GLP-1 Agonists: Risks and Rewards

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Welcome to another edition of the monthly 'Amuse-Bouche' series. Like a morsel compliments of the chef, these small but critical scientific bites are created to stimulate your thinking about health and occasionally provide some comic relief. Prior editions.

GLP-1 Agonists: Risks and Rewards

GLP-1 receptor agonists and similar medications—semaglutide (Ozempic, Wegovy), tirzepatide (Mounjaro, Zepbound), and a growing family of successors—have become the most consequential pharmacological development in metabolic medicine.

L-cells in our intestines produce GLP-1. Our body’s own GLP-1 is cleared within minutes after meals. Semaglutide and tirzepatide are structurally modified to resist that clearance, producing days of continuous receptor activation—sustained appetite suppression, changes in reward signaling, and anti-inflammatory activity mediated by pathways in the brain.

GLP-1 receptors are found throughout the body—in the brain’s hypothalamus and reward circuits, the nervous system, gut, heart, kidneys, and muscles. Hence their impact is felt in multiple systems.

Originally approved for type 2 diabetes, these medications were noted to cause significant weight reduction. With widespread use, cardiovascular, liver, kidney, and neuroprotective benefits independent of weight loss have also been identified.

But that effect is not unconditional. Emerging evidence makes clear that a prescription alone is not enough.

The Holy Grail

The hypothalamus is the body’s energy regulator. It continuously integrates hormonal input—leptin, insulin, glucagon, ghrelin, GLP-1, PYY, and CCK. In health, the signaling is effective. In chronic weight gain, the brain grows resistant to leptin and insulin and does not modulate intake.

This system is impacted by physical inactivity, stress, poor sleep, trauma, adverse childhood experiences, mental health conditions, genetic susceptibility, and an environment saturated with ultra-processed foods engineered with unhealthy fats and sugar to override satiety. Will power is not the solution. Drastic diets typically fail.

A Brave New World: What These Medications Can Do

Upon using these medications, many patients describe the quieting of lifelong “food noise”—relief from the brain’s persistent preoccupation with eating. They have been able to shift the needle with weight loss that had eluded them.

The SELECT trial demonstrated a 20% reduction in major cardiovascular events—heart attack, stroke, and cardiovascular death. The ESSENCE trial found semaglutide resolved metabolic liver disease (MASH) in 63% of patients versus 34% on placebo.

The unifying mechanism across these benefits appears to be reduction of chronic low-grade inflammation.

A 2025 JAMA Psychiatry paper showed reduced alcohol craving and consumption with low-dose semaglutide. GLP-1 receptor activation in the brain’s mesolimbic dopamine pathway dampens the reinforcing value of alcohol, nicotine, and other substances.

A Double-Edged Sword: What These Medications Can Harm

Published data shows 30–40% of weight loss without structured exercise and increased protein intake is lean mass, and greater muscle loss correlates with worse blood sugar control. Weight and BMI may signal success, but as muscle mass falls, metabolic rate drops and bone density declines.

The populations at greatest risk—older adults, women with lower lean mass, patients with poor protein intake, sedentary individuals, and those with depression or addiction history—represent a large proportion of patients currently prescribed these drugs.

Other negative effects have been reported.

Slowed gastric motility—nausea, vomiting, reflux, constipation, bloating—are dose-dependent, generally improve with time, and respond to slower titration.

Reduced nutrient intake—fatigue, dizziness, hair loss, menstrual disruption—signal that the body is not getting enough fuel or nutrients.

Energy deficit—muscle wasting, weakness, slowed heart rate, bone loss—weight is lost from all compartments, not just adipose tissue.

Protein deficiency—progressive lean mass loss, frailty, neurotransmitter depletion. Severe cases can thin the heart muscle wall, cause scarring, and lead to irregular heart rhythms.

Biliary and pancreatic stress—gallstones, cholecystitis, pancreatitis—result from rapid lipid mobilization.

Dehydration—kidney injury, electrolyte imbalance—arise when fluid intake drops alongside food intake.

Ocular effects. Optic neuropathy, macular edema, retinal detachment, vitreous hemorrhage, and rare cases of blindness have been reported.

Neurological effects. Some patients develop dysesthesia or allodynia—burning, prickling, or electric sensations, or pain from normally painless stimuli like light touch.

Anhedonia. These drugs dampen dopaminergic signaling and can deepen low energy, worsen depression, and produce an inability to feel pleasure in some individuals

Eating disorders. These drugs are contraindicated in patients who have eating disorders and have not been studied in that context. They may trigger relapse in susceptible individuals.

Tolerance. Many patients report diminishing efficacy over time. Because GLP-1 agonists occupy receptors continuously, cells respond by pulling those receptors off their surface, a process called tachyphylaxis.

Long-term consequences are unknown. Cancer has not been identified in humans but has been noted in mouse models.

How Can We Make GLP-1 Medications Work Better

Protein Amplifies the Benefits of GLP-1 Medications

Protein is the only macronutrient that serves as a direct structural building block for tissue and organs. The daily target for someone on GLP-1 medications is intentional protein intake of 1.2–1.6 grams per kilogram of ideal body weight per day. In my practice, I recommend approximately two servings of protein-rich whole foods like lentils and chicken, or eggs and Greek yogurt, at the beginning of every meal with vegetables, nuts, and whole grains.

•   Neurotransmitter synthesis. Dopamine and serotonin are built from amino acids in dietary protein. A patient eating inadequate protein is depleting the raw materials the brain needs—while taking a drug that simultaneously dampens the system those neurotransmitters serve.

•   Endogenous GLP-1 production. Protein is one of the most potent stimulators of the body’s own GLP-1 secretion from intestinal cells, synergizing with the medication.

•   Satiety per calorie. Protein suppresses ghrelin (the hunger hormone) more effectively and for longer than carbohydrates or dietary fats.

•   Thermic effect. Approximately 25–30% of calories are burned to digest protein, compared to 6–8% for carbohydrates and 2–3% for fats.

•   Bone maintenance. The organic bone matrix is made of collagen, which is a protein.

•   Hormonal orchestration. Protein simultaneously triggers insulin for nutrient delivery and glucagon (different from GLP-1) for metabolic balance—a dual signal no other macronutrient produces. It drives growth hormone and IGF-1 for muscle anabolism. It suppresses cortisol-driven catabolism.

Vegetables and fruits provide micronutrients—a 2026 review of nearly half a million adults found rising deficiency rates in vitamin D, B12, iron, and calcium on GLP-1 medications.

Dietary fiber promotes the body’s own GLP-1 production by feeding the gut microbiome, which generates short-chain fatty acids that activate our own GLP-1.

Carbohydrates, especially complex carbohydrates like lentils, beans, quinoa, oats, brown rice, and bread, remain necessary for fuel. The goal of GLP-1 medications is to reduce consumption of junk food—or riff-raff, as I call it. Fluid intake is critical.

Why All This Talk of Resistance Training

Aerobic exercise retains value for cardiovascular fitness and can increase endogenous GLP-1 secretion by up to 25%. Walking and Pilates support mobility and core stability. But they don’t generate the mechanical load required to boost muscle and stimulate bone growth.

When muscle contracts against a genuinely challenging load, it activates satellite cells for repair, triggers the mTOR protein synthesis pathway, recruits Type II fast-twitch fibers (the fibers most rapidly lost during weight loss), upregulates GLUT4 transporters for insulin-independent glucose uptake, promotes bone remodeling, and restores dopamine D2 receptor density.

A six-month study found patients receiving structured resistance training and protein guidance at GLP-1 initiation lost 13% of body weight with only 3% lean mass loss. Contracting muscle also secretes myokines—irisin, BDNF, FGF21—that act on the brain, adipose tissue, and liver. GLP-1 drugs independently elevate these same molecules, meaning drug and exercise amplify each other.

For patients who have never lifted weights, the barrier is not the science—it is knowing where to start. A certified personal trainer, a physical therapist, or a structured beginner program can bridge that gap. The goal is loading muscle and bone enough to nudge the body to invest resources in them. I do grip strength and sit-to-stand tests with patients in my practice and obtain body composition scans at least once each year. Discussing two to three simple, body-weight strength training exercises is a common in my practice.

What Happens When the Medication Stops

One year after stopping semaglutide, STEP 1 participants regained two-thirds of their weight loss. A 2026 study of 333,687 veterans found that stopping—even temporarily—elevated the risk of heart attack, stroke, and death, with three years of benefit erased within eighteen months.

Discontinuation rates run 36–81% in real-world settings—driven largely by cost, which for many patients remains the single biggest barrier to sustained use. Health economic analyses from the SELECT trial have found semaglutide cost-effective when cardiovascular benefits are included, and as drug prices fall with competition, the case that treating earlier costs less than treating later will only strengthen.

Recent papers have reported that gradual tapering—reducing semaglutide to zero over nine weeks with exercise and diet coaching—produced stable weight, compared to large regain with abrupt cessation. Patients who combined exercise with treatment kept off 5.1 kilograms one year after stopping.

Since this societal experiment of GLP-1 use is about under ten years in the making, we do not truly understand the long-term effects.

Checks and Balances

Before initiation

•     Baseline body composition assessment, not BMI alone

•     Dietary assessment focusing on protein intake

•     Screening for disordered eating, emotional triggers, and reward system function

•     Muscle strength and functional capacity assessment

•     Food security screening

At initiation

•    Protein target of 1.2–1.6 g/kg/day

•    Resistance training prescribed as part of the treatment protocol, tailored to ability

•    Hydration and micronutrient monitoring (vitamin D, B12, iron, calcium, thiamine)

•    Consider a baseline eye exam

During treatment

•    Body composition reassessment at ideally six and twelve months

•    Screening for excessive suppression: fatigue, weakness, hair loss, slowed heart rate

•    Monitoring for mood changes and neurological symptoms

•    Protein and exercise adherence reviewed at every visit

If tapering

•    Gradual dose reduction—never abrupt cessation

•    Intensified resistance and other types of exercise and dietary planning

•    Cardiovascular and endocrine monitoring

Seek an obesity medicine specialist, a registered dietitian experienced with GLP-1 therapy, or a practice that treats these medications as part of a comprehensive plan rather than a standalone prescription.

Conclusion

GLP-1 receptor agonists are the most powerful metabolic tool medicine has deployed at scale. But they are tools, not cures.

Used without safe-guards, these medications risk producing improvement that collapses when the drug is removed. Used with them, they can change lives.

Select References

1. Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and cardiovascular outcomes in obesity without diabetes. N Engl J Med. 2023;389(24):2221-2232. doi:10.1056/NEJMoa2307563

2. Sanyal AJ, Newsome PN, Kliers I, et al. Phase 3 trial of semaglutide in metabolic dysfunction–associated steatohepatitis (ESSENCE). N Engl J Med. 2025;392(21):2089-2099. doi:10.1056/NEJMoa2413258

3. Hendershot CS, Bremmer MP, Paladino MB, et al. Once-weekly semaglutide in adults with alcohol use disorder: a randomized clinical trial. JAMA Psychiatry. 2025;82(4):395-405. doi:10.1001/jamapsychiatry.2024.4789

4. Xie Y, Choi T, Al-Aly Z. GLP-1RA discontinuation and risks of major adverse cardiovascular events in adults with type 2 diabetes: a target emulation trial. BMJ Medicine. 2026;5(1):e002150. doi:10.1136/bmjmed-2025-002150

5. Mozaffarian D, et al. Nutritional priorities to support GLP-1 receptor agonist therapy for obesity. Am J Clin Nutr. 2025;122:344-367. doi:10.1016/j.ajcnut.2025.04.023

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Proof of Life: Work along with Play

It has been a year since I started writing the Amuse-bouche series. This is the 12th op-ed. Time flies when you are having fun.

I bought a Seca body composition scan device for the office. More on this in the near future. Excited that my patients, friends, and family can check their muscle mass and body composition without radiation exposure as often as they'd like. Muscle mass and strength strongly correlate with health and longevity.

Cheers!