Dr Robert Kushner on GLP-1s, appetite biology and coming off the drug

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Episode Summary

This week Mikki talks with Dr Robert Kushner, an obesity medicine physician, educator and researcher with over four decades in the field. He is Professor Emeritus at Northwestern University Feinberg School of Medicine, a founder and the first chair of the American Board of Obesity Medicine, and a past president of The Obesity Society. He was also the corresponding author on the STEP 1 semaglutide trial published in the New England Journal of Medicine in 2021, and sat on the steering committee for SELECT — so he has watched this field from the inside, before and after GLP-1 receptor agonists arrived.

The conversation traces what clinicians actually understood about obesity in the 1980s and 90s, Bob's own leptin trial and why it did not deliver, and how reframing obesity as a biological disease led researchers to the gut hormones. From there it moves into the practical territory: how the clinical conversation has shifted from counting calories to diet quality, which side effects are real and which are social media noise, what happens to muscle mass and physical function, how dose escalation should actually work, why hunger returning is not the same as weight regain, and what the evidence says about stopping. Bob is careful throughout to separate what the trials show from what is still unknown, which makes this a useful listen whether you work with clients on these medications or are weighing them up yourself.

Key Topics

• What clinicians believed about obesity three decades ago — excess body fat was known to cause system-wide harm, but the mechanisms, and appetite dysregulation in particular, were not understood, and weight regain after lifestyle intervention was already expected
• Bob's own leptin trial in the 1990s, published in JAMA, and why leptin turned out to be a useful biological signal rather than a treatment — it defends against weight loss but was never built to stop overeating
• The STEP 1 result and why it changed the field: 15% average weight loss at 68 weeks against a previous benchmark of 6–9%, with a third of participants losing 20%
• How the clinical conversation shifted from quantity to quality — when the medication does the heavy lifting, the questions become whether someone is eating enough, staying hydrated and getting sufficient protein, rather than how to control cravings
• Which side effects are real and which are overstated: GI effects are the genuine shared profile and can be substantially reduced through diet during dose escalation, while hair thinning and facial fat loss follow large weight loss by any route
• Muscle mass, sarcopenia and the groups who need watching, alongside the consistent finding that physical function and quality of life improve in trials — possibly because fatty infiltration of muscle resolves
• Dose escalation in the real world versus the trial protocol, and why there are still no pretreatment predictors of who will respond
• Why appetite drifting back is normal and not a failure — Bob's framing of restored appetite regulation at a lower body weight, with "the amplitude smaller than it was before"
• Benefits beyond weight loss, including SELECT's 20% reduction in cardiovascular events on top of standard care, plus sleep apnoea, knee osteoarthritis, MASH and psoriasis — driven both by weight loss and by independent mechanisms
• Cost and access, microdosing, extending the interval between injections, and where bariatric surgery still fits

Chapters

00:00 Introduction
05:13 Obesity medicine before GLP-1s
13:34 Gut hormones and the STEP 1 result
21:00 From calorie counting to diet quality
25:00 Side effects and social media myths
29:54 Muscle mass, function and exercise
35:08 Dose escalation and who responds
40:30 When hunger comes back
46:37 Stopping the drug, cost and access
52:24 Benefits beyond weight loss
57:37 Long-term safety and microdosing
1:01:10 Coming off, surgery and what's next

Guest / Resources

Dr Robert Kushner

• Professor Emeritus, Northwestern University Feinberg School of Medicine
• Founder and first chair of the American Board of Obesity Medicine
• Past president of The Obesity Society
• Author or editor of 15 books, 56 book chapters and 230 original and review articles
• Website: drrobertkushner.com

Books

• Six Factors to Fit: Weight Loss that Works for You! — written for the patient
• Patient-Centered Weight Management: The Six Factor Professional Program and Toolkit — written for the clinician

Trials and studies discussed

• STEP 1 — once-weekly subcutaneous semaglutide, New England Journal of Medicine, 2021. 1,961 adults, 68 weeks, ~15% average weight loss. Bob was the corresponding author
• STEP 1 extension — the off-treatment follow-up showing weight regain after stopping
• SELECT — semaglutide versus placebo in 17,