Doctors Test the Limits of What Obesity Drugs Can Fix

Lesa Walton suffered for years from rheumatoid arthritis. “It was horrible,” said Ms. Walton, 57, who lives in Wenatchee, Washington. “I was getting sicker and sicker.”

She also suffered from high blood pressure and was obese. Doctors advised her to diet and exercise, which she did, to no avail.

She then found a doctor who prescribed Wegovy, one of the new obesity drugs. Not only did she lose more than 50 pounds, she said; her arthritis disappeared and she no longer needed pills to lower her blood pressure.

Her new doctor, Dr. Stefie Deeds, an internist and obesity medicine specialist in private practice in Seattle, said Ms. Walton exemplifies a growing movement in obesity medicine.

Proponents call this “obesity first.” The idea is to treat obesity with drugs approved for this purpose. As obesity is brought under control, they note, the patient’s other chronic illnesses tend to improve or disappear.

“We are treating the medical condition of obesity and its associated complications at the same time,” Dr. Deeds said.

Others are wary. Obese people may be discouraged when a doctor mentions their weight. And yes, new obesity drugs could have unexpected benefits beyond obesity, like reducing inflammation. But the drugs are expensive and many of the other potential benefits have not been shown in rigorous studies.

Dr. Gordon Guyatt, a clinical trials expert at McMaster University in Ontario, said the prudent approach is to use drugs — often inexpensive generics — that have been well tested and shown to treat conditions that often accompany obesity, such as high blood pressure, hypertension. cholesterol levels, arthritis and sleep apnea.

Obesity drugs, he said, are aimed at treating obesity.

Yet many doctors, like Dr. Deeds, are struck by stories like Ms. Walton’s, whom they say they see often in their offices. There is reason to believe that the drugs’ effects on medical problems other than obesity may be independent of weight loss, they say.

The idea of ​​treating obesity first is a departure from standard medical practice. When patients suffer from obesity and other associated chronic illnesses like high blood pressure, high blood sugar, and sleep apnea, many doctors prescribe medications for each illness. They may also advise exercise and diet changes – but often without any clear guidance and, as decades of studies have repeatedly shown, with no real prospects for weight loss for most people. people.

Starting with a powerful new obesity drug, like Novo Nordisk’s Wegovy or Eli Lilly’s Zepbound, in addition to diet and exercise, doctors hope that while they treat obesity, using a medication alone, associated conditions will improve.

As Dr. Caroline M. Apovian, an obesity medicine specialist at Brigham and Women’s Hospital in Boston, says: “You lose weight and you’ve treated high blood pressure, fatty liver disease, diabetes, high cholesterol. , high triglycerides.

Dr. Apovian, who has advised companies that make obesity drugs, says patients are happy to take one drug instead of several and, of course, to lose weight after years of failed diet attempts.

Experts also describe another benefit: Patients often continue taking obesity medications, while many who take medications they need to be healthy, like statins, drop them.

Yet there are still few examples of rigorous studies showing that the medical problems accompanying obesity disappear when it is treated. Large clinical trials that randomly assign patients to an obesity treatment or a placebo are needed to determine whether the drug has the desired effect on several conditions.

This may not be the case.

Medical history is full of examples of treatments that everyone thought would work until a clinical trial showed otherwise.

Experts widely expected menopausal hormones to prevent heart disease, and Wyeth, the maker at the time of the wildly popular Prempro, even asked the Food and Drug Administration to list protection against the disease heart conditions on the medication label. But when the National Institutes of Health conducted a large and rigorous study, the Women’s Health Initiative, researchers had to end the clinical trial prematurely for safety reasons: women taking the drug had an increased risk of heart disease. , blood clots, strokes and breast problems. cancer.

Then there was a federal study asking whether beta-carotene, a widely used antioxidant supplement, could reduce the risk of cancer and heart disease. The supplement had no effect and slightly increased the risk of lung cancer in smokers and those exposed to asbestos.

Two federal studies examined whether a high-fiber diet reduced the risk of colon cancer. The researchers were surprised to find no such evidence.

Still, there is reason to think that new obesity drugs might be different. They appear to have effects on the brain and body that go far beyond simply reducing food cravings.

These effects can occur almost immediately, said Dr. Susan Z. Yanovski, co-director of the Office of Obesity Research at the National Institute of Diabetes and Digestive and Kidney Diseases. She noted that when Novo Nordisk conducted a clinical trial of Wegovy in people with heart disease, heart complications decreased early in treatment, before patients lost a lot of weight.

The company now reports that it also saw improvement in kidney function, independent of weight loss. Participants taking Wegovy who lost very little weight showed the same type of improvement in kidney function as those who lost a lot.

A recent Novo Nordisk study testing Ozempic in people with diabetes and kidney disease found the same thing: Kidney function was better preserved in the group taking Ozempic, an effect independent of weight loss. Dr. Florian MM Baeres, the company’s vice president of global medical affairs, noted that participants’ starting weight also didn’t matter. The effect on the primary outcome was the same, he said, “whether you start from a BMI above 30 or below 30.”

Much of the effect could be due to the drugs’ ability to reduce inflammation, said Dr. Daniel Drucker, an obesity researcher at the Lunenfeld-Tanenbaum Research Institute at Toronto’s Mount Sinai Hospital. This happens before weight loss.

Dr. Drucker, who helped discover the new drugs and advises the companies that make them, was stunned by the response from patients after the media reported on a paper he co-authored showing that tirzepatide or Zepbound, an obesity medication, may reduce inflammation. In mice.

Not just in mice, patients told him in emails. A woman who had suffered from rheumatoid arthritis for years sent Dr. Drucker photos of her hands before and almost immediately after starting Zepbound for obesity. In the previous photo, her hands were swollen and painful, despite the arthritis medication she was taking. In the after photo, the swelling and pain were gone.

“Within a few days, all my joint pain disappeared,” the woman said in a telephone interview; she requested anonymity out of concern that future employers might learn of her illness.

Eli Lilly and Novo Nordisk, the makers of Zepbound and Wegovy, are testing variations of these drugs in hopes that they will be even more effective at causing weight loss.

So far, in addition to results in people with heart disease, Novo Nordisk found in another clinical trial that Wegovy improved physical functioning, such as the ability to exercise, in people with diabetes and heart failure. Eli Lilly discovered that Zepbound could help with sleep apnea. Other ongoing trials are testing obesity drugs as treatments for depression, drug addiction, schizophrenia, Parkinson’s disease and Alzheimer’s disease. Dozens of other companies are working on new obesity drugs that could be applied to other conditions.

“This is how clinical research on new drugs should be conducted,” said Dr. Ezekiel Emanuel, co-director of the Healthcare Transformation Institute at the University of Pennsylvania.

But it will take a long time to determine which drugs effectively treat which conditions. Clinical trials take years and cost millions of dollars. Many doctors may not be willing to wait.

“I’m very sympathetic to clinicians who say, ‘As researchers get more data, we’ll try this approach,'” Dr. Emanuel said. It’s common in oncology, he added, that once a drug is approved, doctors can use it for other diseases at their discretion.

With obesity drugs, he added, off-label experimentation – such as a recent small study indicating that one of the drugs could slow the progression of Parkinson’s disease – shows “what a miraculous set of drugs it is about,” with effects that were “totally unexpected.

Others are warning against “obesity first,” including representatives from companies like Eli Lilly and Novo Nordisk, saying it is prudent to wait for clinical trial results.

Dr. Scott Hagan, a primary care physician in Seattle, goes further, moving toward an “obesity last” approach.

If a patient presents with obesity and obesity-related conditions, they begin by treating the associated conditions with medications that they know can be effective. Only later, when patients are comfortable with him and other conditions do not improve, will he consider trying obesity medications, Dr. Hagan said.

Obese people, he added, tend to have a long history of strained relationships with doctors who blame them for their weight, even if they have spent years, even decades, trying diets and doing exercises. exercise. Many of them, he says, will be discouraged if the first thing he tries to treat is their obesity.

“My priority,” he says, “is to establish trust in a relationship. »