THE off-label use of semaglutide (Ozempic; Novo Nordisk) for the treatment of obesity has been blamed for a recent supply shortage of the medication, which is indicated for type 2 diabetes. However, many experts say the satiety medication and others like it are game-changing additions to the treatment armamentarium for obesity.
Demand for the injectable glucagon-like peptide-1(GLP-1) agonist semaglutide has soared in the past 12 months in the wake of a large manufacturer-sponsored randomised trial (STEP 1), published in the New England Journal of Medicine (NEJM), which found once-weekly semaglutide 2.4 mg was associated with an average weight reduction of 15% at 18 months, compared with 2.4% with placebo in people with overweight or obesity.
However, access issues have quickly come to the fore. In Australia, where semaglutide 0.5 mg and 1 mg is approved and subsidised for the treatment of type-2 diabetes, the Therapeutic Goods Administration (TGA) warned in May that off-label prescribing of the drug to people with obesity had caused a supply shortage. Doctors were told to limit prescribing of semaglutide to its approved use in people with diabetes.
The manufacturer, Novo Nordisk, told InSight+ that it has applied for semaglutide 2.4 mg to be registered with the TGA for weight management under the brand name it already uses overseas, Wegovy.
There is also another GLP-1-based medication on the horizon for obesity treatment: tirzepatide. A phase 3 trial published in the NEJM on 4 June found half of patients with obesity randomly allocated to moderate doses of tirzepatide once-weekly lost at least 20% of their body weight at 72 weeks, compared with only 3% in the placebo group. Both groups received 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 the new GLP-1 agonists become indicated in Australia for weight loss, experts fear their price tag will put them out of reach of most patients with obesity.
Dr Priya Sumithran, an endocrinologist and Group Leader of the Obesity Research Group at the University of Melbourne summarised the hope and concern felt by researchers in the field.
“The last few years have seen a huge 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,” she told InSight+. “However, the big question now is whether patients will be able to afford to access them.
“The way we fund or reimburse these medicines will need to change if people are going to be able to benefit from them equitably,” she said.
Patients with insufficiently controlled type 2 diabetes can access semaglutide on the Pharmaceutical Benefits Scheme (PBS) for $42 a month or $6.80 concessionally.
People with obesity, by contrast, pay around $133 a month if they access the drug off-label. It’s a treatment most Australians with obesity – 30% of the population – can’t afford, especially given the high prevalence of obesity among people on low incomes.
Still, many who can afford it will pay, given semaglutide is associated with much greater average weight loss compared with placebo than the medications currently registered for obesity in Australia – phentermine (Duromine; iNova), naltrexone and bupropion (Contrave; Currax), liraglutide (Saxenda; Novo Nordisk) and orlistat. Liraglutide, the only GLP-1 agonist registered for obesity, costs three times as much as semaglutide ($387) and has the inconvenience of being taken daily rather than weekly.
Novo Nordisk, manufacturer of both semaglutide and liraglutide, told InSight+ the two drugs were not equivalent.
“Saxenda (liraglutide 3 mg) is the only GLP-1 approved for use in weight loss in Australia,” the company said in a statement. “Saxenda (liraglutide 3 mg) is a different molecule with different dosing and different indications to 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 the prescribing of semaglutide for the treatment of obesity, as many specialists and GPs are already doing.
“Why should people with obesity have to pay three times the cost for a medication when an effective and cheaper medication is available?” she told InSight+.
Professor Samaras, like many of her colleagues, believes the barriers to accessing medications for obesity represent an important equity issue.
However, the Pharmaceutical Benefits Advisory Committee (PBAC) has estimated that subsidising semaglutide for Australians with obesity would cost more than $1 billion annually over 6 years in the current market.
The PBAC considered semaglutide for obesity at its March 2022 meeting and decided not to recommend the requested listing. Doing so would have required “extremely high investment” with “very uncertain implications for the PBS and broader health budget”, the PBAC said.
It also questioned the drug’s long term efficacy on hard outcomes, saying that the sponsor’s modelled reductions in comorbidities with ongoing treatment were “highly uncertain” given no longer term data were available.
Dr Liz Sturgiss, a general practitioner and researcher at Monash University noted that the semaglutide STEP 1 study showed “some improvements in cardiovascular risk factors, like blood pressure, glycated haemoglobin and cholesterol with treatment”.
“Although the trial only reported most of these as secondary endpoints, rather than part of the outcomes, it is promising as it is one of the first trials for obesity medications that are looking at outcomes other than weight.”
She added: “Equity is a major issue in the management of obesity in Australia.”
A disease that kills
Professor Samaras said part of the access problem with obesity medications and also bariatric surgery came down to stigma around the disease.
“There are misleading narratives in the media that people who are obese just want to lose weight for cosmetic reasons, or that they’re to blame for their condition,” she said.
“The fact is, obesity kills people,” she said. “The major cancers in Australia today all have obesity accelerating them, and obesity is a risk factor for diabetes, cardiovascular disease, fatty liver disease and cirrhosis and arthritis.”
Professor Samaras criticised a “monocular glucocentric view about obesity”, saying many people who were obese maintained normal glucose levels but had significant obesity-associated comorbidities or were at risk of them.
Even modest reductions in weight could relieve significant health burdens, Professor Samaras said. For instance, a weight reduction of 5 kg might assist some patients in their blood pressure and lipid management.
Other patients may have greater weight reduction goals to access interventions such as cardiac transplantation or to ensure good outcomes following cancer therapy or joint replacement, she said.
The place of medication
Professor Samaras said new GLP-1 agonists were good additions to the treatment armamentarium for obesity, alongside lifestyle interventions and if necessary, bariatric surgery.
“For people who’ve already tried diet and exercise again and again and again, you add in whatever is necessary and safe, commensurate with the impact of obesity on that individual,” she said.
Bariatric surgery now had 20-year outcomes reported in the literature; however, with almost no access to the surgery in the public system, it too was out of reach to many patients, she said.
Professor Samaras said GLP-1 agonists should be considered before a trial of bariatric surgery.
The new medications could also be useful for people who regained weight in the years after successful bariatric surgery, she said.
Evidence was also accumulating to support the use of GLP-1 agonists to mitigate the obesity-inducing effects of antipsychotic medications, according to Professor Samaras, who is involved in a trial co-prescribing semaglutide and clozapine.
Professor Samaras stressed that no medication or surgery would work without lifestyle change.
This was actually one of the PBAC’s reasons for not recommending the listing of semaglutide for obesity – it was “unlikely” that the benefits of semaglutide seen in clinical trials would be “fully realised in Australian practice without the intensive diet and exercise counselling co-administered in the trial program”, the PBAC said.
Risks and contraindications
The main side effects of the new GLP-1 receptor agonists are gastrointestinal – nausea, diarrhoea and constipation.
In the semaglutide obesity study, 4.5% of participants in the treatment arm discontinued treatment due to gastrointestinal events.
Professor Samaras commented: “Some people can be exquisitely sensitive and may take the lowest dose and vomit for one week. They might respond better to a different medication.”
There are also questions about the safety of GLP-1 agonists in the context of significant alcohol consumption given the small risk of pancreatitis, Professor Samaras said. However, she added that, anecdotally, semaglutide could actually reduce a patient’s interest in alcohol.
Professor Samaras said the biggest concern with the new drugs was the lack of long term safety data. The longest follow-up period is only about 3 years for semaglutide.
“However, one needs to remember that obesity itself is not a benign condition,” she added.
In general, NPS MedicineWise notes that there is no legal impediment to prescribing medications off-label, but the onus is on the prescriber to defend their prescription for an indication that is not listed in the product information.
A spokesperson for the TGA said the shortage on semaglutide is expected to resolve on 31 August 2022.
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