Semaglutide, Tirzepatide, GLP-1, and GIP: What Are They and Why Have They Caused Such a Stir?

In recent years, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) analogues, such as semaglutide, tirzepatide, and others, have become a real phenomenon not only in medicine, but also in economics, society, and popular culture. They are actively discussed on social media and blogs, celebrities share their experiences of using them, and pharmaceutical companies earn billions of dollars from them worldwide. Let's take a look at what these drugs are, how they work, and why they have caused such a stir. There are several reasons for the increased attention to GLP-1 and GIP analogues and their incredible popularity.

First of all, these drugs have proven to be very effective in treating type 2 diabetes and have demonstrated previously unattainable effectiveness in the medical treatment of obesity, allowing patients who receive them to lose up to 20-25% of their initial body weight. Obesity is not only a cosmetic problem, but also a serious chronic disease that significantly increases the risk of developing diabetes, cardiovascular disease, certain types of cancer, musculoskeletal disorders, and other serious health problems.

It has also been found that, in addition to effectively treating diabetes and obesity, semaglutide, tirzepatide, and similar drugs reduce the risk of heart attacks, strokes, and death from cardiovascular causes by 20%. This is an impressive result, allowing these drugs to be considered as more than just "weight loss aids." Research into their potential for treating fatty liver disease, alcohol and nicotine addiction, and even Alzheimer's disease is ongoing.

Analogs of GPP-1 and GIP burst onto the public scene, becoming incredibly popular among celebrities who wanted to lose weight. The experiences of such media personalities as Elon Musk, Serena Williams, Oprah Winfrey, Whoopi Goldberg, Kate Winslet, Khloe Kardashian, and others openly declaring that they use Ozempic, Wegovy, Mounjaro, or Zepbound for weight loss has generated huge demand for these drugs, making them "trendy" and "mainstream." People saw them as a "magic shot" for rapid weight loss, which created a frenzy for GLP-1 and GIP analogues, which were often used for non-medical reasons. High demand led to a shortage of these drugs in markets in various countries. Patients who needed them to treat diabetes couldn't get them, while people who wanted to lose weight often bought the new "magic shots" without a doctor's prescription, through friends, via telemedicine startups, and often without medical reasons, sparking heated medical and ethical debates in society.

Novo Nordisk (manufacturer of semaglutide drugs – Ozempic, Vegovy) and Eli Lilly (manufacturer of tirzepatide drugs – Mounjaro, Zepbound) have become some of the most valuable companies in the world, and the global market for GLP-1/GIP analogues is projected to grow to $150 billion by 2030.

All this explains the incredible interest in these drugs. But it's time to take a closer look at the physiology of carbohydrate metabolism, the pharmacology of GLP-1 and GIP analogues, and how a poisonous lizard from Arizona helped in their development.

GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide) are two major incretin hormones that are produced in the intestine in response to food intake and stimulate insulin secretion by the β-cells of the pancreas, providing up to 50-70% of insulin secretion after a meal through the so-called incretin effect. In addition, incretin hormones have a number of metabolic, protective, and regulatory effects in various organs and tissues of the body (see Figure 1).

Figure 1. Mechanisms of action of GLP-1: ↑ – increase, enhancement; ↓ – decrease, weakening

GPP-1 and GIP act as complementary hormones of the incretin effect, complementing each other in the regulation of insulin secretion, glucose, appetite, and lipid metabolism. Below is a comparative table of the main characteristics and effects of GPP-1 and GIP.

GIP and GLP-1 are incretin hormones with a common primary effect of stimulating insulin secretion in response to food intake, but with significant differences in additional physiological effects, particularly with regard to the regulation of glucagon secretion, effects on appetite and lipid metabolism, and bone metabolism. The combined action of GLP-1 and GLP-3 provides an additive effect on insulin secretion, improving glycemic control in type 2 diabetes, which is useful in the development of combination drugs.

Patients with type 2 diabetes and obesity have reduced production of their own incretin hormones GLP-1 and GIP. In addition, these hormones are rapidly (within minutes) broken down by the enzyme dipeptidyl peptidase-4 (DPP-4), which poses an obvious problem for their potential therapeutic use. To solve this problem, scientists have created analogues of GLP-1 and GLP-3 – synthetic (artificial) versions of the hormones that act in a similar way but are not broken down quickly by DPP-4. They can be administered as injections once a day, and some even once a week.

The history of the development of incretin analog drugs covers several stages: the discovery and identification of the functions of these peptide hormones in humans, the search for similar compounds in animals, and the creation, study, and approval of their synthetic analogues for clinical use.

The effects of GPP-1, GIP, and their inactivation by the enzyme DPP-4, leading to short-term action, are described above. To solve the problem of rapid inactivation of incretins, scientists began to search for similar compounds in the animal world. In particular, exendin-4 was discovered in the secretions of the venom glands of the Arizona gila monster (Heloderma suspectum), which actively interacts with human GLP-1 receptors while being resistant to the action of DPP-4 (see Figure 2).

Figure 2. Arizona gila monster, from whose venom exendin-4 was isolated, interacting with human GLP-1 receptors

Exendin-4 became the basis for the creation of the first synthetic GLP-1 analogue, exenatide, which was approved in 2005 for the treatment of type 2 diabetes mellitus. The clinical success of exenatide is based on its ability to effectively mimic incretin effects, its resistance to DPP-4, and its longer duration of action compared to native human GLP-1.

This new approach has made it possible to create effective synthetic analogues of GLP-1 and GIP that overcome the limitation of rapid inactivation of native hormones in the body. Today, GLP-1 analogues of different generations are available, both short- and long-acting, with different structures and durations of effect, making it possible to tailor therapy to the needs of patients with type 2 diabetes and obesity . In particular, a dual-action combination drug has been developed and approved for use, which is simultaneously an agonist of GLP-1 and GIP receptors – tirzepatide

(see Table 2).

The most well-known GLP-1 analog, semaglutide, was first approved in the US in 2017 for the treatment of type 2 diabetes as a subcutaneous injection drug called Ozempic. In 2019, semaglutide in tablet form for oral administration, Rybelsus, was approved for the same indication. Wegovy, an injectable form of semaglutide for the treatment of obesity, was approved in 2021. Later, other indications for semaglutide drugs were approved, including prevention of cardiovascular events in patients with type 2 diabetes mellitus, obesity, and overweight; reducing the risk of decreased glomerular filtration rate, end-stage renal disease, and cardiovascular mortality in patients with diabetes mellitus and chronic kidney disease; treating metabolic dysfunction-associated steatohepatitis (MASH) with moderate to advanced liver fibrosis (different indications may currently be approved in different countries).

In terms of obesity treatment, patients in clinical trials with semaglutide lost up to 12-15% of their initial body weight. This was a real breakthrough in drug therapy for obesity, as previously used drugs resulted in a loss of only 5-7% of initial body weight.

The latest dual-action GLP-1 analogue, tirzepatide, which also affects GIP receptors, was approved in the US in 2022 as the drug Mounjaro for the treatment of type 2 diabetes, and in 2023 as Zepbound for the treatment of obesity and excess weight, as well as obstructive sleep apnea syndrome in obese individuals. In clinical trials of obese patients, tirzepatide showed even more impressive results in terms of weight loss from baseline, with an average reduction of 20-24%, and in some cases more than 30%, and became the first drug to outperform bariatric surgery (surgical procedures on the stomach and intestines aimed at treating obesity) in terms of effectiveness in studies.

But there is a downside. Therapy with GLP-1 and GIP analogues is associated with certain side effects, the risk of developing macro- and micronutrient deficiencies, noticeable cosmetic defects and loss of muscle mass during rapid weight loss, and weight regain after discontinuation of therapy. There are contraindications to the use of these drugs. They are expensive, and access to them may be limited due to shortages, including for patients with type 2 diabetes, while some people use these drugs for "cosmetic" purposes. But we will discuss that next time.

So, semaglutide, tirzepatide, and other GLP-1 and GIP analogues are drugs that have demonstrated unmatched effectiveness in the medical treatment of obesity and related potentially fatal diseases and complications. These drugs have significantly changed the paradigm of treatment for type 2 diabetes, obesity, and excess weight, causing a real scientific revolution and generating a lot of buzz.