Do patients on Glucagon-like peptide-1 (GLP-1) receptor agonists stay on them long-term?

Duration of GLP-1 Receptor Agonist Therapy

Most patients do not stay on GLP-1 receptor agonists indefinitely—real-world evidence shows 20-50% discontinue within the first year, and approximately half experience treatment failure requiring medication changes within 3.5-4 years. 1, 2

Real-World Discontinuation Patterns

The reality of GLP-1 therapy differs substantially from the idealized long-term use suggested by clinical trials:

• High early discontinuation rates occur in 20-50% of patients within the first 12 months of starting therapy, driven primarily by gastrointestinal side effects (nausea, vomiting), high medication costs, and insurance coverage issues 1

• Treatment failure occurs in approximately 51% of patients after a mean duration of 50 months, with half of all patients failing by 42 months (3.5 years) 2

• Predictive factors for earlier treatment failure include baseline HbA1c >9.0% and male gender, suggesting certain populations require earlier treatment intensification 2

Glycemic Efficacy Over Time

The glucose-lowering benefits of GLP-1 receptor agonists follow a predictable trajectory:

• Maximum HbA1c reduction occurs within the first year (approximately -1.2%), with this effect plateauing thereafter 2

• After 4 years, only one-third of patients maintain adequate glycemic control on GLP-1 monotherapy, with the remaining two-thirds requiring treatment intensification 2

• At 1 year, only 26% of patients achieve HbA1c <7.0% and 47% achieve HbA1c <7.5%, indicating many require additional agents from the outset 2

Guideline-Directed Treatment Evolution

Current diabetes management guidelines explicitly acknowledge that GLP-1 therapy is not indefinite for most patients:

• No single medication or combination has demonstrated durable effects, and for many patients, injectable medications become necessary within 5-10 years of diabetes diagnosis, often requiring progression beyond GLP-1 monotherapy 3

• When patients fail to maintain glycemic targets on GLP-1 therapy, treatment intensification with SGLT2 inhibitors, basal insulin, or prandial insulin is recommended 3

• Regular review of therapy response is mandated, with consideration to stop or reduce doses if minimal benefits exist or harm outweighs benefit 3

Special Populations and Long-Term Use

Patients with Type 2 Diabetes and CKD

• GLP-1 receptor agonists are recommended as preferred add-on therapy in patients with CKD who are not achieving glycemic targets on metformin and/or SGLT2 inhibitors 3

• These patients may continue therapy longer due to cardiovascular and kidney protective benefits beyond glucose lowering, with evidence showing reduced all-cause mortality (RR 0.85) and 3-point MACE (RR 0.84) 4

• No dose adjustment is required for most GLP-1 agents (dulaglutide, liraglutide, semaglutide) across CKD stages, facilitating continued use 3

Patients Using GLP-1 for Weight Loss (Without Diabetes)

• These patients face even higher discontinuation rates due to lack of the glycemic imperative that drives continued use in diabetes 1

• Cost becomes a more significant barrier when insurance coverage is limited for obesity indications versus diabetes 1

Practical Dosing Realities

Real-world practice reveals significant deviations from trial protocols:

• Patients frequently use much lower doses than those evaluated in clinical trials, contributing to suboptimal efficacy and earlier treatment failure 1

• Dose escalation is often limited by gastrointestinal side effects, preventing patients from reaching target therapeutic doses 1

Clinical Decision Points for Continuation vs. Discontinuation

Continue GLP-1 therapy when:

• HbA1c remains above individualized target and patient tolerates medication 3
• Cardiovascular or kidney disease is present (liraglutide, dulaglutide, or injectable semaglutide preferred for CV benefits) 3
• Weight loss benefits are clinically meaningful and sustained 3

Consider discontinuation or dose reduction when:

• HbA1c falls substantially below individualized target (e.g., <6.5% or 48 mmol/mol) 3
• Gastrointestinal side effects persist beyond initial titration period and impair quality of life 1
• Treatment failure occurs (inability to maintain glycemic targets despite adequate dosing) 2
• Cost burden becomes prohibitive and alternative effective therapies exist 3

Intensify or switch therapy when:

• Glycemic targets are not met after 3-6 months of optimal GLP-1 dosing 3
• Treatment failure occurs at 3-4 years (add basal insulin, SGLT2 inhibitor, or switch to combination therapy) 3, 2

Common Pitfalls

• Assuming GLP-1 therapy will be lifelong without planning for eventual treatment intensification in most patients 2
• Failing to titrate to adequate doses due to premature acceptance of gastrointestinal side effects, leading to suboptimal efficacy 1
• Not recognizing that the 4-year mark represents a critical inflection point where two-thirds of patients will require treatment modification 2
• Overlooking cost as a primary driver of discontinuation, particularly in patients without robust insurance coverage 1