What are the recommended injectable Glucagon-like peptide-1 (GLP-1) receptor agonists for the management of Type 2 Diabetes Mellitus (T2DM)?

Injectable GLP-1 Receptor Agonists for Type 2 Diabetes Mellitus

Injectable GLP-1 receptor agonists are recommended as add-on therapy for all patients with type 2 diabetes who have established atherosclerotic cardiovascular disease (ASCVD), regardless of HbA1c level or metformin use, with the strongest evidence supporting liraglutide, semaglutide, and dulaglutide for reducing major adverse cardiovascular events and mortality. 1, 2

FDA-Approved Injectable GLP-1 Receptor Agonists

The currently available injectable GLP-1 receptor agonists include:

Once-weekly agents:

• Dulaglutide (Trulicity) - indicated as adjunct to diet and exercise for glycemic control and to reduce major adverse cardiovascular events in adults with T2DM and established CVD or multiple CV risk factors 3
• Semaglutide (Ozempic) - indicated for glycemic control and to reduce major adverse cardiovascular events in adults with T2DM and established CVD 4
• Exenatide extended-release - once-weekly formulation 5

Daily agents:

• Liraglutide (Victoza) - indicated for glycemic control in adults and pediatric patients ≥10 years, and to reduce major adverse cardiovascular events in adults with T2DM and established CVD 6
• Lixisenatide - once-daily administration 5

Twice-daily agent:

• Exenatide (immediate-release) - requires twice-daily dosing 5

Clinical Indications and Patient Selection Algorithm

Step 1: Identify patients with established ASCVD

• Prior myocardial infarction, ischemic stroke, unstable angina with ECG changes, myocardial ischemia on imaging, or revascularization of coronary, carotid, or peripheral arteries 1, 2
• These patients should receive GLP-1 receptor agonists independent of HbA1c level or whether on metformin 1, 2

Step 2: Identify high-risk patients without established ASCVD

• Age ≥55 years with coronary, carotid, or lower extremity artery stenosis >50% 1, 2
• Left ventricular hypertrophy 1, 2
• eGFR <60 mL/min/1.73 m² 1, 2
• Albuminuria (UACR ≥30 mg/g, particularly >300 mg/g) 1, 2
• GLP-1 receptor agonists can be considered in these patients to reduce MACE risk 1, 2

Step 3: Determine when to prioritize GLP-1 RAs over SGLT2 inhibitors

• Choose GLP-1 RAs first when: 1, 2

  • Primary goal is reducing MACE and cardiovascular death (strongest evidence for ASCVD patients)
  • Substantial weight loss is a priority
  • Patient is overweight or obese
  • eGFR is consistently <45 mL/min/1.73 m²
  • Patient prefers once-weekly subcutaneous dosing

• Choose SGLT2 inhibitors first when: 1

  • Heart failure (particularly HFrEF) predominates
  • Chronic kidney disease predominates
  • Primary goal is reducing heart failure hospitalization

Cardiovascular Outcomes Evidence

The strongest cardiovascular benefit evidence comes from: 1

• Liraglutide (LEADER trial): HR 0.87 (95% CI 0.78-0.97, p=0.01) for 3-point MACE; HR 0.78 (95% CI 0.66-0.93, p=0.007) for stroke 1
• Semaglutide (SUSTAIN-6): HR 0.74 (95% CI 0.58-0.95, p=0.02) for 3-point MACE 1
• Dulaglutide (REWIND): HR 0.88 (95% CI 0.79-0.99, p=0.026) for 3-point MACE 1

Important caveat: GLP-1 receptor agonists have no effect on reducing heart failure hospitalization risk, making them safe but not beneficial for preventing heart failure 1. They should be used with caution in acute decompensation 1.

Timing of Initiation

Initiate GLP-1 receptor agonists: 2

• At the time of T2DM diagnosis in a patient with clinical ASCVD
• At the time of ASCVD diagnosis in a patient with T2DM
• At hospital discharge after admission for an ASCVD- or diabetes-related clinical event

Absolute Contraindications

Do not prescribe GLP-1 receptor agonists in patients with: 2, 7, 3, 4

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

Note: Hashimoto's thyroiditis is NOT a contraindication 7

Relative Contraindications and Cautions

Exercise caution in patients with: 2, 3, 4

• History of pancreatitis (consider other antidiabetic therapies; GLP-1 RAs have not been studied in these patients)
• Severe gastrointestinal disease, including severe gastroparesis
• History of diabetic retinopathy

Practical Implementation

Initiation protocol: 2

1. Start at the lowest dose and up-titrate slowly to mitigate gastrointestinal side effects (particularly nausea)
2. Reduce doses of insulin secretagogues or insulin:
   • Decrease sulfonylurea dose by 50%
   • Reduce basal insulin dose by 20%

Common adverse effects to counsel patients about: 2, 7

• Nausea (up to 44%) - typically transient, resolves within 4-8 weeks
• Diarrhea (13-18%)
• Constipation (10-30%)
• Injection site reactions (more common with long-acting agents)

Choosing Between Agents

Once-weekly agents (dulaglutide, semaglutide, exenatide ER): 5, 8

• More profound effects on overnight and fasting plasma glucose
• Greater HbA1c reduction
• Lower rates of nausea
• Increased incidence of injection site reactions
• Better adherence due to convenient dosing

Daily agents (liraglutide, lixisenatide): 5, 8

• Liraglutide has demonstrated superior glycemic control compared to other GLP-1 treatment options
• Short-acting agents maintain effect on gastric emptying during long-term treatment

Twice-daily exenatide: 5

• Reduced effectiveness on overnight and fasting plasma glucose
• Less convenient dosing

Semaglutide demonstrates the greatest efficacy for both HbA1c reduction and weight loss among available GLP-1 receptor agonists 5, 9

Additional Benefits Beyond Glycemic Control

All GLP-1 receptor agonists provide: 5, 10, 11, 8

• Weight reduction (mechanism: reduced appetite via CNS effects, delayed gastric emptying)
• Low intrinsic risk of hypoglycemia (glucose-dependent insulin secretion and glucagon suppression)
• Potential improvements in blood pressure, lipid parameters, and inflammatory markers

Renal benefits: 1, 9

• 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
• May prevent new-onset macroalbuminuria, though no effect on hard renal endpoints has been demonstrated 9

Position in Treatment Algorithm

GLP-1 receptor agonists are recommended as: 5, 10

• Preferred first injectable glucose-lowering therapy for type 2 diabetes, even before insulin treatment
• Second-line therapy in combination with metformin, sulfonylureas, thiazolidinediones, or basal insulin
• A means of enhancing glucose control while offsetting weight gain associated with insulin and some oral agents