A comprehensive review in The Lancet reveals how the latest incretin-based drugs are reshaping obesity and diabetes treatments, delivering powerful weight loss while simultaneously protecting heart, kidney and metabolic health.
Review: GLP-1 receptor agonists and next-generation incretin-based medicines: metabolic, cardiovascular, and renal benefits. Image credit: Gecko Studio / Shutterstock
In a recent review published in lancetresearchers synthesized decades of research on incretin-based drugs. This review focuses explicitly on glucagon-like peptide-1 (GLP-1) receptor agonists, new multireceptor agonists, and emerging oral small molecule therapies.
Analysis in this review confirmed that synthetic GLP-1 drugs, such as semaglutide and tirzepatide, originally developed to control blood sugar levels, provide clinically validated protective effects on cardiovascular disease (CVD), chronic kidney disease (CKD), and metabolic dysfunction-associated fatty liver disease (MASLD)-related outcomes, including improvements in steatosis- and fibrosis-related endpoints. The review also highlights new research into “next generation” treatments that have shown weight loss effects of up to about 24% in clinical trials, approaching the magnitude of weight loss reported with some surgical interventions.
background
Type 2 diabetes (T2D) and its frequent comorbidity, obesity, have traditionally been treated as separate clinical struggles. The former was primarily managed with insulin or metformin to control blood sugar levels, while the latter was often treated with lifestyle interventions and less effective medications.
Relatively recently, the field has been revolutionized by the advent of incretin-based therapies, synthetic drugs that mimic intestinal hormones, stimulate insulin production, and suppress a patient’s appetite. These drugs, particularly glucagon-like peptide-1 (GLP-1) receptor agonists such as semaglutide and tirzepatide, have been clinically validated to treat both conditions and trigger a metabolic cascade that significantly improves disease outcome.
However, clinical studies are increasingly recognizing that patients with metabolic diseases frequently experience a cluster of systemic complications, including heart failure (HF), chronic kidney disease (CKD), and fatty liver disease, which have historically not been comprehensively addressed by single-targeted drugs. Recent research seeks to address this gap by developing a new generation of incretin-based drugs that simultaneously target multiple metabolic pathways, with the aim of improving both metabolic control and downstream organ health.
About reviews
This review utilizes literature identified through database searches including PubMed, focuses on key advances reported through October 2025, and summarizes evidence from the major randomized trials and clinical development programs in this field.
This review describes several types of treatments, including:
- Monoagonists: liraglutide, dulaglutide, semaglutide.
- Dual agonists: tirzepatide (GLP-1/GIP) and sulbodutide (glucagon/GLP-1).
- Triple agonist: Retatortide (GIP/GLP-1/Glucagon).
- Oral small molecule: Orforglipron.
This review evaluates these agents across diverse patient populations, including those with clinically established T2D, obesity, CVD, and CKD. Rather than conducting a new meta-analysis, the authors synthesized results from major randomized clinical trials, highlighting outcomes related to glycated hemoglobin (HbA1c), weight loss, major cardiovascular events (MACE), and decreased renal function reported in large cardiovascular outcomes trials (CVOTs), obesity randomized controlled trials, and early clinical development studies.
This review further examines the safety and tolerability data reported across these trials, with particular focus on emerging considerations such as gastrointestinal side effects and loss of lean body mass associated with significant weight loss.
Review the findings
This review confirmed that incretin-based treatments not only achieved their intended goals of T2D and obesity management, but also demonstrated clinically meaningful benefits across multiple organ systems.
Analysis of cardiovascular outcomes trials (CVOT) revealed consistent benefits. For example, the SELECT trial reported that semaglutide reduced the risk of MACE by 20% in obese but nondiabetic people (hazard ratio (HR) 0.80, 95% confidence interval (CI) 0.72 to 0.90). However, some secondary outcomes did not reach statistical significance in the hierarchical testing procedure.
Similarly, for kidney health, the FLOW trial demonstrated that semaglutide reduced the risk of severe kidney outcomes, including kidney failure and death, by 24% (HR 0.76, 95% CI 0.66 to 0.88). These findings place GLP-1 receptor agonists among the most effective pharmacological strategies currently available to reduce cardiometabolic and renal risks in high-risk populations.
Data regarding newer agents are even more striking, with tirzepatide demonstrating significantly greater weight loss (20.2%) than semaglutide (13.7%) in head-to-head trials. In a phase 2 study, letaltortide, a GIP/GLP-1/glucagon-based triple agonist, achieved average weight loss of up to 24.2% over 48 weeks.
Finally, oral interventions such as orforglipron have demonstrated weight loss of up to 11.2% over 72 weeks, providing a needle-free alternative for patients with metabolic diseases who prefer oral treatment.
This review also highlights the success of these synthetic drugs in treating comorbidities. Tirzepatide has been shown to significantly reduce the apnea-hypopnea index in patients with obstructive sleep apnea. Based on these findings, the U.S. Food and Drug Administration has approved obstructive sleep apnea as a new treatment indication for tirzepatide.
Additionally, both semaglutide and tirzepatide have been shown in clinical trials to improve metabolic dysfunction-associated fatty liver disease (MASLD), reduce systemic inflammation, and improve liver-related outcomes such as steatosis resolution and fibrosis-related endpoints.
Importantly, this review also notes that individual responses to incretin-based treatments can vary widely and that weight is usually regained when treatment is discontinued, highlighting the chronic nature of obesity management.
conclusion
This review elucidates the physiological benefits of synthetic incretin-based drugs, highlighting both their unprecedented clinical efficacy against T2D and obesity and their broad range of non-targeted metabolic benefits against heart, kidney, and liver diseases. Additionally, current advances in triple agonists and oral formulations highlight how treatment barriers are expected to be further lowered and treatment outcomes improved.
However, the authors note that significant weight loss may be accompanied by loss of lean body mass, highlighting the need for further research into dosing strategies and interventions that preserve muscle while promoting fat loss. Furthermore, while the efficacy of these synthetic agents is significantly higher, the burden of gastrointestinal adverse events remains a challenge and dose escalation must be carefully monitored.
Reference magazines:
- Nowak, MA, K. R. Tuttle, MH Chope, and M. Blücher (2026). Glucagon-like receptor agonists and next-generation incretin-based medicines: metabolic, cardiovascular, and renal benefits. Lancet, 407(10531), 892–908. DOI – 10.1016/s0140-6736(25)02105-1. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2825%2902105-1/fulltext
