C ARDIOVASCULAR R ISK R EDUCTION in T2D

Transcription

1 COMPLETE PROGRAM AGENDA AND FAQs The iq&a Medical Intelligence Zone for C ARDIOVASCULAR R ISK R EDUCTION in T2D Focus on the Role of PPAR Agonists for Comprehensive Cardiometabolic Risk Management in the Setting of Diabetes and ACS QUESTIONS and CONTENT OVERVIEW A. Michael Lincoff, MD Vice Chairman, Department of Cardiovascular Medicine Cleveland Clinic Professor of Medicine Cleveland Clinic Lerner College of Medicine Cleveland, Ohio Question # 1: Can you summarize the mechanisms, role, and classification of PPAR receptors and their role in cardiometabolic and atheroinflammatory processes leading to ASHD in diabetic patients? Question # 2: Can you provide a roadmap to help us understand the variable benefit/toxicity ratios observed among different PPARs, and where aleglitazar fits into this class? Question # 3: What is the importance of the AleNephro trial and what did it teach us about the renal safety of aleglitazar? Question # 4: What are the implications of the AleNephro study as they relate to your ongoing CV outcomes trial, AleCardio? Question # 5: How did previous clinical and imaging trials with TZDs, especially pioglitazone, serve as a nidus of enthusiasm to investigate other PPAR agonists, and influence your design of the AleCardio CV outcomes trial? YOUR QUESTIONS EXPERT ANSWERS

2 Question # 6: How did clinical trial development, especially SYNCHRONY, help translate what appeared to be balanced alpha/ gamma PPAR agonism of aleglitazar into a better real world assessment of its beneficial or possible, off-target effects? Question # 8: Given your extensive investigative experience in post-acs outcome trials, why did you design AleCardio as you did? What was the critical period of modifiable risk you were focused on? Question # 9: Can you bring us up to date on where the AleCardio Trial currently stands as far as enrollment and other ongoing monitoring dimensions, including safety signals? Question # 10: If, in fact, the AleCardio Trial yields results that suggest dual, alpha/gamma PPAR antagonism can reduce CV events in patients with T2D, how might you explain the mechanistic underpinnings of its CV risk-mitigating effects? And what is the post-acs time frame for seeing these effects? Jorge Plutzky, MD Director, The Vascular Disease Prevention Program Cardiovascular Division Brigham and Women s Hospital Associate Professor of Medicine Question # 11: What are the atheroinflammatory processes that connect diabetes to ASHD? And what role do PPARs play in these signaling systems leading to atherosclerosis in T2D? Question # 12: What do the studies with the PPAR agonist rosiglitazone teach us about its role in T2D and can we generalize the results of these studies to other PPAR modulating agents? Why or why not? Question # 13: How does insulin resistance affect the development of ASHD in patients with T2D? And how might insulin sensitization and targeted PPAR agonism inhibit the atheroinflammatory process? Question # 14: What do cardiovascular specialists need to know about the three PPARs, their mechanism of action, fatty acid metabolism, insulin sensitivity, and their role in mitigating progression of atherosclerosis? Question # 15: With respect to biomarkers associated with atheroprogression what did we learn from the SYNCHRONY trial evaluating the safety and effects of the dual alpha/gamma PPAR agonist, aleglitazar? Question # 16: What have we learned from the FIELD and ACCORD trials as they relate to CV risk reduction in diabetes, and directions for future assessment of PPAR-based cardiometabolic modulation? Question # 17: What would the rationale be, if any, for intervening with PPAR-based cardiometabolic risk factor management early, perhaps in patients with dysglycemic syndromes prior to overt manifestations of T2D? R. Scott Wright, MD Consultant, Cardiovascular Diseases Professor of Medicine College of Medicine The Mayo Clinic Rochester, Minnesota Question # 18: What is the relationship between diabetes and acute coronary disease and how might diabetes-associated risk factors be mitigated? Question # 19: What present and near future pharmacologic strategies are likely to play a role in reducing cardiovascular risk in patients with T2D? Question # 20: What do imaging studies teach us about the relationship between dual PPAR agonism and atherosclerotic plaque development in patients with CAD? Question # 21: What is the role of insulin resistance in the progression of ASHD in patients with T2D? Question # 22: What is our current thinking about agents that impact glycemic control in T2D and CV risk? And where might dual PPAR agonists fit into this scheme? Question # 23: What is the rationale for the ALECARDIO trial, which is designed to evaluate the role of the dual PPAR agonist aleglitazar on CV risk in ACS patients with T2D? Question # 24: Why have current therapies for CV risk reduction in diabetes not yet achieved optimal results? And where does a dual PPAR strategy fit into this unmet need for risk reduction? Question # 25: From purely a lipid profile perspective, what should our goals be for optimizing CV risk reduction in T2D? Luis M. Ruilope, MD Associate Professor of Internal Medicine Complutense University of Madrid Head, Hypertension Unit Hospital Octubre Madrid, Spain Question # 26: How did you approach testing the renal safety of the dual PPAR agonist aleglitazar? What was the AleNephro study design? YOUR QUESTIONS EXPERT ANALYSIS

3 Question # 27: What were the results of the AleNephro study? And can you also review your findings related to mitigation of proteinuria? Question # 28: Can you postulate on what the mechanism(s) might be for the reduction of proteinuria seen in patients on aleglitazar in the AleNephro study? Question # 29: Based on the findings you report in the AleNephro studies, what are the clinical and renal safety implications for using aleglitazar in the diabetic patient at risk for CVD? Question # 30: The AleNephro trial was conducted with patients taking aleglitazar for a period of one year. Is that considered sufficient to evaluate renal safety and GFR effects of a medication? Question # 31: What were the findings in the AleNephro Study related to secondary end points such as glycosylated Hgb, blood pressure and lipids? Question # 32: What was the side effect and adverse event profile in the AleNephro trial? Question # 33: Based on all the data available thus far, what are the take home messages from the AleNephro trial evaluating renal safety of aleglitazar? James A. Underberg, MD, MS, FACPM, FACP, FASH, FNLA Preventive CV Medicine, Lipidology and Hypertension Clinical Assistant Professor of Medicine NYU Medical School & NYU Center for CV Prevention Director, Bellevue Hospital Lipid Clinic New York, New York Question # 34: What did the ACCORD and ADVANCE trials teach us about more versus less intensive control of T2D and its impact on risk of CV disease? Question # 35: What did the ENHANCE and ASAP trials teach us about the effects of lipid management on surrogate markers such as carotid IMT for progression of atherosclerosis in patients with FH? Question # 36: What cardiometabolic targets should new therapies focus on to address residual CV risk in diabetic patients, and therefore, what are the implications and rationale for dual PPAR agonists? Question # 37: What important information does the Phase II SYNCHRONY Trial with aleglitazar and pioglitazone give us about the potential CV risk-mitigating effects of dual PPAR agonism? Question # 38: What did we learn from the PERISCOPE trial that used IVUS to evaluate pioglitazone s effect on surrogate markers of ASHD? Question # 39: Can you please give us your evidence-based, multitargeted roadmap for comprehensive cardiometabolic risk reduction in patients with diabetes at risk for ASHD? Question # 40: What is your perspective on the evolving landscape of new, more potent LDL-reducing agents targeting new receptors and deploying new mechanisms of action? Philippe Gabriel Steg, MD, FESC, FACC Director, Coronary Care Unit Hôpital Bichat-Claude Bernard Professor of Cardiology University Paris VII Paris, France Question # 41: What do think are the implications of the FREEDOM Trial for treating diabetic patients with progressive ASHD? Question # 42: Based on our understanding of vasculopathic mechanisms in T2D, what are the most significant unmet therapeutic needs in diabetic patients with coronary artery disease? Question # 43: What did we learn from the CARDS trial about optimizing CV risk reduction in high-risk patients with diabetes? Question # 44: Based on your parsing out of biomarkers and modifiable risk factors that may play a role in CV risk in diabetes, what is the rationale for investigating dual, alpha/ gamma PPAR agonists for CV risk reduction in T2D? Question # 45: What is the role of obesity as a generator of ASHD in diabetic patients? Michael Davidson, MD Clinical Professor Department of Medicine Director of Preventive Cardiology The University of Chicago Pritzker School of Medicine Chicago, Illinois Question # 46: What have cardiologists learned about the possible benefits or limitations of the glucocentric (HA1c) approach to reducing CV risk in diabetes, and where should we be focused moving into the future? Question # 47: What cardiometabolic markers in diabetic patients should we be most focused on in order to reduce residual CV risk? YOUR QUESTIONS EXPERT DISCUSSION

4 Question # 48: Based on trials published thus far, how should we align PPAR alpha- and gamma-agonists with specific, risk-stratified subsets of patients with T2D to optimize CV outcomes? And how will SYNCHRONY and AleCardio improve our understanding of these issues? Question # 49: What is it about the triglyceride/hdl ratio that seems to be a biomarker sweet zone for predicting CV risk and progressions of ASHD in diabetic patients? Question # 50: What is the interaction between the triglyceride/hdl ratio biomarker and PPAR agonists and clinical outcomes? Question # 51: What is your perspective on the evolving landscape of new, more potent LDL-reducing agents targeting new receptors and deploying new mechanisms of action? Peter P. Toth, MD, PhD Director of Preventative Cardiology CGH Medical Center Sterling, Illinois Professor of Clinical Family and Community Medicine University of Illinois College of Medicine Peoria, Illinois Question # 52: What have intravascular imaging studies such as PERISCOPE and CHICAGO taught us about the relationship between PPAR agonists and their effect on atheroprogression in patients with diabetes? Question # 53: Mechanistically, exactly how does insulin resistance induce atheroprogression in diabetes, and what interfaces and therapeutic targets should we focus on to reduce CV risk? Question # 54: From a vascular perspective, how and why do we think a dual, alpha/gamma PPAR agonist, such as aleglitazar, might affect atherogenesis and/or play a role in comprehensive cardiometabolic management of diabetic patients with ASHD? Question # 55: How might the mechanistic underpinnings of dual, alpha/gamma PPAR agonism provide a rationale for CV risk-mitigating effects? And what is the post-acs time frame for seeing these effects? Matthew A. Cavender, MD Research Fellow TIMI Study Group Brigham and Women s Hospital Question # 57: Why might a dual PPAR agonist provide the kind of cardiometabolic protection that diabetic patients may require to reduce CV risk? Question # 58: What are the results from the SYNCHRONY trial and how do these findings support the rationale for further study of the dual PPAR agonist, aleglitazar, in the setting of ASHD and diabetes? Question # 59: What are the most important, ongoing clinical trials focused on CV risk reduction in diabetic patients that cardiologists and diabetic specialists be aware of? Question # 60: What is the unmet need in the area of CV risk reduction in T2D? Professor John E. Deanfield, BA Hons (Cantab), BChir MB, FRCP BHF Vandervell Chair of Congenital Heart Disease Director, Centre for Cardiovascular Prevention & Outcomes Deputy Cardiovascular Program Director, UCL Partners University College of London School of Life and Medical Sciences London, United Kingdom Question # 61: What are the unique aspects of ASHD in the setting of diabetes that have created the need for a collaborative effort among CV and diabetic specialists? Question # 62: What did the CARDS trial teach us about the efficacy of statins in the setting of CAD and T2D? And, about the need for residual risk reduction in maximally treated patients, especially those with diabetes? Question # 63: What are the principal cardiometabolic targets for reducing CV risk in diabetes? Question # 64: What are the advantages of intervening earlier rather than later to mitigate live CV risk burden in patients with diabetes? And which risk factors are most important? Question # 65: Can lifestyle modifications achieve the cardiometabolic target goals that have been associated with CV risk reduction? And what did we learn from the ORIGIN Trial? Question # 56: Why should CV specialists be interested in the evolving science and medicine of cardiovascular risk reduction in T2D? YOUR PATIENTS EXPERT CONSULTATIONS

5 Christie M. Ballantyne, MD Director, Center for Cardiovascular Disease Prevention Methodist DeBakey Heart Center Chief of the Section of Cardiovascular Research Baylor College of Medicine Director of Atherosclerosis Laboratory Professor of Medicine Baylor College of Medicine Houston, Texas Question # 66: What are the important relationships and unmet therapeutic needs in patients with diabetes who also are at risk for ASHD? And what might be the role for dual PPAR agonists? Question # 67: What did we learn from the ORIGIN trial, and can we apply any of its findings to CV risk reduction or management of diabetic patients? Question # 68: What did we learn from the FIELD and ACCORD trials about high risk patients with diabetes, CVD, and high triglycerides and low HDL? Question # 69: In your view, how might an agent with dual PPAR agonism such as aleglitazar address the unmet need for residual CV risk reduction in T2D that you allude to? Question # 70: Why does it appear that the HDL/triglyceride ratio is so important as a biomarker of CV risk in diabetic patients? And what are the implications for PPAR-based interventions? Question # 71: What did the CHICAGO study teach us about the differential effects of PPAR agents versus other mechanistic approaches to modifying surrogate markers for ASHD? Rafael Carmena, MD, PhD, FACP, FRCP Edin Professor of Internal Medicine and Endocrinology University of Valencia Chief of the Endocrine and Nutrition Service University Hospital Valencia, Spain Question # 75: How do the CHICAGO, ACT-NOW Study, and PERISCOPE trials help us refine our thinking about the possible role of PPAR agonists for CV risk reduction in patients with T2D? Question # 76: How would you summarize the translational dimensions of the CHICAGO, ACT-NOW Study, and PERISCOPE trial in terms of the rationale for PPAR therapy to mitigate progression of ASHD? Question # 77: What are the implications of the SYNCHRONY Phase II Trial evaluating the dual PPAR agonist, aleglitazar? Question # 78: What did we learn from the CARDS trial as it relates to CV risk reduction in T2D? Question # 79: Why should cardiovascular specialists be focused on CV risk reduction in patients with diabetes? Question # 80: What is the current role of fibrates in achieving residual CV risk reduction in patients with T2D? Question # 81: Based on what we know, including the PROACTIVE trial, why might a dual alpha- and gamma-ppar agonist become a foundation agent for comprehensive cardiometabolic risk reduction in diabetic patients? Robert J. Chilton, DO, FACC Associate Professor Department of Medicine Division of Cardiology The University of Texas Health Science Center at San Antonio San Antonio, Texas Question # 72: What is evolving thinking about PPAR agonists for CV risk reduction in T2D? How have ultrasound studies with IVUS in the PERISCOPE trial helped us understand these agents better? Question # 73: Based on the mechanism of action for PPARs, what is the rationale for evaluating a dual, alpha- and gamma- PPAR agonist to achieve CV risk reduction in T2D? Question # 74: Can you share your multi-factorial approach to reducing CV risk in the patient with T2D? Darren K. Mcguire, MD, MHSc, FAHA, FACC Associate Professor of Medicine Associate of the Donald W. Reynolds Cardiovascular Clinical Research Center Director, Parkland Hospital and Health System Outpatient Cardiology Clinics University of Texas Southwestern Medical Center Dallas, Texas Question # 82: What is the current status of the glucose hypothesis for mitigating CV risk in patients with T2D? Question # 83: What is the pitfall of focusing exclusively on glycemic control to mitigate atheroprogression in patients with diabetes? YOUR PATIENTS OPTIMAL INTERVENTIONS

6 Question # 84: Why have the FDA and EMA concurred on the current recommendation to require evaluation of CV outcomes as a criterion for approving medications for diabetes? Question # 85: Although it s an older trial, what did the UKPDS trial teach us about optimizing treatment for patients with T2D? And what about the claim that this study has been misinterpreted? Question # 86: What did the results of the primary end points in ADVANCE and ACCORD teach us about the relationship between glycemic control and CV outcomes? Question # 87: What do the studies with the PPAR agonists rosiglitazone and pioglitazone (ProActive) teach us about the role of this class of agents in the setting of ASHD and diabetes? Can we generalize the results of these studies to other agents with dual, alpha-gamma PPAR agonism in the TZD class? Question # 88: Were there signals observed, at intermediate, surrogated marker, or clinical trial levels, that might indicate where to look for indications of CV toxicity with other PPAR agonists under investigation? Question # 89: How do we differentiate the mechanisms and clinical effects among PPAR agonists? Question # 90: Why, from a cardiometabolic risk perspective, might a dual alpha and gamma PPAR agonist make sense to lower residual risk of ASHD in patients with T2D? Gilles Montalescot, MD, PhD Professor of Cardiology Institut de Cardiologie Hôpital la Pitie-Salpêtrière Paris, France Question # 91: Why has CV risk management for diabetic patients become a top priority for cardiovascular specialists? And what has the FREEDOM Trial taught in this regard? Question # 92: What have the FREEDOM and ARCTIC Trials taught us about interventional versus surgical management of diabetic patients with ASHD, and platelet function testing? Question # 93: If the glucocentric-only approach has failed as a dominant strategy for CV risk reduction in T2D, what other biomarkers, strategies, and metabolic parameters do we still need to focus on and why? Deepak L. Bhatt, MD, MPH, FACC, FAHA, FSCAI Chief of Cardiology, VA Boston Healthcare System Director, Integrated Interventional Cardiovascular Program Brigham and Women s Hospital and the VA Boston Healthcare System Senior Investigator, TIMI Group Question # 94: What are the unmet needs for post-acs residual risk reduction in patients with diabetes? Question # 95: In aggregate, what have clinical trials taught us about those biomarkers and risk factors in diabetes that require the most aggressive intervention? Question # 96: Why are regulatory agencies in the U.S. and Europe requiring large CV outcome trials to support approvals for emerging therapies for diabetes? Question # 97: What do contemporary clinical trials tell us about the relationship between specific biomarkers and CV risk in diabetes and what is the evidentiary basis to suggest dual alpha/gamma PPAR agonism may play a role in modulating cardiometabolic risk? Question # 98: What is your systematic therapeutic roadmap for addressing residual CV risk in the diabetic patient? Paul Ridker, MD Eugene Braunwald Professor of Medicine Director, Center for Cardiovascular Disease Prevention Brigham and Women s Hospital Question # 99: What have landmark CV outcome trials such as JUPITER taught us about the relationship between statins and development of diabetes? Is this an issue that should concern us? Question # 100: What is the relationship among diabetes, innate immunity, and atheroinflammation? And what kind of investigations might emanate from our deeper understanding of how this triad is linked? Question # 101: What are atheroinflammation-mitigating agent are under evaluation in clinical trials? YOUR CLINICAL CASES EXPERT STRATEGIES

7 Question # 102: Why are statins associated with an increased risk of developing diabetes? What are the mechanisms? Question # 103: What have you and others extracted from work in diabetes to help better understand the drivers of atherosclerotic heart disease, in general? Question # 105: How do you interpret the imaging studies evaluating pioglitazone s effect on plaque progression and what are the clinical implications for patients with diabetes? Question # 106: How do we apply the results of imaging studies to therapeutic strategies for CV risk reduction in diabetes? Question # 107: Robin Choudhury, MD Wellcome Trust Senior Research Fellow, Clinical Science University of Oxford Consultant Cardiologist, John Radcliffe Hospital Clinical Director, Oxford Acute Vascular Imaging Centre Oxford, England Why is insulin resistance a pivotal mechanism causing pathobiological changes in macrovascular disease associated with diabetes? And what role might PPAR alpha and gamma agonists play? Question # 104: What have imaging studies taught us about the relationship between PPAR agonism and atherosclerotic plaque development in patients with CAD? YO U R Q U ESTI O NS E X P E R T A N A LY S I S