Primary Care, Study Up on Older Weight Loss Meds

The rise of glucagon-like peptide 1 (GLP-1) receptor agonists for weight loss has encouraged many patients of Sriram Machineni, MBBS, to try medication for obesity. But not quite in the way they might expect.

“Patients come through the door asking for a GLP-1, and when they’re told that they wouldn’t be eligible for a GLP-1 with their insurance, then they’re willing to use other therapies,” said Machineni, director of the Fleischer Institute Medical Weight Center at Montefiore Medical Center and Einstein College of Medicine, in New York City, who has specialized in obesity treatment for over a decade.

The explosion of interest in GLP-1s may be leading some patients and clinicians to consider older medications for weight loss that are more affordable and accessible. While the older drugs may not cause weight loss as quickly or dramatically as GLP-1s, they can still be effective in reducing excess body weight.

Non–GLP-1 medications include different combinations of phentermine, bupropion-naltrexone, topiramate, and metformin. Phentermine can be prescribed on its own or with topiramate. Bupropion and naltrexone can also be prescribed off-label as two separate scripts or as the single medication Contrave. Metformin is also prescribed off-label.

A recent study in JAMA Network Open found prescriptions for medications to treat obesity dispensed by retail pharmacies increased from 800,000 in June 2018 to 1.5 million in February 2024. At the beginning and end of the study period, phentermine kept its place as the most dispensed drug for obesity, going from 648,000 to 740,000 monthly prescriptions by February 2024.

Prescriptions for Wegovy, the second most commonly prescribed drug in the study, jumped nearly fivefold in 2023, but phentermine remained at the top by nearly 250,000 prescriptions. The data only included brand names and did not include generic or compounded versions.

“A GLP-1 isn’t the answer for everybody,” Sarah Ro, MD, medical director of the University of North Carolina Physicians Network Weight Management Program in Chapel Hill, North Carolina, said. “We need to incorporate effective use of these oral agents first.”

Older agents are also important for people who start a GLP-1 but then their insurance stops coverage, said Jamie Kane, MD, an internal medicine physician, chief of the Section of Obesity Medicine at Northwell Health, and chief medical officer at Luro Health, which works with community health centers to provide weight management programs.

“Sometimes the patient gets disappointed and thinks, ‘Well, that’s it. I give up,’” Kane said. “The reality is there’s intensive behavioral therapy and older generations of medications that still function well.”

Even if the statistical weight loss is lower than with GLP-1s, combining these drugs with intensive behavioral therapy yields “pretty good results,” Kane said. A loss of around 10% of body weight is a reasonable result. Engaging in intensive behavioral therapy often results in far greater losses, he said.

But many primary care providers do not feel comfortable prescribing these older agents, Machineni said. The gaps in obesity management within primary care need to change, Kane said.

“There aren’t enough obesity specialists to take care of the public health failure surrounding obesity, so primary care doctors need to get more comfortable managing this as a complex and chronic disease,” he said.

Several 2- and 3-day courses on obesity medicine exist specifically for primary care physicians (PCPs). These courses provide training not only on obesity medications — GLP-1s and older agents — but also on the pathophysiology of obesity, the value of different drug combinations, and incorporating behavioral interventions into treatment plans. And often PCPs are familiar with the older drugs.

“All of these agents are medications that primary care providers use for other conditions anyway, apart from phentermine,” Machineni said. “These are medications that have been around for a long time.”

The biggest difference in using these older therapies for obesity is that clinicians often prescribe them off-label.

“But off-label therapy is very common in other disease states, so there’s no reason why obesity should be different,” Machineni said.

Obesity causes, contributes to, or worsens more than 200 other diseases.

“We really have to provide patients care, whether we can give them the best and latest drug or not,” Machineni said. “Treatment of obesity should be treated just like treatment of diabetes or high blood pressure in primary care. We don’t turn them away because we don’t have options or we’re not comfortable with using the drug.”

Older Medications for Treating Obesity

Kane said about 25% of his patients are not taking any medications for obesity, with his remaining patient population split between GLP-1s and the older medications, though some patients take both.

Metformin, for instance, although most often prescribed for type 2 diabetes, results in modest weight loss for some patients and can complement the other drugs. Clinicians familiar with the full armamentarium of obesity medications tend to mix and match them based on patients’ individual needs.

“It tends to be about matching the potential side effects with the beneficial effects and other comorbid conditions they have or other medications they’re already on,” Kane said.

For example, “phentermine and bupropion-naltrexone both can have a very activating response,” he said. “You feel energized, but if someone has arrhythmia or anxiety or insomnia, we have to use them judiciously.”

The side effects of bupropion-naltrexone, in particular, can include heart palpitations, anxiety, insomnia, headaches, and reflux, and many of his patients cannot tolerate the combination.

Kane therefore uses three options most often: Phentermine by itself, phentermine with topiramate (Qsymia), or phentermine with metformin. Topiramate’s appetite-suppressing effect occurs via a different mechanism than the effect in phentermine, and it offers a boost to metabolism, so the effects of using both together is additive, he said.

Machineni takes a similar approach.

“First and foremost, we look at the expected side effect profile and the contraindications,” he said. “For example, we wouldn’t use phentermine in someone who has uncontrolled high blood pressure or a history of heart attack or strokes.”

Assessing possible side effects goes beyond looking at patients’ existing medical conditions to considerations about their lifestyle as well.

“Topiramate is a good medication for certain conditions, but if someone is an airline pilot, I would not want to use it because topiramate has a nasty side effect of mental fogginess and forgetfulness,” Machineni said.

Next, he looks at cost. The US Food and Drug Administration–approved versions of these medications — such as Contrave and Qsymia — are often expensive and may not be covered by insurance. But prescribing the medications off-label separately — naltrexone and bupropion instead of Contrave and phentermine and topiramate instead of Qsymia — can be far more affordable whether covered by insurance or not.

“After that, we look at the efficacy and other effects the drug can have,” Machineni said. “If the patient has prediabetes, metformin might be a good option. If someone has migraines, topiramate is a good option because it treats migraines also.”

In looking at efficacy, Machineni cautions physicians not to dismiss drugs whose “average” effectiveness appears low. Metformin, for example, is often disregarded because weight loss is usually modest and doesn’t occur in everyone.

Ro said about 20%-30% of her patients respond to metformin.

“It’s hit or miss if you’re going to be a responder,” she said. “When it works, it works well.”

Bite-Sized Nutrition Advice

What works for a majority of his patients, however, is prescribing one of these medications alongside care emphasizing behavioral interventions, particularly counseling on diet.

“You don’t get out of my office without a behavioral intervention,” Kane said. “The meds take a few minutes to discuss, but it’s really working on nutrition education and logistics, along with exercise and managing sleep and stress and executive function.”

He works with his patients to come up with ideas for healthy meals that work for them, learning how to cook and shop and eat in a way that improves satiety, and, consequently, the effectiveness of the medications.

That approach may sound intimidating to many PCPs because of concerns about limited time during visits and reimbursement barriers. But Ro, who has conducted more than 1000 dietary assessments for patients, has found ways to work it into visits in bite-size pieces.

In rural North Carolina, where she said “obesity is waging a war” on her patients, people often lack the time or insurance coverage for dietitian visits. She takes on that role but with a simplified approach to dietary counseling that she incorporates into visits without overwhelming the doctor or the patient.

The key to success is taking small steps, starting with a lifestyle inventory to identify their eating habits, she said.

“You can’t give personalized counseling if you don’t know what they’re eating,” Ro said.

Most often, the problem is a diet comprised almost entirely of ultraprocessed foods and sugar-heavy beverages, and they need smaller, more actionable goals.

“As I titrate up their metformin, I say, ‘Instead of three soda bottles per day, could we do one a day?’” Ro said.

“These patients are dying for somebody to tell them concrete, actionable goals that make sense to them,” Ro said. “They come back and they lost 10 lb because they switched out sweet tea with unsweetened tea and little bit of Stevia. They’re crying in my office because, for the first time, they’re seeing success, not with a GLP-1 but with metformin and topiramate and somebody walking them through what to do.”

Despite her success in helping patients make changes to their diet, Ro said, “You can’t do lifestyle alone because we know obesity is a disease in the brain.” But beginning treatment of that dysfunction with an anti-obesity medication opens the door to gradually reducing intake of sugar and ultraprocessed food.

“It’s the food that drives the weight gain, so that’s what I focus on,” she said.

Exercise plays only a small role in weight loss, so discussions about physical activity come later.

“What I’m doing doesn’t require a 10-hour course on nutrition. It’s basic — let’s do less processed foods, let’s eat more eggs and Greek yogurt, and add a little banana.”

Machineni is a consultant for Rhythm Pharmaceuticals, Eli Lilly, and Skye Biotech and he has run clinical trials for Eli Lilly, Rhythm Pharmaceuticals, Novo Nordisk, and Boehringer Ingelheim. Ro and Kane had no disclosures. 

Tara Haelle is a science/health journalist based in Dallas.