Expert: Following Decades of Challenges, Anti-Obesity Drugs Have Leapt Forward in Recent Years

In an interview with Pharmacy Times, Sheldon Litwin, MD, a cardiologist at the Medical University of South Carolina, discussed the significant recent advances in anti-obesity drugs.

Q:Do you have any insights into why anti-obesity medications seem to have leapt forward in recent years, particularly with regard to efficacy? What are the key developments to make them so effective?

Sheldon Litwin, MD: So, people have been trying to make weight loss drugs for a long time. I mean, for 100 years or more, you go back and there's historical things. And the early drugs weren't very effective. Many of them had ill effects. And so that was a big burden on the field for a long time. And it's I think it was just partly bad luck, but multiple drugs that were meant for weight loss had to be withdrawn from the market because of some kind of adverse effects, and several of them were cardiovascular effects. And as it turns out, they were all different.

So, there was the Fen-Phen debacle that happened in the 80s and 90s, and millions of patients were prescribed this off-label combination of phentermine and fenfluramine. And the reason so many people got it is because it worked. It was effective. But it turned out that fenfluramine, which was a serotonin agonist could cause pulmonary hypertension or heart valve disease in a small percentage of patients. But, of those millions of patients, it turned out to be a, you know, a reasonable number. So, fenfluramine got taken off the market. Phentermine is still there—it’s actually the oldest weight loss drug that we have. It’s been prescribed for more than 50 years, has a very long track record, and is safe, but people still equate that with the problems that happen when they took phentermine and fenfluramine together.

And then there was a drug called sibutramine, which was also a centrally acting, worked on the adrenergic nervous system, supposed to be appetite suppressant—wasn’t that great, but it caused high blood pressure, and got taken off the market because of effects related to that. And then there was a drug called rimonabant, which was an endocannabinoid receptor antagonist. So, cannabinoids are the active ingredient in marijuana. And it’s pretty well-known that when people use marijuana it stimulates appetite makes them hungry. People get the munchies. And we actually use marinol as a drug to stimulate appetite in people who are underweight and don’t want to eat. And so, they thought, well, if we block that receptor, that would be good. If that’s the thing that makes you hungry, you block it, it takes away appetite. And it turns out that it was associated with increased suicidality. So, cannabinoids not only make people hungry, they make them feel good. And when you inhibit that receptor, then we cause depression and other effects. So, that drug got taken off the market. And then there was another one more recently where there was a small increase in cancer. So, there’s four different weight loss drugs in the last 20 years that got withdrawn from the market because of some ill effect. And they were all different, but it led a lot of healthcare providers to believe that all weight loss drugs were dangerous, and that we shouldn’t use them. So that was part of the inhibition in the field.

The other real change is that there's been weight stigma that's been there for a very long time. And there's the perception that that people that struggle with obesity simply lack willpower and don't have the personal qualities needed to stick to a good diet or to exercise regularly, to have high levels of physical activity, and this was a personal failure. And there's been a push for many years—multiple societies, the American Heart Association, the American Medical Association, the Diabetes Association, all of which have said, obesity is a disease. It's not it's not a personal failure. But that perception hasn't really permeated until now. And so they're sort of the two things that held the field back—or three I guess. One is that the drugs weren't that great. Two, the perception that they are unsafe, and then three, the notion that it was cheating and that, you know, we shouldn't do that, that people should just suck it up and work harder on their diet and their exercise. and that would be good enough.

So, I think, sort of, we have more effective drugs. We have drugs that now we know are safe. We have big companies, pushing hard marketing them, which is a change. So, most of the companies making weight loss drugs in the past were small companies, didn’t have deep pockets, didn't have the marketing or the outreach ability. And now we've got them. And so, I think there's a number of things that have changed and now they've all coalesced sort of at the same time, and now there's this explosion of public awareness and desire to use these medications.

Q:Many of these treatments do have some adverse effects. What are pharmacists’ roles in educating patients and helping to manage these?

Sheldon Litwin, MD: So, I think everybody has a role here and it's going to be the pharmacist, the dietitians, the providers. You know, I’m a cardiologist and my cardiology colleagues have been very, very reluctant to jump into this field, and say, it’s not something I want to deal with. somebody else needs to prescribe these medicines—it’s primary care, it's endocrinology, it's someone else's problem, it's not mine. But it's really all of ours. And so, pharmacists are managing all sorts of medications. These days, they're managing anticoagulants, managing insulin, managing lots and lots of drugs. And often sort of, they have more time or patient comes in to refill their medications and says, Hey, I'm feeling this, I'm having this side effect, I'm having this problem. And so, I think they can have a very big role in helping people to understand the dose escalations that are required with the new drugs, and the things that we can do to help overcome the side effects.

So, the big side effects of the increasing base therapies are nausea, and other GI side effects. Some people get vomiting, some people get diarrhea or constipation from them. And most of these are overcome-able with slow increases in dose and with altering the food intake, especially in the day or two, after people take their dosing. There are other anti-nausea medicines and things that are sometimes used for people who can't tolerate it otherwise. So, I think there's potentially a very big role for pharmacists in helping get appropriate patients on the meds and then sort of fighting through the dose escalation that has to occur.

Q:The American Academy of Pediatrics recently released new guidelines for childhood obesity, which have gotten a lot of attention. In particular, many critics have raised concerns about the use of anti-obesity medications in children as young as 12. Can you respond to this?

Sheldon Litwin, MD: So, the data in children and adolescents is relatively new. We know the drugs work in young people. We know that obesity today starts younger and younger. Sort of the fastest growing segment of the population with increasing obesity is children. And people's weight at age 18, or 20, or whatever you look at, is highly predictive of what's going to happen subsequently. And we also know that heart disease starts to develop in young people. So, data going back to the Korean War showed that young men or soldiers who died in combat who had autopsies had evidence of atherosclerotic streaks in their aorta, you know, around the time that they're going to the army, which was like age 18 back then. And today, there's abundant evidence that now those changes are starting much, much earlier. And so, atherosclerosis is a disease that typically develops over 20, 30, 40 years. And, if it's starting in 10-year-olds, instead of 20-year-olds or 30-year-olds, then it's going to manifest itself sooner. Today, there are children with diabetes, there are children with non-alcoholic fatty liver disease, there are children with hypertension, with all these things that we never had in kids before. And it's almost entirely driven by obesity and physical inactivity.

So, you know, is it right to use these kind of high potency drugs in kids? And the answer is probably—at least in selected people. And of course, we have to think long and hard about risks and benefits in young people. And yet, the risks seem really to be very low. I mean, we haven't had these drugs—we’ve only been using them really for 5 to 10 years, and the high potency ones probably about 5 years or so. So, we don't know what happens if 20 years, 30 years of usage, and whether there's some risk associated with that, but they seem to be quite safe in general. And again, the incretin drugs are for analogues of naturally occurring hormones. It's not really something exogenous, it's just giving you a pharmacologic type of effect as opposed to a physiologic dose. So, much higher levels than what we would get on our own. But I mean, it makes sense that treating something earlier, rather than waiting until people have diabetes or starting to have the ravages of diabetes, which mostly aren’t reversible, that it would be better to tackle these things early on.

Q:Is there anything you want to add?

Sheldon Litwin, MD: No, I think the important things to me are that at least, in my field, to get cardiologists feeling that this is our problem, that we need to deal with it, we need to address it. And at least up until now, the other either weight loss medications, diabetes medications, the percent that are prescribed by cardiologists is very, very small. Even though the vast majority of people we see, and a huge proportion of the heart disease that we deal with, is caused by the effects of diabetes. So, I think everyone needs to become comfortable with these drugs, we need to figure out what the role is.

You know, the other big issue with the new drugs is the cost. And they’re very, very expensive drugs. I don't know if they have to be or not, but they are. And when we're prescribing them for diabetes, they're usually covered by insurance, although there may be a higher copay. But if we're giving them just for weight loss in patients that don't have diabetes, at this point in time, most insurance plans and most federal plans like Medicare are not covering the cost of the medicines. And they're retailing for about $1,300 a month or $16,000 a year, which is not affordable for most of my patients. So, access is still a big issue.

And then there's been lots of public press about Hollywood stars, people that want lose 5 pounds before their wedding, or their prom, or whatever, trying to get these drugs, and people that really don't have significant obesity wanting to use them for more cosmetic type of effects. And then there's been shortages of both semaglutide and tirzepatide due to manufacturing issues and also due to the high demand for the drugs, and so some people that have diabetes that really could benefit from these drugs have had a hard time getting them because they've been in short supply. Hopefully, that piece will be ending soon. But I'm not sure that the cost problems are going to go away in the immediate future, unless something else changes