by Julie Rafferty, Tufts University

Credit: Pixabay/CC0 Public Domain

We've all seen the ads and read about celebrities who have successfully lost weight using one of the new weight loss medications like Ozempic, Wegovy and Zepbound that have exploded in popularity over the past year.

One-half of U.S. adults recently surveyed say they would like to take these drugs and 93 million Americans meet the generally accepted medical criteria to use them. In fact, according to one pharmaceutical company, as many as 25,000 people are starting their new weight loss drug every week.

But we've experienced the phenomenon of miracle weight loss diets and medications coming onto the scene before. Is the current crop another "flash in the pan?"

Tufts Now recently spoke to several faculty experts to gain insights into these drugs' future potential for solving the epidemic chronic diseases of overweight and obesity.

How do these drugs work? What long term effects, if any, will they have on patients who will need to take them for the rest of their lives to maintain their weight loss? Do the costs of these drugs—$12,000–$16,000 per person per year—limit who has access or threaten to bankrupt the health care system? Can costs be offset by major declines in type 2 diabetes, hypertension, high cholesterol, sleep apnea, osteoarthritis, heart disease and certain cancers, all of which are tied to obesity?

Is an effort that focuses equally on medications and a food-is-medicine approach to healthy living a less costly, more effective and more equitable route to lasting weight loss success?

How do these medications work?

All the new weight loss drugs mimic the action of a naturally occurring substance called glucagon-like peptide 1 (GLP-1). GLP-1 activates a receptor to produce a biological response. GLP-1 is produced in the intestine after eating. It and the drugs that mimic it stimulate insulin secretion and slow food emptying from the gastrointestinal tract so patients feel full longer.

Unlike naturally-occurring GLP-1, which lasts for only minutes in the body, GLP-1-mimicking drugs can last for days.

These medications also seem to affect the appetite pathway in the brain, reducing food cravings, says Richard Siegel, co-director of the Diabetes and Lipid Center at Tufts Medical Center and associate professor at Tufts University School of Medicine.

GLP-1's ability to increase insulin secretion was first identified in the late 1980s, says Andrew S. Greenberg, director of the Obesity and Metabolism Team at the Jean Mayer USDA Human Nutrition Research Center on Aging (HNRCA).

"Then, almost by accident, scientists saw that GLP-1 also could stimulate a bit of weight loss," Greenberg says.

By 2005 the first drug to mimic GLP-1, exenatide (Byetta), was introduced to treat type 2 diabetes, a condition tied to obesity. By 2014, another GLP-1 drug used to treat type 2 diabetes, liraglutide (Saxenda), was approved to treat overweight and obesity in conjunction with diet and exercise. Still on the market, people who take Saxenda, on average, lose about 6% of their body weight.

In 2021, Wegovy became the first drug since Saxenda to be approved by the U.S. Food and Drug Administration specifically for long-term weight management in adults with obesity or overweight. Made by Novo-Nordisk, Wegovy and the company's type 2 diabetes medication Ozempic, contain a newer GLP-1 agonist, semulglutide, that makes weight loss even more successful. Studies show patients on Wegovy lose as much as 15% of their body weight over time.

Another new weight loss medication, Eli Lilly's Zepbound (tirzepatide), was approved in 2023. Zepbound mimics GLP-1 and another digestive hormone, GIP.

"By targeting GIP receptors in the brain as well as GLP-1, it may increase a sense a satiety and reduce intake even more than those that target GLP-1 receptors alone," Greenberg says. Clinical trials suggest Zepbound may be even more effective in producing weight loss than Wegovy/Ozempic.

Greenberg published a paper indicating that another hormone, when combined with GLP-1 agonist drugs, may reduce rates of gastric emptying even further. "Within a few days of publication, drug companies were contacting me to learn more about it," he says. Many other drugs are racing through development, as well.

What are the side effects?

The latest generation of weight loss drugs—Wegovy and Zepbound—are taken as weekly injections. Saxenda is a daily injection. New drugs in development may one day be taken orally, Greenberg says.

Nausea, vomiting and diarrhea are the most common side effects after taking these drugs, but in many patients, adjusting the dosage and gradually bringing patients up to a higher weekly dose can ease symptoms, says Brian Downey, director of General Cardiology Services at Tufts Medical Center and assistant professor at Tufts School of Medicine.

Spicy or fatty foods can make nausea worse, says Kelly Nguyen, a clinical pharmacy specialist in the Cardiology Department at Tufts Medical Center. Patients are counseled to avoid those foods and may be given anti-nausea medications until their system adjusts to the weight loss drugs.

Patients are also advised that the medications can impact the effectiveness of certain medications, including diabetes medications such as insulin, leading to lower blood sugars.

As with anyone who loses a lot of weight, patients on these medications experience loss of skin elasticity and skin folds. Loss of muscle mass is also a side effect as weight loss continues.

"This can be particularly problematic in older individuals, which is why combining weight loss with resistance training exercises is so important," says Siegel.

Greenberg notes that drugs which help build muscle mass may be one way to help with this side effect.

Women of child-bearing age need to be aware that the new weight loss medications may interfere with oral contraceptives. "I counsel patients in that situation to use physical barrier contraceptives during the first few weeks they are beginning the medication as we titrate the dosage," says Nguyen.

At a certain point—around 12–18 months after beginning treatment—weight loss plateaus. If patients stop using the drug, the weight will return, Siegel notes.

Another major "side-effect" of the drug is drug shortages, which have occurred as their popularity has grown and manufacturers struggle to keep up.

"Shortages of medications can be so problematic," says Downey.

"If a patient decides to begin the medication, we help them get authorization from their insurance company, but then entry-level doses are unavailable. Or a patient stops taking the medication for a period of time and then resumes due to shortages, in which case we need to restart them on lower doses and gradually build up to the optimal dose again, just as we did when they first started."

What about surgery rather than medication?

Gastric bypass and other types of weight loss surgery have been available for decades and involve altering sections of a person's digestive system to help them lose weight.

Surgery can be very invasive, although less invasive endoscopic procedures have been developed recently and are offered at a few medical centers, including Tufts, for those who can't or won't undergo surgery, Siegel says. Patients who pick these options must monitor how much they eat going forward, consuming several small meals throughout the day, even if they want to eat more.

While surgery, for some people, may be a more appealing option than taking medication for the rest of their lives, Siegel notes that weight loss will plateau for these patients, as well.

"In some cases, patients may then want to add weight loss medications to their treatment plan because they are looking for more help. The medications enable them to think less about food, feel fuller and lose more weight," Siegel says.

Have any safety red flags been raised so far?

The first GLP-1 agonist went on the market nearly 20 years ago. As yet, no serious red flags have been raised and the medications have been used in thousands of patients.

Research suggests GLP-1 drugs have a host of other benefits besides weight loss, including increasing efficient kidney function, increasing the number and survival of insulin-producing beta cells, decreasing sleep apnea and having a wide range of positive effects on heart muscle, heart rate and overall cardiac function, Greenberg says.

A paper published in the New England Journal of Medicine in the fall of 2023 showed that in patients with obesity and heart failure, treatment with semaglutide even reduced cardiac symptoms and physical limitations, enabled patients to exercise more and lose more weight than placebo, Greenberg adds.

Do we still need to diet and exercise to lose weight?

If paid for by health insurance at all, medications or surgery are usually only covered for those with a BMI of 30 or higher, or 27 and higher if a person also has other medical issues such as heart disease, sleep apnea, diabetes, or hypertension.

The Tufts experts emphasized that people taking the new weight loss medications still need a nutrition and exercise plan. "It's really a continuum of care for a chronic disease, which is what we now know obesity is," says Siegel.

"Medication or weight loss surgery is part of an entire treatment package that includes a nutritional plan that emphasizes as much unprocessed foods as possible. You need to eat lots of fresh fruits, vegetables and whole grains. You need to make sure you are getting adequate sleep. Higher protein intake, in combination with regular strength training, can help preserve muscle mass."

Dariush Mozaffarian, director of the Food is Medicine Institute and Jean Mayer Professor of Nutrition at the Friedman School of Nutrition Science and Policy, posits that ultimately a combined GLP-1 agonist-Food Is Medicine approach will be the most cost-effective and equitable way to make the most of these new medicines to attack the obesity epidemic.

"In trials establishing the effectiveness of GLP-1 agonists, researchers saw that weight loss plateaued after 12-18 months, yet patients need to stay on the medications for a lifetime to maintain that weight loss," observes Mozaffarian, who is also a cardiologist and former dean of the Friedman School.

What about access and cost?

By one analysis, if Medicare Part D (the portion of Medicare that covers prescription drugs) were to cover semaglutide weight loss medications for everyone on Medicare with obesity, the costs would equal more than 90% of what Medicare currently expends on all other prescriptions drugs combined.

Medicare currently does not cover the medications if prescribed solely for weight loss, but may cover them if FDA-approved and prescribed for another medically accepted health benefit, such as decreasing stroke risk.

It's unclear that the added pharmaceutical costs would yield lowered health expenditures to treat diseases tied to overweight and obesity.

"Even accounting for their health benefits, one analysis showed the total annual health care cost for patients adhering to the drug doubled in the first year, from approximately $13,000 per person before starting the drug to $26,000 after," Mozaffarian says.

The same study showed that only about 25% of patients on one of the weight loss medications continued taking it long-term, Mozaffarian says.

"We know maintaining healthy habits can be difficult, especially for people who lack the money and access to get healthy foods and exercise regularly," Mozaffarian observes.

Food Is Medicine programs that include a prescription grocery program or meals, coaching and telehealth or digital behavior support may cost less than weight loss drugs and can be effective, although perhaps not as effective initially as these medications.

"Our best bet may be to develop and test combined GLP-1 agonist/Food Is Medicine programs that, long term, might turn out to be more effective at keeping weight down and be more cost-effective and equitable," Mozaffarian says.

It is still early days

"If this a nine-inning game, we are still in the first inning in terms of learning what these drugs can do," says Greenberg.

It's not surprising that people gain weight when they stop taking these new weight loss medications, he says. "People regain weight when they stop following a particular weight loss diet, too," Greenberg observes.

People may stop the medications for a host of reasons: temporarily due to pregnancy, or for longer duration due to a change in insurance or a change in what drugs their insurance will cover. "For those who are followed closely, are doing well and have insurance coverage, I suspect adherence will be much higher," says Siegel.

Patients currently take anti-hypertensive meds, statins and a host of other drugs lifelong to treat medical conditions. "As oral versions of this newer crop of weight loss medications come on the market, they will become more acceptable to more patients to continue taking long-term," posits Greenberg.

Greenberg notes that research shows that when a person is obese, even a 5% weight loss results in significant health benefits. "Plateauing in terms of how much these drugs enable a person to lose may not be as much of an issue as it seems," he believes.

"The financial costs and benefits of obesity drugs are also in their early stage of evaluation. As more similar drugs become available, we can anticipate that competition may drive down costs," Greenberg adds.

"Obesity causes a huge percentage of type 2 diabetes, a chronic, long-term disease that also causes blindness, kidney failure, loss of nerve function, stroke and heart disease," Greenberg says.

"All of these conditions are huge burdens for insurance companies and patients. Once efficiently priced drugs can be taken to reduce these health complications of obesity, the cost-benefit analysis may actually be competitive in terms of preventing costs to insurance companies by prescribing these drugs."

Greenberg believes that perhaps the most important benefit of this new class of drugs is that "doctors and patients are now accepting that obesity and its complications are an issue that can be treated."

Journal information: New England Journal of Medicine 

Provided by Tufts University