The correlations between steady-state concentration, duration of action and molecular weight of GLP-1RAs and their efficacy and gastrointestinal side effects in patients with type 2 diabetes mellitus: a systematic review and meta-analysis

ABSTRACT

Background

To assess the influence of steady-state concentration, duration of action and molecular weight of glucagon-like peptide-1 receptor (GLP-1RA) on efficacy and gastrointestinal (GI) side effects in patients with type 2 diabetes mellitus (T2DM).

Methods

PubMed, EMBASE, the Cochrane Center Register of Controlled Trials for Studies and Clinicaltrial.gov were searched from inception to April 2022. Randomized controlled trials (RCTs) comparing GLP-1RA versus non-GLP-1RA agents in patients with T2DM were included. Sensitivity analyses on steady-state concentration, duration of action and molecular weight of GLP-1RA were conducted.

Results

113 RCTs were included. Greater HbA1c reduction between GLP-1RA users versus non-GLP-1RA users was observed in the high-steady-state-concentration stratum and long-acting stratum compared with the low-steady-state-concentration stratum (P_{subgroup difference} = 0.0004) and short-acting stratum (P_{subgroup difference}<0.0001). The risk of GI adverse events in GLP-1RA users versus non-GLP-1RA users was decreased in the high-steady-state-concentration stratum, long-acting stratum and heavy-molecular-weight stratum compared with low-steady-state-concentration stratum (P_{subgroup difference}<0.0001), short-acting stratum (P_{subgroup difference} = 0.002) and light-molecular-weight stratum (P_{subgroup difference} = 0.0008).

Conclusion

GLP-1RA with high steady-state concentration and long duration of action showed better hypoglycemic effect. GLP-1RA with high steady-state concentration, long duration of action and heavy molecular weight was associated with lower risk of GI adverse events.

KEYWORDS:

• glucagon-like peptide-1 receptor
• type 2 diabetes
• glycemic control
• gastrointestinal side effect

Article highlights

• High-concentration and long-acting GLP-1RA exerted better glucose-lowering effect.

• High-concentration and long-acting GLP-1RA conferred lower GI risk.

• The efficacy of GLP-1RA might be optimized by increasing exposure intensity or prolonging the exposure time.

Declaration of interest

L Ji has received fees for lecture presentations and for consulting from AstraZeneca, Merck, Metabasis, MSD, Novartis, Eli Lilly, Roche, Sanofi-Aventis and Takeda. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

A reviewer on this manuscript has disclosed they have received a research grant from Novo Nordisk. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Author contributions

L Ji and X Cai conceptualized this study and designed the systematic review protocol; R Jiao, C Lin and S Bai performed the study selection and data extraction; R Jiao and C Lin performed the statistical analyses; R Jiao, C Lin and X Cai prepared the outlines and wrote the manuscript. All authors contributed to the critical revision of manuscript drafts.

Availability of data and materials

All data relevant to the study are included in the article or uploaded as appendix information. No additional data are available.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/14656566.2023.2181693

Additional information

Funding

This paper was funded by the National Natural Science Foundation of China (No.81970698 and No. 81970708) and the Natural Science Foundation of Beijing Municipality (No.7202216). The funding agencies had no roles in the study design, data collection or analysis, decision to publish or preparation of the manuscript.