Oral Semaglutide Reduces Cardiovascular Events in High-Risk Type 2 Diabetes Patients—A Pill with Powerful Promise

 

1. Purpose of the SOUL Trial

The SOUL trial evaluated whether oral semaglutide (a GLP-1 receptor agonist) reduces major adverse cardiovascular events (MACE) in patients with type 2 diabetes and either atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD), or both.

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2. Key Results

• 14% reduction in MACE (cardiovascular death, nonfatal MI, or nonfatal stroke) with oral semaglutide compared to placebo after 47.5 months.

• Benefit mainly driven by reduction in nonfatal MI (4.0% vs 5.2%).

• Number needed to treat (NNT): 50.

• No significant difference in cardiovascular mortality or major kidney events.

• Hospitalizations for limb ischemia reduced (HR 0.71).

• Coronary revascularization rates were lower (HR 0.75).

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3. Patient Population

• 9,650 patients, average age 66 years.

• 70.7% had coronary artery disease, 42.4% had CKD, and 27% had both ASCVD + CKD.

• More than 90% had hypertension.

• Average diabetes duration: over 14 years.

• About 25% were on SGLT2 inhibitors at baseline, increasing to 50% by study end.

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4. Secondary and Exploratory Outcomes

• Kidney-related endpoints did not reach statistical significance.

• Glycated hemoglobin, body weight, and hs-CRP improved significantly.

• Average weight loss: 4.22 kg (≈10 lbs).

• Adverse GI events were more frequent with semaglutide (15.5% vs 11.6% discontinuation rate).

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5. Oral vs Injectable Semaglutide

• Oral semaglutide helps patients who avoid injections, which are still not widely accepted in cardiology clinics.

• Injectable semaglutide has higher bioavailability (100%) vs oral (0.8%).

• Despite this, oral semaglutide filled an unmet clinical need for those who reject injectables.

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6. Trial Comparison: SOUL vs FLOW

• FLOW trial: Showed benefits for both cardiovascular and renal outcomes.

• SOUL trial: Included healthier patients with better kidney function (mean eGFR 74 vs 47 ml/min in FLOW).

• Fewer patients had advanced CKD in SOUL, possibly explaining lack of kidney benefit.

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7. SGLT2 Inhibitor Use

• Semaglutide’s benefits were independent of SGLT2 inhibitor co-therapy.

• Supports combination use, though evidence is still developing.

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8. Limitations & Cost Concerns

• Majority of patients were white males with relatively well-controlled cardiometabolic risks.

• High use of statins and ACEi/ARBs suggests patients were already on guideline-based therapies.

• Cost of oral semaglutide exceeds $1,000/month, posing access barriers.

• Affordability remains a major limitation despite clinical benefits.

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Take-Home Points

• Oral semaglutide offers a non-injectable option that significantly reduces MACE, especially nonfatal MI, in high-risk type 2 diabetes patients.

• No major kidney benefits were seen, likely due to a healthier CKD population.

• GI side effects are common but manageable.

• This treatment may bridge the gap for patients reluctant to use injections.

• Cost and access are key hurdles for broader adoption.

• Future guidance may support combined use with SGLT2 inhibitors.