What are the indications and usage of Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in various diseases, including Type 2 diabetes, obesity, and neurodegenerative diseases?

Indications and Usage of GLP-1 Receptor Agonists in Various Diseases

GLP-1 receptor agonists (GLP-1 RAs) are primarily indicated for type 2 diabetes management and cardiovascular risk reduction, with emerging evidence supporting their use in obesity, chronic kidney disease, and potential applications in neurodegenerative diseases.

Primary Indications in Type 2 Diabetes

• GLP-1 RAs are recommended as adjuncts to diet and exercise to improve glycemic control in adults with type 2 diabetes 1
• They are indicated to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes mellitus and established cardiovascular disease 1
• GLP-1 RAs with proven cardiovascular benefits are preferred in patients with type 2 diabetes who have established atherosclerotic cardiovascular disease (ASCVD) 2
• In patients with type 2 diabetes and chronic kidney disease (CKD) who haven't achieved glycemic targets despite metformin and SGLT2 inhibitor treatment, long-acting GLP-1 RAs are recommended (Level 1B evidence) 2

Specific Indications in Chronic Kidney Disease

• GLP-1 RAs are appropriate for patients with type 2 diabetes and CKD with eGFR ≥2 mL/min/1.73 m² or UACR ≥30 mg/g, particularly those with existing or high risk of ASCVD 2
• They can be used interchangeably with SGLT2 inhibitors in patients with eGFR below 60 mL/min/1.73 m² or in those with albuminuria who are intolerant of SGLT2 inhibitors 2
• The choice of GLP-1 RA should prioritize agents with documented cardiovascular benefits 2
• Tirzepatide (dual GIP/GLP-1 receptor agonist) shows emerging evidence for kidney protection through reductions in albuminuria and slowing of eGFR decline 3

Role in Obesity Management

• GLP-1 RAs may be preferentially used in patients with obesity, type 2 diabetes, and CKD to promote intentional weight loss 2
• Liraglutide is approved at a 3 mg once daily dose for weight management among obese patients (BMI >30 kg/m²) aged >12 years 2
• GLP-1 RAs have demonstrated substantial weight loss benefits, with semaglutide showing mean weight loss of 14.9% in non-diabetic overweight or obese patients 2

Cardiovascular Benefits

• Long-acting GLP-1 RAs have demonstrated cardiovascular outcome benefits in clinical trials 2
• The LEADER trial showed liraglutide reduced the primary composite outcome of cardiovascular death, non-fatal myocardial infarction, or stroke by 13% compared to placebo in patients with type 2 diabetes at high cardiovascular risk 2
• The SUSTAIN 6 trial demonstrated that weekly semaglutide reduced cardiovascular events by 26% compared to placebo 2
• Recent evidence shows semaglutide 2.4 mg weekly reduced cardiovascular endpoints in non-diabetic patients with pre-existing cardiovascular disease and BMI >27 2

Emerging Applications in Neurodegenerative Diseases

• Preclinical evidence suggests GLP-1 RAs may have neuroinflammatory reducing effects beneficial in Alzheimer's and Parkinson's disease 4
• GLP-1 RAs demonstrate neuroprotective properties through anti-inflammatory, neurotrophic mechanisms in neurodegenerative disorder models 4, 5
• In Parkinson's disease animal models, GLP-1 RAs have shown protection of motor activity and dopaminergic neurons 5
• While promising in preclinical studies, comprehensive clinical trials are still needed to establish their definitive role in neurodegeneration 4, 5

Role in Non-Alcoholic Steatohepatitis (MASH)

• GLP-1 RAs are considered safe to use in metabolic dysfunction-associated steatotic liver disease (MASLD) including compensated cirrhosis 2
• They are recommended for their respective indications of type 2 diabetes and obesity in patients with MASH, as they improve cardiometabolic outcomes 2
• Substantial weight loss induced by GLP-1 RAs could be expected to provide hepatic histological benefits, although this has not been extensively documented 2

Dosing and Administration Considerations

• GLP-1 RAs are available in different formulations: twice daily (exenatide), once daily (lixisenatide, liraglutide), or once weekly (exenatide once weekly, dulaglutide, semaglutide) 2, 6
• To minimize gastrointestinal side effects, start with a low dose of GLP-1 RA and titrate up slowly 2
• For semaglutide, starting dose is 0.25 mg once weekly for 4 weeks, then increase to 0.5 mg once weekly, with potential further increase to 1 mg once weekly if additional glycemic control is needed 1

Safety Considerations and Contraindications

• GLP-1 RAs are contraindicated in patients with personal or family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia syndrome type 2 1, 7
• Common adverse effects include nausea, vomiting, diarrhea, abdominal pain, and constipation 1, 8
• The risk of hypoglycemia is generally low with GLP-1 RAs when used alone but increases when used with sulfonylureas or insulin 2, 7
• Monitor renal function in patients with renal impairment reporting severe adverse gastrointestinal reactions 1, 7
• GLP-1 RAs should not be used in combination with DPP-4 inhibitors 2

Clinical Decision-Making Algorithm

1. For patients with type 2 diabetes:

   • If patient has established ASCVD: Consider GLP-1 RA with proven CV benefits 2
   • If patient has CKD: Consider SGLT2i first, then add GLP-1 RA if glycemic targets not met 2
   • If patient has obesity: Consider GLP-1 RA for dual benefits of glycemic control and weight loss 2

2. For patients with obesity without diabetes:

   • Consider higher-dose GLP-1 RAs (e.g., semaglutide 2.4 mg weekly) for significant weight reduction 2

3. For patients with MASLD/MASH:

   • GLP-1 RAs are appropriate when indicated for diabetes or obesity management 2

4. For patients with neurodegenerative concerns:

   • Currently, insufficient evidence to recommend GLP-1 RAs specifically for this indication outside clinical trials 4, 5