Tirzepatide Beats Semaglutide: What SURMOUNT-5 Means for Men

For years, comparing tirzepatide and semaglutide meant comparing apples to oranges — different trial populations, different endpoints, different study designs. In May 2025, that changed. The SURMOUNT-5 trial, published in the New England Journal of Medicine, put both drugs in the same patients at the same time under identical conditions.

Tirzepatide won. But the part no one's talking about is what the data says specifically about men — and it's not as straightforward as the headlines suggest.

The Top-Line Numbers

SURMOUNT-5 enrolled adults with obesity or overweight (with at least one weight-related comorbidity) and no type 2 diabetes. Over 72 weeks:

The tirzepatide group also showed greater improvements in blood pressure, glycemia, and lipid levels — consistent with the principle that more weight loss produces greater cardiometabolic improvement.

The Men-Specific Data No One's Discussing

Here's the part that matters for this audience: men lost approximately 6% less weight than women in both treatment groups.

SURMOUNT-5 enrolled 35% men — significantly higher than most obesity trials, which typically hover around 20-25%. The trial authors specifically noted that this higher male enrollment may explain why overall weight loss was slightly lower than in previous SURMOUNT studies.

This isn't a failure. It's biology. Men tend to have more lean mass, higher metabolic rates, and different fat distribution patterns (more visceral, less subcutaneous). These factors affect how GLP-1 and GIP agonists interact with the body. The drugs work in men. They just produce slightly less dramatic percentage weight loss because men start with a different body composition.

What This Means in Practical Terms

If the overall mean for tirzepatide was 20.2%, and men lost roughly 6% less, that puts the male average around 14-15% — still clinically significant and still superior to semaglutide's male average. For a 250-pound man, that's approximately 35-38 pounds. On semaglutide, that same man might expect 20-25 pounds.

Both are meaningful. But the gap between the two drugs is consistent regardless of sex.

Why Tirzepatide Works Better: The Dual Agonist Advantage

Semaglutide is a GLP-1 receptor agonist — it targets one receptor. Tirzepatide is a dual GIP/GLP-1 receptor agonist — it targets two. This isn't just a marketing difference; it reflects different pharmacology.

The GIP receptor activation adds an independent mechanism for improved insulin sensitivity, fat metabolism, and appetite regulation. In clinical practice, this translates to:

• More weight loss — consistently 5-7 percentage points more across all comparable trials
• Better GI tolerability — semaglutide tends to cause more nausea and constipation; tirzepatide's most common GI side effect is diarrhea, with significantly less nausea
• Lower dropout rates — 2.7% vs 5.6% GI-related discontinuation tells you which drug people can actually stay on

The Side Effect Profile: Different, Not Just "Less"

Both drugs cause gastrointestinal side effects, primarily during dose escalation. But the profiles are distinct:

Most adverse events in both groups were mild to moderate and occurred during dose escalation — the first 4-8 weeks as the body adjusts. After stabilization at target dose, side effects typically diminish substantially.

The Cardiovascular Angle: SURMOUNT-5 Post Hoc Analysis

A post hoc analysis of SURMOUNT-5 estimated 10-year cardiovascular disease risk using patient-level data. For the first time, researchers could directly compare projected CV risk between the two treatments in the same trial population.

The analysis extrapolated the weight loss, blood pressure, and lipid improvements to estimate how many cardiovascular events could potentially be prevented at a population level. While SURMOUNT-5 was not powered for hard CV endpoints (like SELECT was for semaglutide), the projected benefits tracked with the degree of weight loss — more weight loss, more projected CV risk reduction.

For men, this matters because cardiovascular disease remains the leading cause of death, and visceral fat reduction (where men carry the most excess) is one of the strongest modifiable risk factors.

Cost and Access: The Practical Consideration

Efficacy data only matters if you can actually get the drug. As of 2026:

• Tirzepatide (Zepbound) — list price around $1,087/month; manufacturer savings cards available for commercially insured patients; compounded versions face increasing FDA restrictions
• Semaglutide (Wegovy) — list price around $1,349/month; TrumpRx pricing brings semaglutide injections to $199-349/month and tablets to $149-299/month for eligible patients
• Compounded semaglutide — still available through 503A pharmacies with documented clinical need, typically $150-300/month

The cost differential is real. Semaglutide has more access pathways in 2026 — branded, generic-adjacent pricing programs, and compounded options. Tirzepatide compounding faces the same regulatory pressures. For many men, the choice comes down to what they can access and sustain financially over 12+ months, not which drug is pharmacologically optimal in a controlled trial.

The Bottom Line for Men

SURMOUNT-5 settled the debate: tirzepatide produces significantly more weight loss than semaglutide with better GI tolerability. But for men specifically, three things matter most:

1. Both drugs work in men — the 6% sex gap doesn't negate efficacy; it contextualizes expectations
2. Tirzepatide's advantage is consistent — even with lower male weight loss, the relative superiority over semaglutide holds
3. Access and sustainability trump pharmacology — the drug you can afford and stay on for 12+ months will outperform the "better" drug you take for 3 months and stop

Ask your provider about both options. The right choice depends on your insurance coverage, your GI tolerance profile, and your long-term plan — not just which drug posted the bigger number in a headline.