What is the effect of Glucagon-like peptide-1 (GLP-1) on inflammation?

GLP-1 Effects on Inflammation

GLP-1 receptor agonists demonstrate significant anti-inflammatory effects through multiple mechanisms, making them valuable therapeutic agents beyond glucose control for conditions with underlying inflammatory pathology. 1, 2

Mechanisms of Anti-inflammatory Action

GLP-1 receptor agonists exert anti-inflammatory effects through several pathways:

1. Direct anti-inflammatory effects:

   • Suppression of key inflammatory pathways involving TNF-α, IL-17, and NF-κB 3
   • Reduction of systemic inflammation markers 1, 3
   • Modulation of immune cell function 4

2. Central nervous system mediation:

   • Activation of central neuronal GLP-1 receptors inhibits Toll-like receptor agonist-induced inflammation 5
   • Requires brain-immune networks via a gut-brain GLP-1R axis to suppress peripheral inflammation 5

3. Metabolic improvements with secondary anti-inflammatory benefits:

   • Reduction in epicardial adipose tissue (36% reduction with liraglutide) 1
   • Decreased hepatic fat and steatosis 1
   • Weight loss leading to reduced inflammatory burden 1, 3

Clinical Applications in Inflammatory Conditions

Cardiovascular Disease

• GLP-1 receptor agonists provide cardioprotection through:
  • Improved myocardial substrate utilization
  • Anti-inflammatory and anti-atherosclerotic effects
  • Reduced myocardial ischemia injury
  • Lower systemic and pulmonary vascular resistance 1, 6

Non-alcoholic Fatty Liver Disease (NAFLD)

• GLP-1 RAs reduce hepatic fat and steatosis
• The LEAN trial showed more frequent resolution of NASH with liraglutide (9/23 vs 2/22; p=0.019) and less progression of fibrosis (2/23 vs 8/22; p=0.04) 1
• Meta-analysis of 6 studies confirmed GLP-1 RAs reduce transaminase levels and improve histology 1

Inflammatory Skin Disorders

• Significant improvements in hidradenitis suppurativa and psoriasis through:
  • Direct interaction with inflammatory signaling pathways
  • Reduction in systemic inflammation
  • Weight loss effects 3, 4

Other Inflammatory Conditions

• Emerging evidence for benefits in:
  • Type 1 diabetes
  • Neurodegenerative disorders
  • Diabetic nephropathy
  • Asthma 2

Clinical Considerations and Limitations

1. Differential effects in heart failure:

   • Safe in patients at risk for heart failure
   • Should be used with caution in established heart failure with reduced ejection fraction (HFrEF) due to:
     • No evidence of benefit
     • Trend toward worse outcomes in small RCTs 1
   • Increased heart rate (3-10 beats/min) may be problematic in some cardiac patients 1

2. Common adverse effects:

   • Gastrointestinal effects (nausea, vomiting, diarrhea)
   • Delayed gastric emptying
   • Potential for gallbladder disorders 1

Clinical Recommendations

1. For patients with type 2 diabetes and chronic coronary syndrome:

   • GLP-1 receptor agonists with proven CV benefit are recommended (Class I, Level A evidence) 1
   • Benefits include reduced cardiovascular events independent of glucose control

2. For overweight/obese patients without diabetes:

   • Semaglutide should be considered in overweight (BMI >27 kg/m²) or obese patients with chronic coronary syndrome to reduce CV mortality, MI, or stroke (Class IIa, Level B evidence) 1
   • Anti-inflammatory benefits may contribute to these outcomes

3. For patients with inflammatory skin conditions:

   • Consider GLP-1 RAs as adjunctive therapy for conditions like hidradenitis suppurativa and psoriasis 3, 4
   • Benefits seen with both liraglutide and semaglutide

4. For patients with NAFLD/NASH:

   • GLP-1 RAs show promise in reducing hepatic steatosis and inflammation 1
   • Consider in patients with metabolic syndrome and NAFLD

The anti-inflammatory effects of GLP-1 receptor agonists represent an important therapeutic mechanism beyond glucose control, with potential applications across multiple inflammatory conditions.