Obesity has become a global epidemic, and the incidence of obesity continues to soar in countries around the world. According to the World Health Organization (WHO), 13% of adults worldwide suffer from obesity. More importantly, obesity can further cause metabolic syndrome and various complications, such as type 2 diabetes, hypertension, non-alcoholic steatohepatitis (NASH), cardiovascular disease and cancer.
In June 2021, the FDA approved the listing of Semaglutide, a weight loss drug developed by Novo Nordisk, under the trade name Wegovy. Due to its excellent weight loss effect, good safety, and the promotion of celebrities such as Musk, Semaglutide has become popular all over the world, and even a drug has become difficult to find. According to the 2022 annual report released by Novo Nordisk, the sales of Semaglutide in 2022 reached 12 billion US dollars.
However, Tirzepatide and Retatrutide are also about to be listed. What are the differences between them?
What is the GLP-1 receptor?
GLP-1 is an incretin secreted by L cells in the intestinal system. It affects insulin secretion under multiple complex effects, thereby affecting blood sugar and digestion, producing a series of effects, weight loss is just one of them, and its indications are extending to liver disease and even Alzheimer’s disease. Its full name is Glucagon-like peptide-1 receptor agonists, GLP-1RA, which is GLP-1 glucagon-like peptide-1 receptor.
There are 184 GLP-1 target pipelines in the world, of which the number of single-target, dual-target, triple-target and multi-target drugs reached 97, 60, 21 and 6 respectively. The so-called dual targets and more targets refer to drugs under the joint action mechanism of multiple targets such as GLP-1/GIP dual targets and GLP/GIP/GCGR triple targets.
Semaglutide: GLP-1 receptor agonist, creating a world of miracle drugs
Semaglutide is a GLP-1 receptor agonist developed by Novo Nordisk, a leader in diabetes treatment. The drug can stimulate pancreatic beta cells to secrete insulin, thereby increasing sugar metabolism; and inhibit pancreatic alpha cells from secreting glucagon, thereby reducing fasting and postprandial blood sugar. In addition, it can also reduce food intake by reducing appetite and slowing stomach digestion, ultimately reducing body fat and helping to lose weight.
In February 2021, in a global large-scale clinical trial published in the NEJM journal, Semaglutide subcutaneously injected 2.4mg Semaglutide weekly to reduce weight by an average of 15kg. Three-quarters of people lost more than 10% of their weight, and more than a third lost more than 20% of their weight.
On March 24, 2023, Novo Nordisk’s oral version of semaglutide reached the Phase III clinical endpoint. Patients who took a high dose (50mg) orally once a day had a 2.0% reduction in glycated hemoglobin (HbA1c), and a weight loss of 8.0kg after 1 year.
It can be seen that GLP-1 agonists represented by Semaglutide have not only improved blood sugar reduction and weight loss, but also moved from short-term to long-term, and from injection to oral administration, which has brought convenience to patients. It is worth mentioning that GLP-1R agonists are also pursuing benefits in cardiovascular benefits and renal protection for diabetic patients.
Tirzepatide: GLP-1/GIP dual-target agonist
Lilly’s weight loss drug, tizepatide, mimics the effect of natural GIP on GIP receptors, but shows a preference for cAMP production rather than β-inhibitor recruitment on GLP-1 receptors. Compared with GLP-1, tizepatide has a weaker ability to drive GLP-1 receptor internalization. The drug combines synthetic analogs of two hormones, GLP-1 and GIP. After consumption, the intestines will naturally release these two hormones, making people feel full.
Tirzepatide was approved by the FDA in May 2022 for the treatment of type 2 diabetes in adults. It is the first and currently the only GLP-1/GIP dual-target agonist on the market.
Eli Lilly’s Tirzepatide is still in Phase III clinical trials for weight loss. In the study, the weight loss effect of up to 22.5% was achieved for patients with severe obesity, which is close to the effect of commonly used bariatric surgery (sleeve gastrectomy), and the adverse reactions are relatively smaller.
GIP and GLP-1 are both hormones secreted by the intestine. GLP-1 and GIP together constitute most of the incretin effect, which can promote insulin secretion and play an indispensable role in controlling blood sugar and weight.
The MOA of GIP is not completely consistent with that of GLP-1, but complements each other. Therefore, GLP-1/GIP dual-target agonists can effectively exert the synergistic effect of the two receptors in lowering blood sugar and controlling weight.
Retatrutide: A peptide drug targeting GLP-1R/GCGR/GIPR
Retatrutide (LY3437943) is a peptide drug targeting GLP-1R/GCGR/GIPR developed by Eli Lilly based on the GIP peptide sequence. Its average half-life in humans is up to 6 days, and its half-life in mice is 21 hr (0.47 mg/kg).
Retatrutide is a single peptide modified from the GIP peptide backbone, containing 39 amino acids, which can achieve triple agonist activity in GCGR, GIPR and GLP-1R. Its peptide backbone sequence contains three non-coding amino acid residues at positions 2, 20 and 13. Among them, Aib2 (α-aminoisobutyric acid) helps to improve stability to resist degradation by dipeptidyl peptidase-4 (DPP4); Aib20 helps to optimize GIP activity, pharmacokinetic properties and developability; αMeL13 (α-methyl-L-leucine) helps to optimize glucagon (GCG) and GIP activity. The skeleton is coupled to the C20 fatty diacid part through a linker located at the 17th lysine residue, and the half-life is extended by albumin binding, while providing the required pharmacological properties.
A total of 338 adult obese patients were enrolled in this phase II clinical trial to explore the weight loss effects of three doses of 4mg, 8mg, and 12mg and different starting doses.
The results showed that at 24 weeks of treatment, Retatrutide (1mg, 4mg, 8mg or 12mg) achieved the primary endpoint of efficacy evaluation in obese or overweight (excluding diabetes) adult patients, with an average weight loss of 17.5%.
In terms of secondary endpoints, at 48 weeks of treatment, subjects who received weekly injections of 12mg Retatrutide lost an average of 24.2% of their body weight.
What is the difference in weight loss effects among the three weight loss drugs?
Semaglutide helped one-third of obese people lose at least 20% of their body weight.
More than half of obese people with Tirzepatide lost at least 20% of their body weight
Retatrutide: At 48 weeks of treatment, subjects who received weekly injections of 12mg Retatrutide lost an average of 24.2% of their body weight, beating Eli Lilly’s Tirzepatide and setting a new record for weight loss.