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Insulin Degludec Improves Glycemic Control with Lower Nocturnal Hypoglycemia Risk than Insulin Glargine: A 2-year Randomized Trial in Type 1 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).
S58
Abstracts / Can J Diabetes 36 (2012) S24eS76
The study comprised a 1-yr main period followed by 1-yr extension; subjects maintained prior randomization. Subjects were randomized 3:1 to IDeg or IGlar given subcutaneously once daily with mealtime insulin aspart. Basal insulin was titrated to target pre-breakfast plasma glucose (PG) (>3.9e<5.0mmol/L). Data at end of 2yrs of treatment (EOT) are presented. Of 629 subjects (baseline: mean age 43yrs; diabetes duration 18.9yrs; HbA1c 7.7%; fasting PG 9.3mmol/L), 443 (IDeg: 330; IGlar: 113) completed 2yrs’ treatment. EOT HbA1c reduction was similar: e0.27% (IDeg) vs. e0.24% (IGlar); estimated treatment difference (ETD) IDegeIGlar: 0.04% [95%CI 0.17;0.09], p¼NS. Similar proportions of subjects achieved HbA1c<7% (IDeg: 34%; IGlar: 31%; p¼NS). Rates of overall hypoglycemia (PG<3.1mmol/L or severe) were similar for entire period (37.5[IDeg] vs. 37.4[IGlar] episodes/ pt-yr; estimated rate ratio [ERR] IDeg/IGlar: 1.02 [0.85;1.24]; p¼NS) and maintenance period (16wk to EOT, when mean dose and glycemia stabilized; 34.0 vs. 35.0 episodes/pt-yr; ERR: 0.98 [0.80;1.20]; p¼NS). Nocturnal hypoglycemia was significantly lower with IDeg (3.9 vs. 5.3 episodes/pt-yr; ERR: 0.75 [0.59;0.95]; p¼0.02). Therefore, treating one patient for w9 months with IDeg will avoid one nocturnal hypoglycemic episode. In conclusion, IDeg safely and effectively improves glycemic control with a lower risk of nocturnal hypoglycemia than IGlar when part of 2-yr BB therapy in T1DM. This furthermore provides evidence for the long-term safety of IDeg in T1DM.
197 The Effect of Insulin Degludec on Glycemic Control and Nocturnal Hypoglycemia Compared with Insulin Glargine: a 1-year Randomized Trial in Insulin-naïve People with Type 2 Diabetes BERNARD ZINMAN*, ATHENA PHILIS-TSIMIKAS, YEHUDA HANDELSMAN, HELENA W. RODBARD, BERTRAND CARIOU, THUE JOHANSEN, AZHAR RANA, CHANTAL MATHIEU Toronto, ON; La Jolla, CA; Tarzana, CA; Rockville, MD; Soeborg, Denmark; Leuven, Belgium Insulin degludec (IDeg) is a novel basal insulin with an ultra-long, flat action profile. This 52-wk randomized, open-label, non-inferiority, treat-to-target trial compared efficacy and safety of IDeg to insulin glargine (IGlar) given once daily in insulin-naïve type 2 diabetes subjects inadequately controlled with OADs (metformin±DPP-4 inhibitor). 1030 adults (mean age 59.1 yrs; diabetes duration 9.2 yrs; HbA1c 8.2%; fasting plasma glucose (FPG) 9.7 mmol/L) were randomized 3:1 to IDeg or IGlar. Both basal insulins were titrated to blood glucose targets of 3.9-4.9 mmol/L. Completion rates were 79% (IDeg) and 77% (IGlar). IDeg reduced HbA1c (-1.06%) non-inferior to IGlar (-1.19%) (estimated treatment difference (ETD) IDeg-IGlar: 0.09% [95%CI: -0.04; 0.22]). FPG reductions were significantly larger with IDeg than IGlar (-3.76 vs -3.30 mmol/ L; ETD: -0.43 mmol/L [95%CI: -0.74; -0.13]; p=0.005). Overall confirmed hypoglycemia (PG <3.1 mmol/L and severe requiring assistance) rates were similar for IDeg and IGlar (1.52 vs 1.85 episodes/patient-yr; estimated rate ratio (ERR) IDeg:IGlar: 0.82 [95%CI: 0.64; 1.04]; p=0.11). Nocturnal confirmed hypoglycemia rates were significantly 36% lower with IDeg (0.25 vs 0.39 episodes/ patient-yr; ERR: 0.64 [95%CI: 0.42; 0.98]; p=0.04). Overall severe hypoglycemia was significantly lower with IDeg (0.003 vs 0.023 episodes/patient-yr; ERR: 0.14 [95%CI: 0.03; 0.70]; p=0.02). End-oftrial mean daily insulin doses were 0.59 (IDeg) and 0.60 (IGlar) U/ kg. Mean weight gain was similar: 2.4 kg (IDeg); 2.1 kg (IGlar). Adverse event rates were low and similar between groups. In this treat-to-target trial, IDeg and IGlar provided similar long-term glycemic control, with significantly lower rates of nocturnal hypoglycemia with IDeg.
198 Lower Rates in Overall and Nocturnal Hypoglycemia of Insulin Degludec vs. Insulin Glargine with Treatment Intensification in T2DM in Moderately Good Control (A1c 7.5e8.5%) at Baseline: A Meta-Analysis ALAN J. GARBER, STEPHEN COLAGIURI, HELENA W. RODBARD, VICTOR MILOSEVSKI*, NATHAN LASSOTA, STEPHEN GOUGH Houston, TX; Sydney, Australia; Rockville, MD; Mississauga, ON; Søborg, Denmark; Oxford, UK Current basal insulins increase the risk of hypoglycemia when A1c levels approach normoglycemia. Insulin degludec (IDeg) is a new basal insulin that forms soluble multi-hexamers upon injection, resulting in an ultra-long action profile. We analyzed whether IDeg would improve glycemic control and result in less hypoglycemia compared to insulin glargine (IGlar) in T2DM patients in moderately good control at baseline(A1c 7.5e8.5%). Changes in A1c and fasting plasma glucose (FPG) were analyzed with linear models, and rates of hypoglycemia with a negative binomial regression model. Hypoglycemia was defined as self-reported confirmed hypoglycemia (PG <56 mg/dL) or severe episodes requiring assistance; nocturnal confirmed hypoglycemia if onset between 00:01 and 05:59. Analysis included patient level data from all 5 open-labeled randomized treat-to-target phase 3a trials in T2DM in which IDeg (n¼930) or IGlar (n¼446) were given once daily. A1c decreased from 8.0% at baseline in both groups to 7.0 vs. 6.9% at end of trial for IDeg vs. IGlar, respectively (treatment difference: 0.08; p¼0.08). Observed FPG decreased from 9.0 to 6.1 mmol/L for IDeg and from 8.9 to 6.3 mmol/L for IGlar, achieving a significant difference of e0.36 mmol/L; p<0.01. The rate ratio (IDeg/IGlar) of hypoglycemia (0.80; p¼0.02) and nocturnal hypoglycemia (0.69; p¼0.01) were both statistically significantly lower for IDeg vs. IGlar. In conclusion, T2DM patients with baseline A1c of 7.5e8.5% treated with IDeg showed comparable improvement in A1c, significantly greater reduction in FPG, and significantly lower reductions (by 20%, 31%) in rates of overall and nocturnal hypoglycemia compared to IGlar.
199 Insulin Degludec Results in Consistently Lower Rates of Nocturnal Hypoglycemia Despite Lower FPG Levels Compared to Insulin Glargine in Seven Trials with T1DM or T2DM DAVID L. RUSSELL-JONES*, STEFANO DEL PRATO, MARI-ANNE GALL, NATHAN LASSOTA, MICHAELA DIAMANT Guildford, UK; Pisa, Italy; Soeborg, Denmark; Amsterdam, Netherlands Basal insulin analogs have a reduced risk of hypoglycemia compared to neutral protamine Hagedorn insulin but hypoglycemia remains a major impediment to achieving recommended fasting plasma glucose (FPG) targets. Insulin degludec (IDeg), a new basal insulin that forms soluble multi-hexamers after subcutaneous injection, has an ultra-long and stable glucose-lowering effect, with low day-to-day variability. These properties may lead to less nocturnal hypoglycemia. We investigated the relationship between FPG and nocturnal confirmed hypoglycemia from all phase 3a, randomized, treat-totarget (FPG <5 mmol/L; <90 mg/dL) clinical trials in which oncedaily IDeg and insulin glargine (IGlar) were compared. Trials (type 1 diabetes [T1DM]: 2 trials [n¼957]; type 2 diabetes [T2DM]: 5 trials [n¼3360]) were open labeled and 26 or 52 weeks in length. Confirmed hypoglycemia was defined as plasma glucose (PG) <3.1 mmol/L (56 mg/dL) or severe episodes requiring assistance, and nocturnal hypoglycemia occurring between 00:01 and 05:59. For all trials (7 out of 7), mean end-of-trial FPG levels were consistently lower for IDeg than IGlar, reaching statistical significance in 3 trials (Table). Similarly, IDeg was associated with a 23e40% lower rate of nocturnal confirmed hypoglycemia relative to IGlar, which was statistically significant in 4 out of 7 trials, regardless of type of
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).
S58
Abstracts / Can J Diabetes 36 (2012) S24eS76
The study comprised a 1-yr main period followed by 1-yr extension; subjects maintained prior randomization. Subjects were randomized 3:1 to IDeg or IGlar given subcutaneously once daily with mealtime insulin aspart. Basal insulin was titrated to target pre-breakfast plasma glucose (PG) (>3.9e<5.0mmol/L). Data at end of 2yrs of treatment (EOT) are presented. Of 629 subjects (baseline: mean age 43yrs; diabetes duration 18.9yrs; HbA1c 7.7%; fasting PG 9.3mmol/L), 443 (IDeg: 330; IGlar: 113) completed 2yrs’ treatment. EOT HbA1c reduction was similar: e0.27% (IDeg) vs. e0.24% (IGlar); estimated treatment difference (ETD) IDegeIGlar: 0.04% [95%CI 0.17;0.09], p¼NS. Similar proportions of subjects achieved HbA1c<7% (IDeg: 34%; IGlar: 31%; p¼NS). Rates of overall hypoglycemia (PG<3.1mmol/L or severe) were similar for entire period (37.5[IDeg] vs. 37.4[IGlar] episodes/ pt-yr; estimated rate ratio [ERR] IDeg/IGlar: 1.02 [0.85;1.24]; p¼NS) and maintenance period (16wk to EOT, when mean dose and glycemia stabilized; 34.0 vs. 35.0 episodes/pt-yr; ERR: 0.98 [0.80;1.20]; p¼NS). Nocturnal hypoglycemia was significantly lower with IDeg (3.9 vs. 5.3 episodes/pt-yr; ERR: 0.75 [0.59;0.95]; p¼0.02). Therefore, treating one patient for w9 months with IDeg will avoid one nocturnal hypoglycemic episode. In conclusion, IDeg safely and effectively improves glycemic control with a lower risk of nocturnal hypoglycemia than IGlar when part of 2-yr BB therapy in T1DM. This furthermore provides evidence for the long-term safety of IDeg in T1DM.
197 The Effect of Insulin Degludec on Glycemic Control and Nocturnal Hypoglycemia Compared with Insulin Glargine: a 1-year Randomized Trial in Insulin-naïve People with Type 2 Diabetes BERNARD ZINMAN*, ATHENA PHILIS-TSIMIKAS, YEHUDA HANDELSMAN, HELENA W. RODBARD, BERTRAND CARIOU, THUE JOHANSEN, AZHAR RANA, CHANTAL MATHIEU Toronto, ON; La Jolla, CA; Tarzana, CA; Rockville, MD; Soeborg, Denmark; Leuven, Belgium Insulin degludec (IDeg) is a novel basal insulin with an ultra-long, flat action profile. This 52-wk randomized, open-label, non-inferiority, treat-to-target trial compared efficacy and safety of IDeg to insulin glargine (IGlar) given once daily in insulin-naïve type 2 diabetes subjects inadequately controlled with OADs (metformin±DPP-4 inhibitor). 1030 adults (mean age 59.1 yrs; diabetes duration 9.2 yrs; HbA1c 8.2%; fasting plasma glucose (FPG) 9.7 mmol/L) were randomized 3:1 to IDeg or IGlar. Both basal insulins were titrated to blood glucose targets of 3.9-4.9 mmol/L. Completion rates were 79% (IDeg) and 77% (IGlar). IDeg reduced HbA1c (-1.06%) non-inferior to IGlar (-1.19%) (estimated treatment difference (ETD) IDeg-IGlar: 0.09% [95%CI: -0.04; 0.22]). FPG reductions were significantly larger with IDeg than IGlar (-3.76 vs -3.30 mmol/ L; ETD: -0.43 mmol/L [95%CI: -0.74; -0.13]; p=0.005). Overall confirmed hypoglycemia (PG <3.1 mmol/L and severe requiring assistance) rates were similar for IDeg and IGlar (1.52 vs 1.85 episodes/patient-yr; estimated rate ratio (ERR) IDeg:IGlar: 0.82 [95%CI: 0.64; 1.04]; p=0.11). Nocturnal confirmed hypoglycemia rates were significantly 36% lower with IDeg (0.25 vs 0.39 episodes/ patient-yr; ERR: 0.64 [95%CI: 0.42; 0.98]; p=0.04). Overall severe hypoglycemia was significantly lower with IDeg (0.003 vs 0.023 episodes/patient-yr; ERR: 0.14 [95%CI: 0.03; 0.70]; p=0.02). End-oftrial mean daily insulin doses were 0.59 (IDeg) and 0.60 (IGlar) U/ kg. Mean weight gain was similar: 2.4 kg (IDeg); 2.1 kg (IGlar). Adverse event rates were low and similar between groups. In this treat-to-target trial, IDeg and IGlar provided similar long-term glycemic control, with significantly lower rates of nocturnal hypoglycemia with IDeg.
198 Lower Rates in Overall and Nocturnal Hypoglycemia of Insulin Degludec vs. Insulin Glargine with Treatment Intensification in T2DM in Moderately Good Control (A1c 7.5e8.5%) at Baseline: A Meta-Analysis ALAN J. GARBER, STEPHEN COLAGIURI, HELENA W. RODBARD, VICTOR MILOSEVSKI*, NATHAN LASSOTA, STEPHEN GOUGH Houston, TX; Sydney, Australia; Rockville, MD; Mississauga, ON; Søborg, Denmark; Oxford, UK Current basal insulins increase the risk of hypoglycemia when A1c levels approach normoglycemia. Insulin degludec (IDeg) is a new basal insulin that forms soluble multi-hexamers upon injection, resulting in an ultra-long action profile. We analyzed whether IDeg would improve glycemic control and result in less hypoglycemia compared to insulin glargine (IGlar) in T2DM patients in moderately good control at baseline(A1c 7.5e8.5%). Changes in A1c and fasting plasma glucose (FPG) were analyzed with linear models, and rates of hypoglycemia with a negative binomial regression model. Hypoglycemia was defined as self-reported confirmed hypoglycemia (PG <56 mg/dL) or severe episodes requiring assistance; nocturnal confirmed hypoglycemia if onset between 00:01 and 05:59. Analysis included patient level data from all 5 open-labeled randomized treat-to-target phase 3a trials in T2DM in which IDeg (n¼930) or IGlar (n¼446) were given once daily. A1c decreased from 8.0% at baseline in both groups to 7.0 vs. 6.9% at end of trial for IDeg vs. IGlar, respectively (treatment difference: 0.08; p¼0.08). Observed FPG decreased from 9.0 to 6.1 mmol/L for IDeg and from 8.9 to 6.3 mmol/L for IGlar, achieving a significant difference of e0.36 mmol/L; p<0.01. The rate ratio (IDeg/IGlar) of hypoglycemia (0.80; p¼0.02) and nocturnal hypoglycemia (0.69; p¼0.01) were both statistically significantly lower for IDeg vs. IGlar. In conclusion, T2DM patients with baseline A1c of 7.5e8.5% treated with IDeg showed comparable improvement in A1c, significantly greater reduction in FPG, and significantly lower reductions (by 20%, 31%) in rates of overall and nocturnal hypoglycemia compared to IGlar.
199 Insulin Degludec Results in Consistently Lower Rates of Nocturnal Hypoglycemia Despite Lower FPG Levels Compared to Insulin Glargine in Seven Trials with T1DM or T2DM DAVID L. RUSSELL-JONES*, STEFANO DEL PRATO, MARI-ANNE GALL, NATHAN LASSOTA, MICHAELA DIAMANT Guildford, UK; Pisa, Italy; Soeborg, Denmark; Amsterdam, Netherlands Basal insulin analogs have a reduced risk of hypoglycemia compared to neutral protamine Hagedorn insulin but hypoglycemia remains a major impediment to achieving recommended fasting plasma glucose (FPG) targets. Insulin degludec (IDeg), a new basal insulin that forms soluble multi-hexamers after subcutaneous injection, has an ultra-long and stable glucose-lowering effect, with low day-to-day variability. These properties may lead to less nocturnal hypoglycemia. We investigated the relationship between FPG and nocturnal confirmed hypoglycemia from all phase 3a, randomized, treat-totarget (FPG <5 mmol/L; <90 mg/dL) clinical trials in which oncedaily IDeg and insulin glargine (IGlar) were compared. Trials (type 1 diabetes [T1DM]: 2 trials [n¼957]; type 2 diabetes [T2DM]: 5 trials [n¼3360]) were open labeled and 26 or 52 weeks in length. Confirmed hypoglycemia was defined as plasma glucose (PG) <3.1 mmol/L (56 mg/dL) or severe episodes requiring assistance, and nocturnal hypoglycemia occurring between 00:01 and 05:59. For all trials (7 out of 7), mean end-of-trial FPG levels were consistently lower for IDeg than IGlar, reaching statistical significance in 3 trials (Table). Similarly, IDeg was associated with a 23e40% lower rate of nocturnal confirmed hypoglycemia relative to IGlar, which was statistically significant in 4 out of 7 trials, regardless of type of