What is the appropriate approach for initiating GLP-1 (Glucagon-like peptide-1) therapy for a patient?

Initiating GLP-1 Receptor Agonist Therapy

For patients with type 2 diabetes, GLP-1 receptor agonists should be initiated as second-line therapy after metformin, or as first-line injectable therapy in patients with established cardiovascular disease, heart failure, or chronic kidney disease—independent of A1C level. 1

Patient Selection for GLP-1 RA Therapy

Primary Indications (Highest Priority)

• Patients with established atherosclerotic cardiovascular disease (ASCVD) should receive a GLP-1 RA with proven cardiovascular benefit (liraglutide, semaglutide, or dulaglutide) regardless of current A1C or other glucose-lowering medications. 1
• Patients with chronic kidney disease (eGFR >20 mL/min/1.73 m²) should receive semaglutide as first-line therapy, as it demonstrates beneficial effects on cardiovascular, mortality, and kidney outcomes. 1
• Patients with indicators of high ASCVD risk should receive GLP-1 RA therapy independent of A1C and with or without metformin use. 1

Secondary Indications

• Patients requiring A1C reduction of 1-2% who are already on metformin should add a GLP-1 RA, considering individual preference, weight-lowering goals, and injection frequency tolerance. 1
• Patients with A1C >10% or blood glucose ≥300 mg/dL should receive insulin as first injectable therapy; however, if not already on GLP-1 RA, this should be started concurrently as combination therapy provides superior efficacy with lower hypoglycemia risk and favorable weight profile. 1, 2

Absolute Contraindications

• History of medullary thyroid cancer or multiple endocrine neoplasia type 2 (MEN2) 1, 3
• Previous hypersensitivity reaction to the specific GLP-1 RA 3
• Pregnancy or breastfeeding 1, 3

Relative Contraindications and Cautions

• History of pancreatitis requires consideration of alternative therapy 1, 3
• Active gallbladder disease warrants caution 1
• History of gastroparesis may limit tolerability 1
• Proliferative diabetic retinopathy requires monitoring when using semaglutide or dulaglutide, as rapid glucose improvement may temporarily worsen retinopathy 1, 3

Specific Agent Selection

When Cardiovascular Disease is Present

Choose semaglutide (Ozempic 0.5-1 mg weekly), liraglutide (Victoza 1.2-1.8 mg daily), or dulaglutide (Trulicity 0.75-1.5 mg weekly) as these have demonstrated cardiovascular benefit in outcome trials. 1, 4

When Chronic Kidney Disease is Present

Semaglutide is the preferred agent based on dedicated kidney outcomes data showing benefits on cardiovascular, mortality, and kidney outcomes. 1

When Maximum Weight Loss is Desired

Semaglutide provides the greatest weight reduction among GLP-1 RAs, with A1C lowering of 1-2% when added to metformin. 1

When Oral Administration is Preferred

Oral semaglutide (Rybelsus) is appropriate and provides similar efficacy to injectable formulations. 1, 3

Initiation Protocol

Pre-Initiation Steps

• If patient is on sulfonylurea with well-controlled A1C or history of hypoglycemia, wean or discontinue the sulfonylurea before starting GLP-1 RA. 1
• If patient is on insulin, consider reducing total daily insulin dose by approximately 20% when initiating GLP-1 RA. 1
• Verify adequate renal function, though GLP-1 RAs are effective regardless of kidney function down to eGFR >20 mL/min/1.73 m². 1

Starting Doses and Titration

• Semaglutide (Ozempic): Start 0.25 mg subcutaneously weekly for 4 weeks, then increase to 0.5 mg weekly; may increase to 1 mg weekly after at least 4 weeks if additional glycemic control needed. 3
• Liraglutide (Victoza): Start 0.6 mg subcutaneously daily for 1 week, then increase to 1.2 mg daily; may increase to 1.8 mg daily after at least 1 week if tolerated. 5

Patient Education at Initiation

• Instruct patients to monitor glucose more closely for the first 4 weeks, especially if on insulin, sulfonylurea, or glinides. 1
• Educate regarding gastrointestinal side effects (nausea, vomiting, diarrhea, abdominal pain), which are transient and typically improve over time. 1, 6, 7
• Warn about symptoms of pancreatitis (persistent severe abdominal pain, sometimes radiating to back, with or without vomiting) and instruct to seek immediate care if these occur. 3
• Educate regarding symptoms of dehydration (lightheadedness, orthostasis, weakness) and to hold medication if experiencing severe gastrointestinal losses or low oral intake. 1
• For patients with diabetic retinopathy, emphasize the need for monitoring as rapid glucose improvement may temporarily worsen retinopathy. 3

Monitoring Requirements

Initial Phase (First 3 Months)

• Monitor for gastrointestinal adverse effects, which are most common and typically resolve within weeks. 6, 7
• Monitor renal function when initiating or escalating doses in patients reporting severe gastrointestinal reactions, as acute kidney injury has been reported with severe dehydration. 3
• Check A1C at 3 months to assess treatment effectiveness. 2

Ongoing Monitoring

• Reassess A1C every 3 months until at goal, then every 3-6 months. 2
• Monitor for hypoglycemia if used with insulin or sulfonylureas. 3
• In patients with history of diabetic retinopathy, monitor for progression. 3

Critical Drug Interactions

Medications Requiring Dose Adjustment

• When combining GLP-1 RA with sulfonylureas, reduce sulfonylurea dose to minimize hypoglycemia risk. 3
• When combining GLP-1 RA with insulin, reduce insulin dose by approximately 20% to minimize hypoglycemia risk. 1, 3

Medications to Avoid

• Do not use GLP-1 RAs together with DPP-4 inhibitors as there is no added glucose-lowering benefit beyond the GLP-1 RA alone. 1

Medications Requiring Caution

• GLP-1 RAs delay gastric emptying and may impact absorption of oral medications; monitor clinical response of concomitant oral medications, though clinically significant interactions are rare. 3

Common Pitfalls to Avoid

• Do not delay GLP-1 RA initiation in patients with established cardiovascular disease or chronic kidney disease while trying additional oral agents, as these patients benefit from GLP-1 RA independent of glycemic control. 1
• Do not use sliding scale insulin alone without optimizing basal insulin or adding GLP-1 RA first, as this approach is ineffective. 8
• Do not continue sulfonylureas when advancing to complex insulin regimens beyond basal insulin, as this significantly increases hypoglycemia risk. 8
• Do not share GLP-1 RA pens between patients even if needle is changed, as this poses risk for blood-borne pathogen transmission. 3
• Do not obtain GLP-1 RAs from non-licensed or unregulated sources due to increased risk of serious complications from counterfeit or improperly stored medications. 6

When to Consider Fixed-Ratio Combination Products

For patients requiring both GLP-1 RA and basal insulin, consider fixed-ratio combination products (insulin degludec/liraglutide [IDegLira] or insulin glargine/lixisenatide [iGlarLixi]) to reduce injection burden. 1