GLP-1 Therapies Newsletter
Issue #42June 22, 20268 studies

Tirzepatide users lost 14.7% of body weight vs. 10.8% with semaglutide — but Black and Hispanic patients were overrepresented in the lowest-response group

GLP-1 drugs are everywhere right now — but this week's research digs into what they actually do (and don't do) once you get past the weight loss headline. From muscle loss to liver protection to who's getting left out of the benefits, here's what the data says.

⚖️ Tirzepatide vs. Semaglutide: More Weight Lost, But Not Equally

In a propensity-matched real-world cohort of 10,339 patients on each drug, tirzepatide was associated with meaningfully greater weight loss than semaglutide — and the gap was wide:

  • Mean body weight reduction: 14.7% with tirzepatide vs. 10.8% with semaglutide. High-response rates (≥15% loss in year 1) were nearly doubled: 42.6% vs. 21.6%.
  • Tirzepatide was also associated with faster monthly weight loss (2.54% vs. 2.18%) and lower rates of gastrointestinal side effects, based on AI-assisted review of clinical notes.
  • The demographic split matters: women and White patients were overrepresented among high responders for both drugs, while Black and Hispanic patients were overrepresented in the minimal weight loss group (<5% loss).

Why it matters: Real-world data from 20,678 matched patients suggests tirzepatide may be associated with greater and faster weight loss than semaglutide — but the demographic disparities in response suggest that drug choice alone won't close gaps in obesity outcomes across populations.

Top 20% journal 🔗 PNAS nexus Journal Article 🗓️ Jun 18

Key Findings

🏥 Surgery Still Leads at 1 Year — But Comes With More ER Visits

A retrospective study of 45,093 patients with obesity and type 2 diabetes compared three treatments at 1 year:

  • Adjusted probability of achieving ≥20% body weight loss AND HbA1c below 5.7%: 24.0% for sleeve gastrectomy, 13.2% for tirzepatide, and 3.0% for semaglutide.
  • Emergency department visits within 1 year were more frequent after sleeve gastrectomy than after either medication.
  • New prescriptions for acid reflux and nausea were highest in the surgery group, though all three groups had some.
💡 Sleeve gastrectomy may be associated with the highest likelihood of hitting combined weight and blood sugar targets at 1 year, but the safety data suggests the tradeoffs are real — and tirzepatide's gap over semaglutide is substantial.
🥇 Top 1% journal 🔗 The lancet. Diabetes & endocrinology Journal Article 🗓️ Jun 17

💪 GLP-1 Drugs and Muscle Loss: How Much Are You Losing?

Two separate meta-analyses this week looked at lean body mass (muscle and non-fat tissue) loss during GLP-1 treatment:

  • Across 36 randomized trials, GLP-1 receptor agonists were associated with -1.51 kg of lean mass and SGLT2 inhibitors (a related diabetes drug class) with -1.04 kg. Lean mass made up ~28% of total weight lost.
  • A separate analysis of obesity-dose GLP-1 trials (7 studies, 821 patients) found an absolute lean mass loss of -1.74 kg, with semaglutide specifically linked to -5.44 kg of lean mass loss.
  • A third meta-analysis comparing interventions head-to-head found: diet + exercise = -1.8 kg lean mass lost; GLP-1 drugs = -4.8 kg; bariatric surgery = -9.1 kg — with GLP-1s and surgery both attributing ~33-34% of total weight loss to lean mass.
💡 GLP-1 drugs appear to cause more lean mass loss than diet and exercise alone, which may support the case for adding resistance training and adequate protein to any GLP-1-based weight loss plan.
🎖️ Top 10% journal 🔗 Diabetes/metabolism research and reviews Systematic Review 🗓️ Jun 19

🏛️ The ACP Just Updated Its Obesity Drug Guidelines

The American College of Physicians released a living clinical guideline this week for outpatient obesity treatment:

  • First-line for obesity (BMI ≥30): semaglutide and tirzepatide — both with moderate-certainty evidence.
  • Second-line: phentermine-topiramate (low certainty); third-line: liraglutide; fourth-line: naltrexone-bupropion.
  • For overweight adults (BMI 27–30) with type 2 diabetes, high blood pressure, sleep apnea, or cardiovascular disease: semaglutide and tirzepatide are again first-line, with liraglutide as second-line.
  • The guideline is paired with a living systematic review of 69 trials (112,511 participants) showing semaglutide probably reduces mortality and major cardiovascular events, and both semaglutide and tirzepatide produced the greatest weight loss vs. placebo.
💡 The formal elevation of semaglutide and tirzepatide to first-line status by a major U.S. medical organization could influence prescribing, insurance coverage decisions, and clinical training going forward.
🥈 Top 2% journal 🔗 Annals of internal medicine Journal Article 🗓️ Jun 15

❤️ Semaglutide Linked to Lower Heart Event Risk — Even Without Prior Heart Disease

A real-world study matched 48,184 semaglutide 2.4 mg users to 96,368 non-users — all overweight/obese adults without diabetes but with cardiovascular risk factors:

  • Semaglutide was associated with a 41% lower risk of the primary 3-point cardiovascular event composite (heart attack, stroke, all-cause death) — HR: 0.59.
  • Risk of the broader 5-point composite (adding heart failure hospitalization and coronary procedures) was 35% lower — HR: 0.65.
  • Mean follow-up was only 9 months, so long-term effects remain uncertain.
💡 These real-world findings are consistent with a possible cardiovascular benefit of semaglutide even in people without existing heart disease — though the short follow-up and observational design mean causation can't be established.
🥉 Top 5% journal 🔗 American journal of preventive cardiology Journal Article 🗓️ Jun 15

🧠 GLP-1 Drugs May Suppress Hunger Long-Term — But the Effect Shifts

A 60-week double-blind randomized trial (120 adults, semaglutide 2.4 mg vs. placebo) tracked how eating behavior changed over time:

  • At week 20, semaglutide users consumed 294.6 kcal less at a test meal than placebo. At week 40: 250.1 kcal less. At week 60: 238.3 kcal less — all statistically significant.
  • Appetite suppression and reduced hunger were significant at week 20, but the groups did not differ significantly on those subjective measures at weeks 40 or 60.
  • Reduced responsiveness to food (measured by the Power of Food Scale) was significant at weeks 20 and 40, but not week 60.
💡 Calorie reduction appears to persist across 60 weeks of semaglutide treatment even as some of the subjective hunger-suppressing effects fade — suggesting the mechanism supporting weight maintenance may shift over time.

⚠️ GLP-1 Drugs and Ketoacidosis Risk in Non-Diabetic Patients

A disproportionality analysis of the FDA's adverse event database (7.3 million reports) flagged an emerging safety signal:

  • Among non-diabetic patients, ketoacidosis (a dangerous buildup of blood acids) was reported in 261 semaglutide cases and 209 tirzepatide cases.
  • Semaglutide had a reporting odds ratio of 3.15 (meaning it appeared 3x more than expected); tirzepatide's was 1.22 — both statistically significant.
  • Hospitalization was required in 74.3% of semaglutide cases and 71.3% of tirzepatide cases.
  • Tirzepatide reports increased sharply: from 1–2 cases per quarter in 2022 to 28–34 per quarter by 2025.
💡 Both drugs are associated with ketoacidosis signals in non-diabetic users — a population not traditionally considered high-risk for this condition — suggesting clinicians may want to monitor for it, especially as tirzepatide use grows.
🔗 Cureus Journal Article 🗓️ Jun 16

🏥 GLP-1 Drugs for Antipsychotic Weight Gain: Real-World Data

A retrospective chart review of 47 psychiatric inpatients on antipsychotics who were started on semaglutide:

  • Mean weight loss: 3.15 kg at 3 months, 7.27 kg at 6 months, 9.33 kg at 9 months, and 12.25 kg at 12 months — all statistically significant (p < .001).
  • 83% had abnormal blood sugar at baseline; 66% had type 2 diabetes. Those without diabetes lost more weight than those with it.
  • Improvements in BMI and HbA1c were also significant; most side effects were gastrointestinal and did not lead to stopping the medication.
💡 In a small inpatient psychiatric cohort, semaglutide was associated with progressive weight loss over 12 months, supporting the case for larger randomized trials in people with serious mental illness on antipsychotics.
🥉 Top 5% journal 🔗 Schizophrenia bulletin Journal Article 🗓️ Jun 15

Implications

This week's research paints a more complete — and more complicated — picture of GLP-1 drugs than the headlines usually offer. Yes, they work for weight loss and may protect the heart. But they also come with real lean muscle loss (roughly a third of total weight lost), an emerging ketoacidosis signal in non-diabetic users, and a persistent racial disparity in who responds best. The ACP's new guidelines formalize what the data has been pointing toward — but the harder work of figuring out who benefits most, how to preserve muscle, and how to close access gaps is still very much ongoing.

Studies in this issue

Primary sources used for this newsletter.

  1. Weight loss patterns with tirzepatide compared to semaglutide
    main storyPNAS nexus2026-06-18PMID 42311474
  2. One-year results of semaglutide, tirzepatide, and weight-loss surgery for obesity in type 2 diabetes
    key findingThe lancet. Diabetes &amp; endocrinology2026-06-17PMID 42309121
  3. How Diabetes Drugs Affect Lean Body Mass in People: A Review of Clinical Trials
    key findingDiabetes/metabolism research and reviews2026-06-19PMID 42319968
  4. Semaglutide and its impact on weight gain and metabolism in patients taking antipsychotic medications
    key findingSchizophrenia bulletin2026-06-15PMID 42297449
  5. Medication and Lifestyle Changes for Overweight or Obese Adults Outside of Pregnancy: Updated Treatment Guidelines
    key findingAnnals of internal medicine2026-06-15PMID 42296496
  6. Semaglutide 2.4 mg and heart event risk in overweight or obese people without artery disease: The SCORE primary prevention study
    key findingAmerican journal of preventive cardiology2026-06-15PMID 42291047
  7. Ketoacidosis risk in non-diabetic obese patients using Semaglutide compared to Tirzepatide
    key findingCureus2026-06-16PMID 42299163
  8. Short- and Long-Term Effects of Semaglutide 2.4 mg on Eating, Appetite, and Food Cravings in a 60-Week Controlled Trial
    key findingThe American journal of clinical nutrition2026-06-20PMID 42323166

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