Aims/hypothesis Glucagon-like peptide (GLP)-1-based therapies have been suggested to improve hepatic steatosis. We assessed the effects of the GLP-1 receptor agonist liraglutide and the dipeptidyl peptidase (DPP)-4 inhibitor sitagliptin on hepatic steatosis and fibrosis in patients with type 2 diabetes. Methods In this 12 week, parallel, randomised, placebo-controlled trial, performed at the VU University Medical Center between July 2013 and August 2015, 52 overweight patients with type 2 diabetes treated with metformin and/or sulphonylurea agent ([mean ± SD] age 62.7 ± 6.9 years, HbA_1c 7.3 ± 0.7% or 56 ± 1 mmol/mol) were allocated to once daily liraglutide 1.8 mg (n = 17), sitagliptin 100 mg (n = 18) or matching placebos (n = 17) by computer generated numbers. Both participants and researchers were blinded to group assignment. Hepatic fat content was measured using proton magnetic resonance spectroscopy (¹H-MRS). Hepatic fibrosis was estimated using three validated formulae. Results One patient dropped out in the sitagliptin group owing to dizziness, but no serious adverse events occurred. At week 12, no between-group differences in hepatic steatosis were found. Liraglutide reduced steatosis by 10% (20.9 ± 3.4% to 18.8 ± 3.3%), sitagliptin reduced steatosis by 12.1% (23.9 ± 3.0% to 21.0 ± 2.7%) and placebo lessened it by 9.5% (18.7 ± 2.7% to 16.9 ± 2.7%). Neither drug affected hepatic fibrosis scores compared with placebo. Conclusions/interpretation Twelve-week liraglutide or sitagliptin treatment does not reduce hepatic steatosis or fibrosis in type 2 diabetes. Trial registration ClinicalTrials.gov NCT01744236 Funding Funded by the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 282521 – the SAFEGUARD project.

Aims/hypothesis This study aimed to investigate the acute renal effects of the glucagon-like peptide-1 receptor agonist (GLP-1RA) exenatide in type 2 diabetes patients. Methods We included overweight (BMI 25–40 kg/m²) men and postmenopausal women, aged 35–75 years with type 2 diabetes (HbA_1c 48–75 mmol/mol; 6.5–9.0%) and estimated GFR ≥ 60 ml min⁻¹ 1.73 m⁻². Exenatide or placebo (NaCl solution, 154 mmol/l) was administrated intravenously in an acute, randomised, double-blind, placebo-controlled trial conducted at the Diabetes Center VU University Medical Center (VUMC). GFR (primary endpoint) and effective renal plasma flow (ERPF) were determined by inulin and para-aminohippurate clearance, respectively, based on timed urine sampling. Filtration fraction (FF) and effective renal vascular resistance (ERVR) were calculated, and glomerular hydrostatic pressure (P_GLO) and vascular resistance of the afferent (R_A) and efferent (R_E) renal arteriole were estimated. Tubular function was assessed by absolute and fractional excretion of sodium (FE_Na), potassium (FE_K) and urea (FE_U), in addition to urine osmolality, pH and free water clearance. Renal damage markers, BP and plasma glucose were also determined. Results Of the 57 patients randomised by computer, 52 were included in the final analyses. Exenatide (n = 24) did not affect GFR (mean difference +2 ± 3 ml min⁻¹ 1.73 m⁻², p = 0.489), ERPF, FF, ERVR or P_GLO, compared with placebo (n = 28). Exenatide increased R_A (p < 0.05), but did not change R_E. Exenatide increased FE_Na, FE_K, urine osmolality and pH, while FE_U, urinary flow and free water clearance were decreased (all p < 0.05). Osmolar clearance and renal damage makers were not affected. Diastolic BP and mean arterial pressure increased by 3 ± 1 and 6 ± 2 mmHg, respectively, whereas plasma glucose decreased by 1.4 ± 0.1 mmol/l (all p < 0.05). Conclusions/interpretation Exenatide infusion does not acutely affect renal haemodynamics in overweight type 2 diabetes patients at normal filtration levels. Furthermore, acute GLP-1RA administration increases proximal sodium excretion in these patients. Trial registration ClincialTrials.gov NCT01744236 Funding The research leading to these results has been funded from: (1) the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement number 282521 – the SAFEGUARD project; and (2) the Dutch Kidney Foundation, under grant agreement IP12.87.

OBJECTIVE: To investigate effects of dipeptidyl peptidase-4 inhibitor (DPP-4I) sitagliptin or glucagon-like peptide 1 (GLP-1) receptor agonist liraglutide treatment on renal hemodynamics, tubular functions, and markers of renal damage in overweight patients with type 2 diabetes without chronic kidney disease (CKD). RESEARCH DESIGN AND METHODS: In this 12-week, randomized, double-blind trial, 55 insulin-naïve patients with type 2 diabetes (mean ± SEM: age 63 ± 7 years, BMI 31.8 ± 4.1 kg/m2, glomerular filtration rate [GFR] 83 ± 16 mL/min/1.73 m2; median [interquartile range]: albumin-to-creatinine ratio (ACR) 1.09 mg/mmol [0.47–3.31]) received sitagliptin (100 mg/day), liraglutide (1.8 mg/day), or matching placebos. GFR (primary end point) and effective renal plasma flow (ERPF) were determined by inulin and para-aminohippuric acid clearance, respectively. Intrarenal hemodynamic variables were estimated. Absolute and fractional excretions of sodium (FENa), potassium, and urea (FEU) and renal damage markers (ACR, neutrophil gelatinase–associated lipocalin [NGAL], and kidney injury molecule-1 [KIM-1]) were measured. Plasma renin concentration (PRC) and glycated hemoglobin (HbA1c) were assessed. At weeks 2 and 6, estimated GFR and fractional electrolyte excretions were determined. RESULTS: At week 12, GFR was not affected by sitagliptin (−6 mL/min/1.73 m2 [95% CI −14 to 3], P = 0.17) or liraglutide (+3 mL/min/1.73 m2 [−5 to 11], P = 0.46), compared with placebo. Sitagliptin modestly reduced estimated glomerular hydraulic pressure (PGLO; P = 0.043). ERPF, other intrarenal hemodynamic variables, renal damage markers, and PRC did not change for both treatments. Both agents reduced HbA1c. Only at week 2, sitagliptin increased FENa and FEU (P = 0.005). CONCLUSIONS: Twelve-week treatment with sitagliptin or liraglutide does not affect measured renal hemodynamics. No sustained changes in tubular functions or alteration in renal damage markers were observed. The validity and clinical relevance of the slight sitagliptin-induced PGLO reduction remains speculative.

Background: Early identification of people at risk of functional decline is essential for delivering targeted preventive interventions. Objective: The aim of this study is to identify and predict trajectories of functional decline over 9 years in males and females aged 60-70 years. Methods: We included 403 community-dwelling participants from the InCHIANTI study and 395 from the LASA study aged 60-70 years at baseline, of whom the majority reported no functional decline at baseline (median 0, interquartile range 0-1). Participants were included if they reported data on ≥2 measurements of functional ability during a 9-year follow-up. Functional ability was scored with 6 self-reported items on activities of daily living. We performed latent class growth analysis to identify trajectories of functional decline and applied multinomial regression models to develop prediction models of identified trajectories. Analyses were stratified for sex. Results: Three distinct trajectories were identified: no/little decline (219 males, 241 females), intermediate decline (114 males, 158 females), and severe decline (36 males, 30 females). Higher gait speed showed decreased risk of functional limitations in males (intermediate limitations, odds ratio [OR] 0.74, 95% CI 0.57-0.97; severe limitations, OR 0.42, 95% CI 0.26-0.66). The final model in males further included the predictors fear of falling and alcohol intake (no/little decline, area under the receiver operating curve [AUC] 0.68, 95% CI 0.62-0.73; intermediate decline, AUC 0.63, 95% CI 0.56-0.69; severe decline, AUC 0.79, 95% CI 0.71-0.87). In females, higher gait speed showed a decreased risk of intermediate limitations (OR 0.51, 95% CI 0.38-0.68) and severe limitations (OR 0.18, 95% CI 0.07-0.44). Other predictors in females were age, living alone, economic satisfaction, balance, physical activity, BMI, and cardiovascular disease (no/little decline, AUC 0.80, 95% CI 0.75-0.85; intermediate decline, AUC 0.74, 95% CI 0.69-0.79; severe decline, AUC 0.95, 95% CI 0.91-0.99). Conclusion: Already in people aged 60-70 years, 3 distinct trajectories of functional decline were identified in these cohorts over a 9-year follow-up. Predictors of trajectories differed between males and females, except for gait speed. Identification of people at risk is the basis for targeting interventions.