New Developments in Anti-Obesity Medications Show Promise

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Although scientists have long been working on anti-obesity medications, several key failures in recent decades have made this a challenge.

In an interview with Pharmacy Times, Sheldon Litwin, MD, discussed his presentation at the American College of Cardiology 2023 Scientific Session titled “Anti-Obesity Medications: Practical Approaches to Improve Weight Health.” Litwin noted that although scientists have long been working on anti-obesity medications, several key failures in recent decades have made this a challenge. New options, however, seem to be overcoming the problems.

Q: What are the key classes of medications or options?

Sheldon Litwin, MD: New additions to the armamentarium are the ones that have gotten the most attention, and these are medications that are based on what we call incretins. So, incretins are hormones that are secreted from the gut in response to a meal, and they stimulate insulin secretion, which is why they're called incretins. And the one that has been explored the most at this point is something called a GLP-1 agonist, meaning it mimics this hormone called GLP-1, which is glucagon-like peptide-1. And these hormones are naturally occurring hormones, but when given in pharmacologic doses, they have impressive effects on weight. And the mechanisms are not entirely understood. Obviously, as I mentioned, there's effect on insulin secretion. There is a change in gastric emptying, which is slowed. And it's thought that slowing gastric emptying makes people stay more satiated for a longer period of time after eating, and that may decrease appetite. And there's probably other effects, but the most important effect is a central effect in the brain, simply reducing appetite and making people feel less hungry. And so that's how this and other incretin medications seem to work.

There are older classes of medicines, some of which are effective, some of which aren't. The one that I like to use is a combination of 2 drugs called phentermine and topiramate. And these 2 drugs are both also central appetite regulatory agents. And the idea was actually an interesting one. It's based on the notion that we have a lot of pathways in our brain that regulate appetite. We want to eat because it's a survival mechanism. And so, if you don't eat, people don't live. And so, there's things that make us inherently hungry. So, researchers came up with the idea that if we inhibit 1 pathway, it probably doesn't do very much. But if you inhibit 2 different pathways, we might get synergistic effects. And by using low doses of each of the 2 drugs—phentermine and topiramate, that act on different pathways—you can minimize side effects and increase the effectiveness. And the fact is that they work and actually work quite well. And we can get almost as much weight loss with phentermine and topiramate as we can get with the newer, increasing kind of pharmacology.

And the older drugs are much less expensive, relatively widely available, but people have some cardiovascular concerns about them, because phentermine is a mild stimulant. As it turns out, those effects are probably not dangerous from a cardiovascular standpoint, but people still worry about them a lot. And so, the new drugs have proven cardiovascular safety and, actually, cardiovascular benefits probably beyond just the weight loss that occurs. And they're very good diabetes medications, and so the new drugs have gotten sort of more attention, you know, more sort of widespread acceptance.

But there are a number of older classes of medications out there and, you know, maybe we can get to this at the end, but there's a lot of new drugs in development as well, targeting different pathways. And there are some people that really don't eat that much but struggle with weight and have significant obesity. And so, in those patients, a drug that simply suppresses appetite isn't going to help very much if people already aren't eating a lot. And so, we need to find things that alter metabolism. And there are actually a number of drugs that have metabolic effects. They're being called controlled metabolic enhancers, or metabolic accelerators. And these are really interesting compounds. And so, the field is exploding today. And I think there's going to be increasing options and the option of using multiple drugs, so maybe an appetite regulatory drug and a metabolic enhancer together would make all kinds of sense.

Q: Which patients should really be considered for these medications?

Sheldon Litwin, MD: So, I mean, obviously, I think everyone agrees that lifestyle change is the first thing that should be tried. And lifestyle generally refers to what we eat; what, how much, and when people would say is important. And it's not just calories. It's the quality of the food intake, and there are people that believe that the timing of the food intake is very important. So, that time restricted eating, you know, there's some evidence that that may be effective in weight management. And physical activity, which is sort of the calories burned, is clearly important for overall health. The genetic background of the human species hasn't changed in the last 3 decades, but the prevalence of obesity has gone up more than 3-fold. And so, you know, it's not a fundamental biologic change, it's a change in lifestyle that has mediated that, and it's the availability of high-density caloric foods, and people doing less and less physical activity is almost certainly one of the major drivers of this epidemic. So, focusing on lifestyle is important. And even if we use drugs, or even if we use surgical procedures, or some combination of those things, healthy lifestyle is important in the long run, on top of that.

The challenge of lifestyle is that it can be effective in the short term, but it's very hard to maintain weight losses. And so, once people have gotten to a certain level of obesity, the body tends to have this setpoint that wants to take it back to that. And if people lose weight, just by a lifestyle change alone, metabolic rates slow, and there's adaptations that make it harder to maintain that weight loss over the long run. So, 6 to 12 months, people are often successful. Beyond 12 months, it's very difficult to maintain substantial amounts of weight loss. Some people do it but most of the time that doesn't happen. So that's where pharmacology comes in.

So, you know, the bar has moved. I think the ideal body mass index, which may not be the perfect metric of obesity, but it's somewhere around 25, at least in Western cultures; it may be a little bit lower than that in Asian populations. And so, the question is, should anybody with a BMI over 25 have access to a weight loss medication and answers? Maybe. You know, maybe, because there's a lot of people, you know, 30% to 40% of the population, they're overweight, but not frankly obese, in which there's still probably detrimental effects of excess fat. And that's 40% of the population. And then the percent of the population where they have higher levels of obesity, where everybody says, yes, we definitely should use medications or surgery, it's a much smaller group of patients. And so, they're the ones that stand to benefit the most. But in terms of overall population health, if we attack just the overweight or the mild obesity groups, we would probably get a lot of bang for our buck in terms of preventing strokes, heart disease, those sorts of things. So, you know, nobody knows exactly what the right answer is. But for sure, the people that fall into the high obesity categories and those that have diabetes and other obesity-associated conditions stand to benefit from the use of these drugs.

Q: How do you decide when to go from lifestyle changes alone to pharmacologic interventions?

Sheldon Litwin, MD: Yeah, so age, duration, severity, things that have been tried before. You know, the reality is that pretty much every patient or almost every patient I see that’s struggling with obesity, and especially those that have some cardiovascular disease associated with it, have tried lifestyle approaches, and typically multiple times, multiple different ones. And we all know this, and it's most of the time not an issue that people don't care about, it's just that they haven't been effective for whatever reason. And we all know it's hard, it's hard to reduce food intake if you're hungry. And again, when people have maybe been successful in the short term and then regained weight and seen this happen multiple times, people get discouraged. It's hard to maintain the momentum. And, you know, we have busy lives, we sit at computers, we sit at our desks and work and so it's very challenging. So, I would say the majority of the time, the people that I'm talking to have already tried a significant lifestyle approach on multiple occasions and are ready to move on and to try something else. For somebody who has never tried it before, then yes, obviously, we need to counsel strongly about that and say we should try that first. We should give it a good 6 months or more, see if we can make progress and if you can, you know, if you're one of those people that that's able to achieve substantial weight loss and keep it off, great, we're done. You don't need to take more pills or shots or whatever it is that we're talking about. But I think, again, today most people have already made substantial attempts to do things on their own and have not been successful.

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