Obesity is a widespread and escalating health concern in the United States. Nearly 42% of Americans are obese, a significant increase from 30% in 2000. This alarming rise underscores the urgent need for effective and sustainable weight management strategies. While lifestyle modifications, including diet and exercise, remain fundamental, their limited effectiveness as standalone interventions necessitates exploring adjunctive treatments, particularly for individuals with a body mass index (BMI) greater than 30 kg/m2, or 27 kg/m2 or greater with associated complications such as hypertension, diabetes mellitus, and hyperlipidemia.
The Role of Medication in Weight Loss
When diet and exercise alone are insufficient, medication can play a crucial role in achieving clinically significant weight loss. The American Gastroenterological Association (AGA) has established a 3% weight loss as the minimally important difference for determining the effectiveness of medication over lifestyle interventions alone. For instance, an individual weighing 90.7 kg (200 lb) would need to lose an excess of 2.7 kg (6 lb) to demonstrate the added benefit of medication.
Pharmacotherapeutic options for treating obesity have expanded in recent years. Medications should be considered only for patients who have not achieved weight loss goals with diet and lifestyle changes, and after an extensive discussion of the risks and benefits.
Several drugs are effective for weight loss in obese or overweight adults. However, it remains unclear whether they improve overall health outcomes.
FDA Approved Medications for Weight Loss
The Food and Drug Administration (FDA) has approved several medications for long-term weight management when used in conjunction with a reduced-calorie diet and increased physical activity in patients with a BMI of 30 kg per m2 or greater, or 27 kg per m2 or greater who have comorbid conditions such as hypertension, diabetes, or dyslipidemia. These medications work through various mechanisms to reduce appetite, increase satiety, or decrease nutrient absorption. Despite their indication for long-term therapy, the optimal duration of treatment is unclear; the available evidence was limited to one to two years. Relatively high rates of attrition in studies also raise concern about the utility of these agents in ongoing treatment.
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A summary of several medications commonly used for weight loss is presented below.
Glucagon-Like Peptide-1 (GLP-1) Agonists
Multiple glucagon-like peptide-1 (GLP-1) agonist medications, created for the treatment of type 2 diabetes mellitus, are now labeled for the treatment of obesity. These subcutaneous injectable medications are effective for weight loss and aid in treating type 2 diabetes.
GLP-1 agonists are contraindicated for patients with a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2 and who are receiving treatment with dipeptidyl-peptidase-4 inhibitors.
Semaglutide
Semaglutide (Ozempic), administered at a dosage of 2.4 mg injected subcutaneously weekly, combined with lifestyle interventions, has demonstrated the most significant weight loss results. Semaglutide produces an average of nearly 11% total body weight loss. Semaglutide has a number needed to treat (NNT) of 2 (95% CI, 2 to 4) for producing weight loss of 10% or more and an NNT of 3 (95% CI, 2 to 5) for producing weight loss of 15% or more. In patients with type 2 diabetes, semaglutide reduces A1C by at least 1.0%.
Liraglutide
Liraglutide (Saxenda) is another glucagon-like peptide-1 agonist with similar effects as semaglutide, but it has less apparent benefit. Treatment with liraglutide results in a 4.8% total body weight loss and has an NNT of 6 (95% CI, 5 to 9) for producing weight loss of 10% or more and an NNT of 11 (95% CI, 8 to 18) for producing a weight loss of 15% or more. In patients with type 2 diabetes, liraglutide reduces A1C by approximately 0.5%. Liraglutide leads to treatment discontinuation for adverse effects, with an NNH of 20 (95% CI, 14 to 30).
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Phentermine/Topiramate ER
Phentermine/topiramate ER, with a maximum oral dosage of 15 mg/92 mg once daily, produces an average 8.5% total body weight reduction. It has an NNT of 3 (95% CI, 3 to 4) for producing weight loss of 10% or more and an NNT of 4 (95% CI, 3 to 7) for producing weight loss of 15% or more. Phentermine/topiramate ER leads to treatment discontinuation for adverse effects, with an NNH of 10 (95% CI, 7 to 16). Despite the concern for increased blood pressure with phentermine monotherapy, improved blood pressure control was observed after phentermine/topiramate ER treatments.
The medication is contraindicated in patients with uncontrolled hypertension, history of cardiovascular disease, or untreated hyperthyroidism. Topiramate is a teratogen, which requires that women have effective contraception if they use this medication.
Naltrexone/Bupropion ER
Naltrexone/bupropion ER, with a maximum oral dosage of 16 mg/180 mg twice daily, produces an anticipated average 3% total body weight reduction. This medication has an NNT of 7 (95% CI, 4 to 18) for producing weight loss of 10% or more and an NNT of 12 (95% CI, 6 to 30) for producing weight loss of 15% or more. Naltrexone/bupropion ER may be useful in treating comorbid depression and tobacco use. Naltrexone (Revia) as monotherapy or in combination with any medication may interfere with acute pain management and perioperative treatment that requires opioids. Naltrexone/bupropion ER is contraindicated in patients with seizure disorders; individuals with hypertension should be monitored.
Phentermine Monotherapy
Phentermine monotherapy, with an oral dosage of 15 to 37.5 mg once daily, is the most commonly used anti-obesity medication. Phentermine produces an average 3.6% total body weight reduction and has an NNT of 6 (95% CI, 3 to 11) for producing weight loss of 10% or more. Phentermine monotherapy leads to treatment discontinuation for adverse effects, with an NNH of 13 (95% CI, 8 to 27).
Diethylpropion
Diethylpropion, with a maximum oral dosage of 75 mg controlled-release once daily midmorning, or an oral dosage of 25 mg immediate-release three times daily with meals, produces an average 5.4% total body weight reduction and has an NNT of 4 (95% CI, 2 to 12) for producing weight loss of 10% or more. This medication is contraindicated in patients with uncontrolled hypertension, history of cardiovascular disease, or untreated hyperthyroidism.
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Orlistat
Orlistat inhibits gastrointestinal tract lipase and is available over the counter as 60-mg capsules or by prescription as 120-mg capsules. It is taken orally three times daily with meals. Orlistat produces an average 2.8% total body weight reduction and has an NNT of 7 (95% CI, 6 to 10) for producing weight loss of 10% or more. Discontinuation for adverse effects is not different from placebo. Adverse effects include flatulence, oily spotting, and fecal urgency and incontinence. Orlistat is contraindicated in patients with malabsorption diseases, such as pancreatic insufficiency. When using orlistat long term, consider supplementing the diet with fat-soluble vitamins.
Gelesis100
Gelesis100 is a superabsorbent hydrogel that is dosed as three capsules (2.25 g per dose) taken with water before lunch and dinner. The capsules absorb water and grow into a space-occupying matrix within the gut that increases satiety and decreases food consumption. Unlike intragastric balloons that require procedural removal, the gel is degraded in the colon and excreted.
Lifestyle Interventions
Dietary strategies emphasizing reduced caloric intake, regardless of the nutrient composition, are important for weight loss. Behavioral interventions such as motivational interviewing and encouraging physical activity lead to additional weight loss when combined with dietary changes. Medication regimens for concomitant medical problems should take into account the effect of specific agents on the patient's weight.
Family physicians can assist patients in setting weight loss goals, improving nutrition, increasing physical activity, addressing barriers to change, and developing strategies to maintain long-term lifestyle changes. Adherence to a diet with a deficit of 500 kcal per day, regardless of macronutrient composition, is most effective for weight loss. Various commonly used diet plans result in a similar degree of weight loss, regardless of the specific dietary composition of macronutrients (carbohydrate, protein, and fat). Adherence to calorie reduction is the most important factor; any diet in which caloric intake is less than caloric expenditure will lead to weight loss. A deficit of at least 500 kcal per day can be achieved with intake of 1,200 to 1,500 kcal for women and 1,500 to 1,800 kcal for men. Diet plans with multiple components can be overwhelming and lead to poor adherence. A simpler approach using a single dietary adjustment may produce weight loss similar to more complex plans. For example, encouraging a patient to increase dietary fiber intake produces comparable adherence and weight loss to encouraging compliance with the many goals of the American Heart Association diet. Worksite interventions are gaining in popularity, and family physicians can encourage patient participation. Increasing physical activity is an important part of any weight loss plan.
Bariatric Surgery
Physicians should consider referring patients for bariatric surgery if they have a body mass index of 40 kg per m2 or greater. For those with obesity-related comorbid conditions, patients should be considered for adjustable gastric banding or other bariatric surgical approaches if they have a body mass index of 30 to 39.9 kg per m2. The most commonly performed procedures for weight loss are Roux-en-Y gastric bypass, sleeve gastrectomy, and adjustable gastric banding. Bariatric surgery is the most effective intervention for weight loss in obese patients, and it leads to improvement in multiple obesity-related conditions, including remission of diabetes.
Considerations for Older Adults
Weight loss in older adults can be intentional or unintentional. Unintentional weight loss in adults older than 65 years is generally defined as a 5% or greater loss of body weight in a six- to 12-month period and is associated with increased morbidity and mortality. Weight loss can be assessed by numerical documentation or, if no baseline weight is available, corroboration with a change in clothing size or from a relative may be used. Cachexia syndrome is associated with weight loss (greater than 5%) within 12 months attributed to a known chronic illness such as cancer, chronic obstructive pulmonary disease, or chronic kidney disease. The pathophysiology of unintentional weight loss is not well understood. Body composition and lean body mass decrease with age. Lean body mass can decrease up to 0.7 lb (0.3 kg) per year between 20 and 30 years of age. Fat mass continues to increase until 65 to 70 years of age. Therefore, total body weight usually peaks at 60 years of age with only small decreases after that.
Unintentional weight loss in older adults is a diagnostic challenge. There are no validated clinical guidelines, and the differential diagnosis is broad. However, once identified, unintentional weight loss should be evaluated. Patients 18 years and older presenting with weight loss are up to 12.5 times more likely than those without weight loss to have cancer. For people older than 60 years, more than one in 10 presenting with weight loss will be diagnosed with cancer. In community-dwelling older adults, unintentional weight loss causes are most often classified as organic or psychosocial. Prospective and retrospective studies in inpatient and outpatient settings have demonstrated that overall non-malignant diseases are more common causes of unintentional weight loss than malignant causes. However, malignancy accounts for up to one-third of cases of unintentional weight loss.
A baseline evaluation for unintentional weight loss includes a complete history and physical examination focusing on symptoms that could indicate the cause of weight loss. An article on the comprehensive in-office geriatric assessment published in American Family Physician reviewed tools to assess cognitive impairment, depression, and functional status, all of which can lead to weight loss. Medication and supplement use should be reviewed. Physical examinations should assess any concerning findings from the history and include assessment of the oral cavity and dentition and examination for heart, lung, gastrointestinal, or neurologic abnormalities. Shared decision-making and goals of care should guide diagnostic evaluation.
Initial workup for most patients should include laboratory studies and imaging. Laboratory tests include complete blood count, basic metabolic panel, liver function tests, thyroid function tests, C-reactive protein level, erythrocyte sedimentation rate, glucose measurement, lactate dehydrogenase measurement, protein electrophoresis, ferritin, urinalysis, and fecal occult blood testing. Low albumin and elevated total white blood cell count, platelets, calcium, or inflammatory markers are most associated with cancer.
Appropriate follow-up of patients with unexplained, unintentional weight loss is needed if the initial evaluation is unclear. Studies suggested that if the initial evaluation was normal and screening tests were negative, no further workup is needed, and a three- to six-month observation period is warranted. However, a more recent study with more extensive follow-up (up to 66 months) in 2,677 patients indicated that extended follow-up would result in identifiable causes of weight loss (most often undetected malignancy) and, typically, a diagnosis was found within six to 28 months of the initial evaluation. Autopsies were required to establish the diagnosis in 14 patients. The length and frequency of follow-up should be specific to the clinician and patient.
Treatment should focus on the underlying cause and often involves a multidisciplinary team, including dentists; dietitians; speech, occupational, or physical therapists; and social service workers. Decreased saliva production, ill-fitting dentures, periodontal disease, and weakened mastication muscles can lead to poor dentition and impaired chewing. A cross-sectional, self-administered study distributed to more than 100,000 community-dwelling older adults in Japan found a significant correlation between having fewer teeth and lower weight in both sexes. According to the Choosing Wisely campaign by the American Geriatrics Society, appetite stimulants and high-calorie supplements should be avoided secondary to lack of evidence on long-term survival and quality of life. Treatment should instead focus on feeding assistance, addressing contributing medications, providing appealing foods, and social support as indicated. Supplementation, if given, should provide extra calories but not replace scheduled meals and snacks. A Cochrane review of mostly poor-quality studies (N = 10,187) noted that supplementation provides a small but consistent weight gain in older patients; however, there was no statistically significant change in mortality overall. When limited to undernourished patients (n = 2,461), supplementation had a statistically significant mortality benefit (relative risk = 0.79; 95% CI, 0.64 to 0.97).
Despite the lack of evidence of benefits and potential harms, appetite stimulants such as megestrol (Megace) and mirtazapine (Remeron) are prescribed. Adverse effects of megestrol include gastrointestinal upset, insomnia, impotence, hypertension, thromboembolic events, and adrenal insufficiency. Mirtazapine, a serotonin antagonist used to treat depression, has weight gain as a known adverse effect in up to 12% of patients. However, no literature exists solely looking at mirtazapine use for unintentional weight loss.
Concerns Regarding Compounded GLP-1 Medications
FDA is aware that some patients and health care professionals may look to unapproved versions of GLP-1 (glucagon-like peptide-1 (GLP-1) receptor agonists) drugs, including semaglutide and tirzepatide, as an option for weight loss. This can be risky for patients, as unapproved versions do not undergo FDAâs review for safety, effectiveness and quality before they are marketed.
Compounded drugs should only be used in patients whose medical needs cannot be met by an FDA-approved drug. Patients should obtain a prescription from their doctor and fill the prescription at a state-licensed pharmacy.
A compounded drug might be appropriate if a patientâs medical need cannot be met by an FDA-approved drug, or the FDA-approved drug is not commercially available. However, compounded drugs are not FDA approved. This means the agency does not review compounded drugs for safety, effectiveness or quality before they are marketed. The agency has identified some areas of concern for compounded GLP-1 drugs. FDA is working with its state regulatory partners and will continue to communicate with compounders regarding these concerns.
Injectable GLP-1 drugs require refrigeration as indicated in their package inserts. FDA has received complaints that certain compounded GLP-1 drugs have arrived warm or with inadequate ice packs to keep the drug at recommended storage temperatures.
FDA is also aware of compounded semaglutide and tirzepatide products that contain false information on the product label. In some cases, the compounding pharmacies identified on the labels of the products do not exist. In other cases, the labels of the fraudulent compounded medicine contain the name of a licensed pharmacy that, based on information FDA has gathered, did not compound these products. FDA is aware of one reported adverse event associated with a product labeled as compounded tirzepatide from a pharmacy that did not actually compound the product. The adverse event report included symptoms such as redness, site swelling, pain, and a red lump at the injection site.
The agency encourages patients to be vigilant and know the source of their medicine. Carefully check labels of compounded GLP-1 drugs for warning signs such as spelling errors or incorrect addresses and ensure your medicine is provided by a licensed pharmacy and prescribed by a licensed health care provider.
FDA received multiple reports of adverse events, some requiring hospitalization, that may be related to dosing errors associated with compounded injectable semaglutide products. These dosing errors resulted from patients measuring and self-administering incorrect doses of the drug, and in some cases, health care professionals miscalculating doses of the drug. Additionally, the agency has received adverse event reports that may be related to patients prescribed compounded semaglutide or tirzepatide products in doses beyond what is in the FDA-approved drug label. This could mean using more product in a single dose, taking doses more frequently or increasing the amount more quickly (titration schedule). Some of the adverse events are serious and some patients reported seeking medical attention for their symptoms, including nausea, vomiting, diarrhea, abdominal pain and constipation. Health care providers should be vigilant when prescribing compounded semaglutide or tirzepatide products and determining appropriate doses and titration and dosing schedules for patients. The agency also encourages patients to talk with their health care provider or compounder about how to measure and administer the intended dose of compounded semaglutide or tirzepatide.
Retatrutide and cagrilintide cannot be used in compounding under federal law. Additionally, these are not components of FDA-approved drugs and have not been found safe and effective for any condition. The agency has issued warning letters to companies distributing active pharmaceutical ingredients, such as retatrutide and certain other GLP-1 drugs.
The agency is aware that some semaglutide products sold by compounders may be the salt forms. These salt forms, including semaglutide sodium and semaglutide acetate, are different active ingredients than are used in the approved drugs. The agency does not have information on whether these salts have the same chemical and pharmacologic properties as the active ingredient in the approved drug, and we are not aware of any lawful basis for their use in compounding.
FDA has received reports of adverse events related to compounded versions of semaglutide and tirzepatide. However, federal law does not require state-licensed pharmacies that are not outsourcing facilities to submit adverse events to FDA so it is likely that adverse events from compounded versions of these drugs are underreported.
The agency investigates reports of suspected counterfeit drugs to determine the public health risks and the appropriate regulatory response.
FDA monitors the internet for fraudulent or unapproved drugs and has issued warning letters to stop the distribution of illegally marketed semaglutide and tirzepatide.
The agency urges consumers not to purchase these products which are of unknown quality and may be harmful to their health.
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