Safety and Efficacy of Incretin-Based Therapies in Patients With Type 2 Diabetes Mellitus and CKD: A Systematic Review and Meta-analysis

Abstract

Background: The pharmacokinetics and pharmacodynamics of antidiabetic therapies for patients with type 2 diabetes are often altered in the context of chronic kidney disease (CKD).

Study design: Systematic review and meta-analysis.

Setting & population: Patients with type 2 diabetes and CKD.

Selection criteria for studies: 2 reviewers independently screened studies identified through bibliographic databases (Cochrane Library, PubMed, Embase, International Pharmaceutical Abstracts), clinical trial registries, and references from pertinent articles and clinical practice guidelines. Eligible studies included randomized controlled trials evaluating incretin-based therapy in adults with type 2 diabetes and estimated glomerular filtration rates < 60mL/min/1.73m².

Interventions: Incretin-based therapies (dipeptidyl peptidase 4 inhibitors and glucagon-like peptide 1 receptor agonists) compared to placebo or active antidiabetic therapies.

Outcomes: Changes in glycated hemoglobin (HbA_1c), hypoglycemia, mortality, change in fasting plasma glucose, cardiovascular events, and end-stage renal disease.

Results: Of 1,619 nonduplicate records screened, 13 studies were included. Compared to placebo, incretin-based therapies significantly reduced HbA_1c levels (n = 9; weighted mean difference, -0.64; 95% CI, -0.79 to -0.48; I² = 43%); however, compared with active comparators, they did not (n = 4; weighted mean difference, -0.07; 95% CI, -0.25 to 0.12; I² = 38%). Incretin-based therapies significantly increased the risk for hypoglycemia compared to placebo (n = 7; relative risk [RR], 1.38; 95% CI, 1.01-1.89; I² = 0%) but no effect was observed versus active comparators (n = 4; RR, 0.24; 95% CI, 0.03-1.94; I² = 52%). Limited evidence exists for all-cause mortality (placebo: n = 7 [RR, 1.21; 95% CI, 0.64-2.29; I² = 0%]; active comparators: n = 3 [RR, 0.70; 95% CI, 0.32-1.54; I² = 0%]).

Limitations: Variation among interventions, small number of studies, heterogeneity between studies, and high risk for attrition bias in 7 of the selected studies.

Conclusions: In patients with moderate or severe CKD, incretin-based therapies are effective in reducing HbA_1c levels. Hypoglycemic events are rare, and wide CIs for the association preclude any definitive conclusions. Likewise, wide CIs were observed for mortality, cardiovascular events, and end-stage renal disease.

Keywords: Type 2 diabetes mellitus (T2DM); antidiabetic therapies; chronic kidney disease (CKD); dipeptidyl peptidase 4 inhibitor (DPP-4); efficacy; epidemiology; glucagon-like peptide 1 (GLP-1) receptor agonist; glycated hemoglobin (HbA(1c)); hyperglycemia; incretin; meta-analysis; pharmacoepidemiology; safety; systematic review.