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ml Insulin Degludec Improves Glycemic Control Similar to Insulin Glargine with a Low Risk of Hypoglycemia in Insulin-naïve People with Type 2 Diabetes
Abstracts / Can J Diabetes 36 (2012) S24eS76
1.29]). Nocturnal hypoglycemia was significantly 25% lower for IDegFF vs IGlar (ERR: 0.75 [0.58; 0.97]; p¼0.0255), and severe hypoglycemia was 26% lower (ERR: 0.74 [0.38; 1.42]). Adverse event rates were low in both groups. Basal insulin doses did not differ; 0.40 (IDegFF) and 0.42 (IGlar) U/kg at 52 weeks. This study demonstrates that IDeg can be administered flexibly at any time of day with similar glycemic control and less nocturnal hypoglycemia than standard OD IGlar given at the same time each day over 52 weeks.
192 200 U/ml Insulin Degludec Improves Glycemic Control Similar to Insulin Glargine with a Low Risk of Hypoglycemia in Insulinnaïve People with Type 2 Diabetes RICHARD BERGENSTAL, ANUJ BHARGAVA, RAJEEV K. JAIN, STUART A. ROSS*, AZHAR RANA, HENRIETTE MERSEBACH, STEPHEN GOUGH Minneapolis, MN; Des Moines, IA; Milwaukee, WI; Calgary, AB; Søborg, Denmark; Oxford, UK Insulin degludec (IDeg) is a new basal insulin that has an ultralong and flat time-action profile with a half-life >42 hours. This 26week, open-label, treat-to-target trial compared the efficacy and safety of once-daily IDeg U200 with 100 U/ml of insulin glargine (IGlar). Insulin-naïve patients with type 2 diabetes (T2D) (n¼457; 57.5 years old, BMI 32.4 kg/m2, HbA1c 8.3%, and fasting plasma glucose (FPG) 9.6 mmol/L were randomized to IDeg U200 or IGlar, both given OD in combination with metformin DPP-4 inhibitor in prefilled pen devices. Basal insulin was titrated weekly to a FPG target of 4e5 mmol/L. At 26 weeks, IDeg U200 effectively reduced HbA1c by 1.30%- points and was non-inferior to IGlar (estimated treatment difference (ETD) IDeg-IGlar: 0.04%-points [95% CI: e0.11; 0.19]). FPG reductions were significantly greater with IDeg U200 than with IGlar (e3.7 vs. e3.4 mmol/L; ETD: e0.42 [e0.82; e0.06], p¼0.02). Rates of overall confirmed hypoglycemia (PG <3.1 mmol/L or requiring assistance) were numerically lower with IDeg U200 vs. IGlar (1.22 and 1.42 episodes/patient-year, respectively; estimated rate ratio (ERR) IDeg/IGlar: 0.86 [95% CI: 0.58; 1.28], p¼0.46). Rates of nocturnal confirmed hypoglycemia (00:01e05:59 hours) also were numerically lower with IDeg (0.18 vs. 0.28 episodes/patientyear, respectively; ERR: 0.64 [95% CI: 0.30; 1.37], p¼0.25). Mean daily basal insulin dose was similar after 26 weeks (IDeg U200, 0.62 U/kg; IGlar, 0.66 U/kg). In this trial in insulin-naïve patients with T2D, insulin degludec 200 U/ml improved glycemic control similar to IGlar with a low risk of hypoglycemia.
193 Selective Somatostatin Receptor Type 2 Antagonism Prevents Hypoglycaemia In Type 1 Diabetic BB Rats NEGAR KARIMIAN*, TAIRAN QIN, MAYOWA OSUNDIJI, YACHI HUANG, TAO LIANG, MICHAEL RIDDELL, DAVID H. COY, MLADEN VRANIC, HERBERT Y. GAISANO Toronto, ON; New Orleans, LA Impaired counterregulation during hypoglycemia in type 1 diabetes (T1D) is partly due to inadequate islet alpha-cell glucagon secretion; this is a limiting factor of intensive insulin treatment. Accentuation of the increased intra-islet somatostatin suppression of hypoglycemia-stimulated alpha-cell glucagon release during T1D has been suggested as one reason. We hypothesized that hypoglycemia can be prevented in autoimmune T1D by selective somatostatin receptor type 2 (SSTR2) antagonism of alpha cells to relieve SSTR2 inhibition, thereby increasing glucagon secretion. Diabetic biobreeding diabetes prone (BBDP) rats (D), that mimic human autoimmune T1D, Vs non-diabetic BBDP(N) rats, underwent 3-h infusion of vehicle or SSTR2 antagonist (SSTR2a) during insulininduced hypoglycaemia in vivo, clamped at 30.5mmol/l. D rats, treated with SSTR2a, needed 95% less glucose infusion than
S57
untreated D rats (p<0.05) to attain hypoglycaemia, implying that attenuated glucagon response to hypoglycemia in diabetic BB rats was restored by SSTR2a. To monitor real-time glucagon secretory response directly, we developed thin slices of pancreas in vitro, subjected to perifusion with vehicle vs SSTR2a, as well as simultaneous sequential condition changes of non-stimulatory 7mM glucose (G), followed by stimulatory 1mM G and 20mM arginine (7mM G). 30 uM SSTR2a treatment enhanced glucagon secretion in both N and D BBDP rat slices: 7mM G (by 1-2 fold), 1mM G (2-3 fold), and 20mM arginine (in 7mM G, by 2 fold) (p<0.001) compared to vehicle. Thus, somatostatin may contribute to impaired glucagon responsiveness to hypoglycemia in autoimmune T1D. We conclude that SSTR2 antagonism can enhance hypoglycemia-stimulated glucagon release sufficient for normoglycemic control.
194 Reduced Risk of Hypoglycemia with Insulin Degludec vs Insulin Glargine in Patients with Type 2 Diabetes Requiring High Doses of Basal Insulin: Meta-Analysis of Five Randomized Trials HELENA W. RODBARD, YEHUDA HANDELSMAN, STEPHEN GOUGH, JINA HAHN*, NATHAN LASSOTA, WENDY LANE Rockville, MD; Tarzana, CA; Oxford, UK; Søborg, Denmark; Asheville, NC Insulin Degludec (IDeg) is a new basal insulin that has an ultra-long and flat time-action profile. This study compared IDeg with insulin glargine (IGlar) in patients with type 2 diabetes (T2DM) requiring >60 U/day of basal insulin. This meta-analysis investigated HbA1c, fasting plasma glucose (FPG), and rates of overall confirmed (PG<3.1 mmol/L or requiring assistance) and nocturnal (00:0105:59 hours) confirmed hypoglycemia in a pooled population of T2DM patients receiving >60 U of basal insulin at trial completion. Five phase-3a, open-label, randomized, treat-to-target trials with IDeg (n¼2,262) vs. IGlar (n¼1,110) administered once daily by subjects with T2DM were included. Statistical analysis used ANCOVA (HbA1c and FPG) and negative binomial regression (rates of hypoglycemia). At end-oftrial, a similar percentage of IDeg- and IGlar-treated T2DM subjects required >60 U of basal insulin daily [IDeg, 35.1% (795/2262); IGlar, 33.7% (374/1110)]. Similar glycemic control was obtained for IDeg vs IGlar (HbA1c: 0.05%, NS). End-of-trial FPG values were lower with IDeg than IGlar: 0.33 mmol (p¼0.04).There was a 21% lower rate of overall confirmed hypoglycemic episodes for IDeg (rate ratio (RR) IDeg/IGlar: 0.79, p¼0.02) and a 52% lower rate of nocturnal confirmed hypoglycemic episodes for IDeg (RR: 0.48, p<0.0001). In patients with T2DM requiring >60 U/day of basal insulin, at similar levels of HbA1c, IDeg achieves significantly lower rates of hypoglycemia compared with IGlar. These findings are consistent with results for the overall trial population, confirming that IDeg is a safe and effective basal insulin choice for T2DM patients across the spectrum of insulin requirements.
195 Withdrawn
196 Insulin Degludec Improves Glycemic Control with Lower Nocturnal Hypoglycemia Risk than Insulin Glargine: A 2-year Randomized Trial in Type 1 Diabetes BRUCE W. BODE*, SIMON HELLER, CHARLOTTE T. HANSEN, AZHAR RANA, DAVID L. RUSSELL-JONES Atlanta, GA; Sheffield, UK; Søborg, Denmark; Guildford, UK This 2-yr, open-label study compared efficacy and safety of insulin degludec (IDeg), a new, ultra-long-acting basal insulin, and insulin glargine (IGlar), in basalebolus (BB) therapy in type 1 diabetes (T1DM).
1.29]). Nocturnal hypoglycemia was significantly 25% lower for IDegFF vs IGlar (ERR: 0.75 [0.58; 0.97]; p¼0.0255), and severe hypoglycemia was 26% lower (ERR: 0.74 [0.38; 1.42]). Adverse event rates were low in both groups. Basal insulin doses did not differ; 0.40 (IDegFF) and 0.42 (IGlar) U/kg at 52 weeks. This study demonstrates that IDeg can be administered flexibly at any time of day with similar glycemic control and less nocturnal hypoglycemia than standard OD IGlar given at the same time each day over 52 weeks.
192 200 U/ml Insulin Degludec Improves Glycemic Control Similar to Insulin Glargine with a Low Risk of Hypoglycemia in Insulinnaïve People with Type 2 Diabetes RICHARD BERGENSTAL, ANUJ BHARGAVA, RAJEEV K. JAIN, STUART A. ROSS*, AZHAR RANA, HENRIETTE MERSEBACH, STEPHEN GOUGH Minneapolis, MN; Des Moines, IA; Milwaukee, WI; Calgary, AB; Søborg, Denmark; Oxford, UK Insulin degludec (IDeg) is a new basal insulin that has an ultralong and flat time-action profile with a half-life >42 hours. This 26week, open-label, treat-to-target trial compared the efficacy and safety of once-daily IDeg U200 with 100 U/ml of insulin glargine (IGlar). Insulin-naïve patients with type 2 diabetes (T2D) (n¼457; 57.5 years old, BMI 32.4 kg/m2, HbA1c 8.3%, and fasting plasma glucose (FPG) 9.6 mmol/L were randomized to IDeg U200 or IGlar, both given OD in combination with metformin DPP-4 inhibitor in prefilled pen devices. Basal insulin was titrated weekly to a FPG target of 4e5 mmol/L. At 26 weeks, IDeg U200 effectively reduced HbA1c by 1.30%- points and was non-inferior to IGlar (estimated treatment difference (ETD) IDeg-IGlar: 0.04%-points [95% CI: e0.11; 0.19]). FPG reductions were significantly greater with IDeg U200 than with IGlar (e3.7 vs. e3.4 mmol/L; ETD: e0.42 [e0.82; e0.06], p¼0.02). Rates of overall confirmed hypoglycemia (PG <3.1 mmol/L or requiring assistance) were numerically lower with IDeg U200 vs. IGlar (1.22 and 1.42 episodes/patient-year, respectively; estimated rate ratio (ERR) IDeg/IGlar: 0.86 [95% CI: 0.58; 1.28], p¼0.46). Rates of nocturnal confirmed hypoglycemia (00:01e05:59 hours) also were numerically lower with IDeg (0.18 vs. 0.28 episodes/patientyear, respectively; ERR: 0.64 [95% CI: 0.30; 1.37], p¼0.25). Mean daily basal insulin dose was similar after 26 weeks (IDeg U200, 0.62 U/kg; IGlar, 0.66 U/kg). In this trial in insulin-naïve patients with T2D, insulin degludec 200 U/ml improved glycemic control similar to IGlar with a low risk of hypoglycemia.
193 Selective Somatostatin Receptor Type 2 Antagonism Prevents Hypoglycaemia In Type 1 Diabetic BB Rats NEGAR KARIMIAN*, TAIRAN QIN, MAYOWA OSUNDIJI, YACHI HUANG, TAO LIANG, MICHAEL RIDDELL, DAVID H. COY, MLADEN VRANIC, HERBERT Y. GAISANO Toronto, ON; New Orleans, LA Impaired counterregulation during hypoglycemia in type 1 diabetes (T1D) is partly due to inadequate islet alpha-cell glucagon secretion; this is a limiting factor of intensive insulin treatment. Accentuation of the increased intra-islet somatostatin suppression of hypoglycemia-stimulated alpha-cell glucagon release during T1D has been suggested as one reason. We hypothesized that hypoglycemia can be prevented in autoimmune T1D by selective somatostatin receptor type 2 (SSTR2) antagonism of alpha cells to relieve SSTR2 inhibition, thereby increasing glucagon secretion. Diabetic biobreeding diabetes prone (BBDP) rats (D), that mimic human autoimmune T1D, Vs non-diabetic BBDP(N) rats, underwent 3-h infusion of vehicle or SSTR2 antagonist (SSTR2a) during insulininduced hypoglycaemia in vivo, clamped at 30.5mmol/l. D rats, treated with SSTR2a, needed 95% less glucose infusion than
S57
untreated D rats (p<0.05) to attain hypoglycaemia, implying that attenuated glucagon response to hypoglycemia in diabetic BB rats was restored by SSTR2a. To monitor real-time glucagon secretory response directly, we developed thin slices of pancreas in vitro, subjected to perifusion with vehicle vs SSTR2a, as well as simultaneous sequential condition changes of non-stimulatory 7mM glucose (G), followed by stimulatory 1mM G and 20mM arginine (7mM G). 30 uM SSTR2a treatment enhanced glucagon secretion in both N and D BBDP rat slices: 7mM G (by 1-2 fold), 1mM G (2-3 fold), and 20mM arginine (in 7mM G, by 2 fold) (p<0.001) compared to vehicle. Thus, somatostatin may contribute to impaired glucagon responsiveness to hypoglycemia in autoimmune T1D. We conclude that SSTR2 antagonism can enhance hypoglycemia-stimulated glucagon release sufficient for normoglycemic control.
194 Reduced Risk of Hypoglycemia with Insulin Degludec vs Insulin Glargine in Patients with Type 2 Diabetes Requiring High Doses of Basal Insulin: Meta-Analysis of Five Randomized Trials HELENA W. RODBARD, YEHUDA HANDELSMAN, STEPHEN GOUGH, JINA HAHN*, NATHAN LASSOTA, WENDY LANE Rockville, MD; Tarzana, CA; Oxford, UK; Søborg, Denmark; Asheville, NC Insulin Degludec (IDeg) is a new basal insulin that has an ultra-long and flat time-action profile. This study compared IDeg with insulin glargine (IGlar) in patients with type 2 diabetes (T2DM) requiring >60 U/day of basal insulin. This meta-analysis investigated HbA1c, fasting plasma glucose (FPG), and rates of overall confirmed (PG<3.1 mmol/L or requiring assistance) and nocturnal (00:0105:59 hours) confirmed hypoglycemia in a pooled population of T2DM patients receiving >60 U of basal insulin at trial completion. Five phase-3a, open-label, randomized, treat-to-target trials with IDeg (n¼2,262) vs. IGlar (n¼1,110) administered once daily by subjects with T2DM were included. Statistical analysis used ANCOVA (HbA1c and FPG) and negative binomial regression (rates of hypoglycemia). At end-oftrial, a similar percentage of IDeg- and IGlar-treated T2DM subjects required >60 U of basal insulin daily [IDeg, 35.1% (795/2262); IGlar, 33.7% (374/1110)]. Similar glycemic control was obtained for IDeg vs IGlar (HbA1c: 0.05%, NS). End-of-trial FPG values were lower with IDeg than IGlar: 0.33 mmol (p¼0.04).There was a 21% lower rate of overall confirmed hypoglycemic episodes for IDeg (rate ratio (RR) IDeg/IGlar: 0.79, p¼0.02) and a 52% lower rate of nocturnal confirmed hypoglycemic episodes for IDeg (RR: 0.48, p<0.0001). In patients with T2DM requiring >60 U/day of basal insulin, at similar levels of HbA1c, IDeg achieves significantly lower rates of hypoglycemia compared with IGlar. These findings are consistent with results for the overall trial population, confirming that IDeg is a safe and effective basal insulin choice for T2DM patients across the spectrum of insulin requirements.
195 Withdrawn
196 Insulin Degludec Improves Glycemic Control with Lower Nocturnal Hypoglycemia Risk than Insulin Glargine: A 2-year Randomized Trial in Type 1 Diabetes BRUCE W. BODE*, SIMON HELLER, CHARLOTTE T. HANSEN, AZHAR RANA, DAVID L. RUSSELL-JONES Atlanta, GA; Sheffield, UK; Søborg, Denmark; Guildford, UK This 2-yr, open-label study compared efficacy and safety of insulin degludec (IDeg), a new, ultra-long-acting basal insulin, and insulin glargine (IGlar), in basalebolus (BB) therapy in type 1 diabetes (T1DM).