Wegovy is the first weight loss drug to be approved for major heart disease prevention, after the US Food & Drug Administration gave the green light last week for the semaglutide to be used to reduce the risk of cardiovascular death, heart attack and stroke in adults with cardiovascular disease, and either obesity or overweight.
As a GLP-1 receptor agonist, semaglutide should be used in conjunction with a reduced calorie diet and increased physical activity, added the agency.
John Sharretts, MD, director of the Division of Diabetes, Lipid Disorders and Obesity at the FDA’s Centre for Drug Evaluation and Research, said this patient population “has a higher risk of cardiovascular death, heart attack and stroke”, and that providing a treatment option “proven to lower this cardiovascular risk is a major advance for public health”.
Medpage Today reports that underpinning the approval was the 17 600-patient SELECT trial, which included patients with overweight and obesity (with or without diabetes) as well as pre-existing cardiovascular disease.
The phase 3 study showed that semaglutide significantly reduced the composite of cardiovascular death, heart attack and stroke by 20% (HR 0.80, 95% CI 0.72-0.90). In the three-year study, where both groups received standard-of-care medical treatment, these major adverse cardiac events occurred in 6.5% of patients on semaglutide and 8% of those on placebo.
“Semaglutide 2.4 mg is the first weight management therapy proven in a rigorous randomised trial to reduce the risk of cardiovascular events, which establishes overweight or obesity as a modifiable risk factor for cardiovascular disease,” said study investigator Michael Lincoff, MD, of the Cleveland Clinic, when the data were presented at the American Heart Association annual meeting last year.
The FDA noted that the GLP-1 receptor agonist should not be used with other agents in the class, or with other semaglutide-containing products.
Wegovy was first approved in June 2021 for chronic weight management in adults with obesity (BMI of 30 or greater) or who were overweight (BMI 27 or greater) with at least one weight-related condition. This indication was later expanded to include children with obesity, aged 12 and older.
Semaglutide is also approved for type 2 diabetes as an injectable (Ozempic) and oral drug (Rybelsus).
Consistent with the GLP-1 agonist class, common side effects with semaglutide include nausea, diarrhoea, vomiting, constipation, abdominal pain, headache, fatigue, dyspepsia, dizziness, abdominal distension, eructation, hypoglycaemia in patients with diabetes, flatulence, and gastro-oesophageal reflux disease.
Other warnings and precautions in the labelling include pancreatitis, gall bladder problems, hypoglycaemia, acute kidney injury, hypersensitivity reactions, diabetic retinopathy, increased heart rate, and suicidal behaviour or thinking.
“The prescribing information for Wegovy contains a boxed warning to inform healthcare professionals and patients about the risk of thyroid C-cell tumours,” the agency noted. “Because of this risk, Wegovy should not be used in patients with a personal or family history of medullary thyroid carcinoma or in patients with a rare condition called Multiple Endocrine Neoplasia syndrome type 2.”
To stop or not to stop?
Meanwhile, however, millions of people who have shed kilos and boosted their health using drugs like Wegovy are facing a new dilemma: what happens if they stop taking them?
Many worry, rightly, that they’ll regain weight and revert to old habits. In clinical trials, patients who paused the drugs put back on most of the weight they lost.
More than 3m prescriptions for the new medications are dispensed each month in the US, and include semaglutide, the drug in Ozempic and Wegovy, and tirzepatide, the drug in Mounjaro and Zepbound.
But many people don’t stick with it. One recent study published in the journal Obesity found that just 40% of patients who filled a prescription for semaglutide in 2021 or 2022 were still taking it a year later.
Doctors who treat obesity stress that the disease is a chronic condition that must be managed indefinitely, like heart disease or high blood pressure.
The new injectable drugs work by mimicking hormones in the gut and the brain to regulate appetite and feelings of fullness. They were designed – and tested – to be taken continuously, experts said.
“We are not an injection shop,” said Andres Acosta, MD, PhD, an obesity researcher and medical adviser at the Mayo Clinic. “I don’t think they should be used in intermittent fashion. It’s not approved for that. They don’t work like that.”
Despite that directive, some patients who achieved their health and weight goals with the drugs are looking for an off-ramp, said Amy Rothberg, MD, a University of Michigan endocrinologist who directs a weight-management and diabetes treatment programme.
“Many of them want to step down or de-escalate their dose,” she said. “And they’re also wanting to ultimately discontinue the medication.”
Taking ‘a breather’
The reasons for pausing the drugs can vary, said Katherine Saunders, MD, an obesity expert at Weill Cornell Medicine and co-founder of the obesity treatment company Intellihealth. Some patients don’t like side effects such as nausea and constipation.
Others want to stop for holidays or special occasions – or just because they don’t want to take the weekly shots indefinitely.
One of Saunders’ patients, a 53-year-old man, lost nearly 32kg last year using tirzepatide. He told Saunders he wanted to take “a breather” from the medication to see how his body reacted. On her advice, he has been stretching out injections to every 10 days or two weeks, instead of weekly, since December.
Other patients have been forced to ration or halt doses because the drugs are costly – $1 000 to $1 300 per month – and insurance coverage varies or because demand has far outstripped supply, Rothberg noted.
“It’s being imposed on them,” she said. “By necessity, they have to go off the medication and kind of figure it out.”
But hoping the drugs’ benefits will last even after stopping them ignores the fundamental biology of obesity, experts said. The disease affects the way the body processes and stores energy, causing it to accumulate weight.
The new drugs alter that process and when patients stop, the disease returns, often with a vengeance.
Many people dropping off the medications report a sharp rise in symptoms of obesity. They include so-called food noise or intrusive thoughts of food, raging hunger, and decreased feelings of fullness when they eat.
“These drugs are just a super-suppressor of these native signals,” Rothberg said. “And we should expect that’s going to occur.”
Tara Rothenhoefer (48) of Florida, lost more than 90kg after joining a clinical trial for tirzepatide nearly four years ago. She now takes the lowest dose of the drug every four to eight weeks, but she worries when her weight fluctuates by a few pounds.
“It scares the daylights out of me to see the numbers on the scale going up,” she said.
Some patients who stop the drugs and start again find they can’t tolerate the medication, winding up with severe gastrointestinal side effects, Acosta said. Others find the drugs don’t work as well when they restart them, Saunders added. But there’s no data on the long-term effects of intermittent use.
“I don’t think it’s a strategy that will work for most individuals, but it could be an option for select patients,” she said.
NEJM Patent SELECT Trial (Restricted access)
Medpage Today article – Wegovy Approved for Major Heart Disease Prevention (Open access)
Medpage Today article – Obesity Drugs Like Wegovy Are Meant for Long-Term Use, but Some Want to Stop
See more from MedicalBrief archives:
Weight loss drug trial suggests significant heart benefit
Obesity drugs may be added to WHO’s essential medicines list
US study finds serious side effects from weight-loss drugs
Half of obese teens on Wegovy return to normal weight – STEP TEENS trial