Treating Obesity as a Disease
A review and assessment of recent literature for the clinical applications of new research in treating obesity as a disease. Plus: Extra commentary with our new podcast, After Hours.
October 2021
Volume 10, Issue 1

Chapter 3: Comparing Obesity Medications

2018;39 (2):79-132

Medications for obesity management have a long history. Treatments dating back to the 18th century included soap and vinegar mixed with a variety of purgatives. In the late 19th and early to mid-20th century, thyroid hormone, dinitrophenol, and amphetamines were used as treatments until negative side effects became apparent. In the 1950s, derivates of amphetamines such as phentermine were developed for treating obesity, along with serotonergic drugs and monoamine reuptake inhibitors.

The discovery of leptin in 1994 marked the understanding of obesity as a hormonal disorder with new approaches to identifying medications for treating obesity. Leptin is a hormone made in adipose tissue. Leptin deficiency is associated with severe obesity and other endocrinopathies. Treatment with recombinant leptin reverses the obesity caused by leptin deficiency, indicating a hormonal mechanism for this rare genetic disorder. However, leptin treatment does not cause weight loss in people who are not leptin deficient.

Anti-obesity medications should be used in combination with a reduced-calorie diet and increased physical activity for chronic weight management in adult patients with an initial BMI of >30 kg/m2 or in adult patients with a BMI of >27 kg/m2 who have comorbidities of obesity such as type 2 diabetes, hypertension, or dyslipidemia. FDA-approved medications for weight management in patients with obesity are divided into two groups: short-term use and chronic or long-term use.  

Medications approved for short-term use (usually <12 weeks) include older sympathomimetic amines benzphetamine, diethylpropion, phendimetrazine, and phentermine. Medications approved for long-term treatment of obesity include orlistat, liraglutide, the combination of phentermine/topiramate extended release, and the combination of naltrexone and bupropion sustained release.

Medications for Short Term Use

Sympathomimetic medications

Sympathomimetic drugs benzphetamine, diethylpropion, phendimetrazine, and phentermine are noradrenergic drugs that the FDA tested and approved before 1973. These medications were not approved using modern safety standards and there are no cardiovascular outcome studies. These drugs work by increasing norepinephrine and dopamine. Phentermine, approved in 1959, is the most prescribed anti-obesity medication in the United States. Although there are few long-term studies, there is vast clinical experience with phentermine which is generally thought to be safe and well-tolerated. Side effects of sympathomimetic amines are adrenergic in nature, such as dry mouth, insomnia, or nervousness. Sympathomimetic drugs may also increase heart rate and blood pressure which should be monitored. These medications should not be used in patients with a history of cardiovascular disease.

Medications for Long-Term Use


Orlistat is a pancreatic lipase inhibitor that works by decreasing fat digestion. Treatment with orlistat results in weight loss of about 9-11% of body weight at 1 year, compared with about 5-6% in a placebo group. One study showed a 37% reduction in the development of type 2 diabetes in patients in patients with impaired glucose tolerance. Long-term adherence to orlistat is poor due to the side effect of steatorrhea that occurs if one deviates from a strict low-fat diet. Orlistat can cause decreases in fat-soluble vitamins, so a vitamin supplement should be taken. There have also been rare cases of severe liver injury reported with orlistat.


Liraglutide is a glucagon-like peptide-1 (GLP-1) agonist that is a satiety hormone. Studies have shown that liraglutide 3 mg produces 9% weight loss, about 17-18 pounds on average after 1 year of treatment, compared with a loss of 4.5 pounds in the placebo-treated group and 8.5 pounds in an orlistat-treated comparator group.

All GLP-1 medications are contraindicated in people with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2. Liraglutide should not be prescribed in patients with a history of pancreatitis or gastroparesis. If there is not at least 4% weight loss by 16 weeks on the full dose, the medication is ineffective and should be discontinued. A cardiovascular outcome in patients with type 2 diabetes showed that liraglutide lowered the rate of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, and nonfatal stroke.

Phentermine/Topiramate Extended Release 

Phentermine/Topiramate Extended Release has lower doses of phentermine than what is usually prescribed for phentermine monotherapy. Phentermine reduces appetite by increasing norepinephrine in the hypothalamus. Topiramate reduces appetite through its effect on GABA receptors. In published studies, Phentermine/Topiramate Extended Release produced weight loss of about 9-11% compared to about 2% in the placebo group. This weight loss is greater than in clinical trials with other drugs, although no head-to-head studies exist. In a meta-analysis, the average weight loss was about 34 pounds at 30 weeks of treatment. Improvements in blood pressure, glucose, lipids, and sleep apnea were observed.

Naltrexone/Bupropion Sustained Release 

Bupropion is approved as treatment for depression and for smoking cessation. It reduces appetite by through adrenergic and dopaminergic pathways in the hypothalamus. Bupropion stimulates the pro-opiomelanocortin neurons in the hypothalamus to produce pro-opiomelanocortin (POMC), which is broken down to produce α-melanocyte stimulating hormone which reduces hunger. Another breakdown product of POMC, β-endorphin stimulates hunger. As monotherapy, bupropion only has a modest effect on weight loss because of β-endorphin. Naltrexone is approved as monotherapy for the treatment of alcohol and opioid addiction. It works by blocking the receptor for β-endorphin, thus allowing α-melanocyte stimulating hormone to act on the melanocortin-4 receptor system resulting in lowered appetite. Bupropion and naltrexone also have effects in the mesolimbic dopamine reward pathways, reducing cravings and hedonic eating. Studies have shown weight loss of about 9% for naltrexone/bupropion compared to about 1.8% for placebo. There were also significant improvements in waist circumference, insulin resistance, HDL cholesterol, triglycerides, and quality of life. Because bupropion increases pulse and both bupropion and naltrexone increase blood pressure, this medication should not be used in patients with uncontrolled hypertension and blood pressure and pulse should be monitored.

Comparison of Medications for Chronic Weight Management

There are no head-to-head comparisons medications for chronic weight management. An analysis of available studies has shown that all approved medications produce significantly greater weight loss compared to placebo. These studies reported a weight loss of >5% in 23% of patients treated with placebo compared to 44% of patients treated with orlistat, 55% of patients treated with naltrexone/bupropion, 63% of patients treated with liraglutide, and 75% of patients treated with phentermine/topiramate.


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