bluuebunny/crossref_metadata_2025_split huggingface dataset:
Improving Appropriate Basal Insulin Use in Clinical Practice—Impact of Physician Education on T2D Clinical Management
Authors: LARKIN AMY , LACOUTURE MICHAEL , LE ANNE 
Published: June 2018

Although insulin is among the most effective antihyperglycemic agents, initiation is often delayed. We studied whether online continuing medical education (CME) could improve the clinical performance and confidence of primary care physicians (PCPs) and endocrinologists (endos) regarding use of basal insulin. The CME activity consisted of an online, 30-minute, video-based roundtable panel discussion. Educational effects were assessed using 3 case-based and 1 self-efficacy repeated pair pre-/post-assessment questions and McNemar’s chi-squared test. The activity launched online August 16, 2016, and data were collected through December 20, 2016. Overall improvements were seen for PCPs (n = 197; P &lt;.001) and endos (n = 27; P =0.014). Relative percent changes from pre- to post-assessment were between 15% and 126% for PCPs and -4% to 40% for endos. While only 7% of PCPs and 19% of endos answered all 4 questions correctly on the pre-assessment, 28% of PCPs and 41% of endos answered all correctly on the post-assessment. The greatest improvements were seen in dosing strategies for preventing hypoglycemia (44% improvement in PCP, P &lt;.001, and 18% in endos, P = 0.025), individualizing therapy in a patient with high glucose variation (23% improvement in PCP, P &lt;.001, and 7% in endos, P = 0.4), and insulin initiation (8% improvement in PCP, P = 0.039, and 22% in endos, P = 0.058). PCPs reported a confidence level of 2.86 on the pre-assessment and 3.45 on the post -assessment, for a total confidence shift of 20.6%. Endos reported a confidence level of 4.04 on the pre-assessment and 4.44 on the post -assessment for a confidence shift of 10.1%. This study demonstrates the success of an online, roundtable activity in improving performance of PCPs and endos regarding use of newer basal insulins. Studies have shown that case questions are an effective way to measure clinical performance in practice; therefore this activity is expected to translate into improved T2D management in clinical care.

Disclosure
A. Larkin: None. M. LaCouture: None. A. Le: None.
Ultra-rapid Lispro (URLi) Shows Faster Absorption of Insulin Lispro vs. Humalog® during Insulin Pump (CSII) Use in Patients with T1D
Authors: KAZDA CHRISTOF M. , LEOHR JENNIFER , LIU RONG , HARDY THOMAS , REDDY SHOBHA , CHUA SHANE P.C. , GUO XIAONAN , HOVELMANN ULRIKE , KAPITZA CHRISTOPH 
Published: June 2018

URLi (LY900014), a novel ultra-rapid mealtime insulin in Phase 3 development, is shown to reduce postprandial glucose after subcutaneous injection. This study evaluated the pharmacokinetics and pharmacodynamics (PD) of URLi via CSII. In a double-blind, randomized cross-over study, 24 adult patients with T1D received URLi or insulin lispro (Humalog®; HL) for 3 days. Mixed meal tolerance tests (MMTT) were conducted on Days 1 and 3 after catheter insertion using a standard (1.5 U/min) single-wave bolus. URLi showed faster insulin lispro absorption on both days compared to HL. URLi reduced time to early half-maximal drug concentration by 37% (-8.5 min) and 32% (-5.3 min) compared to HL on Days 1 and 3 (both p&lt;0.0001). Area under the insulin lispro concentration time curve (AUC) for the first 15 min was &gt;50% higher than HL after dosing with URLi on Days 1 and 3 (p&lt;0.005). URLi reduced 1-hour postprandial glucose excursion of the MMTT by 45% on Day 1 (p=NS) and 47% on Day 3 (p=0.059) compared with HL (Figure). Accelerated URLi absorption was associated with trends toward lower postprandial glucose excursion for the entire MMTT (57% and 20% reductions in ∆AUC[0-5h] on Days 1 and 3; both NS). The study was not powered for PD assessment which may contribute to the lack of statistical significance. No differences were seen in the number or severity of hypoglycemic events or local tolerability between URLi and HL.

Disclosure
C.M. Kazda: Employee; Self; Eli Lilly and Company. J. Leohr: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. Employee; Spouse/Partner; Accenture. Stock/Shareholder; Spouse/Partner; Accenture. R. Liu: Employee; Self; Eli Lilly and Company. Employee; Spouse/Partner; Eli Lilly and Company. T. Hardy: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. S. Reddy: None. S.P.C. Chua: Employee; Self; Eli Lilly and Company. X. Guo: None. U. Hovelmann: None. C. Kapitza: Research Support; Self; ADOCIA, Boehringer Ingelheim GmbH, Dance Biopharm, Eli Lilly and Company, Johnson & Johnson Services, Inc., MedImmune, MSD K.K., Mylan, Nordic Bioscience, Novo Nordisk Inc., Poxel SA, Roche Diagnostics Corporation, Saniona, Sanofi-Aventis, Senseonics, Zealand Pharma A/S.
Total and Severe Hypoglycemia Is Reduced with Use of Inhaled Technosphere Insulin (TI, Afrezza®) Relative to Insulin Aspart in Type 1 Diabetes
Authors: BLONDE LAWRENCE , POMPILIO FRANK , BRUCE SIMON R. , GRANT MARSHALL L. , KENDALL DAVID M. 
Published: June 2018

Hypoglycemia (HG) and fear of HG limit effective insulin therapy and contribute to suboptimal glycemic control. Ultra-short acting insulins reduce HG risk by providing their glucose-lowering effect early and reducing the risk of late postprandial HG. AFFINITY-1, a treat-to-target study in T1D on multiple daily injection therapy, demonstrated one such ultra-short acting insulin, TI (Afrezza®), was non-inferior to SC aspart in A1C reduction (Bode et al, Diabetes Care 2015). Consistent with its action profile, a lower rate of HG was observed in TI users overall, particularly in the 2-5 h post-meal interval and in those achieving target A1C&lt;7%.
In this post-hoc analysis of patients with reported A1C values at end of treatment, mean rates for all HG and severe HG obtained from combined SMBG and AE reporting were significantly lower with TI than with aspart (Figure). A negative binomial regression including treatment, region, type of basal insulin, and A1C at end of treatment yielded an LS-mean HG rate for patients on TI 26% lower than comparable patients on aspart across the entire A1C range (mean ratio:0.74, 95% CI: 0.68-0.81).
TI’s rapid onset and ultra-short action provide insulin when needed at meals and between meals.
This profile improves overall and prandial glucose control and, as demonstrated in AFFINITY-1, has the potential to reduce the risk of late post-meal HG.

Disclosure
L. Blonde: Other Relationship; Self; AstraZeneca. Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; Intarcia Therapeutics, Inc.. Other Relationship; Self; Lexicon Pharmaceuticals, Inc.. Advisory Panel; Self; Janssen Pharmaceuticals, Inc.. Other Relationship; Self; Janssen Scientific Affairs, LLC.. Speaker's Bureau; Self; Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Merck & Co., Inc., Novo Nordisk Inc.. Speaker's Bureau; Self; Novo Nordisk Inc.. Other Relationship; Self; Novo Nordisk Inc., Sanofi. Advisory Panel; Self; Sanofi. Speaker's Bureau; Self; Sanofi US. F. Pompilio: Employee; Self; MannKind Corporation. Stock/Shareholder; Self; MannKind Corporation, Amgen Inc. S.R. Bruce: Consultant; Self; MannKind Corporation, Oramed Pharmaceuticals, Inc. M.L. Grant: Employee; Self; MannKind Corporation. Stock/Shareholder; Self; MannKind Corporation. D.M. Kendall: Employee; Self; MannKind Corporation. Employee; Spouse/Partner; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company.
Lower Pharmacokinetic and Pharmacodynamic Within-Day Variability of Individual Clinical Doses of Insulin Glargine 300 U/ml vs. Glargine 100 U/ml in T1DM
Authors: FANELLI CARMINE , LUCIDI PAOLA , CANDELORO PAOLA , CIOLI PATRIZIA , ANDREOLI ANNA MARINELLI , BOLLI GEREMIA B. , PORCELLATI FRANCESCA 
Published: June 2018

Previous studies have examined variability of pharmacokinetics (PK, plasma insulin concentration) and pharmacodynamics (PD, glucose infusion rate, GIR) of basal insulins at steady-state (SS) and at fixed doses in all subjects studied. To establish within-day PK/PD variability of individual, different, doses of insulin Glargine 300 U/ml (Gla-300) vs. Glargine 100 U/ml (Gla-100) that people with T1DM use in real life. Eighteen T1DMs [age 40±11 years, diabetes duration 26±12 years, BMI 23.4±2.1 kg/m2, A1C 7.2±0.5% (55±6 mmol/mol)] were studied after 3 month treatment with Gla-300 and Gla-100 titrated to fasting euglycemia, with a 24 h euglycemic clamp (randomized, crossover). The individual basal insulin doses that subjects used (0.35±0.Gla-300, 0.28±0.07 Gla-100, U/kg) were injected s.c. in the clamp study. Prior to clamp, glycemic control was comparable with Gla-300 and Gla-100. In the clamp, the individual doses of Gla-300 and Gla-100 resulted in 24 h PK/PD bioequivalence, but in lower variability indices of PK/PD with Gla-300 vs. Gla-100 (Table).
In conclusion, at clinical, individual doses used by T1DMs in real life, Gla-300 has lower PK/PD within-day variability vs. Gla-100. These results may explain the lower glycemic variability and lower risk for hypoglycaemia reported in clinical studies with Gla-300 vs. Gla-100.

Disclosure
C. Fanelli: Advisory Panel; Self; Sanofi. Other Relationship; Self; Menarini Group. P. Lucidi: Other Relationship; Self; Abbott, Menarini Group, Sanofi-Aventis. P. Candeloro: None. P. Cioli: None. A. Marinelli Andreoli: None. G.B. Bolli: Speaker's Bureau; Self; Menarini Group, Sanofi. Research Support; Self; Sanofi. F. Porcellati: Advisory Panel; Self; Sanofi. Board Member; Self; Sanofi. Other Relationship; Self; Medtronic. Board Member; Self; Eli Lilly and Company.
Prediction of Nonsevere Hypoglycemia—The Influence of Glycemic Variability in the HypoAna Study
Authors: AGESEN RIKKE M. , KRISTENSEN PETER L. , BECK-NIELSEN HENNING , NØRGAARD KIRSTEN , JENSEN TONNY , THORSTEINSSON BIRGER , TARNOW LISE , PEDERSEN-BJERGAARD ULRIK 
Published: June 2018

Introduction: In the struggle for tight glycemic control many type 1 diabetes patients daily experience large blood glucose fluctuations. It has been demonstrated that increased glucose variability is a predictor of hypoglycemia, which is the main limiting factor for achieving the recommended HbA1c target. The relationship between glucose variability and hypoglycemia might seem intuitive, but the exact nature of the relationship is difficult to elucidate. In this study we wanted to clarify the relationship between occurrence of non-severe hypoglycemia and glycemic variability in type 1 diabetic patients at high risk of severe hypoglycemia.
Material and Methods: 72 patients participated for 4 x 3 days of blinded CGM recordings during a 2-year randomized balanced cross-over study with human insulins (regular/NPH) and insulin analogs (aspart/detemir). CGM recordings were used to calculate the coefficient of variation (CV) in glucose.
Results: Treatment with insulin analogs resulted in a significant lower nocturnal CV (mean 29.2%, SD 9.1) than treatment with human insulin (mean 36.9%, SD 9.1) (p&lt;0.0001). CV was a significant risk marker of nocturnal asymptomatic hypoglycemia ?3.9 mmol/l in a multivariate analysis. A 1% increase in CV corresponds to a 5% (p&lt;0.0001) increase in asymptomatic hypoglycemia. CV did not predict hypoglycemia during daytime at this threshold.
Conclusion: Treatment with insulin analogs provides less glycemic variability during night-time. The coefficient of variation in patients suffering from recurrent severe hypoglycemia predicts the occurrence of especially nocturnal hypoglycemia.

Disclosure
R.M. Agesen: None. P.L. Kristensen: Other Relationship; Self; Eli Lilly and Company. H. Beck-Nielsen: None. K. Nørgaard: Research Support; Self; Roche Diabetes Care Health and Digital Solutions. Advisory Panel; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. Research Support; Self; Novo Nordisk A/S. Advisory Panel; Self; Medtronic. Speaker's Bureau; Self; Medtronic, Zealand Pharma A/S, Novo Nordisk A/S. Research Support; Self; Zealand Pharma A/S. T. Jensen: Stock/Shareholder; Self; Novo Nordisk A/S. B. Thorsteinsson: None. L. Tarnow: Stock/Shareholder; Self; Novo Nordisk A/S. U. Pedersen-Bjergaard: Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Novo Nordisk A/S. Research Support; Self; Novo Nordisk A/S. Advisory Panel; Self; Sanofi-Aventis. Consultant; Self; Medtronic.
The Use of Supportive Tools and Education Enables Self-Titration with Insulin Glargine 300 (Gla-300) or 100 U/mL (Gla-100) in People with Type 2 Diabetes (T2DM)—Results from TAKE CONTROL, INNOVATE, and AUTOMATIX
Authors: KVAPIL MILAN , BONNEMAIRE MIREILLE , GOYEAU HARMONIE , PAPANAS NIKOLAOS , POPESCU LUIZA , SCHULTES BERND , SIEBER JOCHEN , DUVNJAK LEA 
Published: June 2018

Supporting people with T2DM with education and titration tools may empower them to optimize basal insulin self-titration in order to reach glycemic targets. Three multicenter, randomized, open-label, parallel-group studies have investigated self-titration (supported by either a paper algorithm, web tool or device) vs. physician-led titration in people with T2DM, switching to or initiating Gla-300 (TAKE CONTROL and AUTOMATIX) or Gla-100 (INNOVATE). Fasting blood glucose targets for self-titration were 80-130 mg/dL (4.4-7.2 mmol/L) in TAKE CONTROL and 90-130 mg/dL (5.0-7.2 mmol/L) in both INNOVATE and AUTOMATIX. Self-titration resulted in greater or similar mean HbA1c reductions from baseline vs. physician-led titration (Table). By using self-titration with Gla-300, more people with T2DM achieved fasting glucose targets without confirmed or severe hypoglycemia vs. physician-led titration (TAKE CONTROL and AUTOMATIX). Severe hypoglycemia and other safety outcomes were similar between titration arms in all 3 studies. Self-titration with Gla-300 and Gla-100 using either a paper or device-based algorithm resulted in improved or similar reductions in HbA1c, without an increased risk of hypoglycemia or safety concerns.

Disclosure
M. Kvapil: None. M. Bonnemaire: Employee; Self; Sanofi. Stock/Shareholder; Self; Sanofi. H. Goyeau: Employee; Self; Sanofi. Stock/Shareholder; Self; Sanofi. N. Papanas: None. L. Popescu: Employee; Self; Sanofi. Stock/Shareholder; Self; Sanofi. B. Schultes: Advisory Panel; Self; Novo Nordisk A/S, Sanofi, AstraZeneca, Eli Lilly and Company, Bayer AG, Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Sanofi, Eli Lilly and Company, MSD K.K., Bayer AG, Boehringer Ingelheim GmbH. J. Sieber: Employee; Self; Sanofi. Stock/Shareholder; Self; Sanofi. L. Duvnjak: None.
Impact of Endogenous Insulin Adjustment Methods on the Assessment of Insulin Pharmacokinetics and Pharmacodynamics
Authors: CHUNG SANG M. , PENZENSTADLER JUSTIN A. , KHURANA MANOJ , SAHAJWALLA CHANDRAHAS 
Published: June 2018

Assessing reliable insulin pharmacokinetics (PK) and pharmacodynamics (PD) following an exogenous insulin administration is a scientific challenge due to the circulating endogenous insulin. Effect of exogenous insulin on the endogenous insulin through the sensitive glucose homeostatic system in the body could further confound the PK/PD data. We compared results of PK/PD parameters of methods in literature for the estimation of insulin PK and PD, namely total method without adjustment (method 1), a simple baseline method (method 2), elimination rate constant method (method 3), empirical C-peptide correction method (method 4), and conventional PK/PD modeling method (method 5). We also developed new PK/PD modeling method reflecting the effect of glucose on endogenous insulin release based on C-peptide (method 6). Subject-level time-matching insulin and glucose concentrations without external glucose administration were collected from clinical trials with regular human insulin administration to healthy subjects under fasting conditions (n=23). Primary insulin PK parameters (i.e., the maximum concentration (Cmax) and area under the concentration-time profile (AUC)) were estimated using subjects’ insulin, glucose and C-peptide level data. Our results indicate that insulin AUC and Cmax differ by up to 32 and 17%, respectively, among different methods. Further, the contribution of endogenous insulin to total insulin AUC is estimated to be approximately 55% but varies depending upon estimation methods. Insulin PD parameters are apparently similar among different methods (e.g., area under the glucose concentration-time profile; 8121.4 and 8293.3 mg/dL*min for method 1-5 and method 6, respectively).
The results call for a careful selection of the method for the assessment of insulin PK and PD parameters depending upon the objectives of study as the relationship between PK and PD could vary among methods and may lead to misinterpretation of data.

Disclosure
S.M. Chung: None. J.A. Penzenstadler: None. M. Khurana: None. C. Sahajwalla: None.
Electron Microscopic Findings of Insulin-Induced Local Amyloidosis
Authors: SENDUR SULEYMAN , KATIPOGLU KUBRA , KOCKARA OZGE , GÖKÖZ ÖZAY , KAYMAZ FIGEN , DAGDELEN SELCUK 
Published: June 2018

Introduction: Insulin-induced local amyloidosis (ILA) was firstly described in 1983, but still underdiagnosed. Here we describe clinicopathological and electron microscopic findings of a case with ILA. Case: A 52-year-old male with type 2 diabetes mellitus for 14 years, on basal-bolus insulin (i.e., insulin lispro and glargine), had noticed 2x2 cm mass at injection site. MRI showed a fibrous mass at the subcutaneous tissue. Punch biopsy of the lesion revealed amyloid deposition surrounded by giant cells. Immunohistochemistry studies proved that amyloid material is insulin. Electron microscopic evaluation (EM) revealed both extra-, and intracellular amyloid fibrils (Figure 1A,B). Discussion: Local amyloid deposition due to insulin injection could be seen in both types of diabetes. Despite earlier reports were associated with porcine insulin, subsequent publications linked also with human insulin and recombinant insulin analogues. High doses of insulin and inappropriate insulin injections are the major risk factors. Extracellular amyloid deposits in ILA arises primarily from exogenous insulin, but the precise mechanism of pathogenicity remains to be established. There are only few case reports of ILA with EM. To the best of our knowledge, here in this case we have firstly showed intracellular accumulation of those amyloid fibrils as well as extracellular compartment, which might have further clinical implications.

Disclosure
S. Sendur: None. K. Katipoglu: None. O. Kockara: None. Ö. Gököz: None. F. Kaymaz: None. S. Dagdelen: None.
Identification of Subpopulations Exhibiting the Greatest Cardiovascular Benefit from Long-Acting Glucagon-Like Peptide-1 Receptor Agonists—A Combined Analysis of Large Cardiovascular Outcome Trials
Authors: KANG YU MI , CHO YUN KYUNG , CHOI JONG HAN , WOO CHANGYUN , LEE WOO JE , PARK JOONG-YEOL , JUNG CHANG HEE 
Published: June 2018

Background: By combining the results of three large cardiovascular outcome trials (CVOTs) of glucagon-like peptide 1 receptor agonists (GLP-1 RAs), we aimed to investigate the overall effect of GLP-1 RAs on major cardiovascular events (MACE) and identify subpopulations exhibiting the greatest cardiovascular (CV) benefit.
Methods: Three multicenter, randomized, double-blind, placebo-controlled CVOTs of long-acting GLP-1 RAs were included: LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results), SUSTAIN-6 (Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes) and EXSCEL (Exenatide Study of Cardiovascular Event Lowering). The primary endpoint was three-point MACE (i.e., CV death, non-fatal myocardial infarction, and non-fatal stroke). Overall effect estimates were calculated as hazard ratios (HRs) and 95% confidence intervals (CIs) using the random-effects model; pre-defined subgroup analyses were performed.
Results: Overall, significant risk reductions in MACE (relative risk [RR]: 0.88 [95% CI: 0.81-0.97]) and CV death (RR: 0.85 [95% CI: 0.75-0.95]) were observed. Subgroup analysis indicated significant racial differences in this CV benefit (P for test of difference &lt; 0.001). Risk reductions were observed in subjects of black race (RR: 0.78 [95% CI: 0.60-0.99]) and Asians (RR: 0.35 [95% CI: 0.09-1.32]). However, post-hoc analysis using Bonferroni correction revealed that only Asians exhibited a significantly greater CV benefit from treatment, compared with subjects of white race (P &lt; 0.0001).
Conclusions: Long-acting GLP-1 RAs reduced risks of MACE and CV deaths in diabetic study populations, and racial difference in the CV benefit was observed. The existence of extra CV benefit in Asians and the underlying mechanisms should be investigated in the future.

Disclosure
Y. Kang: None. Y. Cho: None. J. Choi: None. C. Woo: None. W. Lee: None. J. Park: None. C. Jung: None.
Lesser eGFR Decline with Dulaglutide Regardless of Weight Changes in People with Type 2 Diabetes and Moderate to Severe Chronic Kidney Disease (AWARD-7)
Authors: TUTTLE KATHERINE R. , LAKSHMANAN MARK , RAYNER BRIAN L. , BUSCH ROBERT S. , ZIMMERMANN ALAN G. , WOODWARD BRAD , BOTROS FADY T. 
Published: June 2018

Body weight (BW) changes may affect muscle mass and thus creatinine (Cr) levels. Estimating glomerular filtration rate (eGFR) by Cr-based equations may not accurately reflect changes in kidney function when BW changes. Dulaglutide (DU) treatment was associated with BW loss and lesser eGFR (Cr-CKD-EPI) decline in people with T2D and moderate to severe CKD compared to insulin glargine (IG) (Table). The aim was to evaluate if the lesser eGFR decline observed with DU is related to BW loss. eGFR was evaluated with Cr-based equations (MDRD, CKD-EPI) compared to cystatin C-CKD-EPI equation. Cystatin C is not affected by muscle mass changes. CrCL was evaluated with the Cockcroft-Gault equation. BL characteristics were similar between treatments ([mean±SD] eGFR (Cr-CKD-EPI): 38.3±12.8 mL/min/1.73m2, A1c: 8.6±1.0%, age: 64.6±8.6 y, T2D duration: 18.1±8.7 y). All equations consistently show that eGFR remained stable with DU, but significantly decreased with IG regardless of BW loss in DU or gain in IG (Table). Since BW is a factor in CrCL calculations, compared to eGFR equations, BW loss in DU led to bias toward greater reductions in CrCL. This bias disappeared when using lean BW (Table).
In conclusion, compared to IG, DU was associated with lesser eGFR decline in people with T2D and moderate to severe CKD regardless of BW changes.

Disclosure
K.R. Tuttle: Consultant; Self; Eli Lilly and Company, Boehringer Ingelheim GmbH, AstraZeneca, Gilead Sciences, Inc. M. Lakshmanan: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. Stock/Shareholder; Spouse/Partner; Eli Lilly and Company. B.L. Rayner: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Speaker's Bureau; Self; Novartis AG, Servier. Advisory Panel; Self; AstraZeneca. R.S. Busch: Speaker's Bureau; Self; AbbVie Inc., AstraZeneca. Research Support; Self; Bayer AG, Intarcia Therapeutics, Inc.. Advisory Panel; Self; Janssen Pharmaceuticals, Inc.. Speaker's Bureau; Self; Amgen Inc.. Research Support; Self; Sanofi US. Speaker's Bureau; Self; Eli Lilly and Company, Boehringer Ingelheim Pharmaceuticals, Inc.. Research Support; Self; Amarin Corporation. A.G. Zimmermann: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. Employee; Spouse/Partner; Eli Lilly and Company. Stock/Shareholder; Spouse/Partner; Eli Lilly and Company. B. Woodward: Employee; Self; Eli Lilly and Company. F.T. Botros: Employee; Self; Eli Lilly and Company.