What are the treatment options for patients who may benefit from Glucagon-like peptide-1 (GLP-1) receptor agonists?

GLP-1 Receptor Agonist Treatment Options

GLP-1 receptor agonists are indicated as adjunct therapy to diet and exercise for glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes, and to reduce major adverse cardiovascular events in adults with type 2 diabetes and established cardiovascular disease. 1

Primary Patient Populations Who Benefit

Type 2 Diabetes with Cardiovascular Disease or High CV Risk

• Patients with established atherosclerotic cardiovascular disease (ASCVD) should receive GLP-1 receptor agonists with proven cardiovascular benefit: specifically liraglutide, semaglutide, or dulaglutide. 2
• These agents reduce major adverse cardiovascular events (MACE) by 13-26%, with liraglutide reducing the composite outcome of cardiovascular death, non-fatal MI, or stroke from 14.9% to 13% (RR 0.87, p=0.01). 3
• Semaglutide demonstrated even greater benefit, reducing MACE from 8.9% to 6.6% (RR 0.74,95% CI 0.58-0.95). 3
• Cardiovascular benefits extend to non-diabetic patients with pre-existing cardiovascular disease and BMI >27, where semaglutide 2.4 mg weekly reduced cardiovascular endpoints from 8.2% to 6.5% (p=0.001). 3

Type 2 Diabetes with Chronic Kidney Disease

• For patients with CKD not achieving glycemic targets on metformin and/or SGLT2 inhibitors, add a long-acting GLP-1 receptor agonist (liraglutide, dulaglutide, or semaglutide). 3
• GLP-1 receptor agonists retain glucose-lowering efficacy even with eGFR as low as 15 ml/min/1.73 m², including dialysis patients. 2
• These agents reduce albuminuria and slow eGFR decline, with liraglutide showing significantly greater MACE reduction in patients with eGFR <60 ml/min/1.73 m² compared to those with eGFR ≥60 ml/min/1.73 m². 3
• In moderate-to-severe CKD (stages G3-G4), dulaglutide produced similar glycemic control to insulin glargine but resulted in significantly slower GFR decline. 3

Type 2 Diabetes Requiring Injectable Therapy

• When injectable therapy is needed, GLP-1 receptor agonists are the preferred first choice over insulin. 3
• GLP-1 receptor agonists produce HbA1c reductions of 0.8-1.5% and weight loss of 1.5-3.5 kg, with low hypoglycemia risk due to their glucose-dependent mechanism. 2
• Compared to insulin, GLP-1 receptor agonists have similar or better HbA1c reduction, lower hypoglycemia risk, and cause weight loss rather than weight gain. 3

Type 2 Diabetes with Dyslipidemia

• GLP-1 receptor agonists produce favorable lipid changes, specifically decreasing triglycerides and increasing HDL cholesterol. 2
• These lipid effects contribute to the overall cardiovascular benefits observed in outcome trials. 2

Specific Agent Selection

Liraglutide (Victoza)

• Initiate at 0.6 mg subcutaneously once daily for one week, then increase to 1.2 mg daily; if additional glycemic control is needed, increase to 1.8 mg daily after one week at 1.2 mg. 1
• Can be injected at any time of day, independently of meals, in the abdomen, thigh, or upper arm. 1
• Demonstrated cardiovascular benefit in the LEADER trial with 13% relative risk reduction in MACE. 3

Semaglutide (Ozempic)

• Available as both subcutaneous weekly injection and oral formulation. 3
• Oral semaglutide (14 mg daily) was non-inferior to subcutaneous liraglutide (1.8 mg daily) for HbA1c reduction (-1.2% vs -1.1%) but superior for weight loss (-4.4 kg vs -3.1 kg, p=0.0003). 4
• Demonstrated cardiovascular benefit in SUSTAIN 6 trial with 26% relative risk reduction in MACE. 3

Dulaglutide

• Requires once-weekly subcutaneous injection. 3
• Demonstrated cardiovascular benefit in outcome trials. 3
• Particularly effective in CKD, showing slower GFR decline compared to insulin glargine. 3

Absolute Contraindications

Do not prescribe GLP-1 receptor agonists in patients with: 1

• Personal or family history of medullary thyroid carcinoma (MTC)
• Multiple Endocrine Neoplasia syndrome type 2 (MEN2)
• Previous serious hypersensitivity reaction to liraglutide, semaglutide, or any excipients

For patients with non-MTC thyroid cancer history, GLP-1 receptor agonists can be used with regular thyroid function monitoring. 5

Safety Considerations and Dose Adjustments

Gastrointestinal Side Effects

• Nausea, vomiting, and diarrhea occur in 15-20% of patients but are typically transient and occur mainly during initial treatment. 2
• These symptoms are dose-dependent and more frequent with short-acting than long-acting formulations. 3
• Slow titration is essential to minimize gastrointestinal symptoms. 3

Hypoglycemia Risk Management

• When combining GLP-1 receptor agonists with insulin or sulfonylureas, reduce the dose of these agents to minimize hypoglycemia risk. 2, 1
• In moderate-to-severe CKD, hypoglycemia rates are reduced by half even with concurrent insulin therapy. 2
• Adult patients taking insulin secretagogues or insulin have increased hypoglycemia risk; dose reduction of these agents is necessary. 1

Pancreatitis

• Discontinue promptly if pancreatitis is suspected; do not restart if confirmed. 1
• Use with caution in patients with history of pancreatitis. 3

Acute Kidney Injury

• Monitor renal function when initiating or escalating doses, particularly in patients with severe gastrointestinal reactions (nausea, vomiting, diarrhea, dehydration). 6, 1
• Use caution when initiating or escalating doses in patients with pre-existing renal impairment. 1

Peri-operative Management

• For patients taking GLP-1 receptor agonists for weight loss, hold for at least three half-lives (3 weeks for semaglutide) before elective procedures. 3
• For patients with type 2 diabetes, consult endocrinology regarding risks/benefits of holding the drug and bridging therapy recommendations. 3
• Consider aspiration risk reduction strategies including postponement, clear fluid diet, prokinetics (metoclopramide or erythromycin), and point-of-care gastric ultrasound. 3

Cardiovascular Monitoring

• Heart rate typically increases by approximately 5-7.5 bpm but has not been associated with higher adverse cardiovascular outcomes. 3, 6
• Monitor for diabetic retinopathy progression in patients with pre-existing retinopathy, as rapid glucose improvement may temporarily worsen retinopathy. 6

Heart Failure Considerations

• Exercise caution in patients with heart failure with reduced ejection fraction (HFrEF), particularly those with recent decompensation, as small trials showed no benefit and numerically increased risk. 2
• If heart failure predominates over atherosclerotic disease, SGLT2 inhibitors are preferred over GLP-1 receptor agonists. 2

Combination Therapy Strategies

With Basal Insulin

• When additional glucose lowering is needed despite GLP-1 receptor agonist therapy, adding basal insulin is reasonable. 3
• Consider fixed-ratio combination products (IDegLira or iGlarLixi) for patients on both GLP-1 receptor agonist and basal insulin. 3

Beyond Basal Insulin

• Patients unable to maintain glycemic targets on basal insulin plus oral medications can intensify with GLP-1 receptor agonists, SGLT2 inhibitors, or prandial insulin. 3
• GLP-1 receptor agonists should be considered prior to prandial insulin to minimize hypoglycemia and weight gain risks. 3

Cancer Risk Assessment

• There is no conclusive evidence linking GLP-1 receptor agonists to increased risk of non-medullary thyroid cancer, pancreatic cancer, or breast cancer. 5
• The EXSCEL trial specifically reported no difference in pancreatic cancer incidence between exenatide and placebo. 5
• Major cardiovascular guidelines do not identify breast cancer as a safety concern with GLP-1 receptor agonist therapy. 5