GLP-1 Receptor Agonists in Type 2 Diabetes
Primary Recommendation
GLP-1 receptor agonists are preferred as the first injectable glucose-lowering therapy for type 2 diabetes when oral agents fail to achieve glycemic targets, prioritized over insulin due to superior cardiovascular and renal protection, weight loss benefits, and minimal hypoglycemia risk. 1
Mechanism of Action
GLP-1 receptor agonists work through multiple complementary pathways 1:
- Glucose-dependent insulin secretion enhancement - stimulates pancreatic β-cells only when glucose is elevated, explaining the low hypoglycemia risk 1, 2
- Glucagon suppression - inhibits α-cell glucagon release during hyperglycemia 1
- Delayed gastric emptying - slows nutrient absorption and reduces postprandial glucose spikes 1, 2
- Central appetite suppression - reduces calorie intake through CNS GLP-1 receptor activation 1, 2
Clinical Efficacy
Glycemic Control
- HbA1c reduction of 0.5-1.0% when used alone or in combination with oral agents 1, 3
- Long-acting agents (liraglutide 1.8mg daily, semaglutide, dulaglutide) reduce HbA1c by 0.20-0.34% more than basal insulin 3, 4
- Comparable or superior efficacy to sulfonylureas and DPP-4 inhibitors 3
Weight Loss
- Weight reduction of 2.3-5.5 kg across all agents, with semaglutide showing greatest effect 5, 3
- Weight loss is independent of nausea and represents a true metabolic effect 3
Cardiovascular and Renal Protection
- Reduce major adverse cardiovascular events (MACE) including myocardial infarction, stroke, and cardiovascular death in patients with established atherosclerotic disease 1
- Liraglutide, lixisenatide, exenatide weekly, semaglutide, dulaglutide, and albiglutide have demonstrated cardiovascular benefits 1
- Greater MACE reduction in patients with eGFR <60 mL/min/1.73m² compared to those with preserved renal function 1
- Reduce albuminuria and slow eGFR decline 1
Available Agents and Dosing
Short-Acting (Primarily Target Postprandial Glucose)
- Exenatide - 5 mcg twice daily, increase to 10 mcg after 1 month; inject within 60 minutes before meals 6, 4
- Lixisenatide - once daily administration 1, 4
Long-Acting (Target Both Fasting and Postprandial Glucose)
- Liraglutide - once daily injection 1, 5
- Dulaglutide - once weekly injection 5, 4
- Semaglutide - once weekly injection or daily oral formulation 5, 4
- Exenatide extended-release - once weekly injection 5, 4
Long-acting agents are preferred due to better fasting glucose control, improved gastrointestinal tolerability, and more convenient dosing schedules that enhance adherence 4
Clinical Positioning
When to Initiate
- First injectable therapy when metformin ± other oral agents fail to achieve HbA1c targets within 3 months 1
- Preferred over insulin in patients needing injectable therapy, unless extreme hyperglycemia (HbA1c >9% or FPG ≥11.1 mmol/L) with symptoms is present 1
- Mandatory consideration in patients with established atherosclerotic cardiovascular disease, chronic kidney disease, or heart failure, independent of HbA1c 1
Combination Therapy
- Effective with metformin, sulfonylureas, thiazolidinediones, or basal insulin 1
- When combining with sulfonylureas or insulin, reduce the dose of these agents to prevent hypoglycemia 1, 6
- Can add basal insulin to long-acting GLP-1 agonists if additional glucose lowering needed 1
Hospital Use
- Sitagliptin (DPP-4 inhibitor) plus basal insulin is as effective as basal-bolus insulin in non-ICU patients with mild hyperglycemia (<10 mmol/L), with fewer injections and reduced hypoglycemia 1
- Exenatide plus basal insulin achieved 78% of glucose readings in target range versus 63% with basal-bolus insulin 1
- Increased gastrointestinal side effects limit inpatient use 1
Renal Dosing Considerations
eGFR 30-59 mL/min/1.73m² 1
- Dulaglutide, liraglutide, semaglutide - no dose adjustment required
- Exenatide - use caution when initiating or escalating dose
- Lixisenatide - no dose adjustment required
eGFR 15-29 mL/min/1.73m² 1
- Dulaglutide, liraglutide, semaglutide - no dose adjustment required
- Exenatide weekly formulation - avoid use 6
- Lixisenatide - not recommended
eGFR <15 mL/min/1.73m² or Dialysis 6
- Exenatide should not be used in severe renal impairment or end-stage renal disease 6
- Use caution with all agents; consider alternative therapies
Adverse Effects and Management
Gastrointestinal (Most Common)
- Nausea and vomiting occur mainly during initial treatment, gradually diminish over time 1, 6
- Start at low doses and titrate slowly to minimize GI symptoms 7, 2
- Short-acting agents have more GI side effects than long-acting formulations 4
Pancreatitis
- Acute pancreatitis is rare but established with GLP-1 agonists, particularly exenatide 7, 6
- Discontinue immediately if pancreatitis suspected; do not restart 6
- Consider alternative therapies in patients with history of pancreatitis 7, 6
Hypoglycemia
- Intrinsically low risk due to glucose-dependent mechanism 1, 2
- Risk increases when combined with sulfonylureas or insulin - reduce doses of these agents when initiating GLP-1 agonists 1, 6
Acute Kidney Injury
- Post-marketing reports of acute kidney injury, sometimes requiring hemodialysis 6
- Often associated with dehydration from nausea/vomiting 6
- Use caution in renal transplant patients 6
Gallbladder Disease
- Increased risk of cholelithiasis and cholecystitis 6
- Obtain gallbladder studies if symptoms develop 6
Perioperative Aspiration Risk
- Pulmonary aspiration during general anesthesia reported in patients on GLP-1 agonists 1, 6
- Instruct patients to inform surgeons of GLP-1 use before elective procedures 6
- Consider withholding before surgery based on institutional protocols 1
Immunogenicity
- Patients may develop antibodies to exenatide 1, 6
- If worsening glycemic control occurs, consider alternative therapy 1
Contraindications
Absolute contraindications 6:
- History of severe hypersensitivity to exenatide or any GLP-1 agonist
- Drug-induced immune-mediated thrombocytopenia from exenatide products
- Type 1 diabetes (not indicated)
Relative contraindications/cautions 6:
- History of pancreatitis
- Severe renal impairment (eGFR <30 mL/min/1.73m²)
- Severe gastrointestinal disease (gastroparesis)
- Planned surgery requiring general anesthesia
Drug Interactions
Oral Medications
- Delayed gastric emptying reduces absorption of oral drugs 6
- For narrow therapeutic index drugs (contraceptives, antibiotics), take at least 1 hour before GLP-1 injection 6
- Alternatively, take with meals when GLP-1 is not administered 6
Warfarin
- Post-marketing reports of increased INR with bleeding 6
- Monitor prothrombin time more frequently after initiating or changing GLP-1 dose 6
Key Clinical Pearls
- Long-acting agents are superior to short-acting for HbA1c reduction and have better tolerability 4
- Semaglutide demonstrates greatest efficacy for both glucose lowering and weight reduction among available agents 5
- Cardiovascular benefits are most pronounced in patients with eGFR <60 mL/min/1.73m² 1
- Never share injection pens between patients, even with needle changes 6
- Tachyphylaxis to gastric emptying effects occurs with long-acting agents but glucose-lowering efficacy persists 5