Tackling the obesity challenge through innovation

A growing public health crisis 

A key milestone achieved: Recognition

Obesity is not just an aesthetic concern. It is a chronic condition defined by the WHO as an abnormal and excessive fat accumulation that can be detrimental to our health. Obesity is a gateway for more than 200 health complications and several non-communicable diseases, such as type 2 diabetes, cardiovascular diseases, sleep apnea, mental disorders, and cancer. It is also associated with a lower life expectancy and quality of life.  

Obesity has no symptoms and labeling it a chronic disease has raised long-standing controversies. Going unnoticed for several years, it wasn't until 1948 that obesity was included in the International Classification of Diseases. Recognized by the World Health Organization (WHO) in 1997, Medicare in 2003, the American Medical Association (AMA) in 2013, and in several other countries later on (e.g., Italy in 2019, European Union in 2021), obesity is finally starting to receive global attention. 

Recognition marks the first important step to combat obesity and its consequences by removing a significant obstacle to developing, establishing, and covering obesity-related services.

A highly undiagnosed condition

Despite the big step forward, obesity is still a highly undiagnosed condition, and only 2% of people with obesity are medically treated.  

The WHO recommends an international body mass index (BMI) cut-off point classification, calculated as weight in kilograms divided by height in meters squared. A BMI>25 classifies overweight, and a BMI>30 obesity.

The BMI is a helpful statistical index to follow the progression of obesity worldwide. Still, it doesn't distinguish between excess fat, muscle, or bone mass, nor does it take into account factors such as age, sex, ethnicity (e.g., studies show that Asian populations could suffer more severe health consequences at lower BMIs than other ethnic groups), and localized fat accumulation (e.g., people with visceral fat accumulation might have a BMI<25 and yet this condition is the most dangerous for our health). Therefore, the BMI metric underestimates the health-related consequences and the global prevalence of obesity. 

New studies point to another indicator, the waist-to-height ratio (WHtR), as a simpler and more predictive tool for obesity and its health-related consequences. Other methods include skinfold thickness tests, waist-to-hip comparisons, bioelectrical impedance analysis (to analyze body composition), and imaging tests, such as ultrasounds, CT scans, and MRI scans. In combination, doctors usually prescribe tests to help diagnose obesity-related health risks: blood tests to examine cholesterol and glucose levels, liver function tests, diabetes screening, thyroid tests, and heart tests (ECG or EKG).

Obesity around the world

Currently, more than 2bn people worldwide are either overweight or obese. For the first time in human history, obesity is a more significant global health crisis than hunger; the number of overweight people is three times higher than the number of people undernourished (estimated to be around 800mn globally). 

Obesity prevalence is higher among women and lower socioeconomic groups and increases with age. Early onset obesity is also gaining ground, with a prevalence of overweight and obesity among children aged 5-19 of 21%, from just 4% in 1975.

Obesity is a global phenomenon

The United States has the highest prevalence of overweight (including obesity) among high-income countries, affecting nearly three out of four adults (40% obese). In Switzerland and France, this number stands at around 40%. Despite these staggering figures, this is only half the picture.

Obesity is not a high-income countries problem. Today around 77% of obese adults are in low and middle-income countries. More than half of the world's obese people live in 10 countries, 8 of which are low-income countries: Brazil, China, Egypt, India, Indonesia, Mexico, Pakistan, and Russia. In Somalia, obesity prevalence is around 7%, a number greater than the global average in 1975 of 4.5%.  

Obesity is a global phenomenon, and currently, some countries face a double burden: high prevalence of undernutrition and overweight/obesity.   

Overweight and obesity rates are also driving the rise of another pandemic: diabetes. The number of adult people with diabetes rose from 108mn in 1980 to 537mn and is predicted to reach 643mn by 2030 and 783mn by 2045. Obesity accounts for 80-85% of the risk of developing type 2 diabetes.

A complex disease that fights back

Current recommendations to treat obesity are based on the underlying physiological property that fat accumulation is driven by an energy imbalance between consumed and expended calories. This could result from many exogenous and endogenous factors (genetic, behavioral, physiological, psychological, social, environmental, etc.).

Some people believe that obese lack willpower, but the truth is that their condition drives so significant physiological and metabolic changes that weight loss and weight loss maintenance become extremely challenging. Once obesity develops, the body sets its "weight point" at an increased value. For example, an obese adult that loses a substantial amount of weight through drastic calorie restriction will also see a drop in his metabolic rate. Therefore, to maintain his weight, the same individual would have to consume fewer calories and have stronger willpower than someone who has never been obese. Long-term weight loss becomes a lifelong struggle.   

The mechanisms underlying excess body-fat accumulation are numerous, and their interaction is not fully understood. Therefore, in this document, we won't focus on the individual causes of obesity but solely on the possible drivers of the obesity pandemic to find the real culprit based on the current scientific literature. 

Sleep

At the individual level, sleeping less than 6 hours per night increases the risk of gaining weight. However, no clear trend seems to be correlated with the obesity pandemic. Adults sleep as much today as they did in the 1960s, while children and teenagers have lost an average of 1 hour of sleep during the same timeframe.    

In France and Canada, where obesity prevalence is respectively 10% and 30%, sleep duration among adults has even increased. 

Physical activity 

We have observed a decline in physical activity worldwide since the 1970s. This is not surprising; we spend more time in front of screens, and rapid economic development, technological advancements, and automation have led us to a more sedentary life.

However, there seems to be no scientific consensus on the role of physical activity as the main culprit for today's obesity pandemic.   

Besides, the scientific evidence that physical activity contributes significantly to weight loss is not firmly established. 

Although the role of physical activity in the obesity pandemic is still unclear, its benefits are not questioned. Physical activity helps maintain weight by regulating hunger and satiety and improving our overall health. 

If physical activity is not responsible for the obesity pandemic, who is?  

Food

The obesogenic environment in which we live has undoubtedly had a significant role in the global increase in obesity prevalence. Since the 1970s, the average caloric intake has exploded worldwide, from 2200 calories available per inhabitant per day to almost 3000 today. The prevalence of obesity has followed this increase. (The graph below shows the calories available, not the calories consumed - but by subtracting the food waste from the available calories, we notice the same upward trend).  

Calorie intake (the energy our body can get from a nutrient) varies according to the macronutrients ingested (lipids, carbohydrates, proteins) and according to the energy required to digest them, which also depends on the kind of processing it undergoes; the more the product is processed, chewed or cooked, the more calories are assimilated (e.g., if we eat a raw egg, our body assimilates 65% of its proteins, 95% if the same egg is cooked). Interesting fact: the evolution of the human brain and its size can be directly linked with the innovation of cooking (since our body could devote more energy to this organ instead of using it for digestion).  

In 1902, Wilbur Olin Atwater created this chart to quantify the nutritional content of macronutrients.

For the same quantity of food in grams, our body assimilates fewer calories from proteins than carbohydrates and lipids. While proteins are therefore linked to a higher metabolism (and also increased satiety), both sugar and fat are processed at almost no cost by our body.

Is there a single culprit among the main macronutrients, proteins, carbohydrates, and lipids, for the obesity pandemic? The graph below shows that carbohydrates and lipids have caused the number of available calories to explode.  

Putting aside proteins, whose availability has not increased significantly compared to lipids and carbohydrates, it remains to be seen if there is enough evidence to point to a single macronutrient among those two.    

In the 1960s, the sugar industry funded research that downplayed the risks of sugar and shifted the blame to fats. Over the last 10-15 years, many theories have accused sugar. Have scientists reached a consensus on this debate?

Looking at the trend of available macronutrients in singular countries with a high prevalence of obesity, we find no clear answer. In Egypt, carbohydrates have caused the number of calories to explode; in the United States, Germany, and Mexico, both carbohydrates and lipids have spiked, while in France, lipids have seen a sharp rise, despite a drop in carbohydrates. No matter what macronutrient prevails, obesity has progressed.

Current research finds no apparent difference between sugar and fat for weight gain. Conversely, reducing carbohydrates or lipids seems to have a similar effect on weight loss. Therefore, it is a high-energy diet that predisposes to excess weight gain, irrespective of its macronutrient content. 

Besides the number of calories ingested, another significant change has occurred in our society over the last 50 years: the widespread availability of cheap, ultra-processed food. Since the 1970s, the world has had increasingly easy access to high-energy, palatable, ultra-processed food, which is high in easily assimilated carbs and lipids, and which, in addition, is extremely cheap. Today more calories are available at a lower price while simultaneously, healthy and affordable food retailers disappear.

The effects of ultra-processed foods on our bodies are being studied, and some preliminary works show no encouraging results. This food promotes even more weight gain by modifying satiety and appetite.  

The obesity pandemic was not triggered by a sudden rise in the number of poorly disciplined and self-indulgent people but by our environment, which offers greater availability of highly rewarding, energy-dense food.

Genetics 

It remains to explore just one more factor believed to significantly influence obesity development: genetics. We know that significant changes in our genetic footprint do not happen in such a small timeframe. Genetics cannot explain the obesity pandemic, but its role is nonetheless essential. 

Genetics makes us more or less vulnerable to the environment in which we live. An "obesogenic" environment promotes obesity by offering more calories and requiring minimal physical activity. 

With the progress of whole-exome sequencing (WES) and genome sequencing analysis, researchers have identified more than 1'000 genes or associations of genes that would reinforce weight gain. The central nervous system (CNS) and neuronal pathways have emerged as the major drivers of body weight increase for genetic obesity by making us feel more hungry and storing more (or spending less) energy. A 2019 study showed that having a higher number of obesogenic genes increases the chances of developing obesity.

Obesity is weighing down the economy 

Obesity has severe consequences for our health and also for our society.

The economic costs of obesity are estimated to be more than $2tn, or 3% of the global GDP, and are expected to escalate to $18tn, or 3.3% of the global GDP, by 2060. China, the U.S., and India are expected to reach respectively $10tn, $2.5tn, and $850bn of economic costs for obesity. Economic costs include both the direct costs (medical and social care, representing 32% of the total) and the indirect costs (costs following premature mortality and productivity losses). Several countries devote >8% of their healthcare budget to obesity-related services.

Obesity is also the main reason for reduced life expectancy and a leading cause of death. People don't die because of obesity but because of the associated comorbidities. The higher the BMI, the higher the risk of dying from related comorbidities. In 2019 obesity (not including its related comorbidities alone) killed more than 5mn people around the world and became the fifth leading cause of death, following hypertension, smoking, air pollution, and diabetes. 

Estimates show that slowing the progression of obesity prevalence worldwide by only 5% below projected levels could provide around $430bn of savings every year. 

Acknowledging the tremendous burden obesity places upon health and health systems and recognizing obesity as a growing public health issue is only the first step. But it is essential to finally effectively address this challenge by filling the gaps in prevention, diagnostics, reimbursement, and treatment.   

A much-needed shift in the treatment paradigm 

Bariatric surgery is associated with several complications 

Weight loss treatments include lifestyle changes, anti-obesity medications (AOMs), and bariatric surgery. The graph below shows the body weight loss achieved through the different treatment modalities. Bariatric surgery is the most effective solution, and multiple guidelines recommend it for individuals with severe obesity or those with moderate obesity that have associated comorbidities. The procedure leads to reductions in weight ranging from 15% to 35% with a long-term success rate of around 70% (a weight loss of 20% is usually maintained for up to 20 years after the intervention). Complications (inflections, chronic nausea, acid reflux, etc.) occur in 15% of the cases.   

Studies show that undergoing bariatric surgery can significantly reduce the risk of death, increase a person’s lifespan and decrease the health risks associated with severe obesity. Therefore, in cases where obesity is associated with disability or comorbidities, the treatment is considered medically necessary and not just a cosmetic treatment. 

The other treatment modalities mainly include drugs for weight loss. This alternative has historically been less effective than bariatric surgery and less invasive. The field has been littered with multiple clinical failures, given the difficulty of assessing drug safety in patients with comorbidities. 

In 1999, Orlistat (sold as Ally, by GlaxoSmithKline or Xenical by (Roche) was the first FDA-approved medication for long-term use in weight loss. Other drugs began to appear in the early 2000s, including phentermine/topiramate (Qsymia, by Vivus), naltrexone/bupropion (Contrave, by Currax Pharmaceuticals), and liraglutide (Saxenda, by Novo Nordisk). Saxenda made up 56% of the global obesity prescription drug market as of 2019.

These medications help people lose 5% to 10% of their weight, an amount that is usually associated with improvements in cardiovascular risk factors like diabetes, hypertension, high cholesterol, and obstructive sleep apnea, as well as improvements in mobility. However, they either are too expensive (and not very well covered by health insurance), have too-mild efficacy or have too severe side effects. In addition to these barriers, the reluctance from physicians to see obesity as a disease to be treated with drugs made the obesity market not so attractive for big biopharma companies for several years.   

Innovation is finally lending a helping hand  

Lifestyle modification through low-fat and low-calorie diets and increased physical activity generally result in a 3-10% loss of initial body weight. Still, people usually tend to gain their weight back. Recognizing obesity as a chronic disease also means treating it as such. 

Several anti-obesity medications have been around for decades, but most have failed commercially. But a new class of drugs called glucagon-like peptide 1 (GLP-1) agonists could potentially change the outlook for people living with obesity. In June 2021, the FDA-approved semaglutide (Wegovy, by Novo Nordisk), a drug that results in more than 15% weight reduction in those with obesity. Semaglutide is a new generation of highly effective hormone-based obesity medications starting to approach the 25% to 30% weight loss mark that has only been achieved with bariatric surgery. The drug mimics a hormone called glucagon-like peptide-1 (GLP-1), secreted in the gut, and targets receptors throughout the body, including the brain (giving it the satiety signal).  

Significant barriers to break down

Despite the recent progress, bariatric interventions and the prescription of anti-obesity pharmacotherapies remain low relative to the proportion of eligible individuals. They are still limited by poor insurance coverage (reimbursement in the U.S. is granted only if obesity causes patients to be disabled or to have one or more comorbid illnesses such as hypertension, diabetes, or sleep apnea), high rate of complications, and a common misconception that weight loss can be achieved through lifestyle modification (even if true in some cases, in most of the cases the body undergoes significant physiological and metabolic changes that make weight loss and weight loss maintenance very hard to achieve).

Most of the time, people are left with no choice but to manage the downstream consequences of obesity. To address the dangerous comorbidities of obesity, medical technologies are increasingly replacing drugs with more localized therapy and fewer systemic side effects (neuromodulation devices, intravascular lithotripsy, etc.). 

Recent guidelines recognizing obesity as a disease, and the increasing evidence supporting the benefits of weight loss, could incentivize insurance companies to expand the coverage of bariatric surgery and weight loss drugs, promoting access to obesity treatment, screening, and counseling.

A multi-front war

Prevention

A healthy lifestyle can help prevent obesity, but it will not be enough to stop the progression of the pandemic in today's world. New policies and prevention measures that reshape our environment and the way we provide food and obesity-related services will be necessary, i.e., taxes for high-calorie foods, healthier food more readily available at lower prices, and better access to personalized counseling that incorporates information from genetics, the gut microbiome, and wearable sensors.

Recent guidelines in the U.S. emphasize preventing obesity in women as an effective way to stop the progression of the pandemic. With the obesity prevalence rising worldwide, maternal overweight and obesity rates have followed the same trend. Studies have shown that maternal overweight and obesity are associated with alterations in placental structure and function and even epigenetic alternations that can lead to long-term consequences in the offspring, including a higher risk for obesity and cardiometabolic diseases.

The use of next-generation–sequencing technology is central to obesity research. It will continue to drive the identification of new genetic variants that predict the risk of developing obesity and the range of cardiac and metabolic conditions that may come with it.  

Genetic screening for obesity should be part of our routine check-ups. Knowing the genetic susceptibility to obesity could permit the personalization of obesity therapy. Microbiome tests and online counseling could also be important in delivering personalized advice to patients. Novo Nordisk is working with startup Digbi Health to explore how a person's genes, proteins, gut bacteria, and lifestyle data can help predict the risk of obesity and associated comorbidities. The microbiota, the collection of microorganisms in our intestines, influences how we process food and our immune system and cognitive functions. Novo Nordisk also partnered with Noom to offer behavior change programs to people with obesity. Ksana Health is developing a remote measurement platform, Vira, for tracking behavior patterns and forming personalized care plans.  

Meanwhile, in the food-tech space, MycoTechnology is utilizing fungi-based food-processing platforms to transform the flavor and value of agricultural products. They're using mushrooms to produce non-caloric organic sweeteners aiming at ultimately replacing 100% of the sugar content in different products. The benefits of non-caloric sweeteners keep provoking controversies; contrary to what most food-tech companies promise, recent research suggests that consuming non-caloric sweeteners might induce weight gain.

Prevention is still in its early innings but holds an incredible potential to transform how we approach the obesity problem. 

A new era of weight loss pharmacotherapy

A new class of drugs that promises to close the gap between bariatric surgery's efficacy and pharmacotherapy's non-invasive nature is emerging. Novo Nordisk 's GLP-1, Wegovy, was first approved for treating diabetes but last year has been repurposed to treat obesity. Giving the drug to diabetic patients, the company realized that the product markedly enhanced weight loss, comparable to bariatric surgery results. On a phase 3 trial data, one-third of treated patients without type 2 diabetes lost more than 20% of their body weight over about a year and a half. The treatment is given once a week by self-injection under the skin, but an oral version is under development. Obesity treatments might be the next blockbuster drugs. Wegovy is expected to bring more than $3.7bn in sales to the company by 2025.    

Eli Lily, Novo Nordisk 's main rival in diabetes, has developed a similar compound, tirzepatide (marketed as Mounjaro), approved for the treatment of type 2 diabetes in May of 2022, but not yet approved for use as an anti-obesity medication. The company is working with the FDA on a timeline for approval. Amgen has recently released early data on a similar compound, called AMG 133, reaching comparable results. 

Eli Lily and Novo Nordisk know that expanding insurance coverage of their drug is critical. Wegovy and Mounjaro are under clinical trials to demonstrate that the drugs also improve cardiovascular outcomes in obese patients. Positive results might improve reimbursement coverage for GLP-1 drugs and further expand the obesity drug market. 

This year Novo Nordisk has started a collaboration with Swiss biotech EraCal Therapeutics, to explore new treatments aimed at food intake regulation, suppressing appetite, and other characteristics of metabolism.  

While most historic anti-obesity pharmacotherapies have been hampered by an unfavorable imbalance between efficacy and safety, companies are working on safer alternatives. Gelesis is developing a hydrogel designed to mimic the effect of ingested raw vegetables once in the stomach. Adults receiving Gelesis' pill achieved 5% or greater weight loss.

The obesity treatment market is in the midst of a real transformation and our Biotech360 strategy is exposed to this emerging opportunity. 

Drugs for genetically-driven obesity 

Obesity heritability is around 70%. Exposure to an obesogenic environment increases the risk of obesity in individuals carrying many genetic mutations.

For a long time, obesity was considered a too complex disease to be driven by a single genetic mutation. Genetic studies have identified a relatively prevalent monogenic component, due to mutations in genes controlling appetite and satiety (i.e., genes associated with the expression of leptin and its receptors, a hormone regulating the energy balance by inhibiting hunger). 

This year the FDA and E.U. Commission have finally approved the first drug for a rare monogenic (i.e. derived from a single gene disorder) cause of obesity, setmelanotide (brand name Imcrivee), developed by Rhythm Pharmaceuticals. Imcrivee targets a leptin receptor, the melanocortin-4 receptor (MC4R) pathway, responsible for regulating weight and hunger for treating a genetically-driven eating disorder known as Bardet-Biedl Syndrome (BBS). BBS is a rare affliction that affects approximately 5,000 individuals in the U.S. and Europe. The company is exploring 31 additional genes linked to other obesity-related indications with much larger patient populations (200k patients only in the U.S.). Thanks to the advancements in sequencing technology, today, individuals carrying monogenic mutations can be screened for less than $300, making identifying patients that could profit from this treatment relatively easy. Imcrivee uses Exact Sciences's newly acquired companion diagnostic developed by PreventionGenetics in collaboration with Rhythm Pharmaceuticals.

Our Bionics portfolio benefits from these newly developed genetic tests. 

Catalysts

• Results from ongoing clinical trials might push for reimbursement coverage. A new medication, semaglutide (Wegovy, by Novo Nordisk), approved in 2021 for weight loss, is undergoing the SELECT study to demonstrate that the drug lowers the incidence of major adverse cardiovascular events. Medicare does not cover medicines for obesity. Linking the drug to cardiovascular disease prevention among obese patients might convince insurance companies to cover the treatment. 

• New policies for expanded access to obesity-related services. So far, solutions have not been adopted to halt the obesity pandemic. The broader healthcare community needs increased recognition of obesity as a chronic disease. It might result in new policies and guidelines to expand patients' access to treatments and screening. 

• Innovation. The development of new genetic and diagnostic tests is in progress. But good screening for obesity does not help if there is no effective and easily accessible treatment. New drugs for weight loss with effectiveness comparable to bariatric surgery are emerging. 

Risks

• New drugs disappointment. The SELECT study is due to be completed by September 2023. Disappointing results might bring expectations back to earth. 

• Lack of insurance coverage. Effective obesity medications are cost-prohibitive, but health insurance rules exclude them because, unlike other diseases, excessive weight is not believed to threaten patients' lives. While attitudes around obesity have improved in recent years, a stigma exists within the healthcare community. Gaining insurance coverage is critical for adoption. 

• Lack of trained providers. A lack of healthcare providers trained in obesity treatment poses a significant barrier to effective care.