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Business Standard
21-07-2025
- Health
- Business Standard
The Johnson & Johnson Files: Unhealthy truths and defective hip implants
A tale of defective hip implants exposes India's weak medical oversight - and how multinationals treat Indian patients worse than those in rich countries premium Prosenjit Datta Listen to This Article The Johnson & Johnson Files: The Indian Secrets of a Global Giant by Kaunain Sheriff M. Published by Juggernaut 379 pages ₹599 In 1998, Johnson & Johnson (J&J) — known for everything from band aids to baby powder — took over DePuy for a whopping $3.5 billion dollars. DePuy Inc, a Warsaw-based company, was one of the largest and most respectable names in hip and knee implants in the world. It was the second-largest player in these areas in the US market and had a presence in 23 countries, including India. It was a great buy — within just over a decade, it became
Indian Express
15-07-2025
- Health
- Indian Express
‘After obesity, GLP-1 research focused on Alzheimer's… hypothesis centres on its ability to reduce inflammation in brain… this is different from current approaches'
By Lotte Bjerre Knudsen and Kaunain Sheriff M What is GLP-1? What does it do in the body, and why has it become such a powerful tool in treating diabetes and obesity? GLP-1 is both an incretin hormone and a neurotransmitter. In physiology, it is secreted from the small intestine and from the hindbrain after we eat a meal. It travels to the pancreas, where it helps to regulate our blood sugar by increasing insulin and decreasing glucagon. This is what we call the incretin effect. This effect is blood glucose-dependent, meaning it is only if the blood glucose is elevated that it has an effect here. GLP-1 also impacts centres in the brain associated with control of hunger and satiety, to effectively tell us that we have had enough to eat and need to stop eating. There are receptors that GLP-1 binds to in many organs in the body, and GLP-1 also has beneficial effects in many of these organs, such as the kidney, liver, and cardiovascular system. GLP-1's effects in the pancreas and brain are the important ones to help control blood glucose and body weight. When did the idea first come up that GLP-1 could actually be turned into a drug? Was there a moment, in the lab, or in a conversation, that made you think this could really work? The biology of GLP-1 was always a good one. It might have started with the knowledge around its potential in diabetes — not just through incretin effects, but also involving glucagon and the fact that it's glucose-dependent. Almost at the same time — going back to around 1990 — there was a growing realisation that GLP-1 had significant activity in the brain as well. So, the early thinking around GLP-1's potential in obesity actually emerged around that time. Fast forward a few years, and we also began to understand its effects on the cardiovascular system. The biology was there — and it kept unfolding into more and more interesting areas. But the real challenge in the early years was druggability (the ability of a protein to bind a modulator and produce a desired therapeutic effect). When I started working on GLP-1 in the early 1990s, I actually worked on three projects that failed before landing on the one that finally succeeded. We went through a lot of learning and had three different projects before the one that turned out to work. Eventually, I started looking around — in our environment, in ongoing company efforts — and got this idea around using fatty acids. That approach was being explored in the company, but it was completely unproven at the time. Still, I decided to give it a try. That led to the first molecule we got registered — for the treatment of diabetes in 2009, and for obesity in 2014. From there, we kept refining the approach and developing better molecules. It's been a 25-year journey — translating from lab to clinic, going back to the lab, then forward again — to get where we are today. The big 'hurray' moment came when we finally solved the biggest problem with GLP-1: in its natural form, it's incredibly short-acting — just about two minutes. And now, we've been able to extend that to up to 160 hours. You mentioned that the idea of using fatty acids was unproven at the time but ended up being a breakthrough. Why fatty acids, specifically? What made you think they could solve the druggability challenge with GLP-1? The reason natural GLP-1 is so short-lived is that it is chopped up by metabolic enzymes known as DPP-4 and cleared by the kidneys. The technique we use is called fatty acid acylation. We have pioneered that, but nowadays it is much more widely used. The basic concept is that you attach a fatty acid to your drug molecule, in this case, GLP-1. That will allow the drug to bind to a natural protein called albumin via the fatty acid. Albumin is a protein that plays a crucial role in transporting various substances throughout the body, including fatty acids. By attaching to albumin, you protect the drug from degradation, from being cleared by the kidneys, and ensure that it reaches the GLP-1 receptors that are present in various organs throughout the body. We already had some experience with exploring this fatty-acid acylation technology, and I felt confident that we could also leverage the technology to solve the druggability problem of GLP-1. Extending GLP-1 activity from just two minutes to up to 160 hours is a huge leap — what does that mean in terms of how the drug works in the body and its impact on patients? A lot of things need to happen after we eat. Something needs to happen in our pancreas to help regulate blood sugar, something needs to happen in our brain to tell us to stop eating, and so on. GLP-1 plays an important role in that, although it is not the only hormone involved in those processes. But in physiology, GLP-1 works for just a few minutes, so after you eat a meal and GLP-1 is secreted naturally, it gives an immediate effect that lasts maybe 30 minutes. By creating a GLP-1 analogue that works for 24 hours a day, whether it is given once daily or once weekly, we ensure that there is a sustained effect. So, if you have type 2 diabetes, it helps you to regulate your blood sugar 24 hours a day. If you have obesity, it helps you to control your hunger and what you eat throughout the day. If you are at risk of cardiovascular disease, it consistently helps dampen inflammation, and lowers blood pressure and some blood lipids. And these diseases often overlap, so for many people several of the effects of GLP-1 will be beneficial. What were some of the toughest moments of the 25-year journey? Was there a day, a result, or a conversation when it really hit you — that you'd done it? Not really — because there was always a way forward. When you make medicines, it takes time. You have to solve a lot of problems. There are multiple tasks: there's the invention, there's the specific molecule, then you have to figure out how to manufacture it, how to design a clinical program, a toxicology program. You might encounter unexpected issues, and you have to solve them. So, I don't recall [any] single day where I thought, 'oh my God, we've done it'. Of course, the process comes with a lot of challenges, but that's just how it is when you're making medicines — especially when you're proposing something entirely new. Naturally, there are going to be even more hurdles. We were the first ones to solve the druggability problem for GLP-1. We were the first to have it approved for obesity in 2014 — at a time when no one else was working on that. We were also the first to apply for a cardiovascular indication for GLP-1 in 2016, and we are still the only ones to have conducted a kidney outcome trial. We were the first to explore liver outcomes, and we're currently the only ones testing GLP-1 in Alzheimer's disease. Semaglutide was designed for type 2 diabetes, but it ended up transforming weight loss treatments too — something few people saw coming. When did that shift begin for you? Actually, that's not true in our case, though it may be true for other companies. We developed it for both diabetes and obesity at the same time. We conducted our first clinical trial with weight loss as the primary endpoint back in 2001. Because we had that dual focus, we ended up learning that you actually get more weight loss in people without diabetes. In fact, you get about twice as much weight loss in people without diabetes compared to those with diabetes. And if we hadn't done that, I don't think GLP-1 would have ever been developed for obesity. If people had only looked at the diabetes clinical trials, they would've seen weight loss of just 2–3 kilograms — which isn't all that compelling. It's helpful, of course, especially compared to weight gain, but it's nowhere near enough to get approval for the treatment of obesity. So it's not true that semaglutide was developed primarily for diabetes. It is true that it was first approved for diabetes, but the obesity trials followed just a few years behind. And because of that early focus — and the 20 years we've spent talking with physicians about obesity — we were in a position to design the SELECT trial as far back as 2015. That was when we started recognizing the independent effects of GLP-1 on inflammation, which is a key mechanism in cardiovascular disease. This trial is truly a landmark. No one had ever shown that pharmacologically induced weight loss could also deliver a cardiovascular benefit — and that has only been demonstrated with semaglutide. Why is this a landmark? It is a landmark because it was completely novel. It's also a landmark because it has changed the way we view the treatment of obesity. It's not just about weight loss — it's about cardiovascular benefits. The fact that fewer people are actually dying, fewer people are having heart attacks, and fewer people are experiencing strokes makes a profound difference. It has also changed the perception of the disease itself. Now we know that you can not only lower a person's body weight, but you can do it in a way that is fundamentally different from what we had before — where many older obesity medications actually increased cardiovascular risk or carried psychiatric or suicidal side effects. That's why it's a landmark trial. The emergence of GLP-1 has shown that the brain and gut are intertwined. In fact, we hear that 'the gut is the new brain'. Your thoughts? I would phrase it a bit differently, because I'm a pharmacologist. People often talk about the gut-brain axis, and I see that more as a physiological concept. For me, GLP-1 has effects on many different organs. In physiology, GLP-1 is secreted from the gut or the hindbrain. In that context, you see small peaks in GLP-1. What we do in pharmacology is create steady-state, high levels of GLP-1 — and that affects various organs. It works on the pancreas to treat diabetes; it acts on the brain to help people feel more satiated, less hungry, and change how they eat; it works on the gut to reduce inflammation; it also has effects on the heart, kidneys, and other areas of the brain. So, I see it more as a multi-organ effect — not just a gut–brain connection. We now understand how it impacts various organs in healthy, beneficial ways. Where does the GLP-1 research go from here? Especially with respect to Alzheimer's? With GLP-1, the current focus is on Alzheimer's disease. Our realisation, after thinking about this for quite some years, was that we needed to conduct large trials in order to prove whether it actually works. That's what we're doing now, and we should have those results in the second half of this year. Until then, it's really difficult to say anything definitive because doing trials in Alzheimer's disease is extremely challenging. There has been very little progress for decades, so this is a completely new concept in Alzheimer's research. We have to be patient for a little longer to see if it actually works. Our hypothesis centres around some of the other effects GLP-1 has on the brain, particularly its ability to reduce inflammation. That's a mechanism that hasn't been fully explored in Alzheimer's. It's very different from the traditional approaches of targeting amyloid (proteins that form plaques in the brain and affect neuron function and lead to cognitive decline) and tau (protein that disrupts the neuron's internal transport system and impacts communication between cells). What we're doing is exploring the metabolic impact of GLP-1 in people with Alzheimer's. What is the scientific hypothesis behind GLP-1's role in brain diseases? How might it actually be working in the brain? The central hypothesis is inflammation in the brain. Inflammation is one of the earliest processes involved in many diseases. At the tissue level, things begin to change, triggered by different pathological stimuli — whether from genetics, the environment, or other factors. It's often one of the first signs that cells are sensing something is wrong. You see similar patterns in other conditions. In diabetes, for example, the pancreas doesn't function properly. In people with obesity, certain neurons become imbalanced, which can affect behaviour, like eating more or making less healthy food choices. In neurological diseases, inflammation in brain cells leads to imbalances in how those cells function. That's where GLP-1 comes in. The idea is to see whether GLP-1 can help correct that imbalance. It acts on many different pathways, and we know there are GLP-1 receptors throughout the brain. These receptors — which are the molecular targets GLP-1 binds to — give us a way to influence brain function at a cellular level. At this juncture, what do we know — and don't know — about the long-term side effects of GLP-1 treatments? It is important to say that there can be side effects with all medicines. This is prescription-only medicine, and the decision to start using a prescription medicine should always be made in close consultation with your doctor. For all GLP-1 receptor agonists, the most common adverse events are gastrointestinal, and usually mild to moderate and transient in nature. But GLP-1 is a very well-described class of medicine. GLP-1 medicines have been used to treat type 2 diabetes for about 20 years, and for the treatment of obesity for about 10 years. Our first GLP-1 receptor agonist for type 2 diabetes was launched 15 years ago. Semaglutide has been studied in robust clinical development programs where more than 52,000 people have received it, and millions of people have used these products in the real world. Lotte Bjerre Knudsen is Chief Scientific Adviser for Research at Danish pharma giant Novo Nordisk, and the driving force behind the company's research and development in the GLP-1 receptor agonist space for more than 30 years. Kaunain Sheriff M is National Health Editor at The Indian Express
