What are the alternatives to Trulicity (dulaglutide) for diabetes treatment?

Alternatives to Trulicity (Dulaglutide)

For patients requiring an alternative to Trulicity, other GLP-1 receptor agonists with proven cardiovascular benefit—specifically semaglutide or liraglutide—are the preferred first-line alternatives, followed by SGLT2 inhibitors (empagliflozin, canagliflozin, or dapagliflozin) if cardiovascular disease, heart failure, or chronic kidney disease are present. 1

GLP-1 Receptor Agonist Alternatives (Same Drug Class)

Within the GLP-1 RA class, the strongest alternatives are:

• Semaglutide (weekly subcutaneous or daily oral): Provides very high glucose-lowering efficacy, superior weight loss compared to dulaglutide, and proven MACE reduction in patients with type 2 diabetes and cardiovascular disease 1

  • No dose adjustment required for renal impairment 1
  • Half-life of 7 days with weekly dosing 1

• Liraglutide (daily subcutaneous): Offers high glucose-lowering efficacy, proven reduction in MACE and cardiovascular death, and particularly strong benefits in patients with eGFR <60 mL/min/1.73 m² 1, 2

  • No dose adjustment required for renal impairment 1, 2
  • Half-life of 13 hours requiring daily administration 1

• Exenatide (weekly or twice daily): Provides intermediate glucose-lowering efficacy with favorable CKD outcomes, though not recommended with moderate renal impairment for the twice-daily formulation 1

All GLP-1 RAs share similar adverse effect profiles: gastrointestinal symptoms (nausea, vomiting, diarrhea) in 15-20% of patients, which typically resolve with dose titration over several weeks 1, 2. They carry theoretical risks of thyroid C-cell tumors (based on rodent data), pancreatitis, and biliary disease 1, 2.

SGLT2 Inhibitors (Different Drug Class)

When GLP-1 RAs are contraindicated or not tolerated, SGLT2 inhibitors are the preferred alternative:

• Empagliflozin, canagliflozin, or dapagliflozin are recommended for patients with type 2 diabetes and established cardiovascular disease, heart failure (particularly HFrEF), or CKD (eGFR 30-60 mL/min/1.73 m² or albuminuria) 1
  • These agents reduce MACE, heart failure hospitalization, cardiovascular death, and CKD progression 1
  • Glucose-lowering efficacy diminishes below eGFR 45 mL/min/1.73 m², but cardiovascular and kidney benefits persist until dialysis 1
  • Key adverse effects: DKA risk (rare in T2D), genital mycotic infections, volume depletion, and Fournier gangrene (very rare) 1
  • Discontinue 3-4 days before scheduled surgery to mitigate DKA risk 1

Dual GIP/GLP-1 Receptor Agonist

• Tirzepatide: Provides very high glucose-lowering efficacy and very high weight loss, superior to dulaglutide in head-to-head comparisons 1, 3
  • Cardiovascular and heart failure outcomes are under investigation 1
  • Half-life of 5 days with weekly dosing 1
  • May impair oral drug absorption during dose titration; not recommended for gastroparesis 1

Other Alternatives (Lower Priority)

DPP-4 inhibitors (sitagliptin, linagliptin) offer neutral cardiovascular effects and may be considered when GLP-1 RAs and SGLT2 inhibitors are not suitable, though they provide inferior glucose-lowering efficacy and no weight loss 1

• Saxagliptin is contraindicated in heart failure due to increased hospitalization risk 1

Metformin should be considered as add-on therapy if eGFR >30 mL/min/1.73 m² and may provide cardiovascular benefits 1

Clinical Decision Algorithm

1. If cardiovascular disease or high cardiovascular risk is present: Prioritize semaglutide or liraglutide for MACE reduction 1

2. If heart failure (especially HFrEF) or CKD is present: Prioritize SGLT2 inhibitors (empagliflozin, canagliflozin, dapagliflozin) 1

3. If maximum weight loss is the priority: Consider tirzepatide or semaglutide 1, 3

4. If renal impairment (eGFR 30-60): Semaglutide, liraglutide, or dulaglutide require no dose adjustment; SGLT2 inhibitors maintain cardiovascular/kidney benefits 1

5. If GI intolerance is a concern: Consider slower dose titration, dietary modifications (smaller meals, avoiding high-fat foods), or switching to DPP-4 inhibitors 1

Critical Perioperative Consideration

All GLP-1 RAs, including dulaglutide alternatives, delay gastric emptying and increase aspiration risk. Stop weekly GLP-1 RAs (semaglutide, dulaglutide) one week before elective surgery and daily agents (liraglutide) the day before to minimize pulmonary aspiration risk, though this recommendation must be balanced against glycemic control deterioration 1.