GLP-1 Agonist Therapy for Type 2 Diabetes
Direct Recommendation
GLP-1 receptor agonists should be initiated in patients with type 2 diabetes who have established atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (eGFR <60 mL/min/1.73m² or albuminuria ≥30 mg/g), or high cardiovascular risk factors—regardless of baseline HbA1c level or current metformin use. 1, 2
Primary Indications: When to Start GLP-1 Agonists
Cardiovascular Disease (Highest Priority)
Initiate immediately in patients with established ASCVD (prior myocardial infarction, stroke, coronary/carotid/peripheral artery disease) independent of glycemic control, as these agents reduce major adverse cardiovascular events (MACE) and cardiovascular death. 1, 2
Start at diabetes diagnosis if ASCVD is present, at ASCVD diagnosis if diabetes exists, or at hospital discharge after an ASCVD-related event. 2
Prefer agents with proven cardiovascular benefit: liraglutide, semaglutide, or dulaglutide. 3
High Cardiovascular Risk (Without Established ASCVD)
- Initiate in patients ≥55 years with coronary, carotid, or lower extremity artery stenosis >50%, left ventricular hypertrophy, eGFR <60 mL/min/1.73m², or albuminuria (UACR ≥30 mg/g). 1, 2
Chronic Kidney Disease
Start GLP-1 agonists in patients with eGFR <60 mL/min/1.73m² or albuminuria ≥30 mg/g, particularly if UACR >300 mg/g. 2
These agents can be used safely down to eGFR 2 mL/min/1.73m² or even in dialysis patients with no dosage adjustments required. 1, 3
Use when SGLT2 inhibitors are not tolerated or when additional glycemic control is needed beyond metformin and SGLT2 inhibitors. 1
Glycemic Control Indications
Add GLP-1 agonists when metformin alone fails to achieve HbA1c targets (preferred over other oral agents). 1, 2
Choose GLP-1 agonists over insulin when additional glucose-lowering is needed beyond oral agents to avoid hypoglycemia and weight gain. 2
These agents reduce HbA1c by 0.8-1.5%. 3
Obesity Management
- GLP-1 agonists are particularly indicated in patients with type 2 diabetes and obesity due to weight reduction effects of 1.5-3.5 kg (or 2-4 kg in some studies). 3, 2
Choosing GLP-1 Agonists Over SGLT2 Inhibitors
Prioritize GLP-1 agonists when the primary goal is reducing MACE and cardiovascular death (stronger evidence for MACE reduction in established ASCVD). 2
Choose GLP-1 agonists when substantial weight loss is a priority, patient prefers once-weekly subcutaneous dosing, or eGFR is consistently <45 mL/min/1.73m². 2
If heart failure with reduced ejection fraction (HFrEF) predominates over atherosclerotic disease, prefer SGLT2 inhibitors over GLP-1 agonists due to small trials showing no benefit and numerically increased risk of death/heart failure hospitalization with liraglutide in recent decompensation. 3
Dosing and Administration
Start semaglutide at 0.25 mg once weekly for 4 weeks, then increase to 0.5 mg once weekly; if additional glycemic control is needed after at least 4 weeks, increase to 1 mg once weekly. 4
Administer once weekly at any time of day, with or without meals. 4
Start at the lowest dose and up-titrate slowly to minimize gastrointestinal side effects (nausea, vomiting, diarrhea). 2
Liraglutide and dulaglutide require similar gradual titration. 3
Managing Concurrent Medications
When initiating GLP-1 agonists with insulin or sulfonylureas, reduce the dose of these agents: decrease sulfonylurea by 50% or reduce basal insulin by 20% to minimize hypoglycemia risk. 3, 2
GLP-1 agonists have low intrinsic hypoglycemia risk due to their glucose-dependent mechanism. 3
Contraindications and Cautions
Absolute Contraindications
Personal or family history of medullary thyroid carcinoma (MTC) or Multiple Endocrine Neoplasia syndrome type 2 (MEN2). 2, 4
Known hypersensitivity to the specific GLP-1 receptor agonist. 2, 4
Relative Contraindications
History of pancreatitis (consider another antidiabetic therapy; discontinue promptly if pancreatitis is suspected). 2, 4
Severe gastrointestinal disease. 2
History of diabetic retinopathy (monitor closely, as complications have been reported). 2, 4
Common Side Effects and Management
Gastrointestinal symptoms (nausea, vomiting, diarrhea) occur in 15-20% of patients but are typically transient and occur mainly during initial treatment. 3
Longer-acting agents (once-weekly formulations) have lower rates of nausea but increased incidence of injection site reactions. 5, 6
Monitor renal function in patients with renal impairment reporting severe gastrointestinal reactions (risk of acute kidney injury). 4
Additional Clinical Benefits
GLP-1 agonists produce favorable changes in lipid profiles: decreased triglycerides and increased HDL cholesterol. 3
Small increases in heart rate are of unknown clinical relevance. 5
Never share a GLP-1 agonist pen between patients, even if the needle is changed. 4