What is the approach to GLP-1 receptor agonist therapy?

GLP-1 Receptor Agonist Therapy Approach

GLP-1 receptor agonists should be initiated with a low starting dose and titrated upward over several weeks to minimize gastrointestinal side effects, administered as once-daily or once-weekly subcutaneous injections (or oral formulations), with selection based on cardiovascular disease status, A1C reduction needs, weight loss goals, and injection frequency preference. 1

Patient Selection and Indications

Primary Indications

• Adjunct to diet and exercise for glycemic control in adults with type 2 diabetes 2, 3
• Cardiovascular risk reduction in patients with type 2 diabetes and established cardiovascular disease 1, 2, 3
• Weight management in patients with obesity or overweight with weight-related comorbidities 4, 5

When to Prioritize GLP-1 RAs First

• Patients with established atherosclerotic cardiovascular disease (ASCVD) should receive a GLP-1 RA with proven cardiovascular benefit 1
• Consider GLP-1 RAs before insulin in patients not meeting A1C goals on oral agents, as they provide lower hypoglycemia risk and favorable weight profiles 1
• For A1C 1.5-2.0% above goal, GLP-1 RAs typically lower A1C by 1-2% when added to metformin 1

Contraindications

• Personal or family history of medullary thyroid carcinoma (MTC) 2
• Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) 2
• Known hypersensitivity to the specific GLP-1 RA or its components 2
• History of pancreatitis requires careful consideration; the ADA suggests considering alternative therapy 2

Specific Agent Selection

Available Formulations by Frequency

• Once-weekly injections: semaglutide (Ozempic), dulaglutide, exenatide once-weekly 6, 5
• Once-daily injections: liraglutide (Victoza), lixisenatide 3, 6
• Twice-daily injections: exenatide b.i.d. 6
• Oral formulation: semaglutide (Rybelsus) 6, 5

Selection Criteria

• If cardiovascular disease is present, select a GLP-1 RA with proven cardiovascular benefit (semaglutide or liraglutide) 1, 2, 3
• Semaglutide demonstrates greater efficacy for both glucose lowering and weight reduction compared to other GLP-1 RAs 6, 4
• Once-weekly formulations have more profound effects on fasting plasma glucose and A1C compared to short-acting agents 6
• Short-acting agents (exenatide b.i.d., lixisenatide) maintain greater effects on gastric emptying but have reduced effectiveness on overnight and fasting glucose 6

Dosing and Titration Protocols

Liraglutide (Victoza) Dosing

• Start at 0.6 mg subcutaneously once daily to improve gastrointestinal tolerability 7, 8
• After at least 1 week, increase to 1.2 mg once daily 7
• If additional glycemic control is needed, increase to the maximum dose of 1.8 mg once daily 7, 8
• Administer at any time of day, independent of meals 7

Semaglutide (Ozempic) Dosing

• Start at 0.25 mg subcutaneously once weekly for 4 weeks 2
• After 4 weeks, increase to 0.5 mg once weekly 2
• If additional glycemic control is needed after at least 4 weeks at 0.5 mg, increase to 1 mg once weekly 2
• Administer once weekly at any time of day, with or without meals 2
• If a dose is missed, administer within 5 days of the missed dose 2

Injection Technique

• Inject subcutaneously in the abdomen, thigh, or upper arm 2
• Never share pens between patients, even if the needle is changed 2

Combination Therapy Strategies

With Basal Insulin

• For patients on both GLP-1 RA and basal insulin, consider fixed-ratio combination products (IDegLira or iGlarLixi) to reduce injection burden 1
• GLP-1 RA plus insulin combination provides greater efficacy, durability of glycemic effect, and weight/hypoglycemia benefits compared to insulin intensification alone 1, 9
• In severe hyperglycemia (A1C >10% or glucose ≥300 mg/dL), combine basal insulin with GLP-1 RA from the start 9

With Other Glucose-Lowering Agents

• Do NOT combine GLP-1 RAs with DPP-4 inhibitors, as there is no added glucose-lowering benefit beyond the GLP-1 RA alone 1
• Continue metformin if already prescribed and tolerated, as it provides complementary mechanisms 9
• When used with sulfonylureas or insulin, consider lowering the dose of these agents to reduce hypoglycemia risk 2, 7, 5

With SGLT2 Inhibitors

• Add an SGLT2 inhibitor if the patient has cardiovascular disease, heart failure, or chronic kidney disease for additional cardiovascular and renal benefits 9

Monitoring and Follow-Up

Initial Monitoring

• Check A1C every 3 months to assess treatment effectiveness 9
• Monitor for hypoglycemia, especially during the first 1-2 months after initiation, particularly if combined with sulfonylureas or insulin 9, 7
• Daily blood glucose monitoring is not required unless combined with a sulfonylurea 7

Ongoing Assessment

• Reevaluate medication plan and adherence every 3-6 months to avoid therapeutic inertia 1, 9
• Monitor patients with a history of diabetic retinopathy, as GLP-1 RAs have been associated with diabetic retinopathy complications in clinical trials 2
• Monitor renal function in patients with renal impairment who report severe gastrointestinal reactions 2

Adverse Effects and Management

Common Gastrointestinal Effects

• Nausea, vomiting, diarrhea, abdominal pain, and constipation occur in ≥5% of patients 2, 5
• These effects are most common during initiation and titration, and typically diminish over time 10, 7, 4
• The low starting dose and gradual titration strategy specifically addresses gastrointestinal tolerability 7
• Real-world discontinuation rates are 20-50% within the first year, often due to gastrointestinal side effects 4

Serious Adverse Events

• Pancreatitis has been reported; discontinue promptly if suspected and do not restart if confirmed 2, 5
• Acute kidney injury can occur, particularly in the setting of severe gastrointestinal losses causing dehydration 2, 5
• Hypersensitivity reactions including anaphylaxis have been reported; discontinue if suspected and seek medical advice 2, 5
• Real-world studies show no clear increase in risks of severe pancreatitis, pancreatic cancer, or thyroid disorders 4

Hypoglycemia Risk

• GLP-1 RAs increase insulin production in a glucose-dependent manner, so intrinsic hypoglycemia risk is low 7, 8
• Hypoglycemia risk increases when combined with sulfonylureas or insulin; reduce doses of these agents proactively 2, 7, 5
• Prescribe glucagon for emergent hypoglycemia when initiating combination therapy with insulin 9

Pregnancy Considerations

• Discontinue GLP-1 RAs in women at least 2 months before a planned pregnancy due to the long washout period for semaglutide 2

Mechanism of Action

Glucose-Lowering Effects

• Augmentation of hyperglycemia-induced insulin secretion in a glucose-dependent manner 10, 6
• Suppression of glucagon secretion at hyper- or euglycemia 6
• Deceleration of gastric emptying, preventing large postprandial glycemic increments 10, 6

Weight Loss Effects

• Reduction in calorie intake through central appetite suppression 10, 6
• Weight loss of 1.8-3.4 kg observed in clinical trials 8
• Semaglutide demonstrates greater weight reduction efficacy compared to other GLP-1 RAs 6, 4

Critical Pitfalls to Avoid

Therapeutic Inertia

• Do not delay treatment intensification or modification for patients not meeting individualized goals 1
• Do not delay insulin intensification while trying multiple oral agents at A1C >10%, as this prolongs exposure to severe hyperglycemia 9

Drug Interactions

• GLP-1 RAs delay gastric emptying, which may impact absorption of concomitantly administered oral medications 2
• However, no dose adjustments are needed for acetaminophen, oral contraceptives, atorvastatin, griseofulvin, lisinopril, or digoxin 7

Medication Safety

• Patients obtaining GLP-1 RAs from non-licensed and unregulated sources face increased risk of serious complications 5
• Real-world studies show patients often use much lower doses than evaluated in clinical trials, reducing effectiveness 4

Real-World Effectiveness Considerations

Adherence and Outcomes

• Real-world weight reduction tends to be lower than in randomized controlled trials 4
• However, outcomes approach trial results when focusing on highly adherent patients 4
• High discontinuation rates (20-50%) within the first year are common in real-world practice 4

Cost and Access

• High costs and lack of insurance coverage are major drivers of early discontinuation 4
• Consider cost when selecting specific agents, as recommended by the ADA 1