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Dr. Chris Thompson

Part IV

What actually acts on the system

Part III made the case that the weight your body defends drifts upward, that the defense is asymmetric, and that effort alone loses to it over time. This part is about the interventions that act on the system itself.

The short answer

Medication and procedures both act on appetite-related physiology, through different levers. Neither has been shown to reset a human set point, and both can reduce the biological pressure to regain. The choice between them rests on their trade-offs rather than on their mechanism.

You can't out-diet a drifted set point, but the biological pressure to regain can be reduced.

That framing is narrower than the marketing you will encounter elsewhere, and it is the one the evidence supports. No trial has shown that any intervention lowers a set point in humans. What the best-fitting models do permit is a new, lower stable weight, provided it sits above the point at which biology begins to push back hard.C-III-08 Every option covered in this part is an attempt to reach that weight.

The options differ in how they act, how long the effect lasts, what they cost, and what they risk. One finding is worth knowing before accepting anyone's framing of one option as a real fix and another as a stopgap: current work places medication and bariatric surgery in the same mechanistic category, differing in degree rather than kind.C-IV-09

The comparison, up front

There is no universally best option, only a best-fitting trade-off. Not sourced here means that no figure is solid enough to quote, not that the option lacks one.

Ongoing medication One-time procedure
Weight change ~17% at 68 weeks ~16.5% at 12 months
Best controlled evidence Large randomized trials One sham-controlled trial (40 MASH patients, 72 weeks): 9.47% vs 3.91%C-IV-03
On stopping ~two-thirds of the loss returns Reversal not documented
Serious risks Mostly gastrointestinal (nausea and diarrhea), usually transient; 4.5% stopped for GI effects vs 0.8% on placebo. Serious-event rate not sourced hereC-IV-18 ~2.2% severe adverse events
Lean mass Some lean tissue goes with any substantial lossC-IV-08 The same; not measured separately for ESG hereC-IV-08
Eligibility BMI 30+, or 27+ with a weight-related conditionC-IV-18 BMI 30–50
Cost Not sourced here Not sourced here

The gaps in the evidence fall on both sides. The full comparison →

  1. How GLP-1s work A satiety signal the body already makes, amplified and made to last longer.
  2. How ESG works Reshaping the stomach from the inside to change how much it holds and how quickly it empties.
  3. Medication vs. procedure The comparison side by side, with neither column winning.
  4. How to think about regain Why it happens, and what helps.
  5. What comes after the drugs The duodenum, the ghrelin-producing lining, and matching treatment to the person, all at an early stage and described as such.
  6. How reversible are the options From fully reversible to permanent.

In practical terms, both categories work, each only for as long as it is in effect, and the difference that matters is which set of trade-offs fits your life.

References

  1. Speakman JR, et al. Set points, settling points and some alternative models. Dis Model Mech. 2011. PMID 22065844
  2. Models of body weight and fatness regulation. Phil Trans R Soc B. 2023. PMC10475878
  3. Hall KD. Mechanisms of weight loss with GLP-1 receptor agonists and bariatric surgery. Obesity. 2024. PMID 38644683
  4. Wilding JPH, et al. Weight regain after withdrawal of semaglutide (STEP 1 extension). 2022. PMID 35441470
  5. Hedjoudje A, Abu Dayyeh BK, Cheskin LJ, et al (incl. Thompson CC). Efficacy and Safety of Endoscopic Sleeve Gastroplasty: A Systematic Review and Meta-Analysis. Clin Gastroenterol Hepatol. 2020. PMID 31442601
  6. Abu Dayyeh BK, et al. MERIT trial: endoscopic sleeve gastroplasty for treatment of class 1 and 2 obesity. Lancet. 2022. PMID 35908555
  7. Abad J, Llop E, Arias-Loste MT, et al. Endoscopic sleeve gastroplasty plus lifestyle intervention in patients with metabolic dysfunction-associated steatohepatitis: a multicenter, sham-controlled, randomized trial. Clin Gastroenterol Hepatol. 2025;23(9):1556-1566.e3. PMID 39694202
  8. Anyiam O, et al. How do glucagon-like peptide-1 receptor agonists affect measures of muscle mass in individuals with, and without, type 2 diabetes: A systematic review and meta-analysis. Obes Rev. 2025. PMID 40181228
  9. Neeland IJ, et al. Changes in lean body mass with glucagon-like peptide-1-based therapies and mitigation strategies. Diabetes Obes Metab. 2024. PMID 38937282
  10. Mechanick JI, et al. Strategies for minimizing muscle loss during use of incretin-mimetic drugs for treatment of obesity. Obes Rev. 2025. PMID 39295512
  11. Linge J, et al. Muscle Mass and Glucagon-Like Peptide-1 Receptor Agonists: Adaptive or Maladaptive Response to Weight Loss? Circulation. 2024. PMID 39401279
  12. Polidori D, et al. How Strongly Does Appetite Counter Weight Loss? Obesity. 2016. PMID 27804272
  13. Wilding JPH, Batterham RL, Calanna S, et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med. 2021;384(11):989-1002. PMID 33567185
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