What are the criteria for initiating a Glucagon-like peptide-1 (GLP-1) receptor agonist in patients with type 2 diabetes?

Criteria for Initiating GLP-1 Receptor Agonist Therapy

GLP-1 receptor agonists should be initiated in patients with type 2 diabetes who have established atherosclerotic cardiovascular disease (ASCVD), regardless of their current HbA1c level or background therapy, to reduce major adverse cardiovascular events and cardiovascular death. 1

Primary Cardiovascular Indications

Patients with type 2 diabetes and established ASCVD represent the strongest indication for GLP-1 receptor agonist therapy. 2, 1 This includes patients with:

• Prior myocardial infarction 2
• Prior stroke 2
• Coronary, carotid, or lower extremity artery stenosis >50% 1
• History of coronary revascularization 2

Initiate GLP-1 receptor agonists at these specific time points: 2, 1

• At the time of type 2 diabetes diagnosis in a patient with clinical ASCVD 2
• At the time of ASCVD diagnosis in a patient with type 2 diabetes 2
• At hospital discharge after admission for an ASCVD-related or diabetes-related clinical event 2

For high-risk primary prevention patients without established ASCVD, initiate GLP-1 receptor agonists when additional cardiovascular risk factors are present: 1

• Left ventricular hypertrophy 1
• eGFR <60 mL/min/1.73 m² 1
• Albuminuria (UACR ≥30 mg/g) 1
• Retinopathy or other end-organ damage 2

Chronic Kidney Disease Indications

**Initiate GLP-1 receptor agonists in patients with type 2 diabetes and chronic kidney disease, defined as eGFR <60 mL/min/1.73 m² or albuminuria ≥30 mg/g.** 1 This indication is particularly strong when UACR >300 mg/g. 1

In advanced CKD (eGFR <30 mL/min/1.73 m²), GLP-1 receptor agonists are the preferred glucose-lowering agent over SGLT2 inhibitors due to lower hypoglycemia risk and cardiovascular event reduction. 2 GLP-1 receptor agonists can be used safely down to eGFR as low as 2 mL/min/1.73 m² with no dosage adjustments required. 1

Glycemic Control Indications

Add a GLP-1 receptor agonist when metformin monotherapy fails to achieve individualized glycemic targets. 2 This represents the traditional indication for GLP-1 receptor agonist therapy. 2

When additional glucose-lowering is needed beyond oral agents, GLP-1 receptor agonists are preferred over insulin to avoid hypoglycemia and weight gain. 2, 1 The 2024 American Diabetes Association guidelines explicitly state that GLP-1 receptor agonists, including dual GIP/GLP-1 receptor agonists, are preferred to insulin. 2

Weight Management Indications

GLP-1 receptor agonists are particularly indicated in patients with type 2 diabetes and obesity due to their weight reduction effects. 2 The glucose-lowering treatment plan should consider approaches that support weight management goals. 2

When to Prioritize GLP-1 Receptor Agonists Over SGLT2 Inhibitors

Choose GLP-1 receptor agonists first when: 1

• The primary goal is reducing major adverse cardiovascular events and cardiovascular death (stronger evidence than SGLT2 inhibitors for MACE reduction) 1
• Substantial weight loss is a priority 1
• Patient prefers once-weekly subcutaneous dosing 1
• eGFR is consistently <45 mL/min/1.73 m² (glycemic benefits of SGLT2 inhibitors are reduced at this level) 2, 1

Choose SGLT2 inhibitors first when: 2

• Heart failure (with reduced or preserved ejection fraction) is present 2
• Prevention of heart failure hospitalizations is the primary goal 2

Absolute Contraindications

Do not initiate GLP-1 receptor agonists in patients with: 2, 3

• Personal or family history of medullary thyroid carcinoma 2, 3
• Multiple Endocrine Neoplasia syndrome type 2 (MEN2) 2, 3
• Known hypersensitivity to the specific GLP-1 receptor agonist 2, 3

Relative Contraindications and Cautions

Exercise caution in patients with: 2

• History of pancreatitis (consider alternative therapy; GLP-1 receptor agonists have not been studied in this population) 3
• Severe gastrointestinal disease or clinically meaningful gastroparesis 2
• History of diabetic retinopathy (monitor closely, particularly with semaglutide) 2, 3
• Prior gastric surgery, including bariatric surgery 2

For specific agents with renal considerations: 2

• Exenatide and lixisenatide are contraindicated in severe renal impairment or end-stage renal disease 2
• Liraglutide and semaglutide should be used with caution in severe renal impairment or end-stage renal disease 2

Practical Implementation

When initiating GLP-1 receptor agonist therapy, reduce doses of concomitant glucose-lowering agents with hypoglycemia risk: 1

• Decrease sulfonylurea dose by 50% 1
• Reduce basal insulin dose by 20% 1

Start at the lowest dose and up-titrate slowly to mitigate gastrointestinal side effects, particularly nausea. 2, 1 For semaglutide, start at 0.25 mg once weekly for 4 weeks, then increase to 0.5 mg once weekly, with optional escalation to 1 mg once weekly after at least 4 additional weeks if needed for glycemic control. 3

Continue metformin and other glucose-lowering agents (except those with high hypoglycemia risk) upon initiation of GLP-1 receptor agonist therapy for ongoing glycemic and metabolic benefits. 2