Nicolai J Wewer Albrechtsen1,2,3, Peter D Mark1, Dijana Terzic1, Lasse H Hansen1, Ulrik Ø Andersen1, Bolette Hartmann2,4, Richard D Carr5,6, Finn Gustafsson7,8, Carolyn F Deacon2,4, Jens J Holst2,4, Jens P Goetze1,2, Peter Plomgaard1,8. 1. Department of Clinical Biochemistry, University of Copenhagen, Copenhagen, Denmark. 2. Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. 3. Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. 4. Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. 5. MSD, Copenhagen, Denmark. 6. University College London, London, UK. 7. Department of Cardiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. 8. Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Abstract
CONTEXT: Combined inhibition of neprilysin and dipeptidyl peptidase 4 (DPP-4) has been shown to augment plasma concentrations of glucagon-like peptide-1(GLP-1) in animal models, but whether this occurs in humans is unknown. OBJECTIVE: To investigate the effects of inhibition of neprilysin by sacubitril/valsartan alone or in combination with a DPP-4 inhibitor (sitagliptin) on plasma concentrations of GLP-1 in healthy men. DESIGN: Two open-labeled crossover studies were performed in human subjects. SETTING: General community. PARTICIPANTS: Nine and 10 healthy young males were included in study 1 and study 2, respectively. INTERVENTION: Study participants received a standardized meal (34% carbohydrates, 45% fat, 21% protein, total caloric content of 2106kJ) combined with a prior dose of either sacubitril/valsartan (194/206mg) or control in study 1, and in study 2, with a prior dose of sitagliptin (2x100mg, given ∼10 hours apart) either alone or with sacubitril/valsartan (194/206mg). MAIN OUTCOME MEASURES: Plasma concentrations of total and intact GLP-1. RESULTS: Sacubitril/valsartan increased postprandial plasma concentrations of total GLP-1 by 67% (tAUC0-240min: 3929±344 vs. 2348±181 min × pmol/L P=0.0023), and increased concentrations of intact GLP-1 plasma concentrations more than sitagliptin alone (tAUC0-240min: 1021±114 vs. 660±80 min × pmol/L, P=0.01). Plasma concentrations of glucose, insulin, and GIP were not significantly (P>0.10) changed upon sacubitril/valsartan treatment. CONCLUSIONS: Sacubitril/valsartan combined with a DPP-4 inhibitor lead to markedly higher concentrations of intact GLP-1 than DPP-4 inhibition alone, supporting a role for both neprilysin and DPP-4 in the metabolism of GLP-1 in humans, a finding which may have therapeutic implications.
CONTEXT: Combined inhibition of neprilysin and dipeptidyl peptidase 4 (DPP-4) has been shown to augment plasma concentrations of glucagon-like peptide-1(GLP-1) in animal models, but whether this occurs in humans is unknown. OBJECTIVE: To investigate the effects of inhibition of neprilysin by sacubitril/valsartan alone or in combination with a DPP-4 inhibitor (sitagliptin) on plasma concentrations of GLP-1 in healthy men. DESIGN: Two open-labeled crossover studies were performed in human subjects. SETTING: General community. PARTICIPANTS: Nine and 10 healthy young males were included in study 1 and study 2, respectively. INTERVENTION: Study participants received a standardized meal (34% carbohydrates, 45% fat, 21% protein, total caloric content of 2106kJ) combined with a prior dose of either sacubitril/valsartan (194/206mg) or control in study 1, and in study 2, with a prior dose of sitagliptin (2x100mg, given ∼10 hours apart) either alone or with sacubitril/valsartan (194/206mg). MAIN OUTCOME MEASURES: Plasma concentrations of total and intact GLP-1. RESULTS:Sacubitril/valsartan increased postprandial plasma concentrations of total GLP-1 by 67% (tAUC0-240min: 3929±344 vs. 2348±181 min × pmol/L P=0.0023), and increased concentrations of intact GLP-1 plasma concentrations more than sitagliptin alone (tAUC0-240min: 1021±114 vs. 660±80 min × pmol/L, P=0.01). Plasma concentrations of glucose, insulin, and GIP were not significantly (P>0.10) changed upon sacubitril/valsartan treatment. CONCLUSIONS:Sacubitril/valsartan combined with a DPP-4 inhibitor lead to markedly higher concentrations of intact GLP-1 than DPP-4 inhibition alone, supporting a role for both neprilysin and DPP-4 in the metabolism of GLP-1 in humans, a finding which may have therapeutic implications.
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