Data from randomized controlled trials (RCTs) comparing the efficacy and safety of thrice-weekly insulin degludec (IDeg 3TW) versus once-daily insulin glargine (IGlar OD) in patients with type 2 diabetes mellitus (T2DM) are scarce and not uniform. Moreover, no systematic review and meta-analysis (SRM) is available for such a comparison. This SRM aimed to compare the effectiveness and safety of IDeg 3TW versus IGlar OD in the available RCTs in T2DM.Electronic databases and registers, which include MEDLINE (via PubMed), Scopus, Cochrane Central Register, and ClinicalTrials.gov, were searched for RCTs conducted among T2DM subjects with IDeg 3TW as intervention and IGlar OD as control from inception to 30 July 2024. The primary outcome was glycated haemoglobin (HbA1c) reduction from baseline; secondary outcomes were the changes in other glycemic parameters and adverse events (AEs). RevMan web was used to conduct meta-analysis using random-effects models. Outcomes were presented as mean difference (MD), odds ratio (OR), or risk ratio (RR) with 95% confidence intervals (CIs).Three RCTs (N = 1171) with study durations ranging from 16-26 weeks and minimal risk of bias were included. IDeg 3TW was less effective than IGlar OD in HbA1c reduction (MD 0.27%, 95% CI [0.14, 0.39],< 0.0001), reduction in mean nine-point self-monitored capillary blood glucose profile (MD 0.45 mmol/L, 95% CI [0.22, 0.67],< 0.0001), and HbA1c reduction <7% (OR 0.69, 95% [0.53, 0.89],= 0.005). IDeg 3TW outperformed IGlar OD regarding the mean daily insulin dose (MD -0.07 U, 95% CI [-0.13, -0.01],= 0.02). However, both groups achieved comparable fasting plasma glucose reduction (MD 0.37 mmol/L, 95% [-0.19, 0.93],0.19), changes in body weight (MD 0.04 kg, 95% CI [-0.46, 0.55],0.86), and overall physical (MD 0.21, 95% CI [-0.62, 1.04],= 0.62) and mental health scores (MD -0.02, 95% CI [-1.05, 1.01],= 0.97). The risks for confirmed hypoglycemia (RR 1.16, 95% CI [0.83, 1.62],= 0.38), nocturnal hypoglycemia (RR 1.18, 95% CI [0.49, 2.84],= 0.71), any AEs (RR 1.04, 95% CI [0.84, 1.30],= 0.71), serious AEs (RR 1.43, 95% CI [0.77, 2.65],= 0.25), and injection-site reactions (RR 1.29, 95% CI [0.56, 2.96],= 0.55) were identical in the two groups.In short-term follow-up, IDeg 3TW was less effective than IGlar OD in glycaemic control; however, their safety profile was comparable. Larger multicenter RCTs comparing the overall benefit-risk ratio are necessary for appropriate clinical practice decisions.PROSPERO: CRD42024593493. Aims/Background Methods Results Conclusion Systematic Review Registeration p p p p p = p = p p p p p p p
