A drug currently under development is on the verge of becoming the Holy Grail of obesity treatment: a medication that induces the same type of weight loss as bariatric surgery. Eli Lilly’s new weight loss drug, retatrutide, has not yet been approved but is already making waves in the media. Phase 2 data on retatrutide and weight loss show promising potential, according to the June 2023 issue of the New England Journal of Medicine, and the results appear even more encouraging than those of other drugs like Wegovy® and Mounjaro®. In the double-blind Phase 2 clinical trial, which examined retatrutide as a weight loss medication, 338 obese or overweight adult participants who did not have type 2 diabetes combined weekly injections of the drug with lifestyle changes over 48 weeks. Participants received various doses of retatrutide, which were increased over the course of the trial to induce weight loss. By the end of the study, those who took the highest dose of 12 mg had lost an average of 22.5% of their body weight, or about 23 kg. The surprising discovery from the study was that researchers suggested participants had not yet reached their weight loss plateau. This could mean that even greater weight loss might be possible with prolonged use of retatrutide. To better understand how retatrutide works, how it compares to other weight loss medications, and when it might receive approval from the U.S. Food and Drug Administration (FDA), let’s explore what we know so far about weight loss with retatrutide.   What is retatrutide? Eli Lilly and Company is testing retatrutide for the treatment of type 2 diabetes and obesity. It mimics three gut hormones, which in turn control glucose levels, reduce appetite, and increase feelings of fullness. Retatrutide is a weekly injection, combined with lifestyle changes such as physical activity and healthy eating habits. Clinical trials on retatrutide have shown remarkable results in treating excess weight and obesity. Studies on GLP-1 drugs used for weight loss, such as Wegovy and Mounjaro, revealed that most participants lost body weight, but not all. However, in the retatrutide weight loss study, every participant taking higher doses of the drug lost weight. By the end of the 11-week Phase 2 trial, all participants taking 8 mg or 12 mg of retatrutide had lost at least 5% of their body weight. Among those taking 12 mg, over 9 out of 10 lost 10% or more of their baseline weight, nearly two-thirds lost 20%, almost half lost 25% or more, and a quarter lost 30% or more. In addition to significant weight loss, the Phase 2 study also showed improvements in other health areas for participants taking retatrutide (compared to those in the placebo group), such as:

• Glucose levels: 72% of participants who were prediabetic at the start of the study returned to normal blood glucose concentrations by the end of the study.
• Blood pressure: Many participants who were taking blood pressure-lowering medications at the start of the study stopped taking at least one hypertension medication by the end, including 41% of those on the 8 mg dose and 30% of those on the 12 mg dose.
• Cardiometabolic measures: Participants showed improvements related to heart health and metabolism, including systolic and diastolic blood pressure, and improved levels of hemoglobin A1c, fasting glucose, insulin (all indicators for assessing the risk or presence of prediabetes or diabetes), and blood lipids.

  How effective is retatrutide for weight loss? Based on the Phase 2 trial results, participants lost a particularly high percentage of body weight with retatrutide, much more than with similar weight loss drugs. On average, participants taking 15 mg of the drug (the highest dose tested) lost up to 22.5% of their body weight by the end of the 72-week trial. This weight loss is about 7.5% higher than seen in studies of other “G” drugs. For comparison, here are the results of other weight loss drugs:

• Semaglutide: Participants taking weekly doses of 2.4 mg of semaglutide (the active ingredient in Wegovy) lost an average of 14.9% of their body weight by the end of a 68-week trial.
• Tirzepatide: Participants taking 5 mg of tirzepatide weekly (the active ingredient in Zepbound and Mounjaro) lost an average of 15% of their body weight by the end of a 72-week trial. Patients taking 15 mg of tirzepatide weekly in the same study lost 22.5% of their total body weight.

  How does retatrutide (3 molecules) compare to weight loss drugs like Wegovy (Ozempic, 1 molecule) and Mounjaro (tirzepatide, 2 molecules)? Like Wegovy and Mounjaro, retatrutide is part of a group of medications informally known as “G” drugs, which mimic gut peptides (also called gastrointestinal hormones) such as glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). These hormones, and the drugs that mimic them, help regulate appetite and make you feel full after eating, thus promoting weight loss.   There are three types of “G” drugs:

• Single agonist drugs: GLP-1 receptor agonists (GLP-1 RA) mimic the GLP-1 hormone and increase insulin secretion, slow digestion, reduce the release of glucagon (the hormone that regulates blood sugar), and increase satiety. Semaglutide-based drugs like Ozempic® or Wegovy® are examples.
• Dual agonist drugs: GLP-1/GIP dual agonists can bind to two receptors, making them more effective at reducing blood sugar and promoting weight loss than GLP-1 RAs alone. Mounjaro, the branded version of tirzepatide, is an example of this type.
• Triple agonist drugs: This is where retatrutide comes in. This “triple G” weight loss drug (currently in trials) binds to GIP, GLP-1, and glucagon receptors, potentially enhancing metabolism. Although research hasn’t yet pinpointed why this triple agonist drug shows such a high percentage of body weight loss compared to the other “G” drugs, it’s thought that the combination of the three receptor agonists amplifies the drug’s effect.

  When will retatrutide be available? Clinical trials take time, so there is no specific FDA approval date for retatrutide yet. If all goes well, it could be approved and available for consumers by around 2026.