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From theory to therapy: Anti-obesity drugs

Up until recently the road for people suffering from obesity to lose weight was long and hard, often impossible, but a new breakthrough drug from Denmark has led to a paradigm shift.

Worldwide obesity has tripled since 1975, according to the World Health Organization (WHO), and the World Obesity Federation estimates that there are 1.1 billion people over the age of five that are obese today, and 1.6 billion are overweight. The extra kilos entail increased risk of severe health conditions like type 2 diabetes, heart diseases and even certain cancers, and the expected global costs of treating obesity-related complications are 1.2 trillion USD by 2025.

For decades scientists have tried to develop effective anti-obesity drugs without causing harmful side effects. Great progress has been made in the management of diseases closely integrated with obesity, including hypertension, adult-onset diabetes and elevated cholesterol, but finding a working anti-obesity medication (AOM) that treats the obesity itself has been hard. Many attempts, and many failures and halted trials due to dubious safety have followed.

If greater weight loss is achieved, it has typically been accompanied with serious acute or chronic adverse effects.”

The pharmacological management of obesity has included amphetamines, thyroid hormones, dinitrophenol and various drug combinations (rainbow pills) that were withdrawn due to serious adverse effects shortly after regulatory approval (Müller et al., Nature Review, 2021). Agents as diverse as mitochondrial uncouplers, sympathomimetics, serotonergic agonists, lipase inhibitors, cannabinoid receptor antagonists and a growing family of gastrointestinal-derived peptides chemically optimized for pharmaceutical use have also been investigated. Many of these approaches, concludes Müller et al., have had a common inability to achieve placebo-adjusted mean weight loss greater than 10% of initial body weight when chronically administered at tolerable doses. If greater weight loss is achieved, it has typically been accompanied with serious acute or chronic adverse effects.

A Danish breakthrough

A major exception to these previous attempts is Danish Novo Nordisk’s semaglutide, which has to say the least, revolutionized the field. It has been named a breakthrough drug all over the world and the first real, potent, and safe treatment of obesity. The once-weekly injection of semaglutide (brand name Wegovy) was FDA approved in June 2021 after a Phase III trial showed that the participants lost 15% of their body weight after 16 months of treatment. Early 2022 it was approved in the UK and the EU as well. At the end of 2022, the FDA also approved it for treating obesity in children aged 12 and upwards after an investigation in teenagers showed a reduced body weight by at least 20% in more than one-third of the participants.

GLP-1 was first discovered at the University of Copenhagen in 1986 by professor Jens Juul Holst, in connection with his work on stomach ulcer surgery.”

So what is the greatness of semaglutide? In short, semaglutide is a glucagon-like peptide-1 (GLP-1) that mimics the GLP-1 satiety hormones in our bodies, which lower blood sugar and curb appetite. GLP-1 was first discovered at the University of Copenhagen in 1986 by professor Jens Juul Holst, in connection with his work on stomach ulcer surgery.

Read more: Jens Juul Holst receives the Novo Nordisk Foundation Lecture prize

Novo Nordisk then used these findings to develop treatments for glucose regulation, mainly in diabetes.

 

3D rendering of Glucagon-like peptide 1 (GLP1, 7-36) molecule, a potent antihyperglycemic hormone. Source: iStock

 

In the 2000s the FDA began approving drugs that mimicked GLP-1 as type 2 diabetes treatments (including Novo Nordisk’s Ozempic, which is the same drug as Wegovy but in a different dose), but scientists had noticed their trial participants also lost weight. So they began to trial these drugs for obesity. Wegovy is today approved as a weight loss drug for adults who have obesity, as well as people with a body mass index (BMI) of at least 27 who also have a weight-related condition, such as high blood pressure or high cholesterol. Experts predict that Novo Nordisk will make about 3-4 billion USD from sales of Wegovy in the USA alone.

 

Diabetes R&D at Novo Nordisk A/S, Denmark, 2018. Oral semaglutide in a tablet.

 

A narrative change

Besides Novo Nordisk, Eli Lilly’s tirzepatide (brand name Mounjaro), also approved for treating diabetes, is on its way to becoming a paradigm-shifting anti-obesity drug. Tirzepatide targets the GLP-1 receptor and it also mimics another hormone involved in insulin secretion, known as glucose-dependent insulinotropic polypeptide (GIP). Studies have shown a 21% drop in body weight.

Obesity is starting to be viewed as a chronic biological disease and beyond the patients’ control through lifestyle changes alone. These new drugs are a promising add-on to eating healthily and exercising.”

There are of course many positive aspects with these new drugs, most obvious saving both lives and healthcare costs, but also changing the narrative on obesity. Obesity is starting to be viewed as a chronic biological disease and beyond the patients’ control through lifestyle changes alone. These new drugs are a promising add-on to eating healthily and exercising.

 

 

However, there are also challenges, including financial ones. Ozempic, approved for people with diabetes but prescribed off-label for weight loss, and Wegovy, approved for weight loss, can carry price tags of more than 1,000 USD a month reports Reuters (Rigby, 2023). In the USA most insurance plans do not cover the drugs. In addition, patients need to be on these drugs longterm and often cannot stop taking them. Data from a Novo-funded study in April last year showed that patients regained two-thirds of their lost weight one year after discontinuing the use of the drug.

Another obstacle that has followed these new drugs is providing access to those who really need them. The drugs have been in short supply at pharmacies worldwide and those who really need injections can not get them.

In March this year the WHO announced that they are considering adding obesity drugs to their essential medicines list.”

That said, the majority of scientists believe that these drugs have and will have a great positive impact on global health. In March this year the WHO announced that they are considering adding obesity drugs to their essential medicines list. A panel of advisers will review new requests for drugs to be included, with an updated essential medicines list due in September. The request to consider obesity drugs was submitted by three doctors and a researcher in the USA and it covers the active ingredient liraglutide in Novo Nordisk’s obesity drug Saxenda, which will come off patent soon, allowing for cheaper generic versions, reports Reuters. It could also pave the way for Wegovy to be recommended for low- and middle-income countries.

Featured photo: Obesity R&D at Novo Nordisk A/S, Måløv, Denmark, 2015. Photo: Jesper Edvardsen

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