GLP-1 and GIP Agonists: The Panacea or The Curse

These drugs work. That needs to be said first, because what follows is going to be nuanced, and nuance is easily mistaken for scepticism. Semaglutide and tirzepatide produce weight loss at a scale no behavioural intervention has ever matched in clinical trials – 15 to 22 percent mean body weight reduction over 68 to 72 weeks.

What is in dispute, and almost never discussed honestly, is what that weight loss is actually made of and what happens when you stop. In the STEP 1 body-composition substudy, roughly 39 percent of the total weight lost was lean body mass. That includes water and glycogen, not only skeletal muscle – but the muscle component is not zero, and in a patient already losing 3 to 8 percent of muscle mass per decade, it matters. The STEP 1 extension trial followed participants for a year after discontinuation: without active lifestyle support, they regained two-thirds of the weight.

Used well, these drugs are a bridge – from a condition where change was impossible to one where change can be maintained. For some patients, the biology requires lifelong therapy, and there is no clinical shame in that. The panacea framing is wrong because it implies the drugs solve the problem alone. The curse framing is wrong because it dismisses genuinely effective pharmacology.

You can find a companion essay for this podcast episode at dmitrysokolovmd.com.

Transcript

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These drugs work. That needs to be said first because what follows is going to be nuanced, and nuance is easily mistaken for skepticism. Semaglutide and terasepatide, GLP1 receptor agonists and dual GLP1 GIP agonists, produce weight loss at a scale that no behavioral intervention has ever matched in clinical trials. 15 to 22% mean body weight reduction over 68 to 72 weeks. For some patients, these are the most effective pharmacological tools we have ever created for obesity. That is not in dispute. What is in dispute, and what is almost never discussed honestly in public, is what that weight loss is actually made of, what happens when you stop, and what it does to the person psychologically when they realize the answer to both of those questions. Let me walk through the pharmacology briefly, because it matters for understanding everything that follows. GLP1, glucagon-like peptide 1, is an incretin hormone. Your gut releases it after you eat. It signals to the pancreas to produce insulin in a glucose-dependent manner, it slows gastric empting, and critically, it acts on the hypothalamus to reduce appetite. What semaglitite does is mimic that hormone, but with a much longer half-life. One subcutaneous injection per week produces sustained appetite suppression that the endogenous hormone cannot achieve. Terzepatite goes further. It is a dual agonist. It activates both the GLP-1 receptor and the GIP receptor, glucose-dependent insulinotropic polypeptide. This dual mechanism appears to produce greater weight loss than the GLP1 agonism alone. The Surmount 1 trial showed mean weight reductions of 20-22% with terzepatite at the highest dose, compared with roughly 15% with semaglitite in the STEP trials. The clinical effect patients report most consistently is the disappearance of what they describe as food noise, the constant intrusive preoccupation with eating. For someone who has spent decades fighting that signal, losing it is not merely convenient, it is, in their words, transformative. And I understand why. Because for a subset of patients, particularly those with morbid obesity, who have failed every dietary intervention, who cannot exercise because their body mass makes it painful or dangerous, who are trapped in a cycle of caloric excess and metabolic dysfunction, these drugs represent something that nothing else has provided, a way out of the abyss. And that is when the honest clinical conversation begins. Not whether they work, but what the work actually consists of. When someone loses 15% of their body weight on some maglatide, the question every clinician should be asking is what is the composition of that loss? In the step one body composition substudy, with 140 participants assessed with DEXA, the data show a total fat mass reduction of approximately 8.4 kg and a lean body mass reduction of approximately 5.3 kg. That is a ratio of roughly 1.6 kg of fat lost for every 1 kg lean tissue lost. Or expressed differently, approximately 39% of the total weight lost was lean body mass. Now, here's an important distinction. Lean body mass on a DEXA scan is not the same as skeletal muscle. It also includes total body water, glycogen stores, and the connective tissue that was structurally necessary to support a larger body. When someone loses a large amount of weight rapidly, a significant portion of that lean mass reduction is water and glycogen depletion, not contractile muscle. So these 5.3 kilograms do not represent 5.3 kilograms of functional muscle. However, while the lost skeletal muscle component is smaller, it is not zero. And in patients who are not resistance training, it is clinically meaningful. So the lean mass versus skeletal muscle distinction matters, but it does not eliminate the concern. In a well-managed weight loss program with structured resistance training 3 to 5 times a week, protein intake at least 1.6 grams per kilogram per day, adequate sleep and progressive overload, the target composition of weight loss is roughly 1 part muscle to 3-4 parts fat. Published case series of patients on semaglotite and terzepatite who followed structured resistance training and high protein intake have shown lean mass losses as low as 7% of total weight. And in some cases, lean mass actually increased while fat mass decreased substantially. But without that concurrent effort, without the resistance training, without the protein, the default ratio is materially worse. And for someone in their 40s or 50s who is already losing muscle mass at 3 to 8% per decade, any additional lean tissue loss matters. It is an unnecessary withdrawal from a finite account. There are also specific mechanical harms that can arise from rapid weight loss. And I want to be clear here that these are not the side effects of drugs we're discussing today, these are the consequences of rapid fat loss from any modality, including bariatric surgery and severe caloric restriction. When someone loses a large volume of subcutaneous fat rapidly, the protective fat pad around the fibular head at the knee thins. The common perineal nerve, which wraps around that bony prominence, becomes exposed and vulnerable to compression. The clinical literature calls this slimmer's paralysis, which represents as food drop, an ability to dorsiflex the ankle. There are now published case reports of bilateral perineal neuropathy in patients who happen to be taking semaglitite and terzepatide, and the origin is mechanical, not neurotoxic. It is the rate of the fat loss, not the drug, that causes this nerve injury. A literature review published this year identified 380 cases of perineal nerve paralysis following rapid weight loss across all modalities. Some required surgical decompression, some did not fully recover. Now, I said at the beginning that these drugs work, and I want to be equally clear that they don't have to mean permanent dependence for every patient. In my clinical experience, the most intelligent use of GLP1 GIP agonists for a specific subset of patients is as a bridge, not a destination. Think of it this way: a person who is morbidly obese with BMI 40, 50, 60 plus, is stalled. They cannot exercise meaningfully because their joints cannot tolerate it. They cannot sustain a caloric deficit because the food noise is neurologically overwhelming. They have tried and failed, not once, but repeatedly across years or decades. They're not lazy, but they are rather trapped in a physiological state that their willpower alone cannot override. The GLP1 GIP agonist gets them out of that stall. It suppresses the noise, it reduces the body mass to a point where exercise becomes possible, where joints stop hurting, where the metabolic environment begins to normalize. And during that window, that is where the real work begins. The resistance training, the dietary restructuring, the habit formation, the slow and glamorous process of building the physiological and behavioral infrastructure that will sustain the loss when the drug is eventually reduced or removed. Used this way, the drugs act as a bridge from a condition where change was impossible to a condition where change can be maintained with meaningful but not gargantean effort. But I also want to be honest about this. For many patients, particularly those with severe metabolic dysfunction, these drugs may not be a temporary bridge. They may become long-term or even lifelong therapy. And there is no clinical shame in that. We don't ask the patients on antihypertensives to earn their blood pressure through behavioral grit. We don't frame lifelong statin use as a failure of discipline. If the biology requires pharmacological support to maintain a healthy weight, that is chronic disease management, not dependency. The clinical conversation should accommodate both possibilities, temporary and long term, without moralizing either. The step one extension trial followed 327 participants for one year after semaglotide was discontinued. The treatment phase had produced mean weight loss of 17.3% over 68 weeks. But after stopping, with no active lifestyle intervention support during the follow-up year, participants regained two-thirds of their prior weight loss. So the net weight loss from baseline to week 120 was 5.7%, down from 17.3%. The cardiometabolic improvements, blood pressure lipids, HBA1C, and inflammatory markers reverted towards baseline in parallel with the weight. This is not the failure of the drug. The drug performed as designed during its administration. This is rather a demonstration of the chronicity of the obesity. A disease that does not resolve because you treated it for 68 weeks any more than hypertension resolves because you took an antihypertensor for 68 weeks. But there is something else that the dry relapse data does not reveal to us and what I observe in clinical practice. A crucial psychological dimension. A patient who loses 20 kilograms on semaglotide experiences a profound shift in how they see themselves and how others see them. Their clothes fit differently, their energy levels change, their social interactions change. They build a whole new identity around this new body. And then the drug stops because of cost, side effects, supply shortages, or a clinical decision. And the weight returns. But what some patients are left with is not just the weight returning, but a much deeper question. Was the change actually mine? I want to be careful here because this is where the tension in this topic lives. I've just told you correctly that obesity is a chronic metabolic condition, that the biology drives the relapse, that there is no shame in needing pharmacological support. And now I'm telling you that some patients experience the pharmacologically assisted result as psychologically different from behaviorally earned one. Both of these things are true at the same time. The medicine says one thing, the patient's experience says something that does not fully align with it, and the answer is not to dismiss either. The patient who arrives at weight loss through consistent work, the training log, the dietary discipline, the sleep architecture rebuilt week by week, often reports an internal settlement that I've not seen reliably replicated by pharmacological intervention alone. It is the piece of evidence. Evidence that you did the thing. And when that evidence is absent, some patients experience hollowness they did not anticipate, not because the drug failed, but because the psychological reward of sustained personal effort is a different category of experience from physiological and physical result alone. This is not an argument against the drugs or moralization of obesity. It is a clinical observation about what patients actually report, and it suggests that the prescribing conversation should prepare patients for the psychological dimension of treatment. The honest position is this GLP1 and GIP agonists are powerful, effective pharmacological tools for weight management. For patients with severe obesity who have exhausted behavioral approaches, they can be the intervention that makes change possible when nothing else could, and that is a genuine clinical contribution. But the composition of weight loss matters as much as the magnitude. Yes, lean body mass on a DEXA scan includes water and glycogen, not just the muscle, but the actual skeletal muscle component must be protected through concurrent resistance training, adequate protein intake, and structured recovery. Without that, the default outcome is physiologically costly. The relapse data are unambiguous. Two-thirds of weight regain within one year of stopping. For some patients, lifelong therapy is the appropriate clinical response, and that is chronic disease management, not a lifestyle and willpower failure. And the psychological dimension, the question of ownership of whether the change feels like cures, isn't just a moral judgment on pharmacological treatment. It is a clinical reality that belongs in the conversation well before the first injection, not after the last one. The panacea framing is wrong because it implies that these drugs solve the problem alone. The curse framing is also wrong because it dismisses genuinely effective pharmacology. And the reality sits between the two. These drugs are, depending on the patient, either a bridge or a highway. And in either case, the question is the same what are you building alongside them?