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Indianapolis, IN, United States

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Eriksen E.F.,University of Oslo | Keaveny T.M.,University of California at Berkeley | Gallagher E.R.,inVentiv Health | Krege J.H.,Lilly United States LLC
Bone | Year: 2014

Teriparatide is a skeletal anabolic treatment for patients with osteoporosis at high risk for fracture. Because adequate clinical trials have not yet been conducted to assess the efficacy of teriparatide for reducing the risk of hip fracture, we review here the literature regarding how treatment with teriparatide affects the hip in patients with osteoporosis. Teriparatide increases cancellous bone volume, improves bone architecture, and - uniquely among osteoporosis treatments - increases cortical thickness and cortical porosity. By bone scan and positron emission tomography, teriparatide increases bone formation throughout the skeleton, including the hip. Consistent with these findings, studies using dual-energy X-ray absorptiometry and quantitative computed tomography for longitudinal assessment of changes at the hip have consistently shown increases in areal and volumetric bone mineral density, cortical thickness, and finite element-estimated hip strength in patients treated with teriparatide. Finally, in clinical fracture-outcome trials, treatment with teriparatide has been shown to reduce the risk of nonvertebral fracture, a composite endpoint that includes hip fracture. Taken together, this body of evidence suggests that teriparatide positively affects the hip in patients with osteoporosis. © 2014 Elsevier Inc.


Buse J.B.,University of North Carolina at Chapel Hill | Bergenstal R.M.,International Diabetes Center at Park Nicollet | Glass L.C.,Eli Lilly and Company | Heilmann C.R.,Eli Lilly and Company | And 4 more authors.
Annals of Internal Medicine | Year: 2011

Background: Insulin replacement in diabetes often requires prandial intervention to reach hemoglobin A1c (HbA1c) targets. Objective: To test whether twice-daily exenatide injections reduce HbA1c levels more than placebo in people receiving insulin glargine. Design: Parallel, randomized, placebo-controlled trial, blocked and stratified by HbA1c level at site, performed from October 2008 to January 2010. Participants, investigators, and personnel conducting the study were masked to treatment assignments. (ClinicalTrials.gov registration number: NCT00765817) Setting: 59 centers in 5 countries. Patients: Adults with type 2 diabetes and an HbA1c level of 7.1% to 10.5% who were receiving insulin glargine alone or in combination with metformin or pioglitazone (or both agents). Intervention: Assignment by a centralized, computer-generated, random-sequence interactive voice-response system to exenatide, 10 μg twice daily, or placebo for 30 weeks. Measurements: The primary outcome was change in HbA1c level. Secondary outcomes included the percentage of participants with HbA1c values of 7.0% or less and 6.5% or less, 7-point selfmonitored glucose profiles, body weight, waist circumference, insulin dose, hypoglycemia, and adverse events. Results: 112 of 138 exenatide recipients and 101 of 123 placebo recipients completed the study. The HbA1c level decreased by 1.74% with exenatide and 1.04% with placebo (between-group difference, -0.69% [95% CI, -0.93% to -0.46%]; P < 0.001). Weight decreased by 1.8 kg with exenatide and increased by 1.0 kg with placebo (between-group difference, -2.7 kg [CI, -3.7 to -1.7]). Average increases in insulin dosage with exenatide and placebo were 13 U/d and 20 U/d. The estimated rate of minor hypoglycemia was similar between groups. Thirteen exenatide recipients and 1 placebo recipient discontinued the study because of adverse events (P < 0.010); rates of nausea (41% vs. 8%), diarrhea (18% vs. 8%), vomiting (18% vs. 4%), headache (14% vs. 4%), and constipation (10% vs. 2%) were higher with exenatide than with placebo. Limitations: The study was of short duration. There were slight imbalances between groups at baseline in terms of sex, use of concomitant glucose-lowering medications, and HbA1c levels, and more exenatide recipients than placebo recipients withdrew because of adverse events. Conclusion: Adding twice-daily exenatide injections improved glycemic control without increased hypoglycemia or weight gain in participants with uncontrolled type 2 diabetes who were receiving insulin glargine treatment. Adverse events of exenatide included nausea, diarrhea, vomiting, headache, and constipation. Primary Funding Source: Alliance of Eli Lilly and Company and Amylin Pharmaceuticals. © 2011 American College of Physicians.


Mease P.J.,Swedish Medical Center | Hanna S.,I3 Statprobe | Frakes E.P.,Lilly United States LLC | Altman R.D.,University of California at Los Angeles
Journal of Rheumatology | Year: 2011

In this literature review, the mechanisms underlying pain associated with osteoarthritis (OA) are discussed, along with evidence for the efficacy of medications thought to act centrally to relieve OA pain. We survey the cascade of events from inflammation to activation of nociceptive and neuropathic pathways, to the development and maintenance of central and peripheral sensitization. Preclinical and clinical evidence for the sensitization hypothesis is discussed, along with recently identified genetic variations that may increase sensitivity to pain in patients with OA. Evidence is presented for the efficacy of centrally acting analgesics for OA pain (opioids, antiepileptics, tricyclic antidepressants, and serotonin/norepinephrine receptor inhibitors). The Journal of Rheumatology Copyright © 2011. All rights reserved.


Krege J.H.,Lilly United States LLC | Wan X.,Lilly United States LLC
Bone | Year: 2012

Purpose: In the Fracture Prevention Trial, the risks of any nonvertebral fracture (relative risk [RR] 0.65, P= 0.04) and any fragility nonvertebral fracture (RR 0.47, P= 0.02) were significantly reduced in the teriparatide 20. μg/day (teriparatide) versus placebo group. The purpose of this analysis was to examine the efficacy of teriparatide versus placebo on a variety of other nonvertebral fracture outcomes. Materials and methods: The Fracture Prevention Trial was a double-blind trial of postmenopausal women with osteoporosis and vertebral fractures randomly assigned to teriparatide ( N= 541) or placebo ( N= 544) administered by daily self-injection for a median of 19. months and a median follow-up of 21. months. All patients received calcium and vitamin D supplementation. Reports of nonvertebral fractures were collected from patients at each visit and confirmed by review of a radiograph or written radiology report. Nonvertebral fractures were recorded for the following sites: distal radius/wrist, humerus, rib/clavicle, hip, ankle, distal foot, pelvis, or other. Pathological fractures and fractures of the face, skull, metacarpals, fingers and toes were excluded. Fractures were classified by investigators as fragility or traumatic fractures. The three endpoints considered were six nonvertebral sites (nonvert-6), a set of common nonvertebral fractures described in a Food and Drug Administration Guidance document for the treatment and prevention of postmenopausal osteoporosis (FDA), and a European Union major set (major) of nonvertebral fractures. Results: For teriparatide versus placebo, the point estimates for the RR of nonvert-6 (RR 0.54, P= 0.06; fragility RR 0.32, P= 0.014), FDA (RR 0.60, P= 0.15; fragility RR 0.38, P= 0.05), and major (RR 0.52, P= 0.02; fragility RR 0.38, P= 0.02) nonvertebral fracture endpoints were smaller than for the all nonvertebral fracture endpoint. Lower RRs were observed when the outcomes were limited to fragility fractures, and significant reductions in traumatic nonvertebral fractures were not observed. Conclusion: In the Fracture Prevention Trial, the risk reduction for nonvertebral fracture in patients treated with teriparatide versus placebo depended on the set of nonvertebral fractures included in the analysis; lower RRs were observed for nonvertebral fractures most likely to be of osteoporotic origin. No significant reductions in traumatic nonvertebral fractures were observed. © 2011 Elsevier Inc.


Clemow D.B.,Lilly United States LLC
Postgraduate Medicine | Year: 2014

To raise awareness, this article provides a commentary on the frequent underdosing of atomoxetine for the treatment of adult attention-deficit/hyperactivity disorder (ADHD) that may be associated with poor patient outcomes. Data suggest an adequate atomoxetine dose for sufficient duration is important for ADHD symptom improvement. Despite the recommended 80 mg/day target dose, real-world data show that an approximately 60 mg/day average adult atomoxetine dose is utilized. This article discusses the factors that may contribute to this suboptimal dosing. Atomoxetine dose titration, setting patient expectations, and the importance of keeping the patient at target dose for an adequate length of time (about 4−6 weeks) prior to judging efficacy are also discussed. © Postgraduate Medicine.


Houston J.P.,Lilly United States LLC
Psychosomatics | Year: 2011

To develop an adult self-report instrument for provisional diagnosis of four common mental disorders in primary care patients. Primary care patients were evaluated during routine clinic visits with a self-report screening tool comprised of 85 DSM-IV symptom-based candidate questions. Patients with a physician-assessed provisional diagnosis for generalized anxiety disorder (GAD), major depressive episode (MDE), past/present mania, and adult attention-deficit/hyperactivity disorder (ADHD), or none of these, completed additional self-report clinical questionnaires, and then were interviewed on the telephone by a trained rater for a SCID/ACDS diagnosis. Responses to the symptom-based candidate questions were used to calculate sensitivity and specificity for a SCID/ACDS diagnosis (GAD, N = 24; MDE, N = 89; Mania, N = 24; ADHD, N = 65) and to select the optimal four questions for each diagnosis to be included in the instrument. Analyses resulted in a 17-item instrument for provisional differential diagnosis of GAD, MDE, past/present mania, and ADHD. Comparison of limited symptom-based versus full DSM-IV criteria-based diagnosis showed minimal differences for relative diagnostic accuracy. Sensitivities and specificities, respectively, were 83% and 75% for GAD, 80% and 80% for MDE, 83% and 82% for mania, and 82%and 73% for ADHD. Based on this preliminary work, the Provisional Diagnostic Instrument-4 is a brief, easily scored, self-report instrument that may assist primary care physicians to identify potential cases of GAD, MDE, past/present mania, and ADHD. Copyright © 2011 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.


Sontag A.,Lilly United States LLC | Krege J.H.,Lilly United States LLC
Journal of Bone and Mineral Metabolism | Year: 2010

After the occurrence of the first fracture, osteoporosis is no longer a "silent" disease, and the patient's risk for future fracture is increased several fold. We assessed the location of first osteoporotic fractures among women with osteoporosis. The Multiple Outcomes of Raloxifene Evaluation (MORE) trial was a fracture outcomes study of postmenopausal women with osteoporosis. All subjects received supplements containing 500 mg elemental calcium and 400-600 IU vitamin D. We assessed the location of first fractures among women with osteoporosis and no previous fractures at baseline from the placebo group of this trial after 3 years of follow-up. Prespecified fracture sites included vertebral fractures and nonvertebral fractures as defined in the MORE study protocol. Among 875 women (mean age, 64.5 ± 7.4 years) with no prevalent vertebral or nonvertebral fractures, 9% experienced their first fracture event during the trial. Fractures of radius and spine each occurred in 3% of patients. Fractures at other individual sites included ankle (0.6%), metatarsal (0.6%), humerus (0.5%), rib (0.5%), patella (0.3%), leg (0.2%), hip (0.2%), and clavicle (0.1%). These data suggest that for postmenopausal women with osteoporosis but no previous fractures, skeletal care should include a focus on preventing spine and radius fractures. © The Japanese Society for Bone and Mineral Research and Springer 2009.


Rosen R.C.,New England Research Institutes, Inc. | Allen K.R.,New England Research Institutes, Inc. | Ni X.,Lilly United States LLC | Araujo A.B.,New England Research Institutes, Inc.
European Urology | Year: 2011

Background: Despite widespread adoption of the six-item erectile function (EF) domain of the International Index of Erectile Function (IIEF) as a clinical trial end point, there are currently no objective data on what constitutes a minimal clinically important difference (MCID) in the EF domain. Objective: Estimate the MCID for the IIEF EF domain. Design, setting, and participants: Anchor-based MCIDs were estimated using data from 17 randomized, double-blind, placebo-controlled, parallel-group clinical trials of the phosphodiesterase type 5 inhibitor (PDE5-I) tadalafil for 3345 patients treated for 12 wk. Measurements: The anchor for the MCID is the minimal improvement measure calculated using change from baseline to 12 wk on IIEF question 7: "Over the past 4 weeks, when you attempted sexual intercourse how often was it satisfactory for you?" MCIDs were developed using analysis of variance (ANOVA)- and receiver operating characteristic (ROC)-based methods in a subset of studies (n = 11) by comparing patients with and without minimal improvement (n = 863). MCIDs were validated in the remaining six studies (n = 377). Results and limitations: The ROC-based MCID for the EF domain was 4, with estimated sensitivity and specificity of 0.74 and 0.73, respectively. MCIDs varied significantly (p < 0.0001) according to baseline ED severity (mild: 2; moderate: 5; severe: 7). MCIDs consistently distinguished between patients in the validation sample classified as no change or minimally improved overall and by geographic region, ED etiology, and age group. MCIDs did not differ by age group, geographic region, or ED etiology. Current analyses were based on 17 clinical trials of tadalafil. Results need to be replicated in studies using other PDE5-Is or in nonpharmacologic intervention studies. Conclusions: The contextualization of treatment-related changes in terms of clinically relevant improvement is essential to understanding treatment efficacy, to interpreting results across studies, and to managing patients effectively. This analysis provides, for the first time, anchor-based estimates of MCIDs in the EF domain score of the IIEF. © 2011 European Association of Urology.


Smith P.K.,Duke University | Goodnough L.T.,Stanford University | Levy J.H.,Emory University | Poston R.S.,University of Arizona | And 3 more authors.
Journal of the American College of Cardiology | Year: 2012

Objectives: The objective of this study was to characterize the bleeding, transfusion, and other outcomes of patients related to the timing of prasugrel or clopidogrel withdrawal before coronary artery bypass grafting (CABG). Background: There is little evidence to guide clinical decision making regarding the use of prasugrel in patients who may need urgent or emergency CABG. Experience with performing CABG in the presence of clopidogrel has raised concern about perioperative bleeding complications that are unresolved. Methods: A subset of the TRITON-TIMI 38 study (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel- Thrombolysis In Myocardial Infarction 38), in which patients with acute coronary syndrome were randomized to treatment with aspirin and either clopidogrel or prasugrel, underwent isolated CABG (N = 346). A supplemental case report form was designed and administered, and the data combined with the existing TRITON-TIMI 38 database. Baseline imbalances were corrected for using elements of the European System for Cardiac Operative Risk Evaluation and The Society of Thoracic Surgeons predictive algorithm. Results: A significantly higher mean 12-h chest tube blood loss (655 ± 580 ml vs. 503 ± 378 ml; p = 0.050) was observed with prasugrel compared with clopidogrel, without significant differences in red blood cell transfusion (2.1 U vs. 1.7 U; p = 0.442) or the total donor exposure (4.4 U vs. 3.0 U; p = 0.463). All-cause mortality was significantly reduced with prasugrel (2.31%) compared with 8.67% with clopidogrel (adjusted odds ratio: 0.26; p = 0.025). Conclusions: Despite an increase in observed bleeding, platelet transfusion, and surgical re-exploration for bleeding, prasugrel was associated with a lower rate of death after CABG compared with clopidogrel. (A Comparison of Prasugrel [CS-747] and Clopidogrel in Acute Coronary Syndrome Subjects Who Are to Undergo Percutaneous Coronary Intervention; NCT00097591) © 2012 American College of Cardiology Foundation.


Clemow D.B.,Lilly United States LLC | Walker D.J.,Lilly United States LLC
Postgraduate Medicine | Year: 2014

This article reviews the literature concerning attention-deficit/hyperactivity disorder (ADHD) medication misuse, abuse, dependence, diversion, and malingering. The review covers nonmedical use (NMU) of both stimulant (methylphenidate and amphetamine) and nonstimulant (α-adrenergic agonists and atomoxetine) prescription medications, and provides a discussion on the relevance for ADHD treatment today. The neural basis for ADHD medication mechanisms of action (increased norepinephrine and dopamine signaling) and their neurobiochemical relationship to the abuse potential is explored. Regionally-specific, stimulant-induced elevations in brain dopamine appear to be integral to both efficacy in ADHD and potential for abuse. In addition to the prevalence of misuse and diversion, additional topics discussed include the potential safety concerns associated with NMU of prescription ADHD medications and the cost to payers of prescription drug diversion (eg, increased emergency department visits associated with misuse). The evidence describing the difficulty in detecting malingering for the purpose of illicit access to ADHD medications for subsequent misuse or diversion is also summarized. Moreover, the effect of ADHD medications in patients with comorbid substance use disorder and the controversial potential linkage of stimulant prescription use with subsequent substance use disorder are explored. Overall, the data suggest that ADHD medication misuse and diversion are common health care problems for stimulant medications, with the prevalence believed to be approximately 5% to 10% of high school students and 5% to 35% of college students, depending on the study. Stimulant effectiveness and speed of action are deemed desirable to enhance attention and focus performance for activities like studying, but stimulants are also misused recreationally. Conversely, the data suggest a lack of abuse potential and lack of actual medication misuse for the nonstimulant medications. Although they can be efficacious for the treatment of ADHD, the nonstimulants lack a mechanism of action linked to the abuse potential and they lack the desirable effects (speed of action, stimulant feel) that make stimulants susceptible to NMU. In light of these findings, the data suggest a need for close screening and therapeutic monitoring of ADHD medication use. In addition, nonstimulants might be an appropriate alternative for patients with concern about abuse and physicians concerned with general misuse and diversion. © Postgraduate Medicine.

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