Obesity: tirzepatide and semaglutide, the two innovative molecules compared

The Italian Medicines Agency has given the green light to the marketing of a new drug indicated for the treatment of obesitydel overweight in the presence of at least one comorbidity and the type 2 diabetes: The tirzepatide. The molecule is therefore now available on the Italian market upon medical prescription and takes us a step forward compared to what we have witnessed today with the effects of semaglutide.

Thanks to its ability to activate both the GIP receptor that the GLP-1in clinical trials treatment with tirzepatide – developed by the pharmaceutical company Lilly – resulted in a significant weight reduction in both adult patients with obesity and in those who were overweight with at least one related comorbidity, as well as having demonstrated important results in glycemic control in adults with type 2 diabetes. But what are tirzepatide and semaglutide? And how do they work?

Tirzepatide and semaglutide, the two molecules compared

Tirzepatide is the first, and currently the only, treatment capable of activate both GIP hormone receptors (glucose-dependent insulinotropic polypeptide) which those of GLP-1 (glucagon-like peptide-1) and represents an evolution of the new class of drugs – GLP-1 agonists – of which semaglutide is the progenitor.

The latter, in particular, acts only on the second: it is based, as we had explained, on a mechanism that increases the production of insulin by limiting the secretion of glucagon, the hormone that increases glycogenolysis, i.e. the release of stored carbohydrates in the liver. In this way it causes a feeling of satiety and keeps blood sugar under control, helping to reduce the calories consumed daily.

Unlike semaglutide, tirzepatide, by binding both receptors, increases insulin secretion at the pancreatic level, insulin sensitivity and reduces food intake. But what differentiates it from semaglutide is precisely GIP receptor agonismanother “gastroenterormone” that acts on mechanisms related to weight: it has beneficial actions at the level of adipose tissue, reduces caloric intake and the feeling of nausea.

How to read it in this investigation«GIP and GLP-1 are released by the neuroendocrine cells where they are produced in response to the appearance of some nutrients, including glucose, in the intestinal lumen. Their receptors are expressed in pancreatic beta-cells and […] they enhance insulin secretion in a calcium-dependent manner and only in the presence of an elevation in glucose concentration.” If its functionality is mimicked here you get the benefits already listed: satiety, blood sugar control and overall lower calorie intake. Tirzepatide activates both, semaglutide only one.

What the studies say

The approval for tirzepatide in weight management is based on a robust clinical trial programme. In particular, on Phase 3 Surmount-1 studyconducted in adults with obesity or overweight with at least one weight-related comorbidity, but without type 2 diabetes, and in the subgroup of participants with obesity or overweight and type 2 diabetes studied in clinical trials Surpass. In the phase 3 clinical study the drug, in addition to diet and exercise, demonstrated with the first maintenance dosage of 5 mg (achieved after 4 weeks of treatment) a weight reduction of 16% at the 72nd week. Furthermore, with the maximum maintenance dose of 15 mgtirzepatide demonstrated a weight loss to date of 22.5%.

As for semaglutide, the phase 3 Step 1 clinical trial (Semaglutide Treatment Effect in People with Obesity) showed after 68 weeks that the group of patients subjected to the treatment recorded the greatest weight loss, equal to average reduction of 14.9% in body weightcompared to 2.4% in the group that received a placebo.

Some studies already have compared the two drugs. The first direct comparison was published on JAMA Internal Medicineinvolved 18,386 US adults and essentially showed that the probability of achieving a weight loss of 5%, 10% and 15% was higher for those taking tirzepatide than for those taking semaglutide. «The results of the study indicate that tirzepatide offers a greater effectiveness in weight loss without a significant increase in the risk of gastrointestinal side effects compared to semaglutide – the authors wrote – future studies will have to compare the effect of tirzepatide and semaglutide on other key end points such as, for example, the reduction of major adverse cardiovascular events”.

As for the type 2 diabetesthe results of the use of tirzepatide are equally comforting: the Surpass program evaluated the efficacy and safety of tirzepatide as monotherapy and as an adjunct to several standard drugs for type 2 diabetes. Overall, the five global pivotal studies of the program Surpass demonstrated a reduction in glycated hemoglobin and weight.
Type 2 diabetes strikes in Italy around 4 million people and is characterized by high levels of glucose in the blood due to reduced sensitivity to insulin on the part of liver, muscle and adipose tissue cells and/or reduced secretion of insulin, the hormone that regulates blood sugar by the pancreas. The risk of developing the disease increases with age and the presence of obesity.

The side effects

The most common side effects recorded for tirzepatide – which is approved for the treatment of weight management in adults with Body Mass Index ≥30 kg/m2 or who are overweight with at least one weight-related comorbidity, in addition to a low-calorie diet and increased physical activity – are type gastrointestinalsuch as nausea and diarrhea. Constipation and vomiting have been observed in less than one in ten people. In general, these reactions were mostly mild or moderate in severity and occurred more often during dose escalation and decreased over time.

For semaglutide the studies have identified similar effects such as nausea, vomiting and bowel disorderswith irregularities in intestinal function.

The global and Italian obesity situation

In 2021, WHO recognized obesity as one chronic, progressive and relapsing disease that is striking over a billion people in the world. As we had said, according to estimates they will reach the impressive threshold of 1.9 billion in 2035, i.e. one in four peoplewith an estimated economic impact of 4.32 trillion overall on the planet’s economies. Beyond 1.2 million deaths every year in Europe they are related to obesity or being overweight: on the other hand, every 5 units above body mass index 25 are associated with a 31% greater risk of premature mortality. In Italy, more than 25 million people I’m overweight and 6 million (12% of the population) suffer from obesity. The main complications of obesity concern cardiovascular diseases, type 2 diabetes and 13 types of cancer and are among the main causes of global mortality.

«Despite the progress made in recent years, obesity remains a very complex condition to deal with for health professionals and systems, with important cultural and healthcare deficiencies, due to its multifactorial nature, its chronic and progressive course, and the many clinical complications associated and, ultimately, to the difficulty in obtaining lasting results in reducing body weight – he explained Rocco Barazzonipresident of Sio, the Italian Obesity Society – today we are finally entering a new phase in the treatment of obesity, with a new pharmacological paradigm that will allow us not only to provide answers to care needs that have so far been largely unsatisfied, restoring time and quality of life to patients, but also to prevent the numerous associated pathologies in the end and to reduce their currently dramatic impact”.

SCIENTIFIC SOURCES CITED IN THIS ARTICLE:

• Study published on Jama Internal Medicine
• Study published on The New England Journal of Medicine
• Study published on The New England Journal of Medicine of the program Surpass
• Study published on The New England Journal of Medicine Surmount-1