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Researchers have long sought effective and safe weight loss medications but, as history shows, this has not been one of pharmacology’s greatest triumphs — yet.
Amphetamine, sibutramine and rimonabant are among several anti-obesity medications that fell by the wayside because of adverse events. So, will the ‘repurposing’ of incretin-based therapies, a mainstay of type 2 diabetes management, buck that trend?
The Government argues that, “using the latest treatments to tackle obesity will contribute to cutting waiting lists by reducing the number of people who suffer from weight-related illnesses, who tend to need more support from the NHS and could end up needing operations linked to their weight – such as gallstone removal or hip and knee replacements”.2
Increasing evidence
On average, incretin-based anti-obesity medications reduce body weight by 15-20 per cent even without major lifestyle changes.3 However, up to 20 per cent of people taking this class of drugs do not experience clinically significant body weight loss and the benefits cease if people stop using the medicine.3 Nevertheless, increasing evidence supports incretin-based
anti-obesity therapies.
Subcutaneous semaglutide, a glucagon-like peptide-1 (GLP-1) analogue, is approved for overweight and obese people. Oral semaglutide, currently in development as a weight loss medication, is also effective. During the OASIS 1 study, 667 patients (BMI at least 30kg/m2 or 27kg/m2 and weight-related co-morbidities) received oral semaglutide 50mg once daily or placebo. The patients did not have type 2 diabetes.
After 68 weeks, mean body weight losses were 15.1 and 2.4 per cent respectively. Patients using oral semaglutide were 14.7 and 18.5 times more likely to show body weight reductions of at least 10 and 20 per cent compared with placebo.4
Subcutaneous semaglutide has also be shown to improve cardiometabolic risk factors in overweight or obese people with or without type 2 diabetes.4 In August, Novo Nordisk announced initial results from the SELECT study, which enrolled 17,604 obese and overweight people (BMI at least 27kg/m2) aged 45 years and older with established cardiovascular disease and no history of diabetes.
Once-weekly subcutaneous semaglutide (2.4mg) reduced the risk of major adverse cardiovascular events (cardiovascular death, non-fatal myocardial infarction or non-fatal stroke) by 20 per cent compared with placebo. Improvements in each element contributed to the reduction. Novo Nordisk will present detailed results later this year.5
Wegovy launch sees demand soar
Weight loss agent Wegovy (semaglutide injection) from Novo Nordisk was unveiled to great fanfare at the beginning of September in what was described as a “controlled and limited launch”. The weekly injection works by mimicking the hormone glucagon-like peptide-1 (GLP-1) to suppress appetite.
NICE has stipulated that semaglutide should be available only through specialist NHS weight management services or privately “through a registered healthcare professional”, in conjunction with a reduced calorie diet and increased physical activity. Experts say this would mean only around 35,000 people would have access to Wegovy in hospital settings, but many thousands more could be eligible in primary care under the NICE criteria.
Wegovy is indicated as an adjunct to a reduced-calorie diet and increased physical activity for weight management, including weight loss and weight maintenance, in adults with an initial body mass index (BMI) of ≥30kg/m2 (obesity) or ≥27kg/m2 to <30kg/m2 (overweight) in the presence of at least one weight-related comorbidity, such as hypertension or cardiovascular disease.
Patients need to meet the criteria for referral to specialist weight management services, which includes that conventional treatment has been unsuccessful.
Government pilot
In June the Government launched a £40m two-year pilot to explore how approved drugs can be made safely available to more people by expanding specialist weight management services outside of hospital settings in order to involve GPs.
When it announced the pilot, the Government said NHS England was working to implement recommendations from NICE to make “the newest and most effective obesity drugs” available to patients through specialist weight management services, “subject to negotiating a secure long-term supply of the products at prices that represent value for money for taxpayers”.
Describing the scheme as a “welcome step forward” in tackling obesity, the chair of the BMA’s board of science, David Strain, called for greater clarity on how the scheme would be funded. “The Government must ensure that general practice has the right resources to support an intervention that, although it will improve the quality of lives of thousands of people in the long term, will take a considerable time to realise the benefits for the health service.”
The scheme should not come at the expense of “upstream preventive strategies” such as tackling junk food advertising,
he said.
Supply problems
The crossover between treatments for weight loss and diabetes has led to supply issues with semaglutide (Ozempic) for type 2 diabetes – partly caused by off-label prescribing for weight loss. In response, the Government says Ozempic should only be prescribed and used for its licensed indication.
Tackling obesity is a key part of the NHS Long Term Plan, says NHS medical director Professor Sir Stephen Powis. “Pharmaceutical treatments offer a new way of helping people with obesity gain a healthier weight and [the new pilots] will help determine if these medicines can be used safely and effectively in non-hospital settings.”
NICE was thought to be considering another drug, tirzepatide, for weight loss – but in guidance issued in early September it was only recommended for type 2 diabetes.
With demand for Wegovy outstripping supply, pharmacies offering private weight loss services have reported long waiting lists of people registering an interest. Many companies, including Boots, Superdrug and various online pharmacies, are currently offering Wegovy privately for about £200 a month.
Tirzepatide and NICE
Tirzepatide is an agonist at glucose-dependent insulinotropic peptide (GIP) and GLP-1 receptors. During the SURMONT-2 study, 938 adults with BMIs of at least 27kg/m2 and type 2 diabetes received once weekly injections with tirzepatide 10mg, tirzepatide 15mg or placebo. After 72 weeks, mean body weight reductions were 12.8, 14.7 and 3.2 per cent respectively.
Among those receiving tirzepatide 15mg, 65 per cent lost at least 10 per cent of their body weight; 48 and 31 per cent shed at least 15 and 20 per cent of their body weight respectively.6 In June, NICE rejected tirzepatide as an anti-obesity medication. Whether the growing evidence base changes NICE’s mind remains to be seen.
As 10-20 per cent of patients regain substantial body weight after surgery, combining anti-obesity medications and bariatric surgery is logical.3,7 The BARI-OPTIMISE study assessed liraglutide, a GLP-1RA, 3mg once daily combined with a calorie-controlled diet in 70 people who lost 20 per cent or less body weight at least a year after bariatric surgery. After 24 weeks, body weight declined by 8.8 per cent with liraglutide and 0.5 per cent with placebo.8
Adverse events
In general, incretin-based anti-obesity medications seem well tolerated. For example, in SURMONT-2, the most common adverse events were gastrointestinal, such as nausea, vomiting and diarrhoea. Six per cent of the tirzepatide 10mg group, 9 per cent of those receiving 15mg tirzepatide and 7 per cent of placebo recipients developed serious adverse events; 4, 7 and 4 per cent respectively withdrew because of adverse events.6
New safety signals can, however, emerge when a drug is used in a large number of patients. In July, the European Medicines Agency (EMA) announced a review of the risk of thoughts of suicide or self-harm in people taking GLP-1RAs for type 2 diabetes or weight loss. The EMA says it is unclear whether the reports are linked to the medicines, underlying conditions or other factors. The review is expected to conclude in November this year.9
The MHRA also has concerns. “We are currently reviewing safety data on the risk of suicidal thoughts and thoughts of self-harm associated with … GLP-1 receptor agonists, used for treating both type 2 diabetes and weight loss,” says Dr Alison Cave, MHRA chief safety officer.
Between 2020 and July 2023, the MHRA received five reports involving semaglutide and “suicidal and self-injurious behaviour”.
Between 2010 and July 2023, the MHRA received 12 reports involving liraglutide and “suicidal and self-injurious behaviour”.
“We will carefully consider all available evidence and communicate any further advice to patients and healthcare professionals as appropriate,” Dr Cave says.
Delivering the promise
In June, the Government announced a £40m two-year pilot evaluation of “ways to make obesity drugs accessible to patients living with obesity outside of hospital settings”.2 The pilots would explore, for example, “how GPs could safely prescribe [anti-obesity medications] and how the NHS can provide support in the community or digitally”2 (see below).
Fundamentally, managing obesity resembles the care of other chronic diseases, combining lifestyle intervention, risk factor modification, pharmacotherapy and surgery.3,7 Pharmacists should remind people that, obesity medications notwithstanding, a healthy lifestyle remains important. Optimising diet and eating habits, correcting unhealthy behaviours and increasing physical activity sustains weight loss in up to 20 per cent of patients.3
Obesity is a chronic, multifactorial problem that medications alone will not solve. People with obesity need long-term, multifactorial, flexible, individually tailored care.3 “We should not promote one form of treatment by dismissing the other options,” remarked Lingvay and colleagues. “We need to combine our efforts and use the right tools, at the right time, and for the right person to achieve optimal care and maximise health benefits for our patients.”3
References
2. New drugs pilot to tackle obesity and cut NHS waiting lists
3. Lancet Diabetes & Endocrinology 2023; 11:541
4. Lancet 2023; DOI: 10.1016/s0140-6736(23)01185-6
6. Lancet 2023; DOI: 10.1016/s0140-6736(23)01200-x
7. JAMA Surgery 2023; DOI: 10.1001/jamasurg.2023.2931
8. JAMA Surgery 2023; DOI: 10.1001/jamasurg.2023.2930
9. EMA statement on ongoing review of GLP-1 receptor agonists
10. NPIS
11. Drugs 2010; 70:1487-503
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