Ozempic, Wegovy, Mounjaro – three new medications used to treat obesity – seemed to be all over the news and social media in 2023. You’ve likely seen or read about their effectiveness, their side effects, their cost and what happens when you quit taking them. But as we grapple with the increasing epidemic of obesity and its complementary health issues, researchers at Wake Forest University School of Medicine are looking to an older, generic drug for answers.
First approved by the Food and Drug Administration in 1959, phentermine is one of the most commonly prescribed medications to treat obesity; however, it was originally approved for short-term use (up to 12 weeks) only. There are few studies on its long-term effects and safety. Kristina Henderson Lewis, MD, MPH, SM, and Jamy Ard, MD, are changing that with the Long-term Effectiveness of the Anti-obesity Medication Phentermine (LEAP) trial.
“Obesity is a chronic disease, and we’re starting to recognize that much like diabetes and hypertension, many people will need medication to treat it,” says Lewis, associate professor of epidemiology and prevention, implementation science and weight management. “And probably that medication is going to have to be given long term for many of them, just like with high blood pressure. Treating obesity, we need a similar approach.
“Forty percent of US adults – people from across all walks of life, all age groups, races, genders – are now impacted by obesity,” she says.
|“We’ve been dealing with this obesity epidemic now for 30 years, and we’ve always been on the search for better treatments that get more response across a broader population. We’ve seen the evolution of those treatments and now we’re just breaking down that next barrier.”
- Jamy Ard, MD, professor of weight management.
And while the newer medications, such as Ozempic, are very effective, they have two barriers that are critical when considering a disease that impacts almost half of the US population: availability and cost. Phentermine, on the other hand, is available in generic form, which means it is widely available and inexpensive.
“If we’re going to treat everyone who wants to be treated, regardless of whether they can afford a really expensive out-of-pocket medication, we need to know phentermine is a safe option and if it’s effective long term,” Lewis says.
“It’s about access and equity,” says Ard, professor of epidemiology and prevention and weight management and vice dean for clinical research. “If a drug is super-effective but only 3% of the population can afford it or the health system can’t bear the cost of coverage for many people who need it, we need to look at alternatives.”
In addition to the effectiveness, or how much weight is lost, another important question for LEAP is the long-term safety of phentermine. In theory, it could increase a person’s blood pressure because it works in part by increasing levels of norepinephrine. However preliminary research led by Drs. Lewis and Ard, using electronic health records, shows that the longer-term use of phentermine is actually associated with decreases, not increases, in blood pressure. This is likely because patients taking the medicine long term are able to sustain weight loss, which is known to lower blood pressure. LEAP’s researchers are seeking a more concrete answer about what actually happens to blood pressure for patients taking this medication long term.
Other health outcomes being measured by LEAP include lipid levels, blood sugar levels and waist circumference. Heart disease and diabetes rates have increased alongside obesity rates, so if phentermine can help with weight loss, will it also help reduce comorbidities?
Accurate Representation by Design
The LEAP trial will enroll 900 people across five clinical sites and follow them for two years, taking care to actively recruit a cohort that represents “typical” patient populations. During the double-blind study, participants are randomized to receive either phentermine or a placebo, receive an online membership to WW (formerly Weight Watchers) and have regular clinic visits with a health care practitioner trained in treating obesity. Working with Nick Pajewski, PhD, associate professor of biostatistics and data science and principal investigator of the data coordinating center for LEAP, Ard says they should finish recruiting by the end of September.
To ensure accurate patient representation, Lewis says, the inclusion criteria for participants was purposefully kept very broad – for example, ages 18 to 70, body mass index between 27 and 44.9 – and including people who have diabetes or hypertension. (Although people with conditions such as heart disease or stroke are excluded.)
“When I was trained in medical school and residency, we really didn’t get a lot of instruction on how to help patients with weight loss. But obesity is a medical condition that’s driven by physiology, and we need to treat it as a disease and stop sending the message that it’s a personal failure or that it’s the patient’s fault if they find dietary changes impossible to implement or sustain.”
- Kristina Henderson Lewis, MD, associate professor of epidemiology and prevention.
And the team was very intentional when creating recruitment strategies to ensure diversity. For example, Ard says the targeted enlistment of underrepresented groups is around 30%, and they want about 25% of participants to be men, who typically do not participant in weight loss studies. Fortunately, Lewis says, there’s a long list of people signing up to participate in LEAP.
“People are voting with their feet. They want medical treatment for obesity,” she says. “The rate-limiting step at this point is having enough resources to fund the research staff so we could do these studies more efficiently, such as taking five months to recruit 1,000 people instead of 24 months.”
Both Lewis and Ard expressed appreciation for the LEAP participants and their willingness to give two years of their lives to the study. Having regular clinic visits, taking medication and sharing large amounts of information is a huge commitment and shows the need and the desire for more effective obesity treatment options.
“We’ve been dealing with this obesity epidemic now for 30 years, and we’ve always been on the search for better treatments that get more response across a broader population,” Ard says. “We’ve seen the evolution of those treatments and now we’re just breaking down that next barrier.”
Changing Mindset and Improving Options
Along with the evolution of how we treat obesity, Lewis and Ard discussed the need to evolve how we think about it.
“When I was trained in medical school and residency, we really didn’t get a lot of instruction on how to help patients with weight loss,” Lewis says. “It was sort of like, ‘They need to eat less and move more’ and making it all about behaviors. But obesity is a medical condition that’s driven by physiology, and we need to treat it as a disease and stop sending the message that it’s a personal failure or that it’s the patient’s fault if they find dietary changes impossible to implement or sustain.”
By doctors treating obesity like they would diabetes or hypertension, patients are having better outcomes. That, in turn, helps physicians and patients realize it isn’t about a personal failing or willpower. It’s about pathways in the brain, the “conversation between the gut and the brain” that makes it so difficult to lose weight and keep it off long-term with lifestyle change alone.
Ard, who has worked in weight management and obesity treatment for over 25 years, thinks the shift is overdue.
“A lot of perspective about weight gain is sort of baked into our broader culture and internalized,” says Ard. “How we think about the causes of obesity and the responsibility to deal with it is foisted on the individual, and we assign virtue based on this perception that they are able to resist temptation.”
Ard also sees the conversation starting to shift from simply losing weight to the quality of weight loss and the health benefits that accrue.
“Instead of focusing on eating smaller portions, since that is going to be taken care of by the medication, we could make sure the quality of what’s being eaten is ideal to get the best outcome in terms of maintaining lean mass, physical function and how you feel,” he says.
Findings from LEAP could help shape that conversation and pave the way for future studies. For example, if LEAP shows benefit from prescribing phentermine and it is safe, how does it compare to other anti-obesity medications? Does it become an affordable first-line treatment, much like metformin for diabetes? If so, at what point do you move a patient to the next treatment option?
Nick Pajewski, PhD, associate professor of biostatistics and data science, is the principal investigator of the data coordinating center for LEAP.
Both Lewis and Ard have ideas for what might come next, but first, they need to finish recruiting and enrolling participants for LEAP then collect two years’ worth of follow-up data. LEAP’s data coordinating center, led by Pajewski, will then pull together information collected across all participating sites and analyze the trial’s results.
“We’re trying to answer a lot of really big questions,” Lewis says. “So we’ve had to innovate and be efficient with how we use the funding. What we’re learning about methods of recruitment and collecting data with this study will pay forward into other clinical trials in our health care system.”