What are the recommended GLP-1 (Glucagon-like peptide-1) medications for the treatment of type 2 diabetes?

GLP-1 Receptor Agonists for Type 2 Diabetes

GLP-1 receptor agonists should be added to metformin and lifestyle modifications in adults with type 2 diabetes and inadequate glycemic control, with priority given to patients with established atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD), or those requiring weight loss, as these agents reduce all-cause mortality, major adverse cardiovascular events (MACE), and stroke. 1, 2

When to Initiate GLP-1 Receptor Agonists

First-Line Indications (Independent of HbA1c)

Patients with established ASCVD or high cardiovascular risk should receive GLP-1 receptor agonists as part of initial treatment, regardless of baseline HbA1c levels. 2

• Start GLP-1 receptor agonists in patients with documented ASCVD (prior myocardial infarction, stroke, or peripheral artery disease) 2
• Initiate in high-risk patients defined as: age ≥55 years with coronary, carotid, or lower extremity artery stenosis >50%, left ventricular hypertrophy, eGFR <60 mL/min/1.73m², or albuminuria 2
• The decision to treat with GLP-1 receptor agonists to reduce MACE, heart failure hospitalization, cardiovascular death, or CKD progression should be made independently of glycemic control 2

Diabetic Kidney Disease

For patients with eGFR <60 mL/min/1.73m² or albuminuria ≥30 mg/g, add GLP-1 receptor agonists, particularly if SGLT-2 inhibitors are not tolerated. 2

• GLP-1 receptor agonists can be used safely in patients with eGFR as low as 2 mL/min/1.73m² without dosage adjustments 2
• No dose modification required for any degree of renal impairment 2

Inadequate Glycemic Control on Metformin

When metformin alone fails to achieve HbA1c targets after approximately 3 months, add a GLP-1 receptor agonist rather than a DPP-4 inhibitor. 1

• GLP-1 receptor agonists are preferred over insulin when additional glucose-lowering is needed beyond oral agents 2
• Reassess HbA1c within 3 months of adding GLP-1 therapy 1
• Target HbA1c between 7-8% in most adults; deintensify if HbA1c falls below 6.5% 1

Weight Management Priority

Prioritize GLP-1 receptor agonists in patients with type 2 diabetes and obesity where weight reduction is an important treatment goal. 1, 2

• GLP-1 receptor agonists cause dose-dependent weight loss (1.0-2.0 kg with liraglutide 1.2-1.8 mg) 3
• Weight loss effects are more pronounced with newer agents like semaglutide 4

Specific GLP-1 Receptor Agonist Options

FDA-Approved Agents

Semaglutide (Ozempic):

• Start at 0.25 mg once weekly for 4 weeks, then increase to 0.5 mg once weekly 5
• If additional glycemic control needed after at least 4 weeks, increase to 1 mg once weekly 5
• Administer subcutaneously in abdomen, thigh, or upper arm at any time of day, with or without meals 5
• Indicated to improve glycemic control and reduce risk of major adverse cardiovascular events in adults with type 2 diabetes and established cardiovascular disease 5

Liraglutide (Victoza):

• Approved for adults and pediatric patients aged 10 years and older with type 2 diabetes 6
• Reduces risk of major adverse cardiovascular events in adults with type 2 diabetes and established cardiovascular disease 6
• Demonstrated cardiovascular benefits in the LEADER trial, reducing composite outcomes for myocardial infarction, stroke, and cardiovascular death 1

Dosing Frequency Options

Once-weekly agents: Exenatide once weekly, dulaglutide, albiglutide, and semaglutide provide more convenient dosing with profound effects on overnight and fasting plasma glucose 4, 7

Once-daily agents: Lixisenatide and liraglutide 4, 7

Twice-daily agents: Exenatide b.i.d. (less commonly used due to inconvenient dosing) 4

Oral preparation: Oral semaglutide demonstrates clinical effectiveness close to once-weekly subcutaneous preparation 4

Cardiovascular Outcomes Evidence

Liraglutide and empagliflozin (SGLT-2 inhibitor) have demonstrated cardiovascular mortality reduction in patients with established ASCVD. 1

• The LEADER trial showed liraglutide reduced composite outcomes for myocardial infarction, stroke, and cardiovascular death 1
• Dulaglutide showed cardiovascular benefits in the REWIND trial, including in patients without established cardiovascular disease 2
• Whether other agents in the same class have similar benefits and whether treatments benefit lower-risk patients remains unknown 1

Mechanism and Clinical Effects

GLP-1 receptor agonists work through multiple mechanisms:

• Augment hyperglycemia-induced insulin secretion 4
• Suppress glucagon secretion at hyper- or euglycemia 4
• Decelerate gastric emptying, preventing large post-meal glycemic increments 4
• Reduce calorie intake and body weight 4

Long-acting GLP-1 receptor agonists have more profound effects on overnight and fasting plasma glucose and HbA1c compared to short-acting agents. 4

Combination Therapy Considerations

When combining with insulin secretagogues or insulin, reduce the dose of the secretagogue or insulin to minimize hypoglycemia risk. 5

• GLP-1 receptor agonists can be combined with basal insulin in either free- or fixed-dose preparations 4
• Self-monitoring of blood glucose may be unnecessary in patients receiving metformin combined with a GLP-1 receptor agonist 1

Contraindications and Warnings

Absolute contraindications:

• Personal or family history of medullary thyroid carcinoma 5
• Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) 5
• Known hypersensitivity to the specific GLP-1 receptor agonist or product components 5

Important warnings:

• Pancreatitis has been reported; discontinue promptly if suspected and do not restart if confirmed 5
• Monitor patients with history of diabetic retinopathy, as complications have been reported 5
• Never share pens between patients, even if needle is changed 5
• Monitor renal function in patients with renal impairment reporting severe gastrointestinal reactions 5
• Discontinue in women at least 2 months before planned pregnancy due to long washout period 5

Adverse Effects

The most common adverse reactions are gastrointestinal and occur in ≥5% of patients: nausea, vomiting, diarrhea, abdominal pain, and constipation 5, 4, 7

• Gastrointestinal side effects are typically transient, occurring early in treatment 8, 3
• Nausea led to withdrawal in only 4% of subjects in clinical trials 8
• Minor hypoglycemia occurs more frequently with GLP-1 receptor agonists when combined with insulin secretagogues, but major hypoglycemia is rare 3
• No intrinsic risk of hypoglycemic episodes when used as monotherapy or with metformin 4

Why NOT DPP-4 Inhibitors

Do not add DPP-4 inhibitors to metformin and lifestyle modifications to reduce morbidity and all-cause mortality, as they show no cardiovascular benefit. 1

• Cardiovascular outcomes trials for DPP-4 inhibitors (sitagliptin, saxagliptin, alogliptin) showed no statistically significant differences in rates of major cardiovascular events compared to placebo 1
• GLP-1 receptor agonists provide superior cardiovascular and mortality benefits 1

Special Populations

Youth with type 2 diabetes and obesity: GLP-1 receptor agonists have shown safety and efficacy for decreasing HbA1c and promoting weight loss 2

Patients with CKD and eGFR ≥30 mL/min/1.73 m²: Treatment should include metformin and an SGLT-2 inhibitor, with GLP-1 receptor agonists recommended if glycemic targets are not achieved 2