as other medical conditions (eg, ASCVD, HFpEF).
Of the 12 trials, 10 specifically investigated the effect of GLP1RAs on MACE in patients with T2D who also had or were at high risk for ASCVD. Most of these trials were conducted to demonstrate the cardiovascular safety of these agents in accordance with the Food and Drug Administration (FDA) requirement for all new antidiabetic drugs. All of the trials demonstrated a lower rate of MACE with GLP1RA therapy.
Six trials10,12,14,16,17,21 demonstrated the superiority of GLP1RA therapy over placebo at reducing MACE (albiglutide, dulaglutide, efpeglenatide, liraglutide, and semaglutide both orally and subcutaneously), while the remaining 4 demonstrated noninferiority.11,13,15,18 These results are primarily generalizable to secondary prevention patients, as most patients enrolled in these trials had preestablished ASCVD. Of note, patients in all of these trials had a mean baseline BMI of ≥30 kg/m2, though the trials were not specifically designed to include patients with obesity. Therefore, these results are primarily generalizable to patients with T2D, ASCVD, and obesity.
The reduction in MACE was primarily driven by a reduction in MI, though 2 trials (SUSTAIN-6 and REWIND) demonstrated a statistically significant reduction in stroke.12,16 The effect of GLP1RAs on mortality is equivocal based on the inconsistent results of the individual trials. Only 2 trials demonstrated a reduction in cardiovascular death: LEADER (liraglutide) and PIONEER-6 (oral semaglutide).10,15 However, cardiovascular death was not significantly reduced with oral semaglutide in the SOUL trial,21 which had a higher power to detect differences in cardiovascular events than the PIONEER-6 trial. Furthermore, cardiovascular death was a secondary outcome in the PIONEER-6 trial, while GLP1RA superiority was not demonstrated for the primary MACE outcome.15 As such, the mortality benefit observed in the PIONEER-6 trial should be interpreted cautiously.
All-cause death was not significantly reduced in the included trials save for the LEADER and PIONEER-6 trials.10,15 In the EXSCEL trial, the risk of death from any cause was lower with use of exenatide, but this was not considered to be statistically significant (despite an HR of 0.86 and 95% CI of 0.77-0.97) in the hierarchical testing.13 Of these trials, only the LEADER trial demonstrated a significant reduction in MACE, cardiovascular death, and all-cause death.10
Unlike SGLT2 inhibitors, GLP1RAs have not been clearly demonstrated to reduce the risk of heart failure hospitalization in patients with T2D, though further trials are needed. All of the trials included heart failure hospitalization as a secondary outcome, and the hospitalization rate was not significantly lower versus placebo in 9 of the 10 trials. Only the AMPLITUDE-O trial (efpeglenatide) demonstrated a modest but significant reduction in the rate of hospitalization for heart failure (1.5% versus 2.3%; HR, 0.61; 95% CI, 0.38-0.98).17
Meta-analyses that included various cardiovascular outcome trials have demonstrated that GLP1RAs lower the risk of MACE relative to placebo in patients with T2D. Moreover, a reduction in cardiovascular and all-cause death was also observed with GLP1RA therapy when data from these trials were meta-analyzed.24-27 A meta-analysis of 7 cardiovascular outcome trials (LEADER, ELIXA, SUSTAIN-6, EXSCEL, HARMONY OUTCOMES, PIONEER-6, and REWIND) demonstrated a 12% relative reduction in MACE with GLP1RAs (HR, 0.88; 95% CI, 0.82-0.94), as well as a 16% relative reduction in fatal/nonfatal stroke (HR, 0.84; 95% CI, 0.76-0.93) and 9% relative reduction fatal/nonfatal MI (HR, 0.91; 95% CI, 0.84-1.00).24 Additionally, this meta-analysis demonstrated a significant reduction in both cardiovascular death (HR, 0.88; 95% CI, 0.81-0.96) and all-cause death (HR, 0.88; 95% CI, 0.83-0.95). A subsequent meta-analysis of 10 cardiovascular outcome trials (of which 8 were included in this review) demonstrated that GLP1RA therapy reduced MACE (HR, 0.87; 95% CI, 0.81-0.93) and cardiovascular death (HR, 0.86; 95% CI, 0.80-0.92) in patients with T2D.25 However, both of these meta-analyses excluded the trial by Ruff and colleagues18 and the SOUL trial.
A recent meta-analysis of 10 trials that included MACE as a primary or secondary outcome (the SUMMIT and SOUL trials were not included) demonstrated that GLP1RAs reduced MACE (HR, 0.86; 95% CI, 0.80-0.93).26 The risk of cardiovascular death was also lower with GLP1RA therapy (HR, 0.87; 95% CI, 0.81-0.94), though this analysis included the FIGHT trial, which was not included in this review because it did not include MACE as a primary outcome. Another meta-analysis of 5 GLP1RA and 3 SGLT2 inhibitor trials demonstrated that both classes of medications reduced 3-point MACE in patients with T2D.27 However, the risk of heart failure hospitalization was significantly lower with SGLT2 inhibitors (HR, 0.69; 95% CI, 0.61-0.79) but not with GLP1RAs (HR, 0.93; 95% CI 0.83-1.04). This reiterates the probable lack of a benefit in terms of heart failure hospitalization with GLP1RA use specifically in patients with T2D.
Semaglutide is the only GLP1RA available as subcutaneous and oral formulations, both of which have cardiovascular outcome data. Oral semaglutide has lower bioavailability, peak plasma concentrations, and magnitude of HbA1c lowering when compared to subcutaneous semaglutide in patients with T2D.28 The initial cardiovascular safety trials demonstrated a discrepancy in outcomes between oral and subcutaneous semaglutide. Subcutaneous semaglutide was superior at reducing MACE versus placebo in the SUSTAIN-6 trial,12 whereas oral semaglutide was only shown to be noninferior in the PIONEER-6 trial.15 However, the recently published SOUL trial confirmed the cardiovascular benefit of oral semaglutide in patients with T2D and ASCVD.21 There is currently one oral formulation of semaglutide available in the United States (3-mg, 7-mg, and 14-mg tablets); however, a second-generation formulation (1.5-mg, 4-mg, and 9-mg tablets) is currently being reviewed by FDA.
Only one study to date has demonstrated a reduction in MACE with a GLP1RA in a population without T2D. The SELECT trial was conducted in patients with overweight/obesity and ASCVD but without T2D.19 Semaglutide—at the weight management dose of 2.4 mg subcutaneously weekly, which is higher than the dose for glycemic control in T2D—significantly reduced occurrence of the primary outcome of 3-point MACE, with a relative risk reduction similar to that reported in patients with T2D (HR, 0.80; 95% CI 0.72-0.90). Though cardiovascular the risk of death was lower with semaglutide, the reduction was not statistically significant, and thus all other secondary outcomes were considered to be exploratory.
There are preliminary data to suggest that tirzepatide, a combined GLP1RA and glucose-dependent insulinotropic polypeptide receptor agonist, is beneficial in patients with HFpEF and obesity.20 Tirzepatide neither worsened nor improved LVEF in this population, but reduced the risk of adverse heart failure events in the SUMMIT trial.20 Further, GLP1RA therapy, specifically subcutaneous semaglutide, may improve symptom management in patients with HFpEF and obesity. The STEP-HFpEF and STEP-HFpEF DM trials evaluated subcutaneous semaglutide versus placebo in patients with obesity (BMI ≥30 kg/m2) and HFpEF, with or without T2D.22,23 Semaglutide showed a benefit in the co-primary endpoints of change in body weight and symptoms based on the KCCQ-CSS, yet these trials were not adequately powered to assess adverse cardiovascular or heart failure outcomes. There are currently no data from large-scale clinical trials of GLP1RA therapy in patients with HFpEF without obesity or patients with heart failure with reduced ejection fraction.
Overall, the data in patients with heart failure are not as robust as for SGLT2 inhibitors, which should be prioritized over GLP1RAs in patients with HFpEF at this time.
Further clinical trials will contribute to the overall cardiovascular outcome evidence for GLP1RAs. The SURPASS-CVOT trial, which was published in December 2025 after our systematic literature search was conducted, compared the effect of tirzepatide (up to 15 mg subcutaneously weekly) versus dulaglutide (1.5 mg subcutaneously weekly) on 3-point MACE in 13,165 patients with T2D and ASCVD.29 The mean patient age was 64 years, 29% were female, and mean BMI at baseline was 33 kg/m2. In a modified intention-to-treat analysis, tirzepatide was noninferior, but not superior, to dulaglutide with respect to MACE (12.2% vs 13.1%; HR, 0.92; 95% CI, 0.83-1.01; P = 0.003 for noninferiority, P = 0.09 for superiority) over a median of 4 years.
The rate of drug discontinuation due to an adverse event (mostly gastrointestinal events) was higher with tirzepatide (13.2% vs 10.1% with dulaglutide). In the SURMOUNT-MMO trial (ClinicalTrials.gov identifier, NCT05556512), patients with an elevated BMI (≥27 kg/m2) and ASCVD (but without T2D) were randomized to tirzepatide or placebo for up to 5 years.30 The primary endpoint is a composite of all-cause death, nonfatal MI, nonfatal stroke, coronary revascularization, or adverse heart failure events. The reported actual enrollment is 15,374, and the completion date is estimated for 2027.
There are a number of practical considerations when initiating a GLP1RA with respect to dosage form and cost. The majority of GLP1RAs discussed in this review are once-weekly subcutaneous injections, with the exception of lixisenatide (daily) and oral semaglutide (daily). While injections may not be a preferred dosage form for some patients (eg, those with needle phobia or who are functionally dependent), once-weekly administration may be favored over an oral medication that must be taken daily.
Patient access to GLP1RA therapy in practice is challenging due to high cost and ongoing drug shortages, primarily due to the rise of these medications in popular culture (particularly semaglutide) and an increase in approved indications for these therapies. Fortunately, FDA approved the first generic versions of subcutaneous GLP1RAs (exenatide and liraglutide) in 2024.
The findings of this review suggest that the decision to initiate a GLP1RA for cardiovascular disease prevention may be guided by a combination of a patient’s HbA1c, BMI, and ASCVD history or risk factors. A GLP1RA may be considered in patients with T2D and ASCVD (or at high risk for ASCVD), in the absence of contraindications, to reduce the risk of MACE. This aligns with both the American Diabetes Association guidelines on cardiovascular disease and risk management as well as the Diabetes Canada guidelines.31,32 Similarly, subcutaneous semaglutide may be recommended in patients with ASCVD and overweight/obesity with or without T2D for MACE risk mitigation.
Tirzepatide may be a reasonable alternative in patients with overweight/obesity and HFpEF to prevent heart failure hospitalizations. Ultimately, the decision to initiate a GLP1RA in these populations should remain patient-centered and include a discussion of the patient’s values and preferences, potential cardiovascular benefits, and potential risks of gastrointestinal-related adverse events.
Potential limitations of this systematic review include the lack of quantitative synthesis of the evidence (though this review aimed to assess cardiovascular outcomes in different patient populations, including those with T2D, obesity, ASCVD, and heart failure), the lack of a priori registration on a systemic review registry, and the use of a single database to identify relevant articles. However, Ovid MEDLINE includes PubMed, as well as Publisher, In-Data-Review, In-Process, and PubMed-not-MEDLINE records from the National Library of Medicine, so it was postulated that all relevant RCTs would be indexed in this database.
Conclusion
Treatment with GLP1RAs has been demonstrated to result in a consistent reduction in MACE in patients with T2D, which appears to be driven primarily by a reduction in MI. The GLP1RAs may also reduce the risk of cardiovascular death, though it is unclear whether this is a class effect. Liraglutide is the only GLP1RA to date demonstrated to reduce both MACE and cardiovascular death risk.
Among the currently available GLP1RAs, subcutaneous semaglutide is the only GLP1RA that has been shown to reduce MACE in patients with overweight/obesity and ASCVD but without T2D. There are initial data that support a potential role for GLP1RAs in improving symptomatology and reducing adverse heart failure events in patients with obesity and HFpEF. Though overall serious adverse events were similar to placebo, discontinuation due to a gastrointestinal-related adverse event was common with GLP1RA therapy.