Lepodisiran, an Extended-Duration Short Interfering RNA Targeting Lipoprotein(a): A Randomized Dose-Ascending Clinical Trial.

Importance: Epidemiological and genetic data have implicated lipoprotein(a) as a potentially modifiable risk factor for atherosclerotic disease and aortic stenosis, but there are no approved pharmacological treatments. Objectives: To assess the safety, tolerability, pharmacokinetics, and effects of lepodisiran on lipoprotein(a) concentrations after single doses of the drug; lepodisiran is a short interfering RNA directed at hepatic synthesis of apolipoprotein(a), an essential component necessary for assembly of lipoprotein(a) particles. Design, Setting, and Participants: A single ascending-dose trial conducted at 5 clinical research sites in the US and Singapore that enrolled 48 adults without cardiovascular disease and with lipoprotein(a) serum concentrations of 75 nmol/L or greater (or ≥30 mg/dL) between November 18, 2020, and December 7, 2021; the last follow-up visit occurred on November 9, 2022. Interventions: Participants were randomized to receive placebo or a single dose of lepodisiran (4 mg, 12 mg, 32 mg, 96 mg, 304 mg, or 608 mg) administered subcutaneously. Main Outcomes and Measures: The primary outcome was the safety and tolerability of the single ascending doses of lepodisiran. The secondary outcomes included plasma levels of lepodisiran for 168 days after dose administration and changes in fasting lipoprotein(a) serum concentrations through a maximum follow-up of 336 days (48 weeks). Results: Of the 48 participants enrolled (mean age, 46.8 [SD, 11.6] years; 35% were women), 1 serious adverse event occurred. The plasma concentrations of lepodisiran reached peak levels within 10.5 hours and were undetectable by 48 hours. The median baseline lipoprotein(a) concentration was 111 nmol/L (IQR, 78 to 134 nmol/L) in the placebo group, 78 nmol/L (IQR, 50 to 152 nmol/L) in the 4 mg of lepodisiran group, 97 nmol/L (IQR, 86 to 107 nmol/L) in the 12-mg dose group, 120 nmol/L (IQR, 110 to 188 nmol/L) in the 32-mg dose group, 167 nmol/L (IQR, 124 to 189 nmol/L) in the 96-mg dose group, 96 nmol/L (IQR, 72 to 132 nmol/L) in the 304-mg dose group, and 130 nmol/L (IQR, 87 to 151 nmol/L) in the 608-mg dose group. The maximal median change in lipoprotein(a) concentration was -5% (IQR, -16% to 11%) in the placebo group, -41% (IQR, -47% to -20%) in the 4 mg of lepodisiran group, -59% (IQR, -66% to -53%) in the 12-mg dose group, -76% (IQR, -76% to -75%) in the 32-mg dose group, -90% (IQR, -94% to -85%) in the 96-mg dose group, -96% (IQR, -98% to -95%) in the 304-mg dose group, and -97% (IQR, -98% to -96%) in the 608-mg dose group. At day 337, the median change in lipoprotein(a) concentration was -94% (IQR, -94% to -85%) in the 608 mg of lepodisiran group. Conclusions and Relevance: In this phase 1 study of 48 participants with elevated lipoprotein(a) levels, lepodisiran was well tolerated and produced dose-dependent, long-duration reductions in serum lipoprotein(a) concentrations. The findings support further study of lepodisiran. Trial Registration: ClinicalTrials.gov Identifier: NCT04914546.

Muvalaplin, an Oral Small Molecule Inhibitor of Lipoprotein(a) Formation: A Randomized Clinical Trial.

Importance: Lipoprotein(a) (Lp[a]) is associated with atherosclerotic disease and aortic stenosis. Lp(a) forms by bonding between apolipoprotein(a) (apo[a]) and apo B100. Muvalaplin is an orally administered small molecule that inhibits Lp(a) formation by blocking the apo(a)-apo B100 interaction while avoiding interaction with a homologous protein, plasminogen. Objective: To determine the safety, tolerability, pharmacokinetics, and pharmacodynamic effects of muvalaplin. Design, Setting, and Participants: This phase 1 randomized, double-blind, parallel-design study enrolled 114 participants (55 assigned to a single-ascending dose; 59 assigned to a multiple-ascending dose group) at 1 site in the Netherlands. Interventions: The single ascending dose treatment evaluated the effect of a single dose of muvalaplin ranging from 1 mg to 800 mg or placebo taken by healthy participants with any Lp(a) level. The multiple ascending dose treatment evaluated the effect of taking daily doses of muvalaplin (30 mg to 800 mg) or placebo for 14 days in patients with Lp(a) levels of 30 mg/dL or higher. Main Outcomes and Measures: Outcomes included safety, tolerability, pharmacokinetics, and exploratory pharmacodynamic biomarkers. Results: Among 114 randomized (55 in the single ascending dose group: mean [SD] age, 29 [10] years, 35 females [64%], 2 American Indian or Alaska Native [4%], 50 White [91%], 3 multiracial [5%]; 59 in the multiple ascending dose group: mean [SD] age 32 [15] years; 34 females [58%]; 3 American Indian or Alaska Native [5%], 6 Black [10%], 47 White [80%], 3 multiracial [5%]), 105 completed the trial. Muvalaplin was not associated with tolerability concerns or clinically significant adverse effects. Oral doses of 30 mg to 800 mg for 14 days resulted in increasing muvalaplin plasma concentrations and half-life ranging from 70 to 414 hours. Muvalaplin lowered Lp(a) plasma levels within 24 hours after the first dose, with further Lp(a) reduction on repeated dosing. Maximum placebo-adjusted Lp(a) reduction was 63% to 65%, resulting in Lp(a) plasma levels less than 50 mg/dL in 93% of participants, with similar effects at daily doses of 100 mg or more. No clinically significant changes in plasminogen levels or activity were observed. Conclusion: Muvalaplin, a selective small molecule inhibitor of Lp(a) formation, was not associated with tolerability concerns and lowered Lp(a) levels up to 65% following daily administration for 14 days. Longer and larger trials will be required to further evaluate safety, tolerability, and effect of muvalaplin on Lp(a) levels and cardiovascular outcomes. Trial Registration: ClinicalTrials.gov Identifier: NCT04472676.

Ultra rapid lispro showed greater reduction in postprandial glucose versus Humalog in children, adolescents and adults with type 1 diabetes mellitus.

AIM: This study compared the pharmacokinetics, glucodynamics and tolerability following single subcutaneous doses of ultra rapid lispro (URLi) versus Humalog in children (6-11 years), adolescents (12-17 years) and adults (18-64 years) with type 1 diabetes mellitus (T1D). MATERIALS AND METHODS: The study was a randomized, two-period, subject- and investigator-blind, crossover design in participants with T1D. Participants received a 0.2 U/kg bolus dose immediately before a liquid mixed meal tolerance test. Insulin lispro and glucose concentrations were measured. RESULTS: The study included 13 children, 14 adolescents and 15 adults. Consistently across the age groups, onset of appearance was 4-5 min faster, the early 50% tmax was reduced by 7-13 min, and exposure in the first 15 min was increased by 3.5-6.5-fold following URLi compared with Humalog (all p < .01). Exposure after 3 h was decreased by 37-58% (p = .02) and the duration was reduced by 56 min (p = .006) in children and 36 min (p = .022) in adolescents with URLi compared with Humalog. The maximum and overall exposure were similar between treatments. Postprandial glucose at 1 h was reduced by 42 mg/dl in children (p = .008), 19 mg/dl (p = .195) in adolescents and 34 mg/dl (p = .018) in adults following URLi versus Humalog. The glucose excursion during a 5-h test meal period was reduced by 16% in children and 9% in adolescents compared with Humalog. URLi was well tolerated in all age groups. CONCLUSIONS: URLi showed an accelerated insulin lispro absorption and greater postprandial glucose reduction compared with Humalog in children, adolescents and adults with T1D.

Evaluation of the Pharmacokinetic Profile of Ultra Rapid Lispro Administered Subcutaneously at Different Injection Sites.

PURPOSE: Ultra rapid lispro (URLi) is a novel insulin lispro formulation developed to more closely match physiological insulin secretion and improve postprandial glucose control. This study compared the pharmacokinetic profile and glucodynamic response of URLi when administered subcutaneously into the abdomen, upper arm, or thigh. An intravenous (IV) bolus administration was included to determine the absolute bioavailability at each injection site. METHODS: In this Phase I, randomized, open-label, 4-period, crossover study, healthy subjects received a single dose of 15 U URLi subcutaneously into the abdomen, upper arm, or thigh, or by intravenous injection. Serum insulin lispro concentrations and glucodynamic response during a 10-hour euglycemic clamp procedure were assessed after URLi administration. FINDINGS: Total insulin lispro exposure was similar for the abdomen, upper arm, and thigh, and absolute bioavailability was ∼65% at each subcutaneous (SC) injection site. Total and peak insulin action were similar across these SC injection sites. The onset of appearance was <1 minute, and the time to early half-maximal drug concentration occurred at ∼10 minutes across these three SC injection sites. Onset of insulin action occurred at ∼22 minutes, and the early insulin action (for the first hour) was also similar across these SC injection sites. URLi was well tolerated after single SC injections and IV bolus administration. IMPLICATIONS: The pharmacokinetic and glucodynamic profiles of URLi were similar after a single SC dose into the abdomen, upper arm, or thigh. The rate of insulin lispro absorption and early insulin action were maintained regardless of the SC injection site. The current study supports SC injection of URLi into the abdomen, upper arm, and thigh. CLINICALTRIALS: gov identifier: NCT03232983.

Pharmacokinetics and Pharmacodynamics of Human Regular U-500 Insulin Administered via Continuous Subcutaneous Insulin Infusion Versus Subcutaneous Injection in Adults With Type 2 Diabetes and High-Dose Insulin Requirements.

INTRODUCTION: Human regular U-500 insulin (U-500R) is approved for subcutaneous (SC) injection in patients with diabetes requiring >200 units/day of insulin. Here, pharmacokinetic and pharmacodynamic (PK/PD) profiles following U-500R administered by continuous subcutaneous insulin infusion (CSII) and SC injection in adults with type 2 diabetes (T2D) on high-dose insulin were studied. METHODS: In this randomized, crossover, euglycemic clamp study, patients received a 100-unit bolus of U-500R via SC injection or CSII with basal infusion using a U-500R specific pump. PK parameters were estimated using non-compartmental methods. PD estimates were derived from the glucose infusion rate during the euglycemic clamp procedure. RESULTS: When corrected for the basal infusion, the PK profiles for the 100-unit bolus of U-500R were similar for CSII and SC injection. Without correction for basal infusion, PK and PD profiles showed a greater insulin concentration and effect when U-500R was administered via CSII compared to SC injection, primarily due to basal insulin infusion for CSII. The ratio of geometric least squares AUC0-tlast means SC:CSII (90% CI) is 0.857 (0.729, 1.01) with correction (mean AUC0-tlast: 5230 pmol*L/h [SC injection] and 6070 pmol*L/h [CSII, with correction]) and 0.424 (0.361, 0.499) without correction (mean AUC0-tlast: 12300 pmol*L/h [CSII, without correction]). Median time-to-peak insulin concentration was six hours (range 0.5-8 hours) via SC injection and five hours (0.5-12 hours) via CSII. CONCLUSIONS: In adults with T2D on high-dose insulin, U-500R PK/PD parameters were similar for a 100-unit bolus when given by SC injection or CSII via a U-500R pump.

A Euglycemic Glucose Clamp Study to Evaluate the Bioavailability of LY2963016 Relative to Insulin Glargine in Healthy Chinese Subjects.

Insulin glargine (IGlar) and LY2963016 (LY IGlar) are long-acting insulin analogs with identical primary amino acid sequences. We conducted a randomized, open-label, 2-treatment, 2-period, crossover study in healthy Chinese subjects to evaluate the relative bioavailability of LY IGlar to IGlar and pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of LY IGlar. Subjects (n = 58) were randomized to receive single subcutaneous doses (0.5 U/kg) of LY IGlar and IGlar with a ≥7-day washout period between study treatments. Serum was collected before and up to 24 hours after dosing to assess PK characteristics. PD characteristics were assessed by euglycemic clamp up to 24 hours after dosing. Linear mixed-effects models were used to fit the log-transformed primary PK (maximum observed concentration and area under the concentration-time curve from time 0 to 24 hours) and PD parameters (maximum glucose infusion rate and total amount of glucose infused during clamp period). The geometric least squares means ratios (90% confidence interval) of LY IGlar to IGlar for maximum observed concentration and area under the concentration-time curve from time 0 to 24 hours were 0.961 (0.887-1.04) and 0.941 (0.872-1.01), respectively. The geometric least squares means ratios (90% confidence interval) of LY IGlar to IGlar were 0.91 (0.85-0.98) for maximum glucose infusion rate and 0.89 (0.82-0.97) for total amount of glucose infused during clamp period. LY IGlar demonstrated similarity to IGlar in PK and PD characteristics following single-dose (0.5 U/kg) administration in healthy Chinese subjects.

Ultra Rapid Lispro (URLi) Accelerates Insulin Lispro Absorption and Insulin Action vs Humalog® Consistently Across Study Populations: A Pooled Analysis of Pharmacokinetic and Glucodynamic Data.

BACKGROUND AND OBJECTIVE: Ultra rapid lispro (URLi) is a novel insulin lispro formulation developed to more closely match physiological insulin secretion and improve postprandial glucose control. This pooled analysis compared the pharmacokinetics and glucodynamics between URLi and Humalog® in healthy subjects and patients with type 1 or type 2 diabetes mellitus. METHODS: The analysis included four randomized, double-blind, crossover, single-dose studies (healthy subjects [n = 74], patients with type 1 diabetes [n = 78], and type 2 diabetes [n = 38]) evaluating subcutaneous doses of 7, 15, or 30 U of URLi and Humalog during an 8- to 10-h euglycemic clamp procedure. RESULTS: The pooled analysis showed an ~ 5-min faster onset of appearance, an ~8-fold greater exposure in the first 15 min, a 43% reduction in exposure beyond 3 h, and a 68-min shorter exposure duration with URLi vs Humalog across all study populations and dose range. Compared with Humalog, URLi had a 10-min faster onset of action, a 3-fold greater insulin action in the first 30 min, a 35% reduction in insulin action beyond 4 h, and a 44-min shorter duration of action across all populations and dose range. Overall exposure and insulin action were similar between URLi and Humalog for each dose level and study population. CONCLUSIONS: Across the studied populations and dose range, URLi consistently demonstrated a faster absorption, reduced late exposure, and overall shorter exposure duration compared with Humalog. Similarly, URLi demonstrated earlier insulin action while reducing late insulin action and shorter insulin action compared with Humalog across the study populations and dose range. CLINICAL TRIAL REGISTRATION: NCT02942654 (registered: 21 October, 2016), NCT03286751 (registered: 15 September, 2017), NCT03166124 (registered: 23 May, 2017), and NCT03305822 (registered: 5 October, 2017).

Pharmacokinetic and Glucodynamic Responses of Ultra Rapid Lispro vs Lispro Across a Clinically Relevant Range of Subcutaneous Doses in Healthy Subjects.

PURPOSE: Ultra rapid lispro (URLi) is a novel insulin lispro formulation developed to more closely match physiological insulin secretion and improve postprandial glucose control. This study compared the pharmacokinetic and glucodynamic parameters of URLi and Lispro (Humalog®) at 3 dose levels in healthy subjects. METHODS: This randomized, 6-period, subject- and investigator-blind, crossover study included 42 healthy subjects. At each period, subjects received a single subcutaneous dose of 7, 15, or 30 U of URLi or Lispro followed by a 10-h automated euglycemic clamp. Insulin lispro and blood glucose concentrations were measured. FINDINGS: Across all 3 doses, insulin lispro appeared in the serum 2-5 min faster, and exposure was 6- to 8-fold greater in the first 15 min, with URLi versus Lispro. Exposure beyond 3 h postdose was 45%-52% lower, and duration of exposure was 67-86 min shorter with URLi versus Lispro for all dose levels. Onset of insulin action was 7-9 min faster and insulin action was ~3-fold greater in the first 30 min with URLi versus Lispro across the dose levels. Insulin action beyond 4 h was reduced by 32%-45%, and duration of action was reduced by 47-67 min, with URLi versus Lispro for all 3 dose levels. Overall exposure and total glucose infused were similar between URLi and Lispro at each dose level. Dose proportionality was observed for maximum and overall exposure after URLi. Less than dose-proportional increases in maximum and total glucose infused were observed and were similar for both URLi and Lispro. IMPLICATIONS: URLi exhibited ultra-rapid pharmacokinetic and glucodynamic parameters across all 3 dose levels studied and exhibited dose-proportional increases in exposure in healthy subjects. ClinicalTrials.gov identifier: NCT03286751.

Bioequivalence of Ultra Rapid Lispro (URLi) U100 and U200 Formulations in Healthy Subjects.

INTRODUCTION: Ultra rapid lispro (URLi) is a novel insulin lispro formulation that was developed to more closely match physiological insulin secretion. The aims of this study were to demonstrate the bioequivalence (BE) of a concentrated formulation (U200) of URLi to the U100 formulation of URLi after subcutaneous (SC) administration and to evaluate the glucodynamics (GD) of these formulations. METHODS: This phase 1, randomized, two-sequence, four-period, double-blind, replicate crossover study was conducted in 68 healthy subjects. At each dosing visit, subjects received a 15-U SC dose of either U100 URLi or U200 URLi followed by a 10-h euglycemic clamp procedure. Serum insulin lispro and blood glucose concentrations were measured, and the glucose infusion rate was continuously adjusted during the clamp to maintain the target blood glucose. RESULTS: Bioequivalence of U200 URLi relative to U100 URLi was demonstrated. The 90% confidence intervals (CIs) of the ratios of geometric least squares (LS) means for the maximum insulin concentration and total exposure were within the BE limits of 0.80-1.25. Additionally, the 90% CIs for the ratios of geometric LS means for maximum glucose infusion rate and total glucose infused were within the BE limits. The early 50% tmax occurred at approximately the same time for the U100 and U200 URLi formulations, and the insulin exposure within the first 15 min was similar for both formulations. The tolerability of the two URLi formulations was comparable. CONCLUSIONS: This study demonstrated that the U100 and U200 URLi formulations are bioequivalent. The accelerated insulin absorption observed for the U100 formulation was maintained with the U200 URLi formulation. Further, the GD were similar for both formulations, supporting the ability of individuals to transfer from U100 to U200 URLi in a 1:1 unit conversion. TRIAL REGISTRATION: NCT03616977.

Ultra rapid lispro lowers postprandial glucose and more closely matches normal physiological glucose response compared to other rapid insulin analogues: A phase 1 randomized, crossover study.

AIMS: To compare the pharmacokinetic (PK) and glucodynamic (GD) characteristics of ultra rapid lispro (URLi; Eli Lilly and Company, Indianapolis, Indiana), Fiasp® (Novo Nordisk, Bagsvaerd, Denmark), Humalog® (Eli Lilly and Company) and NovoRapid® (Novo Nordisk), in patients with type 1 diabetes (T1D). MATERIALS AND METHODS: This was a randomized, double-blind, four-period, crossover study, conducted in 68 patients with T1D. Patients received the same individualized subcutaneous dose of each study drug immediately prior to a liquid test meal. For comparison, 12 healthy subjects received the same test meal. RESULTS: URLi had a significantly faster insulin absorption compared to the other insulins tested. Early half-maximal drug concentration was reached 13 minutes after administration of URLi, which was 6 minutes faster than Fiasp, 13 minutes faster than Humalog, and 14 minutes faster than NovoRapid (all P <0.0001). Early insulin exposure was significantly greater and late insulin exposure was reduced after URLi compared to the other insulins. URLi achieved the greatest numerical reduction in postprandial glucose (PPG) at 2 hours post-meal (7 mg/dL vs Fiasp) and was significantly different from Humalog (21 mg/dL) and Novo Rapid (29 mg/dL). Additionally, glucose excursions over the first 3 hours post-meal with URLi were comparable to those in healthy subjects. CONCLUSIONS: URLi demonstrated the fastest insulin absorption and the greatest numeric PPG-lowering effect compared to the other insulins tested. URLi more closely matched the early physiological glucose control observed in healthy subjects.

Pharmacokinetics and Glucodynamics of Ultra Rapid Lispro (URLi) versus Humalog® (Lispro) in Younger Adults and Elderly Patients with Type 1 Diabetes Mellitus: A Randomised Controlled Trial.

BACKGROUND: Ultra rapid lispro (URLi) is a novel insulin lispro formulation developed to more closely match physiological insulin secretion and improve postprandial glucose control. This study compared the pharmacokinetics, glucodynamics, safety, and tolerability of URLi and Humalog® in patients with type 1 diabetes mellitus (T1DM). METHODS: This was a phase I, two-period, randomised, double-blind, crossover glucose clamp study in younger adult (aged 18-45 years; n = 41) and elderly (aged ≥65 years; n = 39) patients with T1DM. At each dosing visit, patients received either URLi or Humalog (15 units subcutaneously) followed by a 10 h automated euglycaemic clamp procedure. Serum insulin lispro and blood glucose were measured. RESULTS: Insulin lispro appeared in serum 6 min faster, and exposure was 7.2-fold greater over the first 15 min postdose with URLi versus Humalog in both age groups. Exposure beyond 3 h postdose was 39-41% lower, and exposure duration was reduced by 72-74 min with URLi versus Humalog in both age groups. Onset of insulin action was 11-12 min faster, and insulin action was 3-fold greater over the first 30 min postdose with URLi versus Humalog in both age groups. Insulin action beyond 4 h postdose was 44-54% lower, and duration of action was reduced by 34-44 min with URLi versus Humalog in both age groups. Overall exposure and total insulin action remained similar for both treatments. URLi and Humalog were well tolerated. CONCLUSION: In patients with T1DM, URLi showed ultra-rapid pharmacokinetics and glucodynamics, with the differences between URLi and Humalog in elderly patients mirroring those in younger adults. ClinicalTrials.gov identifier: NCT03166124.

Pharmacokinetics and Glucodynamics of Ultra Rapid Lispro (URLi) versus Humalog® (Lispro) in Patients with Type 2 Diabetes Mellitus: A Phase I Randomised, Crossover Study.

BACKGROUND AND OBJECTIVE: Ultra rapid lispro (URLi) is a novel insulin lispro formulation developed to more closely match physiological insulin secretion and improve postprandial glucose control. This study compared the insulin lispro pharmacokinetics and glucodynamics, safety and tolerability of URLi and Humalog® after a single subcutaneous dose in patients with type 2 diabetes mellitus (T2DM). METHODS: This was a phase I, randomised, two-period, two-treatment, double-blind, crossover study in 38 patients with T2DM. At each dosing visit, patients received either 15 units of URLi or Humalog, followed by a 10 h automated euglycaemic clamp procedure. Serum insulin lispro and blood glucose were measured. RESULTS: Insulin lispro appeared in the serum 5 min faster (p < 0.0001) and exposure was 6.4-fold greater in the first 15 min (p < 0.0001) with URLi versus Humalog. Exposure beyond 3 h postdose was 26% lower and the duration of exposure was 51 min shorter with URLi versus Humalog. Onset of insulin action was 13 min faster (p < 0.0001) and insulin action was 4.2-fold greater within the first 30 min (p < 0.0001) with URLi versus Humalog. Insulin action beyond 4 h postdose was 20% lower (p = 0.0099) with URLi versus Humalog. Overall insulin lispro exposure and total glucose infused were similar for URLi and Humalog. Both treatments were well tolerated. CONCLUSIONS: This is the first study to investigate URLi in patients with T2DM using a euglycaemic clamp procedure. URLi demonstrated ultra-rapid pharmacokinetics and glucodynamics in patients with T2DM. CLINICALTRIALS. GOV IDENTIFIER: NCT03305822.

Basal insulin peglispro increases lipid oxidation, metabolic flexibility, thermogenesis and ketone bodies compared to insulin glargine in subjects with type 1 diabetes mellitus.

AIMS: When treated with basal insulin peglispro (BIL), patients with type 1 diabetes mellitus (T1DM) exhibit weight loss and lower prandial insulin requirements versus insulin glargine (GL), while total insulin requirements remain similar. One possible explanation is enhanced lipid oxidation and improved ability to switch between glucose and lipid metabolism with BIL. This study compared the effects of BIL and GL on glucose and lipid metabolism in subjects with T1DM. MATERIALS AND METHODS: Fifteen subjects with T1DM were enrolled into this open-label, randomised, crossover study, and received once-daily stable, individualised, subcutaneous doses of BIL and GL for 4 weeks each. Respiratory quotient (RQ) was measured using whole-room calorimetry, and energy expenditure (EE) and concentrations of ketone bodies (3-hydroxybutyrate) and acylcarnitines were assessed. RESULTS: Mean sleep RQ was lower during the BIL (0.822) than the GL (0.846) treatment period, indicating greater lipid metabolism during the post-absorptive period with BIL. Increases in carbohydrate oxidation following breakfast were greater during BIL than GL treatment (mean change in RQ following breakfast 0.111 for BIL, 0.063 for GL). Furthermore, BIL treatment increased total daily EE versus GL (2215.9 kcal/d for BIL, 2135.5 kcal/d for GL). Concentrations of ketone bodies and acylcarnitines appeared to be higher following BIL than GL treatment. CONCLUSIONS: BIL increased sleeping fat oxidation, EE, ketone bodies, acylcarnitines and post-prandial glucose metabolism when switching from conventional insulin, thus, restoring metabolic flexibility and increasing thermogenesis. These changes may explain the previously observed weight loss with BIL versus GL.

Attenuated suppression of lipolysis explains the increases in triglyceride secretion and concentration associated with basal insulin peglispro relative to insulin glargine treatment in patients with type 1 diabetes.

AIMS: To test the hypothesis that, as well as lowering weight and increasing plasma triglyceride (TG) levels and hepatic fat compared with insulin glargine (GL) in patients with type 1 diabetes, the attenuated peripheral effects of basal insulin peglispro (BIL) may include increased free fatty acid flux to the liver, causing increased very-low-density lipoprotein (VLDL)-TG secretion and lipid oxidation, and decreased TG adipose tissue deposition. METHODS: In this open-label, randomized, 2-period crossover study, 14 patients with type 1 diabetes received once-daily, individualized, stable BIL or GL doses for 3 weeks. Palmitate flux was assessed using [9,10-3 H]palmitate infusion. VLDL-TG secretion, clearance and oxidation rate were assessed using primed-constant infusion of ex vivo labelled [1-14 C]VLDL-TG, while VLDL-TG storage rate was assessed using [9,10-3 H]VLDL-TG bolus injection. RESULTS: The VLDL-TG concentration and secretion rate, and palmitate flux were statistically significantly higher during BIL than during GL treatment (58%, 51% and 35%, respectively). The ratios of least squares (LS) geometric means for VLDL-TG clearance and oxidation were 0.92 (95% confidence interval [CI] 0.72, 1.17) and 1.31 (95% CI 0.91, 1.90), respectively. The difference in LS means for VLDL-TG storage rate was -0.36 (95% CI -0.83, 0.12). CONCLUSIONS: BIL-treated patients had higher effective lipolysis, VLDL-TG secretion and VLDL-TG concentration compared with GL-treated patients, explaining the increased plasma TG concentrations reported previously. Data support attenuated effects of BIL on lipolysis, in addition to the recently described hepato-preferential glucodynamic effects.

LY2963016 Insulin Glargine and Insulin Glargine (Lantus) Produce Comparable Pharmacokinetics and Pharmacodynamics at Two Dose Levels.

LY2963016 (LY IGlar) and Lantus (IGlar) are insulin glargine products with identical amino acid sequences. This was a phase 1 single-site, randomized, subject- and investigator-blinded, 4-treatment, 4-period crossover study to compare the pharmacokinetic (PK) and pharmacodynamic (PD) properties of LY IGlar and IGlar at 2 different doses. Fasted healthy subjects were randomly assigned to receive 2 single doses of LY IGlar and IGlar (0.3 and 0.6 U/kg for each product). Blood samples were collected up to 24 hours postdose to assess PK, and a euglycemic clamp lasting up to 24 hours postdose was conducted to assess PD. Twenty-four healthy subjects aged 23 to 52 years participated in the study. The primary PK parameters (area under the concentration versus time curve from 0 to 24 hours [AUC0-24 ] and maximum observed drug concentration [Cmax ]) and PD parameters (total amount of glucose infused during the clamp [Gtot ] and maximum glucose infusion rate [Rmax ]) were not statistically different between LY IGlar and IGlar at either dose. No safety concerns were noted with either drug. The study demonstrated that the PK and PD parameters for LY IGlar and IGlar were comparable following single doses at both 0.3 and 0.6 U/kg.

Quantification of Basal Insulin Peglispro and Human Insulin in Adipose Tissue Interstitial Fluid by Open-Flow Microperfusion.

BACKGROUND: Restoration of the physiologic hepatic-to-peripheral insulin gradient may be achieved by either portal vein administration or altering insulin structure to increase hepatic specificity or restrict peripheral access. Basal insulin peglispro (BIL) is a novel, PEGylated basal insulin with a flat pharmacokinetic and glucodynamic profile and altered hepatic-to-peripheral action gradient. We hypothesized reduced BIL exposure in peripheral tissues explains the latter, and in this study assessed the adipose tissue interstitial fluid (ISF) concentrations of BIL compared with human insulin (HI). METHODS: A euglycemic glucose clamp was performed in patients with type 1 diabetes during continuous intravenous (IV) infusion of BIL or HI, while the adipose ISF insulin concentrations were determined using open-flow microperfusion (OFM). The ratio of adipose ISF-to-serum concentrations and the absolute steady-state adipose ISF concentrations were assessed using a dynamic no-net-flux technique with subsequent regression analysis. RESULTS: Steady-state BIL concentrations in adipose tissue ISF were achieved by ∼16 h after IV infusion. Median time to reach steady-state glucose infusion rate across doses ranged between 8 and 22 h. The average serum concentrations (coefficient of variation %) of BIL and HI were 11,200 pmol/L (23%) and 425 pmol/L (15%), respectively. The ISF-to-serum concentration ratios were 10.2% for BIL and 22.9% for HI. CONCLUSIONS: This study indicates feasibility of OFM to measure BIL in ISF. The observed low ISF-to-serum concentration ratio of BIL is consistent with its previously demonstrated reduced peripheral action.

Duration of action of two insulin glargine products, LY2963016 insulin glargine and Lantus insulin glargine, in subjects with type 1 diabetes mellitus.

AIMS: LY2963016 (LY IGlar) and Lantus (IGlar) are insulin glargine products manufactured by distinct processes, but with identical amino acid sequences. This study compared the duration of action of LY IGlar and IGlar in subjects with type 1 diabetes mellitus (T1DM). MATERIALS AND METHODS: This was a randomized, double-blind, single-dose, two-period, crossover study. Twenty subjects underwent 42-hour euglycaemic clamps after a single subcutaneous 0.3-U/kg dose of LY IGlar or IGlar. In this study, the duration of action was defined as the time required for blood glucose levels to rise consistently above a predefined cut-off of 8.3 mmol/L (150 mg/dL) from a state of euglycaemia. Blood samples were collected to measure blood glucose for pharmacodynamic (PD) evaluations. RESULTS: End of action was reached within 42 hours in 26 of 40 clamps (13 LY IGlar and 13 IGlar). The median duration of action for all subjects was 37.1 and 40.0 hours, and the mean duration of action (calculated using only patients who reached end of action) was 23.8 and 25.5 hours for LY IGlar and IGlar, respectively. The duration of action was demonstrated to be similar between the treatments using time-to-event analysis (log-rank test of equality p = .859). Following administration of LY IGlar and IGlar, the PD parameters of maximum glucose infusion rate (R max ) and total glucose infusion during the clamp (G tot ) were comparable. CONCLUSION: LY IGlar and IGlar had similar duration of action and comparable PD parameters in subjects with T1DM.

Novel hepato-preferential basal insulin peglispro (BIL) does not differentially affect insulin sensitivity compared with insulin glargine in patients with type 1 and type 2 diabetes.

AIMS: Basal insulin peglispro (BIL) is a novel PEGylated basal insulin with a flat pharmacokinetic and glucodynamic profile and reduced peripheral effects, which results in a hepato-preferential action. In Phase 3 trials, patients with T1DM treated with BIL had lower prandial insulin requirements, yet improved prandial glucose control, relative to insulin glargine (GL). We hypothesized that this may be because of an enhanced sensitivity to prandial insulin with BIL resulting from lower chronic peripheral insulin action. MATERIALS AND METHODS: Two open-label, randomized, 2-period crossover clinical studies were conducted in 28 patients with T1DM and 24 patients with T2DM. In each study period, patients received once-daily, individualized, stable, subcutaneous doses of BIL or GL for 5 weeks before a euglycaemic 2-step hyperinsulinemic clamp procedure (with [6,6- 2 H2 ]-glucose in 12 of the patients with T1DM). M-values were derived from the clamp procedure for all patients, with rate of glucose appearance (Ra) and disappearance (Rd) and insulin sensitivity index (SI) determined from the clamps with [6,6- 2 H2 ]-glucose. RESULTS: There were no statistically significant differences between BIL and GL in key measures of hepatic (% Ra suppression during the low-dose insulin infusion; 78.7% with BIL, 81.8% with GL) or peripheral (M-value and M/I during the high-dose insulin infusion, Rd and SI) insulin sensitivity in patients with T1DM or T2DM. CONCLUSIONS: The need to reduce prandial insulin observed with BIL during phase 3 trials cannot be explained by the differential effects of BIL and GL on sensitivity to prandial insulin in either T1DM or T2DM.

Pharmacokinetics of the Long-Acting Basal Insulin LY2605541 in Subjects With Varying Degrees of Renal Function.

The pharmacokinetics of LY2605541 (basal insulin peglispro), a novel long-acting basal insulin analogue, was evaluated in 5 groups of subjects with varying degrees of renal function based on creatinine clearance: normal renal function (>80 mL/min), mild renal impairment (51-80 mL/min), moderate renal impairment (30-50 mL/min), severe renal impairment (<30 mL/min), or end-stage renal disease (ESRD) requiring hemodialysis. Serial blood samples for pharmacokinetic analyses were collected up to 12 days following a single 0.33 U/kg subcutaneous dose of LY2605541. The apparent clearance (CL/F) and half-life across groups were not affected by renal function. Cmax values were lower in subjects with increasing severity of renal impairment; however, the small decrease in Cmax did not affect the overall exposure. Regression analysis showed that LY2605541 clearance is independent of renal function (slope = 0.000863; P = .885). The mean fraction of LY2605541 eliminated by a single hemodialysis session was 13% in subjects with ESRD. LY2605541 was generally well tolerated in healthy subjects and those with renal impairment following a single 0.33 U/kg subcutaneous dose. Given these data, no dose adjustment of LY2605541 based on pharmacokinetics is recommended in renal impairment or in patients undergoing hemodialysis.