Inside the body with Retatrutide

Retatrutide is a 39-residue peptide with Aib at positions 2 and 20, alpha-methyl-leucine at position 13, and a fatty diacid attached through a linker to Lys17 (Cell Discovery 2024; PubChem structure). In a phase 1b multiple-ascending-dose study in people with type 2 diabetes its pharmacokinetics were dose-proportional with a half-life of about 6 days, supporting once-weekly dosing. The sources cited here do not measure albumin binding or protease resistance for retatrutide, so the contribution of the lipid and of each modified residue to its duration of action is not stated here.[src][src][src]

Cryo-EM structures of retatrutide bound to GLP-1R, GIPR and GCGR in complex with Gs (PDB 8YW3, 8YW4, 8YW5) show how a single peptide engages all three class B GPCRs. In vitro it shows balanced GCGR and GLP-1R activity and relatively more GIPR activity. In a phase 2 study in adults with type 2 diabetes, pre-specified exploratory questionnaires showed greater reductions in overall appetite, hunger and prospective food consumption than placebo at the higher doses at week 24, and the two highest doses reduced Eating Inventory perceived hunger and disinhibition; these reductions correlated modestly with weight loss at week 36 (r about 0.3). Central mechanisms are inferred from incretin receptor biology; these questionnaires are patient-reported and exploratory, and the studies did not directly image brain circuits.[src][src][src]

A short Lilly report (Diabetes Obes Metab 2023) is titled as showing that retatrutide delays gastric emptying; its abstract was not available to check, so the species studied, size and time course of the delay are not summarised here. Delayed gastric emptying is a recognised effect of GLP-1 receptor agonists and is thought to contribute to satiety and to the gastrointestinal adverse events (nausea, vomiting, diarrhoea, constipation) reported in the phase 2 and phase 3 trials.[src][src][src]

In the 24-week phase 2 trial in type 2 diabetes, HbA1c fell by up to about 2.0 percentage points (placebo-unadjusted least-squares mean change), with two of the higher-dose groups giving significantly greater HbA1c reductions than dulaglutide, and there were no reports of severe hypoglycaemia. In the phase 3 TRANSCEND-T2D-1 monotherapy trial, treatment-regimen HbA1c changes were -1.69% to -1.94% versus -0.81% with placebo at 40 weeks. The trials measured glycaemia, not insulin secretion directly in these reports; attributing the effect to glucose-dependent GIP and GLP-1 signalling on beta cells is an inference from receptor pharmacology.[src][src][src]

In a DXA sub-study of the phase 2 type 2 diabetes trial, total fat mass fell by up to 26.1% (pooled second-highest dose group) versus 4.5% with placebo at 36 weeks, and the authors reported that the proportion of lean mass loss relative to weight loss was similar to other obesity treatments. The mouse work (animal-only evidence) attributed part of the weight loss to GCGR-mediated increases in energy expenditure on top of GIPR- and GLP-1R-driven reduction in food intake. A human energy-expenditure effect is not demonstrated in the studies cited here.[src][src]

In the phase 2a MASLD sub-study (n=98, participants with at least 10% baseline liver fat), the mean relative change in liver fat at 24 weeks was +0.3% with placebo versus -42.9%, -57.0%, -81.4% and -82.4% across increasing retatrutide doses; normal liver fat (below 5%) was reached by 0% with placebo and 27%, 52%, 79% and 86% respectively. Reductions were significantly related to weight loss, abdominal fat and insulin-sensitivity measures. Glucagon receptor signalling in hepatocytes is a plausible contributor but this sub-study did not separate direct from weight-mediated effects. The published results report liver fat, not liver biopsy (histology) outcomes.[src]

A post hoc analysis of the two phase 2 trials (eGFR at least 45) found that, versus placebo, the highest dose reduced urine albumin-to-creatinine ratio by 37.0% (95% CI -57.3 to -7.0) at 36 weeks in type 2 diabetes, and the two higher doses reduced it by 28.0% and 31.5% at 48 weeks in obesity without diabetes, with creatinine-based eGFR increases of 5.3 and 8.5 mL/min/1.73 m2 in the obesity study but not in the diabetes study. Most participants had normal albuminuria, so absolute changes were modest. These are post hoc and hypothesis-generating. TRANSCEND-CKD, a phase 2b mechanistic trial (n=146 randomised; primary endpoint measured GFR by iohexol clearance at 24 weeks), has published its design; that paper names TRIUMPH-Outcomes (NCT06383390) as the ongoing cardio-kidney outcome trial. No results from either are cited here.[src][src]

Phase 2 post hoc analyses reported reductions in non-HDL cholesterol, apolipoprotein B, triglyceride-rich lipoproteins and (in the obesity trial) hs-CRP and IL-6. The phase 2 obesity trial reported dose-dependent heart-rate increases that peaked at 24 weeks and declined thereafter. In TRIUMPH-3 (severe obesity with established cardiovascular disease), Lilly reported that MACE occurred less frequently than anticipated in both the retatrutide and placebo arms; the pre-specified in-study hazard ratios (pooled doses versus placebo) were 0.82 (95% CI 0.55 to 1.22) for MACE-5 and 1.12 (0.64 to 1.96) for MACE-3. Both intervals include no effect, so these topline data neither show nor exclude a cardiovascular benefit.[src][src][src]