Rationale and Design of the CAROLINA Trial: An Active Comparator CARdiOvascular Outcome Study of the DPP-4 InhibitorLINAgliptin in Patients With Type 2 Diabetes at High Cardiovascular RiskJulio Rosenstock1, Nikolaus Marx2, Steven E. Kahn3, Bernard Zinman4, John J. Kastelein5, John Lachin6, Erich Bluhmki7, Arno Schlosser8, Dietmar Neubacher7, Sanjay Patel9, Odd Erik Johansen10, Hans-Jüergen Woerle111Dallas Diabetes and Endocrine Center at Medical City, Dallas, TX, USA; 2Department of Internal Medicine, University Hospital Aachen, Aachen, Germany; 3Department of Medicine, University of Washington, Seattle, WA, USA; 4Mount Sinai Hospital,University of Toronto, Toronto, Canada; 5Department of Vascular Medicine, University of Amsterdam, Amsterdam, The Netherlands; 6Biostatistics Center, George Washington University, Rockville, MD, USA; 7Boehringer Ingelheim, Biberach, Germany;8Boehringer Ingelheim, Alkmaar, The Netherlands; 9Boehringer Ingelheim, Bracknell, UK; 10Boehringer Ingelheim, Asker, Norway; 11Boehringer Ingelheim, Ingelheim, Germany • Treating hyperglycemia in type 2 diabetes mellitus (T2DM) can reduce the onset and progression • CAROLINA is a head-to-head, event-driven, multicenter, randomized, double-blind, active Study Interventions
Statistical Analysis
• Clinical studies of most glucose-lowering drugs have failed to demonstrate of microvascular complications; however, the effect on macrovascular complications remains comparator study designed to compare treatment with linagliptin versus glimepiride both as • Patients will enter a 2-week, open-label, placebo run-in phase up to 4 weeks before being • The primary objective of CAROLINA is to demonstrate the non-inferiority (by means of comparing monotherapy or as add-on therapy to metformin or α-glucosidase inhibitors (NCT01243424) randomly assigned to 1 of the following treatment groups (Figure 1): the upper limit of a 2-sided 95% confidence interval with the non-inferiority margin of 1.3) of a beneficial effect on CV complications, which is the leading cause of • The successful management of T2DM complications may be limited by the anti-diabetic drugs – Masked linagliptin 5 mg plus placebo once daily, or treatment with linagliptin versus glimepiride with respect to time to first occurrence of any of the Patient Recruitment and Eligibility
currently available; limitations include: • Approximately 700 trial centers in 45 countries will participate to ensure that at least 6000 patients – Masked glimepiride 1–4 mg plus placebo once daily • Long-term efficacy of oral glucose-lowering drugs is equivocal and AEs can – Adverse events (AEs) and contraindications in certain patient populations • If non-inferiority is achieved, the secondary primary objective is to demonstrate CV superiority of • After a starting dose of 1 mg/day, glimepiride will be up-titrated to a potential maximum dose linagliptin versus glimepiride with a hypothesized risk reduction of 20% limit their use in certain at-risk patient populations – Inadequate efficacy to maintain treatment goals beyond 5 to 10 years • Patients with T2DM without optimal glycemic control and at high risk of CV events will be enrolled of 4 mg/day at 4-week intervals during the first 16 weeks of treatment (if the fasting bloodglucose values are >110 mg/dL [6.1 mmol/L]) • At an estimated annual CV event rate of 2% for the primary event definition for glimepiride, – Concerns regarding cardiovascular (CV) safety – Other inclusion criteria are body mass index ≤45 kg/m2, and age ≥40 and ≤85 years 631 events will be required to provide 91% power to yield the upper limit of the adjusted 95% • Concerns regarding the CV safety of some treatment modalities requires • Patients on previous glimepiride treatment may continue on their current dose (e.g., if the • The oral anti-diabetic drug linagliptin, a dipeptidyl peptidase (DPP)-4 inhibitor, has recently • At screening, the dose of anti-diabetic background therapy should have been stable for at least 8 weeks confidence interval for a hazard ratio <1.3 at a 1-sided α level of 0.025 assuming equal risks and further investigation in large, head-to-head, active-comparator studies glimepiride dose was ≥4 mg/day, the masked starting dose will be 4 mg/day) become available for the treatment of T2DM 80% power to demonstrate superiority at a true hazard ratio of 0.8 • The masked dose of glimepiride can be altered to prevent recurrent hypoglycemic events at any time – In clinical trials, linagliptin once daily improved glycemic control without weight gain and • All other secondary analyses will be exploratory with no correction for multiple hypotheses • Although there is a need for the development of new anti-diabetic therapies Glycemic Entry Criteria
demonstrated a benign safety and tolerability profile without the need for dose adjustment in testing. All statistical tests and confidence intervals will be 2-sided with a significance level with increased efficacy, it is essential to explore long-term safety, in Insufficient glycemic control defined as:
Figure 1: Study design
Masked linagliptin 5 mg/day
Interim Assessments
HbA1c 6.5–8.5% while patient is treatment naïve or treated with: • An independent Data Monitoring Committee (DMC) will perform formal interim analyses of the • The CAROLINA trial is investigating the long-term impact on CV morbidity Screening
primary outcome and, in consultation with the Steering Committee and the Sponsor, will decide and mortality of treatment with linagliptin in a patient population α-glucosidase inhibitor monotherapy (e.g., acarbose, voglibose), or on the number and timepoints of the interim analyses without sharing the results iii) metformin plus α-glucosidase inhibitor (e.g., acarbose, voglibose), or • With preliminary evidence from short-term trials suggesting that DPP-4 inhibitors are associated Masked glimepiride 1–4 mg/day
– The DMC might recommend terminating the trial after an interim analysis HbA1c 6.5–7.5% while patient is treated with: with potential CV benefits, long-term studies are now required • The CAROLINA study population at an earlier stage of T2DM may provide Sub-Studies
• In keeping with the spirit of comparative effectiveness testing for new diabetes drugs, ideally glinide monotherapy (e.g., repaglinide, nateglinide), or • Several sub-studies are planned to explore key epidemiologic information and further examine an opportunity to test the impact of DPP-4 inhibitors and sulfonylureas on long-term CV outcome trials need to have active comparators iii) metformin plus sulfonylurea (combination maximal up to 5 years), or the potential benefits of linagliptin and glimepiride (Table 1) • The CAROLINA (CARdiOvascular Safety of LINAgliptin) trial will investigate the long-term iv) metformin plus glinide (combination maximal up to 5 years), or impact on CV morbidity and mortality of treatment with linagliptin or glimepiride, a widely used α-glucosidase inhibitor plus sulfonylurea (combination maximal up to 5 years), or Randomization at Visit 2 (Study Week 0; Baseline) vi) α-glucosidase inhibitor plus glinide (combination maximal up to 5 years) *16-week titration phase: glimepiride uptitrated from 1 mg/day to 4 mg/day at 4-week intervals Table 1: Outline of planned sub-studies
– The trial will be conducted with linagliptin versus glimepiride both administered as monotherapy or as add-on therapy to metformin or α-glucosidase inhibitors Sub-study
Primary outcome
CV Risk Entry Criteria
• In addition to important efficacy and safety parameters, the trial will include a number of sub-studies • After randomization, study visits are scheduled to occur monthly until 4 months, and then designed to advance further our understanding of DPP-4 inhibition in the management of patients High risk of CV events defined as any 1 (or more) of a), b), c), or d):
• CAROLINA, as an active control trial, is unique among CV outcomes – All patients, including those who discontinue treatment, will be followed up until the end of the study studies of DPP-4 inhibitors as it aims to demonstrate the non-inferiority of • Rescue treatments to maintain glucose levels at HbA1c ≤7.5% (58 mmol/mol) are permitted treatment with linagliptin versus glimepiride with respect to time to first throughout the study and include metformin, pioglitazone, or insulin Documented coronary artery disease (≥50% luminal diameter narrowing of left main coronary occurrence of any of the components of the primary composite CV outcome – Dosing will be according to local labeling and at the investigator’s discretion artery or in at least 2 major coronary arteries in angiogram) iii) Percutaneous coronary intervention >6 weeks • All patients should be provided healthy lifestyle advice • If non-inferiority is achieved, the secondary primary objective is to Primary Outcomes
iv) Coronary artery bypass grafting >4 years or with recurrent angina following surgery • The protocol also encourages the treatment of all other CV risk factors (lipid levels, blood pressure, • The time to the first occurrence of any of the following components of the MACE composite demonstrate CV superiority of linagliptin versus glimepiride with a Ischemic or hemorrhagic stroke (>3 months) micro/macroalbuminuria, smoking) according to local or regional guidance for primary or secondary vi) Peripheral occlusive arterial disease variability and CV biomarkers (oxidation, Evidence of vascular related end-organ damage: Moderately impaired renal function (as defined by Modified Diet in Renal Disease [MDRA] formula) Assessments
• The more homogeneous early stage of the study population in the with estimated glomerular filtration rate 30–59 mL/min/1.73 m2 CAROLINA trial will provide valuable information on the maintenance of Random spot urinary albumin:creatinine ratio ≥30 µg/mg in 2 of 3 specimens in the previous 12 months – Physical examination, vital signs, laboratory markers (including lipid profile), a check for AEs Impact on insulin secretion rate assessed by long-term glycemic control following DPP-4 inhibition iii) Proliferative retinopathy defined as retinal neovascularization or previous retinal laser coagulation therapy – Hospitalization for unstable angina pectoris and concomitant therapies, 12-lead electrocardiogram (ECG) Age ≥70 years (<25% of the study population) • The CV death component includes sudden cardiac death and death due to: • At selected visits as part of sub-studies: • In addition, the impact of glimepiride treatment on CV outcomes will be At least 2 of the following CV risk factors (<25% of the study population): – Collection of biomarkers (fasting proinsulin, C-peptide, antibodies toward the pancreatic β cell, Systolic blood pressure >140 mm Hg (or on at least 1 blood pressure-lowering treatment) troponin T, inflammatory markers, endothelial function markers, and markers of oxidative stress), pharmacogenetic sampling, periods with continuous glucose monitoring, periods with • The sub-studies will also help further our knowledge regarding the – Cerebrovascular event (intracranial hemorrhage or non-hemorrhagic stroke) iv) LDL-cholesterol ≥135 mg/dL (3.5 mmol/L) (or specific current treatment for this lipid abnormality) mixed meal tolerance testing for detailed β cell function assessment, cognitive function tests, and treatment and management of T2DM, as well as the mechanism of action of a self-reporting depression questionnaire assessment of CV prophylactic properties Safety Evaluations
Secondary Outcomes
Key Exclusion Criteria
• The occurrence of and time to each of the following events: CV death (including fatal stroke and • Treatment sustainability (need for rescue treatment to maintain glycated hemoglobin (HbA1c) Use of rescue therapy and disease trajectory fatal MI), non-fatal MI, non-fatal stroke, hospitalization for unstable angina pectoris, stable angina • Any treatment with other glucose-lowering drugs (e.g., rosiglitazone, pioglitazone, GLP-1 receptor pectoris, transient ischemic attack, hospitalization for congestive heart failure, hospitalization for agonists, DPP-4 inhibitors, or any insulin) • Treatment with anti-obesity drugs 3 months prior to screening • The incidence and intensity of AEs, physical examination, vital signs, ECG, change from baseline • Uncontrolled hyperglycemia with a fasting glucose level >240 mg/dL (>13.3 mmol/L) Boehringer Ingelheim would like to thank the patients and staff participating in this study. This work was supported by Boehringer Ingelheim. Medical writing support was provided by Paul MacCallum • Active liver disease or impaired hepatic function as per specific enzyme criteria • The proportion of patients with asymptomatic, symptomatic, and severe hypoglycemic episodes of Envision Scientific Solutions during the preparation of this poster and was supported by • The change from baseline in weight and proportion of patients with ≤2% or >2% weight gain • Any previous (or planned within next 12 months) bariatric surgery or intervention Boehringer Ingelheim. The authors were fully responsible for all content and editorial decisions, and • Pre-planned coronary artery re-vascularization within next 6 months • AEs of special interest (hypersensitivity reactions, skin lesions, hepatic events, renal AEs, pancreatitis) were involved at all stages of poster development.
Poster: 1103-P, 71st Scientific Sessions of the American Diabetes Association, San Diego, California, June 24–28, 2011
Author Contact Information: Dr Odd Erik Johansen, Boehringer Ingelheim, Drengsrudbekken 25, 1373 Asker, Norway. Tel: +47 91817674
Boehringer Ingelheim 2011


Annals of Internal Medicine Blood Tests to Diagnose Fibrosis or Cirrhosis in Patients With Chronic Hepatitis C Virus Infection A Systematic Review Roger Chou, MD, and Ngoc Wasson, MPH Background: Many blood tests have been proposed as alternatives let count, age–platelet index, APRI, and Hepascore had medianto liver biopsy for identifying fibrosis or cirrhosis. positive likelihood

Management of patients with coronary artery disease

MANAGEMENT OF PATIENTS WITH CORONARY ARTERY DISEASE Department of Periodontics and Oral MedicineUniversity of Michigan - School of DentistryTelephone: (734) 763-3375 FAX: (734) 764-2469CAD Common in General Population• > 60 million with cardiovascular disease• Heart disease leading cause of death- More than 30% of deaths- Most are acute myocardial infarction- > 5l4,000 die each ye

Copyright © 2010-2019 Pdf Physician Treatment