What this is
- This review evaluates the role of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in reducing cardiovascular and renal risks in type 2 diabetes mellitus (T2DM).
- It discusses both injectable and oral GLP-1 RAs, focusing on recent trials like PIONEER 6 and SOUL.
- While injectable GLP-1 RAs have strong evidence for cardiorenal protection, oral options like semaglutide show cardiovascular benefits but limited renal outcomes.
Essence
- Oral GLP-1 RAs, particularly semaglutide, show cardiovascular benefits in T2DM but lack strong evidence for renal outcome improvement. Injectable GLP-1 RAs remain the gold standard for cardiorenal risk reduction.
Key takeaways
- Oral semaglutide demonstrated cardiovascular safety and non-inferiority in reduction compared to placebo in the PIONEER 6 trial. However, it did not significantly reduce major kidney outcomes.
- The SOUL trial showed a significant reduction in among patients receiving oral semaglutide, with an incidence of 12.0% in the semaglutide group vs. 13.8% in the placebo group.
- Orforglipron, an investigational oral GLP-1 RA, shows promise in glycemic control and weight loss, but cardiovascular and renal outcome data are still pending.
Caveats
- Evidence for renal outcome improvement with oral GLP-1 RAs is limited, with no significant reductions observed in major kidney outcomes in recent trials.
- The PIONEER 6 trial's findings are based on a relatively modest sample size and short duration, which may affect the generalizability of its results.
Definitions
- MACE: Major adverse cardiovascular events, including cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke.
Simplified
Introduction
Cardiovascular (CV) and renal complications are significant contributors to morbidity and mortality in patients with type 2 diabetes mellitus (T2DM) [1]. As a chronic, multisystem disease, T2DM predisposes patients to atherosclerosis, heart failure, and progressive kidney disease due to complex metabolic and inflammatory mechanisms [2]. Historically, glucose-lowering therapies were developed solely to control hyperglycemia, with little emphasis on macrovascular and renal endpoints. However, this paradigm shifted with the emergence of glucagon-like peptide-1 receptor agonists (GLP-1 RAs), which have demonstrated favorable effects on both cardiovascular and renal outcomes [3, 4]. Large cardiovascular outcome trials involving injectable GLP-1 RAs such as liraglutide, semaglutide, dulaglutide, and albiglutide have shown GLP-1 RAs are associated with consistent reduction in major adverse cardiovascular events (MACE) and progression of renal disease [5–9]. These findings have reshaped treatment guidelines, positioning GLP-1 RAs as preferred agents in patients with T2DM and high CV or renal risk [10]. However, the injectable GLP-1 RA presents limitations in terms of medication adherence, injection fatigue, and cold-chain storage requirements. The introduction of oral GLP-1 RAs, specifically oral semaglutide, has overcome these limitations for patients unwilling or unable to use injectable therapies [11] Despite the pharmacokinetic differences, the potential of oral GLP-1 RAs to mimic the beneficial effects seen in injectable forms is of emerging clinical interest [12]. This review explores current evidence from randomized controlled trials, particularly the PIONEER 6 (the Peptide Innovation for Early Diabetes Treatment) [13] and the SOUL (the Semaglutide Outcomes Study) [14], and evaluates the potential impact of orforglipron, an investigational oral non-peptide GLP-1 RA [15]. Furthermore, landmark trials evaluating subcutaneous GLP-1 RAs are included to contextualize the clinical significance of GLP-1 mediated cardiorenal protection (Table 1).
| Trials/ Published year | GLP-1 RA (Route) | Study Population ()N | MACE Definition | Cardiovascular Outcomes | Renal Outcomes |
|---|---|---|---|---|---|
| PIONEER-6 (2019) [] [13] RCT | Semaglutide (oral) vs. placebo | T2DM with high CV risk= 3183N | CV death, nonfatal MI, or nonfatal stroke | Non-inferior to placebo for MACE (HR 0.79; 95% CI 0.57–1.11) | Renal outcomes were not primary endpoints |
| SOUL (2025) [] [14] RCT | Semaglutide (oral) vs. placebo | T2DM with established CV disease or multiple risk factors= 9650N | CV death, nonfatal MI, or nonfatal stroke | Significant reduction in MACE compared with placebo (HR 0.86; 95% CI 0.77–0.96) | No significant reduction in major kidney outcomes |
| ACHIEVE-1 (2025) [] [19] RCT | Orforglipron (oral) vs. placebo | T2DM treated with diet and exercise= 559N | Not assessed | CV outcomes were not evaluated | Renal outcomes were not evaluated |
| LEADER (2016) [] [6] RCT | Liraglutide (subcutaneous) vs. placebo | T2DM with high CV risk= 9340N | CV death, nonfatal MI, or nonfatal stroke | Significant reduction in MACE and CV mortality | Reduced incidence of new-onset nephropathy (secondary outcome) |
| SUSTAIN-6 (2016) [] [7] RCT | Semaglutide (subcutaneous) vs. placebo | T2DM with CV risk= 3297N | CV death, nonfatal MI, or nonfatal stroke | Significant reduction in MACE | Reduced new or worsening nephropathy, driven primarily by reduced progression to macroalbuminuria |
| REWIND (2019) [] [8] RCT | Dulaglutide (subcutaneous) vs. placebo | T2DM, majority without prior CV disease= 9901N | CV death, nonfatal MI, or nonfatal stroke | Significant reduction in MACE | Reduced composite renal outcome, largely attributable to lower rates of new macroalbuminuria |
| EXSCEL (2017) [] [23] RCT | Exenatide extended-release (subcutaneous) vs. placebo | T2DM= 14,752N | CV death, nonfatal MI, or nonfatal stroke | Non-inferior to placebo for MACE | Renal outcomes were not primary endpoints |
| ELIXA (2015) [] [24] RCT | Lixisenatide (subcutaneous) vs. placebo | T2DM with recent acute coronary syndrome= 6068N | CV death, nonfatal MI, nonfatal stroke, or hospitalization for unstable angina | No significant difference in MACE compared with placebo | Modest reductions in albuminuria without significant effects on hard renal endpoints |
| HARMONY Outcomes (2018) [] [10] RCT | Albiglutide (subcutaneous) vs. placebo | T2DM with established CV disease= 9463N | CV death, nonfatal MI, or nonfatal stroke | Significant reduction in MACE | Renal outcomes were not primary endpoints |
| FLOW (2024) [] [25] RCT | Semaglutide (subcutaneous) vs. placebo | T2DM with CKD= 3533N | CV death included as a component of the renal composite endpoint | CV outcomes assessed as part of the composite endpoint | Significant reduction in the composite kidney outcome, including kidney failure, sustained decline in eGFR rate of at least 50%, or kidney-related death |
| AMPLITUDE-O (2021) [] [9] RCT | Efpeglenatide (subcutaneous) vs. placebo | T2DM with established CV disease or CKD plus additional CV risk factors= 4,076N | Nonfatal MI, nonfatal stroke, or death from CV or undetermined causes | Significant reduction in MACE vs. placebo | Significant reduction in the composite renal (secondary) outcome, including macroalbuminuria, ≥ 30% increase in urinary albumin-to-creatinine ratio, sustained ≥ 40% decline in eGFR for ≥ 30 days, renal-replacement therapy for ≥ 90 days, or sustained eGFR < 15 mL/min/1.73 m² for ≥ 30 days |
| SURPASS-4 (2021) [] [26] RCT | Tirzepatide (subcutaneous) vs. insulin glargine | T2DM with increased CV risk= 2002N | CV death, nonfatal MI, nonfatal stroke, or hospitalization for unstable angina | CV safety; not powered for superiority | Renal outcomes were not primary or secondary endpoints |
Discussion
Mechanism of Action of GLP-1 RAs and Rationale for Cardiorenal Protection
GLP-1 is an incretin hormone secreted by L-cells in the small intestine in response to nutrient ingestion. It enhances glucose-dependent insulin secretion, suppresses glucagon release, delays gastric emptying, and promotes satiety [16]. GLP-1 RAs are analogs or mimetics of endogenous GLP-1 that bind to the GLP-1 receptor on pancreatic β-cells and other tissues [17]. Beyond glycemic control, GLP-1 receptors are expressed in cardiovascular tissues, the central nervous system, and renal glomeruli. These agents exert pleiotropic effects, including anti-inflammatory and anti-atherogenic properties, modulation of blood pressure, and improvements in endothelial function. Renal benefits are believed to be mediated via reduction in albuminuria, tubular-glomerular feedback, and direct renal hemodynamic effects (Fig. 1). These mechanisms provide the biological plausibility for cardiorenal benefits observed in GLP-1 RA outcome trials [5, 7, 13].
Overview of the physiological effects of GLP-1 receptor agonists across major organ systems. Abbreviations: GIT, gastrointestinal tract; GLP-1, glucagon-like peptide-1
Oral GLP-1 RAs: Innovation and Clinical Rationale
Semaglutide is the first and only GLP-1 RA currently approved by the U.S. Food and Drug Administration and the European Medicines Agency for both subcutaneous and oral forms [18]. The development of oral semaglutide, a peptide-based GLP-1 RA co-formulated with sodium N-[8-(2-hydroxybenzoyl) amino] caprylate (SNAC), did overcome the challenge of peptide degradation in the gastrointestinal tract. This innovation allowed for the first oral formulation of a GLP-1 RA, offering a more convenient alternative to injectable agents while maintaining comparable efficacy in glycemic control. However, oral semaglutide requires strict administration conditions, including ingestion in a fasting state with a limited volume of water and a mandatory post-dose fasting interval, factors that may compromise adherence and real-world therapeutic effectiveness [13].
More recently, orforglipron, a non-peptide, small molecule GLP-1 RA, has emerged in clinical trials. Unlike oral semaglutide, orforglipron does not require special co-formulation strategies and bypasses the limitations of enzymatic degradation and poor absorption. This pharmacologic profile supports the potential for once-daily, food-independent dosing, offering greater convenience and the prospect of improved treatment adherence [19]. Early studies have shown promising glycemic control and weight loss outcomes, with large cardiovascular outcome trials are underway [19–21].
Randomized Controlled Trials (RCT) on Oral Semaglutides
PIONEER 6: Non-Inferiority Trial Evaluating CV Safety of Oral Semaglutide [] [13]
The PIONEER 6 trial was a double-blind, placebo-controlled, randomized trial for CV outcomes evaluating the safety of oral semaglutide in patients with T2DM and high CV risk. There were 3,183 participants with CV or chronic kidney disease randomized to receive either oral semaglutide or placebo over a median follow up of 15.9 months [13]. The primary endpoint, a composite of MACE (CV death, nonfatal myocardial infarction (MI), or nonfatal stroke), occurred in 3.8% of the semaglutide group and 4.8% of the placebo group. While the difference was not statistically significant (hazard ratio, 0.79; 95% CI, 0.57–1.11, P < 0.001 for noninferiority), the study met criteria for non-inferiority. Notably, semaglutide was associated with a 51% relative risk reduction in CV death (HR, 0.49; 95% CI, 0.27–0.92), though this was a secondary outcome [13]. Although limited by its short duration and modest sample size, PIONEER 6 confirmed the CV safety of oral semaglutide and hinted at a potential favorable CV mortality signal warranting further investigation.
SOUL: Semaglutide Outcomes Study [] [14]
The SOUL trial, completed in 2024, expanded upon PIONEER 6 with a larger cohort of over 9,600 patients with T2DM and established CVD or multiple risk factors [14]. Participants were randomized to receive oral semaglutide or placebo and were followed for a median of 3.6 years [14]. This study demonstrated a statistically significant reduction in MACE (a composite of death from CV causes, nonfatal MI, or nonfatal stroke) compared to placebo among patients with T2DM and high CV risk. The incidence of MACE assessed in a time-to-first event analysis was 12.0% in the oral semaglutide group versus 13.8% in the placebo group (HR 0.86, 95% CI, 0.77–0.96; P = 0.006). There was a significant reduction in nonfatal MI (HR, 0.74; 95% CI, 0.61–0.90). However, there was no significant difference in nonfatal stroke (HR, 0.88; 95% CI, 0.70–1.11) or CV mortality (HR, 0.93; 95% CI, 0.80–1.09) between the groups. Additionally, oral semaglutide did not significantly reduce major kidney outcomes with event rates of 8.4% and 9.0% in the semaglutide and placebo groups, respectively (HR, 0.91; 95% CI, 0.81–1.05) [14]. These results suggest a favorable trend in CV outcomes consistent with studies of injectable semaglutides.
ACHIEVE-1: A Study of Orforglipron in Adult Participants With Type 2 Diabetes and Inadequate Glycemic Control With Diet and Exercise Alone [] [19]
Orforglipron is a non-peptide, oral GLP-1 RA that binds to the GLP-1 receptor with high affinity and acts as a selective partial agonist [19]. The flexibility in dosing, lack of fasting requirements, and robust glycemic efficacy make orforglipron as a potential oral option. In ACHIEVE-1 trial, a phase 3, double-blind, placebo-controlled trial, once-daily oral orforglipron significantly reduced glycated hemoglobin (HbA1c) over 40 weeks in patients with T2DM managed with diet and exercise alone [19]. Mean HbA1c reductions ranged from − 1.24% to − 1.48% across the 3-mg, 12-mg, and 36-mg doses, compared with − 0.41% with placebo (P < 0.001 for all doses). Orforglipron was also associated with dose-dependent weight loss, with mean body-weight reductions of − 4.5%, − 5.8%, and − 7.6%, respectively, versus − 1.7% with placebo. There were no cardiovascular or renal outcomes evaluated in this study [19]. Ongoing phase 3 trials such as ATTAIN-Outcomes [22] is expected to address these endpoints.
Major Randomized Controlled Trials on Subcutaneous GLP-1 RAs for Cardiovascular and Renal Outcomes
LEADER: Liraglutide Effect and Action in Diabetes:Evaluation of Cardiovascular Outcome Results [] [6]
The LEADER trial enrolled 9,340 patients with T2DM and high CV risk. Once-daily subcutaneous liraglutide significantly reduced the incidence of the primary MACE outcome; CV death, nonfatal MI or nonfatal stroke, by 13% (HR 0.87; 95% CI 0.78–0.97), and CV death by 22% (HR 0.78; 95% CI 0.66–0.93) compared with placebo. Renal outcomes (defined as the new onset of persistent macroalbuminuria or doubling of the serum creatinine level accompanied by an estimated glomerular filtration rate (eGFR) ≤ 45 mL/min/1.73 m², the need for continuous renal-replacement therapy, or death from renal disease) also improved, with a 22% lower risk of new-onset nephropathy (HR 0.78; 95% CI 0.67–0.92), supporting both cardiovascular and renal protection [6].
SUSTAIN-6: Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes [] [7]
SUSTAIN-6 randomized 3,297 T2DM patients to once-weekly subcutaneous semaglutide or placebo [7]. Semaglutide reduced the primary MACE endpoint (CV death, nonfatal MI, or nonfatal stroke) by 26% (HR 0.74; 95% CI 0.58–0.95), driven primarily by significant reduction in nonfatal stroke (HR 0.61) and nonfatal MI (HR 0.74). The trial also demonstrated renal benefits, with semaglutide reducing new or worsening nephropathy by 36% (HR 0.64; 95% CI 0.46–0.88), largely attributable to decreased progression to macroalbuminuria [7].
REWIND: Researching CardiovascularEvents With a Weekly Incretin in Diabetes [] [8]
The REWIND trial included 9,901 participants, 69% of whom had no prior CVD, and followed them for a median of 5.4 years [8]. Once-weekly dulaglutide resulted in a 12% reduction in the primary MACE outcomes (CV death, nonfatal MI, or nonfatal stroke) (HR 0.88; 95% CI 0.79–0.99), demonstrating CV benefit even in a predominantly primary-prevention population. Renal outcomes (defined as the development of a urinary albumin-to-creatinine ratio > 33.9 mg/mmol in participants with a lower baseline value, a sustained ≥ 30% decline in eGFR [i.e., based on two consecutive eGFR measurements], or initiation of chronic renal replacement therapy) also improved, with a 15% reduction in composite kidney events (HR 0.85; 95% CI 0.77–0.93), mainly driven by reduced development of new macroalbuminuria [8].
EXSCEL: ExenatideStudy of Cardiovascular Event Lowering [] [23]
EXSCEL evaluated once-weekly exenatide extended release in more than 14,000 T2DM patients [23]. The study met its non-inferiority requirement for cardiovascular safety but did not achieve superiority for reducing MACE (CV death, nonfatal MI, or nonfatal stroke) (HR 0.91; 95% CI 0.83–1.00). Although exenatide improved glycemic and weight outcomes, CV benefit was not statistically significant, and renal outcomes were not a primary focus [23].
ELIXA: Evaluation of Lixisenatide in Acute Coronary Syndrome [] [24]
ELIXA enrolled 6,068 patients with T2DM shortly after an acute coronary syndrome. Using a 4-point MACE definition that included CV death, nonfatal MI, or nonfatal stroke and hospitalization for unstable angina, lixisenatide showed CV safety with no increased risk (HR 1.02; 95% CI 0.89–1.17), but without reduction of major CV events compared to placebo [24]. Renal outcomes showed modest reduction in albuminuria but no significant hard-renal endpoint benefits [24].
HARMONY Outcomes: Albiglutide andCV Outcomes in Patients with Type 2 diabetes and CV Disease [] [10]
In 9,463 patients with established CV disease, once-weekly albiglutide reduced the risk of 3-point MACE (CV death, nonfatal MI, nonfatal stroke) by 22% (HR 0.78; 95% CI 0.68–0.90) [10]. Although albiglutide is no longer commercially available, HARMONY Outcomes provided evidence supporting GLP-1 RA-mediated cardiovascular protection in high-risk populations [10].
FLOW: A Research Study to See How Semaglutide WorksCompared With Placebo in People With T2DM and Chronic Kidney Disease [] [25]
FLOW is the first dedicated renal outcomes trial for a GLP-1 RA, studying once-weekly semaglutide in patients with T2DM and chronic kidney disease (CKD). Semaglutide significantly reduced the primary composite kidney endpoint comprising renal failure, sustained decline in eGFR, or death from kidney/CV causes, by approximately 24% (HR 0.76; 95% CI ~ 0.66–0.88). In addition, semaglutide was associated with favorable effects on CV outcomes and all-cause mortality. These findings established semaglutide as the first GLP-1 receptor agonist to demonstrate kidney disease–modifying efficacy in a dedicated renal outcomes trial [25].
AMPLITUDE-O: Effect of Efpeglenatide on Cardiovascular Outcomes [] [9]
AMPLITUDE-O enrolled 4,076 patients with T2DM and either established CV disease or CKD plus additional CV risk factors [9]. Using a 3-point MACE definition that included nonfatal MI, nonfatal stroke, or death from CV or undetermined causes, once-weekly subcutaneous efpeglenatide significantly reduced the risk of MACE compared with placebo (HR 0.73; 95% CI 0.58–0.92), meeting criteria for both non-inferiority and superiority [9]. Renal outcomes were prespecified secondary endpoints and included a composite of incident macroalbuminuria, an increase in urinary albumin-to-creatinine ratio of ≥ 30% from baseline, sustained decline in eGFR of ≥ 40% for ≥ 30 days, renal-replacement therapy for ≥ 90 days, or a sustained eGFR of < 15 ml per minute per 1.73 m2 for ≥ 30 days. Efpeglenatide significantly reduced the composite renal outcome compared with placebo (HR 0.68; 95% CI 0.57–0.79), with the benefit largely driven by lower rates of new-onset macroalbuminuria [9].
SURPASS-4: Efficacy and Safetyof Tirzepatide Once Weekly Versus Insulin Glargine in Patients With Type 2 Diabetes and Increased Cardiovascular Risk [] [26]
SURPASS-4 enrolled 2,002 patients with T2DM and increased CV risk and compared once-weekly subcutaneous tirzepatide with insulin glargine [26]. CV safety was assessed using a 4-point MACE definition including CV death, nonfatal MI, nonfatal stroke, or hospitalization for unstable angina. Tirzepatide was not associated with an increased risk of MACE compared with glargine (HR 0.74; 95% CI 0.51–1.08), although the trial was not powered to assess CV superiority. Renal outcomes were not prespecified primary or secondary endpoints in this trial [26].
Guideline Perspectives and Clinical Implementation
The American Diabetes Association and European Society of Cardiology (ESC) recommend injectable GLP-1 RAs with proven CV benefit for patients with T2DM and established CV disease or high CV risk [27, 28]. In 2019, the ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases assigned a Class I, Level A recommendation for the use of GLP-1 RAs in patients with T2DM and established atherosclerotic CV disease or at high or very high CV risk [29, 30]. Although more evidence is needed, oral semaglutide is now considered an alternative to injectable agents when administration barriers exist [28]. Orforglipron, pending CV outcome results, may expand the usage of GLP-1 RA therapy, particularly in primary prevention.
Conclusions
Oral GLP-1 RAs are a significant advancement in the treatment of T2DM, offering glycemic control, improved CV outcomes and potential cardiorenal protection. Although there is limited data with no reduction in renal outcomes, oral semaglutide has demonstrated CV safety and hints of CV benefit including reduction in MACE. Further RCTs assessing CV and renal outcomes are needed. In comparison, subcutaneous GLP-1 RAs have robust evidence supporting their use for reducing CV and renal events. Subcutaneous GLP-1 RAs remain the gold standard for cardiorenal protection, but oral formulations are potentially closing the gap.
Key References
Author Contributions
All authors reviewed this paper and contributed significantly
Funding
None.
Data Availability
Publicly available data from published papers.
Declarations
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Competing interests
The authors declare no competing interests.
Footnotes
References
Associated Data
Data Availability Statement
Publicly available data from published papers.