Expanding Applications and Developmental Status of Glucagon-Like Peptide-1 (GLP-1) Drugs

GLP-1 drugs, as a novel class of therapies combining glucose-lowering, weight-loss, and anti-inflammatory effects, have expanded from their initial use in treating type 2 diabetes (T2D) to encompass obesity and various complications. They also show potential value in new indications such as neurodegenerative diseases and substance use disorders, thereby reshaping public health strategies for chronic disease intervention. This article systematically reviews the current application landscape, expansion directions, efficacy variations, safety profile, and future challenges of GLP-1 drugs, providing a comprehensive reference for understanding their clinical value and developmental potential.

1. Core Applications and Efficacy Landscape of GLP-1 Drugs

1.1 Leading Drugs and Clinical Positioning

Widely used GLP-1 drugs in clinical practice include semaglutide, tirzepatide, etc., categorized by dosing frequency into short-acting (e.g., exenatide twice daily) and long-acting (e.g., dulaglutide once weekly) formulations. Approved indications cover T2D and obesity, with some drugs also indicated for patients with comorbid cardiovascular disease, chronic kidney disease, or metabolic liver disease. Among them, tirzepatide (a GLP-1R/GIPR dual agonist) demonstrates superior efficacy in both glucose-lowering and weight loss. Head-to-head trials show it significantly outperforms semaglutide in reducing HbA1c and body weight. Semaglutide, conversely, has more extensive clinical evidence for cardiovascular and renal protection in complication management, applicable to a broader patient base.

1.2 Dose Optimization and Administration Routes

To enhance efficacy, higher-dose GLP-1 drugs are under continuous development. For instance, semaglutide 7.2 mg once weekly achieved 20.7% weight loss in clinical trials, and oral semaglutide 50 mg once daily reached 15.1% weight loss. These doses are awaiting regulatory approval. Oral and injectable formulations show minor pharmacodynamic differences, but oral forms require higher doses to achieve comparable plasma concentrations and have a slightly higher incidence of gastrointestinal adverse reactions.

1.3 Use in Special Populations

In children and adolescents, liraglutide and semaglutide have been tested in clinical trials, showing modest glucose-lowering and weight-loss effects with no adverse impact on growth, development, or bone age. However, long-term safety data remain insufficient. In type 1 diabetes (T1D), GLP-1 drugs as adjuvant therapy can improve glycemic control and weight loss, but ketoacidosis risk requires vigilance. Multiple clinical trials are currently exploring safe application protocols for GLP-1 drugs in T1D.

2. Expanding Indications Beyond T2D and Obesity

2.1 Cardiometabolic Diseases

The cardiovascular benefits of GLP-1 drugs are well-established. Semaglutide reduces the risk of major adverse cardiovascular events by 20% in obese individuals with cardiovascular disease but without T2D. Both tirzepatide and semaglutide can improve symptoms in patients with heart failure with preserved ejection fraction (HFpEF). In renal and liver diseases, semaglutide delays the progression of diabetic kidney disease, and tirzepatide improves metabolic dysfunction-associated steatohepatitis (MASH), with some benefits independent of weight loss. Additionally, GLP-1 drugs can improve walking ability in patients with peripheral arterial disease and alleviate symptoms of obstructive sleep apnea.

2.2 Neurodegenerative Diseases and Substance Use Disorders

Real-world data suggest a reduced risk of Parkinson's disease, Alzheimer's disease, and dementia among GLP-1 drug users. However, results from clinical trials are inconsistent, with some studies showing no cognitive improvement, possibly due to insufficient blood-brain barrier penetration or inadequate dosing. In substance use disorders (SUDs), semaglutide and liraglutide can reduce the incidence and relapse rates of alcohol use disorder (AUD) and cannabis use disorder (CUD), as well as decrease alcohol consumption and smoking. The mechanism may involve modulation of reward pathways and dopamine availability, but validation through large-scale clinical trials is needed.

2.3 Other Potential Indications

GLP-1 drugs are also being explored for inflammatory bowel disease, psoriatic arthritis, migraine, and polycystic ovary syndrome, primarily based on their anti-inflammatory and metabolic regulatory mechanisms. Most of these investigations are in early trial stages, and efficacy is not yet established.

3. Efficacy Heterogeneity and Safety Challenges

3.1 Individual Efficacy Variation

Significant inter-individual variation exists in glycemic and weight-loss responses to GLP-1 drugs. Approximately 10-17% of patients experience less than 5% weight loss, while 32-40% achieve over 20% weight loss. Key factors influencing efficacy include sex (better response in females), baseline BMI (higher BMI correlates with better response), and renal function. However, no reliable biomarkers or genetic testing tools currently predict responsiveness. Genetic factors have a minor influence, with GLP1R variants showing no significant association with response.

3.2 Safety and Tolerability

Common adverse reactions are primarily gastrointestinal, such as nausea, diarrhea, and constipation. Incidence is dose-dependent, with higher-dose formulations having slightly higher discontinuation rates. Regarding long-term safety, GLP-1 drugs do not increase the risk of suicidal ideation, but potential risks like acute kidney injury (related to dehydration) and gallbladder disease require vigilance. In special populations, data on use during pregnancy are limited, and discontinuation before conception is currently advised. Perioperative aspiration risk needs assessment, but emergency surgery patients do not require routine drug discontinuation.

3.3 Optimizing Healthy Weight Loss

Weight loss with GLP-1 drugs is often accompanied by lean body mass loss (accounting for about 14-20% of total weight loss), potentially increasing sarcopenia risk, especially in the elderly and frail. Combining with myoprotective agents (e.g., myostatin inhibitors) can reduce lean mass loss. Concurrent exercise and a high-protein diet can also improve body composition, promoting healthier weight loss.

4. Novel GLP-1 Drugs and Future Directions

4.1 Next-Generation Drug Development

Novel agents in late-stage clinical trials include triple agonists (e.g., retatrutide, targeting GLP-1R/GIPR/GCGR), oral small-molecule GLP-1RAs (e.g., orforglipron), and GLP-1R agonist/GIPR antagonists (e.g., maridebart cafraglutide). These aim for greater weight loss, better tolerability, or more convenient dosing. Notably, retatrutide has shown weight loss of 25-35%, offering a new direction for obesity treatment.

4.2 Combination Therapy Strategies

Combination formulations of GLP-1 drugs with SGLT-2 inhibitors, antihypertensives, and lipid-lowering agents are under development, potentially enabling one-stop management of cardiometabolic diseases. Combinations with myoprotective or anti-inflammatory drugs could address limitations of GLP-1 monotherapy.

4.3 Unresolved Key Issues

Core questions requiring clarification include: the dose-efficacy relationship for new indications, long-term safety (especially rare adverse events), durability of efficacy (preventing weight regain after discontinuation), accessibility, and cost control. Furthermore, optimizing patient selection through precision medicine to reduce non-responders is a key future research focus.

5. Summary and Outlook

GLP-1 drugs have evolved from simple glucose-lowering agents to multi-faceted therapies for chronic diseases, with continuously expanding applications and emerging new formulations, providing more effective treatment options for patients with T2D, obesity, and related complications. However, challenges like efficacy heterogeneity, long-term safety, and accessibility limit their full potential. Future efforts should focus on confirming efficacy for expanded indications through large-scale clinical trials, optimizing dosing regimens and combination strategies, while reducing costs and improving accessibility to maximize their public health value. With deepening mechanistic understanding and ongoing drug development, GLP-1 drugs are poised to play a role in more chronic diseases, potentially becoming a core therapy for improving the human health span.

Original Article：

Drucker DJ. The expanding landscape of GLP-1 medicines. Nat Med. 2026 Jan;32(1):47-57.