New Data on Retatrutide is out and it Needs to Be Talked About

Dr. Spencer Nadolsky and Dr. Carl welcome David White, a nurse practitioner and an expert in glucagon and GIP, to discuss the new data on Retatrutide. David, who participated in the Phase 3 trial, shares his personal journey into the research of GLP-1 medications during his master's thesis and how he ended up being a participant in the Retatrutide trial, where he experienced significant weight loss.

David explains that Retatrutide is a triple agonist, targeting GLP-1, GIP, and glucagon receptors. He compares it to existing medications like Semaglutide (GLP-1 only) and Tirzepatide (GLP-1 and GIP), highlighting that the addition of glucagon activity in Retatrutide enhances insulin sensitivity, lipid catabolism (reducing triglycerides and cholesterol), and potentially increases energy expenditure. The mechanism includes direct peripheral action due to glucagon's expression in the liver and kidney, leading to blood pressure lowering effects.

David recounts his experience in the trial, revealing he was in the 12 mg group. He experienced typical GI side effects (mild nausea, loose stools, heartburn) during the dose escalation phase (first 5-6 months), which subsided once he reached a steady dose. He lost approximately 30% of his body weight, going from 240 lbs to 167 lbs, and his BMI decreased from 34-35 to 24. After stopping Retatrutide, he transitioned to Tirzepatide with similar appetite suppression benefits.

The discussion shifts to the SURMOUNT-1 (Triumph) trial, an 80-week study (with a 24-week extension) focusing on obesity with comorbidities like osteoarthritis and OSA. The trial enrolled patients with an average BMI of 40, 36% pre-diabetic. Key findings at 80 weeks showed: 19% weight loss in the 4 mg group, 25.9% in the 9 mg group, and 28.3% in the 12 mg group. Patients on 12 mg who continued for the full 104 weeks achieved 30.3% weight loss. Categorical weight loss was impressive, with 93% losing over 10% and 45% of the highest dose group losing over 30%.

Side effects were generally comparable to Tirzepatide, with 25-40% experiencing nausea, primarily during dose escalation. Discontinuation rates due to GI side effects were low (2-4.5%). Notable adverse events included a higher rate of UTIs (cause unclear) and dizziness/hypotension, especially in patients with pre-existing hypertension, necessitating careful blood pressure medication management. Significant cardiometabolic improvements included an 11-12 point drop in systolic blood pressure, 41% reduction in triglycerides, 20% reduction in LDL, and 92-95% of pre-diabetics reverting to normal glycemic status. Improvements in knee arthritis pain (70% reduction) and sleep apnea events (60% reduction) were also observed.

The TRANSCEND trial, a 40-week study on type 2 diabetes patients not on other anti-hypoglycemic medications, showed remarkable A1C reductions. The 4 mg group had a 1.7% A1C reduction, while the 9 mg and 12 mg groups saw a 1.9% reduction. Average A1C dropped to 6.2% (4 mg), 6.0% (9 mg), and 5.9% (12 mg). Weight loss in this diabetic population was also strong: 11.5% (4 mg), 15.5% (9 mg), and 17% (12 mg), significantly outperforming placebo.

The hosts discuss the practical application of Retatrutide. They anticipate its use in patients on Tirzepatide who have plateaued or have a significant amount of weight to lose. Dosage transition strategies are considered, with a potential switch from 15 mg Tirzepatide to 4 mg Retatrutide. The importance of comprehensive care and physician oversight is emphasized due to the potency of the drug. Lily's efforts to classify Retatrutide as a biologic are noted, aiming for patent protection, while also stating a desire for accessibility. Upcoming trials like Triumph 8 (low dose Retatrutide) and Triumph 3 (Retatrutide in patients with cardiovascular disease) are expected to provide further insights into its broader utility.