Key Points: Question: What is the effect on glycemic control of adding once-weekly tirzepatide vs thrice-daily prandial insulin lispro to insulin glargine treatment in inadequately controlled basal insulin–treated type 2 diabetes? Findings: In this randomized clinical trial (N = 1428), mean change in hemoglobin A1c (HbA1c) at week 52 was −2.1% with tirzepatide vs −1.1% with insulin lispro; treatment differences were statistically significant with less hypoglycemia and more body weight reduction with tirzepatide. Meaning: Adding once-weekly tirzepatide vs prandial insulin lispro to insulin glargine in basal insulin-treated patients with type 2 diabetes and inadequate glycemic control resulted in greater reductions in HbA1c along with more weight loss and less hypoglycemia. Importance: Tirzepatide is a glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist used for the treatment of type 2 diabetes. Efficacy and safety of adding tirzepatide vs prandial insulin to treatment in patients with inadequate glycemic control with basal insulin have not been described. Objective: To assess the efficacy and safety of tirzepatide vs insulin lispro as an adjunctive therapy to insulin glargine. Design, Setting, and Participants: This open-label, phase 3b clinical trial was conducted at 135 sites in 15 countries (participants enrolled from October 19, 2020, to November 1, 2022) in 1428 adults with type 2 diabetes taking basal insulin. Interventions: Participants were randomized (in a 1:1:1:3 ratio) to receive once-weekly subcutaneous injections of tirzepatide (5 mg [n = 243], 10 mg [n = 238], or 15 mg [n = 236]) or prandial thrice-daily insulin lispro (n = 708). Main Outcomes and Measures: Outcomes included noninferiority of tirzepatide (pooled cohort) vs insulin lispro, both in addition to insulin glargine, in HbA1c change from baseline at week 52 (noninferiority margin, 0.3%). Key secondary end points included change in body weight and percentage of participants achieving hemoglobin A1c (HbA1c) target of less than 7.0%. Results: Among 1428 randomized participants (824 [57.7%] women; mean [SD] age, 58.8 [9.7] years; mean [SD] HbA1c, 8.8% [1.0%]), 1304 (91.3%) completed the trial. At week 52, estimated mean change from baseline in HbA1c with tirzepatide (pooled cohort) was −2.1% vs −1.1% with insulin lispro, resulting in mean HbA1c levels of 6.7% vs 7.7% (estimated treatment difference, −0.98% [95% CI, −1.17% to −0.79%]; P <.001); results met noninferiority criteria and statistical superiority was achieved. Estimated mean change from baseline in body weight was −9.0 kg with tirzepatide and 3.2 kg with insulin lispro (estimated treatment difference, −12.2 kg [95% CI, −13.4 to −10.9]). The percentage of participants reaching HbA1c less than 7.0% was 68% (483 of 716) with tirzepatide and 36% (256 of 708) with insulin lispro (odds ratio, 4.2 [95% CI, 3.2-5.5]). The most common adverse events with tirzepatide were mild to moderate gastrointestinal symptoms (nausea: 14%-26%; diarrhea: 11%-15%; vomiting: 5%-13%). Hypoglycemia event rates (blood glucose level <54 mg/dL or severe hypoglycemia) were 0.4 events per patient-year with tirzepatide (pooled) and 4.4 events per patient-year with insulin lispro. Conclusions and Relevance: In people with inadequately controlled type 2 diabetes treated with basal insulin, weekly tirzepatide compared with prandial insulin as an additional treatment with insulin glargine demonstrated reductions in HbA1c and body weight with less hypoglycemia. Trial Registration: ClinicalTrials.gov Identifier: NCT04537923 This study examines the efficacy and safety of tirzepatide vs insulin lispro adjunctive therapy to insulin glargine among those receiving basal insulin with inadequately controlled type 2 diabetes. [ABSTRACT FROM AUTHOR]