Tuning a multi-model predictive control AHCL algorithm to the PK/PD properties of URLi may result in improved performance vs Lispro with no increased safety concerns.
This was a randomized, ...double-blind, inpatient, 2-period crossover study in 22 adults with T1D on insulin pumps. Each URLi and Lispro treatment period had a 4-day inpatient visit with insulin doses calculated using the tuned AHCL algorithm. To challenge the algorithm, tests included unannounced exercise, 1 hr delayed bolus, underbolus, and overbolus.
Participants (59% male) had mean ±SD age 43.4±13.77 years, T1D duration 25.9±9.61 yrs, and HbA1c 7.6±0.47%. Mean time in range (TIR; 70-180 mg/dL) during the overall inpatient period: URLi 79.4%; Lispro 78.7 % (p=0.80) with a trend towards decreased time <70 mg/dl (1.5 vs 2.4, p=0.08) for URLi. URLi had a significant difference in Level 1 hypoglycemia (30 vs 55 events, p = 0.01) but not Level 2 (4 vs 9 events, p=0.3). TIRs were similar including during meal/challenge periods (Table) with a trend towards greater TIR during the postprandial period and reduced time <70 mg/dl during exercise for URLi. There was greater TIR during overbolus with Lispro. No severe hypoglycemia events occurred.
Results suggest reduced hypoglycemia with URLi vs Lispro with comparable glycemic control. The AHCL algorithm showed promising glycemic performance in a supervised setting when used with URLi or Lispro.
Disclosure
R. Pollom: None. E. Dassau: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. M. Katz: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. L. Nosek: None. H. Coester: None. E. Zijlstra: Other Relationship; Eli Lilly and Company, Speaker's Bureau; Gan & Lee Pharmaceuticals, Novo Nordisk A/S. A. Ghosh: None. A. Haidar: Consultant; Eli Lilly and Company, Other Relationship; Bigfoot Biomedical, Inc., Research Support; Adocia, Dexcom, Inc., Tandem Diabetes Care, Inc. R. Jones: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. J. Leohr: None. S. E. Gleissner: None.
Aims
To evaluate the efficacy and safety of ultra‐rapid lispro (URLi) versus lispro in a paediatric population with type 1 diabetes (T1D) in a Phase 3, treat‐to‐target study.
Materials and Methods
...After a 4‐week lead‐in to optimize basal insulin, participants were randomized to double‐blind URLi (n = 280) or lispro (n = 298) injected 0 to 2 minutes prior to meals (mealtime), or open‐label URLi (n = 138) injected up to 20 minutes after start of meals (postmeal). Participants remained on pre‐study basal insulin (degludec, detemir or glargine). The primary endpoint was glycated haemoglobin (HbA1c) change from baseline after 26 weeks (noninferiority margin 4.4 mmol/mol 0.4%).
Results
Both mealtime and postmeal URLi demonstrated noninferiority to lispro for HbA1c: estimated treatment difference (ETD) for mealtime URLi −0.23 mmol/mol (95% confidence interval CI −1.84, 1.39) and postmeal URLi −0.17 mmol/mol (95% CI −2.15, 1.81). Mealtime URLi reduced 1‐hour postprandial glucose (PPG) daily mean (P = 0.001) and premeal to 1 hour postmeal PPG excursion daily mean (P < 0.001) versus lispro. The rate and incidence of severe, nocturnal or documented hypoglycaemia (<3.0 mmol/L 54 mg/dL) were similar for all treatments. With mealtime URLi versus lispro, the rate of postdose hypoglycaemia (<3.0 mmol/L) was higher at ≤2 hours (P = 0.034). The incidence of treatment‐emergent adverse events was similar for all treatments. More participants reported an injection site reaction with mealtime URLi (7.9%) versus postmeal URLi (2.9%) and lispro (2.7%).
Conclusions
In children and adolescents with T1D, URLi demonstrated good glycaemic control, and noninferiority to lispro in HbA1c change for mealtime and postmeal URLi. When dosed at the beginning of meals, URLi reduced 1‐hour PPG and PPG excursions versus lispro.
This phase 3, treat-to-target study evaluated efficacy and safety of URLi vs. lispro in 716 pediatric patients (pts) with type 1 diabetes (T1D) . After 4-week lead-in to optimize basal insulin, pts ...were randomized to double-blind URLi (n=280) or lispro (n=298) injected 0-2 min prior to meals, or open-label URLi (n=138) injected up to 20 min after meals (URLi+20) . Pts remained on prestudy basal insulin (degludec, detemir, or glargine) . Primary endpoint was HbA1c change from baseline after 26 weeks.
Noninferiority was shown in HbA1c change with URLi vs. lispro: estimated treatment difference (ETD) -0.02% (95% CI -0.17, 0.13) and with URLi+20 vs. lispro: ETD -0.02% (95% CI -0.20, 0.17) . Postprandial glucose (PPG) measured by self-monitored blood glucose (SMBG) was lower with URLi vs. lispro 1 h after breakfast (p<0.001) and dinner (p=0.006) . URLi significantly reduced 1 h postmeal glucose daily mean vs. lispro (p=0.001) . Total daily insulin dose was similar between treatments.
There were no significant differences among treatments in rate or incidence of severe, nocturnal or documented hypoglycemia (<54 mg/dL) . With URLi vs. lispro, rate of postdose hypoglycemia (<54 mg/dL) was higher at ≤2 h (p=0.034) . Incidence of treatment-emergent adverse events was similar between groups. More pts reported an injection site reaction related event with URLi (7.9%) and URLi+20 (2.9%) vs. lispro (2.7%) . All injection site reactions were mild or moderate in severity. Two URLi patients discontinued the study due to injection site reactions.
In children and adolescents with T1D, URLi demonstrated similar overall glycemic control and greater PPG lowering with an acceptable safety and tolerability profile compared with lispro. URLi dosed at the start of meals or up to 20 min after the start of meals showed noninferiority for HbA1c change from baseline vs. lispro. URLi dosed at the beginning of meals showed lower PPG at 1 h after breakfast and dinner and lower 1 h postmeal glucose daily mean vs. lispro.
Disclosure
R. Wadwa: Advisory Panel; Dompé. Consultant; Beta Bionics, Inc. Research Support; Dexcom, Inc., Eli Lilly and Company, Tandem Diabetes Care, Inc. Other Relationship; Tandem Diabetes Care, Inc. L.M. Laffel: Advisory Panel; Medtronic, Roche Diabetes Care. Consultant; Boehringer Ingelheim International GmbH, Dexcom, Inc., Dompé, Insulet Corporation, Janssen Pharmaceuticals, Inc., Lilly Diabetes, Novo Nordisk, Provention Bio, Inc. D.R. Franco: Advisory Panel; Abbott Diabetes, Medtronic, Novo Nordisk, Sanofi. Research Support; Eli Lilly and Company. Speaker's Bureau; Abbott Diabetes, AstraZeneca, Medtronic, Roche Diabetes Care, Sanofi. M.A. Dellva: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. R.K. Pollom: Employee; Eli Lilly and Company.
Funding
Eli Lilly and Company
URLi is a novel insulin lispro formulation that was developed to more closely match physiological insulin secretion. This 2-site, randomized, 2-period crossover, double-blind study evaluated the ...pharmacokinetics and glucodynamics during a liquid test meal, after a single 0.2 U/kg SC dose of URLi or Humalog in 13 children, 14 adolescents, 15 adults with T1D. Onset of insulin appearance was faster with URLi vs. Humalog in children (1.1 vs. 6.5 min; p=0.0002), adolescents (1.9 vs. 6.4 min; p=0.001), and adults (0.9 vs. 4.8 min; p=0.004). Early exposure (AUC0-15min) was greater with URLi vs. Humalog: 7-fold (p<0.0001) in children, 4 fold (p=0.0003) in adolescents, 5-fold (p<0.0001) in adults; late exposure (AUC3-7h) was reduced by 58% (p<0.0001) in children, 40% (p=0.013) in adolescents, 37% (p=0.021) in adults. Total exposure was similar in URLi and Humalog. At 1h, URLi reduced PPG by 42 mg/dL (p=0.008) in children, 19 mg/dL (p=0.195) in adolescents, 34 mg/dL (p=0.018) in adults, vs. Humalog. At 2h, URLi reduced the PPG by 32 mg/dL (p=0.11) in children, 39 mg/dL (p=0.051) in adolescents and was not statistically different in adults, vs. Humalog. URLi was well tolerated in all age groups.
In summary, URLi accelerated insulin lispro absorption, reduced late exposure and early PPG following a test meal vs. Humalog in children, adolescents, and adults with T1D.
Disclosure
R. Aronson: None. H. Linnebjerg: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. J. Leohr: None. E.S. LaBell: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company, Johnson & Johnson, Novartis AG. D.E. Coutant: Employee; Self; Eli Lilly and Company. Employee; Spouse/Partner; Eli Lilly and Company. Q. Zhang: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. T. Danne: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic, Novo Nordisk A/S, Sanofi. R.K. Pollom: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company.
Funding
Eli Lilly and Company
Introduction
This study compared the efficacy and safety of similar U-100 insulin glargine products, namely, Lilly insulin glargine (LY IGlar; Basaglar
®
) and the reference insulin glargine product ...(IGlar; Lantus
®
), used once daily in combination with oral antihyperglycemic medications (OAMs) in adults with type 2 diabetes (T2D).
Methods
ELEMENT 5 was a phase III, randomized, multinational, open-label, treat-to-target, 24-week trial. Participants were insulin naïve (glycated hemoglobin HbA1c ≥ 7.0% to ≤ 11.0%) or on basal insulin (IGlar, neutral protamine Hagedorn or insulin detemir; HbA1c ≤ 11.0%) and taking ≥ 2 OAMs. The primary objective was to show that LY IGlar is noninferior to IGlar in terms of HbA1c reduction (0.4% noninferiority margin).
Results
The study population (
N
= 493) was predominantly Asian (48%) or White (46%), with similar baseline characteristics between arms (
P
> 0.05). At 24 weeks, LY IGlar was noninferior to IGlar in terms of change in HbA1c level from baseline (− 1.25 vs. − 1.22%, respectively; least squares mean difference − 0.04%; 95% confidence interval − 0.22%, 0.15%). Other 24-week efficacy and safety results were also similar between treatments (
P
> 0.05), including insulin dose; percentage of patients having HbA1c of < 7% and ≤ 6.5%; overall rate and incidence of total, nocturnal, and severe hypoglycemia; adverse events; insulin antibody response; and weight gain. Daily mean 7-point self-monitored blood glucose reduction was similar between treatments at 24 weeks, with no differences at any time point except premorning-meal (fasting) blood glucose (LY IGlar − 2.37 mmol/L; IGlar − 2.69 mmol/L;
P
= 0.007).
Conclusion
Overall, LY IGlar and IGlar combined with OAMs provided similar glucose control and safety findings in this T2D population, which included a greater proportion of Asian patients and had broader background basal insulin experience than a previously studied T2D population.
Trial Registration
ClinicalTrials.gov identifier, NCT02302716.
Funding
Eli Lilly and Company and Boehringer Ingelheim.
Plain Language Summary
Plain language summary available for this article.
Introduction
To compare efficacy and safety of Basaglar
®
insulin glargine 100 units/mL; LY insulin glargine (LY IGlar) to Lantus
®
insulin glargine 100 units/mL; SA insulin glargine (SA IGlar) in ...older (≥ 65 years) or younger (< 65 years) patients with type 2 diabetes (T2D).
Methods
This subgroup analysis of a phase 3, randomized, double-blind, multinational, 24-week study compared LY IGlar and SA IGlar on several clinical efficacy (change in glycated hemoglobin (A1c), basal insulin dose, weight) and safety outcomes (incidence of adverse events, insulin antibodies, hypoglycemia incidence and rates) in patients either ≥ 65 or < 65 years.
Results
Compared with patients aged < 65 years (
N
= 542), patients aged ≥ 65 years (
N
= 214) had a significantly longer duration of diabetes; lower baseline A1c and body weight; and body mass index; and were more likely to report prestudy SA IGlar use. Compared to patients < 65 years, patients ≥ 65 years needed a lower basal insulin dose and experienced lower body weight gain. There were no significant treatment-by-age interactions for the clinical efficacy and safety outcomes, indicating that there was no differential treatment effect (LY IGlar vs SA IGlar) for patients ≥ 65 years vs those < 65 years. Moreover, within each age subgroup, LY IGlar and SA IGlar were similar for all clinical efficacy and safety outcomes.
Conclusions
LY IGlar and SA IGlar exhibit similar efficacy and safety in patients with T2D who are ≥ 65 years and in those < 65 years.
Trial Registration
ClinicalTrials.gov trial registration: NCT01421459.
Funding
Eli Lilly and Company and Boehringer-Ingelheim.
Plain Language Summary
Plain language summary available for this article.
The aim of this phase 3 clinical study was to compare the efficacy and safety of two drugs, Basaglar
®
(LY IGlar) and Lantus (SA IGlar), in patients with type 2 diabetes that were either 65 years of age and/or older or younger than 65 years of age. This study ran for 24 weeks. The factors used to measure efficacy were changes in glycated hemoglobin (A1c), insulin dose, and weight. The safety outcomes were incidence of adverse events, incidence and levels of insulin antibodies, and the incidence and rate of low blood sugar. Compared with patients less than 65 years of age (
N
= 542), patients 65 years of age and older (
N
= 214) had diabetes for a significantly longer time period; had a lower baseline A1c, body weight, and body mass index; and were more likely to report that they used SA IGlar prestudy. Compared to patients less than 65 years of age, patients equal to or older than 65 years of age showed significantly smaller increases in insulin dose and body weight. There were no significant treatment-by-age interactions for the efficacy and safety outcomes, indicating that there was no difference in treatment effect (LY IGlar vs SA IGlar) for patients equal to or older than 65 years of age vs those less than 65 years of age. Moreover, within each age subgroup, LY IGlar and SA IGlar were similar for all clinical efficacy and safety outcomes. LY IGlar and SA IGlar have similar efficacy and safety in patients with T2D who are equal to or older than 65 years of age and in those less than 65 years of age.
Introduction
We compared insulin antibody response (IAR) profiles in patients with type 1 diabetes (T1D) or type 2 diabetes (T2D) who received LY2963016 insulin glargine (LY IGlar) or Lantus
®
...insulin glargine (IGlar) and evaluated the potential relationship between higher IARs and clinical and safety outcomes with a focus on patients who exhibited antibody responses in the upper quartile.
Methods
Data from ELEMENT-1 (52-week open-label in T1D) and ELEMENT-2 (24-week, double-blind study in T2D) were analyzed. Maximum postbaseline IAR levels and proportions of patients in the upper quartile of maximum antibody percent binding (UQMAPB; patients with maximum postbaseline percent binding in the highest 25% of maximum values observed) were compared for differential treatment effects on clinical efficacy outcomes and incidence of adverse events. Continuous outcomes were analyzed by analysis of covariance. Categorical data were analyzed by the Cochran–Mantel–Haenszel or Breslow–Day test.
Results
In both studies (
N
= 532 evaluable patients with T1D;
N
= 730 with T2D), no statistically significant differences between LY IGlar and IGlar were observed for maximum antibody percent binding (MAPB) levels or for proportions of patients in the respective UQMAPB. No statistically significant differential treatment effects were observed in the relationship between MAPB and clinical efficacy and safety outcomes.
Conclusions
Maximum postbaseline IAR levels and the proportion of patients with high IAR levels were similar for LY IGlar and IGlar. High antibody levels did not affect clinical outcomes. These results add further evidence supporting similar IARs of LY IGlar and IGlar.
Funding
Eli Lilly and Company and Boehringer-Ingelheim.
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