NEW YORK — As obesity remains a significant threat to health worldwide, first-generation obesity medications continue to play an important role in clinical practice, according to a recent review article.
The study published in Current Atherosclerosis Reports summarized the pharmacologic profiles, clinical trial evidence and practical considerations for the use of several first-generation obesity medications: phentermine, orlistat, phentermine/topiramate extended-release, bupropion/naltrexone sustained-release and liraglutide 3.0 mg. The researchers sought to understand the mechanisms, benefits and limitations of these medications to help clinicians deliver comprehensive and effective medical obesity treatment that addresses atherosclerosis and other cardiometabolic complications.1
Obesity, a chronic disease that affects 1 in 8 people worldwide, is associated with over 200 complications that impact nearly every organ system. Studies show that long-term excess adiposity can lead to atherosclerotic cardiovascular disease, but obesity remains greatly undertreated despite its high prevalence and clinical burden.
For most people with obesity, lifestyle modification, the foundation of obesity management, is insufficient as a standalone intervention. While earlier guidelines required patients to try lifestyle modifications and fail to achieve certain results before starting medication, the 2025 ACC Expert Consensus Statement on Medical Weight Management for Optimization of Cardiovascular Health recommended initiating obesity pharmacotherapy along with lifestyle interventions, the researchers reported.
Over the past 20 years, obesity treatment has evolved considerably. First approved by the U.S. Food and Drug Administration (FDA) between 1959 and 2014, first-generation obesity medications were the foundation of pharmacologic obesity management. These medications include monotherapies such as phentermine and orlistat, as well as combination therapies such as phentermine/ topiramate extended release and bupropion/naltrexone sustained release. Contrave, for example, is the only FDA-approved oral weight-loss medication combining extended-release naltrexone and bupropion. The weight-loss pill works in two ways to help reduce hunger and control cravings, according to the medication’s website. Liraglutide 3.0 mg (FDA-approved as Saxenda), a glucagon-like peptide-1 (GLP-1) receptor agonist originally developed for Type 2 diabetes, was the first incretin-based therapy approved for obesity.
These first-generation agents differ in mechanism of action, efficacy and side effect profile, each resulting in 5% or more total body weight loss in clinical trials. FDA approval requires this amount of weight loss, because it significantly improves cardiometabolic risk factors associated with obesity and leads to health benefits, the investigators pointed out.
Compared to first-generation obesity medications, second-generation obesity medications, such as semaglutide 2.4 mg and tirzepatide, are associated with more weight loss and greater health improvements, but there are significant barriers to access, including high cost and limited insurance coverage. Also, some patients aren’t appropriate candidates for second-generation medications or don’t require the magnitude of weight loss achieved with these agents. Many patients also require more than one obesity medication, so it’s important for clinicians to be knowledgeable about all the obesity medications available for treatment, including first-generation medications, which have many benefits, the authors explained.
This review found that first-generation obesity medications continued to play an important role in clinical practice, and in appropriately selected patients, these medications can be highly effective. With first-generation obesity medications, mean weight loss is less than newer incretin-based therapies, but trial data demonstrate that a substantial proportion of individuals on first-generation agents achieve 10% or more total body weight loss.
The study authors suggested that first-generation obesity medications are a cost-effective, evidence-based component of comprehensive obesity care. They are also critical tools for addressing atherosclerosis and other cardiometabolic complications of obesity.
Newer guidelines increasingly support earlier use of pharmacotherapy alongside lifestyle modification, a pivot from earlier recommendations. Obesity pharmacotherapy still remains underutilized, even though the American Diabetes Association Standards of Care now identify weight management as a primary goal of treatment in patients with Type 2 diabetes who are overweight or obese, however. Obesity pharmacotherapy is hindered by weight bias, stigma, discrimination, limited provider familiarity and barriers related to cost and insurance coverage, the researchers suggested.
In many cases, first-generation medications might be a preferred option because these medications and their components are often less expensive than second-generation agents, the study pointed out, adding that patients might also achieve their health goals with first-generation medications and benefit from greater flexibility with dosage and administration. These medications have been found to reduce metabolic and hemodynamic abnormalities, such as hypertension, dyslipidemia, hyperglycemia and visceral adiposity, that promote atherosclerotic cardiovascular disease.
In the review, the researchers also discovered that many patients required more than one medication to effectively treat obesity. As a result, many obesity medications that are either currently available or in the pipeline are combinations of two agents. When patients don’t achieve health goals on the highest tolerable dose of one medication, clinicians must be familiar with available obesity medications and know how to combine these medications safely, they advised.
While the treatment strategies have been used among clinicians specializing in obesity medicine for a while, the strategies are beginning to be integrated into primary care and other specialties based on the prevalence of obesity, the authors suggested.
To increase fair access to obesity treatment, it’s critical to have a patient-centered approach that aligns clinical goals with individual preferences and tolerability, according to the review. The accessibility and affordability of first-generation obesity medications make them essential tools for broadening equitable cardiometabolic care, but more clinicians need to have the expertise to achieve success with the full collection of obesity medications, the authors concluded.
The VA has specific guidance for the use of the following weight loss medications:
- phentermine/topiramate (Qsymia),
- orlistat (Xenical, Alli),
- naltrexone/bupropion (Contrave),
- liraglutide (Saxenda),
- semaglutide (Wegovy), or
- tirzepatide (Zepbound).
A chief requirement is that pharmacotherapy with weight management medications “should always be in conjunction with a comprehensive lifestyle intervention (i.e., clinically supported weight management program that targets all three aspects of weight management: behavioral, dietary, physical activity).” The guidance from the VA Pharmacy Benefits Management Services and National Formulary Committee, updated in August 2025, noted that the MOVE! Weight Management Program offers a comprehensive lifestyle intervention and operational definition of comprehensive lifestyle intervention in VA.
“Weight management medications can be initiated any time during participation in a comprehensive lifestyle intervention,” according to the guidance. “The optimal duration for use of a weight management medication and outcomes beyond 2 to 4 years have not been established. Weight management medications should be viewed as long-term therapy, as short-term use results in weight regain.”
The VA pointed out that long-term use of more than a year, “while not always associated with additional weight loss, results in significantly less weight regain compared to lifestyle interventions alone. It is also possible that long term use can improve other comorbid conditions.”
The document also provides some suggestions to clinicians on selecting a weight management medication and said that a number of factors must be considered including each drug’s efficacy, side effects, cautions, warnings, the patient’s comorbidities. It also emphasizes shared decision-making should involve the patient and provider.
“If sufficient weight loss is not achieved within the first 3 months of a maximally tolerated dose of a pharmacotherapy or significant weight gain or regain after initial loss occurs, then the weight management medication should be discontinued,” the VA advises. “A trial of a different weight management medication may be warranted provided the patient continues to adhere to comprehensive lifestyle intervention.”
The VA/DoD Clinical Practice Guideline for the Management of Adult Overweight and Obesity suggests that weight management medications for long-term weight loss be offered to patients with a body mass index greater than 30 kg/m2 and to those with a BMI > 27 kg/m2 who also have obesity associated conditions, in conjunction with comprehensive lifestyle intervention.
Six weight management medications are FDA approved for chronic weight management. Phentermine/topiramate, naltrexone/bupropion and orlistat are available on VA National Formulary with Prior Authorization at the Facility level with Criteria for Use; semaglutide, tirzepatide and liraglutide are available by nonformulary request.
- Schmitz SH, Saunders KH. A Review of First-Generation Obesity Medications. Curr Atheroscler Rep. 2026 Jan 22;28(1):14. doi: 10.1007/s11883-026-01389-0. PMID: 41569 475.
