Doctors test the limits of what obesity drugs can fix

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

She also had high blood pressure and was obese. Doctors told her to go on a 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 has she lost more than 50 pounds, she said; Her arthritis resolved 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 it “obesity first.” The idea is to treat obesity with drugs approved for that use. As obesity comes under control, they note, the patient's other chronic diseases tend to improve or disappear.

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

Others are cautious. Obese people may be discouraged when a doctor mentions their weight. And yes, new obesity drugs could have unexpected benefits beyond obesity, such as reducing inflammation. But the drugs are expensive, and many of the other potential benefits have not been proven 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 l obesity, such as high blood pressure, high blood pressure, cholesterol levels, arthritis and sleep apnea.

Anti-obesity drugs, he said, are intended to treat obesity.

Yet many doctors, like Dr. Deeds, are struck by stories like Ms. Walton's, which they say they see often 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 argue.

The idea of ​​treating obesity first represents a change from usual medical practice. When patients come in with obesity and other related chronic conditions such as hypertension, high blood sugar levels and sleep apnea, many doctors prescribe medications for each condition. They may also recommend exercise and dietary changes, but often without any clear guidance and, as decades of studies have repeatedly shown, without any real prospect that most people will lose weight.

By starting with a powerful new obesity drug, such as Novo Nordisk's Wegovy or Eli Lilly's Zepbound, in addition to diet and exercise, doctors hope that as they treat obesity with just one drug, related conditions will improve.

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

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

Experts also describe another benefit: Patients often continue to take obesity medications, while many who take medications needed for health, such as statins, abandon them.

However, there are still few examples of rigorous studies showing that the medical conditions that accompany obesity disappear 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 desired effect on multiple conditions.

It might not be.

The history of medicine is full of examples of treatments that everyone thought would work until a clinical trial proved otherwise.

Experts 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 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, researchers had to stop the clinical trial early for safety reasons: women taking the drug had a higher risk of heart disease, blood clots, stroke 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 did not, and it slightly increased the risk of lung cancer among 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.

Yet there is reason to think that new obesity drugs could be different. They appear to have effects on the brain and body that go far beyond simply controlling the urge to eat.

Such effects can appear 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 the patients lost much weight.

The company now reports that it also had improvements in kidney function, independent of weight loss. Participants who took Wegovy and lost very little weight had the same kind of improvements in kidney function as those who lost a lot.

A recent Novo Nordisk study testing Ozempic on 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 corporate vice president for global medical affairs, noted that participants' initial weight also did not matter. The effect on the primary outcome was the same, he said, “whether you started from a BMI above 30 or below 30.”

Much of the effect may be due to 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, involved in the discovery of new drugs and a consultant to the companies that make them, was stunned by the response from patients after the media mentioned an article he co-wrote showing that the obesity drug tirzepatide or Zepbound can reduce inflammation. In mice.

Not just in mice, patients told him via email. 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 medications she was taking. In the next 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 fear that future employers might learn of her illness.

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

So far, in addition to results in people with heart disease, Novo Nordisk has 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 found that Zepbound can help with sleep apnea. Other studies currently underway are testing anti-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 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 evaluating which drugs effectively treat certain conditions will take a long time. Clinical trials take years and cost millions of dollars. Many doctors may not be willing to wait.

“I'm very sympathetic to doctors who say, 'As researchers are getting 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 testing — such as a recent small study indicating that one of the drugs might slow the progression of Parkinson's disease — shows “what a set of miracle drugs this is,” with effects which were “completely unexpected.”

Others warn against “obesity first,” including representatives from companies such as Eli Lilly and Novo Nordisk, saying it is prudent to await the results of clinical trials.

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

If a patient comes in with obesity or obesity-related conditions, he starts by treating the related conditions with medications that he knows will work. Only later, when patients feel comfortable with him, and if other conditions have not improved, will he discuss the possibility of trying obesity medications, Dr. Hagan said.

Obese people, he added, tend to have a long history of difficult relationships with doctors who blame them for their weight, despite having spent years, even decades, trying diets and exercise. Many of them, he says, would be discouraged if the first thing he tried to treat was obesity.

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

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