Life after weight loss: What comes after GLP-1?

Introduction

GLP-1s rule the healthcare market now.

Novo Nordisk sold nearly $20B in weight loss drugs in 2023, and given the massive demand for GLP-1s, some predict that the obesity drug market could grow to $100B by 2030. That’s only 4.5 years away!

While industry experts expects there to be plenty of space for multiple competing drugs on the market, all the attention and R&D effort big pharma is giving to this space likely means early stage investors will have fewer opportunities to find hidden gems or undiscovered compounds within the weight loss drug market.

So what would the world look like, and where are some new frontiers that would arise from the eventual maturing of the weight loss market?

The Benefits of Weight Loss

If there’s any doubt about the power of GLP-1s, multiple studies involving GLP-1s have shown substantial benefits to some of the most pressing public health issues, including:

1. Reduce CVD risk in type 2 diabetes patients

2. Slow down chronic kidney disease progression and improve outcomes for diabetic dialysis patients. (I wanted to especially point out that this study was done in Taiwan, and we call ourselves the “Kingdom Dialysis Island” because of the high rates of ESRD.)

3. Reduced the severity of sleep apnea.

…and many more.

Clearly GLP-1s are here to stay, and will see expanded use over time.

Obesity First Approach?

Given the most dramatic and observable effect of GLP-1s is weight loss in obese patients, it does beg the question: could excessive weight be the initial driver of many of the chronic diseases that ails modern people?

While it’s probably an oversimplification to call obesity a disease in the traditional sense (like COVID, cancer, etc), there is growing anecdotal evidence and small scale trials that treating obesity leads to marked improvement in other comorbidities:

1. After taking Wegovy, a lady’s rheumatoid arthritis cleared after years of unsuccessful treatment for RA.

2. Reduced osteoarthritic knee pain in obese patients.

How much healthier would the world be if we could prevent obesity instead? Judging by those stories, reducing weight doesn’t just reduce cardiovascular disease; obesity seems to be the catalyst for a multitude of chronic diseases, and if we want to efficiently tackle the $4.8 trillion (and growing!) spent on healthcare, we’d do well to start from taking a good hard look at preventing obesity.

What happens when weight gain becomes unavoidable?

If the benefits of avoiding weight gain is so clear, what should we do when weight gain becomes unavoidable?

While that might seem like a surprise to some, there are plenty of examples where weight gain isn’t simply just a result of lifestyle neglect:

1. Psychological factors: Conditions such as depression, anxiety, and stress can lead to emotional eating, where individuals consume large quantities of food to cope with their emotions. Eating disorders like binge eating disorder further complicate this, as they involve recurrent episodes of eating large quantities of food, often quickly and to the point of discomfort. This type of disordered eating can lead to significant weight gain over time.

2. Pharmaceutical Drugs: Certain medications can cause weight gain as a side effect. Antidepressants, antipsychotics, corticosteroids, and some medications used for diabetes can increase appetite, alter metabolism, or cause fluid retention, all of which contribute to weight gain. For example, clinically significant weight gain (gaining more than 7% of baseline bodyweight) is seen in 55-70% of patients on atypical antipsychotics.

3. Hormonal Imbalances: Hormonal imbalances, particularly those involving thyroid hormones, and cortisol, can lead to unavoidable weight gain. Hypothyroidism, where the thyroid gland does not produce enough hormones, can slow down metabolism, leading to weight gain. Elevated cortisol levels, often due to chronic stress, can also promote fat storage, especially around the abdomen. These hormonal issues can make weight management incredibly challenging without medical intervention.

Managing weight has always been a particular focus for public health initiatives. With GLP-1s emerging as an effective tool for helping obese patients lose weight, it’s worth revisiting what options there are for keeping people from gaining the weight in the first place, which would be particularly useful for people in the situations we just described.

Solutions to tackle weight gain prevention:

1. Lifestyle modifications: Maintaining a regular exercise routine and a balanced diet are the cornerstone of weight gain prevention for most people. Notably, access to healthy food and exercise options is heavily influenced by socioeconomic status, leading to the emergence of various Social Determinants of Health (SDOH) programs aimed at providing nutritious food and promoting physical activity​​. Even consumer delivery apps are getting into the SDOH action.

   However, adherence to these methods is often challenging for these people. As many of us would admit, we struggle to stick to healthy regimes due to busy lifestyles and lack of motivation, and changes in metabolism and fatigue due to disease or medication can make it challenging for them to maintain a healthy lifestyle, even with these supports in place.

2. Screening for Genetic Causes: While it might be tempting to look towards advancements in gene sequencing and use genetic factors to predict who would be more likely to gain weight, it’s important to remember that only ~5% of obesity cases come from a single genetic mutation. These causes are likely multifaceted, making early life screening complex and difficult to attribute to a single factor. Comprehensive genetic screening and personalized interventions might offer some solutions but are currently not feasible on a large scale.

3. Pharmacological interventions Drugs offer immediate and targeted solutions for preventing weight gain. While not a panacea, these drugs can effectively address clear-cut cases where lifestyle changes alone are insufficient.

Given how powerful GLP-1s have been so far at weight loss, developing drugs for weight gain prevention proves to be an especially intriguing path. Even with all the success with Ozempic and Wegovy, Novo Nordisk recognizes the potential larger value of weight gain prevention, and is already directing their R&D effort and financial resources towards that end.

Key features of a weight gain prevention drug:

Considering patients that need weight gain prevention drugs will likely be on them for an extended period of time, the drug needs to have a few key features beyond preventing weight gain:

1. Localized Mechanism of Action: To minimize systemic side effects, a weight gain prevention drug should have a localized mechanism of action. For example, an intestinally-acting, non-absorbed, non-systemic drug can effectively target the gut without affecting other body systems.

2. Simplified Delivery Method: An oral, small molecule drug offers a convenient and user-friendly delivery method. This ensures higher compliance and ease of use, making it accessible to a broader population

3. Minimal Drug Interactions: Considering many drugs can cause weight gain, avoiding interactions with other medications is crucial. For instance, semaglutide's CNS activity may have some concerns around interactions with antipsychotic medicines.

Designing a drug that facilitates long term use is important in keeping patients’ weight in check as they take other drugs that cause weight gain.

Conclusion:

No matter how you slice it, an ounce of prevention is clearly worth a pound of cure. As GLP-1s gain broader use across the globe for weight loss, it’s worth remembering that the goal really should be to minimize the weight gain in the first place in order to really eliminate obesity once and for all.

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