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15th April 2024
Available evidence does not support a causal association between glucagon-like peptide-1 (GLP-1) receptor agonists and suicidal and self-injurious thoughts and actions, according to the European Medicine Agency (EMA)’s Pharmacovigilance Risk Assessment Committee (PRAC).
This conclusion follows a review into GLP-1 receptor agonists starting in July 2023 after receiving case reports from the Icelandic medicines agency of suicidal thoughts and thoughts of self-injury from people using liraglutide and semaglutide.
At the time, the EMA said it was ‘not yet clear whether the reported cases are linked to the medicines themselves or to the patients’ underlying conditions or other factors‘.
The PRAC review has since included the results of a recent real-world cohort study looking at the association of semaglutide with risk of suicidal ideation.
Based on a large database of electronic health records, it investigated the incidence of suicidal thoughts in patients with overweight and type 2 diabetes mellitus treated with semaglutide or other non-GLP-1 receptor agonist medicines for diabetes or overweight.
The study found no causal association between the use of semaglutide and suicidal thoughts.
The EMA conducted a separate study based on electronic health records. This examined the risk of suicide-related and self-injury-related events in people with type 2 diabetes mellitus and found no causal association between the use of GLP-1 receptor agonists and this risk.
The PRAC also considered additional data from the marketing authorisation holders for semaglutide (brand names Ozempic, Rybelsus and Wegovy), liraglutide (brand names Victoza and Saxenda), degludec/liraglutide (brand name Xultophy), exenatide (brand names Byetta and Bydureon), lixisenatide (brand name Lyxumia), glargine/lixisenatide (brand name Suliqua), and dulaglutide (brand name Trulicity).
After reviewing the available evidence from non-clinical studies, clinical trials, post-marketing surveillance data and the available studies the PRAC announced that no update to the product information is warranted.
It added that close monitoring by the marketing authorisation holders is required and any new evidence on the issue must be reported.
This mirrors a similar conclusion from the US FDA in January 2024, in which it stated: ‘Our preliminary evaluation has not found evidence that use of these medicines causes suicidal thoughts or actions.‘
11th August 2023
Semaglutide has been found to reduce the risk of major adverse cardiovascular events (MACE) by 20% in overweight or obese adults, its manufacturer Novo Nordisk has claimed.
According to headline results from the SELECT study, the anti-diabetic drug semaglutide was able to cut the risk of overweight or obesity experiencing a MACE by 20% compared to placebo.
This randomised, double-blind, placebo-controlled trial, the results of which are yet to be published in a peer-reviewed journal, was designed to evaluate the efficacy of semaglutide 2.4 mg versus placebo, as an adjunct to standard of care, for the prevention of MACE, in overweight or obesity with no prior history of diabetes.
The primary endpoint of the study was defined as the composite outcome of the first occurrence of MACE defined as cardiovascular death, non-fatal myocardial infarction or non-fatal stroke.
Commenting on the findings, Martin Holst Lange, executive vice president for development at Novo Nordisk, said: ‘People living with obesity have an increased risk of cardiovascular disease but, to date, there are no approved weight management medications proven to deliver effective weight management while also reducing the risk of heart attack, stroke or cardiovascular death. Therefore, we are very excited about the results from SELECT showing that semaglutide 2.4 mg reduces the risk of cardiovascular events.‘
He added: ‘SELECT is a landmark trial and has demonstrated that semaglutide 2.4 mg has the potential to change how obesity is regarded and treated.‘
SELECT enrolled 17,604 adults across 41 countries at more than 800 investigator sites and was initiated in 2018.
All participants had pre-existing cardiovascular disease, including a prior myocardial infarction (76.3%) or stroke (23.3%). In addition, enrolled participants were aged ≥45 years with a body mass index (BMI) ≥27 kg/m2.
In total 1,270 first MACEs accrued. The trial achieved its primary objective by demonstrating a statistically significant and superior reduction in MACE of 20% for people treated with semaglutide 2.4 mg compared to placebo. In the trial, semaglutide 2.4mg appeared to have a safe and well-tolerated profile in line with previous semaglutide 2.4mg trials.
Naveed Sattar, professor of metabolic medicine at the University of Glasgow, said: ‘More details are needed on the trials to give it proper consideration, including examination of safety aspects, but even here the top line report also sounded optimistic.
‘The one thing to caution is we do not know to what extent the weight loss effects of semaglutide as opposed to its other direct effects on blood vessels or the heart, account for the 20% reduction in cardiovascular events, and more data are needed to try to work this out.‘
For now, however, this is a good result for patients, especially as progressively more are living with obesity and cardiovascular disease.‘
Novo Nordisk expects to file for regulatory approvals of a label indication expansion for semaglutide 2.4 mg in the US and the EU later in 2023. The detailed results from SELECT will also be presented at a scientific conference later in the year.
In March, NICE recommended Wegovy for use as part of a patient’s treatment for obesity in an NHS specialist weight management service and with the support of a multi-disciplinary team.
5th June 2023
Anti-diabetic drug lead to weight loss, providing a much needed impetus in the fight against the rising global obesity epidemic, but are these drugs the ultimate solution? Rod Tucker investigates.
According to recent data released by Boehringer Ingelheim and Zealand Pharma, their novel glucagon/GLP-1 receptor dual agonist, BI 456906, designed as an anti-diabetic medicine, gave rise to a 14.9% weight loss in those either obese or overweight compared with placebo.
Though not yet commercially available, BI 45609 is likely to join a long list of anti-diabetic treatments being used in the fight against obesity. Such innovations are urgently needed given the inexorable rise in global levels.
For example, a recent report from the World Obesity Federation described how in 2020, an estimated 2.6 billion people globally had a body mass index (BMI) greater than 25 and therefore classed as overweight. This figure is projected to rise to four billion by 2035.
Obesity therefore represents a major public health concern, especially given how it is associated with as many as 18 co-morbidities including cardio-metabolic disorders and several types of cancer.
The pharmacological management of obesity has always been challenging, with the currently available anti-obesity medications often delivering insufficient efficacy. Part of the problem has been unravelling the complex hormonal milieu that exists in obese individuals and which hormones to target with drugs.
Despite this, an incidental finding in the late 1980’s, paved the way for the current paradigm in obesity management, yet it was to take many more years before researchers fully appreciated the implications of what they discovered.
In 1998, it was already known that glucagon-like peptide 1 (GLP-1), a hormone that caused the release of insulin from the pancreas and suppressed glucagon release, also produced an anti-diabetic effect through lowering blood sugar. But when researchers gave an intravenous infusion of GLP-1 to healthy young men, it not only lowered blood glucose but enhanced satiety and fullness, reducing energy intake by up to 12% compared to saline.
At the time, researchers failed to understand the importance of these results and it took more than 20 years to understand the weight-lowering effect of GLP-1 agonists. The importance of this effect came to prominence in a 2017 study of the GLP-1 agonist, semaglutide, in those with type 2 diabetes. The drug led to weight losses of up to five kilograms, prompting a further study – this time in overweight and obese patients without diabetes.
The results showed that a weekly injection of semaglutide to people with a BMI greater than 30 led to a mean reduction in body weight of -14.9% compared to only -2.4% with placebo. As an added bonus, the drug also improved cardiometabolic risk factors.
But GLP-1 was not the only hormonal target in obesity. Glucose-dependent insulinotropic polypeptide (GIP) is a gut hormone responsible for increasing insulin secretion after the intake of oral glucose. The drug tirzepatide, for example, which is a dual GLP-1-GIP agonist, is able to reduce body weight by more than 20 per cent.
Another somewhat counter-intuitive target is the glucagon receptor. Under normal circumstances, stimulation of this receptor increases the release of glucose, but work in 2009 demonstrated how a glucagon-GLP-1 co-agonist, reduced body weight among diet-induced obese mice. Scientists are now taking this innovation a step further with triple receptor agonist drugs, most recently, LY3437943, which has been shown to decrease body weight.
With anti-diabetic drugs now incorporated into obesity management guidelines, have we at last found the silver bullet to stem the rising tide of obesity? Probably not.
It’s widely acknowledged that these new anti-obesity drugs are only one part of a comprehensive approach to obesity management, alongside diet and exercise. Indeed, NICE recommended use of semaglutide alongside a reduced-calorie diet and increased physical activity as a therapeutic option for weight loss in March 2023. Furthermore, once stopped, any weight lost with these drugs is quickly regained, largely because the decline in energy expenditure favouring weight regain persists long after the period of weight loss.
Ultimately, perhaps weight loss per se should not be seen as the most relevant metric. Patients who lose weight with anti-diabetic drugs also need to adopt a healthy diet and accept increased physical activity as a life-long norm.
Although some degree of weight regain is inevitable once treatment has stopped, it is recognised that the adoption of healthy lifestyle habits reduce mortality, irrespective of body mass index.
9th March 2023
A technology appraisal guidance document from NICE has recommended the use of semaglutide for the management of overweight and obesity.
Obesity is a global health problem and the World Obesity Atlas 2023 report has estimated based on current trends, that overweight and obesity will affect over 4 billion people by 2035, reflecting an increase from 38% of the global population in 2020 to more than 50% in 2035. Semaglutide (brand name Wegovy) has a current marketing authorisation ‘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 ≥30 kg/m2 (obesity), or ≥27 kg/m2 to <30 kg/m2 (overweight) in the presence of at least one weight-related comorbidity.’
In its guidance, NICE has recommended use of the drug based on the licensed use, only if it is used ‘for a maximum of 2 years, and within a specialist weight management service providing multidisciplinary management of overweight or obesity.’ Adding that semaglutide should be stopped if an individual fails to achieve less than 5% of the initial weight after 6 months of treatment.
Semaglutide clinical efficacy
In an associated press release from NICE, it was stated that evidence for the effectiveness of the drug in weight loss was derived from the STEP 1 trial. This randomised, double-blind, placebo-controlled trial included nearly 2,000 adults with a body mass index (BMI) of 30 or more and individuals with a BMI of 27 but with ≥1 weight-related coexisting condition and who were not diabetic. Participants received once weekly semaglutide 2.4 mg or placebo. After 68 weeks of treatment, participants receiving semaglutide saw 14.9% mean decrease in their body weight compared to baseline compared to only 2.4% among placebo participants and this difference was statistically significant (p < 0.001).
In the press release, Helen Knight, Director of Medicines Evaluation at NICE, said that ‘it (semaglutide) won’t be available to everyone. Our committee has made specific recommendations to ensure it remains value for money for the taxpayer, and it can only be used for a maximum of two years.’
The release also cites data from a 2019 Health Survey for England, which estimated that 28% of adults in England were obese and a further 36% were overweight and that the government estimated that the current NHS costs of obesity in the UK were £6.1 billion and £27 billion to wider society.
28th September 2022
Semaglutide 2.4 mg given as a weekly subcutaneous injection to patients with obesity but without type 2 diabetes in combination with diet and exercise, led to a significant reduction in their 10-year risk of developing type 2 diabetes compared to placebo according to the findings of a study by US researchers presented at the 58th European Association for the Study of Diabetes (EASD) 2022.
Obesity is a major public health challenge and several lines of evidence from both observational and clinical studies over the past 30 years have clearly demonstrated a strong link between visceral and ectopic fat and the development of a clinical syndrome characterised by atherogenic dyslipidaemia, hyper-insulinaemia/glucose intolerance, hypertension, atherosclerosis and adverse cardiac remodelling and heart failure.
Although diet and exercise are recommended as a first step to reduce obesity, some evidence shows that among obese individuals who have lost weight, multiple compensatory mechanisms encouraging weight gain, can persist for at least 12 months after weight loss.
Semaglutide is a glucagon-like peptide-1 (GLP-1) analogue that is approved as an adjunct to diet and exercise in adults with insufficiently controlled type 2 diabetes mellitus. However, the STEP 1 trial showed that semaglutide at a dose of 2.4 mg weekly in combination with a lifestyle intervention could also result in sustained, clinically relevant reductions in body weight among patients with a body mass index (BMI) > 30.
Moreover, in a further trial (STEP 4), researchers examined the effect of continuing vs withdrawing treatment with semaglutide on weight loss maintenance and showed that after a 20-week run-in period, maintaining treatment with semaglutide 2.4 mg once weekly, compared with switching to placebo resulted in continued weight loss over the following 48 weeks.
With clear evidence that semaglutide could lead to weight loss, whether this also reduced an individual’s risk of developing type 2 diabetes was unclear and was the objective of the study presented at the EASD meeting. Researchers used data from both STEP 1 and 4, to assess an individual’s 10-year risk of developing type 2 diabetes.
The team used the cardiometabolic disease staging tool which uses three unmodifiable factors (age, sex, and race) and five modifiable factors (BMI, blood pressure, glucose level, high-density lipoprotein (HDL) cholesterol, and triglycerides) to predict an individual’s percentage risk of developing the disease over the next 10 years.
Semaglutide and 10-year diabetes risk
For the STEP 1 trial, the 10-year risk scores of developing T2D after 68 weeks of treatment decreased from 18.2% to 7.1% with semaglutide 2.4 mg, and 17.8% to 15.6% with placebo (p < 0.01). In STEP 4, most of the risk score reduction with semaglutide 2.4 mg occurred during weeks 0-20, from 20.6% to 11.4% but the risk score decreased further to 7.7% with continued semaglutide 2.4 mg during weeks 20-68 but increased to 15.4% after a switch to placebo (p < 0.01).
In addition, data from STEP 4 showed that weight loss was 11% for weeks 0 – 20 and a further 9% with continued semaglutide 2.4 mg vs a 6%
regain with switch to placebo for weeks 20 – 68.
The authors concluded that treatment with semaglutide 2.4 mg reduces the 10-year risk of T2D by
~60% adding that sustained treatment was required to maintain this benefit but suggested that semaglutide 2.4 mg could help prevent type 2 diabetes in people with obesity.
Citation
Garvey TW et al. Semaglutide 2.4 mg reduces the 10-year type 2 diabetes risk in people with overweight or obesity Abstract 562. EASD 2022
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