Subcutaneously administered tirzepatide vs semaglutide for adults with type 2 diabetes: a systematic review and network meta-analysis of randomised controlled trials

Aims/hypothesis We conducted a systematic review and network meta-analysis to compare the efficacy and safety of s.c. administered tirzepatide vs s.c. administered semaglutide for adults of both sexes with type 2 diabetes mellitus. Methods We searched PubMed and Cochrane up to 11 November 2023 for RCTs with an intervention duration of at least 12 weeks assessing s.c. tirzepatide at maintenance doses of 5 mg, 10 mg or 15 mg once weekly, or s.c. semaglutide at maintenance doses of 0.5 mg, 1.0 mg or 2.0 mg once weekly, in adults with type 2 diabetes, regardless of background glucose-lowering treatment. Eligible trials compared any of the specified doses of tirzepatide and semaglutide against each other, placebo or other glucose-lowering drugs. Primary outcomes were changes in HbA1c and body weight from baseline. Secondary outcomes were achievement of HbA1c target of ≤48 mmol/mol (≤6.5%) or <53 mmol/mol (<7.0%), body weight loss of at least 10%, and safety outcomes including gastrointestinal adverse events and severe hypoglycaemia. We used version 2 of the Cochrane risk-of-bias tool (ROB 2) to assess the risk of bias, conducted frequentist random-effects network meta-analyses and evaluated confidence in effect estimates utilising the Confidence In Network Meta-Analysis (CINeMA) framework. Results A total of 28 trials with 23,622 participants (44.2% female) were included. Compared with placebo, tirzepatide 15 mg was the most efficacious treatment in reducing HbA1c (mean difference −21.61 mmol/mol [−1.96%]) followed by tirzepatide 10 mg (−20.19 mmol/mol [−1.84%]), semaglutide 2.0 mg (−17.74 mmol/mol [−1.59%]), tirzepatide 5 mg (−17.60 mmol/mol [−1.60%]), semaglutide 1.0 mg (−15.25 mmol/mol [−1.39%]) and semaglutide 0.5 mg (−12.00 mmol/mol [−1.09%]). In between-drug comparisons, all tirzepatide doses were comparable with semaglutide 2.0 mg and superior to semaglutide 1.0 mg and 0.5 mg. Compared with placebo, tirzepatide was more efficacious than semaglutide for reducing body weight, with reductions ranging from 9.57 kg (tirzepatide 15 mg) to 5.27 kg (tirzepatide 5 mg). Semaglutide had a less pronounced effect, with reductions ranging from 4.97 kg (semaglutide 2.0 mg) to 2.52 kg (semaglutide 0.5 mg). In between-drug comparisons, tirzepatide 15 mg, 10 mg and 5 mg demonstrated greater efficacy than semaglutide 2.0 mg, 1.0 mg and 0.5 mg, respectively. Both drugs increased incidence of gastrointestinal adverse events compared with placebo, while neither tirzepatide nor semaglutide increased the risk of serious adverse events or severe hypoglycaemia. Conclusions/interpretation Our data show that s.c. tirzepatide had a more pronounced effect on HbA1c and weight reduction compared with s.c. semaglutide in people with type 2 diabetes. Both drugs, particularly higher doses of tirzepatide, increased gastrointestinal adverse events. Registration PROSPERO registration no. CRD42022382594 Graphical Abstract Supplementary Information The online version contains peer-reviewed but unedited supplementary material available at 10.1007/s00125-024-06144-1.


ESM Table 8
Confidence in effect estimates for the change from baseline in HbA1c (mmol/mol) in comparisons between tirzepatide, semaglutide, and placebo..

ESM Table 11
Network meta-analysis results for the change from baseline in body weight (kg) .......

Selection of the reported result
Overall assessment high risk of bias; L, low risk of bias; S, some concerns ESM Table 3 Risk of bias assessment of included trials for the change from baseline in body weight (kg)

Selection of the reported result
Overall assessment

Placebo
Treatment estimates are mean differences (MDs) and 95% CIs in the column-defining treatment compared to the row-defining treatment.Values lower than 0 favour the column-defining treatment.

Placebo
Treatment estimates are mean differences (MDs) and 95% CIs in the column-defining treatment compared to the row-defining treatment.Values lower than 0 favour the column-defining treatment.

Placebo
Treatment estimates are risk ratios (RRs) and 95% CIs in the column-defining treatment compared to the row-defining treatment.RRs greater than 1 favour the columndefining treatment.

Placebo
Treatment estimates are risk ratios (RRs) and 95% CIs in the column-defining treatment compared to the row-defining treatment.RRs greater than 1 favour the columndefining treatment.

ESM Table 11
Network meta-analysis results for the change from baseline in body weight (kg)

Prandial insulin
Treatment estimates are mean differences (MDs) and 95% CIs in the column-defining treatment compared to the row-defining treatment.Values lower than 0 favour the column-defining treatment.

Placebo
Treatment estimates are risk ratios (RRs) and 95% CIs in the column-defining treatment compared to the row-defining treatment.RRs greater than 1 favour the columndefining treatment ESM Table 14 Network meta-analysis results for the incidence of nausea

Placebo
Treatment estimates are risk ratios (RRs) and 95% CIs in the column-defining treatment compared to the row-defining treatment.RRs lower than 1 favour the columndefining treatment ESM Table 18 Network meta-analysis results for the incidence of serious adverse events

Placebo
Treatment estimates are risk ratios (RRs) and 95% CIs in the column-defining treatment compared to the row-defining treatment.RRs lower than 1 favour the columndefining treatment

ESM Table 4
Evaluation of heterogeneity (prediction intervals) and inconsistency (incoherence) in the network meta-analysis for the change from baseline in HbA1c (mmol/mol)

Table 5
Evaluation of heterogeneity (prediction intervals) and inconsistency (incoherence) in the network meta-analysis for the change from baseline in body weight (kg) Network meta-analysis results for the change from baseline in HbA1c (mmol/mol) Network meta-analysis results for achievement of an HbA1c target of ≤48 mmol/mol (≤6.5%) Network meta-analysis results for achievement of at least a 10% body weight reduction

Table 15
Network meta-analysis results for the incidence of vomitingPlaceboTreatment estimates are risk ratios (RRs) and 95% CIs in the column-defining treatment compared to the row-defining treatment.RRs lower than 1 favour the columndefining treatmentESM Table 16Network meta-analysis results for the incidence of diarrhoeaPlaceboTreatment estimates are risk ratios (RRs) and 95% CIs in the column-defining treatment compared to the row-defining treatment.RRs lower than 1 favour the columndefining treatment ESM Table17Network meta-analysis results for treatment discontinuation due to gastrointestinal adverse events