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Objective: To examine the effect of empagliflozin on liver fat content in individuals with and without type 2 diabetes (T2D) and the relationship between the decrease in liver fat and other metabolic actions of empagliflozin., Research Design and Methods: Thirty individuals with T2D and 27 without were randomly assigned to receive in double-blind fashion empagliflozin or matching placebo (2:1 ratio) for 12 weeks. Participants underwent 75-g oral glucose tolerance testing and measurement of liver fat content with MRS before therapy and at study end. Hepatic glucose production before the start of therapy was measured with 3-3H-glucose., Results: Empagliflozin caused an absolute reduction of 2.39% ± 0.79% in liver fat content compared with an increase of 0.91% ± 0.64% in participants receiving placebo (P < 0.007 with ANOVA). The decrease in liver fat was comparable in both individuals with diabetes and those without (2.75% ± 0.81% and 1.93% ± 0.78%, respectively; P = NS). The decrease in hepatic fat content caused by empagliflozin was strongly correlated with baseline liver fat content (r = -0.62; P < 0.001), decrease in body weight (r = 0.53; P < 0.001), and improvement in insulin sensitivity (r = -0.51; P < 0.001) but was not related to the decrease in fasting plasma glucose or HbA1c or the increase in hepatic glucose production., Conclusions: Empagliflozin is effective in reducing liver fat content in individuals with and without T2D. The decrease in liver fat content is independent of the decrease in plasma glucose concentration and is strongly related to the decrease in body weight and improvement in insulin sensitivity., (© 2024 by the American Diabetes Association.)

Aim: To examine the impact of increased hepatic glucose production (HGP) on the decrease in plasma glucose concentration caused by empagliflozin in individuals living with diabetes and in nondiabetic individuals., Methods: A total of 36 individuals living with diabetes and 34 nondiabetic individuals were randomized to receive, in double-blind fashion, empagliflozin or matching placebo in a 2:1 treatment ratio. Following an overnight fast, HGP was measured with 3- 3 H-glucose infusion before, at the start of, and 3 months after therapy with empagliflozin., Results: On Day 1 of empagliflozin administration, the increase in urinary glucose excretion (UGE) in individuals with normal glucose tolerance was smaller than in those with impaired glucose tolerance and those living with diabetes, and was accompanied by an increase in HGP in all three groups. The amount of glucose returned to the systemic circulation as a result of the increase in HGP was smaller than that excreted by the kidney during the first 3 h after empagliflozin administration, resulting in a decrease in fasting plasma glucose (FPG) concentration. After 3 h, the increase in HGP was in excess of UGE, leading to a small increase in plasma glucose concentration, which reached a new steady state. After 12 weeks, the amount of glucose returned to the circulation due to the empagliflozin-induced increase in HGP was comparable with that excreted by the kidney in all three groups., Conclusion: The balance between UGE and increase in HGP immediately after sodium-glucose cotransporter-2 (SGLT2) inhibition determined the magnitude of decrease in FPG and the new steady state which was achieved. After 12 weeks, the increase in HGP caused by empagliflozin closely matched the amount of glucose excreted by the kidneys; thus, FPG level remained stable despite the continuous urinary excretion of glucose caused by SGLT2 inhibition., (© 2023 John Wiley & Sons Ltd.)

Context: This study addresses the development of a new glucoregulatory mechanism in type 2 diabetes (T2D) patients treated with SGLT-2 inhibitors, which is independent of glucose, insulin and glucagon. The data suggest the presence of a potential trigger factor (s) arising in the kidney that stimulates endogenous glucose production (EGP) during sustained glycosuria., Objective: To investigate effects of SGLT-2 inhibitor therapy together with GLP-1 receptor agonist on EGP and glucose kinetics in patients with T2D. Our 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., Methods: Seventy-five patients received a 5-hour dual-tracer oral glucose tolerance test (OGTT) (intravenous 3-(3H)-glucose oral (1-14C)-glucose): (1) before/after 1 of dapagliflozin (DAPA); exenatide (EXE), or both, DAPA/EXE (acute study), and (2) after 1 and 4 months of therapy with each drug., Results: In the acute study, during the OGTT plasma glucose (PG) elevation was lower in EXE (Δ = 42 ± 1 mg/dL) than DAPA (Δ = 72 ± 3), and lower in DAPA/EXE (Δ = 11 ± 3) than EXE and DAPA. EGP decrease was lower in DAPA (Δ = -0.65 ± 0.03 mg/kg/min) than EXE (Δ = -0.96 ± 0.07); in DAPA/EXE (Δ = -0.84 ± 0.05) it was lower than EXE, higher than DAPA. At 1 month, similar PG elevations (EXE, Δ = 26 ± 1 mg/dL; DAPA, Δ = 62 ± 2, DAPA/EXE, Δ = 27 ± 1) and EGP decreases (DAPA, Δ = -0.60 ± 0.05 mg/kg/min; EXE, Δ = -0.77 ± 0.04; DAPA/EXE, Δ = -0.72 ± 0.03) were observed. At 4 months, PG elevations (EXE, Δ = 55 ± 2 mg/dL; DAPA, Δ = 65 ± 6; DAPA/EXE, Δ = 46 ± 2) and lower EGP decrease in DAPA (Δ = -0.66 ± 0.04 mg/kg/min) vs EXE (Δ = -0.84 ± 0.05) were also comparable; in DAPA/EXE (Δ = -0.65 ± 0.03) it was equal to DAPA and lower than EXE. Changes in plasma insulin/glucagon could not explain higher EGP in DAPA/EXE vs EXE mg/kg/min., Conclusion: Our findings provide 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., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To compare the long-term efficacy of initiating therapy with metformin/pioglitazone/exenatide in patients with new-onset type 2 diabetes mellitus (T2DM) versus sequential addition of metformin followed by glipizide and insulin., Research Design and Methods: Drug-naive patients ( N = 318) with new-onset T2DM were randomly assigned to receive for 3 years either 1 ) combination therapy with metformin, pioglitazone, and exenatide (triple therapy) or 2 ) sequential addition of metformin followed by glipizide and insulin (conventional therapy) to maintain HbA 1c at <6.5% (48 mmol/mol). Insulin sensitivity and β-cell function were measured at baseline and 3 years. The primary outcome was the difference in HbA 1c between the groups at 3 years., Results: Baseline HbA 1c ± SEM values were 9.0% ± 0.2% and 8.9% ± 0.2% in the triple therapy and conventional therapy groups, respectively. The decrease in HbA 1c resulting from triple therapy was greater at 6 months than that produced by conventional therapy (0.30% [95% CI 0.21-0.39]; P = 0.001), and the HbA 1c reduction was maintained at 3 years in patients receiving triple therapy compared with conventional therapy (6.4% ± 0.1% and 6.9% ± 0.1%, respectively), despite intensification of antihyperglycemic therapy in the latter. Thus, the difference in HbA 1c between the two treatment groups at 3 years was 0.50% (95% CI 0.39-0.61; P < 0.0001). Triple therapy produced a threefold increase in insulin sensitivity and 30-fold increase in β-cell function. In conventional therapy, insulin sensitivity did not change and β-cell function increased by only 34% (both P < 0.0001 vs. triple therapy)., Conclusions: Triple therapy with agents that improve insulin sensitivity and β-cell function in patients with new-onset T2DM produces greater, more durable HbA 1c reduction than agents that lower glucose levels without correcting the underlying metabolic defects., (© 2020 by the American Diabetes Association.)