Publications by authors named "Parag Garhyan"

18 Publications

  • Page 1 of 1

Simulation-Based Evaluation of Dose Titration Algorithms for U-500R Insulin by Pump in Subjects with Type 2 Diabetes.

J Diabetes Sci Technol 2021 Sep 1;15(5):1195-1197. Epub 2021 Jul 1.

Endocrine Clinic of Southeast TX PA, Beaumont, TX, USA.

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http://dx.doi.org/10.1177/19322968211026626DOI Listing
September 2021

Insulin, Not the Preservative m-cresol, Instigates Loss of Infusion Site Patency Over Extended Durations of CSII in Diabetic Swine.

J Pharm Sci 2021 03 13;110(3):1418-1426. Epub 2020 Dec 13.

Eli Lilly and Company, Indianapolis, IN.

Insulin infusion sets worn for more than 4-5 days have been associated with a greater risk of unexplained hyperglycemia, a phenomenon that has been hypothesized to be caused by an inflammatory response to preservatives such as m-cresol and phenol. In this cross-over study in diabetic swine, we examined the role of the preservative m-cresol in inflammation and changes in infusion site patency. Insulin pharmacokinetics (PK) and glucose pharmacodynamics (PD) were measured on delivery of a bolus of regular human insulin U-100 (U-100R), formulated with or without 2.5 mg/mL m-cresol, to fasted swine following 0, 3, 5, 7, and 10 days of continuous subcutaneous insulin infusion (CSII). In a subsequent study with the same animals, biopsies were evaluated from swine wearing infusion sets infusing nothing, saline, or U-100R either with or without 2.5 mg/mL m-cresol, following 3, 7, and 10 days of CSII. Exposure to m-cresol did not impact any PK or PD endpoints. PK and PD responses dropped markedly from Days 7-10, regardless of the presence of m-cresol. Histopathology results suggest an additive inflammatory response to both the infusion set and the insulin protein itself, peaking at Day 7 and remaining stable beyond.
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http://dx.doi.org/10.1016/j.xphs.2020.12.008DOI Listing
March 2021

Development and Verification of a Body Weight-Directed Disease Trial Model for Glucose Homeostasis.

J Clin Pharmacol 2021 02 7;61(2):234-243. Epub 2020 Sep 7.

Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida, Orlando, Florida, USA.

Weight loss has been associated with improvement in insulin sensitivity. It is consequently a cornerstone in the management of type 2 diabetes mellitus (T2DM). However, the strictly quantitative relationship between weight loss, insulin sensitivity, and clinically relevant glucose homeostasis biomarkers as well as changes therein as T2DM progresses is not yet fully understood. Therefore, the objective of our research was to establish a body weight-directed disease trial model for glucose homeostasis. To that end, we conducted a model-based meta-analysis using time course data of body weight loss (following lifestyle change or surgical procedure) and corresponding improvement of insulin sensitivity expressed as the Matsuda index. Changes in body weight were best described by a sigmoidal E model, whereas changes in the Matsuda index were best described by a linear model with a slope of 3.49. Once developed and verified, the model-based meta-analysis was linked to a disease-drug trial model for T2DM previously developed by our group to characterize and predict the impact of weight loss on clinically relevant glucose homeostasis biomarkers. The joint model was then used to conduct clinical trial simulations, which showed that weight loss can greatly improve clinically relevant glucose homeostasis biomarkers in T2DM patients.
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http://dx.doi.org/10.1002/jcph.1728DOI Listing
February 2021

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

Diabetes Obes Metab 2018 05 4;20(5):1193-1201. Epub 2018 Feb 4.

Translational Research Institute for Metabolism and Diabetes, Orlando, Florida.

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.
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http://dx.doi.org/10.1111/dom.13215DOI Listing
May 2018

Development and Qualification of a Drug-Disease Modeling Platform to Characterize Clinically Relevant Endpoints in Type 2 Diabetes Trials.

Clin Pharmacol Ther 2018 10 1;104(4):699-708. Epub 2018 Feb 1.

Center for Pharmacometrics & Systems Pharmacology, Department of Pharmaceutics, University of Florida, Lake Nona (Orlando), Florida, USA.

Type 2 diabetes mellitus (T2DM) is a chronic, progressive disease characterized by persistently elevated blood glucose concentration (hyperglycemia). We developed a mechanistic drug-disease modeling platform based on data from more than 4,000 T2DM subjects in seven phase II/III clinical trials. The model integrates longitudinal changes in clinically relevant biomarkers of glycemic control with information on baseline disease state, demographics, disease progression, and different therapeutic interventions, either when given alone or as add-on combination therapy. The model was able to simultaneously characterize changes in fasting plasma glucose, fasting serum insulin, and glycated hemoglobin A1c following administration of sulfonylurea, metformin, and thiazolidinedione as well as disease progression in clinical trials ranging from 16-104 weeks of treatment. The mechanistic components of this generalized mechanism-based platform, based on knowledge of pharmacology, insulin-glucose homeostatic feedback, and diabetes pathophysiology, allows its application to be further expanded to other antidiabetic drug classes and combination therapies.
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http://dx.doi.org/10.1002/cpt.998DOI Listing
October 2018

Hypoglycemia Risk Related to Double Dose Is Markedly Reduced with Basal Insulin Peglispro Versus Insulin Glargine in Patients with Type 2 Diabetes Mellitus in a Randomized Trial: IMAGINE 8.

Diabetes Technol Ther 2017 08;19(8):463-470

1 Eli Lilly and Company , Indianapolis, Indiana, USA .

Background: Basal insulin peglispro (BIL) has a peripheral-to-hepatic distribution of action that resembles endogenous insulin and a prolonged duration of action with a flat pharmacokinetic/pharmacodynamic profile at steady state, characteristics that tend to reduce hypoglycemia risk compared to insulin glargine (GL). The primary objective was to demonstrate that clinically significant hypoglycemia (blood glucose ≤54 mg/dL [3.0 mmol/L] or symptoms of severe hypoglycemia) occurred less frequently within 84 h after a double dose (DD) of BIL than a DD of GL.

Methods: This was a randomized, double-blind, two-period crossover study in patients with type 2 diabetes (T2D) previously treated with insulin (N = 68). For the first 3 weeks of each of the two crossover periods, patients received an individualized dose of BIL or GL once nightly (stable dose for 2 weeks/period). Then, during a 7-day inpatient stay with frequent blood glucose monitoring and standardized meals, one DD of study insulin was given. Glucose was infused if blood glucose was ≤54 mg/dL (3.0 mmol/L) or for symptoms of severe hypoglycemia.

Results: Within 84 h after the DD, a significantly smaller proportion of patients experienced clinically significant hypoglycemia with BIL compared to GL (BIL, 6.6%; GL, 35.5%; odds ratio for BIL/GL 0.13 [95% confidence interval 0.04-0.39]; P < 0.001). Adverse event profiles were similar for the two insulins. Serum alanine aminotransferase and triglyceride levels were significantly higher with BIL versus GL.

Conclusions: BIL has a markedly lower risk of hypoglycemia than GL when replicating a double-dose error in patients with T2D.
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http://dx.doi.org/10.1089/dia.2016.0414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5567880PMC
August 2017

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.

Diabetes Obes Metab 2018 02 10;20(2):419-426. Epub 2017 Oct 10.

Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark.

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- H]palmitate infusion. VLDL-TG secretion, clearance and oxidation rate were assessed using primed-constant infusion of ex vivo labelled [1- C]VLDL-TG, while VLDL-TG storage rate was assessed using [9,10- 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.
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http://dx.doi.org/10.1111/dom.13087DOI Listing
February 2018

Dose Unit Establishment for a New Basal Insulin Using Joint Modeling of Insulin Dose and Glycemic Response.

J Diabetes Sci Technol 2018 01 3;12(1):155-162. Epub 2017 May 3.

1 Eli Lilly and Company, Indianapolis, IN, USA.

Background: For new insulin analogs with properties that vary from human insulin, defining activity in units of human insulin based on glycemic lowering efficacy may be challenging. Here we present a new method that can be used to quantify a unit dose of an experimental insulin when the traditional euglycemic clamp method is not adequate.

Methods: Joint modeling of insulin dose and the glycemic outcome variable hemoglobin A1c (HbA1c), where both were response variables, was used to evaluate insulin unit potency for basal insulin peglispro (BIL). The data were from the Phase 3 program for BIL, which included greater than 5500 patients with type 1 or type 2 diabetes who were treated for 26 or 52 weeks with BIL or a comparator insulin. Both basal-bolus and basal insulin only studies were included, and some type 2 diabetes patients were insulin-naïve.

Results: The analysis showed that 1 unit of BIL, composed of 9 nmol of active ingredient, had similar or slightly greater potency compared to 1 unit insulin glargine or NPH insulin for all populations.

Conclusions: Despite some limitations, the joint modeling of HbA1c and insulin dose provides a reasonable approach to estimate the relative potency of a new basal insulin versus an established basal insulin.
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http://dx.doi.org/10.1177/1932296817707542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5761965PMC
January 2018

Treatment with LY2409021, a glucagon receptor antagonist, increases liver fat in patients with type 2 diabetes.

Diabetes Obes Metab 2017 11 8;19(11):1521-1528. Epub 2017 Jun 8.

Eli Lilly and Company, Indianapolis, Indiana.

Aims: To evaluate whether treatment with LY2409021, a novel, selective glucagon receptor antagonist, is associated with changes in hepatic fat and other safety variables related to the benefit-risk profile for chronic use in patients with type 2 diabetes (T2D).

Methods: Safety and efficacy were assessed in patients with T2D taking metformin and sulphonylurea who were randomized to LY2409021 20 mg (n = 65), placebo (n = 68), or sitagliptin 100 mg (n = 41). Key endpoints included change from baseline to month 6 in hepatic fat fraction (HFF), assessed by magnetic resonance imaging; hepatic aminotransferases; blood pressure; lipid profile; fasting plasma glucose; and glycated haemoglobin (HbA1c).

Results: A significant increase in HFF was seen with LY2409021 vs sitagliptin (least squares [LS] mean difference 3.72%; P < .001) and placebo (4.44%; P < .001), accompanied by significant elevations in alanine aminotransferase levels with LY2409021 vs sitagliptin (6.8 U/L; P = .039) and vs placebo (10.7 U/L; P < .001). No patients had concomitant elevations in bilirubin levels. LY2409021 treatment showed significant HbA1c reductions vs placebo (LS mean difference -0.77%; P < .001) but not sitagliptin (-0.20%; P = .383). Similar results were observed for fasting plasma glucose. LY2409021 was also associated with significant increases in systolic blood pressure vs sitagliptin (4.9 mm Hg; P = .030) and vs placebo (4.3 mm Hg; P = .029), as well as significant increases in body weight and total cholesterol. All effects of LY2409021 were reversible.

Conclusion: In this cohort of patients with T2D, chronic glucagon receptor antagonism with LY2409021 was associated with glucose-lowering but also demonstrated increases in hepatic fat, hepatic aminotransferases, and other adverse effects.
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http://dx.doi.org/10.1111/dom.12958DOI Listing
November 2017

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

Diabetes Technol Ther 2017 05 22;19(5):305-314. Epub 2017 Mar 22.

1 HEALTH-Institute for Biomedicine and Health Sciences , Joanneum Research Forschungsgesellschaft mbH, Graz, Austria .

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.
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http://dx.doi.org/10.1089/dia.2016.0384DOI Listing
May 2017

Treatment with the glucagon receptor antagonist LY2409021 increases ambulatory blood pressure in patients with type 2 diabetes.

Diabetes Obes Metab 2017 08 27;19(8):1071-1077. Epub 2017 Mar 27.

Eli Lilly and Company, Indianapolis, Indiana.

Aims: To assess the effect of LY2409021 on systolic blood pressure (SBP) in patients with type 2 diabetes.

Materials And Methods: This 6-week, randomized, crossover study evaluated the effects of once-daily administration of LY2409021 20 mg vs those of placebo on SBP, diastolic BP (DBP), and mean arterial pressure (MAP) using 24-hour ambulatory BP monitoring (ABPM) in 270 subjects treated with diet/exercise ± metformin. Other measures included changes in glycemic control, serum lipids, and hepatic safety markers.

Results: At 6 weeks of LY2409021 treatment, 24-hour mean SBP was increased, with a least squares mean (LSM) difference of 2.26 mm Hg vs placebo (95% CI: 1.11, 3.40; P  < .001). The 24-hour mean DBP and MAP also increased, with LSM differences of 1.37 mm Hg (95% CI: 0.66, 2.08; P  < .001) and 1.67 mm Hg (95% CI: 0.86, 2.47; P  < .001) vs placebo, respectively. At week 6, LY2409021 treatment reduced glycated hemoglobin (HbA1c) levels, with an LSM difference of -0.49% (-5.4 mmol/mol) (95% CI: -0.56%, -0.42% [-6.1, -4.6 mmol/mol]; P  < .001) vs placebo. Mean HbA1c at baseline was 7.3% (56 mmol/mol). Small but significant changes in serum lipid and aminotransferase levels were observed with LY2409021 treatment (all P  < .05 vs placebo).

Conclusions: Statistically significant increases in BP, MAP and serum lipid levels were observed with LY2409021 treatment at a dose that lowered HbA1c and glucose levels. These effects may limit the clinical utility of LY2409021 as a chronic treatment for type 2 diabetes.
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http://dx.doi.org/10.1111/dom.12904DOI Listing
August 2017

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.

Diabetes Obes Metab 2017 04 7;19(4):482-488. Epub 2017 Feb 7.

Profil, Neuss, Germany.

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- H ]-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- H ]-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.
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http://dx.doi.org/10.1111/dom.12834DOI Listing
April 2017

A Comprehensive Review of Novel Drug-Disease Models in Diabetes Drug Development.

Clin Pharmacokinet 2016 07;55(7):769-788

Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida at Lake Nona (Orlando), 6550 Sanger Road, Room 467, Orlando, FL, 32827, USA.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease, which affects millions of people worldwide. The disease is characterized by chronically elevated blood glucose concentrations (hyperglycaemia), which result in comorbidities and multi-organ dysfunction. This is due to a gradual loss of glycaemic control as a result of increasing insulin resistance, as well as decreasing β-cell function. The objective of T2DM drug interventions is, therefore, to reduce fasting and postprandial blood glucose concentrations to normal, healthy levels without hypoglycaemia. Several classes of novel antihyperglycaemic drugs with various mechanisms of action have been developed over the past decades or are currently under clinical development. The development of these drugs is routinely supported by the application of pharmacokinetic/pharmacodynamic modelling and simulation approaches. They integrate information on the drug's pharmacokinetics, clinically relevant biomarker information and disease progression into a single, unifying approach, which can be used to inform clinical study design, dose selection and drug labelling. The objective of this review is to provide a comprehensive overview of the quantitative approaches that have been reported since the 2008 review by Landersdorfer and Jusko in an increasing order of complexity, starting with glucose homeostasis models. Each of the presented approaches is discussed with respect to its strengths and limitations, and respective knowledge gaps are highlighted as potential opportunities for future drug-disease model development in the area of T2DM.
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http://dx.doi.org/10.1007/s40262-015-0359-yDOI Listing
July 2016

Evaluation of Efficacy and Safety of the Glucagon Receptor Antagonist LY2409021 in Patients With Type 2 Diabetes: 12- and 24-Week Phase 2 Studies.

Diabetes Care 2016 Jul 17;39(7):1241-9. Epub 2015 Dec 17.

Eli Lilly and Company, Indianapolis, IN.

Objective: Type 2 diabetes pathophysiology is characterized by dysregulated glucagon secretion. LY2409021, a potent, selective small-molecule glucagon receptor antagonist that lowers glucose was evaluated for efficacy and safety in patients with type 2 diabetes.

Research Design And Methods: The efficacy (HbA1c and glucose) and safety (serum aminotransferase) of once-daily oral administration of LY2409021 was assessed in two double-blind studies. Phase 2a study patients were randomized to 10, 30, or 60 mg of LY2409021 or placebo for 12 weeks. Phase 2b study patients were randomized to 2.5, 10, or 20 mg LY2409021 or placebo for 24 weeks.

Results: LY2409021 produced reductions in HbA1c that were significantly different from placebo over both 12 and 24 weeks. After 12 weeks, least squares (LS) mean change from baseline in HbA1c was -0.83% (10 mg), -0.65% (30 mg), and -0.66% (60 mg) (all P < 0.05) vs. placebo, 0.11%. After 24 weeks, LS mean change from baseline in HbA1c was -0.45% (2.5 mg), -0.78% (10 mg, P < 0.05), -0.92% (20 mg, P < 0.05), and -0.15% with placebo. Increases in serum aminotransferase, fasting glucagon, and total fasting glucagon-like peptide-1 (GLP-1) were observed; levels returned to baseline after drug washout. Fasting glucose was also lowered with LY2409021 at doses associated with only modest increases in aminotransferases (mean increase in alanine aminotransferase [ALT] ≤10 units/L). The incidence of hypoglycemia in the LY2409021 groups was not statistically different from placebo.

Conclusions: In patients with type 2 diabetes, glucagon receptor antagonist treatment significantly lowered HbA1c and glucose levels with good overall tolerability and a low risk for hypoglycemia. Modest, reversible increases in serum aminotransferases were observed.
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http://dx.doi.org/10.2337/dc15-1643DOI Listing
July 2016

Basal insulin peglispro demonstrates preferential hepatic versus peripheral action relative to insulin glargine in healthy subjects.

Diabetes Care 2014 Sep 19;37(9):2609-15. Epub 2014 Jun 19.

Eli Lilly and Company, Indianapolis, IN

Objective: We evaluated the endogenous glucose production (EGP) and glucose disposal rate (GDR) over a range of doses of basal insulin peglispro (BIL) and insulin glargine in healthy subjects.

Research Design And Methods: This was a single-center, randomized, open-label, four-period, incomplete-block, crossover study conducted in eight healthy male subjects. Subjects had 8-h euglycemic clamps performed with primed, continuous infusions of BIL (5.1 to 74.1 mU/min) in three dosing periods and insulin glargine (20 or 30 mU/m(2)/min) in a fourth period, targeted to achieve 50-100% suppression of EGP. D-[3-(3)H] glucose was infused to assess rates of glucose appearance and disappearance.

Results: Mean BIL and insulin glargine concentrations (targeted to reflect the differences in intrinsic affinities of the two basal insulins) ranged from 824 to 11,400 and 212 to 290 pmol/L, respectively, and increased accordingly with increases in dose. Suppression of EGP and stimulation of GDR were observed with increasing concentrations of both insulins. At insulin concentrations where EGP was significantly suppressed, insulin glargine resulted in increased GDR. In contrast, at comparable suppression of EGP, BIL had minimal effect on GDR at lower doses and had substantially less effect on GDR than insulin glargine at higher doses.

Conclusions: The novel basal insulin analog BIL has relative hepatopreferential action and decreased peripheral action, compared with insulin glargine, in healthy subjects.
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http://dx.doi.org/10.2337/dc14-0210DOI Listing
September 2014

Dose correspondence between olanzapine long-acting injection and oral olanzapine: recommendations for switching.

Int Clin Psychopharmacol 2011 Jan;26(1):35-42

Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, USA.

Oral-to-depot dose correspondence was explored in a 24-week study of olanzapine long-acting injection (LAI). Patients with schizophrenia stabilized on oral olanzapine of 10, 15, or 20 mg/day (n=1065) were randomized to continue their oral treatment or switch directly to a fixed dose of olanzapine LAI [(mg/weeks) 45/4, 150/2, 405/4, or 300/2] without oral supplementation. Six-month relapse rates for each LAI-dose group stratified by earlier oral dose were analyzed using a Cox proportional hazard model assessing risk of relapse relative to each oral dose. Relapse rates for the therapeutic LAI doses (≥ 150 mg) varied depending on earlier oral dose, ranging from 1.5% (patients switched from 10 mg/day to 300 mg/2 weeks) to 18.8% (patients switched from 20 mg/day to 150 mg/2 weeks). Switching from 10 mg/day to 405 mg/4 weeks produced a comparable risk of relapse as remaining on that oral dose [Hazard ratio (HR)=1.03]. Switching from 15 or 20 mg/day to 300 mg/2 weeks produced comparable risk of relapse as remaining on those oral doses (HR=0.68 and 1.13, respectively). Pharmacokinetic modeling was conducted to evaluate the resulting dosing recommendations. Findings suggest that patients can be switched directly from oral to olanzapine LAI without the need for oral supplementation and with a low risk of relapse when initiated on an appropriate LAI dose.
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http://dx.doi.org/10.1097/YIC.0b013e32834093d1DOI Listing
January 2011
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