“Whatever you do, do not think that to be Instagram body beautiful that taking this sort of medication is safe or sensible,” said Wes Streeting, speaking to The Sun newspaper on 15 June 2024.
The shadow health minister was discussing concerns around how patients are inappropriately accessing supplies of semaglutide — a glucagon-like peptide-1 receptor agonist (GLP-1 RA) that simulates the functions of the body’s natural incretin hormones, lowering blood sugar levels after a meal to make people feel fuller sooner.
At lower doses, semaglutide (Ozempic; Novo Nordisk) is indicated for treating type 2 diabetes mellitus (T2DM), while at higher doses (Wegovy; Novo Nordisk) it is prescribed to patients for weight management if they have a BMI of 30 or more, or a BMI of 27 or more and at least one weight-related co-morbidity. Research has shown around half of Wegovy users achieve a weight loss of at least 15%.
But semaglutide has become a victim of its own success — and the latest dieting craze. Private online prescribing “is not wholly controlled” and has led to “unmanageable shortages”, according to Victoria Ruszala, a specialist pharmacist in cardiology and heart failure at North Bristol NHS Trust. This has also led to growing concerns around how easy it is for patients who are not overweight to access the medicine for weight loss.
“Many are getting it ’prescribed’ but in reality, our private prescribing system in the UK is hugely flawed when it is run as a remote/virtual service,” says Philip Newland-Jones, consultant pharmacist in diabetes and endocrinology at University Hospital Southampton NHS Foundation Trust.
“There have been a number of instances of counterfeit semaglutide bought online, with a number of high-profile incidents of harm, one purchase that was found to be insulin causing hospitalisation,” he says.
“People are desperate due to the lack of NHS services offering obesity medication and it’s so easy to get, as many companies, including big name online pharmacies, [see] private obesity medication as a huge cash cow … It’s so easy to get a prescription, which shows how flawed the current system is.”
While Streeting told The Sun he is adamant that “closer clinical oversight and regulation” of semaglutide prescribing will be a priority if the Labour Party wins the general election on 4 July 2024, researchers are publishing a constant stream of study results that suggest semaglutide may have even more to offer patients outside of diabetes or weight loss.
With hesitancy and excitement growing around the GLP-1RA in equal measure, what does the evidence say about semaglutide’s clinical benefit for other indications, and what reservations remain about its effectiveness?
Cardiovascular benefits
In November 2023, results from the ‘Semaglutide and cardiovascular outcomes in obesity without diabetes’ (SELECT) trial, funded by Novo Nordisk, revealed that non-diabetic, overweight adults taking semaglutide for more than three years had a 20% lower risk of heart attack, stroke or death resulting from cardiovascular disease[3]. An accompanying conference abstract and poster, presented at the 31st European Congress on Obesity in May 2024, also indicated that patients may derive cardiovascular benefit from semaglutide regardless of weight loss.
There are clearly wider cardiovascular effects of the medicine beyond the weight loss and appetite suppressant actions
Phillip Newland-Jones, consultant pharmacist in diabetes and endocrinology at University Hospital Southampton NHS Foundation Trust
Meanwhile, preliminary findings of a study based on the SELECT trial by a University College London-led research team, published in May 2024, have also indicated that such cardiovascular benefits were irrespective of starting weight and amount of weight lost.
“There are clearly wider cardiovascular effects of the medicine beyond the weight loss and appetite suppressant actions,” says Newland-Jones, commenting on the research.
“In addition, we do not see the same magnitude of cardiovascular risk reduction from equivalent weight loss from calorie restriction.”
In a published ‘expert reaction’ to the SELECT trial, Tricia Tan, consultant in diabetes, endocrinology and metabolic medicine at Imperial College London and NHS Trust, highlighted the subsequent implication for National Institute for Health and Care Excellence (NICE) guidance, which currently recommends stopping semaglutide treatment in patients who have not lost more than 5% of weight after six months.
“Even people who do not lose [more than] 5% of weight seem to benefit from the treatment,” she explains. “It may be that we should continue treatment in people who have had cardiovascular disease, even if they don’t lose as much weight as we would like.”
This is already the case in the United States where, in March 2024, the US Food and Drug Administration approved Wegovy to treat adults with cardiovascular disease who also have obesity or are overweight — but without diabetes mellitus.
“There are going to be high-risk cardiovascular patients that we would like to start thinking about initiating as well. Those that have come in with an [acute myocardial infarction] AMI or a second or third AMI,” says Paul Wright, consultant cardiovascular pharmacist at Barts Heart Centre in London.
“Hopefully we’ll get endorsements from NICE for high cardiovascular risk, in which case it’s going to open up potentially quite a large cohort of individuals who will be eligible and derive benefit.”
“We should definitely be reviewing all of this rapidly,” adds Ruszala, who is particularly interested in the potential anti-inflammatory properties of GLP-1s.
“It’s driving that cardiovascular-renal-metabolic system where we all start working interdisciplinary and figuring out the answers together, rather than working in siloes. That’s a really powerful thing. As more of these drugs come online, that’s more and more what we’re going to have to do, to figure out where the benefit is biggest.”
Kidney health
“The more we look into it, the more we realise cardiovascular outcomes are really highly linked in with kidney disease as well,” says Helen O’Neil, senior medicines optimisation pharmacist in Tees Valley.
Results from the SELECT trial also indicated that a dose of 2.4mg of semaglutide has potential to combat kidney function decline among individuals with cardiovascular disease who are overweight or have obesity, but without diabetes.
Adverse kidney-related events were experienced by 22% fewer people on semaglutide, while its ability to prevent the onset of macroalbuminuria was highlighted as a pivotal factor in reducing the likelihood of kidney-related complications. The results also indicated semaglutide’s potential to protect kidney function in individuals with a pre-existing kidney impairment, and reduction in urinary albumin-to-creatinine ratio (UACR).
Results from the Novo Nordisk-funded ‘FLOW’ trial, published in May 2024, also suggested that semaglutide reduced the risk of clinically important kidney outcomes and death from cardiovascular causes in patients with T2DM and chronic kidney disease (CKD), with the risk of a primary-outcome event 24% lower in the semaglutide group than placebo.
“CKD is predicted to be the fifth largest cause of mortality by 2040 and so slowing progression of CKD and reducing cardiovascular mortality will reduce NHS spend and is hugely important for patients,” Clare Morlidge, a consultant renal pharmacist and deputy chair of the UK Renal Pharmacy Group, tells The Pharmaceutical Journal, adding that semaglutide is “another medication in the cupboard” for slowing the progression of CKD.
“Its use alongside ACEi/ARB, SGLT2 inhibitors and mineralocorticoid antagonists will help form the pillars of treatment for delaying the progression of CKD and reducing cardiovascular mortality,” she says.
However, O’Neil adds that there is a need for “bigger trials looking at the standard therapies and the impact on top of that, given the expense of the GLP-1s”.
Long-term effectiveness
Despite the promising results, experts have suggested these findings could be limited by the difficulty of separating the benefits of weight loss from semaglutide specifically.
When considering the benefits of semaglutide on cardiovascular outcomes, Bryan Williams, chief scientific and medical officer for the British Heart Foundation, says: “A lot has been made of the potential benefit ‘beyond weight loss’ but my view is that in reality, this is all likely to be due to the reversal of the abnormal and damaging biology of obesity by reversing the weight gain.”
Where resources are scarce, you need to put them to the individuals most at risk
Paul Wright, consultant cardiovascular pharmacist at Barts Heart Centre in London
However, semaglutide is not a permanent solution here. A study abstract presented at the American Society for Metabolic and Bariatric Surgery 2024 Annual Scientific Meeting on 11 June 2024 showed that weight loss from bariatric surgery was maintained at approximately 25% for up to ten years, while patients who stopped GLP-1s regained 50% of the weight lost within one year. Wright points out that regaining lost weight is highly likely to result in subsequent attenuation of wider health benefits.
Wider access to semaglutide is also limited by ongoing supply issues. “Where resources are scarce, you need to put them to the individuals most at risk, and it’s fair to say those individuals with diabetes which is poorly controlled who are deriving good benefit from this medication need to be prioritised over other indications,” says Wright.
Newland-Jones adds that a balance needs to be struck between “utilising these medicines for the significant benefits in all those that meet trial entry criteria and the budgetary constraints we’re currently in”.
“For obesity in particular, these medicines clearly work but are expensive, and it is illogical to say that we try to fix our obesity crisis with medicines taken indefinitely to supress one’s appetite, without tackling the social, financial and environmental aspects that are driving obesity in the first place. Drugs are not the lone solution.”
O’Neil adds that while GLP-1s can be “a really good kick-start” for patients needing to change their relationship with food, there is more to a healthy life than medication — particularly given potential tolerance issues and complications such as pancreatic inflammation[9].
However, with waiting lists for tier 3 weight management services extending into months and even years in some parts of the country, providing adequate support to patients for this remains challenging.
Dual receptor agonists
There is also the possibility semaglutide is starting to make way for dual receptor agonist and combination products, such as tirzepatide (Mounjaro; Eli Lilly and Co). “Dual and triple incretin receptor agonists are where the majority of the newer data [are] going to come from, with regard to areas outside of diabetes,” says Newland-Jones.
Data from the United States have indicated that semaglutide was initiated less frequently following the approval of tirzepatide, while a GlobalData forecast has predicted Mounjaro will surpass Ozempic in sales over the coming years.
Eli Lilly is already looking at tirzepatide for obstructive sleep apnoea and metabolic dysfunction-associated steatohepatitis in ongoing phase II and III trials, that are expected to bring deeper understanding of where the greatest benefits may be for GLP-1s over the next five years.
However, with challenges in shortages, funding and meeting the needs of diabetic populations, change in practice in other areas is unlikely to take place in the immediate future.
