Navigating Weight Loss Medications: Long-Term Use, Discontinuation, and Maintaining Weight Loss

Incidence and Impact of Obesity

A variety of weight-loss medications are available | Image credit: K KStock | stock.adobe.com

The alarming rise in obesity in the United States presents a significant public health crisis, with prevalence among adults aged 20 and older reaching 41.9% from 2017 to March 2020,which is a stark increase from 30.5% in 1999-2000.^1,2 This translates to over 100 million adults classified as obese, with a body mass index (BMI) of greater than or equal to 30 kg/m².³ The escalating trend imposes a substantial financial burden, with annual obesity-related medical care costs nearing $173 billion in 2019 and productivity losses ranging from $3.38 billion to $6.38 billion.^4,5

Furthermore, obesity elevates the risk of severe health conditions, such as cardiovascular disease, type 2 diabetes, respiratory problems, and musculoskeletal disorders.⁶ This impacts both individual well-being and the nation’s overall health. Fortunately, alongside lifestyle changes, several medications are now available to treat or assist with weight loss for patients with obesity or overweight. These are valuable tools in addressing this complex health issue.

FDA-Approved Oral Medications for Weight Loss

Naltrexone-Bupropion

Naltrexone-bupropion (Contrave; Nalpropion Pharmaceuticals, LLC) targets weight management through dual mechanisms of action.⁷ It is proposed that naltrexone and bupropion exert their effects on 2 separate areas of the brain: the hypothalamus and the mesolimbic dopamine circuit. These are key areas involved in appetite regulation and reward processing, respectively.

Naltrexone-bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with a BMI greater than or equal to 30 kg/m², or a BMI greater than or equal to 27 kg/m² with at least 1 weight-related comorbidity (eg, hypertension, type 2 diabetes, or dyslipidemia). Twelve weeks from the maintenance dose, efficacy should be assessed. If a patient has not achieved 5% weight loss, discontinuation is recommended because sustained, clinically meaningful weight loss is unlikely. Naltrexone-bupropion can be discontinued abruptly, as studies have shown no significant increase in adverse effects with abrupt cessation. However, due to its mechanism, patients should be aware that discontinuation may lead to a resurgence of appetite, which may result in weight regain.⁷

Orlistat

Orlistat (Xenical; H2-Pharma, LLC) is an oral reversible inhibitor of gastrointestinal lipases within the stomach and small intestine.⁸ By inactivating gastric and pancreatic lipases, orlistat prevents the breakdown of dietary triglycerides, allowing them to pass undigested through the digestive system, thereby blocking fat absorption and resulting in a caloric deficit that aids in weight control.

Orlistat is available as a prescription medication (120 mg 3 times daily) and as an OTC option (60 mg up to 3 times daily) and should be taken with fat-containing meals.^8,9 The prescription medication is indicated for weight loss and maintenance in conjunction with a reduced-calorie diet, as well as reducing the risk of weight regain after prior weight loss. In contrast, the OTC option is indicated as a weight loss aid for overweight adults. Orlistat is only recommended for long-term use (beyond 3 months) in patients with a 5% body weight reduction.¹⁰ Within 48 to 72 hours of discontinuing orlistat, fecal fat levels return to normal, meaning dietary fat absorption resumes.⁸ Consequently, a high-fat diet post-discontinuation will likely result in weight regain.

Phentermine

Phentermine (Adipex-P; Teva Pharmaceuticals) functions similarly to amphetamines to suppress appetite, though its precise mechanism remains unclear.¹¹ It likely promotes weight loss by stimulating catecholamine release in the hypothalamus, suppressing appetite and reducing food intake.¹² Phentermine is indicated as a short-term adjunct (a few weeks) to lifestyle modifications, including exercise, behavioral modification, and a reduced-calorie diet for weight reduction for patients 17 years or older with a BMI greater than or equal to 30 kg/m², or a BMI greater than or equal to 27 kg/m² with at least 1 weight-related comorbidity.¹¹

A prospective, multicenter, uncontrolled phase 4, open-label study conducted in Mexico from 2015 to 2018 evaluated the 3- and 6-month efficacy and safety of phentermine 15 mg and 30 mg in 932 participants with obesity.¹³ The results indicate the safe and effective use of phentermine for over 3 months. Discontinuation of phentermine doses ranging from 30 mg to 75 mg per day can occur abruptly without the need for tapering, as studies have shown it does not induce amphetamine-like withdrawal symptoms or cravings.¹⁴ Patients may experience a resurgence of appetite post discontinuation, which can lead to possible weight regain.

Phentermine-Topiramate

Phentermine-topiramate (Qsymia; Vivus LLC) combines 2 distinct mechanisms of action to promote weight loss.¹² The exact mechanism of action of topiramate is unclear but likely involves enhancing satiety and suppressing appetite through various pathways, including gamma-aminobutyric acid-mediated activity, ion channel modulation, glutamate receptor inhibition, and carbonic anhydrase inhibition.

This combination medication is indicated in patients 12 years and older with obesity, as well as for adults with overweight who have at least 1 weight-related comorbidity to aid in long-term weight management alongside diet and exercise.The starting dose of phentermine-topiramate is 1 capsule of the 3.75-mg/23-mg strength daily for 14 days, after which the dose should be increased to 1 capsule of 7.5 mg/46 mg daily. After 12 weeks at this strength, assess whether the patient has lost at least 3% of body weight. If the patient has not achieved a 3% weight reduction, increase the dose to 11.25 mg/69 mg daily for 14 days, then increase to the maximum dose of 15 mg/92 mg daily. After 12 weeks at the maximum dose, treatment should be reassessed. If patients have not achieved a 5% weight loss, discontinuation is advised due to unlikely sustained benefit of the medication. Discontinuation of the 15-mg/92-mg strength requires a slow, gradual taper to mitigate the risk of seizures associated with abrupt discontinuation of topiramate. Patients’ appetite may return to normal after discontinuing the medication, contributing to weight regain.¹²

Injectable Weight Loss Medications

Liraglutide and Semaglutide

Liraglutide (Saxenda; Novo Nordisk) and semaglutide (Wegovy; Novo Nordisk), both glucagon-like peptide-1 (GLP-1) receptor agonists (RAs), function by selectively binding to and activating the GLP-1 receptor, mimicking the action of native GLP-1.^15,16 This mechanism regulates appetite and slows gastric emptying, resulting in patients feeling full for more extended periods of time.¹⁶ Liraglutide and semaglutide are indicated as adjuncts to diet and exercise as chronic weight management in adults with a BMI greater than or equal to 30 kg/m² or a BMI greater than or equal to 27 kg/m² with at least 1 weight-related comorbidity, and for patients 12 years and older with obesity.^15,16 Liraglutide has an additional requirement for pediatric patients to have a bodyweight greater than 60 kg.¹⁵

Ongoing monitoring is essential to address potential adverse effects, such as gastrointestinal upset, medullary thyroid carcinoma, and pancreatic health adverse effects. In liraglutide use, it is especially recommended to assess changes in body weight 16 weeks after initiating the drug.¹⁵ If a patient has not achieved at least 4% weight loss, liraglutide should be discontinued because it is unlikely the patient will achieve clinically meaningful weight loss with this drug. Although semaglutide lacks a defined timeline for weight loss efficacy monitoring, similar principles should be applied to ensure patients experience clinically significant weight loss.

For GLP-1 RA discontinuation, a gradual tapering approach is recommended to maintain healthier eating habits and behaviors and to prevent rapid weight gain.¹⁷ Furthermore, carbohydrate-restricted nutrition therapy (CRNT) has shown promise as an effective strategy for tapering off GLP-1 medications.¹⁸

A retrospective, propensity score-matched cohort study among patients with type 2 diabetes at Virta Health, a nationwide telemedicine clinic, evaluated 154 patients’ bodyweight pre-CRNT, at the date of deprescription of GLP-1 RA, and at 6 and 12 months after discontinuation of GLP-1 RA on CRNT. Patients were initially restricted to 30 g of carbohydrates per day, or 50 g if consuming a vegan diet, with the level of carbohydrate restriction later being individualized depending on the patient’s personal goals. The results of this study showed that over 70% of patients were able to maintain greater than or equal to 5% weight loss from GLP-1 RAs 12 months after discontinuation. This approach allows patients to maintain weight loss post discontinuation.¹⁸

Tirzepatide

Tirzepatide’s (Zepbound; Eli Lilly & Co) novel approach to weight management lies in its dual activation of both glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 RAs, mimicking the actions of native GIP and GLP-1.¹⁹ GLP-1 is known to regulate appetite and caloric intake. Adding GIP activation appears to provide a synergistic enhancement of appetite control. Tirzepatide is indicated for long-term weight loss and maintenance in adults with obesity or overweight with at least 1 weight-related comorbidity.¹⁹

There have yet to be studies that address factors to consider when assessing efficacy and discontinuation for tirzepatide; however, since the mechanism of action is similar to GLP-1 RAs, similar principles can be applied. Weight loss should be reevaluated after a set period on the maximum tolerated dose to assess if the patient has achieved clinically significant weight loss. Discontinuation strategies also mirror those of GLP-1 RAs, emphasizing a gradual tapering approach to minimize rebound weight gain and support maintaining healthy lifestyle behaviors.¹⁹

Strategies to Sustain Weight Loss After Medication Discontinuation

A holistic approach emphasizing lifestyle modifications is essential to maintain weight loss after and while stopping medication. Consistent physical activity—aiming for at least 150 minutes of moderate-intensity weekly exercise—is crucial to burn calories and maintain muscle mass.²⁰ Equally important is a healthy, balanced diet focusing on nutrient-dense, protein-rich foods. The Mediterranean diet, which includes moderate amounts of fish, poultry, and dairy while limiting red meat, processed foods, and added sugars, is an example of a nutrient-dense diet that promotes satiety and overall health.²¹ It has been shown to be effective in long-term weight management and reducing the risk for chronic diseases such as heart disease, type 2 diabetes, and cancer.

Sustainable changes that foster satiety and consistency are also significant. Opting for gradual, long-term adjustments over restrictive diets is key in successfully maintaining weight loss after discontinuing medications.

REFERENCES

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17. Is Coming Off Semaglutide Slowly the Key to Preventing Weight Regain? European Association for the Study of Obesity. May 11, 2024. Accessed April 21, 2025. https://easo.org/is-coming-off-semaglutide-slowly-the-key-to-preventing-weight-regain/

18. McKenzie AL, Athinarayanan SJ. Impact of glucagon-like peptide 1 agonist deprescription in type 2 diabetes in a real-world setting: a propensity score matched cohort study. Diabetes Ther. 2024;15(4):843-853. doi:10.1007/s13300-024-01547-0

19. Tirzepatide [prescribing information]. Lilly; December 2024. Accessed April 21, 2025. https://uspl.lilly.com/zepbound/zepbound.html#pi

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