Search Results and Study Selection

The searches in MEDLINE/PubMed (n = 1,721), Cochrane Library (n = 2,253) and Clinical Trials database (n = 125) identified 4,099 records. After removal of 462 duplicates, 3,637 records underwent title and abstract screening, with 3,597 records excluded based on predefined eligibility criteria. A total of 40 full-text articles were assessed for eligibility. Of these, 26 were excluded due to reasons including ineligible study type (n = 21), ineligible study population (people with type 1 diabetes) (n = 2), or no publicly available results (n = 3). Finally, 14 RCTs involving 8,487 participants were deemed eligible for inclusion [2, 5, 15, 16, 21,22,23,24,25,26,27,28,29,30] (Fig. S1).

Study Characteristics

The main characteristics of the included studies are presented in Table 1. One study was published in 2020, two studies in 2021, seven studies in 2023, one study in 2024, and three studies in 2025. Eight studies assessed once-weekly insulin icodec [2, 21,22,23,24,25,26,27], and six studies assessed once-weekly insulin efsitora [5, 15, 16, 28,29,30]. All studies compared a once-weekly basal insulin with a daily basal insulin, such as glargine U100, glargine U300 or degludec, with or without prandial insulin. One trial evaluated two, and one trial evaluated three titration regimens for icodec [22, 23], while one study evaluated two different titration algorithms for efsitora [15]. Data from these arms were not combined and were rather used as different entries in the analyses. Seven trials included insulin-naive participants [2, 5, 16, 21, 23, 25, 27]. Study durations varied, with six trials lasting 26 weeks, four lasting 52 weeks, two lasting 16 weeks, one lasting 32 weeks, and one extending to 78 weeks. Eleven studies were open-label, while three were double-blind. Background glucose-lowering therapies prior to randomization varied across studies and included basal insulin, with or without prandial insulin, with or without other oral or injectable antidiabetics (metformin, DPP-4 inhibitors, SGLT-2 inhibitors, sulfonylureas, GLP-1 RAs, thiazolidinediones) [15, 22, 24, 26, 28, 29], or various combinations of non-insulin medications [2, 5, 16, 21, 23, 25, 27, 30]. In trials where participants were already receiving basal insulin therapy at baseline, pre-randomization basal insulin was discontinued at randomization and replaced by the study-assigned basal insulin regimen (once-weekly or daily), according to the trial protocol. Participants’ mean HbA1c at baseline was 8.28% across all trials, mean age was 59.3 years and mean duration of diabetes was 12.9 years. In total, 2,265 individuals were randomized to receive insulin icodec, 2,293 randomized to receive insulin efsitora, and 3,929 to receive daily basal insulin (glargine or degludec).

Table 1 Βaseline characteristics of included studies

The results of the risk of bias assessment for each included study are summarized in Table S4. Overall, 12 RCTs were rated as having low overall risk of bias. One study was judged to have high risk of bias [16], while one trial was judged to have some concerns [31].

HbA1c

A total of 14 RCTs (8,487 participants) were included in the meta-analysis for the mean change in HbA1c from baseline. Once-weekly basal insulin analogs reduced HbA1c (-0.09% [95% CI -0.15 to -0.03], I2 39.2%) compared to daily basal insulin analogs (Fig. 1). Furthermore, once-weekly basal insulin showed higher odds of achieving an HbA1c < 7.0% (OR 1.32 [95% CI 1.07 to 1.63], I2 64.9%) compared to daily basal insulin (Fig. S2).

Fig. 1The alternative text for this image may have been generated using AI.

Difference in mean change in HbA1c between once-weekly and daily basal insulin analogs

The subgroup analysis based on insulin naivety status revealed no subgroup effect in the change in HbA1c (p for interaction = 0.24) (Fig. S3). The subgroup analysis based on type of intervention, indicated a subgroup effect favoring insulin icodec over insulin efsitora (p for interaction = 0.03) (Fig. S4). There was no subgroup effect based on type of comparator (insulin glargine or degludec, p for interaction = 0.40) (Fig. S5). Of note, in this subgroup analysis, ONWARDS 5 was not included, since the comparator arm included both insulin glargine and insulin degludec. A post hoc sensitivity analysis excluding two trials with trial-specific dosing/titration algorithms [15, 16] resulted in an effect estimate of -0.11% (95% CI -0.17 to -0.05; I² 33.7%) (Fig. S6).

Time in Range

A total of 10 RCTs (5,741 participants) were included in the meta-analysis of TIR. Of the included studies, four reported the mean change in TIR from baseline [5, 21,22,23], whereas the remaining trials reported mean TIR over the specified assessment period without a baseline reference value. TIR was defined as the proportion of time spent with glucose concentrations within the predefined target range 70 and 180 mg/dL. One study reported slightly modified (71–180 mg/dL) [15] target range and another one a narrower (70–140 mg/dL) [21] target range; the latter was not included in the main analysis. In the pooled analysis, participants treated with once-weekly basal insulin achieved higher TIR (1.86% [95% CI, 0.73 to 2.98], I2 34%) (Fig. S7). We also performed a post hoc sensitivity analysis, including the study which defined TIR as 70–140 mg/dL and TIR was higher again in once-weekly basal insulin compared to daily basal insulin (2.05% [95% CI, 0.91 to 3.19]) (Fig. S8), confirming the robustness of the primary findings.

Fasting Plasma Glucose

Thirteen RCTs (7,402 participants) were included in the meta-analysis evaluating the mean change in FPG from baseline. No difference was observed between the treatment arms (0.01 mg/dL [95% CI -2.65 to 2.67], I2 74.7%) (Fig. S9).

A post hoc sensitivity analysis excluding two trials with trial-specific dosing/titration algorithms [15, 16] also showed no difference between once-weekly and daily basal insulin analogs (MD -0.22 mg/dL, 95% CI -0.47 to 0.04; I² 16.3%) (Fig. S10).

Body Weight

Fourteen RCTs (8,487 participants) were included in the meta-analysis evaluating the mean change in body weight from baseline. Meta-analysis showed that once-weekly basal insulin analogs were associated with a small increase in body weight compared to daily basal insulin analogs (0.34 kg [95% CI 0.07 to 0.61], I2 38%) (Fig. S11).

Level 2 or 3 Hypoglycemia

Fourteen RCTs (8,088 participants) were included in the meta-analysis for level 2 or 3 hypoglycemia. The odds of experiencing level 2 or 3 hypoglycemia were similar between once-weekly and daily basal insulin analogs (OR 1.14 [95% CI 0.92 to 1.40], I2 49.1%), indicating no difference in clinically important hypoglycemia risk (Fig. S12).

Risk of Bias Due To Missing Results (Publication Bias)

Publication bias was evaluated for the primary outcome of change in HbA1c using a funnel plot and Egger’s regression test (Fig. S13). Visual inspection of the funnel plot revealed a symmetrical distribution of effect sizes, thus indicating a low risk for publication bias. Egger’s test showed no significant asymmetry (z= -0.38, p = 0.70), further supporting no evidence of small-study effects.