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29th June 2023
The UK Government’s latest scheme to increase access to the anti-diabetic drug semaglutide is designed to reduce levels of obesity and related complications. But past evidence suggests it is doomed to fail. Clinical writer Rod Tucker finds out more.
A two-year pilot scheme, backed by investment up to £40m, is to be launched in the UK to increase accessibility to the anti-obesity treatment semaglutide outside of hospital settings.
Obesity is a leading cause of conditions such as cardiovascular disease, diabetes and cancer, and was reported to be a factor in more than one million admissions to NHS hospitals in 2019/20. According to information released by the Department of Health and Social Care, obesity has an annual cost to the NHS of £6.5bn.
On the face of it, the rationale for widening access to the anti-diabetic treatment appears sensible. Any approach that leads to a reduction in the level of obesity should give rise to a commensurate decrease in the number of individuals developing obesity-related conditions and requiring interventions such as knee and hip replacements. If obesity levels drop, so would the waiting list for these complications. Its a win-win situation.
But there are two other relevant considerations. Firstly, does wider access to semaglutide align with current recommendations for the drug, and secondly, how likely is it that the pilot scheme will be successful?
In March 2023, NICE recommended semaglutide as an option for weight management in adults, alongside a reduced-calorie diet and increased physical activity. However, there were several caveats attached to this recommendation.
Firstly, use of the drug was restricted to a maximum of two years and it could only be prescribed at a specialist weight management service. Secondly, patients were required to have at least one weight-related comorbidity and body mass index (BMI) of at least 35.0 kg/m2, although patients could access the drug if they had a BMI of 30.0 kg/m2 to 34.9 kg/m2 and met the criteria for referral to specialist services.
By broadening access to semaglutide, the pilot scheme is therefore at variance to the NICE guidance. While NICE is sponsored by the Department of Health and Social Care, and purported to be independent of the UK Government, it has been argued that the organisation is not, and indeed cannot be, truly independent of the Government.
To date, NICE has remained silent on the Government’s latest initiative, probably because it goes against everything that was outlined in its draft guidance. The Government has argued that its latest scheme is merely a pilot project to explore if and how the anti-diabetic drug can be made safely available outside of a hospital settings. This will happen, it says, alongside NHS England’s work to implement NICE’s recommendations to make this new class of treatment available to patients through established specialist weight management services.
The evidence for semaglutide is convincing, but it is important to acknowledge that the drug only works when used as an adjunct to diet and exercise. Moreover, it is likely to require life-long use despite the two year restriction imposed by NICE. It is now clear that significant weigh re-gain occurs once patients stop taking the anti-diabetic drug, and another study shows how mean body weight increased by 6.9% after cessation of treatment.
A further barrier to the potential success of the pilot scheme is the growing recognition that obesity is a complex condition and that hypothalamic neuro-inflammatory responses play an important role. As a result, obesity management requires a multi-interventional approach.
Commenting on the pilot scheme, the UK health and social care secretary Steve Barclay said: ‘This next generation of obesity drugs have the potential to help people lose significant amounts of weight when prescribed with exercise, diet and behavioural support.’
But how effective is a primary-based weight management service likely to be? An insightful analysis of GP and nurse practitioner habits in response to a mock scenario, makes for interesting reading. Published in 2020, the study found that overall only 24% of respondents would refer patients to a weight management service. The most common response, in over 80% of cases, was to provide either diet or exercise-based advice.
Despite this, evidence from the US offers some hope that behaviour-based weight-loss interventions, either with or without weight loss medications, result in more weight loss than usual care conditions.
The potential for greater access to an effective anti-diabetic weight-loss drug is to be welcomed. Nevertheless, it can only ever serve to address the consequences and not the root causes of obesity. A huge amount of evidence also makes it abundantly clear that obesity is inextricably linked to socioeconomic and demographic factors. Overweight and obesity are far more prevalent in deprived areas, in those of black ethnicity and in the least well educated. In fact, someone living in the most deprived area is nearly twice as likely to be obese as someone in the least deprived area.
With past behaviour seen as the best predictor of future behaviour, the evidence over the last 30 years does not augur well for the current pilot scheme. A recent analysis has shown how obesity policy in England has involved 14 strategies, published from 1992 to 2020, which contain 689 wide-ranging policies. The authors suggested that the continued failure to reduce the prevalence of obesity in England for almost three decades may be due to either weaknesses in the policies’ design, or to failures of implementation and evaluation.
Obesity represents a growing problem, with 25.9% of adults in England obese and 37.9% overweight. Moreover, we live in an obesogenic environment that is influenced by the availability and affordability of foods, together with varying access to opportunities for physical activity. Consequently, it is perhaps too simplistic to label obesity as an individual’s problem: obesity is an environmental problem that requires a wholesale change with regulatory interventions directed at reducing intake of ultra-processed food and acknowledgement of the impact of socioeconomic factors. Such a change requires additional funding, and considerably more that the currently allocated £40m.
Greater access to the anti-diabetic drug semaglutide is unlikely to single-handedly solve the problem of obesity. Nonetheless, if provided through an adequately funded weight management services as part of a comprehensive package that includes behavioural support, access to exercise facilities and nutritional advice, it might have a noticeable effect on levels of obesity and its health-related consequences.
28th June 2023
Retatrutide gave rise to substantial reductions in body weight in adults with obesity, according to a recent phase 2, randomised placebo-controlled trial.
Retatrutide (formerly LY3437943) is an agonist for the glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon (GCG) receptors. In a phase 1b trial, the drug was shown to produce robust reductions in glucose and bodyweight. In addition to drugs such as semaglutide, it is being explored as a treatment for weight loss.
Continuing to explore the value of the drug, in a recent phase 2 trial published in the New England Journal of Medicine, researchers undertook a double-blind, randomised, placebo-controlled trial in adults with a body mass index (BMI) of 30 or more, or those with a BMI of 27 but with at least one weight-related condition.
The trial randomised participants to subcutaneous retatrutide at doses of 1 mg, 4 mg, 8 mg and 12 mg or placebo, administered once weekly for a total of 48 weeks. The primary endpoint was the percentage change in body weight from baseline to week 24, and researchers also assessed the safety of the drug.
In addition to treatment, all the participants received a lifestyle intervention, including regular counselling sessions delivered by a dietitian or qualified healthcare professional.
A total of 338 participants with a mean age of 48.2 years (48% female) were enrolled and randomised to the different doses or placebo.
After 24 weeks of treatment, weight loss ranged from -7.2% in the 1 mg group through to -17.5% in the 12 mg group, compared to -1.6% in the placebo group. However, at week 48, weight loss increased to -24.2% in the 12 mg group compared to -2.1% in the placebo arm. In addition, at week 48, among those receiving 12 mg of retatrutide, 26% of participants had a body-weight reduction of 30% or more.
Treatment with retatrutide also improved cardiometabolic measures including systolic and diastolic blood pressure, glycated haemoglobin, fasting glucose, insulin and lipids – except for high-density lipoprotein. Furthermore, improvements in blood pressure within the 48-week treatment period resulted in discontinuation of at least one antihypertensive medication in 30% of the participants in the 12 mg group.
Adverse events were reported in 70% of the placebo participants and in 73-94% of retatrutide patients. They were highest in the 8 and 12 mg groups. Serious adverse events occurred in 4% of the retatrutide placebo groups.
Using faecal microbiota transplantation in patients with advanced cirrhosis improves gut flora microbiota and ammonia metabolism, according to a feasibility trial by UK and Swedish researchers.
Data from the prospective, randomised placebo controlled feasibility trial of faecal microbiota transplantation (PROFIT) trial was presented at the European Association for the Study of the Liver (EASL) 2023 congress.
Gut flora and bacterial translocation play an important role in the pathogenesis of the complications of cirrhosis such as hepatic encephalopathy (HE). The antibiotic rifaximin reduces the risk of HE recurrence and HE-related hospitalisations in cirrhosis, possibly through its effects on metabolic function of the gut microbiota and a reduction in ammonia-producing bacteria.
But whether faecal transplantation, by modifying the gut microbiota, could benefit those with cirrhosis is unclear and this was the subject of an abstract (GS-007) presented at the congress. For the study, 50 g of frozen faecal microbiota transplants (FMT) were administered into the jejunum via endoscopy in a ratio of 3:1 (FMT vs placebo). The study was single-blind, so only the investigators were aware of the intervention received by patients. Blood and stool samples were collected at baseline and then after seven, 30 and 90 days.
A total of 32 patients were included in the study. FMT significantly reduced the stool carriage of Enterococcus faecalis and other pathobionts. There was also a significant reduction after 30 days in plasma ammonia (p = 0.0006), with a corresponding higher faecal ammonia (p = 0.011) in the FMT group compared to placebo.
In addition, after 30 days, there was enhancement in the enzymes required for nitrogen assimilation and excretion via the urea cycle, with greater secretion of urinary hippurate (p = 0.0299) in the FMT group.
It was also clear that the use of FMT reduced biomarkers of inflammation but increased biomarkers for gut barrier repair.
The researchers concluded that their data supported a role for FMT in patients with cirrhosis.
Following the PROFIT trial, the same group are about to embark on the PROMISE trial, in which patients with cirrhosis take capsules containing dried stool from a healthy donor, rather than via endoscopy as in the PROFIT trial.
A recent Cochrane review found that faecal transplantation improves clinical and possibly endoscopic remission in ulcerative colitis.
A novel approach using RNA CAR T cell therapy improves clinical symptoms in patients with myasthenia gravis according to a recent phase 1b/2a study.
Chimeric antigen receptor (CAR) T cells represent a versatile new class of effective and molecularly precise therapy in oncology. However, CAR T cell treatment has also been trialled with some degree of success in patients with autoimmune diseases such as systemic lupus erythematosus.
While conventional CAR T-cell engineering relies on DNA to express the CAR, an alternative is to engineer these cells with RNA, to produce RNA CAR T cells. The rationale behind using RNA is that because the molecule is not self-replicating, it would confer more predictable pharmacokinetics and consequently a more favourable safety profile.
In a small scale trial of using RNA CAR T cells published in the Lancet Neurology, researchers examined the value of this approach to treat individuals with myasthenia gravis – commonly known as the ‘snowflake disease’ because it affects each individual differently.
This prototypical autoimmune disease is characterised by autoantibodies that target the neuromuscular junction, which causes chronic fluctuating and potentially debilitating weakness and muscle fatigue. The RNA CAR T cell therapy, known as Descartes-08, was used in adults with generalised myasthenia gravis and a Myasthenia Gravis Activities of Daily Living (MG-ADL) score of 6 or higher gravis.
The study was undertaken in two phases. Initially, patients with Myasthenia Gravis Foundation of America (MGFA) disease class III-IV generalised myasthenia gravis were given three increasing doses of Descartes-08, to identify the maximum tolerated dose. In the second phase, participants with MGFA disease class II-IV received six infusions of the maximum tolerated dose.
The primary objective was to establish the safety and tolerability of Descartes-08, whereas secondary objectives assessed disease severity. Researchers used four validated scales used to assess disease severity: MG-ADL, Quantitative Myasthenia Gravis (QMG), Myasthenia Gravis Composite (MGC), and Myasthenia Gravis Quality of Life 15-revised (MG-QoL-15r).
In total, 14 participants were enrolled, three in phase 1 and 11 in phase 2 and the median follow-up in phase 2 was five months.
Mean improvements from baseline to week 12 were -6 for MG-ADL, -7 for QMG, -14 for MGC and -9 for MG-QoL-15r.
There was no dose-limiting toxicity, cytokine release syndrome or neurotoxicity. Common adverse events were headache, nausea, vomiting and fever, which resolved within 24 hours of the infusion.
Based on these preliminary findings, the researchers suggested that RNA CAR T cell therapy warranted further investigation as a treatment approach for individuals with myasthenia gravis and other autoimmune diseases.
27th June 2023
A higher dose of adalimumab is likely to be more effective for obese patients with hidradenitis suppurativa, according to the findings of a small trial.
Adalimumab (ADA) is one of only two biologic therapies, together with secukinumab, approved by the EMA for the management of hidradenitis suppurativa (HS). However, adalimumab dosing is not weight-based and in two phase 3 trials, just over half of the patients assigned to adalimumab 40 mg/week (ADA40) achieved a clinical response.
Given that patients with HS are four times more likely to be obese compared to the general population, there might be an advantage of using a higher ADA dose in HS patients who are either overweight or obese.
In the current study, published in the Journal of Drugs in Dermatology, a team of US researchers evaluated the effectiveness of adalimumab 80 mg/week (ADA80) versus 40 mg, in overweight and obese patients with moderate to severe HS. The team included patients with a body mass index greater than 25 and who were refractory to treatment with ADA40. A dose of 80 mg was administered for at least three months and improvements were assessed using the HS-Physician Global Assessment.
A total of eight patients with a mean age of 37 years (six females) and with a median body mass index of 36.6 were included in the study and were followed for a median of 13.2 months on ADA80.
Patients experienced a greater improvement in the HS-Physician Global Assessment with ADA80 compared to ADA40 (p = 0.01). In addition, all five patients who had their lesion counts documented achieved a HS clinical response, and all eight patients reported improvements in pain, drainage, lesions and the frequency of disease flares.
While acknowledging the limitations from a small sample size, the researchers suggested that their data indicates a benefit increasing the dose of adalimumab in overweight and obese patients with HS.
Earlier this year, a phase 3 trial found bimekizumab to be an effective treatment for patients with hidradenitis suppurativa.
26th June 2023
The use of bulevirtide in patients with a chronic hepatitis D infection gave rise to a significant treatment response after 48 weeks, according to a recent phase 3 randomised trial.
According to a recent systematic review, an estimated 12 million people worldwide have experienced hepatitis D infection. Hepatitis D (HDV) is a sub-viral agent and unable to replicate alone. However, HDV makes use of hepatitis B surface antigen (HBsAg) to gain entry into hepatocytes and to propagate. Moreover, a chronic HDV and hepatitis B co-infection leads to more severe liver disease and an increased risk for the development of hepatocellular carcinoma.
Bulevirtide (previously known as Myrcludex B) has been shown to significantly reduce HDV RNA serum levels and induce alanine transaminase normalisation in a phase I/IIb trial. Bulevirtide inhibits the entry of HVD into hepatocytes and is currently, approved by the EMA for treatment of chronic HDV infection in plasma (or serum) HDV-RNA positive, adult patients with compensated liver disease.
Despite the EMA approval, there is still limited clinical data available for the drug. As a result, the current study, published in the New England Journal of Medicine, reported on the interim findings from an on-going phase 3 trial in patients suffering from chronic hepatitis D, with or without compensated cirrhosis.
Participants were randomised 1:1:1 to either subcutaneous bulevirtide 2 mg daily or 10 mg daily for 144 weeks, or a control group. This latter group received no treatment for 48 weeks followed by bulevirtide subcutaneously at a daily dose of 10 mg for 96 weeks.
The primary endpoint was a combined viral and biochemical response at week 48. This comprised an undetectable HDV RNA level, or a level that decreased by at least 2 log10 IU per ml from baseline (i.e. the viral endpoint) and normalisation of the ALT level.
There were 150 patients included in the trial. Some 49 patients were assigned to receive 2 mg of bulevirtide, 50 to 10 mg with the remainder assigned to the control arm.
The primary combined endpoint response occurred in 45% of those in the 2 mg dose, 48% in the 10 mg dose, but only 2% of those in the control arm (p < 0.001 for each dose comparison with the control group).
The HDV RNA level at week 48 was not detected in 12% of those receiving the 2 mg dose and 20% of those in the higher dose group although this difference was non-significant (p = 0.41). While the ALT level normalised in 12% of control group patients, normalisation occurred in 51% and 56% of participants in the 2 mg and 10 mg groups respectively.
In addition, a virologic response, i.e. an undetectable HDV RNA level or a level that decreased by ≥2 log10 IU per ml, at week 48 occurred in 71% in the 2 mg and 76% in the 10 mg group compared to only 4% in the control arm.
The researchers reported that the current trial is ongoing to further address the efficacy, safety and side-effect profile of long-term (up to three years or 144 weeks) bulevirtide therapy.
The risk of anaemia is higher among patients aged 70 years and older taking a daily dose of 100 mg of enteric-coated aspirin, according to a post hoc analysis of the ASPREE randomised controlled trial.
The Aspirin in Reducing Events in the Elderly (ASPREE) trial was designed to examine whether a daily dose of 100 mg of aspirin would prolong the healthy life span of older adults. While it is recognised that aspirin use in patients without cardiovascular disease lowers the risk of cardiac events but increases the risk of a major bleed, whether aspirin use also associated with anaemia is less certain.
Details of the ASPREE trial have been already published and revealed a higher all-cause mortality, largely due to cancer-related deaths, in those assigned to daily aspirin compared to placebo.
In the post hoc analysis of the ASPREE trial, published in the Annals of Internal Medicine, researchers investigated the effect of low-dose aspirin on incident anaemia, haemoglobin and serum ferritin concentrations.
Researchers assessed haemoglobin levels annually and ferritin levels at both baseline and after three years. The primary outcome was defined as incident anaemia but researchers also considered changes in haemoglobin and ferritin levels over time.
A total of 18,153 participants with a mean age of 74 years (44% male) were included, of whom 9,047 were randomised to a daily dose of 100 mg of enteric coated aspirin. Participants were followed for a median of 4.7 years after randomisation.
The incidence of anaemia was significantly higher in the aspirin group (hazard ratio, HR = 1.20, 95% CI 1.12 – 1.29). In addition, haemoglobin concentrations declined more steeply in those assigned to aspirin.
By year three, serum ferritin levels had reduced by an average of 11.5% in the aspirin group compared to those assigned to placebo. A higher proportion of patients assigned to aspirin experienced a major bleeding event compared to placebo (3% vs 2.1%). However, in sensitivity analysis, this difference did not account for the levels of anaemia seen between the two groups.
Overall the results suggested that the risk of developing anaemia within five years was 23.5% among those taking low dose aspirin.
23rd June 2023
Vortioxetine improves depressive symptoms, cognitive performance, functioning and health-related quality of life in patients with both major depressive disorder and early-stage dementia, according to a recent trial.
In a significant proportion of patients, depressive symptoms and dementia are related. However, there is insufficient evidence to support the use of antidepressants to treat depression in patients with dementia. Despite this, a recent meta-analysis suggested that the antidepressant, vortioxetine could help patients with major depressive disorder (MDD) recover cognitive function. Whether vortioxetine is able to provide similar benefits in patients with MDD and comorbid early stage dementia is unclear.
For the present study, published in the Journal of Affective Disorders, a team of Spanish and Danish researchers, investigated the effectiveness of vortioxetine at improving depressive symptoms, cognitive performance, functioning and health-related quality of life in patients with both MDD and early-onset dementia.
Eligible patients were aged 55-85 years and had a primary diagnosis of recurrent MDD, with onset before 55 years of age, and comorbid early-stage dementia diagnosed ≥6 months before screening and after onset of MDD.
Treatment with vortioxetine was started at a dose of 5 mg once daily and up-titrated to 10 mg daily in all patients. The dosage could then be either increased to 20 mg or reduced to 5 mg at the investigator’s discretion. The primary endpoint was change from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) total score at week 12.
A total of 82 patients with a mean age of 70.3 years (66%) were included in the study and the most common dementia diagnosis was Alzheimer’s disease (43%).
There were statistically significant and clinically meaningful improvements in the severity of depressive symptoms, based on the MADRS total score, seen at all assessment timepoints up to 12 weeks (p < 0.0001). In fact, at week 12, the mean change from baseline was −12.4.
There were also significant improvements in cognitive performance, daily and global functioning and health-related quality of life. Vortioxetine was well tolerated, and from week four, more than half of patients received the 20 mg dose.
Wine drinking is linked to a lower risk of death from cardiovascular disease but also reduces the risk of developing both cardiovascular and coronary heart disease, according to the findings of a recent meta-analysis.
Previous studies have hinted that the polyphenolic content of wine confers a cardio-protective effect whereas consumption of spirits, increases the risk of ventricular arrhythmias. In fact, evidence points to a J-shaped relationship between wine consumption and vascular risk.
Whether these purported benefits of wine are influenced by potential confounders such as age, gender, smoking status and the duration of follow-up within studies is uncertain. For the present study published in the journal Nutrients, researchers undertook a meta-analysis to examine the association between wine consumption and cardiovascular outcomes and assessed if this association was influenced by personal and study factors. The researchers looked for studies in adults and where the reported outcomes were cardiovascular mortality, cardiovascular disease (CVD) and coronary heart disease (CHD).
There were 25 studies with 1,443,245 subjects included in the final analysis.
Wine consumption was associated with a 24% reduced risk of CHD (relative risk, RR = 0.76, 95% CI 0.69 – 0.84). In addition, there were also significant reductions in the risk of CVD (RR = 0.83, 95% CI 0.70 – 0.98) and for cardiovascular mortality (RR = 0.73, 95% CI 0.59 – 0.90).
In a sensitivity analysis, these associations remained statistically significant. However, publication bias was evidence for the link between wine and CVD but not for either CHD or cardiovascular mortality.
In further analysis, the effects of participants’ mean age, the proportion of women in studies, the duration of follow-up or if whether individuals currently smoked, did not impact on the reported associations.
The researchers did caution that increasing wine consumption could be detrimental for patients who are vulnerable to alcohol due to age, medication or pathology. They also suggested that further research is required to differentiate the observed effects by the type of wine.
Topical testosterone therapy for middle-aged and older men with hypogonadism and either pre-existing or at a high-risk of cardiovascular disease, does increase the risk of adverse cardiac events according to a recent, randomised trial.
The cardiovascular risks of using testosterone therapy in men with hypogonadism are still unclear. Some data suggests that replacement therapy in men who underwent coronary angiography was associated with increased risk of adverse outcomes. Conversely, other data from an observational study revealed a lower mortality in those in receipt of replacement therapy compared with no treatment.
With such conflicting results, the current study, published in the New England Journal of Medicine, was designed to determine if testosterone-replacement therapy increased the incidence of major adverse cardiac events among middle-aged and older men with either pre-existing or a high-risk of cardiovascular disease. Individuals at a high-risk included those with hypertension, dyslipidaemia, type 2 diabetes if aged over 65 years of age.
Researchers undertook a phase 4, randomised, double-blind, placebo-controlled, non-inferiority, event-driven trial. Participants were men aged 45-80 years who reported one or more symptoms of hypogonadism, including decreased sexual desire or libido, decreased spontaneous erections, fatigue or decreased energy. These were then randomised in a 1:1 ratio to either daily transdermal 1.62% testosterone gel or matching placebo.
The primary safety endpoint was the first occurrence of any component of major adverse cardiac events, a composite of death from cardiovascular causes, nonfatal myocardial infarction or nonfatal stroke.
Of the 5,204 men, with a mean age of 63.3 years, included in the trial, some 2,601 were assigned to receive testosterone and followed for a mean duration of 33 months.
The primary cardiovascular endpoint event occurred to a similar extent in both groups (hazard ratio, HR = 0.96, 95% CI 0.78 – 1.17, p < 0.001 for non-inferiority). Similarly, an analysis of secondary outcomes, which were the individual components of the primary composite, also revealed no significant differences between either testosterone therapy and the matching placebo.
Adverse events were similar in the two groups with 45.7% and 44.7% of those in the testosterone and placebo group respectively, experiencing any adverse event. However, there was a significantly higher incidence of nonfatal arrhythmias warranting intervention in the testosterone group (p = 0.001).
Nevertheless, the researchers conducted that testosterone therapy was non-inferior to placebo with respect to the incidence of major adverse cardiac events.
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