The following is a summary of “Emergence of a New Glucoregulatory Mechanism for Glycemic Control With Dapagliflozin/Exenatide Therapy in Type 2 Diabetes,” published in the January 2024 issue of Endocrinology by Cersosimo, et al.
The study addressed the development of a new glucoregulatory mechanism in type 2 diabetes (T2D) patients treated with SGLT-2 inhibitors, which are independent of glucose, insulin, and glucagon. The data suggested the presence of a potential trigger factor arising in the kidney that stimulates endogenous glucose production (EGP) during sustained glycosuria. For a study, researchers sought to investigate the effects of SGLT-2 inhibitor therapy and GLP-1 receptor agonist on EGP and glucose kinetics in patients with T2D. The hypothesis was that increased EGP in response to SGLT2i-induced glycosuria persists for a long period and is not abolished by GLP-1 RA stimulation of insulin secretion and glucagon suppression.
About 75 patients received a 5-hour dual-tracer oral glucose tolerance test (OGTT) before/after dapagliflozin (DAPA), exenatide (EXE), or both (DAPA/EXE) in an acute study, and after 1 and 4 months of therapy with each drug.
In the acute study, during the oral glucose tolerance test (OGTT), the rise in plasma glucose (PG) was notably lower in the exenatide (EXE) group (Δ = 42 ± 1 mg/dL) compared to the dapagliflozin (DAPA) group (Δ = 72 ± 3 mg/dL), and even lower in the DAPA/EXE group (Δ = 11 ± 3 mg/dL) compared to both EXE and DAPA groups. Additionally, the decrease in endogenous glucose production (EGP) was less pronounced in the DAPA group (Δ = −0.65 ± 0.03 mg/kg/min) compared to the EXE group (Δ = −0.96 ± 0.07 mg/kg/min). In contrast, in the DAPA/EXE group (Δ = −0.84 ± 0.05 mg/kg/min), it was lower than EXE but higher than DAPA. At one month, similar PG elevations were observed across groups (EXE, Δ = 26 ± 1 mg/dL; DAPA, Δ = 62 ± 2 mg/dL; DAPA/EXE, Δ = 27 ± 1 mg/dL), as well as comparable decreases in EGP (DAPA, Δ = −0.60 ± 0.05 mg/kg/min; EXE, Δ = −0.77 ± 0.04 mg/kg/min; DAPA/EXE, Δ = −0.72 ± 0.03 mg/kg/min). At four months, the rise in PG remained consistent among groups (EXE, Δ = 55 ± 2 mg/dL; DAPA, Δ = 65 ± 6 mg/dL; DAPA/EXE, Δ = 46 ± 2 mg/dL), while the decrease in EGP was lower in the DAPA group (Δ = −0.66 ± 0.04 mg/kg/min) compared to the EXE group (Δ = −0.84 ± 0.05 mg/kg/min). Interestingly, in the DAPA/EXE group (Δ = −0.65 ± 0.03 mg/kg/min), it mirrored the DAPA group and was lower than EXE. Notably, changes in plasma insulin/glucagon did not account for the higher EGP observed in the DAPA/EXE group compared to EXE.
The study provided strong evidence for the emergence of a new, long-lasting, glucose-independent, insulin/glucagon-independent, glucoregulatory mechanism via which SGLT2i-induced glycosuria stimulates EGP in patients with T2D. SGLT2i plus GLP-1 receptor agonist combination therapy is accompanied by superior glycemic control vs monotherapy.
Reference: academic.oup.com/jcem/article-abstract/109/1/161/7229269