Medical Chronicles: The Making of the "King of Weight-Loss Drugs"

In 2025, there was a remarkable change in the global "drug king" throne. Eli Lilly's "star product", Tirzepatide, topped the list with an impressive sales record of $36.507 billion, becoming the new global drug sales champion.

Right behind it was Semaglutide from its long - time rival Novo Nordisk, with sales reaching $36.1 billion in 2025, ranking second with a narrow gap of $400 million.

Tirzepatide and Semaglutide both belong to the GLP - 1 receptor agonist family. Their successive ascents to the top are not only a major victory for GLP - 1 drugs but also mark a new era in the treatment of metabolic diseases. Their core indications, type 2 diabetes and obesity, are affecting hundreds of millions of patients globally, presenting huge market potential. Especially in recent years, the explosive growth of the weight - loss market has been the key driving force behind this "drug king" change.

In this fierce competition, the rapid rise of Tirzepatide is particularly astonishing. It took less than four years from its approval for marketing in 2022 to claiming the title of "drug king" in 2025, setting a new industry record.

In the eyes of many, the key to its success lies in its innovative dual - target mechanism of action. However, few people know that, like many legendary drugs, Tirzepatide's ascent to the top is no accident. Behind it is a long - ignored target's counter - attack journey, the unremitting perseverance after numerous setbacks in scientific research, and a legend forged by timing, science, and belief.

The Rise of GLP - 1 and the Change of the "Drug King"

The global top 100 drug list is not just a report card of commercial sales; it is also a "wind vane" reflecting the future of the industry. That's why the competition for the "drug king" has always attracted much attention.

Looking back over the past decade or so, the most representative "drug king" was AbbVie's Humira (Adalimumab). It set an extremely long record of topping the list for nine consecutive years (2012 - 2020), with sales rising from $9.3 billion in 2012 to $19.8 billion in 2020, almost defining an era on its own.

Subsequently, the COVID - 19 vaccine Comirnaty jointly developed by Pfizer and BioNTech won the top spot twice, with sales of $36.8 billion in 2021 and $37.8 billion in 2022, thanks to the pandemic dividend. However, its peak was as rapid as a tide and faded quickly as the pandemic subsided.

Since 2023, the "drug king" throne has welcomed a new owner, Merck's PD - 1 inhibitor Keytruda. Its sales reached $25 billion in 2023 and further climbed to $29.5 billion in 2024.

Tirzepatide's ascent to the top this time represents a change of glory and the accelerated rise of a new - generation "drug king". It took less than 4 years from its launch to winning the "drug king" title, showing an astonishing "acceleration" trend compared to Humira's 11 years and Keytruda's 10 years.

Moreover, the era of Tirzepatide may have just begun. Predictions suggest that by 2030, GLP - 1 drugs may occupy nearly half of the top ten best - selling drugs globally, and Tirzepatide is also expected to remain the "drug king" for many years to come.

The birth of each generation of "drug king" is intertwined with arduous exploration, accidental discoveries, and persistent breakthroughs. The development of GLP - 1 drugs from a natural hormone in the human body to the core force in the treatment of metabolic diseases is such a scientific journey spanning more than forty years.

GLP - 1 (Glucagon - like peptide - 1) initially entered the stage as an innovative hypoglycemic drug. After we eat, food (especially carbohydrates and fats) is broken down in the intestine, which stimulates the intestinal L cells to secrete GLP - 1.

Although GLP - 1 does not directly regulate blood sugar, it can promote the secretion of insulin by pancreatic β - cells and inhibit the secretion of the hyperglycemic hormone glucagon by α - cells, thereby reducing post - meal blood sugar fluctuations.

Even more miraculously, GLP - 1 only actively works to lower blood sugar when post - meal blood sugar rises, and its effect weakens when blood sugar levels are normal. It is this unique "glucose - concentration - dependent" mechanism that allows it to effectively lower blood sugar without easily causing hypoglycemia, so it is also regarded as an excellent hypoglycemic drug.

The surprises brought by GLP - 1 drugs to people go far beyond this. In the clinical application for type 2 diabetes, researchers unexpectedly found that patients using GLP - 1 drugs significantly lost weight.

This phenomenon immediately ignited the scientific community's enthusiasm for exploration. Further research found that GLP - 1 receptors are not only distributed in the pancreas but also widely present in the brain's hypothalamus (the appetite center) and the gastrointestinal tract. When the drug activates these receptors, it makes people feel a strong sense of satiety, and it also delays gastric emptying, thereby reducing food intake and absorption and effectively controlling body weight.

It was this discovery that enabled GLP - 1 drugs to make a magnificent transformation from "hypoglycemic weapons" to "weight - loss stars". The pharmaceutical industry began to purposefully develop drugs with both hypoglycemic and weight - loss effects and promoted the continuous iteration and upgrading of GLP - 1 therapies.

The development of GLP - 1 drugs is an evolutionary history from "fighting alone" to "collaborative combat", from "short - acting" to "long - acting" and even "oral".

In this process, Liraglutide developed by Novo Nordisk is an important milestone in the field of GLP - 1 weight - loss drugs. By modifying the human GLP - 1 molecule, its half - life was extended to more than ten hours, enabling a once - daily injection regimen. In 2014, Liraglutide was approved by the FDA for the treatment of obesity, for the first time clearly demonstrating the efficacy of GLP - 1 receptor agonists in weight loss.

Then came the appearance of weekly formulations. Semaglutide, also from Novo Nordisk, significantly extended the half - life through further optimization of the molecular structure, requiring only one injection per week, which significantly improved the convenience of medication. Coupled with its outstanding weight - loss effect, Semaglutide was once popular worldwide.

In order to pursue better efficacy, the current research and development of GLP - 1 weight - loss drugs has entered the era of "multi - target agonists". Eli Lilly's Tirzepatide is a typical representative in this field. As a dual agonist of GIP (Glucose - dependent insulinotropic polypeptide) and GLP - 1 receptors, Tirzepatide further raises the upper limit of weight - loss effect. Head - to - head studies show that Tirzepatide outperforms the single - target drug Semaglutide in multiple weight - loss indicators.

The Counter - attack from "Discarded Piece" to "Ace"

In the battle for the "drug king" title, compared with Tirzepatide's late - comer advantage, Semaglutide's experience is full of drama. In 2024, it lost to Merck's Keytruda (Pembrolizumab) by a narrow margin of $200 million; in 2025, when it finally overtook Keytruda, it was defeated by Tirzepatide in the same track and once again ranked second.

Semaglutide can be regarded as a "pioneer" in the field of GLP - 1 weight - loss drugs and once popularized this multi - billion - dollar market. But why does it always fall short in the race for the "drug king" throne?

The story starts with a long - ignored target, GIP. It was once regarded as a "discarded piece" in the metabolic field but completed a legendary "ace" counter - attack under the persistence of science.

GIP (Glucose - dependent insulinotropic polypeptide) is another natural incretin in the human body. Before the advent of Tirzepatide, the pharmaceutical industry generally believed that the GIP receptor was "ineffective" in diabetic patients. At that time, the GLP - 1 drug market was also dominated by single - target drugs (such as Liraglutide from Novo Nordisk), and major pharmaceutical companies focused their efforts on the research and development competition of the GLP - 1 target.

However, the R & D team at Eli Lilly, led by Dr. Richard DiMarchi, a chemist, put forward a subversive hypothesis: the GIP receptor is not malfunctioning, but just lacks an "ideal partner". Based on this idea, they developed the world's first GLP - 1/GIP dual - target agonist molecule and officially launched the Tirzepatide R & D project in 2016.

The core advantage of Tirzepatide lies in the synergistic effect of GLP - 1 and GIP. An industry expert who once worked at Eli Lilly and participated in the early R & D of Tirzepatide told a reporter from Science and Technology Innovation Board Daily: "When these two targets are activated simultaneously, GIP can not only enhance the hypoglycemic and weight - loss effects of GLP - 1, more importantly, it can significantly inhibit the gastrointestinal adverse reactions such as nausea and vomiting caused by GLP - 1." This means that patients can start using the effective high - dose of GLP - 1 more quickly in a shorter period without having to slowly adjust the medication due to side effects.

In contrast, although Semaglutide can also help the body gradually tolerate and reduce side effects through the "titration" method of gradually increasing the dosage, many weight - loss seekers who are eager to lose weight often lack such patience. Therefore, Semaglutide is often criticized for its "obvious side effects", while Tirzepatide achieves a balance between rapid onset and good tolerance with the "escort" effect of GIP, which is an important reason for its outstanding performance.

It is worth noting that although Tirzepatide is classified as a GLP - 1/GIP dual - target agonist, its molecular design has a stronger ability to activate the GIP target. Therefore, to achieve the ideal weight - loss effect, its clinical dosage is significantly higher than that of the single GLP - 1 receptor agonist Semaglutide.

The use of Tirzepatide usually starts at 2.5 mg, and the dosage is increased about every four weeks. Many people finally maintain a weekly dose of 10 or 15 mg. In contrast, the starting dose of Semaglutide (weight - loss version) is much lower, starting at 0.25 mg and gradually increasing every four weeks, finally maintaining at a weekly dose of 2.4 mg.

Therefore, this also provides a new direction for the subsequent R & D of GLP - 1/GIP dual - target drugs. By enhancing the activity of the GLP - 1 component in the drug, it may be possible to reduce the dosage while maintaining the efficacy, thereby reducing production costs and treatment burdens.

Looking back on Tirzepatide's growth path, its success did not come overnight. It was a battle of "accumulating strength over time" across numerous technical obstacles and internal doubts. Eli Lilly's ability to gain "acceleration" on this path is inseparable from its deep accumulation and long - term persistence in the field of GLP - 1 receptor agonists.

Although Eli Lilly established the R & D direction of developing GLP - 1/GIP dual - target agonists early on, the first - generation molecule was stopped by the FDA due to a short half - life and severe vomiting reactions. For this reason, Eli Lilly's R & D team went through difficult technical challenges and finally significantly extended the half - life and improved the safety. Even after achieving technological breakthroughs, the company also faced significant challenges in internal decision - making. For example, it faced doubts from shareholders when adding R & D budgets.

Tirzepatide was not the first entrant in this field. Before it, MAR701 developed by Marcadia Biotech, a company co - founded by Professor Richard DiMarchi, was the world's first GLP - 1/GIP dual - target agonist to enter clinical trials.

In 2010, Roche acquired Marcadia Biotech for more than $500 million and obtained MAR701. Unfortunately, due to the failure of subsequent clinical trials to meet the expected goals, the project was finally terminated. The story of MAR701 vividly illustrates the gap between the "pioneer" and the "ultimate winner" in drug R & D.

To become a "winner" like Tirzepatide, foresight, patience, and the courage to bear failure are indispensable. True pharmaceutical innovation will not give up easily because of others' failures but focuses on potential tracks for continuous investment and long - term cultivation. If you wait until others create a hit product and then try to catch up, it is often too late.

The birth of every blockbuster new drug must carry countless explorations, optimizations, and perseverances.

This article is from the WeChat official account "Science and Technology Innovation Board Daily", author: Xu Hong. Republished by 36Kr with permission.