What are the considerations for using Ozempic (semaglutide) in a patient with type 2 diabetes, kidney disease, and heart failure?

Ozempic (Semaglutide) in Kidney Disease and Heart Failure

Ozempic is strongly recommended for patients with type 2 diabetes who have both kidney disease and heart failure, as it significantly reduces cardiovascular death, heart failure events, and kidney disease progression in this high-risk population. 1, 2, 3

FDA-Approved Indications

Ozempic is FDA-approved to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes and established cardiovascular disease, in addition to improving glycemic control. 1 This approval is based on demonstrated cardiovascular superiority with a 26% reduction in major adverse cardiovascular events (MACE) in the SUSTAIN-6 trial. 4, 5

Benefits in Kidney Disease

For patients with chronic kidney disease, semaglutide provides substantial renal protection:

• Reduces major kidney disease events by 24% (composite of kidney failure, ≥50% eGFR reduction, or cardiovascular/kidney death) in patients with eGFR 25-75 mL/min/1.73 m² and albuminuria. 2

• Slows eGFR decline by 1.16 mL/min/1.73 m² per year compared to placebo, indicating preserved kidney function over time. 2

• Reduces kidney-related adverse events by 20% across multiple trials in patients with type 2 diabetes and CKD. 6

• Reduces all-cause mortality by 20% in patients with type 2 diabetes and chronic kidney disease. 2

The FLOW trial specifically enrolled patients with type 2 diabetes and CKD (eGFR 50-75 with urinary albumin-to-creatinine ratio >300, or eGFR 25-50 with ratio >100), demonstrating consistent benefits across the spectrum of kidney disease severity. 2

Benefits in Heart Failure

For patients with heart failure, semaglutide provides robust protection against heart failure events:

• Reduces the composite of heart failure events or cardiovascular death by 27% (HR 0.73; 95% CI 0.62-0.87) in patients with type 2 diabetes and CKD. 3

• Reduces heart failure hospitalizations or urgent visits by 27% (HR 0.73; 95% CI 0.58-0.92) in this population. 3

• Reduces cardiovascular death by 29% (HR 0.71; 95% CI 0.56-0.89) in patients with type 2 diabetes and CKD. 3

• Benefits are consistent regardless of baseline heart failure status, with similar risk reductions in patients with (HR 0.73) and without (HR 0.72) pre-existing heart failure. 3

• In patients with established HFpEF (heart failure with preserved ejection fraction), semaglutide reduces the combined endpoint of cardiovascular death or worsening heart failure events by 31% (HR 0.69; 95% CI 0.53-0.89). 7

The American Diabetes Association guidelines note that no increased risk of heart failure hospitalization has been identified with GLP-1 receptor agonists including semaglutide, contrasting with concerns about certain DPP-4 inhibitors. 4

Dosing and Initiation in This Population

Start with 0.25 mg subcutaneously once weekly for 4 weeks, then increase to 0.5 mg once weekly. 1 If additional glycemic control is needed after at least 4 weeks, increase to the maximum dose of 1.0 mg once weekly. 1

Critical dosing considerations:

• If the patient is on insulin or sulfonylureas, reduce their dose by approximately 20% when starting semaglutide to prevent hypoglycemia. 4

• Monitor for volume depletion, especially if the patient is on diuretics; consider reducing diuretic dose if symptoms of dehydration occur. 4

• Monitor renal function closely in patients with renal impairment who experience severe gastrointestinal adverse reactions (nausea, vomiting, diarrhea), as acute kidney injury has been reported. 1

Renal Function Considerations

Renal impairment does not require dose adjustment of semaglutide. 1 The pharmacokinetics of semaglutide are not clinically affected by renal impairment, including in patients with end-stage renal disease. 1 This was demonstrated in studies across all degrees of renal impairment (mild, moderate, severe, ESRD). 1

The FLOW trial specifically enrolled patients with eGFR as low as 25 mL/min/1.73 m², demonstrating both safety and efficacy in advanced CKD. 2

Safety Profile in This High-Risk Population

Serious adverse events occurred in fewer patients treated with semaglutide (49.6%) compared to placebo (53.8%) in the FLOW trial of patients with type 2 diabetes and CKD. 2

Common adverse reactions (≥5% of patients) include:

• Nausea, vomiting, diarrhea, abdominal pain, and constipation. 1
• These gastrointestinal effects are typically transient and diminish over time. 4

Important safety monitoring:

• Educate patients about symptoms of acute kidney injury (decreased urination, swelling, fatigue) and instruct them to seek medical attention if severe gastrointestinal symptoms occur. 1

• Monitor for diabetic retinopathy complications in patients with a history of diabetic retinopathy, as worsening was reported in SUSTAIN-6. 1

• Avoid in patients with personal or family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). 1

Comparison with SGLT2 Inhibitors

While SGLT2 inhibitors (empagliflozin, canagliflozin, dapagliflozin) also demonstrate robust benefits for heart failure hospitalization reduction (31-39% reduction) and CKD progression, 4 semaglutide offers complementary benefits with superior MACE reduction and can be used in patients with more advanced kidney disease (eGFR as low as 25 mL/min/1.73 m²) without the eGFR-related efficacy limitations of SGLT2 inhibitors. 4, 2

The American Diabetes Association guidelines recommend that in patients with type 2 diabetes and established cardiovascular disease or CKD, either an SGLT2 inhibitor or GLP-1 receptor agonist with demonstrated cardiovascular benefit (such as semaglutide) is appropriate. 4 Combination therapy with both classes may be considered, though additive cardiovascular benefits remain unknown. 4

Clinical Algorithm for Use

For patients with type 2 diabetes, kidney disease (eGFR ≥25 mL/min/1.73 m²), and/or heart failure:

1. Initiate semaglutide 0.25 mg weekly regardless of baseline eGFR (as low as 25 mL/min/1.73 m²). 1, 2

2. Reduce insulin dose by ~20% and discontinue or reduce sulfonylureas if HbA1c is well-controlled or history of hypoglycemia exists. 4

3. Titrate to 0.5 mg weekly after 4 weeks, then to 1.0 mg weekly if additional glycemic control needed. 1

4. Monitor renal function if severe gastrointestinal symptoms develop. 1

5. Continue long-term as cardiovascular and renal benefits emerge within 2 years and persist with ongoing treatment. 5, 2

Contraindications and Cautions

Absolute contraindications:

• Personal or family history of medullary thyroid carcinoma. 1
• Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). 1
• Known hypersensitivity to semaglutide or product components. 1

Use with caution:

• History of pancreatitis (has not been studied in this population; consider alternative therapy). 1
• History of diabetic retinopathy (monitor closely as worsening reported in trials). 1
• Active gallbladder disease. 4