Weight Loss Pills, Past and Present
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The need for obesity treatments is urgent — more than two-thirds of U.S. adults are overweight, and more than 40 percent are obese, according to the most recent data from the Centers for Disease Control and Prevention (CDC). Obesity is a leading cause of preventable premature deaths as well as health problems like heart disease, stroke, type 2 diabetes, and certain cancers.
Roughly half of U.S. adults try to lose weight, most often by exercising more, eating less, and adding more fruits and vegetables to their diets, according to the CDC. Many people can lose weight with those approaches, but studies show that the pounds often creep back on when people rely on lifestyle changes alone.
“This is a lifelong disease that requires lifelong intervention, and even when people make lifestyle changes, they still have to fight against weight gain,” says Timothy Garvey, MD, a professor in the department of nutrition sciences and director of the Diabetes Research Center at the University of Alabama at Birmingham. “Medications can stop the processes that cause this weight gain.”
The Troubled History of Early Weight Loss Drugs
The weight loss medications on the market today are generally approved for adults with obesity who have a body mass index (BMI) of 30 or higher, or adults with a BMI of 27 or greater 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 those criteria take drugs to lose weight. One study published in 2019 in Obesity collected prescription data from more than 2.2 million adults eligible for treatment with weight loss medications from 2009 to 2015. The findings indicated that just 1.3 percent of them filled the prescriptions.
Part of the problem comes down to safety concerns, particularly because so many of the first drugs used for weight loss decades ago had potentially life-threatening side effects. Several of those treatments were so dangerous that they were pulled from the market, according to an editorial published in conjunction with the new study in The New England Journal of Medicine. Those included several amphetamines that caused addiction; fenfluramine, which caused heart valve damage; and lorcaserin, which increased the risk of cancer.
Untested, unsafe diet pills have a long history, too. As far back as the 1940s, cocktails of appetite suppressants known as “rainbow pills” were heavily marketed to American women, according to research. The brightly colored capsules often contained amphetamines, diuretics, laxatives, and thyroid hormones to maximize weight loss. They were typically mixed with drugs like benzodiazepines, barbiturates, and antidepressants. By the 1960s, after those potent cocktails of drugs had caused dozens of deaths, the U.S. Food and Drug Administration (FDA) removed them from the market.
“None of these medications were tested in long-term trials prior to repurposing them for the treatment of obesity. This raises the risk that they will have side effects not recognized in short-term therapy,” says Frank Greenway, MD, chief medical officer and a professor at the Pennington Biomedical Research Center at Louisiana State University in Baton Rouge.
In the 1990s, another untested weight loss cocktail known as “fen-phen” started taking off, research notes. This cocktail mixed the psychiatric drug fenfluramine, which boosts levels of the brain chemical serotonin and induces feelings of satiety, with the appetite suppressant phentermine. An older version of fenfluramine, marketed as Pondimin, was on the market for more than two decades, and a newer version called dexfenfluramine, marketed as Redux, was sold for about a year, before both were recalled in 1997 due to concerns that the products caused heart valve defects.
An appetite suppressant called sibutramine, marketed as Meridia, was recalled by the FDA in 2010 after more than a decade on the market, because of an increased risk of cardiovascular events and strokes. Next up, the prescription weight loss drug lorcaserin (Belviq) was recalled by the FDA over cancer concerns in 2020, after more than a decade on the market.
Tougher Testing Requirements
After so many weight loss drugs were recalled over dangerous side effects, in the late 1990s the FDA recommended that new medications to treat obesity undergo year-long clinical trials prior to approval. This guidance didn’t apply to Redux or Meridia because their testing programs were already underway. But it did strengthen testing for the drugs that came next, including Belviq.
“The majority of the removals of anti-obesity medications were seen in drugs that did not go through the year-long trials,” Dr. Greenway says.
All of the medications approved in the last decade have a good track record of safety so far, says Adam Gilden, MD, an associate professor and obesity researcher at the University of Colorado School of Medicine in Aurora. These newer drugs either combine medicines that have good safety records when used individually or those that have been used for a long time to manage type 2 diabetes before gaining traction as obesity treatments.
“So, we can feel good that these medicines are safe,” Dr. Gilden says. “Also, every one of these medicines will be subjected to large post-marketing trials, which will further assess safety and longer-term efficacy.”
Weight Loss Varies With Newer Drugs
While the newer weight loss drugs don’t appear to have the same safety issues as rainbow pills or fen-phen, their effectiveness isn’t necessarily as dramatic as those options, doctors say.
In a review of anti-obesity treatments published in 2021 in Current Obesity Reports, scientists examined clinical trial results for several newer weight loss drugs using a formula designed to create a head-to-head comparisons. Researchers looked at clinical trials where every participant followed lifestyle interventions for weight loss such as diet and exercise changes, while half of the participants took a placebo pill and half took a weight loss medication.
To isolate the effect of weight loss drugs alone, scientists 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 with phentermine-topiramate (Qsymia), followed by 5.4 percent with liraglutide (Saxenda), 4 percent with naltrexone-bupropion (Contrave), and 2.9 percent with orlistat (Xenical).
An even newer obesity drug, semaglutide (Wegovy), helped people with obesity lose 12.4 percent of their body weight in a study published in 2021 in The New England Journal of Medicine that used the same calculations to determine the drug’s effectiveness. Another drug for type 2 diabetes that’s currently being reviewed by the FDA as an obesity treatment, tirzepatide (marketed as Mounjaro for diabetes), helped people with obesity lose almost 21 percent of their weight at the highest dose studied, according to results published in The New England Journal of Medicine.
“I think it is a very exciting time for obesity medicine because we now have several effective treatments to choose from,” says Melanie Jay, MD, an obesity researcher and associate professor at the New York University Grossman School of Medicine.
A Look at the Options
For many patients today, a decision about which weight loss medication to try may come down to several factors, including what other medications they take, which drugs are covered by insurance or are most affordable, and whether people prefer pills or injected medicines, Dr. Jay says.
“I advise people to speak to their physician to choose an initial medication and see how they respond,” Jay says. “It’s not uncommon to switch medications or have to add a second or third medication.”
Here’s what you need to know about the prescription weight loss drugs that are currently approved:
- Tirzepatide (Zepbound) This weekly injected medicine was approved by the FDA in 2023 to treat adults with obesity and overweight adults with at least one weight-related chronic health problem. Tirzepatide mimics two hormones that help regulate insulin secretion and digestion: glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). It is widely believed to be the most potent weight loss drug ever approved for sale: In the Surmount-1 trial, participants using the highest dose lost an average of 22.5 percent of body weight. Common side effects include nausea, diarrhea, vomiting, and constipation; rare but potentially dangerous reactions include severe gastrointestinal disease and acute injury to the pancreas, kidneys, or gallbladder.
- Orlistat (Xenical, Alli) This pill was approved by the FDA in 1999 as a prescription weight loss drug (Xenical) and in 2007 at a lower dose for nonprescription use (Alli). It works in the gut to limit the amount of fat absorbed from foods you eat. Common side effects include diarrhea, gas, stomach pain, and leakage of oily stools. It’s also linked to rare cases of severe liver injury, per the National Institute of Diabetes and Digestive and Kidney Diseases; dangerous interactions with cyclosporine, a drug to prevent organ transplant rejections; and the potential for malnutrition if patients don’t take a multivitamin. Orlistat has been shown to decrease absorption of fat-soluble vitamins as well as some prescription medications, including Amiodarone, which is used to treat irregular heart beats, and ciclosporin, which is used to treat inflammatory diseases like 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 patients ages 12 and older with obesity. This combination pill works to suppress appetite and make people feel full sooner. Common side effects include constipation, dizziness, dry mouth, tingling in hands and feet, and difficulty sleeping. It shouldn’t be used by people with glaucoma or hyperthyroidism, by women who are pregnant or breastfeeding, or by some individuals with a history of heart attack, stroke, heart rhythm disorders, kidney disease, or mood problems.
- Naltrexone-Bupropion (Contrave) This oral drug was approved by the FDA in 2014. It’s a combination of two drugs that are used to treat addiction and depression, and it can help suppress appetite and make people feel full sooner. Common side effects include constipation, dizziness, diarrhea, dry mouth, headache, increased blood pressure, elevated heart rate, insomnia, liver damage, nausea, and vomiting. It shouldn’t be used by people with uncontrolled blood pressure, seizures, a history of anorexia or bulimia, people taking psychiatric drugs containing bupropion (Wellbutrin, Zyban), or individuals dependent on opioids or withdrawing from drugs or alcohol. It can increase suicidal thoughts or actions.
- Liraglutide (Saxenda) This daily injected drug was approved by the FDA in 2014 for adults and in 2020 for children ages 12 and older with obesity. It’s in a family of medicines known as glucagon-like peptide-1 (GLP-1) receptor agonists, which work by mimicking a hormone in the brain that regulates appetite and food consumption. Common side effects include nausea, diarrhea, constipation, abdominal pain, headache, and increased heart rate. Rare side effects include an increased risk of pancreatitis, and it’s been linked to thyroid tumors in animals. In a smaller dose, liraglutide is used as a diabetes medication called Victoza, which should not be used in conjunction with Saxenda.
- Semaglutide (Wegovy) This weekly injected medicine was approved by the FDA in 2021 to treat adults with obesity and overweight adults with at least one weight-related chronic health problem. It’s another GLP-1 receptor agonist that mimics a hormone in the brain that regulates appetite. Common side effects include nausea, diarrhea, vomiting, constipation, stomach pain, headache, and fatigue. It can’t 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 of medicines, it carries an increased risk of pancreatitis and has been linked to thyroid tumors in animals.
Summary
For many people with obesity who struggle to shed excess pounds, prescription weight loss drugs can help when lifestyle changes like cutting calories and exercising more aren’t enough to make a big difference on the scale. But it is important to know the potential risks and side effects of any medication you take, and to discuss the options carefully with your healthcare provider.
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