Don’t Overlook First-Gen Anti-Obesity Medications

With the explosive popularity of glucagon-like peptide 1 (GLP-1) agonists, physicians say a key avenue in treating obesity is being underutilized by many clinicians: First-generation anti-obesity medications (AOMs).

“First-generation medications don’t get as much attention as the newer ones,” said Courtney Younglove, MD, an obesity specialist and founder of Heartland Weight Loss in Overland Park, Kansas. “They’re fantastic, too. They just get overlooked.” 

Older AOMs typically cost less than GPL-1s, are more accessible, and often have low risks, Younglove said. But patients frequently ask for the newer medications, and some doctors don’t assess their full treatment toolbox before prescribing, she said.

Currently, there are six AOMs approved by the US Food and Drug Administration for chronic weight management: Orlistat, phentermine/topiramate extended release, bupropion sustained release/naltrexone, liraglutide, semaglutide, and tirzepatide.

The first four medications are considered first-generation AOMs, according to a 2024 analysis in Diabetes Spectrum, a journal from the American Diabetes Association.

“The advent of new AOMs has transformed the treatment of obesity,” the study author Sarah R. Barenbaum, MD, wrote. “For the first time, there are now second-generation medications whose outcomes can rival those of bariatric surgery. However, first-generation AOMs serve an equally important and enduring role in the treatment of obesity. Whether because of insurance or supply limitations, costs, patient preferences, tolerability, or safety, patients may require a first-generation AOM, and providers must feel comfortable prescribing them.”

Good Candidates for First-Generation AOMs

One group that may benefit from first-generation AOMs are patients whose treatment goals include losing a moderate amount of weight, said Ethan Lazarus, MD, an obesity medicine and family physician and a past president of the Obesity Medicine Association.

Older AOMs are generally appropriate for patients in whom about a 10% loss of body weight would be an adequate result, Lazarus said. If patients need to achieve 20% or more loss of body weight, physicians may want to jump straight to a GLP-1, like Wegovy or Zepbound, he said.

For example, patients who are planning knee replacement surgery, or those with a higher body mass index (BMI) and are considering weight loss surgery, would be good candidates for the latter, he noted.

“If appropriate, we usually follow a stepped approach to treatment,” Lazarus said. “For example, we might start a generic medication, like phentermine. If it is not tolerated, or we do not get the amount of weight loss needed to improve obesity complications, we would transition to a branded oral medication, [like] Contrave or Qsymia, or switch to or add a GLP-1, like Wegovy or Zepbound.”

First-generation AOMs may also be good choices for patients with certain comorbidities, like chronic headaches, said Shagun Bindlish, MD, an internal medicine physician and diabetologist based in Dublin, California.

Patients with a history of migraines, or those who have polycystic ovary syndrome, may benefit from topiramate, Bindlish said, while a phentermine-topiramate combination may help with appetite suppression and impulsivity modulating. The latter can be useful for patients with nighttime eating syndrome and binge eating disorder, she noted.

In addition, bupropion/naltrexone can be beneficial for patients with depression and anxiety and may help with smoking cessation in patients with smoking habits.

“Obesity, as we all know, is not one-size-fits-all,” Bindlish said. “It’s not just about BMI. It’s about tailoring the therapy depending on what other comorbidities they have. That’s why I feel that it’s always good to lay down all the tools and discuss with the patient what will benefit them in their certain circumstances.”

The lower cost of first-generation AOMs also makes them good options for many patients, obesity physicians say. Even with pharmaceutical savings programs, GLP-1s are usually $499 per month or more, Lazarus said.

By contrast, Contrave can be purchased for $99 a month directly through the savings program CurAccess, and Qsymia is generally available through Qsymia.com for $98 a month.

Bindlish said she recently treated a 45-year-old man with class II obesity and high blood pressure who was unable to access GLP-1s through his insurance, despite several prior authorization attempts. Bindlish started the patient on a phentermine-topiramate combination, which worked well, and led to weight loss of about 30 pounds. Since phentermine is a stimulant, Bindlish said they closely monitored the patient’s blood pressure. Ultimately, the weight loss led to better management of the patient’s hypertension, she said.

Patients who are nonresponders to GLP-1s, or who have difficulty tolerating GLP-1–based therapies, may make promising candidates for first-generation AOMs, according to the Diabetes Spectrum analysis. These older medications may also be good choices for patients with lower BMIs and older patients in cases where second-generation AOMs may be too powerful and result in excessive weight loss.

Age should also factor into the decision, Lazarus said. He noted that Wegovy, Saxenda, and Qsymia are approved for patients as young as age 12 years, while other medications are only indicated in adults aged 18 years or older.

Risks of First-Generation AOMs

It’s important to know your patient and be sure there are no contraindications before prescribing older AOMs, Lazarus said. For example, physicians should consider avoiding prescribing phentermine in patients sensitive to stimulants (like caffeine), who suffer from severe insomnia, or who have complicated hypertension, he said.

The three most common side effects of phentermine are dry mouth, constipation, and trouble sleeping, Younglove added. Patients can usually get around these problems by modifying their dosage, taking a stool softener, drinking more water, and not taking the medication in the evening, she said.

Contrave, meanwhile, should be avoided in patients with a history of seizures or those on opioid pain medicine, Lazarus noted. Qsymia should not be prescribed in patients with a history of kidney stones or at risk for pregnancy because Qsymia can cause birth defects.

“If they do not have a contraindication or other concern, by all means we would consider a first-generation obesity medicine,” Lazarus said.

Keep in mind that all these medications can cause gastrointestinal abnormalities and could lead to gastrointestinal side effects, Younglove said.

Orlistat has really “fallen out of favor” due to minimal weight loss and too many side effects, said Lazarus. Younglove also does not prescribe Orlistat because of the side effects, which include an oily discharge from the rectum, she said.

The Diabetes Spectrum analysis includes a comprehensive list of clinical effects, mechanisms of action, and common side effects of all first-generation AOMs.

Dispelling Fears About Older Obesity Meds

Younglove emphasized the importance of dispelling misconceptions surrounding first-generation AOMs. Because the drugs are in the stimulant category (sympathomimetics), there has been concern — even among clinicians — that patients could become addicted to them, she said. There have also been worries about the medications raising patients’ blood pressure.

“There’s a lot of fear around those medications, which is ironic, because we’ll give Adderall to a 6-year-old and not be worried about it at all,” she said. “There is data on long-term use of these medications. There is data on side effects of these medications. They’re not for everyone, but they certainly are fairly benign in terms of risks. They get a bad wrap, but they’re really good medications for a lot of people, and a lot of people do really well with them.” 

Bindlish added that older AOMs have stood the test of time and proved their value, which is something the newer medications still must do. She said that medication choice should always be matched with patients’ individual risk factors, goals, and access.

“It is also critical to set realistic expectations and incorporate these drugs within a broader framework where we consider behavioral, nutritional, and lifestyle interventions,” Bindlish said.