The need for obesity treatment is urgent - more than two-thirds of U.S. adults are overweight and more than 40 percent are obese, according to the latest data from the Centers for Disease Control and Prevention (CDC). Obesity is the leading cause of preventable premature deaths, as well as health problems such as heart disease, stroke, type 2 diabetes and certain cancers.

About half of all U.S. adults try to lose weight, most often by exercising, eating less, and adding more fruits and vegetables to their diet, according to the Centers for Disease Control and Prevention. Many people can lose weight through these methods, but studies show that the pounds often come back if people rely on lifestyle changes alone.

"It's a lifelong disease that requires lifelong intervention, and even when people make lifestyle changes, they still have to deal with weight gain."

says Timothy Garvey, M.D., professor of dietetics and director of the Center for Diabetes Research at the University of Alabama at Birmingham.

"Medications can stop the processes that cause weight gain."

The uneasy history of early weight-loss drugs

Weight-loss drugs on the market today are generally approved for obese adults with a body mass index (BMI) of 30 or higher, or for adults with a BMI of 27 or higher who have at least one weight-related health problem, such as high blood pressure, type 2 diabetes or high cholesterol, according to the National Institute of Diabetes and Digestive and Kidney Diseases.

But very few patients who meet these criteria take weight-loss medications. One study published in 2019 in the journalObesity collected data on prescriptions for more than 2.2 million adults eligible for weight-loss medications between 2009 and 2015. The results showed that only 1.3 percent of them used their prescriptions.

Part of the problem has to do with safety issues, especially because many of the first weight-loss drugs used decades ago had potentially life-threatening side effects. Some of these drugs were so dangerous that they were withdrawn from sale, according to an editorial published with a new study in the New England Journal of Medicine. They include several addictive amphetamines, fenfluramine, which causes heart valve damage, and lorcaserin, which increases the risk of cancer.

Untested, unsafe diet pills have a long history. As early as the 1940s, American women were actively offered appetite suppressant cocktails known as "rainbow pills. The brightly colored capsules often contained amphetamines, diuretics, laxatives and thyroid hormones to maximize weight loss. They were usually mixed with drugs such as benzodiazepines, barbiturates, and antidepressants. By the 1960s, after these potent cocktails of drugs caused dozens of deaths, the FDA withdrew them from sale.

"None of these drugs were tested in long-term trials before they were repurposed to treat obesity. This increases the risk that they will have side effects not recognized with short-term therapy."

says Frank Greenway, M.D., chief medical officer and professor at the Pennington Center for Biomedical Research at Louisiana State University.

In the 1990s, another unproven weight-loss cocktail known as the "phen-phen" appeared on the market. In this cocktail, the psychiatric drug fenfluramine, which increases serotonin levels in the brain and induces a feeling of satiety, was mixed with the appetite suppressant phentermine. An older version of fenfluramine, marketed as Pondimin, had been on the market for more than two decades, and a newer version called dexfenfluramine, marketed as Redux, was on the market for about a year before both drugs were recalled in 1997 over concerns that they caused heart valve defects.

The appetite suppressant drug sibutramine, marketed as Meridia, was recalled in 2010 after more than a decade on the market because of an increased risk of cardiovascular events and strokes. The next prescription weight loss drug, lorcaserin (Belviq), was recalled due to cancer concerns in 2020, after more than a decade on the market.

More stringent testing requirements

After many weight-loss drugs were recalled because of dangerous side effects, in the late 1990s the FDA recommended that new obesity drugs undergo one year of clinical trials before approval. This guidance did not apply to Redux and Meridia because their trial programs were already underway. But it did strengthen testing of the following drugs, including Belviq.

"The majority of obesity drug withdrawals were seen among drugs that had not been in one-year trials," Dr. Greenway says.

All of the drugs approved in the past decade have a good safety record, says Adam Gilden, MD, assistant professor and obesity researcher at the University of Colorado School of Medicine. These new drugs either combine drugs that have a good safety record when used alone or those that have long been used to treat type 2 diabetes before gaining distribution as a treatment for obesity.

"In this way, we can have confidence in the safety of these drugs," Dr. Gilden says. "In addition, each of these drugs will be subjected to major post-marketing trials that will assess safety and long-term efficacy."

Weight loss varies with new medications

While the new weight-loss drugs don't have the same safety issues as rainbow pills or phen-phen, their effectiveness isn't always as significant as those options, doctors say.

In a review of obesity remedies published in 2021 in Current Obesity Reports, scientists examined the results of clinical trials of several newer weight-loss drugs using a formula designed to create a head-to-head comparative analysis. The researchers examined clinical trials in which each participant followed a weight-loss lifestyle, such as diet and exercise changes, while half of the participants took a placebo pill and half took a weight-loss drug.

To isolate the effect of the weight-loss drugs alone, the researchers subtracted the average weight loss in the placebo group from the average weight loss in the medication group. They found that participants lost an average of 6.8 percent of their body weight when taking phentermine/topyramate (Qsymia), followed by 5.4 percent when taking liraglutide (Saxenda), 4 percent when taking naltrexone/bupropion (Contrave) and 2.9 percent when taking orlistat (Xenical).

An even newer obesity drug, semaglutide (Wegovy), helped obese people lose 12.4 percent of their body weight in a study published in 2021 in The New England Journal of Medicine, which used the same calculations to determine the drug's effectiveness. Another type 2 diabetes drug currently being considered by the FDA as a treatment for obesity, tirzepatide (marketed as Mounjaro for diabetes), helped obese people lose nearly 21 percent of their weight at its highest dose, according to results published in The New England Journal of Medicine.

"I think it's a very interesting time for obesity medicine because we now have several effective treatments to choose from," says Melanie Jay, MD, obesity researcher and assistant professor at New York University's Grossman School of Medicine.

Overview of options

For many patients today, the decision about which weight-loss medication to choose may depend on several factors, including what other medications they take, which medications are covered by insurance or most affordable, and whether people prefer pills or injectable medications, says Dr. J.

"I advise people to talk to their doctor to choose a starter medication and see how they respond to it," Jay says. "It's not uncommon to have to change medications or add a second or third."

Here's what you need to know about prescription weight loss medications that are currently approved:

• Orlistat (Xenical, Alli) This pill was approved by the FDA in 1999 as a prescription weight loss drug (Xenical) and in 2007 in a smaller dosage for over-the-counter use (Alli). It acts in the gut to limit the amount of fat absorbed from the food you eat. Common side effects include diarrhea, gas, abdominal pain, and liquid stools. It has also been linked to rare cases of severe liver damage, dangerous interactions with cyclosporine, a drug used to prevent organ rejection in transplants, and the possibility of malnutrition if patients do not take multivitamins. Orlistat has been shown to reduce absorption of fat-soluble vitamins as well as some prescription drugs, including amiodarone, which is used to treat irregular heartbeats, and cyclosporine, which is used to treat inflammatory conditions such as rheumatoid arthritis. Orlistat may also affect the dosage of warfarin, an anticoagulant.
• Phentermine-topiramate (Qsymia) This pill was approved by the FDA in 2012 for adults who are overweight or obese, and in 2022 for obese patients ages 12 and older. This combination pill suppresses appetite and helps people get fuller faster. Common side effects include constipation, dizziness, dry mouth, tingling in the hands and feet, and difficulty sleeping. The drug should not be taken by people with glaucoma or hyperthyroidism, pregnant and lactating women, or those with heart attack, stroke, heart rhythm problems, kidney disease, or mood problems.
• Naltrexone-bupropion (Contrave) This oral medication was approved by the FDA in 2014. It is a combination of two drugs used to treat addiction and depression, and it can suppress appetite and make people satiated faster. Common side effects include constipation, dizziness, diarrhea, dry mouth, headache, increased blood pressure, rapid heart rate, insomnia, liver damage, nausea and vomiting. It should not be taken by people with uncontrolled blood pressure, seizures, a history of anorexia or bulimia, people taking psychiatric drugs containing bupropion (Wellbutrin, Zyban), or people who are dependent on opioids or are in drug or alcohol withdrawal. It can increase suicidal thoughts or actions.
• Liraglutide (Saxenda) This daily-daily drug was approved by the FDA in 2014 for adults and in 2020 for obese children 12 and older. It belongs to a family of drugs known as glucagon-like peptide-1 (GLP-1) receptor agonists, which work by mimicking a hormone in the brain that regulates appetite and food intake. Common side effects include nausea, diarrhea, constipation, abdominal pain, headache, and palpitations. Rare side effects include an increased risk of pancreatitis, and in animals it has been linked to thyroid tumors. In a lower dose, liraglutide is used as a diabetes drug called Victoza, which should not be taken with Saxenda.
• Semaglutide (Wegovy) This weekly injectable drug was approved by the FDA in 2021 to treat obese and overweight adults with at least one weight-related chronic health problem. It is another GLP-1 receptor agonist that mimics a hormone in the brain that regulates appetite. Common side effects include nausea, diarrhea, vomiting, constipation, abdominal pain, headache and fatigue. It should not be used in combination with liraglutide or other GLP-1 receptor agonists that are prescribed for type 2 diabetes. Like other drugs in this family, it carries an increased risk of pancreatitis and has been associated with thyroid tumors in animals.

Summary

For many obese people trying to lose extra pounds, prescription weight loss medications can help when lifestyle changes, such as calorie reduction and exercise, are not enough to make a significant difference on the scale. However, it is important to be aware of the potential risks and side effects of any medication you are taking and to discuss your options carefully with your doctor.

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