BACKGROUND: Tirzepatide is a novel dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist under development for the treatment of type 2 diabetes. In this study, we used continuous glucose monitoring (CGM) to compare the 24 h glucose profile for participants given tirzepatide compared with those given insulin degludec. METHODS: This substudy of the open-label, parallel-group, phase 3 SURPASS-3 trial, was done at 45 sites across six countries (Hungary, Poland, Romania, Spain, Ukraine, and the USA). Eligible participants in the main study were adults with type 2 diabetes, a baseline HbA(1c) of 7·0-10·5% (53-91 mmol/mol), and a BMI of 25 kg/m(2) or more, who were insulin-naive, and treated with metformin alone or in combination with a SGLT2 inhibitor for at least 3 months before screening. Participants in the main study were randomly assigned (1:1:1:1) to receive once-weekly subcutaneous injection of tirzepatide 5 mg, 10 mg, or 15 mg, or once-daily subcutaneous injection of titrated insulin degludec (100 U/mL), using an interactive web-response system. Participants were stratified by country, HbA(1c) concentration, and concomitant oral antihyperglycaemic medication. A subset of these patients with a normal wake-sleep cycle were enrolled into this substudy, and interstitial glucose values were collected by CGM for approximately 7 days at baseline, 24 weeks, and 52 weeks. The primary outcome was to compare pooled participants assigned to 10 mg and 15 mg tirzepatide versus insulin degludec for the proportion of time that CGM values were in the tight target range (71-140 mg/dL) at 52 weeks, assessed in all randomly assigned participants who received at least one dose of study drug and had an evaluable CGM session at either baseline or after baseline. The secondary outcomes were to compare tirzepatide (5 mg, 10 mg, and 15 mg) versus insulin degludec for the proportion and duration of time in tight target range at 24 and 52 weeks. This was a substudy of the trial registered with ClinicalTrials.gov, NCT03882970, and is complete. FINDINGS: From April 1 to Nov 27, 2019, 313 participants were screened for eligibility, 243 of whom were enrolled in CGM substudy (tirzepatide 5 mg, n=64; tirzepatide 10 mg, n=51; tirzepatide 15 mg, n=73; and insulin degludec, n=55). Patients given once-weekly tirzepatide (pooled 10 mg and 15 mg groups) had a greater proportion of time in tight target range compared with patients given insulin degludec (estimated treatment difference 25% [95% CI 16-33]; p<0·0001). Participants assigned to tirzepatide spent significantly more time in tight target range at 52 weeks compared with those assigned to insulin degludec (5 mg 12% [1-22], p=0·031; 10 mg 24% [13-35], p<0·0001; and 15 mg 25% [14-35], p<0·0001). Participants assigned to tirzepatide 10 mg and 15 mg, but not to tirzepatide 5 mg, spent significantly more time in tight target range at 24 weeks compared with insulin degludec (10 mg 19% [8-30], p=0·0008; 15 mg 21% [11-31], p<0·0001). INTERPRETATION: Once-weekly treatment with tirzepatide showed superior glycaemic control measured using CGM compared with insulin degludec in participants with type 2 diabetes on metformin, with or without a SGLT2 inhibitor. These new data provide additional evidence to the effect of tirzepatide and potential for achieving glycaemic targets without increase of hypoglycaemic risk compared with a basal insulin. FUNDING: Eli Lilly and Company.