Tuesday, July 23, 2024

Doctors Test the Limits of What Obesity Drugs Can Fix

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Lesa Walton suffered for years with rheumatoid arthritis. “It was awful,” said Ms. Walton, 57, who lives in Wenatchee, Wash. “I kept getting sicker and sicker.”

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

Then she 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 cleared up, 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 that Ms. Walton exemplifies a growing movement in obesity medicine.

Proponents call it “obesity first.” The idea is to treat obesity with medications approved for that use. As obesity comes under control, they note, the patient’s other chronic diseases tend to improve or go away.

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

Others are wary. People with obesity can be put off when a doctor mentions their weight. And, yes, the new obesity drugs may have unexpected benefits beyond obesity, like reducing inflammation. But the drugs are expensive, and many of the other potential gains have not been demonstrated in rigorous studies.

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

Obesity drugs, he said, are to treat obesity.

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

The idea of treating obesity first is a change from customary medical practice. When patients come in with obesity and other related chronic conditions like high blood pressure, elevated blood sugar levels and sleep apnea, many doctors prescribe drugs for each condition. They may also advise exercise and changes to diet — but often without any clear guidance and, as decades of studies repeatedly showed, without any real prospects that most people will lose weight.

By starting with a powerful new drug for obesity, like Wegovy from Novo Nordisk or Zepbound from Eli Lilly, in addition to diet and exercise, doctors hope that while they treat obesity, using just one drug, the related conditions will improve.

As Dr. Caroline M. Apovian, an obesity medicine specialist at Brigham and Women’s Hospital in Boston, puts it, “You get the weight loss, and you’ve treated the high blood pressure, the fatty liver, the diabetes, the high cholesterol, the high triglycerides.”

Dr. Apovian, who has advised companies that make the obesity drugs, says that patients are thrilled to be taking one drug instead of many and, of course, to be losing weight after years of fruitless attempts at dieting.

Experts also describe another advantage: Patients often keep taking the obesity drugs, while many who are taking drugs they need to be healthy, like statins, abandon them.

Still, there are as yet few examples of rigorous studies to show that medical conditions accompanying obesity go away when it is treated. Large clinical trials that randomly assign patients to an obesity treatment or a placebo are needed to establish whether the medicine has the hoped for effect on multiple conditions.

It may not.

Medical history is stuffed with examples of treatments that everyone thought would work until a clinical trial showed they didn’t.

Experts widely expected menopause 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 put heart disease protection on the drug’s label. But when the National Institutes of Health conducted a large and rigorous study, the Women’s Health Initiative, the researchers had to end the clinical trial early for safety reasons: Women taking the drug had an increased risk of heart disease, blood clots, strokes and breast cancer.

Then there was the federal study asking if beta carotene, a widely used antioxidant supplement, could reduce the risk of cancer and heart disease. The supplement did not, and it slightly increased the lung cancer risk among smokers and those exposed to asbestos.

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

Yet there is reason to think that the new obesity drugs could be different. They seem to have effects on the brain and the body that go far beyond quelling urges to eat.

Those 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, cardiac complications diminished early in the course of treatment, before the patients lost much weight.

The company now reports that they also had improvements in their kidney functions, independent of weight loss. Participants taking Wegovy who lost very little weight had the same sort of improvements in kidney functions as those who lost a lot.

A recent study by Novo Nordisk 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 that was independent of weight loss. Dr. Florian M.M. Baeres, the company’s corporate vice president of global medical affairs, noted that the participants’ starting weight also did not matter. The effect on the primary outcome was the same, he said, “whether you start from a BMI above 30 or under 30.”

A large part of the effect may be the drugs’ ability to reduce inflammation, said Dr. Daniel Drucker, an obesity researcher at the Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital in Toronto. It occurs before weight loss.

Dr. Drucker, who was involved in the discovery of the new drugs and consults for the companies that make them, was stunned by the response from patients after media outlets mentioned a paper he co-wrote showing that the obesity drug tirzepatide or Zepbound can reduce inflammation. In mice.

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

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

Eli Lilly and Novo Nordisk, the makers of Zepbound and Wegovy, are testing variations of the drugs in the hope that they will be even better in eliciting weight loss.

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

“This is the way clinical research on new drugs ought to be done,” said Dr. Ezekiel Emanuel, co-director of the Healthcare Transformation Institute at the University of Pennsylvania.

But assessing which drugs effectively treat which conditions will take a long time. Clinical trials take years and cost millions of dollars. Many doctors may be unwilling to wait.

“I’m very sympathetic to clinicians who say, ‘While the researchers are getting more data, we are going to try this approach,’” Dr. Emanuel said. It is common in oncology, he added, that once a drug is approved, doctors can use it for other illnesses, at their discretion.

With the obesity drugs, he added, the off-label experimenting — like a recent small study indicating that one of the drugs might slow the progression of Parkinson’s disease — shows “what a miraculous set of drugs these are,” with effects that were “totally unexpected.”

Others caution against “obesity first,” including representatives of companies like Eli Lilly and Novo Nordisk, saying that it is prudent to wait for results from clinical trials.

Dr. Scott Hagan, a Seattle primary care doctor, goes further, edging toward an “obesity last” approach.

If a patient comes in with obesity and obesity-related conditions, he starts by treating the related conditions with drugs he knows can work. Only later, when the patients are comfortable with him, and if the other conditions are not improved, will he discuss trying the obesity drugs, Dr. Hagan said.

People with obesity, he added, tend to have a long history of fraught relationships with doctors who blame them for their weight, despite their having spent years, even decades, trying diets and exercise. Many of them, he says, will be put off if the first thing he tries to treat is their obesity.

“My priority,” he said, “is establishing trust in a relationship.”



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