A Review of FDA-Approved Medications for Chronic Weight Management

,

Five medications are currently approved by the FDA for chronic weight management.

Obesity is a worldwide major public health concern. In the US, approximately 74% of adults are either overweight (BMI 25-29.9 kg/m2) or obese (BMI > 30 kg/m2).1 Obesity is associated with serious health complications including type 2 diabetes, hypertension, dyslipidemia, and cardiovascular disease.2 As such, obesity is considered a multi-faceted chronic disease that requires appropriate management. According to the American Association of Clinical Endocrinologists and the American College of Endocrinology, lifestyle modification, consisting of a reduced-calorie diet and physical activity, is the first-line management strategy for overweight and obesity.2 Pharmacotherapy is recommended as an adjunct to lifestyle modifications in patients with a BMI > 30 kg/m2 or in patients with a BMI > 27 kg/m2 in the presence of weight-related comorbidities, such as diabetes, hypertension, and dyslipidemia.2 The recent FDA approval of semaglutide for weight management presents an important advancement in the pharmacotherapy options available to the practitioner as well as to the patient. The aim of this article is to provide a brief overview of the agents that are FDA-approved for chronic weight management.

Pharmacological Agents Approved for Chronic Weight Management

Five medications are currently approved by the FDA for chronic weight management (see Table); these include semaglutide (Wegovy; Novo Nordisk), liraglutide (Saxenda; Novo Nordisk), naltrexone extended-release (ER)/bupropion ER (Contrave; Orexigen Therapeutics Inc), phentermine/topiramate ER (Qsymia; Vivus, Inc), and orlistat (Xenical and Alli).3 Notably, semaglutide, naltrexone ER/bupropion ER, and phentermine/topiramate ER are approved for adult use only, whereas liraglutide and orlistat are also approved for children aged 12 and older.3 None of the approved agents are recommended in pregnancy or in patients planning a pregnancy.3 An additional medication, setmelanotide (Imcivree; Rhythm Pharmaceuticals), is approved for the treatment of obesity caused by 3 rare genetic conditions and is not indicated for weight management in the general patient population.3,4 The choice of which medication to use in a given patient is influenced by patient comorbidities and patient preferences including the route of administration and dosing frequency, as well as cost.

In addition to the aforementioned medications indicated for chronic weight management, several agents are approved for short-term (<12 weeks) use. Clinical guidelines, though, recommend weight loss medications to be used chronically for a sustained effect.2 When comparing the efficacy of weight-loss agents, it is important to note that even a sustained 5% weight loss has been shown to produce a clinically meaningful reduction in triglycerides, blood glucose, blood pressure, and the risk of developing type 2 diabetes.2

Semaglutide (Wegovy)

The most recently approved medication, semaglutide, is a glucagon-like peptide-1 (GLP-1) agonist that is also approved for use in type 2 diabetes. Compared with the other approved agents, semaglutide resulted in the greatest weight loss among patients who used it. Animal studies showed that semaglutide activates neurons in brain regions involved in the regulation of appetite, thus decreasing food intake.

The recommended initial dose is 0.25 mg injected subcutaneously once weekly for 4 weeks with dose increments every 4 weeks to a maintenance dose of 2.4 mg once weekly. The rationale behind this titration is to decrease gastrointestinal adverse effects (AEs) that are associated with the GLP-1 agonist drug class. AEs reported with the use of semaglutide in clinical trials at the rate of > 5% and with frequencies greater than placebo included nausea (44%), diarrhea (30%), vomiting (24%), constipation (24%), abdominal pain (20%), headache (14%), fatigue (11%), dyspepsia (9%), dizziness (8%), abdominal distension (7%), eructation (7%), hypoglycemia in patients with type 2 diabetes (6%), flatulence (6%), gastroenteritis (6%), and gastroesophageal reflux disease (5%). Semaglutide carries a black box warning for thyroid C-cell tumors; a warning that is based on data from animal studies. Semaglutide is contraindicated in patients with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2. Additional warnings include acute kidney

injury, mostly due to volume depletion, as well as acute pancreatitis, acute gallbladder disease, increase in heart rate, and suicidal ideation. Patients with type 2 diabetes, who use semaglutide for weight loss, are at an increased risk for hypoglycemia, especially if they are using insulin or an insulin secretagogue (eg, sulfonylurea), and for diabetic retinopathy complications.

Pharmacists should advise the patient to stay hydrated, rotate injection sites with each injection, and use semaglutide on the same day each week. Patients should not use semaglutide with other GLP-1 agonists.5

Liraglutide (Saxenda)

Like semaglutide, liraglutide is a GLP-1 agonist with similar pharmacology and AE profile. Liraglutide is administered as a subcutaneous injection. The dose is initiated at 0.6 mg daily which is titrated in weekly intervals to a maintenance dose of 3 mg daily. AEs reported with the use of liraglutide in clinical trials at the rate of > 5% and with frequencies greater than placebo included nausea (39.3%), diarrhea (20.9%), constipation (19.4%), vomiting (15.7%), injection site reactions (13.9%), headache (13.6%), hypoglycemia in patients with type 2 diabetes (12.6%), dyspepsia (9.6%), fatigue (7.5%), dizziness (6.9%), abdominal pain (5.4%), increased lipase (5.3%), and upper abdominal pain (5.1%). Liraglutide carries a black box warning for thyroid C-cell tumors; a warning that is based on data from animal studies. Liraglutide is contraindicated in patients with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2, as well as in pregnancy. Additional warnings include acute pancreatitis, acute gallbladder disease, hypoglycemia, especially if used with insulin or an insulin secretagogue, increase in heart rate, renal impairment, mostly due to volume depletion, and suicidal ideation. Caution should be used when initiating liraglutide in patients with renal dysfunction or hepatic impairment. In addition to counseling on injection techniques and AEs, pharmacists should counsel patients to discontinue liraglutide if they have not achieved 4% weight loss from baseline by 16 weeks, as it is not likely that continued treatment would result in clinically meaningful weight loss. Patients should not use liraglutide with other GLP-1 agonists.6

Naltrexone ER/Bupropion ER (Contrave)

Naltrexone is an opioid antagonist which is also indicated for opioid use disorder, and bupropion is a dopamine and norepinephrine reuptake inhibitor which is also indicated for depression and smoking cessation. The 2 medications work synergistically by stimulating 2 areas of the brain involved with the regulation of food intake: the hypothalamus and the mesolimbic dopamine circuit. This medication is available as ER tablets containing 8 mg of naltrexone and 90 mg of bupropion. The recommended initial dose is 1 tablet once daily orally with weekly increments to a maintenance dose of 2 tablets in the morning and 2 tablets in the evening.

AEs reported with the use of naltrexone ER/bupropion ER in clinical trials at the rate of > 5% and with frequencies greater than placebo included nausea (32.5%), constipation (19.2%), headache (17.6%), vomiting (10.7%), dizziness (9.9%), insomnia (9.2%), dry mouth (8.1%), and diarrhea (7.1%). Because bupropion is an antidepressant, naltrexone ER/bupropion ER carries a black box warning for an increased risk of suicidal thoughts and behaviors. Naltrexone ER/bupropion ER is contraindicated in patients with uncontrolled hypertension, chronic opioid use, seizure disorders, anorexia nervosa or bulimia, patients undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs, patients using other bupropion products, and patients who have taken monoamine oxidase inhibitors (MAOIs) within the last 14 days. Other precautions include neuropsychiatric events, which were reported in patients who used bupropion for smoking cessation, hepatotoxicity associated with naltrexone, activation of mania, increase in blood pressure and heart rate, angle-closure glaucoma, and hypoglycemia in patients with type 2 diabetes who are on insulin or an insulin secretagogue.

This medication should also not be used in patients with end-stage renal disease or severe hepatic impairment. Pharmacists should counsel patients to avoid taking this medication with a high-fat meal, since doing so increases systemic exposure to the medication, and to avoid drinking alcohol. If after 12 weeks at the maintenance dose, the patient does not achieve at least 5% weight loss from baseline, naltrexone ER/ bupropion ER should be discontinued.7

Phentermine/Topiramate ER (Qsymia)

Phentermine’s mechanism in weight loss is believed to involve the release of catecholamines in the hypothalamus, leading to decreased appetite and food intake. It is also available as monotherapy for short-term weight management.2 Topiramate produces weight loss by suppressing appetite and enhancing satiety, which is achieved by several possible pharmacological mechanisms.

Phentermine/topiramate ER is taken orally once daily in the morning to avoid insomnia. The initial dose is 3.75 mg/23 mg daily and titrated up to 7.5 mg/46 mg daily after 14 days. After 12 weeks on the latter dose, the patient’s weight loss is evaluated and if the patient does not achieve at least 3% weight loss from baseline, the medication may be discontinued as continued use on this dose is not likely to produce clinically meaningful weight loss. Alternatively, at that point, the dose may be increased to 11.25 mg/69 mg daily for 14 days followed by 15 mg/92 mg daily, which is the maximum recommended dose. If the patient does not achieve at least 5% weight loss from baseline after 12 weeks on the maximum dose, the medication should be discontinued. AEs reported with the use of phentermine/topiramate ER in clinical trials at the rate of > 5% and with frequencies greater than placebo included paresthesia (19.9%), dry mouth (19.1%), constipation (16.1%), upper respiratory tract infection (13.5%), headache (10.6%), dysgeusia (9.4%), insomnia (9.4%), nasopharyngitis (9.4%), dizziness (8.6%), sinusitis (7.8%), nausea (7.2%), back pain (6.6%), fatigue (5.9%), diarrhea (5.6%), blurred vision (5.4%), bronchitis (5.4%), and urinary tract infection (5.2%).

Because it contains phentermine, an amphetamine-like stimulant, this medication is classified as a schedule IV controlled substance. Phentermine/topiramate ER is contraindicated in pregnancy, glaucoma, hyperthyroidism, and within 14 days of MAOI use. Due to teratogenic risk, this medication is available through a Risk Mitigation and Evaluation Strategy (REMS) program. Warnings associated with the use of the medication include an increase in heart rate, suicidal ideation, acute myopia and secondary angle closure glaucoma, cognitive impairment, mood and sleep disorders, metabolic acidosis, elevation in creatinine, kidney stones, oligohidrosis and hyperthermia, and hypokalemia. Patients should have their laboratory chemistry profiles analyzed periodically throughout the treatment.

Additionally, patients should discontinue the medication gradually, since abrupt discontinuation of topiramate can precipitate a seizure. The medication has been shown to increase the risk for hypoglycemia in patients who take antidiabetic medications, the risk for hypotension in patients who use antihypertensive medications, and it may potentiate central nervous system (CNS) depression in patients who drink alcohol or use any other CNS depressants. This agent should not be used in patients with end-stage renal disease or severe hepatic impairment. Pharmacists should advise patients to avoid driving or operating heavy machinery while using this medication, since it may cause dizziness or confusion. Patients should also avoid drinking alcohol and be aware of the medication’s teratogenic risk and potential for drug-drug interactions.8

Orlistat (Alli, Xenical)

Orlistat is the only chronic weight management medication available both over the counter (60 mg capsules) and by prescription (120 mg capsules). This agent acts by inhibiting gastrointestinal lipases, resulting in decreased fat absorption.

The recommended dose of the OTC product is 60 mg 3 times daily while the prescription product is dosed at 120 mg 3 times daily. Orlistat must be taken within 1 hour of a meal containing fat. The patient should be on a reduced-calorie diet that contains approximately 30% of calories from fat. If the patient’s meal is skipped or does not contain fat, the dose of the medication can be omitted. AEs reported within the first year of using prescription orlistat in clinical trials at the rate of > 5% and with incidence which was at least twice seen with placebo were oily spotting (26.6%), flatus with discharge (23.9%), fecal urgency (22.1%), fatty/oily stool (20%), oily evacuation (11.9%), increased defecation (10.8%), and fecal incontinence (7.7%). Orlistat is contraindicated in pregnancy, chronic malabsorption syndrome, and cholestasis. Warnings include decreased absorption of fat-soluble vitamins, rare cases of severe liver injury, increased levels of urinary oxalate, increased risk of cholestasis in patients who achieve substantial weight loss, and increased gastrointestinal AEs in patients who have a diet high in fat (>30% total daily calories from fat).9 The OTC orlistat also contains a warning for organ transplant recipients noting that orlistat can interact with immunosuppressants (eg, cyclosporine).10

Pharmacists should advise patients to take a multivitamin containing fat-soluble vitamins at least 2 hours before or after taking orlistat.9 Furthermore, pharmacists should monitor for drug-drug interactions with this medication.

Conclusion

Medications for chronic weight management differ in their mechanisms, efficacy, safety, and dosing profiles, as well as in their cost of therapy. Patient-specific factors should be considered when choosing a weight loss agent and, once therapy is initiated, it is necessary to monitor the patient’s response and tolerability. Pharmacists should discuss the expected benefits and risks of weight loss agents with their patients, emphasizing that these medications need to be taken long-term for a sustained effect and should be used in conjunction with a healthy lifestyle.

References

1. Obesity and overweight. CDC. Updated March 1, 2021. Accessed June 24, 2021. https://www.cdc.gov/nchs/fastats/obesity-overweight.htm

2. Garvey WT, Mechanick JI, Brett EM, et al. American Association of Clinical Endocrinologists and American College of Endocrinology Comprehensive Clinical Practice Guidelines for Medical Care of Patients with Obesity. Endocr Pract. 2016;22 Suppl 3:1-203. doi:10.4158/EP161365.GL

3. Prescription medications to treat overweight and obesity. National Institute of Diabetes and Digestive and Kidney Health. Updated June 2021. Accessed June 18, 2021. https://www.niddk.nih.gov/health-information/weight-management/prescription-medications-treat-overweight-obesity#available

4. FDA approves first treatment for weight management for people with certain rare genetic conditions. US Food and Drug Administration. Published November 27, 2020. Accessed June 18, 2021. https://www.fda.gov/drugs/drug-safety-and-availability/fda-approves-first-treatment-weight-management-people-certain-rare-genetic-conditions#:~:text=%5B11%2F27%2F2020%5D,POMC

5. Wegovy. Prescribing information. Novo Nordisk; 2021. Accessed June 11, 2021. https://www.novo-pi.com/wegovy.pdf

6. Saxenda. Prescribing information. Novo Nordisk; 2020. Accessed June 14, 2021. https://www.novo-pi.com/saxenda.pdf

7. Contrave. Prescribing information. Nalpropion Pharmaceuticals LLC; 2021. Accessed June 17, 2021. https://contrave.com/contrave-pi/

8. Qsymia. Prescribing information. Vivus, Inc.; 2020. Accessed June 17, 2021. https://qsymia.com/patient/include/media/pdf/prescribing-information.pdf

9. Xenical. Prescribing information. H2-Pharma LLC; 2020. Accessed June 17, 2021. https://xenical.com/pdf/PI_Xenical-brand_FINAL.PDF

10. Alli. Drug label information. GlaxoSmithKline Consumer Healthcare Holdings (US) LLC; 2020. Accessed June 17. 2021. https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=a2d3bd73-f3af-4ea5-a57c-66b0004cfe4f