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Pharmacokinetics (PK) and Pharmacodynamics (PD) of Canagliflozin (CANA) in Pediatric Patients With Type 2 Diabetes Mellitus (T2DM)
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Abstracts / Can J Diabetes 41 (2017) S2–S16
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Pharmacokinetics (PK) and Pharmacodynamics (PD) of Canagliflozin (CANA) in Pediatric Patients With Type 2 Diabetes Mellitus (T2DM) WILLIAM TAMBORLANE†, DAVID POLIDORI*,†, NICHOLAS DI PROSPERO† San Diego, CA CANA, an SGLT2 inhibitor, increases urinary glucose excretion (UGE) and lowers plasma glucose (PG) levels by reducing the renal threshold for glucose (RTG). In this open-label study, patients aged 10 to <18 y with T2DM on a stable metformin dose (mean age=14.6 y; HbA1c=6.9%; BMI=38 kg/m2) received CANA 100 mg (n=8) or 300 mg (n=9) daily for 14 days. PK parameters were similar to historic parameters measured in adults (Table). At Day 14, CANA dose-dependently reduced mean (SD) RTG to 85 (14) and 69 (10) mg/dL with CANA 100 and 300 mg, respectively. Mean UGE increased from 5 (11) to 74 (37) grams and from 0.1 (0.04) to 69 (27) grams with CANA 100 and 300 mg, respectively. Overall, CANA was well tolerated. In pediatric T2DM patients, CANA had PK parameters similar to adults with T2DM and lowered RTG, increased UGE, and lowered PG concentrations.
Table PK Parameters†
Cmax, ng/mL* 951 (429) 3,260 (1,330) 1,227 (481) 4,678 (1,685) tmax, h‡ 1.6 (1.0-2.0) 2.4 (1.0-4.0) 1.5 (1.0-5.0) 1.5 (1.0-2.0) t1/2, h* 11.3 (2.5) 15.2 (6.9) 13.7 (2.1) 14.9 (4.8) † Data are reported at Day 14 for pediatric patients and Day 7 for adult patients. *Data are mean (SD). ‡Data are mean (range).
8 Vitamin D Reverts Androgen Production Induced by NonEsterified Fatty Acid in NCIH295R Cell Line JOANIE FAUBERT, MARIE-CLAUDE BATTISTA, SAMUEL LEBLANC, JEAN-PATRICE BAILLARGEON Sherbrooke, QC Background: Polycystic ovary syndrome (PCOS) is an endocrine disorder that is very frequent and characterized by hyperandrogenism and increased risk to develop type 2 diabetes (T2D). Both hyperandrogenism and T2D development may be caused by nonesterified fatty acid (NEFA) overload in nonadipose tissue. Many studies suggest that vitamin D can counteract lipotoxicity and prevent T2D. The objective of this project was to determine the impact of vitamin D on NEFA-induced androgen synthesis in a human adrenocortical cell line, NCI- H295R. Methods: H295R cells are derived from a human adrenal corticocarcinoma. These cells were stimulated or not with forskolin (Fsk, 10 μM; 1x/day; adenylate cyclase activator), in the absence or presence of oleate (200 μM; 2x/day; monounsaturated fatty acid) and vitamin D (1,25OHD; at 1, 10 or 100 nM; 1x/day). After 48h of treatments, DHEA levels were measured in culture media by ELISA and corrected for protein quantification. Data were analysed with Wilcoxon tests and are reported as means±SEM. Results: DHEA production was increased by 43±9% under Fsk+oleate treatment in comparison to Fsk alone (P<0.0001, n=31). A doseresponse curve with 3 different 1,25OHD concentrations, in addition to Fsk+oleate, revealed that 1,25OHD decreases oleate-induced DHEA production in comparison to Fsk+oleate alone. 1,25OHD at 10 nM reduced oleate-induced DHEA production by 28±6% (n=17, P=0.001), to the same levels than with Fsk alone.
Conclusions: This study shows that lipotoxicity can trigger androgen production in androgen-secreting cells and suggests, for the first time, that vitamin D can decrease the androgen overproduction induced by NEFA. 9 Diabetic Ketoacidosis Risk After Initiating a Sodium-Glucose Cotransporter 2 Inhibitor: A Population-Based Cohort Study MICHAEL FRALICK*, SEBASTIAN SCHNEEWEISS†, ELISABETTA PATORNO† Boston, MA Background: Case reports submitted to the FDA suggest Sodiumglucose cotransporter 2 (SGLT2) inhibitors might be associated with an increased risk of diabetic ketoacidosis (DKA). Methods: To assess the risk of DKA after initiating an SGLT2 inhibitor, we conducted a population-based new initiator cohort study using the Truven MarketScan database. Patients with diabetes mellitus who newly initiated either an SGLT2 inhibitor or a dipeptidyl peptidase-4 (DPP4) inhibitor were included. Our primary outcome was hospitalization for DKA within 180 days of initiating an SGLT2. We matched new initiators of SGLT2 inhibitors with new initiators of DPP4 inhibitors using 1:1 propensity score (PS) matching. We used Cox proportional hazard models to examine the hazard ratio (HR) and 95% CI of DKA. Results: After PS-matching we identified 45,789 pairs of patients initiating SGLT2 inhibitors or DPP4 inhibitors with balanced baseline covariates. There were 58 DKA events (4.23 events per 1000 person-years) among initiators of an SGLT2 inhibitor compared to 29 DKA events (2.01 per 1000 person-years) among initiators of DPP4 inhibitors. The PS-adjusted risk of DKA within 180 days of initiating an SGLT2 inhibitor was 2.1 times greater than the risk for those initiating a DPP4 inhibitor (HR 2.1, 95% CI 1.3 to 3.3). The risk was highest within 60 days of initiating an SGLT2 inhibitor (PS matched HR 3.0, 95% CI 1.6 to 5.5). Conclusion: SGLT2 inhibitors were associated with an increased risk of DKA. Physicians should counsel their patients accordingly and closely monitor those with symptoms suggestive of DKA. 10 CANadian CAnagliflozin REgistry (CanCARE) – A Prospective, Observational, Assessment of Canagliflozin Treatment in Type 2 Diabetes Mellitus (T2DM); Six Month Results VINCENT WOO, HARPREET S. BAJAJ, ALAN BELL, MAUREEN CLEMENT, FERNANDO CAMACHO, NATASHA GEORGIJEV, JENNIFER B. ROSE Winnipeg, MB This real-world Canadian study is evaluating glycemic and safety outcomes over 12 months, for 527 T2DM patients, who were initiated on Canagliflozin (CANA) as part of their usual treatment approach. Of patients meeting enrollment criteria of A1c ≥7.0% and eGFR≥60 mL/min/1.73 m2, mean change in A1c at six months was −0.9 (95% CI: −1.03, −0.79) from baseline of 8.4%. 33% of patients reached A1c target of <7.0% and 41% achieved the composite endpoint of ≥0.5 A1c and ≥3% weight reduction at six months. Significant reductions in weight (−2.9 kg, CI: −3.39, −2.51; n=350), BMI (−1.0, CI: −1.19, −0.86; n=377) and waist circumference (−3.1 cm, CI: −4.08, −2.14; n=362) were observed. By six months, 84%, 52% and 29% of patients experienced >0%, ≥3% or ≥5% weight loss, respectively. Blood pressure reductions (diastolic −2.9, 95% CI: −3.78, −2.00; systolic −4.5, CI: −5.90, −3.14; n=378) were also observed. No significant changes were observed in electrolytes or lipids. 35% of patients reported≥1 Adverse Event (AE), 2.9% reported serious AEs and 15% reported an AE of special Interest: genital mycotic infections (10%), polyuria (3.7%), severe hypoglycemia (1.1%),
Abstracts / Can J Diabetes 41 (2017) S2–S16
7
★
Pharmacokinetics (PK) and Pharmacodynamics (PD) of Canagliflozin (CANA) in Pediatric Patients With Type 2 Diabetes Mellitus (T2DM) WILLIAM TAMBORLANE†, DAVID POLIDORI*,†, NICHOLAS DI PROSPERO† San Diego, CA CANA, an SGLT2 inhibitor, increases urinary glucose excretion (UGE) and lowers plasma glucose (PG) levels by reducing the renal threshold for glucose (RTG). In this open-label study, patients aged 10 to <18 y with T2DM on a stable metformin dose (mean age=14.6 y; HbA1c=6.9%; BMI=38 kg/m2) received CANA 100 mg (n=8) or 300 mg (n=9) daily for 14 days. PK parameters were similar to historic parameters measured in adults (Table). At Day 14, CANA dose-dependently reduced mean (SD) RTG to 85 (14) and 69 (10) mg/dL with CANA 100 and 300 mg, respectively. Mean UGE increased from 5 (11) to 74 (37) grams and from 0.1 (0.04) to 69 (27) grams with CANA 100 and 300 mg, respectively. Overall, CANA was well tolerated. In pediatric T2DM patients, CANA had PK parameters similar to adults with T2DM and lowered RTG, increased UGE, and lowered PG concentrations.
Table PK Parameters†
Cmax, ng/mL* 951 (429) 3,260 (1,330) 1,227 (481) 4,678 (1,685) tmax, h‡ 1.6 (1.0-2.0) 2.4 (1.0-4.0) 1.5 (1.0-5.0) 1.5 (1.0-2.0) t1/2, h* 11.3 (2.5) 15.2 (6.9) 13.7 (2.1) 14.9 (4.8) † Data are reported at Day 14 for pediatric patients and Day 7 for adult patients. *Data are mean (SD). ‡Data are mean (range).
8 Vitamin D Reverts Androgen Production Induced by NonEsterified Fatty Acid in NCIH295R Cell Line JOANIE FAUBERT, MARIE-CLAUDE BATTISTA, SAMUEL LEBLANC, JEAN-PATRICE BAILLARGEON Sherbrooke, QC Background: Polycystic ovary syndrome (PCOS) is an endocrine disorder that is very frequent and characterized by hyperandrogenism and increased risk to develop type 2 diabetes (T2D). Both hyperandrogenism and T2D development may be caused by nonesterified fatty acid (NEFA) overload in nonadipose tissue. Many studies suggest that vitamin D can counteract lipotoxicity and prevent T2D. The objective of this project was to determine the impact of vitamin D on NEFA-induced androgen synthesis in a human adrenocortical cell line, NCI- H295R. Methods: H295R cells are derived from a human adrenal corticocarcinoma. These cells were stimulated or not with forskolin (Fsk, 10 μM; 1x/day; adenylate cyclase activator), in the absence or presence of oleate (200 μM; 2x/day; monounsaturated fatty acid) and vitamin D (1,25OHD; at 1, 10 or 100 nM; 1x/day). After 48h of treatments, DHEA levels were measured in culture media by ELISA and corrected for protein quantification. Data were analysed with Wilcoxon tests and are reported as means±SEM. Results: DHEA production was increased by 43±9% under Fsk+oleate treatment in comparison to Fsk alone (P<0.0001, n=31). A doseresponse curve with 3 different 1,25OHD concentrations, in addition to Fsk+oleate, revealed that 1,25OHD decreases oleate-induced DHEA production in comparison to Fsk+oleate alone. 1,25OHD at 10 nM reduced oleate-induced DHEA production by 28±6% (n=17, P=0.001), to the same levels than with Fsk alone.
Conclusions: This study shows that lipotoxicity can trigger androgen production in androgen-secreting cells and suggests, for the first time, that vitamin D can decrease the androgen overproduction induced by NEFA. 9 Diabetic Ketoacidosis Risk After Initiating a Sodium-Glucose Cotransporter 2 Inhibitor: A Population-Based Cohort Study MICHAEL FRALICK*, SEBASTIAN SCHNEEWEISS†, ELISABETTA PATORNO† Boston, MA Background: Case reports submitted to the FDA suggest Sodiumglucose cotransporter 2 (SGLT2) inhibitors might be associated with an increased risk of diabetic ketoacidosis (DKA). Methods: To assess the risk of DKA after initiating an SGLT2 inhibitor, we conducted a population-based new initiator cohort study using the Truven MarketScan database. Patients with diabetes mellitus who newly initiated either an SGLT2 inhibitor or a dipeptidyl peptidase-4 (DPP4) inhibitor were included. Our primary outcome was hospitalization for DKA within 180 days of initiating an SGLT2. We matched new initiators of SGLT2 inhibitors with new initiators of DPP4 inhibitors using 1:1 propensity score (PS) matching. We used Cox proportional hazard models to examine the hazard ratio (HR) and 95% CI of DKA. Results: After PS-matching we identified 45,789 pairs of patients initiating SGLT2 inhibitors or DPP4 inhibitors with balanced baseline covariates. There were 58 DKA events (4.23 events per 1000 person-years) among initiators of an SGLT2 inhibitor compared to 29 DKA events (2.01 per 1000 person-years) among initiators of DPP4 inhibitors. The PS-adjusted risk of DKA within 180 days of initiating an SGLT2 inhibitor was 2.1 times greater than the risk for those initiating a DPP4 inhibitor (HR 2.1, 95% CI 1.3 to 3.3). The risk was highest within 60 days of initiating an SGLT2 inhibitor (PS matched HR 3.0, 95% CI 1.6 to 5.5). Conclusion: SGLT2 inhibitors were associated with an increased risk of DKA. Physicians should counsel their patients accordingly and closely monitor those with symptoms suggestive of DKA. 10 CANadian CAnagliflozin REgistry (CanCARE) – A Prospective, Observational, Assessment of Canagliflozin Treatment in Type 2 Diabetes Mellitus (T2DM); Six Month Results VINCENT WOO, HARPREET S. BAJAJ, ALAN BELL, MAUREEN CLEMENT, FERNANDO CAMACHO, NATASHA GEORGIJEV, JENNIFER B. ROSE Winnipeg, MB This real-world Canadian study is evaluating glycemic and safety outcomes over 12 months, for 527 T2DM patients, who were initiated on Canagliflozin (CANA) as part of their usual treatment approach. Of patients meeting enrollment criteria of A1c ≥7.0% and eGFR≥60 mL/min/1.73 m2, mean change in A1c at six months was −0.9 (95% CI: −1.03, −0.79) from baseline of 8.4%. 33% of patients reached A1c target of <7.0% and 41% achieved the composite endpoint of ≥0.5 A1c and ≥3% weight reduction at six months. Significant reductions in weight (−2.9 kg, CI: −3.39, −2.51; n=350), BMI (−1.0, CI: −1.19, −0.86; n=377) and waist circumference (−3.1 cm, CI: −4.08, −2.14; n=362) were observed. By six months, 84%, 52% and 29% of patients experienced >0%, ≥3% or ≥5% weight loss, respectively. Blood pressure reductions (diastolic −2.9, 95% CI: −3.78, −2.00; systolic −4.5, CI: −5.90, −3.14; n=378) were also observed. No significant changes were observed in electrolytes or lipids. 35% of patients reported≥1 Adverse Event (AE), 2.9% reported serious AEs and 15% reported an AE of special Interest: genital mycotic infections (10%), polyuria (3.7%), severe hypoglycemia (1.1%),