was supported with a Lilly Endocrine Scholars Award also

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was supported with a Lilly Endocrine Scholars Award also. Footnotes Disclosures N.J.B. enalapril, and 7 topics received 10 mg enalapril (Amount 1; research protocol). There have been no undesireable effects of the mix of enalapril and sitagliptin within this acute study. Desk 1 Subject Features Value:Worth:Worth:Worth: br / SitagliptinEnalapril br / DoseTime /th th align=”still left” colspan=”2″ valign=”bottom level” rowspan=”1″ hr / /th th align=”middle” colspan=”2″ valign=”bottom level” rowspan=”1″ hr / /th th align=”middle” valign=”bottom level” rowspan=”1″ colspan=”1″ 0 Hours /th th align=”middle” valign=”bottom level” rowspan=”1″ colspan=”1″ 6 Hours /th th align=”middle” valign=”bottom level” rowspan=”1″ colspan=”1″ 0 Hours /th th align=”middle” valign=”bottom level” rowspan=”1″ colspan=”1″ 6 Hours /th /thead ACE activity, U/L0.15 0.001 0.0010.04????Enalapril 0 mg37.113.039.310.934.911.034.99.5????Enalapril 5 mg46.018.819.85.2*?45.515.516.66.5*?????Enalapril 10 mg38.311.39.65.6*??33.312.110.17.0*?DPP-4 activity, U/L 0.0010.020.550.49????Enalapril 0 mg33.510.226.712.513.06.910.64.9????Enalapril 5 mg26.86.329.99.09.53.612.03.4????Enalapril 10 mg30.18.231.112.117.28.8?13.34.524-Hour urine Na+ excretion, mEq123.673.0146.161.40.08NANANARenal plasma flow, mL/min/1.73 mol/L20.340.040.0070.04????Enalapril 0 mg529.1148.6522.3225.7574.3155.5606.8154.6????Enalapril 5 mg656.6171.1647.7225.5654.3233.3743.6277.3????Enalapril 10 mg618.3205.2685.68197.0621.1161.8840.3378.5Plasma aldosterone, pg/mL0.89 0.0010.020.27????Enalapril 0 mg154.739.4137.129.5136.443.7146.562.6????Enalapril 5 mg149.681.595.321.3?144.878.970.448.9?????Enalapril 10 mg108.125.868.335.3?130.160.291.322.8?Plasma blood sugar, mg/dL0.05 0.0010.640.04????Enalapril 0 mg102.910.687.07.197.97.789.04.4????Enalapril 5 ODM-203 mg101.08.091.45.096.65.590.76.6????Enalapril 10 mg98.38.589.06.793.04.288.45.5Plasma insulin, U/mL0.570.040.510.94????Enalapril 0 mg20.413.520.219.518.89.616.110.8????Enalapril 5 mg15.516.111.310.817.721.710.26.9????Enalapril 10 mg19.38.313.25.527.536.716.69.3 GP9 Open up in another window Data are presented as meansSD from the means. For post hoc evaluations: * em P /em 0.001 vs period 0; ? em P /em 0.01 vs 0 mg of enalapril; ? em P /em 0.05 vs 5 mg of enalapril; em P /em 0.01 vs placebo; ? em P /em 0.05 vs 0 mg of enalapril. Impact of Treatment on 24-Hour Urine Sodium Excretion, RPF, and Aldosterone Twenty-four hour urine sodium excretion was very similar during sitagliptin and placebo statistically. Sitagliptin alone didn’t have an effect on RPF (Desk 2). ACE inhibition elevated renal blood circulation, and there is an interactive aftereffect of sitagliptin and enalapril on renal blood circulation (Desk 2). There is a substantial dose-dependent upsurge in RPF in response to enalapril during sitagliptin (maximal transformation in RPF as time passes, 169.8 204.4, 280.6 244.7, and 456.3 282.4 mL/min/1.73 mol/L2 after 0 mg, 5 mg, and 10 mg, respectively; em P /em =0.02); this is not really significant during placebo (maximal transformation in RPF as time passes 222.7 126.8, 260.6 237.6, and 375.8 107.4 mL/min/1.73 mol/L2 after 0 mg, 5 mg, and 10 mg, respectively). Enalapril reduced aldosterone concentrations within a dose-dependent way (Desk 2). Sitagliptin didn’t alter the aldosterone response to severe ACE inhibition. Impact of Sitagliptin on Glucose and Insulin Concentrations Glucose concentrations had been considerably lower at baseline with sitagliptin (mean baseline for any 3 groupings 96.3 6.5 mg/dL versus 101.3 9.0 mg/dL with placebo; em P /em =0.04). Blood sugar concentrations decreased considerably over time through the research times (from 101.3 9.0 to 89.0 6.3 mg/dL with placebo and from 96.3 6.3 to 89.5 5.3 mg/dL with sitagliptin; em P /em 0.001; Desk 2). There is no aftereffect of enalapril dosage on blood sugar (Desk 2). Although insulin concentrations reduced through the research considerably, there is no aftereffect of sitagliptin on insulin concentrations (Desk 2). Impact of Sitagliptin on Hemodynamic Ramifications of Severe ACE Inhibition Sitagliptin didn’t affect baseline blood circulation pressure (mean arterial blood circulation pressure [MAP] 97.1 12.8 mm Hg during sitagliptin versus 95.3 12.7 mm Hg during placebo). There is an interactive aftereffect of sitagliptin and ACE inhibitor dosage on transformation in MAP ( em P /em =0.008 for sitagliptinenalapril dosage; Amount 2). Sitagliptin improved the reduction in MAP in response to 0 mg of enalapril ( em P /em =0.02; Amount 2A) and 5 mg of enalapril ( em P /em =0.05; Amount 2B). On the other hand, sitagliptin prevented the reduction in MAP with 10 mg of enalapril ( em P /em =0.02 for sitagliptin impact; Amount 2C). The web impact was that there is a dose-dependent aftereffect of enalapril on blood circulation pressure during placebo (mean transformation in MAP 2.7 2.1, ?0.9 2.5, and ?7.9 2.4 mm Hg during 0 mg, 5 mg, and 10 mg of enalapril, respectively; em P /em =0.02 for dosage impact) however, not during sitagliptin (mean transformation in MAP ?2.3 2.0, ?5.7 2.2, and ?0.9 2.3 ODM-203 mm Hg during 0 mg, 5 mg, and 10 mg enalapril; em P /em =0.38). Open up in another window Amount 2 Change in MAP in response to 0 mg of enalapril (A), 5 mg of enalapril (B), or 10 mg of enalapril (C) after 5-day treatment with sitagliptin (100 mg/day) or placebo. For ANOVA, see Results: Influence of Sitagliptin on Hemodynamic Effects of Acute ACE Inhibition. * em P /em 0.05 vs baseline; ? em P /em 0.05 vs placebo. There was no effect of sitagliptin on baseline heart rate. There was a significant interactive effect of sitagliptin and enalapril ( em P /em =0.03 for sitaenalapril dosetime) on heart rate. Heart rate increased significantly in response to 10 mg of enalapril during sitagliptin but not during placebo (Physique.has served as a consultant for Merck and Company, Novartis, and Boehringer-Ingelheim. 8 subjects ODM-203 received 5 mg enalapril, and 7 subjects received 10 mg enalapril (Physique 1; study protocol). There were no adverse effects of the combination of sitagliptin and enalapril in this acute study. Table 1 Subject Characteristics Value:Value:Value:Value: br / SitagliptinEnalapril br / DoseTime /th th align=”left” colspan=”2″ valign=”bottom” rowspan=”1″ hr / /th th align=”center” colspan=”2″ valign=”bottom” rowspan=”1″ hr / /th th align=”center” valign=”bottom” rowspan=”1″ colspan=”1″ 0 Hours /th th align=”center” valign=”bottom” rowspan=”1″ colspan=”1″ 6 Hours /th th align=”center” valign=”bottom” rowspan=”1″ colspan=”1″ 0 Hours /th th align=”center” valign=”bottom” rowspan=”1″ colspan=”1″ 6 Hours /th /thead ACE activity, U/L0.15 0.001 0.0010.04????Enalapril 0 mg37.113.039.310.934.911.034.99.5????Enalapril 5 mg46.018.819.85.2*?45.515.516.66.5*?????Enalapril 10 mg38.311.39.65.6*??33.312.110.17.0*?DPP-4 activity, U/L 0.0010.020.550.49????Enalapril 0 mg33.510.226.712.513.06.910.64.9????Enalapril 5 mg26.86.329.99.09.53.612.03.4????Enalapril 10 mg30.18.231.112.117.28.8?13.34.524-Hour urine Na+ excretion, mEq123.673.0146.161.40.08NANANARenal plasma flow, mL/min/1.73 mol/L20.340.040.0070.04????Enalapril 0 mg529.1148.6522.3225.7574.3155.5606.8154.6????Enalapril 5 mg656.6171.1647.7225.5654.3233.3743.6277.3????Enalapril 10 mg618.3205.2685.68197.0621.1161.8840.3378.5Plasma aldosterone, pg/mL0.89 0.0010.020.27????Enalapril 0 mg154.739.4137.129.5136.443.7146.562.6????Enalapril 5 mg149.681.595.321.3?144.878.970.448.9?????Enalapril 10 mg108.125.868.335.3?130.160.291.322.8?Plasma glucose, mg/dL0.05 0.0010.640.04????Enalapril 0 mg102.910.687.07.197.97.789.04.4????Enalapril 5 mg101.08.091.45.096.65.590.76.6????Enalapril 10 mg98.38.589.06.793.04.288.45.5Plasma insulin, U/mL0.570.040.510.94????Enalapril 0 mg20.413.520.219.518.89.616.110.8????Enalapril 5 mg15.516.111.310.817.721.710.26.9????Enalapril 10 mg19.38.313.25.527.536.716.69.3 Open in a separate window Data are presented as meansSD of the means. For post hoc comparisons: * em P /em 0.001 vs time 0; ? em P /em 0.01 vs 0 mg of enalapril; ? em P /em 0.05 vs 5 mg of enalapril; em P /em 0.01 vs placebo; ? em P /em 0.05 vs 0 mg of enalapril. Influence of Treatment on 24-Hour Urine Sodium Excretion, RPF, and Aldosterone Twenty-four hour urine sodium excretion was statistically comparable during sitagliptin and placebo. Sitagliptin alone did not affect RPF (Table 2). ACE inhibition increased renal blood flow, and there was an interactive effect of sitagliptin and enalapril on renal blood flow (Table 2). There was a significant dose-dependent increase in RPF in response to enalapril during sitagliptin (maximal change in RPF over time, 169.8 204.4, 280.6 244.7, and 456.3 282.4 mL/min/1.73 mol/L2 after 0 mg, 5 mg, and 10 mg, respectively; em P /em =0.02); this was not significant during placebo (maximal change in RPF over time 222.7 126.8, 260.6 237.6, and 375.8 107.4 mL/min/1.73 mol/L2 after 0 mg, 5 mg, and 10 mg, respectively). Enalapril decreased aldosterone concentrations in a dose-dependent manner (Table 2). Sitagliptin did not alter the aldosterone response to acute ACE inhibition. Influence of Sitagliptin on Glucose and Insulin Concentrations Glucose concentrations were significantly lower at baseline with sitagliptin (mean baseline for all those 3 groups 96.3 6.5 mg/dL versus 101.3 9.0 mg/dL with placebo; em P /em =0.04). Glucose concentrations decreased significantly over time during the study days (from 101.3 9.0 to 89.0 6.3 mg/dL with placebo and from 96.3 6.3 to 89.5 5.3 mg/dL with sitagliptin; em P /em 0.001; Table 2). There was no effect of enalapril dose on glucose (Table 2). Although insulin concentrations decreased significantly during the study, there was no effect of sitagliptin on insulin concentrations (Table 2). Influence of Sitagliptin on Hemodynamic Effects of Acute ACE Inhibition Sitagliptin did not affect baseline blood pressure (mean arterial blood pressure [MAP] 97.1 12.8 mm Hg during sitagliptin versus 95.3 12.7 mm Hg during placebo). There was an interactive effect of sitagliptin and ACE inhibitor dose on change in MAP ( em P /em =0.008 for sitagliptinenalapril dose; Physique 2). Sitagliptin enhanced the decrease in MAP in response to 0 mg of enalapril ( em P /em =0.02; Physique 2A) and 5 mg of enalapril ( em P /em =0.05; Physique 2B). In contrast, sitagliptin prevented the decrease in MAP with 10 mg of enalapril ( em P /em =0.02 for sitagliptin effect; Physique 2C). The net effect was that there was a dose-dependent effect of enalapril on blood pressure.