Written by: George William Ssendagala
Edited by: Natasha Barrow & Caroline Babisz
Over two decades ago, the World Health Organization (WHO) sounded the alarm on obesity, declaring it a global epidemic (1). Fast forward to 2013, and the WHO set an ambitious goal: halt the rise in obesity by 2030. But with just six years left, the numbers tell a different story. By 2035, 54% of the world's population will have an above-healthy weight (2). The economic impact of this global epidemic is a jaw-dropping $4.32 trillion.
Obesity is a multivariate disease caused by a prolonged caloric imbalance between consumed and depleted calories (3). Since its invention in the mid-1830s by Adolphe Quetelet, the Body Mass Index (BMI) has been regarded as the gauge for obesity. According to the WHO, for anyone to be overweight, their BMI should be 25 to 29.9 kg/m2 whereas obese individuals have a BMI >30 kg/m2.
However, there is increasing scepticism suggesting that the current obesity test (BMI) falls short of its intended purpose. For instance, it cannot tell the difference between muscle and fat nor does it account for racial differences. Plus, as we get older, our bones become less and BMI does not factor that in either (4). So, it is clear that while BMI might give us a rough idea, it is not exactly the “Sherlock Holmes” of body measurements. With suggestions popping up, the world needs a standardised measure for obesity that takes into account all the mentioned differences.
Those with obesity are at a higher risk of developing non-communicable diseases (NCDs) (2). NCDs are long-lasting, slow-developing health conditions not caused by infections but influenced by lifestyle choices, the environment, genetics, and physiological factors (5). There is often a delay between becoming obese and experiencing its full health impacts, but early warning signs include high blood pressure, high blood sugar, and low HDL cholesterol (good cholesterol). Over time, obesity can lead to severe conditions like certain cancers, cardiovascular diseases, type 2 diabetes, and hypertension, among others (3).
Since 1990, obesity has more than doubled among adults according to WHO. As of 2020, 42% of all adults were overweight or obese, this is predicted to increase to 54% by 2035. Per current trends, by 2035, two in every five children will be obese or overweight globally, a 17% increase from 2020, the majority of which will be living in middle-income countries (2).
Due to their high BMI, an estimated 68 million children will be suffering from high blood pressure, 27 million from hyperglycemia, and 76 million will have low HDL cholesterol by 2035. In simple terms, the world is on track to raising a generation of sick children!
Obesity’s impetus with critical comorbidities shortens life expectancy while contributing to economic burden and climate change.
In 2019, 10% of the 50.3 million registered deaths were linked to high BMI, with Type 2 diabetes being the leading cause globally, accompanied by other NCDs like stroke, coronary heart disease, and cancer (2).
High BMI also impacts our environment. The increased demand for food production to meet the needs of those with high BMI results in an extra 700 megatons of CO2 equivalent greenhouse gases annually (2). By 2035, the budget to manage this global epidemic will have risen to the tune of $4.32 trillion, rivalling Germany’s GDP.
To a great extent, elevated energy from highly rewarding, energy-density food is responsible for the obesity epidemic (3). Loaded with sugar, salt, and fat often dubbed the "holy trinity" of obesity. These unhealthy, calorie-dense foods have become widely available, even in lower-income communities, thanks to more efficient food processing and distribution models (6).
It’s no coincidence that you find yourself constantly craving your favourite drink or snack. Our preference for unhealthy foods and beverages is fueled by obesogenic marketing (3), which targets all age groups, even the youngest and most vulnerable. These relentless marketing campaigns have also led to differential marketing practices.
An investigation by Public Eye revealed that Nestlé, the world's largest food conglomerate, sold unhealthy infant formulas to consumers in the Global South, unlike the healthier versions sold in the North. For example, cerelac sold in Switzerland had no added sugar while the same snack had 6 g of added sugar per serving in Senegal and South Africa. This raises serious ethical questions about the commitment of global food companies to combating obesity and exposes the inefficacy of local regulations regarding healthy foods if at all they exist!
In association various social, economic, and environmental factors pertinent to food supply are also instigators of obesity. Socially, the availability of highly processed foods, combined with a sedentary lifestyle, creates an environment where obesity can easily take hold.
The Obesity Atlas 2024 highlights a positive correlation between high BMI and economic development, indicating that both developed and developing economies face a high risk of obesity. As these nations grow, so does their vulnerability to this epidemic necessitating interventions to combat obesity at different stages.
To effectively combat obesity, there are three sequential lines of intervention available: lifestyle modifications, pharmacotherapy, and weight loss surgery.
Through a trifecta of diet, physical activity, and behaviour therapy, lifestyle modification remains the foundation of obesity management (7). With unhealthy food suppliers taking advantage of lax policies in different countries, governments need to enact policies that encourage the availability of healthy foods with reduced sugar, fat, and salt while discouraging the availability of obesogenic foods more so aimed at children (8). In the process of curbing pervasive marketing, people should be empowered to decipher food labels and adverts to make responsible choices! Behavioural change patterns in the form of health promotion, nutrition education, sugar tax, and social marketing can act as enforcing catalysts to halt increasing obesity cases (9).
However, for those with a BMI ≥30 (or a BMI ≥27 with comorbid conditions) and an inability to lose weight using lifestyle modifications alone, pharmacotherapy is recommended (10). The action of current pharmacotherapy exploits the glucagon-like peptide-1 (GLP-1), a hormone that can regulate glucose metabolism and appetite. By promoting satiety and slowing gastric emptying while enhancing insulin secretion and inhibiting glucagon release, GLP-1 puts a tight control on blood glucose while discouraging food intake.
Novo Nordisk, the manufacturer of Ozempic and Wegovy, and Eli Lilly, which produces Mounjaro and Zepbound are leading the obesity pharmacotherapy market. According to BCC Research, the anti-obesity drug market will increase more than threefold from $3.2 billion in 2023 to $11.3 billion by 2028, at an estimated compound annual growth rate (CAGR) of 28.9%. The obesity drug market is still unsaturated and as the old titans hold their grip on the market, new entrants are expected.
For those whose BMI is > 40 or > 35 and unable to shed weight using lifestyle modifications or pharmacotherapy, weight loss surgery (bariatric surgery) is recommended (10). Standard bariatric operations can take the form of adjustable gastric banding, biliopancreatic diversion, roux-en-y gastric bypass, and sleeve gastrectomy (11). The effectiveness of bariatric surgery in sustaining weight loss for more than 5 years and improving associated illnesses has been documented (12). While lifestyle intervention can result in 10% or greater weight loss, pharmacotherapy reductions are 5 to 10 % of baseline weight and at least 50% loss of excess body weight after bariatric surgery is reported (13).
In the quest to crack the obesity code, new players are stepping up to the plate, eager to take on the big shots. Here are a few of the over 60 companies in this health showdown that stood out to us:
Resalis is working on developing a new therapeutic drug for obesity and fatty liver disease, called RES-010. Unlike other drugs that suppress appetite, RES-010 works by blocking miR-22, which plays a role in the mentioned morbidities, how? MicroRNAs (miRNAs), are tiny molecules made of RNA, 21-25 nucleotides long, that regulate how genes are expressed. These non-coding RNAs interact with messenger RNAs (mRNAs), which are responsible for making proteins. Since miRNAs can control multiple mRNAs, they can influence important pathways, including those for lipid metabolism. One specific miRNA that Resalis studies is miR-22, which is linked to obesity. Resalis discovered that miR-22 plays a role in promoting obesity and fatty liver disease in mice fed a high-fat diet. However, when miR-22 was removed (knocked out) in these mice, the development of fatty liver disease and obesity was significantly reduced.
In addition to its well-known role in obesity regulation, Ousia Pharma discovered a new way to enhance the hormone GLP-1. By adding MK-801 molecules that can be artfully delivered into the brain to block the N-methyl-D-aspartate (NMDA) receptor that works to influence the brain’s neuroplasticity (14). Neuroplasticity is the brain's ability to form new connections and adapt to new experiences. This combined approach of using GLP-1 with MK-801 has shown a greater impact than using GLP-1 alone, potentially leading to more effective treatments. Ousia Pharma is currently in the preclinical stage of developing this innovative obesity drug, which is part of its broader effort to create drug combinations for various metabolic disorders.
Tiny Health's tagline, “A healthy gut starts in the first 1000 days of life. The benefits last a lifetime,” highlights their mission and niche. They use metagenomics sequencing to detect potential metabolic and immune disorders like obesity and allergies. By focusing on the first 1000 days of a baby's life, they emphasise the importance of gut health during this crucial period. Tiny Health believes that a healthy gut earlier on in life can lead to better health throughout someone’s existence. By testing and correcting any imbalances within these 1000 days, they aim to promote long-term well-being.
Cell replacement therapy (CRT) involves replacing diseased or damaged body cells with healthy ones. This process requires creating functional cells, which is a complex task with many variables. However, data-driven approaches using machine learning can help optimise these protocols. A key concept in optimising CRT protocols is the "digital twin" of embryo development and cell differentiation. Just like a biological embryo, this digital twin uses data from real embryos and cells to guide decision-making. By relying on this computational data, the digital twin helps establish effective protocols and provides accurate information about the identity and composition of cells at each stage. This ensures the generation of functional cells for successful transplantation.
Have you ever heard of “undruggable” disease targets? If not, it means that certain disease targets in the body cannot allow the target drug to bind, which can lead to serious health problems. Think Bioscience has come up with a solution through a synthetic biology platform that entails applied microbiology, enzymology, and data science to tackle these tough targets. Their focus revolves around overcoming the inhibition of the protein tyrosine phosphatase 1B (PTP1B), a hard-to-reach therapeutic target for the treatment of diseases like obesity, diabetes, and cancer. Overcoming a key site for drug binding defines their role in redesigning nature to drug the undruggable through their customised therapeutic molecules that can quickly overcome this.
Contrary to the goals set by the WHO in 2013 to halt the rise in obesity by 2030, no country appears to be on track to meet this target. Instead, we are witnessing an alarming upward trend that could spiral out of control if not urgently addressed. Obesity often accompanies many deadly underlying conditions, significantly impairing the quality of life and productivity of those affected. Monitoring your health to detect early signs of obesity is crucial. As the condition progresses, the shift from lifestyle modification kind of management to pharmacotherapy and weight loss surgery not only becomes more challenging but also significantly increases the financial burden. It is imperative to take proactive steps now to prevent this growing crisis.
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14. Petersen J, Ludwig MQ, Juozaityte V, Ranea-Robles P, Svendsen C, Hwang E, et al. GLP-1-directed NMDA receptor antagonism for obesity treatment. Nature. 2024 May;629(8014):1133–41.
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