GLP-1s & Medications

Pfizer aims to enter the obesity treatment arena with danuglipron, a novel GLP-1 targeting pill

In the competitive landscape of obesity pharmacotherapy, Pfizer is on the cusp of revealing pivotal trial data for its investigational drug danuglipron. This oral medication, administered twice daily, is poised to challenge the market dominance of prominent weight-loss therapies Wegovy and Mounjaro.

Danuglipron operates by influencing the glucagon-like peptide-1 (GLP-1) receptor, which has recently revolutionised the pharmaceutical industry, resulting in substantial economic shifts within the stock market. Through its strategic targeting of this receptor, the drug aims to become a cornerstone in the management of obesity.

Pfizer’s commitment to this endeavour is evident through the initiation of a rigorous Phase 2 trial, designed to thoroughly evaluate danuglipron’s ability to achieve significant weight reduction in individuals with obesity. The financial community, particularly Leerink Partners’ analyst David Risinger, anticipates a full disclosure of the study outcomes potentially by October 31.

For Pfizer, the urgency to diversify its product portfolio has never been greater. The pharmaceutical giant has faced a downturn in its COVID-19 vaccine and therapeutic product demand, compelling a downward revision of its revenue projections. This decline has led to a notable 40% dip in Pfizer’s stock value since the beginning of the year.

The strategic importance of danuglipron has been amplified following Pfizer’s decision in June to discontinue another candidate within its GLP-1 based weight-loss pipeline. The discontinuation was a setback, sharpening the focus on danuglipron as a critical asset in the company’s quest to secure a competitive position in the burgeoning GLP-1 market segment.

As Pfizer prepares to release its findings, the pharmaceutical, obesity care, and weight management industries are watching closely. Danuglipron not only carries the potential to alter the obesity treatment paradigm but also represents a vital opportunity for Pfizer to demonstrate resilience and innovation in the face of shifting healthcare needs. The success of this drug is particularly crucial as Pfizer measures itself against Eli Lilly’s promising GLP-1 oral therapy, which is also vying for a share of this lucrative market.

Weight-loss medication Wegovy to be prescribed by NHS amid limited availability

In the UK, the NHS (National Health Service) in England is gearing up to administer the weight-loss drug Wegovy, also known by its scientific name semaglutide, under a “controlled and limited launch.” This initiative, starting from September 4, 2023, will operate via specialist NHS weight management services, where the drug will be prescribed in conjunction with a regimen involving a reduced-calorie diet and physical exercise. The patients targeted in this program must have a Body Mass Index (BMI) exceeding 30 and at least one weight-related health issue to qualify.

The drug, produced by Danish pharmaceutical company Novo Nordisk, received approval for NHS usage earlier in 2023, a sanction granted by the National Institute for Care and Excellence (NICE), which has recommended its usage be capped at a two-year period.

Addressing the prospects of this new treatment, UK Prime Minister Rishi Sunak heralded the introduction of Wegovy as a potential “game-changer” in the battle against obesity, a condition known to predispose individuals to serious health complications such as hypertension, diabetes, and various forms of cancer. The prime minister expressed optimism that this strategy would alleviate the strain on NHS resources, contribute to the reduction of waiting lists, and foster improved health and longevity among the populace.

Echoing these sentiments, Novo Nordisk anticipates that the drug will enhance the range of options available for individuals grappling with obesity, thus facilitating their journey towards achieving healthier body weights.

Earlier in June, the government had set aside £40 million for a pilot project intended to widen the accessibility of weight-loss injections as part of a robust strategy to curb obesity.

However, the initiative encountered a significant hurdle as Novo Nordisk reported an impending shortage in the supply of semaglutide, a situation anticipated to persist for an unspecified period. Despite this, the company reassured that a “proportion of available supply” would be designated for NHS services, with a firm commitment to prioritising patients demonstrating the “highest unmet medical need.”

An official communication from the NHS noted that in line with the guidance from NICE, measures are underway to inaugurate weight management undertakings, while also making efforts to restore the drug supply, particularly for individuals diagnosed with type 2 diabetes.

According to NHS projections, approximately 50,000 qualified patients in England stand to benefit from Wegovy, provided through NHS specialist weight management facilities capable of offering the necessary multi-disciplinary care.

Backing the efficacy of Wegovy, Novo Nordisk presented findings from a comprehensive five-year research project titled the Select trial. The study, which incorporated 17,604 adults aged 45 and above from 41 different countries, revealed that the drug could diminish the likelihood of heart attacks or strokes in individuals with obesity harbouring cardiovascular diseases by a considerable twenty percent. Participants in this trial were characterised by a BMI exceeding 27, established cardiovascular ailments, and devoid of any diabetes history.

Novo Nordisk’s weight-loss drug Wegovy demonstrates heart benefits in latest trial

Novo Nordisk’s groundbreaking obesity drug, Wegovy, has been shown to offer significant cardiovascular advantages, according to the results of a major late-stage trial announced on Tuesday (8th of August, 2023). This revelation not only highlights the efficacy of the medication but also helps in reshaping its perception beyond merely being a lifestyle drug.

The clinical study, named SELECT, revealed that individuals treated with Wegovy experienced a 20% reduction in the occurrence of heart attack, stroke, or death from heart-related diseases, in comparison to those who were administered a placebo. These findings far exceed the 15-17% reduction that had been anticipated by investors and analysts, although it’s worth noting that the results have not yet been subject to peer review.

Involving a substantial cohort of 17,500 participants, the SELECT trial specifically targeted individuals with overweight or obesity aged 45 or older, with a history of heart disease, but without prior diagnosis of diabetes. The trial, which spanned nearly five years, aimed to determine whether Wegovy’s weekly injection could confer tangible medical advantages.

The announcement of these positive results led to a surge in Novo Nordisk’s shares, propelling them by more than 13% to record highs. Over the past two years, the company’s shares have skyrocketed by almost 150%.

These encouraging outcomes could potentially influence insurers in the U.S. and health authorities in Europe to extend coverage of Wegovy to a broader segment of patients. Currently, some healthcare plans, including the U.S. Medicare health plan, categorise weight-loss treatments as lifestyle drugs. Experts opine that the new data might lead to a reassessment of this stance, particularly in the U.S., where the cost of Wegovy stands at $1,300 per month.

The findings from the trial have also prompted discussions regarding the long-term health benefits of the drug, particularly in terms of potentially lowering the overall healthcare burden and the expenses associated with treating heart disease in populations with overweight or obesity. Some experts, like Dr. Jeff Levin-Scherz, a consultant at Willis Towers Watson, remain cautious, suggesting that medical cost savings might be years away. He postulates that the drugs may prove to be cost-effective in improving patients’ lives but may not necessarily reduce their overall healthcare costs.

Large American corporations, which previously covered weight-loss treatments for their employees, have reduced their support due to escalating costs. However, the landmark data from the SELECT trial illustrates Wegovy’s potential to redefine how obesity is perceived and treated, according to Martin Holst Lange, Novo Nordisk’s executive vice president for development.

Novo Nordisk has expressed plans to submit applications for regulatory approvals of a label indication expansion for Wegovy in the U.S. and the European Union within the year.

Wegovy has already had a transformative impact on the weight-loss market since its U.S. introduction in June 2021. It has not only garnered attention from patients, investors, and celebrities around the globe but also significantly contributed to Novo’s shares’ growth. The injection helps patients feel fuller for more extended periods, resulting in an average weight loss of around 15% when coupled with dietary and exercise changes. The drug is part of the GLP-1 agonists class, initially developed to treat type 2 diabetes.

With obesity affecting over 650 million adults globally, a figure that has tripled since 1975, and approximately another 1.3 billion classified as having overweight, the World Health Organization links these conditions to heightened risks of heart disease and diabetes.

Industry analysts, like Sydbank’s Soren Lontoft Hansen, are optimistic that these better-than-expected results will cause a stir among physicians who prescribe anti-obesity drugs. Furthermore, Barclays analysts project that a positive outcome from the study could boost Wegovy’s uptake by 25% by 2030, provided it receives approval for expanded use.

Novo Nordisk is currently facing challenges to meet the soaring U.S. demand for Wegovy. In May, the company announced it was cutting the supply of starter doses to the U.S. market by half to secure supplies for existing patients. Although larger doses were reported to be in short supply by Reuters, Novo has denied such claims.

The detailed data from the trial is scheduled to be presented at a scientific conference later in 2023, and additional details may be revealed when Novo releases its second-quarter results on Thursday.

Boehringer Ingelheim joins the obesity drug race, unveiling promising results

Boehringer Ingelheim has joined the race for the next generation of obesity drugs, as a recent trial revealed that its treatment helped participants on the highest dose shed an impressive 19% of their body weight.

With its sights set on launching a late-stage trial, Boehringer Ingelheim aims to compete against Eli Lilly’s Mounjaro and Novo Nordisk’s Wegovy in the obesity drug market. Other players, including Pfizer and Regeneron, are also vying to enter the fray.

While direct comparisons are challenging, previous results demonstrated that participants on Mounjaro achieved an average weight loss of 22.5%, while Wegovy study patients experienced around 15% weight reduction.

Boehringer Ingelheim believes that extended use of its drug, as indicated by the continuous weight loss observed in its 48-week trial, could yield even greater results in terms of weight loss during the phase 3 trial, which is currently being discussed with regulatory authorities.

Paola Casarosa, Head of Therapeutic Areas at Boehringer Ingelheim, expressed confidence in observing “an even stronger effect” in the larger and longer phase 3 trial, highlighting the absence of any plateauing of effects as an encouraging finding.

The introduction of the first two obesity drugs has dramatically transformed the fortunes of the pharmaceutical companies involved. Novo Nordisk’s shares have skyrocketed by 247% in the past five years, while Eli Lilly has become the world’s largest pharmaceutical company by market capitalization on the back of hopes for its obesity and Alzheimer’s drugs.

Meeting the surge in demand driven by celebrity endorsements and the use of similar drugs for weight loss in diabetics has posed challenges for these companies. According to the World Health Organization, global obesity rates have tripled since 1975, and a Harvard study predicts that nearly half of Americans will have obesity by 2030.

Boehringer Ingelheim’s survodutide, developed in collaboration with Danish biotech Zealand Pharma, functions by mimicking a hormone called GLP-1 to reduce appetite, similar to existing drugs. However, survodutide also mimics glucagon, a hormone known to accelerate the rate at which the body burns energy.

Casarosa emphasised the importance of finding the right balance, stating that meaningful and impactful weight loss relies on the interplay between food intake and metabolism adjustment.

Moreover, the drug shows potential in addressing fat accumulation in the liver, a condition affecting 70% of patients with obesity and associated with diabetes and cardiovascular problems.

However, approximately a quarter of trial participants dropped out due to side effects, primarily gastrointestinal in nature, akin to the nausea experienced by users of approved obesity drugs. Boehringer Ingelheim believes that such issues can be mitigated by gradually increasing the dosage in future applications.

Wales takes strong action against junk food meal deals to combat obesity crisis

 In a determined effort to address the growing obesity problem, Wales is set to implement strict measures aimed at curbing the promotion and accessibility of unhealthy meal deals and temporary price reductions on foods high in fat, sugar, or salt. With almost two-thirds of adults in Wales classified as having either overweight or obesity, the Labour-led government intends to go beyond the initiatives taken in England by enacting legislation to tackle the promotion of ultra-processed foods.

The Welsh government plans to mirror the UK government’s approach in England to restrict volume promotions, such as buy one get one free deals. Additionally, Wales will introduce proposals targeting meal deals and temporary price reductions, acknowledging the urgency of the crisis and the need for more comprehensive actions.

Lynne Neagle, the Welsh Deputy Minister for Mental Health and Wellbeing, emphasised the pressing nature of the situation, stating, “Rising levels of obesity are causing a significant burden of preventable illness in Wales. We must act immediately.” Neagle clarified that the government does not intend to ban meal deals altogether but aims to shift the focus towards healthier, more nutritionally balanced options. Many meal deals currently include large bags of crisps and snacks that are high in fat and sugar. The objective is to ensure that affordable meal deals are available, which are lower in calories, fat, and sugar.

Research conducted by Public Health Wales revealed that three-quarters of lunchtime meal deals exceed recommended calorie and salt levels for a meal. The unhealthiest lunch options provide two-thirds of the daily calorie intake, over 122% of the daily fat intake, 149% of the recommended sugar intake, and 112% of the daily salt intake. The majority of dinnertime meal combinations exceed average energy requirements.

The researchers concluded that if an individual purchased an average meal deal for lunch five days a week, they could gain more than 6 pounds (2.8 kg) in a year. If they opted for a high-calorie meal deal five days a week, the weight gain could reach 47 pounds (21 kg) within a year.

Neagle clarified that temporary price reductions would not be banned either, stating, “Our aim is to rebalance our food environments so that the healthy choice becomes the easy choice.”

The UK government recently delayed the planned ban on buy one get one free deals for junk food by two years, citing concerns over the cost of living crisis. However, the Welsh government is committed to implementing its restrictions by 2025 and intends to proceed even if the UK government does not follow suit.

Neagle expressed hope for alignment across the UK, stating, “It would be great if England moved forward with these plans. We believe that consistency throughout the UK is beneficial, but we have a responsibility to address the crisis we are currently facing in Wales.”

Neagle dismissed the notion that these measures amount to a “nanny state” intervention, highlighting that tackling obesity extends beyond individual responsibility and encompasses the unhealthy food environment people are exposed to on a daily basis.

The regulations will apply to major food retailers, and the government will also explore measures to curb the purchase of unhealthy food online and offers associated with loyalty cards.

According to the Welsh government, 62% of individuals aged 16 and over in Wales either have overweight or obesity.

James Evans, the Welsh Conservatives’ Shadow Minister for Mental Health and Wellbeing, stressed the need for clear assurances from the Welsh Labour government that meal deals will not be banned and that any new regulations will not increase the average weekly cost for shoppers.

Weight loss injections could be prescribed to children with obesity

UK government officials are contemplating offering weight-loss injections to children with obesity as young as 12 in an effort to combat the escalating childhood obesity problem in the country.

Specialists are currently evaluating if semaglutide injections, a weight-loss medication recently sanctioned for adult use by the NHS, could be beneficial for children with obesity aged between 12 and 17. Health authorities are now encouraging the National Institute for Health and Care Excellence (NICE) to consider providing these injections to teenagers struggling with obesity.

The final decision, expected to be announced in early 2024, is being supported by experts who argue that the medication could prevent more children from needing invasive weight-loss procedures. However, this suggestion has sparked controversy, with some arguing it could lead to an over-medicalisation of children.

Those opposed to the idea of weight loss injections for children raise several concerns. They fear the potential interference of these drugs with the physical and mental growth and development of children. They also highlight the lack of evidence regarding the long-term effects of such treatments on children’s health.

Critics further argue that such injections might encourage an unhealthy emphasis on weight and physical appearance, potentially leading to body image issues and disordered eating. The potential for serious side effects from weight loss injections is another concern. Additionally, they worry about the psychological message these injections could send, implying that a child’s body is unacceptable as it is.

Professor Keith Godfrey, from the National Institute for Health and Care Research’s Southampton Biomedical Research Centre, warns that providing weight-loss injections to children might lead to the unnecessary medicalisation of an entire generation.

Charlotte Summers from Gro Health, a company offering health and wellbeing programs for adults, children, and young people, advocates for a more holistic approach: “By promoting healthy eating habits, regular physical activity, and a positive relationship with food, we can enable our children to attain and maintain a healthy weight throughout their lives. This comprehensive strategy not only contributes to physical wellbeing, but also lays a solid foundation for emotional and mental health. We must collaborate to support our children in adopting a balanced and wholesome lifestyle for a healthier, brighter future.”

Europe set to miss global heart health targets as obesity skyrockets

According to a paper published in European Heart Journal, the flagship journal of the European Society of Cardiology, the prevalence of obesity in Europe has more than doubled over the past 35 years, with over one in five adults affected.

The third report from the ESC Atlas Project updates and expands upon the previous edition with cardiovascular disease (CVD) statistics to 2019, or the latest available year, for the 57 ESC member countries.

CVD is the most common cause of death in the region, accounting for 45% and 39% of fatalities in women and men, respectively. Unfortunately, the report paints a picture of ageing populations and low birth rates. Between 1970 and 2019 the proportion of individuals aged over 65 years increased from a median 9.2% to 17.2%, and the median age increased from 29.6 to 41.1 years. Alongside this, between 1970 and 2018 fertility rates fell from 2.6 to 1.6, below the average of 2.1 live births per woman needed for population replacement.

Each year, an estimated 48,000 new cases of coronary heart disease occur across Europe due to environmental noise pollution.

Professor Adam Timmis, chair of the report writing team, said, “Sociodemographic and environmental risk factors receive relatively little attention from cardiologists but make a substantial contribution to the risk of CVD. Europe now has top-heavy populations and this will exacerbate the growing burden of CVD. The situation is compounded by increasing urbanisation which threatens heart health due to dirty air, noise, social deprivation and stress. It is estimated that up to 40% of people living in the EU are exposed to noise levels beyond the region’s residential limits.”

According to the World Health Organisation (WHO), noncommunicable diseases kill 41 million people each year, equivalent to 71% of all deaths globally. CVD accounts for most of these deaths (17.9 million annually), followed by cancer (9.3 million). The WHO has set targets for noncommunicable diseases to be met by 2025 but the evidence in today’s report suggests that, across ESC member countries, most goals relating to heart health are unlikely to be achieved. For example, the WHO has called for a halt (with reference to 2010) to the rise in obesity. But between 2010 and 2016, the prevalence of obesity rose from 20.4% to 22.7% in women and from 19.2% to 22.2% in men. 

Healthcare professionals will need to be properly trained to deal with the ever-increasing strain of this problem.

Antibiotic consumption and childhood obesity

A growing base of evidence suggests antibiotic use results in microbial disturbances in the gut. These disturbances in the microbiome may contribute to weight gain. In comparisons between individuals, it has been shown that those with obesity have a lower diversity of microbes in their gut. This research is supported by studies in animal models. In infancy, a baby’s microbiome is rapidly developing. It is thus suggested by some researchers that any antibiotic exposure in infancy may impede the establishment of the healthy gut microbiome and have lifelong metabolic consequences.

In a systematic review and meta-analysis, Miller and colleagues showed that the antibiotic use in infancy is indeed related to overweight and obesity in childhood. There were notable differences however by gender with boys appearing to be more affected by antibiotic use than girls.

The authors looked at multiple drugs finding that macrolides were most strongly related to increased obesity risk while narrow-spectrum drugs were not significantly associated. These researchers suggest in the fight against childhood obesity we need to examine antibiotic prescriptions and use across populations.

Efficacy and safety of semaglutide for weight loss in patients with obesity

In this paper, published in The Lancet, the authors sought to assess efficacy and safety of the glucagon-like peptide-1 (GLP-1) analogue semaglutide, in comparison with a similar drug liraglutide, and placebo. The study was done in 8 countries, involving 71 clinical sites, with the primary endpoint being weight loss at week 52.

GLP-1 analogues mimic the function of human GLP-1, which regulates insulin secretion and glucagon secretion. These processes are linked with appetite, satiety and energy intake. This study found that these drugs, which were initially licensed for diabetes treatment, resulted in weight reductions which were significantly greater than the placebo group at 52 weeks. This weight loss is primarily due to the individuals consuming less energy, because of a combination of appetite suppression and enhanced satiety. Semaglutide was found to be the most effective, with weight loss of 11-14%, compared to Liraglutide’s 7-8%. In terms of side-effects, the most common complaint was of nausea. This was found to be dose dependent, so higher doses made side-effects more likely. Overall however, semaglutide was well tolerated, with no unanticipated safety or tolerability outcomes. Semaglutide has been shown to have a good benefit-risk profile which further supports its use as a weight management drug in its own right, instead of just being licensed for diabetes. Phase-3 studies are ongoing.

Cardiovascular Safety of Lorcaserin in Overweight or Obese Patients

In some patients, weight-loss guidelines recommend the use of pharmacological agents as adjuncts to lifestyle modification. Although not many are licensed, they have been shown to be effective for long-term weight management. One of the serious downsides of these drugs is the side-effects. Depending on their sight of action, they have been known to precipitate severe complications in the cardiovascular or neuropsychiatric systems, leading to their removal by regulatory agencies over safety concerns.  

Lorcaserin is a selective serotonin 2c receptor agonist that modulates appetite. It has proven efficacy for weight management in overweight or obese patients. This paper published in the New England Journal of Medicine sought to determine the cardiovascular risk associated with its use as an obesity treatment. From the study of 12,000 patients, it found no increased risk of cardiovascular complications. It also found that alongside significant weight loss there were also reductions in triglyceride levels and in dysglycaemia.  In addition, it was found that there was an improvement in heart rate and blood pressure, which is in contrast to most other weight loss agents. Overall, this drug is an effective adjunct to lifestyle interventions in patients with obesity and cardiovascular disease, and doesn’t increase the risk of cardiovascular events.

How Physiological Changes Associated with Obesity Affect Drug Metabolism

Obesity is known to have a significant impact on many organ systems that are crucial in drug metabolism. As the prevalence of obesity continues to rise, clinicians are being challenged with the problem of dosing in the extreme overweight population. This review article discusses the different physiological changes associated with obesity and how they affect absorption, distribution, drug metabolism and clearance in morbidly obese patients.

The changes that occur in the organs of the body do not correlate linearly with BMI, but also includes factors such as time and individual body composition. For example, in the kidney of an obese patient, renal clearance is initially enhanced by a compensatory hyperfiltration and hyper-perfusion, though, eventually, this declines as a result of a constantly elevated intra-glomerular pressure which leads to chronic kidney disease. Likewise, cardiac output is increased in obese patients in order to provide oxygen and nutrients to the excess tissue. This should mean that that blood flow to the liver increases, however due to non-alcoholic fatty liver disease resulting in steatosis, together with sinusoidal narrowing, blood flow may actually decrease over time.

Obesity also has an effect on the gastric emptying and gut permeability, meaning that drugs are absorbed at different rates to normal. Drug penetration into tissue is also affected, meaning that a higher dose may be needed in order to reach effective concentrations. For example, with antibiotics to treat a local infection, obese patients may require a much higher dose, which can then introduce issues of drug toxicity.

What is clear from these few examples is that with a growing number of obese patients, there needs to be a quantitative system in place that can derive drug dosing recommendations for obese patients. Currently there is a lack of understanding of how obesity affects the pharmacokinetics and pharmacodynamics of drugs, which leads to improper and potentially dangerous dosing of obese patients.

To learn more about obesity, its prevention, and its treatment please look at CCH’s Postgraduate Academic Courses in Obesity Care, and CPD Short Courses in topics such as childhood obesity and behaviour change, designed to up-skill health professionals in this vitally important, and often overlooked, area of care.

Efficacy, Safety, and Mechanisms Of Herbal Medicines Used In The Treatment Of Obesity: A Protocol For Systematic Review

There is a huge amount of conflicting evidence over the potential efficacy of herbal remedies for the treatment of obesity. Although several systematic reviews have been conducted, the market is saturated with poorly evidenced claims, and a huge number of different remedies. This study sets out a protocol for a comprehensive systematic review into herbal remedies and their efficacy at treating obesity.

Herbal medicines can cause weight loss through 5 different mechanisms, namely appetite control, stimulation of thermogenesis, inhibition of fat absorption as well as decreasing lipogenesis.

Efficacy has been evaluated before, however, the authors feel a new systematic review, focussing on clinical trials data is needed. This systematic review will be seen as an update, with all new data plus any new research on active components and methods of action.

Herbal remedies are defined as raw or refined products derived from plants or parts of plants, in this case used for the treatment of obesity. The primary outcomes expected will be an improvement in BMI, waist circumference, waist-hip ratio, body fat and appetite. Secondary outcomes will focus more on the metabolic features of obesity, meaning improvements to cholesterol, low-density lipoprotein, high-density lipoprotein, blood pressure, triglycerides and blood sugar.

The increasing number of randomised controlled clinical trials means that a new and updated review of the mechanisms of action and efficacy of these treatments is needed. They have the potential to become a cheap new therapy in the treatment of obesity or if proven otherwise, then this systematic review will put to rest the debate over their efficacy.