Anti-obesity drugs: the latest news

"For many years, basic research has provided a better understanding of the regulatory mechanisms of body weight, which involve a complex interaction between the brain, adipose tissue, and the digestive system.

Molecules have been identified that, by interfering with various neurotransmitter and metabolic processes, are able to affect all processes involving food intake, hunger/satiety signals, adipose tissue metabolism, and influence numerous hormonal processes that regulate the metabolism of major nutrients. 

This gave rise to drugs that act at these levels, often studied for the purpose of treating diabetes, then extended to the treatment of obesity, in view of their ability to reduce weight, regardless of the presence or absence of diabetes, – notes Professor Lelio Francesco Morricone. – The most innovative ones include:

• semaglutide;
• tirzepatide”.

Semaglutide

Semaglutide is a molecule derived from liraglutide, a GLP-1 hormone analog, through receptors present at the enteric level, and it helps to:

• keep blood glucose levels under control by promoting insulin secretion and reducing glucagon secretion;
• slow gastric emptying, thereby increasing the sense of satiety. 

A very recent study has shown favorable effects on the cardiovascular system, reducing the frequency of heart attack and stroke by 20%, even when used for the treatment of obesity without diabetes.

This drug is able to achieve weight loss of an average of 15% in patients who use it, naturally with variable responses which can be minor, but also much greater. 

Side effects of these drugs often occur in the digestive system, but are almost never such that treatment must be discontinued. Among them: 

• nausea;
• sometimes vomiting;
• bowel disorders.

Long used for the treatment of diabetes and now licensed (at different dosages) for the treatment of obesity, it is already on the market in several European countries and in the United States and should soon become available in Italy as well at a dosage of 2.4 mg per week, with a small subcutaneous injection given only once a week. 

The improper use of semaglutide in lower doses, as used for diabetes, for “slimming” purposes has had an uncontrolled spread, especially in the United States, becoming almost a fashion, so much so that the drug's availability for treating people with diabetes has been exhausted. Therefore, the drug is currently used only for the treatment of diabetes, awaiting the forthcoming marketing of the formulation, which is licensed for the treatment of obesity. Semaglutide is also available in an oral formulation, that is, in capsules that are taken by mouth. 

Being already used for the treatment of diabetes, it is under advanced study (again at a different dosage) for the treatment of obesity.

Tirzepatide 

Tirzepatide is a new drug that acts on both the same enteric receptors on which semaglutide (GLP-1) acts and on other receptors of another “gastroenterhormone,” called GIP, also involved in insulin secretion. 

The Food and Drug Administration (FDA) approved tirzepatide for the treatment of diabetes in May 2022, while its use for the treatment of obesity was approved very recently. The efficacy appears to be remarkable, as demonstrated by the SURMONT studies, which have already been presented to the world scientific community. Specifically, use of the drug for 88 weeks resulted in an average weight loss of 26% from baseline weight, with an absolute weight loss of about 28 kg; more than half of the subjects enrolled in the study achieved a weight loss of more than 25%. 

A large trial is underway to evaluate the effect on mortality and cardiovascular events of tirzepatide, which will be completed within a couple of years. Meanwhile, tirzepatide is also expected to be approved soon in Italy for use in the treatment of diabetes.

"Other very promising drugs are under study. Their availability will require final approval by the European and Italian regulatory authorities, which can only take place after the end of the ongoing studies designed to verify their efficacy and safety," adds Professor Morricone.

Here are the most “promising” molecules:

• retatrutide: this drug is also referred to as a “triple agonist” because it acts simultaneously on the receptors of GLP-1, GIP and Glucagon, a hormone produced by the pancreas. In the preliminary studies (Phase 2), there is a very significant weight loss of about 24% over 48 weeks, with an average absolute loss of about 26 kg at the highest doses tested. More than 90% of patients lose at least 10%, two-thirds 20%, and a quarter more than 30% of their initial weight. Phase 3 study is underway;
• cagrilintide: this drug acts as an analogue of amylin, another hormone involved in body weight regulation. It is being tested, both alone and in combination with semaglutide, and preliminary results are very encouraging.  Ongoing studies will end in 2024, 2025, and 2027, and the effects on obesity and the cardiovascular system will also be investigated;
• survodutide: dual analogs for glucagon and GLP-1 also appear to be able to achieve significant weight declines. Phase 3 study is underway;
• orforglipron: this is a small molecule that always acts on the GLP-1 receptor and is taken orally. Preliminary results show a weight reduction of more than 14% (at least half of the study participants achieved declines of more than 15%). Phase 3 study is underway.

"In conclusion, there are many studies at an advanced stage now that will likely lead to having molecules that are very effective in the treatment of obesity. These will be added in the coming years to those already available or to be available soon (semaglutide 2,4 and tirzepatide).

It should be emphasized, however, that such therapies must be initiated and continued under the guidance of experienced physicians and cannot be a matter of “do it yourself”. In fact, the management of therapy also includes the management of possible side effects and still requires close monitoring by medical specialist. 

Moreover, to be effective, these therapies must always be combined with lifestyle changes and modifications of one's eating habits. The fight against obesity therefore can and will increasingly make use of valuable tools, but if used in the right way and in patients who have the right requirements," Professor Morricone concludes.