The effects of incretin‐based therapies on β‐cell function and insulin resistance in type 2 diabetes: A systematic review and network meta‐analysis combining 360 trials

Aim To evaluate the comparative effects of incretin‐based therapies, including glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) and dipeptidyl peptidase‐4 inhibitors (DPP‐4Is), on β‐cell function and insulin resistance in patients with type 2 diabetes mellitus (T2DM). Materials and Methods Medline, Embase, the Cochrane Library and www.clinicaltrials.gov were searched for randomized controlled trials (RCTs) with a duration of at least 4 weeks. Network meta‐analysis was performed, followed by subgroup analysis and meta‐regression. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was used to assess the quality of evidence. Outcomes of interest include homeostasis model assessment for β cell function (HOMA‐β) and insulin resistance (HOMA‐IR), fasting C‐peptide and fasting plasma glucose (FPG). Weighted mean difference (WMD) with 95% confidence interval (CI) was calculated as the measure of effect size. Results A total of 360 RCTs (74% at least double‐blinded) with 157 696 patients were included. Incretin‐based therapies were compared with six other classes of glucose‐lowering drugs or with placebo. Compared with placebo, a significant increase in HOMA‐β and fasting C‐peptide was detected for GLP‐1RAs (WMD = 20.31 95% CI, 16.34‐24.39 with low quality; WMD = 0.16 ng/mL 95% CI, 0.03‐0.29 with low quality) and for DPP‐4Is (WMD = 9.90 95% CI, 8.27‐11.61 with moderate quality; WMD = 0.09 ng/mL 95% CI, 0.04‐0.14 with moderate quality) separately, while a significant reduction in HOMA‐IR and FPG were found in favour of GLP‐1RAs (WMD = −0.67 95% CI, −1.08 to −0.27 with low quality; WMD = −1.04 mmol/L 95% CI, −1.26 to −0.83 with moderate quality) and DPP‐4Is (WMD = −0.23 95% CI, −0.38 to −0.08 with low quality; WMD = −0.77 mmol/L 95% CI, −0.98 to −0.57 with moderate quality), respectively. Conclusions Incretin‐based therapies not only show an increase in HOMA‐β and fasting C‐peptide level, but also achieve a reduction in HOMA‐IR and FPG in comparison with placebo. Although GRADE scores indicate low to moderate for most comparisons, incretin‐based therapies seem to be an advisable option for long‐term treatment to preserve β‐cell function.