What are the criteria for initiating Glucagon-like peptide-1 (GLP-1) receptor agonist therapy 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 whether they are on metformin. 1, 2

Primary Indications for GLP-1 Receptor Agonists

Established Cardiovascular Disease (Strongest Indication)

• Patients with type 2 diabetes and documented ASCVD should receive a GLP-1 receptor agonist independent of baseline HbA1c or individualized HbA1c target. 1, 2 This includes patients with:

  • Prior myocardial infarction 1
  • Ischemic stroke 1
  • Unstable angina with ECG changes 1
  • Myocardial ischemia on imaging or stress test 1
  • Revascularization of coronary, carotid, or peripheral arteries 1

• The American Diabetes Association, European Society of Cardiology, and American Association of Clinical Endocrinologists all recommend GLP-1 receptor agonists as add-on therapy in this population to reduce major adverse cardiovascular events (MACE). 1

High Cardiovascular Risk Without Established Disease

GLP-1 receptor agonists should be considered in patients aged ≥55 years with any of the following high-risk indicators: 1, 2

• Coronary, carotid, or lower extremity artery stenosis >50% 1
• Left ventricular hypertrophy 1
• eGFR <60 mL/min/1.73 m² 1
• Albuminuria (UACR ≥30 mg/g) 1

The American College of Cardiology and American Heart Association state it is reasonable to initiate GLP-1 receptor agonists in patients with type 2 diabetes who have additional cardiovascular risk factors. 1

Chronic Kidney Disease

Initiate GLP-1 receptor agonists in patients with type 2 diabetes and: 2

• eGFR <60 mL/min/1.73 m² 2
• Albuminuria ≥30 mg/g, particularly UACR >300 mg/g 1
• When SGLT2 inhibitors are not tolerated or contraindicated 1

GLP-1 receptor agonists can be used safely in patients with eGFR as low as 2 mL/min/1.73 m² with no dosage adjustments required. 2

Glycemic Control Indications

Add a GLP-1 receptor agonist when metformin alone fails to achieve glycemic targets. 2 The American Diabetes Association prefers GLP-1 receptor agonists as the next step after metformin monotherapy. 2

Choose GLP-1 receptor agonists over insulin when additional glucose-lowering is needed beyond oral agents. 2 This recommendation prioritizes avoiding hypoglycemia and weight gain associated with insulin therapy. 1

Obesity Management

GLP-1 receptor agonists are particularly indicated in patients with type 2 diabetes and obesity due to their weight reduction effects. 2 This applies to both adults and pediatric patients ≥10 years of age. 3

When to Prioritize GLP-1 Receptor Agonists Over SGLT2 Inhibitors

Use GLP-1 receptor agonists first when the primary goal is reducing MACE and cardiovascular death. 1 The evidence for MACE reduction is strongest with GLP-1 receptor agonists in patients with established ASCVD. 1

Choose GLP-1 receptor agonists when: 1

• Substantial weight loss is a priority 1
• Patient prefers once-weekly subcutaneous dosing 1
• eGFR is consistently <45 mL/min/1.73 m² (SGLT2 inhibitors have reduced glycemic efficacy at this level) 1

In contrast, prefer SGLT2 inhibitors when: 1

• Heart failure with reduced ejection fraction (EF <45%) is present 1
• Reducing heart failure hospitalization is the priority 1

Timing of Initiation

Initiate GLP-1 receptor agonists at these key clinical moments: 1

• At the time of type 2 diabetes diagnosis in a patient with clinical ASCVD 1
• At the time of ASCVD diagnosis in a patient with type 2 diabetes 1
• At hospital discharge after admission for an ASCVD- or diabetes-related clinical event 1
• When switching from dual therapy or multiple glucose-lowering agents that do not include a GLP-1 receptor agonist 1

Contraindications and Cautions

Absolute contraindications: 1, 4

• Personal or family history of medullary thyroid carcinoma 1, 4
• Multiple Endocrine Neoplasia syndrome type 2 (MEN2) 1, 4
• Known hypersensitivity to the specific GLP-1 receptor agonist 4

Relative contraindications and cautions: 1, 4, 3, 4

• History of pancreatitis (consider alternative antidiabetic therapy) 4, 3, 4
• Severe gastrointestinal disease, including severe gastroparesis 3
• History of diabetic retinopathy (monitor closely, particularly with semaglutide) 1, 4

Use with caution in acute decompensated heart failure. 1 While GLP-1 receptor agonists are safe in stable heart failure, they have not shown benefit in preventing heart failure hospitalization. 1

Practical Implementation

When initiating therapy, reduce doses of insulin secretagogues or insulin: 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. 1 For semaglutide, begin at 0.25 mg once weekly for 4 weeks, then increase to 0.5 mg weekly, with optional escalation to 1 mg weekly after at least 4 additional weeks if needed. 4

Discontinue DPP-4 inhibitors before starting a GLP-1 receptor agonist as these mechanisms overlap. 1