What is the role of Ozempic (semaglutide) in reducing cardiovascular risk in a patient with type 2 diabetes and increased cardiovascular risk?

Ozempic for Cardiovascular Risk Reduction in Type 2 Diabetes

Ozempic (semaglutide) significantly reduces major adverse cardiovascular events in patients with type 2 diabetes and established cardiovascular disease, and is FDA-approved for this indication. 1

FDA-Approved Cardiovascular Indication

• Ozempic is specifically indicated to reduce the risk of major adverse cardiovascular events (MACE)—including cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke—in adults with type 2 diabetes mellitus and established cardiovascular disease. 1
• This represents a formal FDA approval beyond glycemic control, positioning semaglutide as a cardioprotective agent in high-risk patients. 1

Evidence of Cardiovascular Benefit

Subcutaneous Semaglutide (SUSTAIN-6 Trial)

• The SUSTAIN-6 trial demonstrated a 26% reduction in MACE with subcutaneous semaglutide compared to placebo (HR 0.74 [95% CI 0.58–0.95]; P < 0.001 for noninferiority and superiority). 2, 3
• This trial enrolled 3,297 patients with type 2 diabetes at high cardiovascular risk (83% had established cardiovascular disease) and followed them for 2 years. 2
• Cardiovascular deaths from cardiovascular causes were significantly reduced (4.7% vs 6.0%; HR 0.78 [95% CI 0.66–0.93]; P = 0.007). 2
• Nonfatal stroke was reduced by 39% (1.6% vs 2.7%; HR 0.61 [95% CI 0.38–0.99]; P = 0.04). 2

Oral Semaglutide Evidence

• The SOUL trial (2025)—the most recent and highest quality evidence—demonstrated that oral semaglutide reduced MACE by 14% in 9,650 patients with type 2 diabetes and atherosclerotic cardiovascular disease or chronic kidney disease (HR 0.86 [95% CI 0.77–0.96]; P = 0.006). 4
• This represents the largest and longest trial (median follow-up 49.5 months) of oral semaglutide's cardiovascular effects. 4
• The earlier PIONEER 6 trial showed noninferiority for cardiovascular safety with oral semaglutide (HR 0.79 [95% CI 0.57–1.11]; P < 0.001 for noninferiority), though it was not powered to demonstrate superiority. 2

Mechanisms of Cardiovascular Protection

• Semaglutide provides cardiac benefits through multiple pathways: reduced myocardial work and filling pressures, pre- and afterload reduction, improved cardiovascular risk profile with lower blood pressure (mean 5.1 mmHg systolic reduction), reduced atherogenesis, upregulated nitric oxide, and suppressed NF-κB activation. 3
• Weight reduction (mean 12.4% in STEP-1) contributes to cardiovascular risk reduction. 3

Clinical Implementation Algorithm

Patient Selection

• Use Ozempic in patients with type 2 diabetes AND established cardiovascular disease (prior MI, stroke, coronary artery disease, peripheral arterial disease). 1
• Consider in patients with type 2 diabetes and multiple cardiovascular risk factors or chronic kidney disease, based on SOUL trial data. 4

Dosing Strategy

• Start at 0.25 mg subcutaneously once weekly for 4 weeks (titration dose). 1
• Increase to 0.5 mg once weekly after 4 weeks. 1
• If additional glycemic control is needed after at least 4 weeks, increase to 1 mg once weekly (maximum dose). 1
• Administer at any time of day, with or without meals, on the same day each week. 1

Monitoring Requirements

• Monitor patients with a history of diabetic retinopathy closely, as retinopathy complications (vitreous hemorrhage, blindness, conditions requiring intravitreal treatment) were increased in SUSTAIN-6 (HR 1.76 [95% CI 1.11–2.78]; P = 0.02). 5
• Monitor renal function in patients with renal impairment who develop severe gastrointestinal adverse reactions. 1
• Regular blood pressure monitoring during titration, as semaglutide reduces systolic blood pressure. 3

Critical Safety Considerations

Contraindications

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

Important Warnings

• Do not use in patients with a history of pancreatitis—consider alternative antidiabetic therapy. 1
• Discontinue immediately if pancreatitis is suspected; do not restart if confirmed. 1
• Use caution in patients with severe renal impairment or prior gastric surgery. 3

Common Adverse Effects

• Gastrointestinal effects (nausea, vomiting, diarrhea, abdominal pain, constipation) are most common, occurring in ≥5% of patients. 1
• These are typically transient and improve with gradual dose titration. 3
• Gastrointestinal adverse events were the primary reason for treatment discontinuation in clinical trials. 5

Pregnancy Planning

• Discontinue Ozempic at least 2 months before planned pregnancy due to the long washout period for semaglutide. 1

Comparative Context

• The American Diabetes Association guidelines note that GLP-1 receptor agonists (including semaglutide) and SGLT2 inhibitors reduce atherosclerotic MACE to a comparable degree in patients with type 2 diabetes and established cardiovascular disease. 2
• However, SGLT2 inhibitors provide additional benefits for heart failure hospitalization and kidney disease progression that semaglutide does not match. 2
• For patients with established cardiovascular disease as the primary concern, semaglutide's 26% MACE reduction makes it a first-line cardioprotective agent. 3, 6

Key Clinical Pitfall

• The most common error is failing to recognize that Ozempic has a formal FDA indication for cardiovascular risk reduction, not just glycemic control—this should drive prescribing decisions in high-risk patients regardless of baseline HbA1c. 1