Effect of tirzepatide versus insulin degludec on liver fat content and abdominal adipose tissue in people with type 2 diabetes (SURPASS-3 MRI): a substudy of the randomised, open-label, parallel-group, phase 3 SURPASS-3 trial

Background Tirzepatide is a novel dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 receptor agonist under development for the treatment of type 2 diabetes. The aim of this substudy was to characterise the changes in liver fat content (LFC), volume of visceral adipose tissue (VAT), and abdominal subcutaneous adipose tissue (ASAT) in response to tirzepatide or insulin degludec in a subpopulation of the SURPASS-3 study. Methods This substudy of the randomised, open-label, parallel-group, phase 3 SURPASS-3 trial was done at 45 medical research centres and hospitals across eight countries (Argentina, Austria, Greece, Hungary, Italy, Romania, Spain, and the USA). Eligible participants were adults with type 2 diabetes, a baseline HbA1c 7·0–10·5% (53–91 mmol/mol), a BMI of at least 25 kg/m2, stable weight, were insulin-naive, and on treatment with metformin alone or in combination with a SGLT2 inhibitor for at least 3 months before screening. In addition to the main study inclusion criteria, substudy participants had a fatty liver index of at least 60. Participants had an MRI scan and were randomised (1:1:1:1) in the main study to subcutaneous injection once per week of tirzepatide 5 mg, 10 mg, or 15 mg, or subcutaneous injection once per day of titrated insulin degludec, using an interactive web-response system, and were stratified by country, HbA1c, and concomitant oral anti-hyperglycaemic medication. The primary efficacy endpoint was the change from baseline in LFC (as measured by MRI-proton density fat fraction [MRI-PDFF]) at week 52 using pooled data from the tirzepatide 10 mg and 15 mg groups versus insulin degludec. Analyses were assessed in the enrolled MRI population, which consisted of participants in the modified intention-to-treat population of the main study who also had a valid MRI at either baseline or after baseline. This is a substudy of the trial registered with ClinicalTrials.gov, number NCT03882970, and is complete. Findings From April 1, 2019, to Nov 15, 2019, 502 participants were assessed for eligibility to participate in this substudy, 296 (59%) of whom were included in the enrolled MRI population and randomly assigned to treatment (tirzepatide 5 mg, n=71; tirzepatide 10 mg, n=79; tirzepatide 15 mg, n=72; and insulin degludec, n=74). Baseline demographics and clinical characteristics were similar across all treatment groups. From an overall mean baseline LFC of 15·71% (SD 8·93), the absolute reduction in LFC at week 52 was significantly greater for the pooled tirzepatide 10 mg and 15 mg groups (–8·09%, SE 0·57) versus the insulin degludec group (–3·38%, 0·83). The estimated treatment difference versus insulin degludec was –4·71% (95% CI –6·72 to –2·70; p<0·0001). The reduction in LFC was significantly correlated (p≤0·0006) with baseline LFC (ρ=–0·71), reductions in VAT (ρ=0·29), reductions in ASAT (ρ=0·33), and reductions in body weight (ρ=0·34) in the tirzepatide groups. Interpretation Tirzepatide showed a significant reduction in LFC and VAT and ASAT volumes compared with insulin degludec in this subpopulation of patients with type 2 diabetes in the SURPASS-3 study. These data provide additional evidence on the metabolic effects of this novel dual GIP and GLP-1 receptor agonist. Funding Eli Lilly and Company.