Pharmacologic Therapy For Obesity

Earn CME/CE in your profession:

Continuing Education Activity

Obesity is a metabolic disease represented by excessive adipose tissue. Its classification is based on the body mass index (BMI), which is a relationship between weight and height. It is a chronic condition associated with high morbidity and mortality; therefore, it requires prompt diagnosis and treatmentt. This activity reviews the evaluation and pharmacologic treatment of obesity and highlights the role of the interprofessional team in evaluating and treating patients with this condition.


  • Review the pharmacological treatment options for patients with obesity.
  • Describe the outcomes of the main studies involving weight loss medications.
  • Summarize the indications for drug-based treatment for obesity.
  • Outline some potential contraindications to the use of weight loss medications.


Obesity is a chronic disease with increasing prevalence worldwide, not only in adults but also in adolescents and children, and is now considered to be a global epidemic.[1]

Epidemiologic studies have defined obesity by the body mass index (BMI), which is calculated by dividing a person’s weight in kilograms by the square of their height in meters. That helps to stratify obesity-related health risks at a population level. A BMI greater than 30 kg/m^2 is considered diagnostic for obesity and it is further subclassified into class 1 (30 to 34.9 kg/m^2), class 2 (35 to 39.9kg/m^2), and class 3 or morbid obesity (≥ 40kg/m^2).

The main therapy for obesity includes weight loss promotion by behavioral therapy, including diet, and a healthy lifestyle with regular physical activity. Weight loss produces a significant reduction in cardiovascular risk factors, prevention of disease, and improvements in self-esteem and function. Greater weight loss produces benefits in overall mortality, but moderate weight loss (5 to 10%), such as that achieved with lifestyle modifications and medications, has also been proven to cause significant improvements in many conditions, including type 2 diabetes, hypertension, dyslipidemia, cardiovascular disease, non-alcoholic fatty liver disease, osteoarthritis, cancer, and sleep apnea.[2][3][4]

Along with these measures, due to the challenges involved in losing and maintaining weight, it is often indicated to implement evidence-based pharmacologic therapy to achieve a better and longer-term response in the management of obesity. Health care providers must have a shared decision with patients for weighing risks and benefits and make the decision for the most appropriate choice of pharmacotherapy that better fits in a patient's profile. If all these measures fail, or if the patient has an urgent requirement to lose weight and has failed pharmacotherapy, surgical intervention can be recommended by bariatric surgery which has also shown to improve morbidity and mortality. Of importance, patients that have failed to engage in a weight loss program and refuse to be assisted in a behavioral program, have a high chance of failure or relapse of obesity following bariatric surgery and, therefore, in this scenario, it should not be recommended.

Issues of Concern

This article will review the evidence for the use of the currently available weight loss medications and the medications or substances that have no evidence of benefit or can be harmful and have been discontinued.

Obesity is a very popular topic, and there is growing literature evaluating the efficacy of multiple compounds in its treatment. Unfortunately, however, there is limited evidence to promote a recommendation or discontinuation of a variety of substances and dietary supplements, and patients continue to purchase a variety of over-the-counter compounds that can actually be harmful. 

Clinicians should warn patients about the potential risks of weight-loss supplements and should monitor patients who choose to take them. The conclusions from a review from 2015 regarding some of these supplements appear below:

Green tea, Garcinia cambogia, conjugated linoleic acid, and chitosan did not show any effect on weight loss, and their use should not be encouraged by health care providers.  

There were inconclusive data regarding the use of chromium, GambisanHoodia gordonii, and Cynanchum auriculatum, and clinicians should not recommend their use due to lack of evidence and potential risk of harm.[5]

Human chorionic gonadotropin (hCG) has also been promoted and advertised as potential weight loss therapy; however, clinical trials have not supported that. Several randomized trials have demonstrated that the hCG injections or pills associated with a very-low-calorie diet (500 kcal/day) are no more effective than placebo in the treatment of obesity.[6] The weight loss effect purely correlates to the caloric restriction. Importantly, very-low-calorie diets are not feasible in the long term compared to conventional diets because the patients tend to regain the weight quickly upon discontinuation of the diet, and their effect on other aspects of health is unclear.  

Sibutramine has been withdrawn from the US and European markets in 2010 after the SCOUT study showed a 16% increase in the incidence of cardiovascular events in the medication group (11.4% versus 10% in the placebo). FDA concluded that risks outweighed the benefits. Of note, the population in the study had a significant percent of cardiovascular risk as represented by patients 55 years of age or older, overweight or obese, and with a history of cardiovascular disease or type 2 diabetes mellitus plus one additional cardiovascular risk factor.[7] In some countries, sibutramine is still prescribed in patients that do not have any of the above criteria, under strict supervision and regulation.  

Another regulated medication for weight loss, Lorcaserin, was withdrawn from the market in February 2020, after a safety clinical trial data that randomized 12,000 patients showed an increased occurrence of various types of cancer compared to placebo (7.7 versus 7.1 percent of patients), the most common being pancreatic, colorectal, and lung cancer. The FDA has not recommended any special cancer screening other than age-appropriate screening for individuals previously on lorcaserin.

Clinical Significance

Due to counteractive adaptive biological responses observed during periods of decreased food intake and increased energy expenditure, sustained weight loss can rarely be achieved exclusively only by these methods.[8][9] The reduction in energy expenditure rate and the increase in appetite observed after weight loss both correlate with hormonal changes that promote weight regain. 

Despite this adaptive mechanism that impairs continued weight loss, the recommendation is that all individuals should adopt a healthy, well-balanced eating pattern, ideally supervised, and maintain a regular physical activity of at least 30 to 60 min of aerobic activity on most days of the week to aid in providing weight and fat loss, improvement in cardiometabolic parameters, and weight maintenance.[10]

Non-pharmacologic Therapy

Lifestyle intervention - Before the initiation of weight loss drug therapy, it is important to have established a lifestyle intervention program, ideally with close monitoring by a dietitian, and long term follow-up as performed in long term trials.[11][12] Discussion of these different ways of lifestyle intervention is beyond the scope of this article, which focuses on medication therapy; however, pharmacologic therapy should be a consideration after all these non-pharmacologic approaches are optimized.

Diet - Dietary adherence is essential for the success of weight loss, regardless of the type of diet chosen. In a study that compared different types of diet, the response was proportional to the adherence.[13] 

Very low-calorie diets can provide faster initial weight loss; however, due to the body's hormonal adaptation, they are challenging to maintain long-term. It is crucial to adhere to a dietary program that continues to provide a negative calorie balance in the long term, and the initiation of medication therapy can help to overcome the stagnation usually observed after the initial months on diet and lifestyle intervention. 

Intermittent fasting dietary patterns can also be considered as a feasible alternative, although studies have shown inconsistent efficacy. A one-year trial with 100 obese individuals compared three groups: alternate-day fasting (patients alternated 25 percent of total energy consumed on fasting days and 125 percent consumed on free days) versus caloric restriction (75 percent of total energy needs ingested daily) versus non-intervention control. After 6 and 12 months, mean weight loss was similar for individuals in the alternate fasting group (-6.8% [95% CI, -9.1% to -4.5%] and -6.0% [95% CI, -8.5% to -3.6%, respectively]) and in the daily constant calorie restriction group (-6.8% [95% CI, -9.1% to -4.6%] and -5.3% [95% CI, -7.6% to -3.0%], respectively), when both were compared to the control group, with similar efficacy.[14]

More importantly, regardless of the diet or lifestyle program chosen, and due to obesity being a chronic disease with an adaptative mechanism, continued surveillance and follow-ups are mandatory to provide better long-term outcomes.

Exercise - Keeping a negative calorie balance by increasing energy expenditure through physical activity is also an important tool in weight loss maintenance. A study published in 2017 revealed that aerobic and anaerobic exercise combined are more efficient than both modalities isolated in the weight loss.[15] The recommendation is for approximately 30 minutes or more, five to seven days a week, to prevent weight gain and to improve cardiovascular health in adults.[16] 

Behavior therapy - This is an important tool to help patients make long-term changes in their eating behavior by modifying and monitoring their food intake, modifying their physical activity, and controlling stimuli in the environment that trigger binge eating. 

Pharmacologic Therapy

After changes in lifestyle to continue obtaining the positive effects of weight loss, it can be beneficial to initiate approved weight loss medications, especially in the case of failure to continue losing weight, or when weight regain has happened. This intervention can also be considered concomitantly to the initiation of a weight loss program after a discussion of risks and benefits with patients. 

Indications: Drug therapy can merit consideration with a BMI >30 kg/m, or a BMI of 27 to 29.9 kg/m in the presence of weight-related complications, in patients who have failed to achieve weight loss goals (at least 5 percent of total body weight in 3 to 6 months) after implementing comprehensive lifestyle intervention. It is important to mention that the initiation of drug therapy should always be accompanied by the maintenance of behavioral and lifestyle changes since, without this combination, medications usually have low success rates.[17][18]

The approved medications usually promote weight loss by decreasing appetite and hunger, increasing satiety, and ultimately reducing caloric absorption or ingestion. Despite that, it is still a challenge to achieve long term weight maintenance and overcome the physiologic trend of regaining the weight that was previously lost.

When deciding to initiate pharmacologic therapy, an individualized approach is necessary, taking into consideration the patient's comorbidities, preferences, insurance coverage, and costs. Single agents are usually preferable to combination therapy. However, different medications can work in combination to optimize response as long as the clinician weighs both safety and interaction profiles.[19]

The goals of obesity medication therapy should be realistic, since setting unrealistic expectations can lead to frustration and treatment abandonment. Treatment should focus on short-term as well as long-term weight reduction, avoidance of weight gain, improvement of health parameters, and management of side effects.[20]

Clinical studies of weight loss medications have traditionally considered a weight loss of 5 to 10% to be significant since this is the percentage recommended by the FDA in trials, and it is associated with clinical improvement in metabolic risk profile.[21] Secondary weight loss outcomes in these trials have also looked at the proportion of individuals with 10% or more weight loss and change in weight from baseline.

Upon initiation of weight loss therapy, it is important to emphasize that drugs can work differently in every patient as the response and side effects can vary significantly. Patients also need to be explained that it is common to achieve a plateau after the initial weight loss, and often when drug treatment is interrupted, weight regain can be expected.

1) Liraglutide is the only glucagon-like peptide-1 receptor agonist (GLP-1RA) approved for the treatment of obesity in patients without diabetes. The other drugs in the class have the positive effect of weight loss, but they have only been FDA-approved as anti-diabetic medications; therefore, they should not be used in patients without diabetes.

GLP-1 is an incretin peptide secreted by the gut following oral food intake. It inhibits gastric emptying and glucagon release and induces glucose-dependent insulin release from the beta cell in the pancreas. The GLP-1RA can be added as a second or third choice to the treatment of type 2 diabetes when patients have not achieved glycemic control. Along with SGLT-2 inhibitors, GLP-1RA is ideal for therapy in patients with diabetes who are also overweight or obese due to their known effect of weight loss. However, in non-diabetic patients, the use of SGLT-2 inhibitors or GLP-1RA other than liraglutide with the purpose of weight loss is off-label. 

In the treatment of obesity, liraglutide has approval at a higher dose than the recommended one for diabetes treatment. It is approved for obesity treatment in adults with BMI ≥30 kg/m or with BMI ≥27 kg/m if at least one weight-related comorbidity is present (e.g., hypertension, type 2 diabetes, dyslipidemia, osteoarthritis). The dose of liraglutide approved for obesity is 3 mg daily, but even an initial dose of 1.2 mg can provide weight loss and can be up titrated as tolerated (see below). Patients can often achieve weight loss with below the maximum dose of liraglutide with fewer side effects and adequate glucose control. 

Randomized controlled trials have reported the efficacy of liraglutide for both diabetes control and weight loss. Several trials have shown sustained weight loss with other cardiovascular benefits in a maximum duration of 2 years. 

In a 20-week study of 564 patients, liraglutide in four different daily doses (1.2, 1.8, 2.4, and 3 mg) showed dose-dependent weight loss compared to placebo or open-label orlistat, with 5.8 kg and 3.8 kg more weight loss than placebo and orlistat, respectively. In the 2-year extension study, the results were similar, and patients on the higher dose (2.4 and 3.0 mg) kept a weight loss of 7.8 kg at the end of the study (total n=92 patients for the higher dose combined). Liraglutide 3.0 mg also had the benefit of a decrease in body fat by 15.4% and lean tissue by only 2.0%. The prevalence of prediabetes and metabolic syndrome after two years was reduced by 52% and 59%, respectively, with simultaneous improvement of blood pressure and lipids.[22]

A 56-week trial compared liraglutide 3 mg with placebo in 3731 patients with BMI ≥30 kg/m or ≥27 kg/m with dyslipidemia and/or hypertension. Mean weight loss was -8.0 kg versus -2.6 kg in the placebo group, with the improvement of several cardiometabolic risk factors, glycated hemoglobin (A1C), and quality of life.[23]

The LEADER trial also showed that liraglutide reduced major cardiovascular events (death of cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) in patients with type 2 diabetes in a lower dose than the dose recommended for obesity (1.8 mg versus 3 mg).[24] There is no cardiovascular outcome data in patients with obesity without diabetes.  

Side effects of liraglutide are mainly gastrointestinal, including nausea and vomiting, which are usually worse at the beginning of therapy or after increment of dose. Nausea and vomiting have seemed to be dose-dependent. Sometimes an intermediate dose that patients can tolerate and that preserves the positive effects of the medication can be chosen. Pancreatitis has also been a finding, although there is no proven causal relationship. Gallbladder disease can predispose to cholelithiasis, and dehydration can occur secondary to persistent nausea and vomiting if the medication is not discontinued.[24] Liraglutide has also shown an association with malignant medullary carcinoma in rodents trial; however, this association remains unproven in humans. 

Dosing and contraindications: Liraglutide is administered subcutaneously as an initial dose of 0.6 mg daily for one week, with 0.6 mg increments weekly until reaching the recommended dose of 3 mg. However, as explained before, many patients can not tolerate the higher dose but still can have benefits on the maximum tolerated dose. There are no data on longer than two years of use of liraglutide. Many other GLP-1RA have come onto the market with a similar response in glucose control, weight loss, and cardiovascular benefits; however, they have not received approval for the treatment of overweight or obese patients without diabetes. Researchers have not studied the medication in pregnancy, and it is contraindicated in patients with a personal or family history of medullary thyroid cancer or multiple endocrine neoplasias (MEN) 2A or 2B. 

2) Orlistat inhibits pancreatic lipases leading to impairment of fat digestion in the gut. Fat is not completely hydrolyzed and, therefore, not absorbed. Weight loss is proportional to the calories lost as fecal fat excretion, which can represent a 30% calorie loss on an average diet.

Several studies have shown its efficacy, including randomized control trials and meta-analysis [25][26]. In a meta-analysis of 12 trials, the orlistat group had a mean weight loss of 8% versus 5% on the placebo group with similar behavioral intervention.[27] Subjects maintained weight loss with continuous therapy up to 24 to 36 months.  

The Xendos study randomly assigned 3304 overweight patients to orlistat or placebo. Twenty-one percent of the patients had impaired glucose tolerance. During the first year, researchers observed a more significant difference between groups (11% versus 6% below baseline in the placebo group). This difference diminished during the next three years of the trial when the orlistat group was 6.9% below the baseline versus 4.1% in the placebo group. Despite a reduced difference by the end of the study, patients in the orlistat group had a lower incidence of diabetes compared to the placebo group (6.2 vs. 9%). In other trials in patients with diabetes, orlistat also provided more weight loss and lower glycated hemoglobin (A1C) at one year compared to placebo.[28]

Other benefits have also been seen in different studies. In a systematic review, orlistat revealed a reduction in systolic and diastolic blood pressure compared to placebo (weighted difference of -2.5 and -1.9 mm Hg, respectively).[29] Orlistat also improved serum lipid values in a multicenter trial, with low-density lipoprotein (LDL) cholesterol reduction by 5 to 10% in patients treated with orlistat and low-fat diet for 48 weeks from baseline[30].

Dosing and contraindications: Patients can use orlistat for up to 4 years in the treatment of obesity. If therapy is to continue for more than four years, a discussion with the patient is to inform then of the lack of more extended studies. The recommended dose is 120 mg three times daily, along with each meal. It is available over the counter in many countries, including the United States. It is a strong recommendation that patients get a daily multivitamin at bedtime due to the decreased absorption of fat-soluble vitamins related to chronic orlistat use. 

The medication has not been studied in pregnancy and should not be a consideration in patients with chronic malabsorption, cholestasis, or calcium oxalate stones.

The most common side effects of orlistat are typically gastrointestinal, including abdominal cramps, increased flatulence, and fecal incontinence. These side effects tend to occur more frequently early during its use and to subside when patients adhere to a low-fat diet (less than 30%) without losing the weight loss effect.[31] FDA identified 13 reports of severe liver injury, although a causal relationship has not been established, since patients were also taking other drugs and had other medical conditions that could have contributed to that. Nevertheless, patients who take orlistat should understand that they need to contact their health care provider if signs or symptoms of liver injury occur. There was no increased frequency of cholelithiasis, cardiovascular, or psychiatric events. 

Due to the fat fecal excretion, levels of fat-soluble vitamins (A, D, E, K) and beta-carotene become impaired by orlistat. Also, it can prolong the international normalized ratio (INR) and prothrombin time in patients taking warfarin by reducing vitamin K levels, requiring reduction of warfarin dose and close monitoring.[32]

Due to fat malabsorption, enteric calcium can bind to the fat excreted in the stools. As a consequence, intestinal oxalate becomes more available to be absorbed and then excreted in the urine. Excessive free oxalate can be deposited in the renal parenchyma causing acute nephrocalcinosis and acute kidney injury.[33]

3) Combination therapies: Due to the chronic aspect of the disease and the need for long term treatment, as well as the potential risk of side effects of different medications, it has been proposed that combination therapy can be more effective by using a lower dose of two medications with the advantage of one drug compensating potential side effects of the other drug and maximizing their efficacy. 

3.1) FDA approved the phentermine-topiramate combination in 2012 for adults with BMI ≥30 kg/m or with a BMI ≥27 kg/m with at least one weight-related comorbidity (e.g., hypertension, diabetes, dyslipidemia) for use along with reduced dietary caloric intake for weight loss. It is not recommended for patients with high cardiovascular risk due to a potential increase in heart rate; however, a 2-year-duration trial has not shown an increase in mortality compared to placebo. Long term data in mortality is not available. It can be the first option in the treatment of obesity, or if the patient did not tolerate or failed liraglutide and/or orlistat, particularly in patients with binge eating disorder. 

In the Conquer trial, which studied 2487 patients, there was a change in body weight of -1.4 kg in the placebo group versus -8.1 in the phentermine-topiramate (7.5/46 mg) after 56 weeks.[34] In an extension study of the initial trial (Sequel) that followed patients for extra 52 weeks, patients on the low dose of the phentermine-topiramate group achieved a mean weight loss of 9.6 kg versus 2.1 kg in the placebo group after 108 weeks from the original baseline.[35] It is evident that the weight loss in the second year was less prominent; however, most participants were able to maintain weight loss, whereas the placebo group had a slight increase in body weight. All individuals were participating in a lifestyle modification program at the same time. 

Participants in the phentermine-topiramate group also showed improved cardiovascular and metabolic variables and lower incidence of diabetes in comparison to placebo. The combination was well tolerated over 108 weeks, with adverse events happening more frequently in the initial phase of the trial. 

The most commonly reported side effects of the medication are paraesthesias, dizziness, dysgeusia, insomnia, constipation, and dry mouth. Patients in the medication-treated groups observed a slight reduction in blood pressure at the expense of a slight increase in heart rate of 1.3 and 1.7 bpm for low and high doses, respectively, versus 0.4 in placebo. However, there were no reported adverse events related to the increase in heart rate. 

In regards to psychiatric side effects, there was no increase in serious suicidal ideation or behavior in the participants during the 108 weeks of observation. There were reports of dose-dependent anxiety-related adverse events (3.1%, 6.5%, and 9.5% for placebo, 7.5/46 mg, and 15/92 mg arms, respectively). However, they were mostly mild in severity.

Dosing and contraindications: There are four different fixed drug combinations for the phentermine-topiramate combination. The starting dose is 3.75/23 mg for 14 days, which should then increase to the recommended dose of 7.5/46 mg. If, after 12 weeks of treatment, a 3 percent loss of baseline body weight does not occur, the recommendation is to increase the dose to 11.25/69 mg for another 14 days and then to 15/92 mg thereafter. If less than 5 percent of body weight is achieved after 12 weeks on the highest dose, the medication should be discontinued gradually to avoid withdrawal symptoms from topiramate.  

The phentermine-topiramate combination is contraindicated during pregnancy due to teratogenicity (risk of orofacial clefts in infants exposed to the medication during the first trimester of pregnancy). It is mandatory to obtain a pregnancy test before starting the drug in childbearing age female and then monthly thereafter. It is also contraindicated in patients with hyperthyroidism or acute angle glaucoma and should not be started on patients who have taken monoamine oxidase inhibitors in the past 14 days. It should also be avoided in patients with a history of kidney stones due to the increased risk related to topiramate. 

Recommended monitoring is as follows:

  • Heart rate every visit
  • Suicidal behavior and ideation screening and discontinuation of the drug if symptoms develop.
  • Visual disturbances, especially acute myopia and signs of increased intraocular pressure
  • Cognitive impairment since topiramate can cause disturbances in attention or memory
  • Electrolytes and creatinine check-up before and during treatment, since topiramate inhibits carbonic anhydrase enzyme predisposing to acidosis, although no significant acidosis has been reported in the trials.

Phentermine can also be used as a monotherapy in the treatment of obesity. It is FDA-approved for a short term treatment (few weeks) in a regimen associated with exercise, behavioral modification, and caloric restriction for patients with BMI  ≥ 30 kg/m, or  ≥ 27 kg/m2 in the presence of additional risk factors (e.g., controlled hypertension, diabetes, hyperlipidemia).

Phentermine acts by suppressing appetite and causing early satiety. It is very often prescribed as monotherapy. The most extended study done with this medication was a 36-week trial dated back in 1968 that evaluated continuous and intermittent administration of phentermine, which led to more weight loss than placebo (-12.2 and -13.0 kg for continuous and intermittent use versus -4.8 kg in the placebo group).[36]

In the same group of sympathomimetic drugs, sibutramine was withdrawn from the US and European markets in 2010 after the study SCOUT showed a 16% increase in the incidence of cardiovascular events (a composite sum of nonfatal heart attack, nonfatal stroke, resuscitation after cardiac arrest and cardiovascular death) in patients receiving treatment with the drug versus the placebo group (more details on section "issues of concern"). 

3.2) Naltrexone-bupropion: Although there are no head-to-head studies available comparing this combination therapy with phentermine-topiramate, based on the results of published trials done with this combination, it is evident that it is less efficacious than the previously mentioned combination. Therefore it is not recommended as first-line pharmacologic therapy for obesity management.

A naltrexone-bupropion combination is a good option; however, for smokers who desire to pursue a combined therapy to quit smoking and mitigate the weight gain, usually following that. The exact mechanism of weight loss associated with this combination is not fully understood; however, they theoretically work synergistically in the hypothalamus and the mesolimbic dopamine circuit suppressing hunger centers.

Bupropion is a weak dopamine and norepinephrine reuptake inhibitor, which stimulates pro-opiomelanocortin (POMC) production and release of alpha-MSH and beta-endorphin that is an endogenous opioid, in vitro. The alpha-MSH activates the melanocortin-4 receptor (MC4R), which acts on reducing food intake, increasing energy expenditure, and causing weight loss. However, after continuous bupropion intake, as a down-regulatory mechanism, beta-endorphin reduces the activity of POMC cells by binding to the inhibitory mu-opioid receptor. Naltrexone that is an opioid antagonist works by blocking the mu-opioid receptor and disrupting the beta-endorphin inhibitory feedback on the POMC cells.[37][38]  

The combination drug received FDA approval in September 2014 as a weight loss medication in addition to diet and exercise in those patients with BMI ≥30 kg/m or ≥27 kg/m in the presence of at least one weight-related comorbidity.

In a multicenter randomized trial, the combination caused a -6.1% reduction in body weight versus -1.3% in the placebo group. Only 50 percent of participants completed the 56 weeks of treatment.

Although mean weight loss was greater with combination therapy than with placebo, mean reductions in blood pressure and heart rate were significantly elevated in the placebo group (-2.1/2.8 versus 0.2/-0.4 mmHg and -0.1 versus 1.5 beats per minute).

The most common side effects of the naltrexone-bupropion combination are nausea, headache, and constipation. 

FDA warns to monitor patients for suicidal behavior and ideation, risk of seizure due to bupropion lowering the seizure threshold, increase in blood pressure and heart rate, hepatotoxicity observed with naltrexone exposure, and angle-closure glaucoma.

Clinicians should avoid using the drug in patients with high cardiovascular risk due to the observed increase in heart rate and blood pressure; however, a cardiovascular safety trial was interrupted in the initial phase due to a breach in confidentiality, but preliminary data had shown a reduction in cardiovascular events, although controversial due to lack of completion of the study. The medication received approval with a warning for an increase in blood pressure and heart rate, but the cardiovascular risk was inconclusive.[39]

Dosing and contraindications: The initial dose is one tablet daily of 8 mg of naltrexone/90 mg of bupropion. The dose should increase, if tolerated, to one tablet twice daily after the first week, and to two tablets twice daily in the fourth week.

It is contraindicated during pregnancy as well as in patients with uncontrolled hypertension, seizure disorder, eating disorder, use of other bupropion-containing products, chronic opioid use, and use of monoamine oxidase inhibitors in the previous 14 days.

Enhancing Healthcare Team Outcomes

To the present moment, there are some options for pharmacotherapy for obesity; however, they are far from being a solution to the problem despite having shown satisfactory results in the improvement of cardiometabolic parameters. Some of them have unacceptable side effects, and it is impossible to predict which person is going to have a better response or who is going to tolerate well.

Some anti-obesity drugs have been withdrawn from the market due to significant side effects. Currently, the only approved drugs in the US are orlistat, liraglutide, phentermine-topiramate, phentermine alone, and bupropion-naloxone. Sibutramine was withdrawn more than ten years ago, and lorcaserin was removed more recently due to an increased risk of various types of cancer.

The currently approved medications lack long-term safety studies.

In view of all these negative aspects and considering the significant adverse effects, limited efficacy, and warnings over the safety of medications, doctors need to endorse the fact that obesity is a chronic condition that requires life long monitoring, accompanied by a low-calorie diet, regular physical activity, and a multidisciplinary team that can provide behavioral counseling and close monitoring with a dietician, primary care provider, endocrinologist and sometimes, psychiatrist or therapist. Bariatric surgery should also merit consideration as an option in patients with refractory obesity who have tried other medical therapies or who have complications from obesity and who have been evaluated by a behavioral therapist who has ruled out binge eating disorder or other compulsive disorders. 

Article Details

Article Editor:

Catherine Anastasopoulou


8/29/2022 7:19:58 PM



Global BMI Mortality Collaboration,Di Angelantonio E,Bhupathiraju ShN,Wormser D,Gao P,Kaptoge S,Berrington de Gonzalez A,Cairns BJ,Huxley R,Jackson ChL,Joshy G,Lewington S,Manson JE,Murphy N,Patel AV,Samet JM,Woodward M,Zheng W,Zhou M,Bansal N,Barricarte A,Carter B,Cerhan JR,Smith GD,Fang X,Franco OH,Green J,Halsey J,Hildebrand JS,Jung KJ,Korda RJ,McLerran DF,Moore SC,O'Keeffe LM,Paige E,Ramond A,Reeves GK,Rolland B,Sacerdote C,Sattar N,Sofianopoulou E,Stevens J,Thun M,Ueshima H,Yang L,Yun YD,Willeit P,Banks E,Beral V,Chen Zh,Gapstur SM,Gunter MJ,Hartge P,Jee SH,Lam TH,Peto R,Potter JD,Willett WC,Thompson SG,Danesh J,Hu FB, Body-mass index and all-cause mortality: individual-participant-data meta-analysis of 239 prospective studies in four continents. Lancet (London, England). 2016 Aug 20;     [PubMed PMID: 27423262]


Torgerson JS,Sjöström L, The Swedish Obese Subjects (SOS) study--rationale and results. International journal of obesity and related metabolic disorders : journal of the International Association for the Study of Obesity. 2001 May;     [PubMed PMID: 11466577]


Abdelaal M,le Roux CW,Docherty NG, Morbidity and mortality associated with obesity. Annals of translational medicine. 2017 Apr;     [PubMed PMID: 28480197]


Apovian CM,Aronne LJ,Bessesen DH,McDonnell ME,Murad MH,Pagotto U,Ryan DH,Still CD, Pharmacological management of obesity: an endocrine Society clinical practice guideline. The Journal of clinical endocrinology and metabolism. 2015 Feb;     [PubMed PMID: 25590212]


Esteghamati A,Mazaheri T,Vahidi Rad M,Noshad S, Complementary and alternative medicine for the treatment of obesity: a critical review. International journal of endocrinology and metabolism. 2015 Apr;     [PubMed PMID: 25892995]


Bosch B,Venter I,Stewart RI,Bertram SR, Human chorionic gonadotrophin and weight loss. A double-blind, placebo-controlled trial. South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde. 1990 Feb 17;     [PubMed PMID: 2405506]


James WP,Caterson ID,Coutinho W,Finer N,Van Gaal LF,Maggioni AP,Torp-Pedersen C,Sharma AM,Shepherd GM,Rode RA,Renz CL, Effect of sibutramine on cardiovascular outcomes in overweight and obese subjects. The New England journal of medicine. 2010 Sep 2;     [PubMed PMID: 20818901]


Rosenbaum M,Goldsmith R,Bloomfield D,Magnano A,Weimer L,Heymsfield S,Gallagher D,Mayer L,Murphy E,Leibel RL, Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight. The Journal of clinical investigation. 2005 Dec;     [PubMed PMID: 16322796]


Rosenbaum M,Hirsch J,Gallagher DA,Leibel RL, Long-term persistence of adaptive thermogenesis in subjects who have maintained a reduced body weight. The American journal of clinical nutrition. 2008 Oct;     [PubMed PMID: 18842775]


Mabire L,Mani R,Liu L,Mulligan H,Baxter D, The Influence of Age, Sex and Body Mass Index on the Effectiveness of Brisk Walking for Obesity Management in Adults: A Systematic Review and Meta-Analysis. Journal of physical activity     [PubMed PMID: 28169568]


Long-term effects of lifestyle intervention or metformin on diabetes development and microvascular complications over 15-year follow-up: the Diabetes Prevention Program Outcomes Study. The lancet. Diabetes     [PubMed PMID: 26377054]


Look AHEAD Research Group.,Wing RR,Bolin P,Brancati FL,Bray GA,Clark JM,Coday M,Crow RS,Curtis JM,Egan CM,Espeland MA,Evans M,Foreyt JP,Ghazarian S,Gregg EW,Harrison B,Hazuda HP,Hill JO,Horton ES,Hubbard VS,Jakicic JM,Jeffery RW,Johnson KC,Kahn SE,Kitabchi AE,Knowler WC,Lewis CE,Maschak-Carey BJ,Montez MG,Murillo A,Nathan DM,Patricio J,Peters A,Pi-Sunyer X,Pownall H,Reboussin D,Regensteiner JG,Rickman AD,Ryan DH,Safford M,Wadden TA,Wagenknecht LE,West DS,Williamson DF,Yanovski SZ, Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. The New England journal of medicine. 2013 Jul 11     [PubMed PMID: 23796131]


Dansinger ML,Gleason JA,Griffith JL,Selker HP,Schaefer EJ, Comparison of the Atkins, Ornish, Weight Watchers, and Zone diets for weight loss and heart disease risk reduction: a randomized trial. JAMA. 2005 Jan 5;     [PubMed PMID: 15632335]


Trepanowski JF,Kroeger CM,Barnosky A,Klempel MC,Bhutani S,Hoddy KK,Gabel K,Freels S,Rigdon J,Rood J,Ravussin E,Varady KA, Effect of Alternate-Day Fasting on Weight Loss, Weight Maintenance, and Cardioprotection Among Metabolically Healthy Obese Adults: A Randomized Clinical Trial. JAMA internal medicine. 2017 Jul 1;     [PubMed PMID: 28459931]


Villareal DT,Aguirre L,Gurney AB,Waters DL,Sinacore DR,Colombo E,Armamento-Villareal R,Qualls C, Aerobic or Resistance Exercise, or Both, in Dieting Obese Older Adults. The New England journal of medicine. 2017 May 18;     [PubMed PMID: 28514618]


Piercy KL,Troiano RP,Ballard RM,Carlson SA,Fulton JE,Galuska DA,George SM,Olson RD, The Physical Activity Guidelines for Americans. JAMA. 2018 Nov 20;     [PubMed PMID: 30418471]


Yanovski SZ,Yanovski JA, Long-term drug treatment for obesity: a systematic and clinical review. JAMA. 2014 Jan 1;     [PubMed PMID: 24231879]


Jensen MD,Ryan DH,Apovian CM,Ard JD,Comuzzie AG,Donato KA,Hu FB,Hubbard VS,Jakicic JM,Kushner RF,Loria CM,Millen BE,Nonas CA,Pi-Sunyer FX,Stevens J,Stevens VJ,Wadden TA,Wolfe BM,Yanovski SZ,Jordan HS,Kendall KA,Lux LJ,Mentor-Marcel R,Morgan LC,Trisolini MG,Wnek J,Anderson JL,Halperin JL,Albert NM,Bozkurt B,Brindis RG,Curtis LH,DeMets D,Hochman JS,Kovacs RJ,Ohman EM,Pressler SJ,Sellke FW,Shen WK,Smith SC Jr,Tomaselli GF, 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. Circulation. 2014 Jun 24;     [PubMed PMID: 24222017]


Garvey WT,Mechanick JI,Brett EM,Garber AJ,Hurley DL,Jastreboff AM,Nadolsky K,Pessah-Pollack R,Plodkowski R, AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY COMPREHENSIVE CLINICAL PRACTICE GUIDELINES FOR MEDICAL CARE OF PATIENTS WITH OBESITYEXECUTIVE SUMMARYComplete Guidelines available at Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 2016 Jul;     [PubMed PMID: 27472012]


Kaplan LM,Golden A,Jinnett K,Kolotkin RL,Kyle TK,Look M,Nadglowski J,O'Neil PM,Parry T,Tomaszewski KJ,Stevenin B,Lilleøre SK,Dhurandhar NV, Perceptions of Barriers to Effective Obesity Care: Results from the National ACTION Study. Obesity (Silver Spring, Md.). 2018 Jan;     [PubMed PMID: 29086529]


Khera R,Murad MH,Chandar AK,Dulai PS,Wang Z,Prokop LJ,Loomba R,Camilleri M,Singh S, Association of Pharmacological Treatments for Obesity With Weight Loss and Adverse Events: A Systematic Review and Meta-analysis. JAMA. 2016 Jun 14;     [PubMed PMID: 27299618]


Astrup A,Carraro R,Finer N,Harper A,Kunesova M,Lean ME,Niskanen L,Rasmussen MF,Rissanen A,Rössner S,Savolainen MJ,Van Gaal L, Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide. International journal of obesity (2005). 2012 Jun;     [PubMed PMID: 21844879]


Wadden TA,Hollander P,Klein S,Niswender K,Woo V,Hale PM,Aronne L, Weight maintenance and additional weight loss with liraglutide after low-calorie-diet-induced weight loss: the SCALE Maintenance randomized study. International journal of obesity (2005). 2013 Nov;     [PubMed PMID: 23812094]


Marso SP,Daniels GH,Brown-Frandsen K,Kristensen P,Mann JF,Nauck MA,Nissen SE,Pocock S,Poulter NR,Ravn LS,Steinberg WM,Stockner M,Zinman B,Bergenstal RM,Buse JB, Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. The New England journal of medicine. 2016 Jul 28;     [PubMed PMID: 27295427]


Torgerson JS,Hauptman J,Boldrin MN,Sjöström L, XENical in the prevention of diabetes in obese subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. Diabetes care. 2004 Jan;     [PubMed PMID: 14693982]


Li Z,Maglione M,Tu W,Mojica W,Arterburn D,Shugarman LR,Hilton L,Suttorp M,Solomon V,Shekelle PG,Morton SC, Meta-analysis: pharmacologic treatment of obesity. Annals of internal medicine. 2005 Apr 5;     [PubMed PMID: 15809465]


Leblanc ES,O'Connor E,Whitlock EP,Patnode CD,Kapka T, Effectiveness of primary care-relevant treatments for obesity in adults: a systematic evidence review for the U.S. Preventive Services Task Force. Annals of internal medicine. 2011 Oct 4;     [PubMed PMID: 21969342]


Kelley DE,Bray GA,Pi-Sunyer FX,Klein S,Hill J,Miles J,Hollander P, Clinical efficacy of orlistat therapy in overweight and obese patients with insulin-treated type 2 diabetes: A 1-year randomized controlled trial. Diabetes care. 2002 Jun;     [PubMed PMID: 12032111]


Siebenhofer A,Jeitler K,Horvath K,Berghold A,Posch N,Meschik J,Semlitsch T, Long-term effects of weight-reducing drugs in people with hypertension. The Cochrane database of systematic reviews. 2016 Mar 2;     [PubMed PMID: 26934640]


Yancy WS Jr,Westman EC,McDuffie JR,Grambow SC,Jeffreys AS,Bolton J,Chalecki A,Oddone EZ, A randomized trial of a low-carbohydrate diet vs orlistat plus a low-fat diet for weight loss. Archives of internal medicine. 2010 Jan 25;     [PubMed PMID: 20101008]


Padwal R,Li SK,Lau DC, Long-term pharmacotherapy for obesity and overweight. The Cochrane database of systematic reviews. 2004;     [PubMed PMID: 15266516]


MacWalter RS,Fraser HW,Armstrong KM, Orlistat enhances warfarin effect. The Annals of pharmacotherapy. 2003 Apr;     [PubMed PMID: 12659605]


Singh A,Sarkar SR,Gaber LW,Perazella MA, Acute oxalate nephropathy associated with orlistat, a gastrointestinal lipase inhibitor. American journal of kidney diseases : the official journal of the National Kidney Foundation. 2007 Jan;     [PubMed PMID: 17185156]


Gadde KM,Allison DB,Ryan DH,Peterson CA,Troupin B,Schwiers ML,Day WW, Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial. Lancet (London, England). 2011 Apr 16;     [PubMed PMID: 21481449]


Garvey WT,Ryan DH,Look M,Gadde KM,Allison DB,Peterson CA,Schwiers M,Day WW,Bowden CH, Two-year sustained weight loss and metabolic benefits with controlled-release phentermine/topiramate in obese and overweight adults (SEQUEL): a randomized, placebo-controlled, phase 3 extension study. The American journal of clinical nutrition. 2012 Feb;     [PubMed PMID: 22158731]


Munro JF,MacCuish AC,Wilson EM,Duncan LJ, Comparison of continuous and intermittent anorectic therapy in obesity. British medical journal. 1968 Feb 10;     [PubMed PMID: 15508204]


Billes SK,Greenway FL, Combination therapy with naltrexone and bupropion for obesity. Expert opinion on pharmacotherapy. 2011 Aug;     [PubMed PMID: 21689063]


Greenway FL,Whitehouse MJ,Guttadauria M,Anderson JW,Atkinson RL,Fujioka K,Gadde KM,Gupta AK,O'Neil P,Schumacher D,Smith D,Dunayevich E,Tollefson GD,Weber E,Cowley MA, Rational design of a combination medication for the treatment of obesity. Obesity (Silver Spring, Md.). 2009 Jan;     [PubMed PMID: 18997675]


Nissen SE,Wolski KE,Prcela L,Wadden T,Buse JB,Bakris G,Perez A,Smith SR, Effect of Naltrexone-Bupropion on Major Adverse Cardiovascular Events in Overweight and Obese Patients With Cardiovascular Risk Factors: A Randomized Clinical Trial. JAMA. 2016 Mar 8;     [PubMed PMID: 26954408]