What are the treatment options for patients who are candidates for Glucagon-Like Peptide-1 Receptor Agonist (GLP1 RA) therapy?

Treatment Options for Patients Who Are Candidates for GLP-1 RA Therapy

Long-acting GLP-1 receptor agonists are recommended as the preferred treatment option for patients with type 2 diabetes who have not achieved individualized glycemic targets despite metformin and SGLT2 inhibitor treatment, or who are unable to use those medications. 1

Primary Indications for GLP-1 RA Therapy

• GLP-1 RAs are indicated as second-line therapy after metformin in patients with type 2 diabetes who have not achieved glycemic targets 1
• GLP-1 RAs with proven cardiovascular benefits should be prioritized in patients with established atherosclerotic cardiovascular disease 2
• GLP-1 RAs are particularly beneficial for patients with obesity as they promote intentional weight loss 1
• For patients with chronic kidney disease (CKD), GLP-1 RAs are effective regardless of kidney function and have low risk for hypoglycemia 1

Available GLP-1 RA Options

Long-Acting (Weekly) Options:

• Dulaglutide: No dosage adjustment needed for CKD; can be used with eGFR >15 ml/min per 1.73 m² 1
• Semaglutide (injection): Weekly administration; no dosage adjustment for CKD but limited data for severe CKD 1
• Exenatide extended-release: Use with eGFR >45 ml/min per 1.73 m² 1

Daily Options:

• Liraglutide: Once daily; no dosage adjustment for CKD but limited data for severe CKD 1, 3
• Semaglutide (oral): Daily administration; first oral GLP-1 RA option 1
• Lixisenatide: Once daily; not recommended with eGFR <15 ml/min per 1.73 m² 1
• Exenatide: Twice daily; use with CrCl >30 ml/min 1

Dosing and Administration Guidelines

• Start with a low dose and titrate slowly to minimize gastrointestinal side effects 1
• For liraglutide: Initiate at 0.6 mg subcutaneously once daily for one week, then increase to 1.2 mg daily; if additional glycemic control is required, increase to 1.8 mg daily after one week 3
• Administer subcutaneously in the abdomen, thigh, or upper arm; timing can be independent of meals for most GLP-1 RAs 3
• When using GLP-1 RAs with insulin, administer as separate injections and never mix 3

Special Populations and Considerations

For Patients with Very Low eGFR (<20 ml/min/1.73 m²):

• Weekly dulaglutide, semaglutide, or daily liraglutide are preferred options 1
• If patient is already on canagliflozin or dapagliflozin, continue for kidney and CV benefits 1

For Patients with Obesity (BMI >35 kg/m²):

• GLP-1 RAs should be considered the second-line drug of choice due to their significant weight loss potential 1
• Semaglutide has demonstrated the greatest efficacy for weight reduction 4

For Patients with Established Cardiovascular Disease:

• Prioritize GLP-1 RAs with documented cardiovascular benefits (liraglutide, semaglutide) 2
• The LEADER trial showed liraglutide reduced major adverse cardiovascular events by 13% compared to placebo 2

Combination Therapy Considerations

• GLP-1 RAs should not be used in combination with DPP-4 inhibitors 1
• When combining with sulfonylureas or insulin, the risk of hypoglycemia increases; consider reducing doses of these agents 1
• For patients on GLP-1 RA and basal insulin combination, fixed-ratio combination products (IDegLira or iGlarLixi) may be considered 1
• Before advancing to multiple daily insulin injections, consider adding a GLP-1 RA to basal insulin for better glycemic control 5

Dual GIP/GLP-1 Receptor Agonists

• Dual GIP/GLP-1 RAs produce greater reductions in HbA1c and body weight compared to single GLP-1 RAs 5
• For patients not meeting glycemic targets, a dual GIP/GLP-1 RA should be considered before intensifying to insulin therapy 5
• Tirzepatide is a dual GIP/GLP-1 RA that has shown significant efficacy for glycemic control and weight reduction 5

Common Side Effects and Management

• Gastrointestinal effects (nausea, vomiting, diarrhea) are most common but tend to diminish over time 3, 6
• Starting with a low dose and titrating slowly helps minimize these side effects 1
• Monitor for acute kidney injury, especially in association with nausea, vomiting, diarrhea, or dehydration 3
• Be aware of delayed gastric emptying, which may impact absorption of concomitantly administered oral medications 3

Important Contraindications

• Personal or family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia syndrome type 2 3
• Serious hypersensitivity reaction to the specific GLP-1 RA or any of its excipients 3
• Never share a GLP-1 RA pen between patients, even if the needle is changed 3

Practical Implementation Tips

• For patients undergoing elective surgeries or procedures, inform healthcare providers about GLP-1 RA use due to risk of pulmonary aspiration during general anesthesia 3
• Discontinue GLP-1 RA if pancreatitis is suspected; do not restart if pancreatitis is confirmed 3
• Monitor for vitamin B12 deficiency in patients on long-term metformin therapy (>4 years) when adding GLP-1 RA 1