GLP-1 receptor agonists not linked to suicidal thoughts, PRAC concludes

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.‘

Type 2 diabetes drug lixisenatide shows potential in slowing Parkinson’s disease progression

The glucagon-like peptide 1 receptor agonist (GLP-1 RA) lixisenatide, commonly used to treat type 2 diabetes, may slow the progression of Parkinson’s disease symptoms, research suggests.

Investigators evaluating lixisenatide reported less progression of motor disability over a 12-month period in patients taking the drug compared with placebo.

But writing in the New England Journal of Medicine, they said lixisenatide was associated with gastrointestinal side effects in the phase two study and longer and larger trials are now needed to determine the impact and safety of the drug.

It is the second trial of a GLP-1 RA diabetes drug to show an effect in Parkinson’s disease with a 2017 study reporting improvement in motor symptoms in patients taking exenatide.

A larger phase three trial of exenatide, led by UK researchers, is due to report later this year.

The latest study enrolled 156 people with early Parkinson’s disease and no motor complications. All of the patients were taking their usual medication, but half also had a daily injection of lixisenatide and half were given a placebo.

After a year, those given lixisenatide showed no progression of motor problems while those on placebo dropped around three points on the assessment scale – classed as a moderate difference but likely to be clinically meaningful.

The difference was still apparent two months after the trial stopped, the researchers said, suggesting a neuroprotective effect.

Gastrointestinal side effects occurred in more than half the participants receiving lixisenatide, and often led to the dose of the drug being halved, but nausea did not appear to be associated with the magnitude of effect of the drug, they said.

The UK researchers said the study was important given it supports what had previously been found with exenatide.

Professor Tom Foltynie, professor of neurology, at the University College London (UCL) Queen Square Institute of Neurology, said: ‘This cumulative clinical data therefore strongly supports the earlier laboratory and epidemiological data, that GLP1 receptor stimulation in the brain has neuroprotective effects relevant to the neurodegenerative processes of Parkinson’s disease.’

But he said the beneficial effects are likely to be restricted to those GLP1 receptor agonists that can cross the blood-brain barrier which ruled out liraglutide and semaglutide.

Yet it is still not clear whether the drugs simply improve dopaminergic signalling to provide symptom relief or have a neuroprotective effect.

‘Phase 3 trial data of the effects of two years exposure to exenatide in patients with Parkinson’s disease will hopefully address this question and will be available in the second half of 2024,’ Professor Foltynie added.

Professor Masud Husain, who co-leads the dementia research team at the University of Oxford, said the results around lixisenatide were ‘really encouraging‘ for people with Parkinson’s disease.

‘However, the findings do not provide conclusive evidence that the drug has a protective effect on the brain to effectively slow down disease progression. We also have to bear in mind the side effects. Nausea occurred in nearly half and vomiting in 13% of people on the medication.’

Last summer, machine learning models accurately predicted sub-types of Parkinson’s disease based on images of patient-derived stem cells.

A version of this article was originally published by our sister publication Pulse.

GLP-1 agonists associated with modest weight loss in real-world setting

18th February 2023

The use of glucagon-like peptide-1 (GLP-1) agonists in patients who have type 2 diabetes and are overweight is associated with a small but significant weight loss after 72 weeks, according to a retrospective analysis of electronic health records by US researchers.

It has long been recognised that obesity is an independent risk factor for cardiovascular disease. In addition, cardiovascular disease is often present in those with type 2 diabetes and presents a major cause of death among such patients.

Despite this elevated risk, lifestyle modification, in particular weight loss, has been shown to be associated with better control of diabetes and and a reduction in cardiovascular risk factors.

Clinical trials in overweight, type 2 diabetic patients have demonstrated that drugs such as semaglutide, which is one of the GLP-1 agonists, achieves superior and clinically meaningful reductions in body weight in comparison to placebo.

However, most of the weight loss clinical trials have included a lifestyle intervention to support patients but in the absence of such support, GLP-1 agonist-associated weight loss is no better than that achieved with other agents such as metformin.

In the current study, US researchers from the University of Pittsburgh, wanted to understand the degree to which GLP-1 agonists induced weight loss when used as a part of routine clinical care, i.e. in the absence of a specific behavioural weight loss intervention.

The team retrospectively examined the electronic health records of those prescribed any drugs from the GLP-1 agonist class and the subsequent weight loss after 72 weeks of therapy.

GLP-1 agonists and real-world weight loss

Outcomes were available for 2,405 participants with a mean age of 48 years (47.4% male) and of whom, 92.1% had type 2 diabetes and a mean baseline body mass index of 37.

Only eight weeks after the first dispensing of a GLP-1 agonist, the mean weight loss was 1.1% and this increased to 2.2% after 72 weeks.

However, some patients did even better. For instance, 11.2% had lost at least 5% of their body weight after eight weeks, but after 72 weeks, this proportion increased to just over a third (33.3%).

In fact, at the 72 week mark, nearly half of the entire cohort (42.7%) had lost weight, with a small proportion of patients (10.5%) managing to lose 10% or more of their body weight.

The authors concluded that the use of GLP-1 agonists prescribed at standard doses led to a modest degree of weight loss in a real-world setting and in the absence of any specific patient support.

Citation
White GE et al. Real-world weight-loss effectiveness of glucagon-like peptide-1 agonists among patients with type 2 diabetes: A retrospective cohort study. Obesity (Silver Spring) 2023.

Review suggests GLP1 agonists offer similar glycaemic control to bariatric surgery

21st December 2022

A meta-analysis has revealed how GLP1 agonists provide a similar degree of glycaemic control to that achieved following bariatric surgery

Glucagon-like peptide-1 (GLP1) receptor agonists provide the same degree of glycaemic control as that achieved following bariatric surgery but the latter still confers the highest reductions in weight according to a systematic review and meta-analysis by researchers from Ontario, Canada.

According to the World Health Organisation, more than 1 billion people worldwide are obese and the organisation has estimated that by 2025, approximately 167 million people – adults and children – will become less healthy because they are overweight or obese. One particular disease linked to obesity is type 2 diabetes.

Moreover, lifestyle interventions such as a decreased caloric intake and increased physical activity in patients with type 2 diabetes, has been shown to result in a weight loss of 8.6%. An alternative approach to lifestyle modification, in those with type 2 diabetes is bariatric surgery, with 5-year outcome data showing that when combined with medical therapy, surgery was more effective than intensive medical therapy alone at decreasing, or in some cases resolving, hyperglycaemia. GLP1 agonists such as semaglutide have been shown to provide a sustained and clinically relevant reduction in body weight.

Nevertheless, there is a lack of evidence directly comparing GLP1 agonists with bariatric surgery in terms of weight loss and glycaemic control. Consequently, for the present study, the Canadian researchers undertook a systematic review and meta-analysis to directly compare the weight-lowering and glycaemic effect of GLP1 agonists and bariatric surgery in adults with obesity, defined as body mass index (BMI) > 25 kg/m² in both randomised trial and observational cohort studies.

The primary outcome was the absolute change in weight from baseline to the end of the study period, whereas secondary outcomes were absolute change in body mass index and glycated haemoglobin (HbA1c) in patients with concurrent type 2 diabetes.

GLP1 agonists weight loss and glycaemic control outcomes

A total of 6 studies, both randomised trials and observational studies, with 332 participants were included in the final analysis.

The pooled treatment effect for the change in weight from baseline between bariatric surgery and GLP1 agonists was −22.68 kg (95% CI −31.41 to −13.96) in randomised trials and −25.11 kg (95% CI −40.61 to −9.60) among the observational studies and in both types of study, these results favoured bariatric surgery.

In terms of body mass index, as with overall weight, there was a higher effect from bariatric surgery compared with the GLP1 agonists across all studies. However, the change in glycaemic control (based on HbA1c) levels, based only on randomise trial evidence (due to missing data with the observational studies), was a nonsignificant difference of −1.28% (95% CI −1.94% to −0.61%).

This finding, the authors suggested, indicated that the improvement in glycaemic control achieved from GLP1 agonists may be comparable with metabolic surgery for patients with type 2 diabetes and obesity.

They concluded that among adults with obesity, bariatric surgery, while still providing the greatest level of weight loss conferred similar effects on glycaemic control to GLP1 agonists.

Citation
Sarma S et al. Weight loss between glucagon-like peptide-1 receptor agonists and bariatric surgery in adults with obesity: A systematic review and meta-analysis. Obesity (Silver Spring) 2022.