Semaglutide in Heart Failure with Reduced Ejection Fraction (HFrEF)
Semaglutide is safe and appropriate for patients with stable HFrEF and type 2 diabetes, offering significant cardiovascular benefit without increasing heart failure hospitalization risk, but should be avoided in those with recent decompensation.
Safety Profile in Stable HFrEF
Semaglutide does not increase heart failure hospitalization risk in patients with stable chronic heart failure, as demonstrated across multiple cardiovascular outcome trials where 14–23.6% of participants had baseline heart failure with no safety signals identified. 1
In the SUSTAIN-6 trial, semaglutide showed a neutral effect on heart failure hospitalization (HR 1.11,95% CI 0.77–1.61), meaning it neither increased nor decreased HF events, which is reassuring for safety. 2
The 2019 AHA/HFSA scientific statement confirms GLP-1 receptor agonists, including semaglutide, are safe in stable chronic HF and should only be avoided in patients with recent heart failure decompensation (within 2–4 weeks). 1
For patients with stable HFrEF, clinicians may initiate or continue semaglutide without interrupting guideline-directed heart failure therapy (ACE inhibitors/ARBs, beta-blockers, SGLT2 inhibitors, mineralocorticoid receptor antagonists). 1
Cardiovascular Efficacy in HFrEF Patients
Semaglutide reduces major adverse cardiovascular events (MACE) by 26% (HR 0.74,95% CI 0.58–0.95) in patients with type 2 diabetes and established cardiovascular disease, a benefit that extends to those with co-existing heart failure. 1
The 2021 ADA Standards of Care assign a Class A recommendation to semaglutide for reducing MACE in adults with type 2 diabetes and established cardiovascular disease, including those with heart failure. 1
Semaglutide lowered cardiovascular mortality by 22% in the SUSTAIN-6 trial and did not increase the risk of heart failure hospitalization in large randomized trials. 1
In the pooled analysis of SELECT, FLOW, and STEP-HFpEF trials, semaglutide reduced the composite of cardiovascular death or worsening heart failure events by 31% (HR 0.69,95% CI 0.53–0.89) in patients with heart failure, including those with HFrEF. 3
Semaglutide reduced worsening heart failure events alone by 41% (HR 0.59,95% CI 0.41–0.82) across heart failure subtypes, though the effect on cardiovascular death alone was not significant (HR 0.82,95% CI 0.57–1.16). 3
Evidence from HFrEF-Specific Populations
In the SELECT trial subanalysis, patients with heart failure with reduced ejection fraction (HFrEF) experienced a 35% reduction in MACE (HR 0.65,95% CI 0.49–0.87) with semaglutide 2.4 mg weekly compared to placebo. 4
The composite heart failure endpoint (cardiovascular death or heart failure hospitalization) showed a trend toward benefit in HFrEF patients (HR 0.79,95% CI 0.58–1.08), though this did not reach statistical significance, likely due to smaller sample size. 4
Patients with HFrEF had higher absolute event rates than those with HFpEF, but semaglutide's relative risk reduction was consistent across both subtypes, with no significant interaction by heart failure type. 4
Serious adverse events were less frequent with semaglutide versus placebo in patients with heart failure, regardless of ejection fraction subtype. 4
Practical Implementation in HFrEF
When to Initiate Semaglutide
Initiate semaglutide in stable HFrEF patients with type 2 diabetes who have been euvolemic on guideline-directed medical therapy for at least 2–4 weeks after any decompensation episode. 1
If a patient has had recent heart failure decompensation, defer semaglutide initiation until euvolemia and stability on guideline-directed therapy are achieved. 1
Do not delay initiation in eligible patients with stable HFrEF and established cardiovascular disease, as early treatment improves cardiovascular outcomes. 1
Dosing and Titration
Start semaglutide at 0.25 mg subcutaneously weekly, increase to 0.5 mg after 4 weeks, then to 1.0 mg (or 2.0 mg if needed) after another 4 weeks, following the ADA-endorsed titration schedule. 1
Existing heart failure medications (ACE inhibitors/ARBs, beta-blockers, SGLT2 inhibitors, mineralocorticoid receptor antagonists) should be continued unchanged when semaglutide is added. 1
Medication Interactions and Adjustments
Combination of semaglutide with SGLT2 inhibitors is recommended for patients with HFrEF, as SGLT2 inhibitors receive a Class I, Level A recommendation for reducing heart failure hospitalizations and cardiovascular death. 1
Saxagliptin should be avoided in heart failure patients because it increases the risk of heart failure hospitalization. 1
Sitagliptin does not raise heart failure risk but also does not provide the cardiovascular mortality benefit demonstrated with semaglutide. 1
Combination of semaglutide with DPP-4 inhibitors is not recommended because no additional glycemic benefit is observed. 1
Renal Considerations in HFrEF
Semaglutide requires no renal dose adjustment and is safe down to eGFR > 15 mL/min/1.73 m², whereas metformin co-prescription requires an eGFR of ≥ 30 mL/min/1.73 m². 1
No dose adjustment is required for semaglutide across all stages of chronic kidney disease, making it a preferred option for HFrEF patients with renal impairment. 1
Contraindications and Cautions
Absolute contraindications include personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2 (MEN 2), based on animal studies showing thyroid C-cell tumor formation. 1
Relative caution is advised for patients with a history of pancreatitis, as semaglutide should be used cautiously, though causality has not been definitively established. 1
Patients with recent heart failure decompensation should avoid GLP-1 receptor agonists until stability is achieved, as recommended by the American Heart Association. 1
Comparative Considerations
SGLT2 inhibitors (e.g., empagliflozin, dapagliflozin) receive a Class I, Level A recommendation for patients with HFrEF to reduce heart failure hospitalizations and cardiovascular death, and should be prioritized as foundational therapy. 1
Thiazolidinediones (e.g., pioglitazone) are contraindicated in heart failure patients due to volume-expansion effects that raise hospitalization risk. 1
Semaglutide provides complementary cardiovascular benefit when added to SGLT2 inhibitors, with no evidence of harm from combination therapy. 1
Key Clinical Pitfalls to Avoid
Do not withhold semaglutide from stable HFrEF patients with type 2 diabetes based solely on their heart failure diagnosis, as the cardiovascular benefit is substantial and the risk of worsening HF is not increased. 1, 3, 4
Do not initiate semaglutide during or immediately after a heart failure decompensation episode; wait until the patient is euvolemic and stable on guideline-directed therapy for at least 2–4 weeks. 1
Do not discontinue guideline-directed heart failure medications (beta-blockers, ACE inhibitors/ARBs, SGLT2 inhibitors, MRAs) when starting semaglutide; these should be continued unchanged. 1
Do not assume semaglutide will reduce heart failure hospitalizations; its primary benefit is MACE reduction and cardiovascular mortality, not HF event reduction. 2, 3