GLP-1 Receptor Agonists in Diabetes Management
Critical Clarification: Agonists vs. Antagonists
GLP-1 receptor agonists (not antagonists) are the therapeutic agents used in diabetes management. There are no GLP-1 receptor antagonists used clinically for diabetes treatment. GLP-1 receptor agonists activate the GLP-1 receptor to lower blood glucose, reduce cardiovascular events, and provide renal protection 1.
Primary Indications and Patient Selection
Type 2 Diabetes with Cardiovascular Disease
GLP-1 receptor agonists with proven cardiovascular benefit (liraglutide, semaglutide, dulaglutide) are recommended for patients with type 2 diabetes and established atherosclerotic cardiovascular disease to reduce major adverse cardiovascular events (MACE), independent of baseline HbA1c. 1
- Established atherosclerotic cardiovascular disease includes: prior myocardial infarction, ischemic stroke, unstable angina with ECG changes, myocardial ischemia on imaging, or revascularization of coronary, carotid, or peripheral arteries 1
- The decision to initiate treatment should be made independently of current glycemic control or HbA1c targets 1
Type 2 Diabetes with High Cardiovascular Risk (No Established CVD)
GLP-1 receptor agonists can be considered in patients aged ≥55 years with specific high-risk indicators: coronary, carotid, or lower extremity artery stenosis >50%, left ventricular hypertrophy, eGFR <60 mL/min/1.73 m², or albuminuria 1
Type 2 Diabetes with Chronic Kidney Disease
GLP-1 receptor agonists with proven cardiovascular benefit are recommended for patients with type 2 diabetes and CKD who do not achieve glycemic targets with metformin and/or SGLT2 inhibitors, or who cannot use these medications. 1
- GLP-1 receptor agonists retain glucose-lowering potency even in advanced CKD (eGFR as low as 15 mL/min/1.73 m²) and among dialysis patients 1
- They reduce albuminuria and slow eGFR decline 1
- In meta-analysis of 8 cardiovascular outcomes trials, GLP-1 receptor agonists significantly reduced composite kidney disease outcomes (macroalbuminuria, eGFR decline, progression to kidney failure, or death from kidney disease) 1
Non-Diabetic Patients with Cardiovascular Disease and Obesity
Semaglutide 2.4 mg weekly is recommended for non-diabetic patients with established cardiovascular disease and BMI ≥27 kg/m² for cardiovascular protection. 2
- This provides a 14% reduction in major adverse cardiovascular events (cardiovascular death, nonfatal MI, or nonfatal stroke) in non-diabetic patients 2
- Mean weight loss of 14.9-17.4% at 68-72 weeks 2
Agent Selection Algorithm
Prioritize Agents with Proven Cardiovascular Benefits
The preferred GLP-1 receptor agonists are 1:
- Liraglutide
- Semaglutide (including oral formulation)
- Dulaglutide
- Albiglutide (not currently available)
Other agents with cardiovascular data include lixisenatide and exenatide (once weekly), though the evidence for cardiovascular benefit is strongest for the agents listed above 1.
For Non-Diabetic Patients
Use semaglutide 2.4 mg weekly specifically, as this is the only GLP-1 receptor agonist with proven cardiovascular benefit in the non-diabetic population. 2
Mechanism of Action
GLP-1 receptor agonists work through multiple pathways 1, 3:
- Enhance insulin secretion in a glucose-dependent manner (low hypoglycemia risk)
- Inhibit glucagon secretion in a glucose-dependent manner
- Delay gastric emptying
- Reduce appetite and food intake via central mechanisms
- Promote weight loss
Dosing and Administration
Initiation Strategy
Start with a low dose and titrate up slowly to minimize gastrointestinal side effects. 1
- All currently available agents require subcutaneous injection, except oral semaglutide 1
- Formulations include once- or twice-daily (exenatide, liraglutide) and once-weekly options (semaglutide, dulaglutide, exenatide extended-release) 3
Combination Therapy Considerations
- Do not combine GLP-1 receptor agonists with DPP-4 inhibitors 1
- When used with insulin or sulfonylureas, reduce doses of these agents to avoid hypoglycemia 1
- In moderate-to-severe CKD, hypoglycemia rates are reduced by 50% even with concurrent insulin therapy 1
Adverse Effects and Contraindications
Common Side Effects
Gastrointestinal symptoms (nausea, vomiting, diarrhea) occur in 15-20% of patients with moderate-to-severe CKD but are usually tolerable with dose titration and abate over several weeks to months 1.
Cardiovascular Effects
Heart rate typically increases by ~5 bpm but has not been associated with higher blood pressure or other adverse events 1.
Contraindications and Cautions
Do not use GLP-1 receptor agonists in patients at risk for thyroid C-cell tumors (e.g., multiple endocrine neoplasia), pancreatic cancer, or pancreatitis based on theoretical risks from preclinical models. 1
- Injection site reactions are rare (<1%) 1
- Use caution in patients with or at risk for malnutrition due to weight loss and gastrointestinal effects 1
- Monitor for signs of acute pancreatitis 2
Peri-Operative Management
Critical Gastroparesis Concern
GLP-1 receptor agonists delay gastric emptying, creating aspiration risk during anesthesia. 1
Pre-Operative Cessation Guidelines
For patients taking GLP-1 receptor agonists for weight loss: hold for at least three half-lives (approximately 88% drug clearance) before elective procedures. 1
- For semaglutide, this means cessation for 3 weeks before surgery 1
For patients with type 2 diabetes: consult with the treating endocrinologist regarding risks and benefits of holding the drug, and recommendations for bridging diabetic therapy. 1
The benefits of GLP-1 receptor agonists in peri-operative glycemic control and potential decrease in postoperative major adverse cardiac events may outweigh gastroparesis risks in diabetic patients 1.
Pre-Operative Assessment
Document the following 1:
- Indication and dose of GLP-1 receptor agonist
- Date drug commenced, dose variations, last dose taken
- Symptoms of nausea, vomiting, or abdominal distention
- Co-prescribed drugs that delay gastric emptying (opioids, proton pump inhibitors, tricyclic antidepressants)
- Recent recreational drug use (alcohol, cannabis)
- Previous gastro-esophageal surgery
Anesthetic Considerations
If patients have not ceased medication as recommended, treat with full stomach precautions or consider gastric ultrasound to evaluate gastric volume 1.
Monitoring Requirements
Monitor the following parameters 2:
- Gastrointestinal symptoms
- Heart rate
- Kidney function every 3-6 months
- Signs of acute pancreatitis
Special Populations
Advanced CKD (eGFR <30 mL/min/1.73 m²)
GLP-1 receptor agonists are particularly valuable in advanced CKD because they retain glucose-lowering potency across the full range of eGFR and among dialysis patients 1.
Kidney Transplant Recipients
For patients with obesity exceeding BMI limits required for kidney transplant listing, GLP-1 receptor agonists can aid with weight loss to facilitate qualification for transplant 1.
Heart Failure
GLP-1 receptor agonists do not increase hospitalization for heart failure and may reduce this risk 1.