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Diabetes drugs re-purposed for obesity have revolutionized medicalized weight loss but at a price, according to JAMA Medical News.
In addition to common, mild-to-moderate digestive issues, clinicians are now observing more serious gastrointestinal side effects plus self-harm behavior, anesthesia complications, serious vision problems and cancer cases among people taking GLP-1 agonists, either to lower their blood sugar or lose weight.
Because the drugs are so widely prescribed these relatively rare complications involve enough patients to concern prescribers, according to some medical experts.
Despite gastrointestinal side effects, demand for weight-loss drugs growing
A recent study by Mahyar Etminan, an epidemiologist at the University of British Columbia, Vancouver, Canada, compared gastrointestinal safety outcomes between the injectable GLP-1 weight-loss drugs semaglutide and liraglutide to an older combination pill, bupropion-naltrexone. Bupropion is an antidepressant and naltrexone blocks the effects of opioids.
The study, published on JAMA Network, recruited 4,144 obese subjects taking liraglutide (brand name Saxenda), 613 taking semaglutide (brand names Wegovy, Ozempic and Rybelsus) and 654 prescribed bupropion-naltrexone. Diabetics were excluded from the study.
In addition to the usual gastrointestinal side effects of nausea, vomiting, diarrhea and constipation, those taking the GLP-1 agonists faced a 9-fold greater relative risk of pancreatitis (pancreas inflammation), a 4-fold greater risk of bowel obstruction and more than 3 times the occurrence of gastroparesis.
Gastroparesis is a condition that weakens the muscular contractions in the stomach that propel food through the digestive tract, thus causing delayed stomach emptying and in turn, causing a person to feel “full” longer. Theoretically, this causes a person to eat less and/or less often. Weight-loss drugs also cause delayed stomach emptying — but in extreme cases, they also can cause stomach paralysis.
Despite the alarming relative risks, the absolute risk of serious gastrointestinal side effects associated with injectable GLP-1 drugs was only about 1% or less per year of use. How can this be?
Think of 100 hypothetical subjects taking a medicine and 100 taking a sugar pill, with two cases of hives among medicated subjects but only one in the placebo group. It is equally correct to conclude that treatment increased the risk of hives by 100% (2 cases vs. 1), or by 1% (one additional case per 100 treated subjects).
Regardless of how one views the data, demand for GLP-1 agonists is growing so rapidly that J.P. Morgan recently doubled its 10-year sales projection for these drugs. These drugs have become blockbusters despite their shortcomings thanks to direct-to-consumer advertising and nearly $26 million in “honoraria” paid to prescribers.
A commenter not involved in the studies mentioned in this article, Dr. Susan Yanovski, co-director of the Office of Obesity Research at the National Institute of Diabetes and Digestive and Kidney Diseases, told JAMA: “When treating millions of people with medications like semaglutide, even relatively rare side effects will occur in a large number of people.”
Acute pancreatitis and gallbladder disease, known side effects of GLP-1 drugs, are listed on the labels for all formulations containing semaglutide and liraglutide. But Etminan said in an interview with JAMA that gastroparesis and bowel obstruction were “a bit more unheard of.”
“Gastroparesis is very new,” he said, adding that his findings support case reports and social media posts by individuals using semaglutide for weight loss.
Yanovski said Etminan’s findings “reinforce that these are potent medications, and all medications have side effects,” but noted that while the relative risk was significantly elevated for the worst gastrointestinal adverse effects their absolute risks remained low.
The study’s limitations included a lack of information on baseline body mass index, or BMI, the quantity of lost weight and whether the drugs were being used for weight loss (and not just diabetes).
‘Caution’ urged for people with history of suicidal thoughts, depression
Based on case reports of depression and suicidal thoughts among GLP-1 users, the European Medicines Agency decided to review GLP-1 prescribing patterns. The agency’s report was due in November 2023. However, on Nov. 7, the agency reported it had not completed the study — while also noting that suicidal behaviors had been reported for other classes of antiobesity drugs.
The prescribing information (PI) for Wegovy, Saxenda and Zepbound GLP-1 agonists includes warnings to monitor patients for depression or suicidal thoughts — but other GLP-1 agonists do not carry the warning.
According to Saxenda’s safety details, 0.3% of those taking the drug in clinical trials reported suicidal ideation compared with 0.1% of placebo subjects. This is another example of a high relative risk (200%) but very low absolute risk (0.2%).
Subjects with a history of depression or suicidal behavior were excluded from Wegovy’s and Saxenda’s clinical trials.
“It’s certainly a good idea for clinicians to use these drugs with caution in people who have a history of suicidality or are currently suicidal and to monitor patients for it,” Yanovski said.
GLP-1 agonists plus anesthesia could be dangerous
While delayed stomach emptying may prolong sensations of satiety it also raises the risk of regurgitation during routine anesthesia applied during surgery.
Pulmonary aspiration — breathing in regurgitated food — is a rare but potentially fatal complication of anesthesia. To reduce risk, surgeons tell patients to avoid solid food for six hours and clear liquids for two hours before scheduled procedures requiring anesthesia (including quick-recovery procedures like colonoscopies).
But during the past year, reports have surfaced describing incidents of patients on GLP-1 agonists who regurgitated during surgery. The JAMA analysis described them as “striking” for the volume of regurgitated food despite having fasted.
In June 2023, the American Society of Anesthesiologists warned physicians to keep patients off daily-use GLP-1 agonists on the day of surgery and to have patients skip taking weekly formulations, like Wegovy and Ozempic, for seven days before surgery.
Delayed stomach emptying could explain why this occurs, said Dr. Girish P. Joshi, an anesthesiologist at the University of Texas Southwestern Medical Center in Dallas who helped develop the new guidance. The U.S. Food and Drug Administration (FDA) in September updated Ozempic’s PI to include this warning. Earlier this year, the FDA added a warning to Saxenda’s PI.
In an October 2023 paper, Joshi wrote that additional, high-quality studies “are urgently needed to investigate the safety” of GLP-1 drugs during anesthesia.
He also noted that patients in the earliest phases of GLP-1 therapy may experience a heightened delay in gastric emptying, which increases the likelihood of a full stomach — and with it the odds of experiencing aspiration issues.
Drugs ‘for life,’ but no long-term safety data
Whether taken for diabetes or weight loss GLP-1 drugs are meant to be taken for life. Yet not much is known about their long-term safety.
The package insert for Wegovy warns that “in rodents, semaglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures.” In other words, the more of the drug given to rats, the greater their risk for thyroid cancer.
Semaglutide is therefore not recommended for people with a family history of thyroid or other cancers of the endocrine system.
Despite this “black box” PI warning a recent study on cancer incidence among semaglutide-treated patients concluded: “Semaglutide use in RCTs [randomized controlled trials] and real-world studies was not associated with an increased risk of any types of cancer, and this conclusion is supported by a high grade of evidence.”
While these researchers did not find a statistically significant association, the incidence of thyroid cancer in the GLP-1 group was double that of the placebo group.
Expensive and not easy to find
Semaglutide drugs are taken as a once-weekly injection, which is considered a benefit compared to a once-daily jab. Liraglutide is a daily shot. Semaglutide is also available as a once-daily pill under the brand name Rybelsus.
In November 2023, the FDA approved Zepbound, another injectable diabetes drug, for weight loss. The active ingredient in Zepbound, tirzepatide, sets this drug apart from Wegovy and Ozempic but it works similarly through a weekly injection.
Tirzepatide is sold as a diabetes drug under the trade name Mounjaro.
Like the other GLP-1 agonists tirzepatide keeps food inside the stomach longer, thereby creating the sensation of fullness, and is associated with the usual digestive side effects of nausea, diarrhea, vomiting, constipation, stomach discomfort and pain, injection site reactions, fatigue, allergic reactions (typically fever and rash), burping and gastroesophageal reflux disease.
And like semaglutide, tirzepatide also causes thyroid C-cell tumors in rats, according to the drug’s PI. Based on the PI’s disclaimer that “It is unknown whether Zepbound causes such tumors, including medullary thyroid cancer, in humans” a full range of safety studies was either not completed or not undertaken by approval time.
According to a KFF Health poll, 45% of adults would take a “safe and effective prescription weight loss drug,” including 59% of those trying to lose weight.
Enthusiasm fell to just 23%, however, when they learned that treatment involved a routine injection, to 16% if either insurance did not cover the $1,200 monthly cost or if the drug was not specifically approved for weight loss, and to 14% after learning the weight loss might last only as long as they were taking the drug.
More than a quarter of respondents reported difficulty affording prescription drugs, with another 31% reporting not taking their medicine as prescribed during the past year due to the cost.
Due to spot shortages of semaglutide products, price increases and uncertain insurance coverage, some patients stop taking the drugs, causing appetite and weight to return.
As with other weight-loss strategies not based primarily on healthy eating, most people regain between 50% and 75% of the weight lost within one year of quitting semaglutide weight-loss drugs.
Due to the popularity of injected weight loss drugs their availability at the proper doses has been an issue, even when insurance picks up all or most of the tab.
For example, Wegovy and Ozempic are started at a low dose which is increased over several weeks until arriving at a maintenance dose. Some patients call pharmacies for days before finding the right dose for their course of treatment.
Finding Wegovy is a part-time job for some patients, Dr. Diana Thiara, medical director of the weight management clinic at the University of California, San Francisco, told the news outlet Boston.com. She said some drive 45 minutes or more for prescriptions, which prevents hourly workers or individuals lacking access to transportation from accessing the medicine.
In an interview with Healthline, Dr. Rekha Kumar, a New York City-based endocrinologist, said: “Normal-weight patients without diabetes might lose weight if they take GLP-1s, but the risks of the medication outweigh the benefit of weight loss just to be thin versus treating a disease.”