The off-label use of semaglutide (Ozempic; Novo Nordisk) for the treatment of obesity has been blamed for a recent supply shortage of the drug, which is indicated for type 2 diabetes. However, many experts say satiety drugs and the like are revolutionary additions to the obesity treatment arsenal.
Demand for injectable semaglutide, a glucagon-like peptide-1 (GLP-1) agonist, has skyrocketed over the past 12 months following a large manufacturer-sponsored randomized trial (STEP 1), published in the New England Journal of Medicine (NEJM), which found that semaglutide 2.4 mg once weekly was associated with an average weight reduction of 15% at 18 months, compared to 2.4% with placebo in overweight or obese people.
However, problems with access soon became apparent. In Australia, where semaglutide 0.5mg and 1mg are approved and subsidized for the treatment of type 2 diabetes, the Therapeutic Goods Administration (TGA) warned in May that off-label prescribing of the drug to obese people had caused a supply shortage. . Physicians have been advised to limit the prescription of semaglutide to its approved use in people with diabetes.
The manufacturer, Novo Nordisk, said Preview+ that he has applied for registration of semaglutide 2.4mg with the TGA for weight management under the brand name he already uses overseas, Wegovy.
There is also another GLP-1 drug on the horizon for the treatment of obesity: tirzepatide. A phase 3 trial published in the NEJM on June 4, half of obese patients randomly assigned to moderate doses of tirzepatide once a week lost at least 20% of their body weight at 72 weeks, compared to only 3% in the placebo group. Both groups received an intensive lifestyle intervention. The drug has not yet been approved anywhere in the world for the treatment of obesity, although it was recently approved in the United States for type 2 diabetes.
Yet even if newer GLP-1 agonists become indicated in Australia for weight loss, experts fear their price will put them out of reach for most obese patients.
Dr Priya Sumithran, endocrinologist and group leader of the Obesity Research Group at the University of Melbourne, summed up the hope and concern felt by researchers in the field.
“The past few years have seen tremendous change and optimism in the field of diabetes and obesity in what is available and what is going to be possible, and we now have several good treatment options imminent,” he said. she declared. Preview+. “However, the big question now is whether patients will be able to afford access to it.
“How we fund or reimburse these drugs will have to change if people are going to be able to benefit equitably from them,” she said.
Unequal access
Patients with insufficiently controlled type 2 diabetes can access semaglutide under the Pharmaceutical Benefits Scheme (PBS) for $42 per month or $6.80 on preferential terms.
Obese people, on the other hand, pay around $133 a month if they access the off-label drug. It’s a treatment that most obese Australians – 30% of the population – cannot afford, especially given the high prevalence of obesity among low-income people.
Yet many who can afford it will pay, given that semaglutide is associated with significantly greater average weight loss compared to placebo than currently registered drugs for obesity in Australia – phentermine (Duromine; iNova) , naltrexone and bupropion (Contrave; Currax), liraglutide (Saxenda; Novo Nordisk) and orlistat. Liraglutide, the only registered GLP-1 agonist for obesity, costs three times as much as semaglutide ($387) and has the disadvantage of being taken daily rather than weekly.
Novo Nordisk, maker of semaglutide and liraglutide, said Preview+ the two drugs were not equivalent.
“Saxenda (liraglutide 3mg) is the only GLP-1 approved for use in weight loss in Australia,” the company said in a statement. “Saxenda (liraglutide 3mg) is a different molecule with different dosage and different indications from Ozempic (semaglutide).”
However, Professor Katherine Samaras, an endocrinologist and researcher at St Vincent’s Hospital in Sydney, said the STEP 1 study provided ample evidence to support prescribing semaglutide for the treatment of obesity, as is already being done. many specialists and general practitioners.
“Why should obese people pay three times the price of a drug when an effective and cheaper drug is available? ” she said Preview+.
Professor Samaras, like many of her colleagues, believes that barriers to access to obesity medications are an important equity issue.
However, the Pharmaceutical Benefits Advisory Committee (PBAC) estimated that subsidizing semaglutide for obese Australians would cost over $1 billion per year over 6 years in the current market.
The PBAC reviewed semaglutide for obesity at its March 2022 meeting and decided not to recommend the requested listing. This would have required “extremely high investment” with “very uncertain implications for PBS and the broader health budget,” the PBAC said.
He also questioned the drug’s long-term effectiveness on evidence-based outcomes, saying the sponsor’s modeled reductions in comorbidities with ongoing treatment were “highly uncertain” given that no longer-term data are available. was available.
Dr Liz Sturgiss, a general practitioner and researcher at Monash University, noted that the STEP 1 study of semaglutide showed “some improvements in cardiovascular risk factors, such as blood pressure, glycated hemoglobin and cholesterol with a treatment”.
“Although the trial only reported most of them as secondary endpoints, rather than as part of the results, it is promising as it is one of the first drug trials against obesity that look at outcomes other than weight.”
She added: “Equity is a major issue in the management of obesity in Australia.”
A disease that kills
Prof Samaras said part of the problem with access to obesity medication and bariatric surgery came down to the stigma surrounding the disease.
“There are misleading stories in the media that obese people just want to lose weight for cosmetic reasons, or that they are responsible for their condition,” she said.
“The fact is obesity kills people,” she said. “The major cancers in Australia today are all hastened by obesity, and obesity is a risk factor for diabetes, cardiovascular disease, fatty liver disease, cirrhosis and arthritis.”
Professor Samaras criticized a ‘monocular glucocentric view of obesity’, saying many obese people maintained normal glucose levels but had significant obesity-associated comorbidities or were at risk.
Even modest weight reductions could alleviate significant health burdens, Professor Samaras said. For example, a 5 kg weight reduction could help some patients manage their blood pressure and lipids.
Other patients may have more important weight reduction goals to access procedures such as heart transplantation or to ensure good outcomes after cancer treatment or joint replacement surgery, she said.
The place of medicine
Professor Samaras said the new GLP-1 agonists are good additions to the obesity treatment arsenal, alongside lifestyle interventions and, if needed, bariatric surgery.
“For people who have tried diet and exercise over and over and over again, you add whatever is necessary and safe, depending on how obesity is impacting that individual,” she said. declared.
Bariatric surgery now had results at 20 years reported in the literature; however, with almost no access to surgery in the public system, it was also out of reach for many patients, she said.
Professor Samaras said GLP-1 agonists should be considered before a trial of bariatric surgery.
The new drugs could also be helpful for people who have regained weight in the years following successful bariatric surgery, she said.
Evidence was also mounting to support the use of GLP-1 agonists to blunt the obesity-inducing effects of antipsychotic drugs, according to Professor Samaras, who is taking part in a trial co-prescribing semaglutide and clozapine.
Professor Samaras stressed that no medicine or surgery would work without lifestyle changes.
This was in fact one of the reasons the PBAC did not recommend listing semaglutide for obesity – it was “unlikely” that the benefits of semaglutide seen in clinical trials would be “fully realized in practice.” Australia without the intensive diet and co-administered exercise advice”. in the trial program,” the PBAC said.
Risks and contraindications
The main side effects of the newer GLP-1 receptor agonists are gastrointestinal – nausea, diarrhea and constipation.
In the semaglutide-related obesity study, 4.5% of participants in the treatment group discontinued treatment due to gastrointestinal events.
Professor Samaras commented: “Some people may be extremely sensitive and may take the lowest dose and vomit for a week. They might respond better to a different medication.
There are also questions about the safety of GLP-1 agonists in the context of heavy alcohol consumption given the low risk of pancreatitis, Professor Samaras said. However, she added that, anecdotally, semaglutide may actually reduce a patient’s interest in alcohol.
Professor Samaras said the main concern with new drugs was the lack of long-term safety data. The longest follow-up period is only about 3 years for semaglutide.
“However, it must be remembered that obesity itself is not a benign condition,” she added.
In general, NPS MedicineWise notes that there are no legal barriers to prescribing off-label medications, but the onus is on the prescriber to defend their prescription for an indication that is not listed in the product information.
A TGA spokesperson said the semaglutide shortage is expected to resolve on August 31, 2022.
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