Comparing Anti-Obesity Medications

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 innovative 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 weight management in patients with obesity are divided into two groups: short-term use and chronic or long-term use.

Medications for Short 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. 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 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:
Semaglutide (wegovy) and Liraglutide (Saxenda) These are injectable medications known as glucagon-like peptide- 1 (GLP-1) agonists. The medications are a synthetic version of a satiety hormone that makes you feel full. 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 a orlistat-treated comparator group. Semaglutide is a once weekly injection with an average weight loss of 15% or about 34 pounds. Weight loss results with semaglutide 2.4 mg are superior to other pharmaceuticals, averaging 15% weight loss, about 35 pounds. But many patients lose much more than the average, with some achieving results comparable to bariatric surgery. 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. These medications should not be used if you have 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 it 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, or nonfatal stroke. A new medication, tirzepatide (Mounjaro) is a "twincreatin" because it acts on two different receptors for hunger hormones GIP and GLP-1. Reported average weight loss is an amazing 22.5%, more than any medication for weight loss, approaching numbers seen with bariatric surgery.

Plenity is an FDA cleared supplement for weight management made from naturally derived cellulose and citric acid. Three capsules are taken twice a day, 20 minutes before lunch and dinner with 16 ounces of water. The capsules swell up to fill your stomach to make you feel full. The ingredients are not absorbed systemically and are eliminated from the body in the same manner as food. The average weight loss with Plenity is about 10% (about 22 pounds).

Orlistat (Xenical, Alli)
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 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 been rare cases of severe liver injury reported with orlistat.

Phentermine/Topiramate Extended Release (Qsymia)
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 (Contrave)
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 due to the effect 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 of 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. The best weight loss results are achieved when AOMs are combined with intensive lifestyle modification. The major benefit of weight loss is improvement of diseases caused by obesity such as diabetes, high blood pressure, abnormal blood lipids and heart disease which can be seen with as little as 5% weight loss. Remember, these medications are not a magic bullet but simply a tool to help you sustain common sense lifestyle changes. There is no perfect medication for obesity. A medication that may work for a family member or a friend may not be the ideal medication for you. Treating obesity can be complicated so it is best to work with a knowledgeable health care professional who is dedicated to working with you over the long term.