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Insulin Degludec has Similar Pharmacokinetic Properties in Subjects with Hepatic Impairment when Compared to Subjects with Normal Hepatic Function
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Abstracts / Can J Diabetes 36 (2012) S24eS76
moderate RI, glycemic efficacy of liraglutide is similar to those with normal renal function, even in those with the greatest RI at baseline. Liraglutide use in patients with RI is not associated with an increased risk of hypoglycemia and appears to be effective and well-tolerated in this population. 122 Insulin Degludec has Similar Pharmacokinetic Properties in Subjects with Renal Impairment and Subjects with Normal Renal Function ISTVÁN KISS, GERHARD AROLD, SUSANNE G. BØTTCHER, CARSTEN ROEPSTORFF, JOVANA KAPOR*, HANNE L. HAAHR Budapest, Hungary; Berlin, Germany; Aalborg, Denmark; Soeberg, Denmark; Mississauga, ON Insulin degludec (IDeg) is a new-generation basal insulin forming soluble multi-hexamers upon subcutaneous injection, resulting in a flat and stable ultra-long action profile. This open-label, parallel-group trial investigated the pharmacokinetic (PK) properties of IDeg in subjects with different grades of renal impairment and subjects with normal renal function (NRF) following single doses of 0.4 U/kg IDeg. Also, the influence of hemodialysis on clearance of IDeg was investigated in end-stage renal disease (ESRD) subjects by administration of two single doses of IDeg, one before and one just after hemodialysis. A total of 30 subjects (mean age: 65.6 years; females/males: 15/ 15; mean body mass index: 28.4 kg/m2) were allocated to one of five renal function groups (N¼6 per group): NRF, mild, moderate, severe renal impairment, or ESRD. PK profiles of IDeg were similar for subjects with normal and impaired renal function. Renal impairment had no statistically significant effect on total exposure (AUCIDeg,0e120h,SD) (area under the curve), maximum concentration (Cmax,IDeg,SD) or apparent clearance (CL/FIDeg,SD) (Table 1). PK profiles of IDeg for subjects with ESRD were similar irrespective of whether subjects received hemodialysis or not. Hemodialysis did not affect CL/FIDeg,SD, and intact IDeg was not detected in dialysate samples collected during dialysis from subjects with ESRD. In conclusion, the ultra-long PK properties of IDeg are preserved in subjects with renal impairment; renal impairment did not result in differences in the PK properties of IDeg compared to subjects with NRF. Hemodialysis did not affect the clearance of IDeg.
Table 1 PK endpoints vs. creatinine clearance
Estimated slope 95% CI Statistical significance
AUCIDeg,0-120h,SD
Cmax,IDeg,SD
CL/FIDeg,SD
e0.138 [e0.390; 0.113] NS
e0.171 [e0.415; 0.073] NS
0.129 [e0.120; 0.378] NS
Estimated slope: a measure of correlation between creatinine clearance and PK endpoint; CI: confidence interval; NS: non-significant (p0.05). Renal impairment was classified based on creatinine clearance (CLCR) estimated by the Cockcroft & Gault formula, and subjects were grouped as: Normal (CLCR >80 mL/ min), mild (CLCR >50e80 mL/min), moderate (CLCR >30e50 mL/min), severe (CLCR 30 mL/min) or end-stage renal disease (ESRD).
123 Insulin Degludec has Similar Pharmacokinetic Properties in Subjects with Hepatic Impairment when Compared to Subjects with Normal Hepatic Function GERHARD AROLD, VIERA KUPCOVÁ, CARSTEN ROEPSTORFF, MALENE HØJBJERRE, NIKOLAI NIKOLOV*, HANNE L. HAAHR Berlin, Germany; Bratislava, Slovakia; Mississauga, ON; Aalborg, Denmark; Soeberg, Denmark Insulin degludec (IDeg) is a new-generation basal insulin that forms soluble multi-hexamers upon subcutaneous injection, resulting in a flat and stable ultra-long action profile.
Table 1 Pair-wise comparison of PK endpoints for IDeg after single dose between subjects with normal hepatic function and subjects with different grades of hepatic impairment Cmax,IDeg,SD
CL/FIDeg,SD
Grade of hepatic impairment
AUCIDeg,0e120h,SD Ratio [90% CI]
Ratio [90% CI]
Ratio [90% CI]
Mild vs. normal Moderate vs. normal Severe vs. normal
0.95 [0.77; 1.16] 1.00 [0.82; 1.22] 0.92 [0.74; 1.14]
0.90 [0.67; 1.20] 0.77 [0.58; 1.03] 0.75 [0.55; 1.02]
1.05 [0.86; 1.29] 0.98 [0.80; 1.19] 1.06 [0.85; 1.31]
Grade of hepatic impairment according to the Child-Pugh classification
This open-label, parallel-group study investigated the pharmacokinetic (PK) properties of IDeg in subjects with different grades of hepatic impairment and in subjects with normal hepatic function following single-dose administration of 0.4 U/kg IDeg. A total of 24 subjects (mean age: 47.4 years; females/males: 16/8; mean body mass index: 26.0 kg/m2) were allocated to one of 4 hepatic function groups (N¼6 per group): mild, moderate, severe hepatic impairment, or normal hepatic function. In the severe hepatic impairment group 3 subjects had diabetes. Blood samples for PK analysis were collected before and up to 120 hours after IDeg administration. The mean PK profiles of IDeg were similar for subjects with normal and impaired hepatic function. In addition, hepatic impairment had no statistically significant effect on total exposure (AUCIDeg,0e120h,SD) (area under the curve), maximum concentration (Cmax,IDeg,SD) or apparent clearance (CL/FIDeg,SD) (Table 1). A test of monotonous trend between AUCIDeg,0e120h,SD and grade of hepatic impairment was not significant (p-value: 0.63). IDeg was safe and well tolerated. In conclusion, the ultra-long PK properties of IDeg are preserved in subjects with hepatic impairment; there were no differences in the PK properties of IDeg between subjects with normal hepatic function and those with different grades of hepatic impairment.
124 DPP-4 Inhibition Improves Cardiac Function Following Experimental Myocardial Infarction: Potential Non-GLP-1 Mediated Effects KIM CONNELLY*, YANLING ZHANG, ANDREW ADVANI, RICHARD E. GILBERT Toronto, ON Background: Both GLP-1R agonists and DDP-4 inhibitors lower glucose by increasing GLP-1, an incretin hormone that in addition to its anti-hyperglycaemic effects, may also influence cardiac function. However, beyond their effects on GLP-1, DDP-4 inhibitors also prevent the degradation of several other biologically active proteins, including stromal cell-derived factor-1 (SDF-1), an anti-apoptotic and proangiogenic chemokine that is elaborated in response to ischemic injury. To test the hypothesis that the additional effects of DPP-4 may be relevant in the in vivo setting, we compared the DPP-4 inhibitor, saxagliptin with the GLP-1R agonist, liraglutide. Methods: F344 rats with streptozotocin (STZ)-diabetes were randomized to receive the DPP-4 inhibitor, saxagliptin (10 mg/kg/ d), liraglutide (0.2 mg/kg, bid) or vehicle. Two weeks later animals underwent experimental MI, induced by ligation of the left anterior descending coronary artery. Cardiac function, assessed by conductance catheterisation and echocardiography, was examined 4 weeks post-MI. Results: When compared with untreated post-MI rats, those receiving saxagliptin had lower lung weight (a marker of pulmonary congestion), improved fractional shortening and better diastolic function (p < 0.05 for all). By contrast, liraglutide-treated animals closely resembled those that had received vehicle. Neither saxagliptin nor liraglutide affected blood glucose in this model of DM1.
Abstracts / Can J Diabetes 36 (2012) S24eS76
moderate RI, glycemic efficacy of liraglutide is similar to those with normal renal function, even in those with the greatest RI at baseline. Liraglutide use in patients with RI is not associated with an increased risk of hypoglycemia and appears to be effective and well-tolerated in this population. 122 Insulin Degludec has Similar Pharmacokinetic Properties in Subjects with Renal Impairment and Subjects with Normal Renal Function ISTVÁN KISS, GERHARD AROLD, SUSANNE G. BØTTCHER, CARSTEN ROEPSTORFF, JOVANA KAPOR*, HANNE L. HAAHR Budapest, Hungary; Berlin, Germany; Aalborg, Denmark; Soeberg, Denmark; Mississauga, ON Insulin degludec (IDeg) is a new-generation basal insulin forming soluble multi-hexamers upon subcutaneous injection, resulting in a flat and stable ultra-long action profile. This open-label, parallel-group trial investigated the pharmacokinetic (PK) properties of IDeg in subjects with different grades of renal impairment and subjects with normal renal function (NRF) following single doses of 0.4 U/kg IDeg. Also, the influence of hemodialysis on clearance of IDeg was investigated in end-stage renal disease (ESRD) subjects by administration of two single doses of IDeg, one before and one just after hemodialysis. A total of 30 subjects (mean age: 65.6 years; females/males: 15/ 15; mean body mass index: 28.4 kg/m2) were allocated to one of five renal function groups (N¼6 per group): NRF, mild, moderate, severe renal impairment, or ESRD. PK profiles of IDeg were similar for subjects with normal and impaired renal function. Renal impairment had no statistically significant effect on total exposure (AUCIDeg,0e120h,SD) (area under the curve), maximum concentration (Cmax,IDeg,SD) or apparent clearance (CL/FIDeg,SD) (Table 1). PK profiles of IDeg for subjects with ESRD were similar irrespective of whether subjects received hemodialysis or not. Hemodialysis did not affect CL/FIDeg,SD, and intact IDeg was not detected in dialysate samples collected during dialysis from subjects with ESRD. In conclusion, the ultra-long PK properties of IDeg are preserved in subjects with renal impairment; renal impairment did not result in differences in the PK properties of IDeg compared to subjects with NRF. Hemodialysis did not affect the clearance of IDeg.
Table 1 PK endpoints vs. creatinine clearance
Estimated slope 95% CI Statistical significance
AUCIDeg,0-120h,SD
Cmax,IDeg,SD
CL/FIDeg,SD
e0.138 [e0.390; 0.113] NS
e0.171 [e0.415; 0.073] NS
0.129 [e0.120; 0.378] NS
Estimated slope: a measure of correlation between creatinine clearance and PK endpoint; CI: confidence interval; NS: non-significant (p0.05). Renal impairment was classified based on creatinine clearance (CLCR) estimated by the Cockcroft & Gault formula, and subjects were grouped as: Normal (CLCR >80 mL/ min), mild (CLCR >50e80 mL/min), moderate (CLCR >30e50 mL/min), severe (CLCR 30 mL/min) or end-stage renal disease (ESRD).
123 Insulin Degludec has Similar Pharmacokinetic Properties in Subjects with Hepatic Impairment when Compared to Subjects with Normal Hepatic Function GERHARD AROLD, VIERA KUPCOVÁ, CARSTEN ROEPSTORFF, MALENE HØJBJERRE, NIKOLAI NIKOLOV*, HANNE L. HAAHR Berlin, Germany; Bratislava, Slovakia; Mississauga, ON; Aalborg, Denmark; Soeberg, Denmark Insulin degludec (IDeg) is a new-generation basal insulin that forms soluble multi-hexamers upon subcutaneous injection, resulting in a flat and stable ultra-long action profile.
Table 1 Pair-wise comparison of PK endpoints for IDeg after single dose between subjects with normal hepatic function and subjects with different grades of hepatic impairment Cmax,IDeg,SD
CL/FIDeg,SD
Grade of hepatic impairment
AUCIDeg,0e120h,SD Ratio [90% CI]
Ratio [90% CI]
Ratio [90% CI]
Mild vs. normal Moderate vs. normal Severe vs. normal
0.95 [0.77; 1.16] 1.00 [0.82; 1.22] 0.92 [0.74; 1.14]
0.90 [0.67; 1.20] 0.77 [0.58; 1.03] 0.75 [0.55; 1.02]
1.05 [0.86; 1.29] 0.98 [0.80; 1.19] 1.06 [0.85; 1.31]
Grade of hepatic impairment according to the Child-Pugh classification
This open-label, parallel-group study investigated the pharmacokinetic (PK) properties of IDeg in subjects with different grades of hepatic impairment and in subjects with normal hepatic function following single-dose administration of 0.4 U/kg IDeg. A total of 24 subjects (mean age: 47.4 years; females/males: 16/8; mean body mass index: 26.0 kg/m2) were allocated to one of 4 hepatic function groups (N¼6 per group): mild, moderate, severe hepatic impairment, or normal hepatic function. In the severe hepatic impairment group 3 subjects had diabetes. Blood samples for PK analysis were collected before and up to 120 hours after IDeg administration. The mean PK profiles of IDeg were similar for subjects with normal and impaired hepatic function. In addition, hepatic impairment had no statistically significant effect on total exposure (AUCIDeg,0e120h,SD) (area under the curve), maximum concentration (Cmax,IDeg,SD) or apparent clearance (CL/FIDeg,SD) (Table 1). A test of monotonous trend between AUCIDeg,0e120h,SD and grade of hepatic impairment was not significant (p-value: 0.63). IDeg was safe and well tolerated. In conclusion, the ultra-long PK properties of IDeg are preserved in subjects with hepatic impairment; there were no differences in the PK properties of IDeg between subjects with normal hepatic function and those with different grades of hepatic impairment.
124 DPP-4 Inhibition Improves Cardiac Function Following Experimental Myocardial Infarction: Potential Non-GLP-1 Mediated Effects KIM CONNELLY*, YANLING ZHANG, ANDREW ADVANI, RICHARD E. GILBERT Toronto, ON Background: Both GLP-1R agonists and DDP-4 inhibitors lower glucose by increasing GLP-1, an incretin hormone that in addition to its anti-hyperglycaemic effects, may also influence cardiac function. However, beyond their effects on GLP-1, DDP-4 inhibitors also prevent the degradation of several other biologically active proteins, including stromal cell-derived factor-1 (SDF-1), an anti-apoptotic and proangiogenic chemokine that is elaborated in response to ischemic injury. To test the hypothesis that the additional effects of DPP-4 may be relevant in the in vivo setting, we compared the DPP-4 inhibitor, saxagliptin with the GLP-1R agonist, liraglutide. Methods: F344 rats with streptozotocin (STZ)-diabetes were randomized to receive the DPP-4 inhibitor, saxagliptin (10 mg/kg/ d), liraglutide (0.2 mg/kg, bid) or vehicle. Two weeks later animals underwent experimental MI, induced by ligation of the left anterior descending coronary artery. Cardiac function, assessed by conductance catheterisation and echocardiography, was examined 4 weeks post-MI. Results: When compared with untreated post-MI rats, those receiving saxagliptin had lower lung weight (a marker of pulmonary congestion), improved fractional shortening and better diastolic function (p < 0.05 for all). By contrast, liraglutide-treated animals closely resembled those that had received vehicle. Neither saxagliptin nor liraglutide affected blood glucose in this model of DM1.