A sweeping Lancet review reveals how modern incretin-based drugs are reshaping treatment for obesity and diabetes, delivering powerful weight loss while simultaneously protecting the heart, kidneys, and metabolic health.
Review: GLP-1 receptor agonists and next-generation incretin-based medications: metabolic, cardiovascular, and renal benefits. Image Credit: Gecko Studio / Shutterstock
In a recent review published in The Lancet, researchers synthesized decades of research on incretin-based medications. The review focuses explicitly on Glucagon-Like Peptide-1 (GLP-1) receptor agonists, newer multi-receptor agonists, and emerging oral small-molecule therapies.
The review’s analysis confirms that synthetic GLP-1 medications like semaglutide and tirzepatide, originally developed to control blood sugar, offer clinically validated protection against cardiovascular disease (CVD), chronic kidney disease (CKD), and metabolic dysfunction-associated steatotic liver disease (MASLD)-related outcomes, including improvements in steatosis and fibrosis-related endpoints. The review further highlights emergent research on “next-generation” therapies with weight-loss efficacy of up to about 24% in clinical trials, approaching weight-loss magnitudes reported in some surgical interventions.
Background
Type 2 diabetes (T2D) and its frequent comorbidity, obesity, have traditionally been treated as separate clinical battles. While the former was primarily managed with insulin or metformin to control glucose levels, the latter was often treated with lifestyle interventions or less effective pharmacotherapy.
The relatively recent advent of incretin-based therapies, synthetic medications that mimic gut hormones to promote insulin production and suppress patients’ appetites, revolutionized the field. These medications, particularly Glucagon-Like Peptide-1 (GLP-1) receptor agonists such as semaglutide and tirzepatide, have been clinically validated to treat both conditions, triggering metabolic cascades that significantly improve disease outcomes.
However, clinical research increasingly recognized that patients with metabolic diseases frequently experience clusters of systemic complications, including heart failure (HF), chronic kidney disease (CKD), and fatty liver disease, that single-target drugs historically failed to address comprehensively. Recent research has sought to address this gap by developing a new generation of incretin-based medications that simultaneously target multiple metabolic pathways, aiming to improve both metabolic control and downstream organ health.
About the review
The present Review summarizes evidence from major randomized trials and clinical development programs in the field, drawing on literature identified through database searches including PubMed and focusing on key advances reported through October 2025.
The review discusses several classes of therapies, including:
Mono-agonists: Liraglutide, dulaglutide, and semaglutide.
Dual agonists: Tirzepatide (GLP-1/GIP) and survodutide (glucagon/GLP-1).
Triple agonists: Retatrutide (GIP/GLP-1/glucagon).
Oral small molecules: Orforglipron.
The review evaluates these drugs across diverse patient populations, including those with clinically established T2D, obesity, CVD, and CKD. Rather than conducting a new meta-analysis, the authors synthesize findings from major randomized clinical trials, highlighting outcomes related to glycated hemoglobin (HbA1c), body weight reduction, major adverse cardiovascular events (MACE), and kidney function decline as reported in large cardiovascular outcomes trials (CVOTs), obesity randomized controlled trials, and early-phase clinical development studies.
The review further examines safety and tolerability data reported across these trials, focusing particularly on gastrointestinal side effects and emerging considerations such as reductions in lean body mass accompanying substantial weight loss.
Review findings
The review confirms that incretin-based therapies have not only achieved their intended goal of T2D and obesity management but have also demonstrated clinically meaningful benefits across multiple organ systems.
The analysis of cardiovascular outcomes trials (CVOTs) revealed consistent benefits. For example, the SELECT trial reported that semaglutide reduced the risk of MACE by 20% (Hazard Ratio (HR) 0.80, 95% confidence interval (CI) 0.72–0.90) in people with obesity but without diabetes, although several secondary outcomes did not reach statistical significance under hierarchical testing procedures.
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 0.66–0.88). These findings place GLP-1 receptor agonists among the most effective pharmacological strategies currently available for reducing cardiometabolic and renal risk in high-risk populations.
The data on 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 Phase 2 trials, retatrutide, a GIP/GLP-1/glucagon based triple agonist, achieved a mean bodyweight reduction of up to 24.2% over 48 weeks.
Finally, oral interventions such as orforglipron have demonstrated weight reduction of up to 11.2% at 72 weeks, offering a needle-free alternative for patients with metabolic disease who may prefer oral therapies.
The review also highlights the success of these synthetic medications in treating comorbidities. Tirzepatide was 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 therapeutic indication for tirzepatide.
Additionally, both semaglutide and tirzepatide showed promise in improving metabolic dysfunction-associated steatotic liver disease (MASLD), mitigating systemic inflammation, and contributing to improvements in liver-related outcomes, including steatosis resolution and fibrosis-related endpoints, in clinical trials.
Importantly, the review also notes that individual responses to incretin-based therapies can vary substantially, and weight regain commonly occurs if treatment is discontinued, highlighting the chronic nature of obesity management.
Conclusions
The present review elucidates the physiological benefits of synthetic incretin-based medications, highlighting both their unprecedented clinical efficacy against T2D and obesity and their extensive non-target metabolic benefits against heart, kidney, and liver diseases. It further reveals how current advances in triple agonists and oral formulations promise to further lower barriers to treatment and enhance therapeutic outcomes.
However, the authors note that substantial weight loss can be accompanied by reductions in lean body mass, underscoring the need for further research into dosing strategies and interventions that preserve muscle while promoting fat loss. Furthermore, while the efficacy of these synthetic drugs is remarkably high, the burden of gastrointestinal adverse events remains a challenge that requires carefully monitored dose escalation.
Journal reference:
Nauck, M. A., Tuttle, K. R., Tschöp, M. H., & Blüher, M. (2026). Glucagon-like receptor agonists and next-generation incretin-based medications: metabolic, cardiovascular, and renal benefits. The 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