Paving the Road to Game-Changing Weight Loss in America
Robert Kushner, MD, helped show the effectiveness of new anti-obesity medications that also help reduce cardiovascular disease risk.
By Christina Frank
For people with obesity, new medications like Ozempic and Wegovy—brand names for the anti-obesity drug semaglutide—have been game-changers. They’ve become so popular, in fact, that the companies that make these drugs have been unable to keep up with demand.
“I don’t think anyone really foresaw the incredible increased demand for these medications,” says Robert Kushner, MD, ’80, ’82 GME, professor of Medicine in the Division of Endocrinology, Metabolism and Molecular Medicine and of Medical Education.
Kushner was one of the first investigators to understand the true power of these medications. He was the lead author on a seminal 2021 paper published in the New England Journal of Medicine that evaluated the effectiveness of semaglutide in people with obesity. The study found that semaglutide was up to two times more effective than current weight loss drugs.
Kushner’s work was heralded as a top 10 paper by the Clinical Research Forum and took home the 2022 Herbert Pardes Clinical Research Excellence Award.
He attributes the drugs’ skyrocketing popularity at least partially to social media influencers. While he acknowledges that many influencers do not have clinical obesity and are inappropriately using the drugs for cosmetic weight loss purposes, he believes the attention they’ve drawn to these medications is important.
“Patients are coming in asking for these drugs because they’ve seen them on social media and in the news,” Kushner says. “Obesity is a serious disease like hypertension and diabetes that we really need to start paying more attention to, and these drugs mean we can actually do something about it quite effectively in selected individuals.”
HIGHER LIKEIHOOD OF LOSING WEIGHT
Prior to semaglutide, prescription weight loss drugs (such as Xenical, Contrave, and phentermine) worked by augmenting or changing signaling in the brain or by blocking fat absorption.
The new medications rely on a different mechanism entirely by targeting gut hormones. Glucagon-like peptide-1 (GLP-1), a hormone released in response to food intake, makes patients feel full, stimulates insulin release, inhibits glucagon secretion, and regulates gastric emptying. Semaglutide mimics GLP-1, reducing hunger and food cravings.
Kushner says patients often perceived older medications as dangerous or had negative connotations of them as an “easy way out,” but that perception is being challenged for newer therapies.
“There’s a much greater chance that someone will respond to these current drugs than to previous ones,” he says. “The likelihood of losing 5 percent, 10 percent, 15 percent, or 20 percent of your body weight is significantly higher than with the older medications.”
Kushner stresses that there is no so-called “ideal body weight.” These drugs alter what’s called a set point by creating a new body weight balance or equilibrium. How much weight any given person with obesity needs to lose is largely determined by their specific weight-related health complications.
“We now know that certain medical complications of obesity respond to different levels of weight loss,” Kushner says. “For example, if your blood sugar or your blood pressure is elevated, 3 percent or 5 percent weight loss will have an immediate effect. But if you come in with obstructive sleep apnea or fatty liver disease, 3 to 5 percent weight loss doesn’t seem to have the same impact on improving those complications. You need to lose 10 percent or more of your body weight to make a difference. To resolve urinary incontinence, a common complication of obesity, losing 7 percent of your body weight or more may be necessary.”
REDUCING CARDIOVASCULAR RISK AND IMPROVING QUALITY OF LIFE
The effects of semaglutide on cardiovascular disease has cardiologists eager to harness the drug’s protective benefits.
Results from the randomized, double-blind SELECT (Semaglutide Effects on Heart Disease and Stroke in Patients with Overweight or Obesity) trial published in December 2023 have shown that semaglutide may reduce the risk of cardiovascular events such as heart attacks and strokes in people with obesity. In August, Novo Nordisk (the manufacturer of Wegovy) released topline results that found that 2.4 mg of semaglutide injected once a week caused on average a 20 percent reduction in major adverse cardiovascular events in people with overweight or obesity. Kushner serves on the steering committee for the SELECT trial.
At Northwestern, a clinical trial showed that the drugs can also help patients with heart failure and obesity lose weight while also improving symptoms and increasing exercise capacity (see sidebar).
Other studies have shown that people with complications of obesity were able to get off of medications for blood pressure, heartburn, and diabetes entirely as a result of the weight loss.
“Quality of life goes up,” Kushner says.
GETTING PRIMARY CARE PHYSICIANS ONBOARD
Right now, says Kushner, the “hottest area” in new weight loss drug development is combining two or even three synthesized gut hormones into one medication. While semaglutide only targets GLP-1 receptors, newer drugs such as tirzepatide (Mounjaro) targets GLP-1 as well as GIP (glucose-dependent insulinotropic polypeptide).
Kushner was also a co-author on a study published in Nature Medicine in October 2023 that showed tirzepatide, an antidiabetic drug currently used to treat type 2 diabetes, was effective in helping individuals without diabetes who are overweight or have obesity lose weight in combination with other lifestyle changes. The FDA approved tirzepatide in November.
“And indeed, the weight loss is greater with that drug than with the semaglutide alone,” he says. “As you start combining these different hormones together, you get an array of metabolic effects on inflammation, on fatty liver, on the fat cell itself, and on insulin release. So that’s why we are going in this direction. We’re really improving the health of individuals and how much weight loss we can achieve.”
Kushner stresses that a critical piece of the continued success of these drugs is for primary care professionals to engage fully in caring for their patients with obesity. At the moment, he says, these providers often refer patients with obesity to specialists such as obesity medicine physicians or endocrinologists.
“Obesity is very challenging at the primary care level,” he says. “It’s complex. There’s not a lot of training in this disease. It takes time to work with these individuals, and to be fair, primary care professionals have multiple other medical problems to address.”
Right now, there just aren’t enough specialists to be able to handle the 42 percent of the American adult population that has a diagnosis of obesity. Over time, Kushner says, as there’s more familiarity with these anti-obesity drugs, they’ll be used in primary care.
“It’s a very, very exciting time in this field, and we have to keep moving it upstream and not just keep it with the specialist,” he says. “It’s all part of the paradigm shift in how we’re thinking about obesity.”
Listen to Robert Kushner discuss his study on the use of semaglutides to treat obesity in the February 2021 episode of Breakthroughs Podcast, “A Promising Obesity Drug with Robert Kushner, MD“.