Dr Ambrish Mithal decodes Ozempic and other GLP-1 drugs, with Raj Ganpath

The Hindu

18-07-2025

If you've ever tried to lose weight, cutting calories and spending long hours in the gym, this thought must have occurred to you: 'I wish there were a pill I could pop and take care of it.' Turns out that there may be a possibility, going by the host of GLP-1 drugs, including Ozempic, Wegovy, and Rybelsus, that have flooded the market. What is also clear, however, is that while these drugs may be an effective tool for some people, old-school lifestyle choices, exercise, nutrition, stress management, and sleep cannot be ignored.
Fitness and nutrition coach, Raj Ganpath, co-founder of The Quad, talks to endocrinologist Dr Ambrish Mithal, the author of the recently-released book, The Weight Loss Revolution, to decode what these drugs are, who should or should no be taking them and why this does not mean you stop working out and eating well.
Edited extracts of an interview
Raj Ganpath (RG): Thank you for writing the book, the first book on weight loss drugs and how to use them in India. So, my first question to you is, what is the problem with weight loss today, and why do you think the existing solutions — exercise, nutrition, and lifestyle changes — don't work?
Dr Ambrish Mithal (AM): The first is that we have to understand why there is a sort of epidemic of obesity: weight loss is a problem because there is too much weight gain these days. And that, of course, is dependent on the environment we grow up in, as well as our habits, which are very different from those of the generation before us. I think the environment encourages unhealthy eating and easy quick fixes, and that's why the prevalence of obesity is going up.
The second part, of course, is that we have always been trained, even as endocrinologists, to think of obesity as basically because someone is eating too much and not exercising. That is still true to some extent, but the difference is understanding that obesity is a brain disease. Some people genuinely have excessive food cravings that they cannot control, and it's not right to blame them for that; sometimes they need assistance.
Going further, it appears that a significant component of obesity or excess weight is caused by the way our brain is wired, suggesting that we need to address this aspect.
RG: Obesity is considered an aesthetic problem for most people. But you're talking about this more as a disease. You've explained this again in the book (that) obesity is now referred to as ABCD, which stands for adiposity-based chronic disease. The existing solutions of lifestyle changes (eat less, move more, be mindful about what you're eating) work for some people, you would agree. But it doesn't work for a significant number of people. So, what do you think is the difference in approach?
Dr AM: Unfortunately, that is still not understood. Who are the people who require this help, at a very micro level, it's not understood, and that's a real active area of research right now. The issue here is that whenever that happens, you choose very crude conservative criteria.
For example, it's understood that if someone's body mass index is over 30 (regardless of its drawbacks, the BMI remains the most widely used tool), you probably require pharmacological assistance to lose weight. And then if you are thinking of obesity as a disease, which it is or ABCD, as you very correctly said, then if you have disease manifestations associated with obesity, like diabetes, hypertension, or fatty liver, then maybe even at a BMI of 27, you may require this medication.
But we have not cracked that code yet, so we are falling back on conventional BMIs and the existence of co-morbidities, as everyone has got used to that during COVID as defining factors to decide who requires this or not. In addition, the commitment of the patient to their lifestyle has to be very solid. And because these drugs actually result in positive changes, which that same person was unable to achieve despite the years of effort, that motivates people a lot into lifestyle. So it's a combination.
RG: Another very interesting point that you mentioned in the book is that there is a big difference between weight loss and weight gain. There are people who repeatedly lose and gain weight, and they believe they're losing and gaining the same weight over and over again. But you make a very interesting point that when you lose weight, you lose fat and muscle, but when you gain the weight back, you gain mostly fat. So, as a result, if you are someone who loses weight and gains weight over and over again, over a period of time, even if your body weight remains the same, your body composition changes. How does that affect someone from a metabolic and health perspective?
Dr AM: The point you mentioned is something that really bothers me in clinical practice with people who go through like numerous diets and plans and then keep putting it back on. That also bothers me with the drugs because if you take the drug intermittently, drop it, take it for some time and drop it, exactly what you said happens. So I think that is a very important point. If you lose muscle by such yo-yo dieting or weight management programs, you will be more prone to falls and fractures. Connected with that is the fact that it impacts osteoporosis; if muscles are weak, bones also become weak because they're not getting that stimulus right.
Much more interesting is the fact that muscles play an important role in our insulin glucose metabolism. If you lose muscle mass, it's almost the same thing as putting on fat. Skeletal muscles are very important in controlling insulin, and if you have poor skeletal muscle mass, your insulin resistance will increase and therefore your chances of all the metabolic complications or worsening of those complications like diabetes, like again, fatty liver will increase.
So it's not just about fat or about weight. It's also about losing muscle whenever you go on crash diet programs.
RG: There is a difference between weight loss and weight management. Data tells us that less than 10% of people are able to retain their results for more than a couple of years. How do GLP-1 drugs help, in this regard?
Dr AM: I'm so glad that as a fitness expert and coach, you brought up this point. This is something we are struggling with because of all the social media noise.
I think what happened in weight management was that we had lifestyle changes, which we've been harping on for 40 years, and then they had bariatric surgery for the severely obese. There was a huge gap between. Now that gap has been actually filled in. That bridge has been built between lifestyle and surgery, and that actually is a long bridge because a huge number of people fall into it. That is where GLP drugs fit in. They help us lose anywhere between 10% and 20%, or even 22%, of our baseline weight, and they have completely changed the game. This is just the beginning of the explosion of GLP 1, and you'll see fascinating progress in this as the years pass.
RG: Glucagon-like peptide one (GLP-1) drugs is becoming a big word now. What are these drugs? What do they do? Can you help us understand the science behind it a little bit?
Dr AM: GLP-1 is a hormone that is secreted from our gut. When we eat something, there's a secretion of GLP-1 1, and it has multiple actions that have been discovered. But it has three primary actions. One action is on the pancreas to stimulate insulin secretion to help metabolise your food. At the same time, it suppresses the anti-insulin hormone, which is glucagon. That is the primary action of GLP one.
The second action is that they slow down gastric emptying and stomach movement. And the third action, which was only recently understood and emphasised, is that the same GLP one travels to the brain, and it tells you to stop eating, controls your satiety. GLP 1 drugs act through the same pathway, the same receptor where the GLP 1 binds. So you have a different molecule binding to the same receptor. With molecular engineering, you keep modifying the molecule to make it more effective.
The first GLP one we used was in 2005, so it's 20 years of experience with this molecule. In 2015-16, they were able to crack the code on how the brain's action on appetite and satiety is more pronounced. That really crossed the threshold, and that's what made big news. For the first time, we had a drug that could cause 15% weight loss, which was unheard of. The predecessors, which we have used liberally over the years, caused 4 or 5% the same story.
RG: It feels like this is such an easy way out, and there's no price to pay. But there are side effects. So what are these?
Dr AM: So there's no molecule, no drug discovered, that didn't have side effects. So let's talk of the short term side effects, which many people or most people actually face is gut related side effects, the most common amongst them being nausea, rarely vomiting but nausea. So that's one. You can get severe constipation, significant episodes of diarrhoea or upper abdominal bloating because of gastric slowing slowing of the stomach movement.
The good news is that they are managed by the normal medicines, and they usually go away in most patients in a few weeks. Also, some people feel drained out or complain about a change in their relationship with food, saying that they don't enjoy it anymore.
More significant side effects could be very, very rare pancreatitis, an exceedingly rare thing, not yet firmly established with these drugs. But there is a suspicion that they increase pancreatitis.
The other thing you read, which can certainly put people off, is thyroid cancer. That cancer is very rare, and there's no evidence in humans at the moment to say that that cancer is increased. Again, if there's no family history of thyroid cancer and there's no history of medullary thyroid cancer, you can be very relaxed about that.
The third is the muscle loss. The important point about muscle loss is that it is not a drug side effect. Muscle loss is a part of weight loss. Roughly 20% of the weight that we lose will be muscle. The last, but important one is a very rare, unproven report of some eye related problems which are being researched thoroughly.
RG: In your book, you said there are people who microdose on this. How does that work?
Dr AM: This is the US phenomenon when there was a shortage, and so other companies were allowed to make the drug. Then this phenomenon really picked up. And then people started controlling this, saying, 'It's my body. I know best, you know, so I'll just adjust the dose.'
Microdosing, I suspect, will not be harmful unless it's done totally randomly. But I don't know how much of a benefit it offers. Apparently, there are clinics in the West that do these kinds of things, but I would not recommend them at this stage.
RG: There are also positive side effects of this medicine, right?
Dr AM: Research-wise, this is the most fascinating area. Drugs originally discovered for diabetes were found to have profound weight loss effects to the extent that they became weight loss drugs. Because of that, they also have other effects that clearly reduce cardiovascular events; what we call heart-related complications, go down in people who take these drugs. Diabetes patients, who are at high risk for these complications, are significantly benefiting.
Also, the progression of kidney failure clearly goes down, and the need for dialysis and transplant goes down in people who are treated with these drugs. (There is also) Amazing data on the liver, the squeezing out of fat from the liver. What is most fascinating is the impact on the brain. Some of the data in Alzheimer's is absolutely amazing. Even in Parkinson's, there is some data, but we don't have the final clinical trials yet to say yes, they work. It's being tried to reduce alcoholism. They found that it works in some people, and they develop an aversion to alcohol. Those are the happy side effects that are being reported.