Are new weight-loss drugs key to solving the obesity epidemic?

Obesity and being overweight pose massive public health challenges in many parts of the world. Today, 38% of the global population above five years old is overweight or obese, according to the World Obesity Federation. The figure might increase to as much as 51% in 2035. Overweight is defined as a Body Mass Index above 25 kg/m² and obesity as a Body Mass Index above 30 kg/m². WHO reports obesity affects more than 13% of the global population (26% in high-income countries), a steep rise compared to only 4.3% (8.8%) in 1975.

Obesity is a serious medical problem as it is associated with cardiovascular diseases, hypertension, hepatic steatosis, sleep apnea syndrome, metabolic abnormalities like type 2 diabetes or dyslipidemia, musculoskeletal disorders, or even cancer (especially colon, ovarian, and breast cancer). In addition, it could significantly impact people’s psychosocial health.

Until recently, bariatric surgery was the most effective option to treat obesity. But it applies only to people with severe obesity (BMI>35 kg/m² in the presence of comorbidities or >40kg/m²). While effective, this solution has clear limitations, such as:

• Potentially severe post-operative complications.
• Addressing only a fraction of the obese population, as no effective solution was available for people with a lower BMI who often end up developing morbid obesity at a later stage in their lives.

Over the past few years, new drugs initially targeting type 2 diabetes have provided additional promising treatment alternatives, effectively reducing weight with generally good clinical and biological tolerance. One of the most well-known drugs of this kind are Liraglutide and Semaglutide. Sold under brand names such as Saxenda (Liraglutide), Ozempic or Wegovy (Semaglutide), these drugs have triggered a tsunami of social media frenzy. The U.S. Food and Drug Administration (FDA) also approved Zepbound (Tirzepatide) for chronic weight management on November 8, 2023 (the drug has been in use to treat type 2 diabetes since 2022).

How do these drugs work and who is a good candidate for these treatments? What are the benefits and risks? What might be the impact on the insurance and reinsurance industry? This article aims to provide a high-level summary of these drugs’ functions, potential risks, and future developments.

Mechanism of action of GLP-1 analogs

Semaglutide and Liraglutide belong to a group of medication known as glucagon-like peptide-1 (GLP-1) receptor agonist, which mimics the effects of the GLP-1 hormone, a natural digestive hormone that helps control blood sugar levels.

Initially launched in the late 2010s (Novo Nordisk started selling Ozempic in 2017 in the U.S.), GLP-1 analogs were originally intended solely to stimulate insulin release in type 2 diabetic patients. But GLP-1 analogs also proved to be highly effective in fostering weight loss, as shown in the following key study results:

• Semaglutide (Wegovy 2.4 mg - a weekly injection produced by Novo Nordisk) reduced body weight by an average of 14.8% after 104 weeks of treatment.
• Liraglutide (Saxenda 3 mg – once-a-day injection also produced by Novo Nordisk) achieved a >5% weight loss for 63% of people compared to 27% for placebo after 56 weeks.
• Tirzepatide (Zepbound, a weekly injection produced by Eli Lilly and Cocombines, a GLP-1 analog with glucose-dependent insulinotropic peptide (GIP)) was proved to achieve a 20.9 % total mean weight loss after 72 weeks, compared to 3.8% for placebo.

Listed below are some of the key factors contributing to these positive results:

• GLP-1 inhibits food intake, decreases hunger, and increases weight loss by acting on various parts of the brain.
• GLP-1 inhibits gastric emptying.
• In rodents, GLP-1 has been proven to increase energy expenditure – the role of these mechanisms in humans requires further investigation.

The results of a randomized double-blinded trial (SELECT) to study the effects of Semaglutide were published on November 11, 2023. The study included 17,604 obese participants with established cardiovascular disease. In this study, treatment with a once-a-week dose of 2.4 mg Semaglutide was associated with a 20% decreased risk of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke over up to five years.

In addition to weight loss and cardiovascular risk protection, GLP-1 analogs have shown a positive effect in preventing renal disease, sleep apnea, hypertension, reducing liver fat accumulation such as in non-alcoholic steatohepatitis or NASH, and possibly reducing the risk of osteoarthritis in the long run.

Side effects and concerns

The previous generation of weight management drugs carries a bad reputation due to their side effects. Lorcaserin increased cancer risk (withdrawn in 2021), Rimonobant increased the risk of suicide/depression (withdrawn in 2008), and Mediator is alleged to have caused between 220 and 300 deaths from valvulopathy and pulmonary arterial hypertension (withdrawn in 2009).

The most prominent side effects of GLP-1 analogs are gastrointestinal problems (nausea, vomiting, and diarrhea) and, in some cases, increased heart rate and headache. Contraindications include personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2 and pregnancy.

There were concerns about a potential increased risk of pancreatitis and pancreatic cancer, but data collected so far show no such indication: a recent metanalysis that included 43 trials showed no statistically significant association with pancreatitis (OR 1.24 [0.94, 1.64]; P=0.13) or pancreatic cancer (OR 1.28 [0.87, 1.89]; P=0.20).

Some of the not well-known adverse gastrointestinal effects are gastroparesis (stomach's motility is slowed down) and bowel obstruction. The risk for pulmonary aspiration resulting from gastroparesis is rare but potentially a serious complication during anesthesia.

Furthermore, another serious adverse event has also been reported and is currently under investigation. The European Medicines Agency (EMA)’s safety committee is reviewing data based on 150 reports on the risk of suicidal thoughts and thoughts of self-harm linked to GLP-1 analogs, including Ozempic/ Wegovy and Saxenda.

Cost/benefit analysis of GLP-1 analogs

Today, social security systems rarely reimburse treatment with GLP-1 analogs, and prices remain comparatively high. In the U.S., the drugs cost up to $1,300 per month, and Medicare does not cover it. In France, the cost is 100 to 200 € each month, which is not covered by national social security.

This high cost is expected to decrease over the long term, considering these drugs’ significant potential to prevent a considerable size of the population from the wide range of obesity-driven diseases. In the UK, Ozempic can be prescribed by primary care practitioners for patients with a BMI above 35 kg/m² and at least one comorbidity.

Future developments of anti-obesity drugs

Several drugs combining a GLP-1 analog with other pharmacological targets are currently being developed and tested. Examples include:

• Survodutide is a dual GLP-1 and glucagon receptor agonist in phase 2 development for the treatment of non-alcoholic steatohepatitis (NASH), liver fibrosis, type 2 diabetes, and obesity.
• Since two hormones seem to be working better than one, why not try three? The triple–hormone-receptor agonist Retatrutide includes GLP-1, GIP, and glucagon which has been tested in a phase 2 study in patients with obesity. Participants in the study treated with the higher dose lost 24 % or more of their initial weight.

Potential impacts on Life & Health (re)insurance

While it is still too early to assess accurately, we predict there will be a significant medium to long-term impact of GLP-1 drugs on the life and health (re)insurance business. Here is our view:

• Given the wide-ranging positive outcomes of these drugs on obesity and cardiovascular diseases and the significance of these diseases in mortality and morbidity causes, we can assume that these drugs will improve mortality and morbidity trends, which will lead to improved overall experience of Life & Health (re)insurance portfolios in the long term.
• The size of the impact depends on how widespread these drugs will become, both in the general and insured population, with drug costs remaining a challenge today.
• (Re)insurance companies could also consider utilizing these drugs as part of their prevention and engagement solutions in various ways such as encouraging policyholders to solicit treatment options through premium discounts to improve their health.

Conclusion

While there is no such thing as a magic treatment to fight overweight or obesity, GLP-1 analogs appear to be highly efficient in reducing obesity, cardiovascular risk, and comorbidities. With limited side effects reported so far, studies suggest GLP-1 has a favorable overall cost/benefit equation and significant potential to help people with weight-related medical problems. Its cost will most likely decrease with large-scale use. As such, the drugs will have far-reaching impacts on our industry in the next few years. These treatments will be used as an adjunct to diet and exercise.

Starting physical activity is not so easy and can even be dangerous to some people. Taking the first step to change one’s lifestyle as well as keeping the motivation to continue is very difficult, as initial results are often discouraging, and people often don’t know how to start or stay motivated once they do begin. By amplifying the effects of lifestyle changes, GLP-1 analogs can become a trigger to boost patients’ confidence and motivation by allowing them to get better results earlier.

References:

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7. As Semaglutide’s Popularity Soars, Rare but Serious Adverse Effects Are Emerging | Gastroenterology | JAMA | JAMA Network
8. Lilly's tirzepatide shows additional 21.1% weight loss after 12 weeks of intensive lifestyle intervention