GLP-1 Receptor Agonists Are the Next Best Agent for Cardiovascular Protection
If an SGLT2 inhibitor is not tolerated in a patient with type 2 diabetes and established ASCVD, initiate a GLP-1 receptor agonist with proven cardiovascular benefit (liraglutide, semaglutide, or dulaglutide) as the next-line agent for cardiovascular risk reduction. 1
Guideline-Based Recommendation Hierarchy
The 2019 ADA/EASD consensus explicitly states: "If SGLT2i not tolerated or contraindicated, use GLP-1 RA" in patients with established ASCVD 1. This represents the clearest directive from major guidelines when SGLT2 inhibitors cannot be used.
Why GLP-1 Receptor Agonists Are the Alternative
For patients with established atherosclerotic cardiovascular disease, the level of evidence for MACE benefit is greatest for GLP-1 receptor agonists 1. The 2018 ACC Expert Consensus specifically recommends considering GLP-1 RAs first when patient and clinician priorities include:
- Reducing MACE and cardiovascular death 1
- Substantial weight loss 1
- Therapy when eGFR consistently <45 mL/min/1.73 m² (where SGLT2 inhibitor efficacy decreases) 1
Cardiovascular Outcome Evidence
GLP-1 receptor agonists reduce all-cause mortality and major adverse cardiovascular events with high certainty evidence 2. The American Heart Association notes that GLP-1 RAs have the strongest evidence for MACE reduction in patients with prior myocardial infarction, ischemic stroke, or coronary/carotid/peripheral revascularization 2.
GLP-1 receptor agonists are most effective for stroke prevention, reducing non-fatal stroke more than SGLT2 inhibitors 2. This is particularly relevant for patients with established ASCVD where atherosclerotic events are the primary concern.
Specific Agent Selection
Among GLP-1 receptor agonists with proven cardiovascular benefit:
- Semaglutide demonstrated a 26% reduction in MACE (HR 0.74,95% CI 0.58-0.95) in the SUSTAIN-6 trial, including significant reductions in non-fatal stroke (HR 0.61,95% CI 0.38-0.99) 3
- Liraglutide showed cardiovascular benefit in the LEADER trial with a hazard ratio of 0.87 (95% CI 0.78-0.97) for MACE 4
- Dulaglutide is FDA-approved to reduce cardiovascular death, non-fatal MI, or non-fatal stroke in adults with T2D and established CVD 1
Important Clinical Considerations
Contraindications to Avoid
Do not use GLP-1 receptor agonists if the patient has 1:
- Personal or family history of medullary thyroid cancer
- Multiple endocrine neoplasia syndrome type 2 (MEN2)
- History of serious hypersensitivity reaction to the drug
- Severe renal impairment or ESRD (for exenatide and lixisenatide specifically)
Common Tolerability Issues
Consider alternative agents if the patient has 1:
- Persistent nausea, even at low doses
- History of pancreatitis
- History of gastroparesis
- History of proliferative retinopathy (specifically for semaglutide)
Practical Initiation Strategy
When starting a GLP-1 receptor agonist 1:
- If A1C is well-controlled at baseline or there is a history of frequent hypoglycemic events, reduce sulfonylurea dose by 50% or basal insulin dose by 20%
- Educate patients that gastrointestinal side effects (nausea, vomiting) are common initially but typically diminish over time
- Start with lower doses and titrate gradually to improve tolerability
Why Not Other Agents?
The guidelines are explicit that in patients with established ASCVD, the decision to treat with a GLP-1 receptor agonist or SGLT2 inhibitor should be considered independently of baseline HbA1c or individualized HbA1c target 1. This means cardiovascular protection, not glycemic control, is the primary goal.
Other glucose-lowering agents (DPP-4 inhibitors, sulfonylureas, thiazolidinediones) lack the robust cardiovascular outcome trial data demonstrating MACE reduction that GLP-1 receptor agonists possess 5, 6. The American Diabetes Association recommends SGLT2 inhibitors or GLP-1 RAs as add-on therapies specifically for their cardiovascular benefits 1.
Renal Protection Consideration
While SGLT2 inhibitors have superior evidence for preventing CKD progression 1, GLP-1 receptor agonists can be used interchangeably with SGLT2 inhibitors in patients with eGFR below 60 mL/min/1.73 m² or in those with albuminuria who are intolerant of SGLT2 inhibitors 1. GLP-1 RAs show antiproteinuric effects and some renal benefits, though less robust than SGLT2 inhibitors 7.