The effectiveness of GLP-1 analogues compared to DPP-4 inhibitors for beta cell function and diabetes related complications among adults with type 2 diabetes: a systematic review and meta-analysis

Abstract

Continued loss of beta cell function is responsible for progressive deterioration of plasma glucose control and complications characteristic of type 2 diabetes. Two classes of incretin-based antihyperglycaemic agents, dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1(GLP-1) analogues, have shown favourable effects on beta cell function. The aim of this systematic review was to provide a comprehensive synthesis of randomised clinical studies comparing the effectiveness of GLP-1 analogues to DPP-4 inhibitors in improving beta cell function and managing diabetes related complications. A search of PubMed, EMBASE and national and international clinical trials databases was conducted for randomised controlled trials that compared GLP-1 analogues to DPP-4 inhibitors, either alone or in combination with metformin, in adults with type 2 diabetes. Methodological quality of included studies was assessed using the Joanna Briggs Institute (JBI) critical appraisal checklist, and research data was extracted using the JBI data extraction tool. Outcomes included beta cell function (measured by homeostasis model assessment-beta [HOMA-beta], plasma connecting peptide [C-peptide] and proinsulin to insulin [PI/I] plasma concentration ratio) glycated haemoglobin (HbA1c), fasting and postprandial plasma glucose levels, diabetes related complications, and adverse drug events. Seven randomised controlled trials including 2661 participants were included in this review. The overall quality of included studies was good. Treatment duration ranged from 24 to 52 weeks in the included studies and included a number of different dosages. Results of meta-analysis showed that GLP-1 analogues, at different dosages and duration, were associated with statistically significant improvements in beta cell function compared to DPP-4 inhibitors as measured by HOMA-beta; mean difference 23% and 25% for high dose GLP-1 analogues after 26 and 52 weeks, respectively (p<0.00001); 18.5% and 16.7% for low dose GLP-1 analogues after 26 and 52 weeks, respectively (p<0.00001). Treatment with GLP-1 analogues showed a greater reduction in glycated haemoglobin (HbA1c) compared to treatment with DPP-4 inhibitors: a mean difference of -0.52% and -0.68% (-5.67mmol/moL and - 7.41mmol/moL) for high dose GLP-1 analogues after 26 and 52 weeks, respectively (p<0.00001); and -0.38% and -0.45% (-4.14mmol/moL and -4.91mmol/moL) for low dose GLP- 1 analogues after 26 and 52 weeks, respectively (p<0.00001). Treatment with GLP-1 analogues resulted in a greater reduction in fasting plasma glucose compared to DPP-4 inhibitors: a mean difference of -1.23 mmol/L and -1.47 mmol/L (-22.16 mg/dL and -26.49 mg/dL) for high dose GLP-1 analogues after 26 and 52 weeks, respectively p<0.00001); and -1.01mmol/L and -0.84mmol/L (-18.20mg/dL and -15.13 mg/dL) for low dose GLP-1 analogues after 26 and 52 weeks, respectively (p<0.00001). No studies reported outcomes for diabetes related complications. However, DPP-4 inhibitors were associated with fewer gastrointestinal adverse events compared to GLP-1 analogues. There were no differences in other adverse events such as headache and infection. The findings showed that GLP-1 analogues had greater beneficial effects on pancreatic beta cell function and plasma glucose control than DPP-4 inhibitors, but caused more gastrointestinal adverse events. Longer term safety data is required to better identify the contribution of GLP-1 analogues in reducing diabetes related microvascular complications, and determine their long term pancreatic and cardiac effects.