How Weight Loss Pills Have Changed — and What That Means for Safety

“[Obesity] 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 the director of the Diabetes Research Center at the University of Alabama in Birmingham. “Medications can stop the processes that cause this weight gain.”

Early Weight Loss Drugs

As far back as the 1940s, cocktails of appetite suppressants known as “rainbow pills” were heavily marketed to American women. The capsules often contained amphetamines, diuretics, laxatives, and thyroid hormones to maximize weight loss and were typically mixed with drugs like barbiturates to mask side effects.

“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, the 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 nicknamed fen-phen took off. It contained the psychiatric drug fenfluramine, which boosts levels of

Tougher Drug Testing Requirements

All the medications approved in the past decade have a good track record of safety so far, says Adam Gilden, MD, an associate professor and obesity medicine specialist at the University of Colorado School of Medicine in Aurora.

He says these newer drugs either combine medicines with good individual safety records 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 adds. “Also, every one of these medicines will be subjected to large post-marketing trials, which will further assess safety and longer-term efficacy.”

“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 a professor at the New York University Grossman School of Medicine in New York City.

Weight Loss Drug Options

For many people today, choosing a weight loss medication may come down to several factors, including what other medications they take, which drugs their insurance covers, affordability, and whether they 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,” says Jay. “It’s not uncommon to switch medications or have to add a second or third medication.”

Here’s what you need to know about currently approved prescription weight loss drugs.

Tirzepatide (Zepbound)

Common side effects: Nausea, diarrhea, vomiting, and constipation.

Interactions and risks: Rare but potentially dangerous reactions include severe gastrointestinal disease and acute injury to the pancreas, kidneys, or gallbladder.

Semaglutide (Wegovy)

How it works: It’s another GLP-1 receptor agonist that mimics a hormone in the brain that regulates appetite.

Common side effects: Nausea, diarrhea, vomiting, constipation, stomach pain, headache, and fatigue.

Interactions and risks: 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, including tirzepatide and liraglutide, it carries an increased risk of pancreatitis and has been linked to thyroid tumors in animals.

Orforglipron (Foundayo)

How it works: Orforglipron works like other GLP-1 receptor agonists, meaning it mimics a hormone that regulates appetite and fullness. But because it’s a small-molecule drug, it enters the bloodstream more easily and works when taken on a full stomach, unlike semaglutide.

Common side effects: This drug may cause abdominal pain, constipation, diarrhea, vomiting, nausea, headache, gas, bloating, and fatigue.

Interactions and risks: Rare adverse effects include gallbladder disease, kidney injury, retinal damage in people with type 2 diabetes, and pancreatitis. People using another GLP-1 receptor agonist shouldn’t use orforglipron. This medication has been linked to thyroid tumors in animal studies.

Naltrexone-Bupropion (Contrave)

Common side effects: Constipation, dizziness, diarrhea, dry mouth, headache, increased blood pressure, elevated heart rate, insomnia, liver damage, nausea, and vomiting.

Liraglutide (Saxenda)

How it works: 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: Nausea, diarrhea, constipation, vomiting, dizziness, hypoglycemia (low blood sugar), and increased heart rate. Rare side effects include an increased risk of pancreatitis, gallbladder disease, allergic reactions, and suicidal ideation. It’s also been linked to thyroid tumors in animals.

Phentermine-Topiramate (Qsymia)

How it works: This combination pill suppresses appetite and makes people feel full sooner.

Common side effects: Constipation, dizziness, dry mouth, tingling in hands and feet, brain fog or cognitive impairment, depression, and difficulty sleeping.

Interactions and risks: People with closed angle glaucoma or hyperthyroidism, those who are pregnant or breastfeeding, and some individuals with a history of heart attack, stroke, heart rhythm disorders, kidney disease, or mood problems shouldn’t use it.

Orlistat (Xenical, Alli)

How it works: Orlistat works in the gut to limit the amount of fat you absorb from food.

Common side effects: Diarrhea, gas, stomach pain, and oily stool leakage.

Interactions and risks: It’s linked to rare cases of severe liver injury, dangerous interactions with cyclosporine (a drug to prevent organ transplant rejections), and the potential for malnutrition if patients don’t take a multivitamin.

Evidence suggests orlistat decreases the absorption of fat-soluble vitamins as well as some prescription medications, including Amiodarone (used to treat irregular heartbeats). It may also affect the dosage of warfarin, an anticoagulant.

What to Consider Before Taking Weight Loss Pills