Kidney- and SGLT2-Inhibitor-Based Glycemic Regulation to Optimize Management of T2D

Transcription

1 Click Here to View at: The iq&a interactive Diabetes Intelligence Zone for Kidney- and SGLT2-Inhibitor-Based Glycemic Regulation to Optimize Management of T2D A Roadmap for Clinical Use at the Front Lines of Practice Ralph A. DeFronzo, MD Professor of Medicine School of Medicine Diabetes and Metabolic Disorders (DMD) Track Diabetes Research Unit Barter Research Unit, UTHSCSA UTHSCSA Graduate School of Biomedical Sciences San Antonio, Texas, USA Question # 1: Can you outline new mechanisms of action involving SGLT2 inhibitors and their impact on glucose homeostasis? Question # 2: Can you illuminate the role of the kidney in glucose homeostasis, both in normal individuals and those with T2D, and its role to other glycemicregulating systems in patients with diabetes? Question # 3: Exactly which glucose-transporting mechanisms in the kidney are being targeted with agents such a dapagliflozin to improve glycemic control in T2D? Question # 4: What are the clinical implications of employing SGLT2-linked mechanisms to shift the glucose reabsorption threshold to the left in order to improve glycemic control and achieve ADA target goals? Question # 5: Which of the available oral antidiabetic agents (OADs) have been shown to improve attainment of ADA and AACE target goals for T2D? This activity is supported by an independent medical education grant from the Bristol-Myers Squibb and AstraZeneca Pharmaceuticals LP, Alliance Partners YOUR QUESTIONS Visit us at EXPERT ANSWERS

2 Question # 6: What do you anticipate would be a reasonable sequencing strategy for deploying currently available oral agents in combination with SGLT2 inhibitors such as dapagliflozin in T2D? Question # 7: What do we still need to know about SGLT2 inhibitors to deploy them as foundation agents in T2D? Question # 8: Are SGLT2 inhibitors such as dapagliflozin most likely to be effective in T2D patient with high, moderate, or low levels of HA1c elevation? Or is their efficacy independent of glycemic status? Vivian Fonseca, MD, FRCP (Program Chair) Professor of Medicine and Pharmacology Tulis-Tulane Alumni Chair in Diabetes Chief, Section of Endocrinology Tulane University Health Sciences Center New Orleans, Louisiana, USA Question # 9: Because SGLT2 inhibitors produce glycosuria and an accompanying osmotic diuresis, are their effects on sodium and potassium balance/excretion problematic or beneficial? Question # 10: Should we consider SGLT2 inhibitors such as dapagliflozin and canagliflozin as being suitable for combination therapy with all other ADA-endorsed agents, including insulin, incretin-targeted therapies, and metformin? Question # 11: In combination with which other glycemia-regulating therapies will SGLT2 inhibitors play an important adjunctive role in T2D management? Question # 12: Which patients with T2D do you feel are ideal candidates for either monotherapy or combination therapy with dapagliflozin or canagliflozin? What are the windows of opportunity for their use within the framework of ADA guidelines? Question # 13: What definitive, long-term CV outcome trials are currently in progress with SGLT2 inhibitors; and, do we have any signals or early data regarding CV outcomes with dapagliflozin or canagliflozin? Question # 14: Do the positive effects of SGLT2 inhibitors on key cardiometabolic biomarkers, including HA1c reduction, weight, BP control, and risk of severe hypoglycemia, suggest they are more likely to have positive effects on CV outcomes? Question # 15: What is the therapeutic advantage of targeting kidneymediated glucose homeostasis as a strategy for optimizing comprehensive management of patients with T2D? Question # 16: What has the American and European experience been thus far with the SGLT2 inhibitors? Question # 17: how should we ideally sequence SGLT2 inhibitors such as dapagliflozin or canagliflozin? What role will weight loss play? Question # 18: What might be the rationale and role for using an SGLT2 inhibitor in a patient with T2D on metformin whose HA1c level is still 7.9 percent despite metformin therapy? Question # 19: What is the clinical rationale for using SGLT2 inhibitors in patients with T2D? Charles F. Shaefer Jr., MD, FACP Assistant Clinical Professor of Medicine Medical College of Georgia Augusta, Georgia, USA Question # 20: Can you explain how SGLT2 inhibitors work on kidneymediated glucose homeostasis, and why they may play a foundation role in T2D therapy? Question # 21: What advantages does the insulin-independence mechanism of SGLT2 inhibition offer with respect to combined use with other agent and reduced risk of hypoglycemia? Question # 22: In what way does kidney-mediated glucose homeostasis play a foundation role in glycemic control in patients with T2D and how does SGLT2 inhibition improve glycemic control at this metabolic interface? Question # 23: How has our understanding of genetically-based glycosuria led to the discovery of SGLT2-mediated glycemic control and the potential therapeutic advantages of down-regulation of glucose reabsorption? Question # 24: How effective are the SGLT2 inhibitors such as dapagliflozin and canagliflozin in reducing HA1c and how easily are they used in combination with other agents? Question # 25: What makes SGLT2 inhibition of glucose reabsorption at the level of the kidney unique as compared to other glycemiaregulating mechanisms or therapies? Question # 26: What are the effects of SGLT2-mediated inhibition of glucose reabsorption in individuals without elevated glucose levels? What determines whether these agents will be effective in an individual patient? Question # 27: Are there other SGLT transport systems in the body besides the SGLT2 variant? And how does our understanding of familial (genetic) hyperglycosuria help predict what we might expect, efficacy and safety-wise, with the deployment of SGLT2 inhibitors for treatment of T2D? YOUR QUESTIONS EXPERT ANALYSIS

3 Question # 28: What potential collateral cardiovascular benefits weight loss, diuresis, and BP reduction have been observed in clinical registration trials evaluating such SGLT2 inhibitors as dapagliflozin and canagliflozin? Are there any drug interactions or comorbid conditions that require vigilance when these agents are used? Question # 29: Based on reports from Europe, where dapagliflozin is currently available, and within the U.S., where canagliflozin has been approved, what is your and your colleagues experience and your perspective on the role of these agents in the current and future T2D treatment algorithm? Question # 30: What is the current status of cardiovascular safety data for the SGLT2 inhibitors? Question # 31: Based on the available data, how do you interpret the benefitto-risk equation for the oral SGLT2 co-transport inhibitors such as dapagliflozin and canagliflozin? Any cautionary notes that you would offer to optimize their safe and effective use? Question # 32: Some diabetes experts believe the class of SGLT2 inhibitors represents a breakthrough in therapy for T2D? In what respect is this true? Is the weight loss clinically significant? Question # 33: Recent neutral results demonstrating non-inferior CV outcomes for DPP-4 antagonists and basal insulin compared to standard therapy suggest the road to the diabetic heart is more elusive than we might have thought. Where might SGLT2 inhibitors fit into the CV outcome story for T2D? Question # 34: Where in the treatment paradigm or T2D therapy are SGLT2 inhibitors such as dapagliflozin ideally positioned to optimize comprehensive patient management? Are there risks? John Buse, MD, PhD Professor of Medicine Director, Diabetes Care Center Chief, Division of Endocrinology Executive Associate Dean for Clinical Research University of North Carolina School of Medicine Chapel Hill, North Carolina, USA Question # 35: Is there a clinical rationale for the use of SGLT2 inhibitors for T2D and how do their mechanisms of action help achieve ADA and AACE target goals for HA1c? Question # 36: Do the studies suggest a role for these agents as monotherapy in T2D or as complementary agents in combination with other OADs; how should these agents be sequenced? Question # 37: How does the presence of renal disease affect the action, efficacy and/or side effects of agents working through SGLT2 inhibition? And are certain levels of GFR incompatible with these agents? Question # 38: What is the role of glucose lowering and HA1c target goal attainment as a strategy for lowering risk of microvascular disease in diabetes? Question # 39: Based on current clinical trial data, which patients with T2D will make good candidates for SGLT2-mediated intervention for glycemic control, and does the underlying HA1c level play a role in patient selection? Question # 40: What do we still need to know about the SGLT2 inhibitors and their likely role in the management paradigm for T2D? Question # 41: What do we still need to know to connect the dots in the association between microalbuminuria and cardiovascular risk? George Bakris, MD Professor of Medicine Director, Hypertension Center University of Chicago Medical Center Chicago, Illinois, USA Question # 42: What role do glucose transporters play as part of normal homeostasis and why are they potentially important therapeutic targets for patients with diabetes? Question # 43: What are the efficacy results (HA1c level reductions) that have been reported in trials evaluating dapagliflozin, canagliflozin, and other SGLT2 inhibitors? And what is the side effect profile of this drug class? Question # 44: Is there any basis to think that SGLT2 inhibition may be harmful to the kidney? Or protective? Question # 45: What hemodynamic states, age factors, concomitant drug intake, or co-morbid conditions associated with T2D require special vigilance when considering the use of SGLT2 inhibitors for glycemic control in diabetes? Question # 46: At what points in the natural history of diabetes and/or at what HA1c levels do such SGLT2 inhibitors as dapagliflozin seem to be most effective and beneficial as part of comprehensive management of T2D? Question # 47: Which subsets of patients with T2D based on HA1c level, age, existing glycemic therapies, and other factors do you feel are ideally suited for treatment with SGLT2 inhibitors such as dapagliflozin or canagliflozin? Question # 48: Can you describe the underlying mechanisms of action for weight loss with the SGLT2 inhibitors? And what is the degree of weight loss? Question # 49: How reliable are SGLT2 inhibitors for producing weight loss? And how do they compare to GLP-1 agonists in their ability to achieve weight loss? Question # 50: From a mechanistic and glucose homeostasis perspective, why are SGLT2 inhibitors unlikely to cause hypoglycemia? YOUR QUESTIONS EXPERT DISCUSSION

4 Question # 51: What patient types with T2D based on HA1c level or weight status are likely to be especially amenable to such agents as dapagliflozin or canagliflozin? In what patients should we, as clinicians, consider using these agents as part of our T2D treatment plan? Question # 52: Why has it taken so long to understand the importance of SGLT2 co-transporters as therapeutic targets and employ them in the clinical setting? Question # 53: Based on the trials, data, and safety signals we have with dapagliflozin and canagliflozin thus far, how do you see the benefit-to-risk ratios for SGLT2 inhibitors at the present time? Question # 54: How important do you think the blood pressure-lowering benefits are of the SGLT2 inhibitors? Vincent Woo, MD Endocrinology Section Department of Internal Medicine University of Manitoba Health Sciences Centre Diabetes Research Group Winnipeg, Canada Question # 55: What is the scope of disease burden associated with T2D? Question # 56: What are the current glycemic (HA1c) target goals recommended by the ADA and AACE for patients with T2D? Question # 57: Which patient subgroups with T2D are likely to be the most responsive to agents that inhibit SGLT2 transport system? Question # 58: Are there any significant safety issues and/ or adverse side effects that we need to consider when thinking about SGLT2 inhibitors? Question # 59: What is the likely role of SLGT2-inhibiting agents such as dapagliflozin, and how are such agents likely to fit into the sequencing strategies and treatment algorithms for T2D? Question # 60: What is the basic mechanism of action involving SGLT2 inhibitors and why does this action have an impact on glucose homeostasis? Question # 61: How do you perceive the likely benefit-to-risk equation for SGLT2 inhibitors based on the clinical trial data we have thus far, and how do you think it will compare to other agents currently used on the T2D toolkit? Question # 62: What emerging agents with novel mechanisms of action are likely to provide complementary therapies for patients with T2D? Professor Paolo Pozzilli, MD Professor of Diabetes and Clinical Research Centre for Diabetes Barts and The London School of Medicine & Dentistry London, United Kingdom Professor of Endocrinology & Metabolic Diseases University Campus Bio-Medico Rome, Italy Question # 63: What are the fundamentals of so-called personalized therapy advocated by the ADA/EASD guidelines for T2D management? Question # 64: In what ways are the SGLT2 inhibitors such as dapagliflozin a major advance in mitigating the hazards of hypoglycemia encountered with many of the current foundation therapies for T2D? Question # 65: What definitive, long-term CV outcome trials are currently in progress with SGLT2 inhibitors; and, do we have any signals or early data regarding CV outcomes with dapagliflozin or canagliflozin? Question # 66: Can you review the effects of SGLT2 inhibitors on key cardiometabolic biomarkers and clinical effects, including HA1c reduction, weight, BP control, and risk of severe hypoglycemia? Do the early pooled analyses for CV outcomes show differences for dapagliflozin and canagliflozin? Question # 67: What do we still need do know about this emerging foundation therapy for T2D? Question # 68: Why does a mechanism of action that is independent of insulin activity offer such appeal as a foundation therapy in T2D? Question # 69: Which subsets of patients with T2D based on HA1c level, age, and other factors do you feel are especially appropriate for treatment with SGLT2 inhibitors such as dapagliflozin or canagliflozin? Question # 70: Do the SGLT2 inhibitors have unique efficacy at the higher HA1c levels and, if so, what levels of HA1c reduction should we expect in patients with poor control? Anthony Barnett, MD, FRCP Professor of Medicine University of Birmingham Honorary Consultant Physician and Clinical Director Diabetes/Endocrinology/Weight Management Heart of England NHS Foundation Trust Birmingham, UK Question # 71: What do we need to be aware of in terms of the risk of hypoglycemia when SGLT2 inhibitors are used as monotherapy versus combination therapy in patients with T2D? YOUR PATIENTS EXPERT CONSULTATIONS

5 Question # 72: What is the most common side effect observed with SGLT2 inhibitor use? How problematic is it? How common? How easily are these side effects managed? Question # 73: Based on the epidemiology of T2D, and therapeutic options currently available, is there an unmet need for new oral therapies for T2D? Question # 74: From a practical perspective, are there any safety factors that should be considered when clinicians consider incorporating use of SGLT2 inhibitors in the daily management of T2D? Question # 75: how should we, as front line clinicians, ideally sequence such SGLT2 inhibitors as dapagliflozin or canagliflozin within the treatment algorithm for T2D? Which patients are the best candidates? Question # 76: Are there specific triggers or clinical findings that would suggest the need for employing an SGLT2 inhibitor earlier rather than later in the disease course of someone with T2D? How important is weight as a trigger? Question # 77: Are there any factors that would deter you from recommending use of an SGLT2 inhibitor? Question # 78: What do we know about the importance of achieving HA1c target goals and the risk of microvascular and macrovascular disease in T2D? Question # 79: What has been your experience with dapagliflozin in the UK and how have you been using it at the front lines of T2D practice? How have you been using this SGLT2 inhibitor, specifically? Question # 80: How would you approach a patient who has failed therapy on metformin and a second-line agent, and has episodes of hypoglycemia? What factors would suggest that an SGLT2 is an optimal choice is in this patient? Mark E. Williams, MD Clinical Investigator Section on Clinical Research at Joslin Senior Staff Physician at Joslin Clinic Co-Director of Dialysis at Beth Israel Deaconess Medical Center Associate Professor of Medicine Harvard Medical School Question # 81: From a mechanistic perspective what is the primary effect that we observe from SGLT2-mediated changes in glucose homeostasis at the level of the kidney? Question # 82: What is the role of SGLT2 inhibition in diabetic patients who are tightly controlled? Question # 83: How broad is the applicability of the SGLT2 inhibitors, as far as their value as monotherapeutic agents, as well as in combination with other glycemic therapies? Question # 84: In which patient subsets would dapagliflozin or canagliflozin be considered for monotherapy? How would you identify such patients? Question # 85: What are the side effects with these agents that we need to take note of? Question # 86: What is the pathophysiology of weight loss in patients on SGLT2 inhibitors? Question # 87: How does the mechanism of action of SGLT2 inhibitors mitigate against the risk of hypoglycemia? Question # 88: How might these agents potentially be beneficial to kidney function in the setting of T2D? Richard E. Pratley, MD Director, Florida Hospital Diabetes Institute Senior Scientist Translational Research Institute for Metabolism and Diabetes Professor, Sanford Burnham Medical Research Institute Orlando, Florida, USA Question # 89: What evidence-, trial-, and mechanism-based sequencing strategies do you advocate for SGLT2 inhibitors? Where should they be positioned on the treatment algorithm of individualized care for T2D? Question # 90: Based on the studies that are currently available for dapagliflozin and canagliflozin, does the data suggest these new agents will play a great role as monotherapy, as combination therapy, or perhaps, both? Question # 91: Is the weight loss that is observed with the SGLT2 inhibitors clinically meaningful? And how does is compare to weight loss seen with GLP-1 agonists? Question # 92: Are SGLT2 inhibitors uniquely appropriate in T2D patients with cardiometabolic syndrome, where weight loss, HA1c control, reduction in triglcyerides, and BP lowering are among the pillars of clinical management? Question # 93: What might be the evidence-based role for using an SGLT2 inhibitor in a patient with T2D on a sulfonylurea whose HA1c level is still 7.9 percent despite oral sulfonylurea therapy? Question # 94: What might be the rationale and targeted role for using an SGLT2 inhibitor in a patient with T2D on metformin who has documented episodes of hypoglycemia, elevated BP, and whose HA1c level is still 8.1 percent despite metformin therapy? YOUR PATIENTS OPTIMAL INTERVENTIONS

6 Question # 95: What are the advantages of oral SGLT2 inhibitors such as dapagliflozin and canagliflozin when mitigating the risk of hypoglycemia is a key, individualized target goal in a patient with T2D? Question # 96: How would you approach a patient on metformin with a GFR of 30 ml/min and a HA1c level of 8.3? Question # 97: Based on mechanism of action, what do you expect the durability of efficacy would be with an SGLT2 inhibitor and why? What advantage might this offer over other oral agents? Question # 98: How will renal function affect the efficacy of agents acting on kidney-mediate glucose homeostasis? Question # 99: Why do we think SGLT2 inhibitors might have a positive effective on CV risk biomarkers, and potentially, therefore, on CV outcomes? Question # 100: What have we already learned about the use of dapagliflozin and canagliflozin based on our experience in Europe and the U.S., respectively? Robert Henry, MD Chief, Center for Metabolic Research Chief, VA Endocrinology & Metabolism Professor of Medicine in Residence University of California San Diego San Diego, CA, USA Question # 101: What is the status of the kidney as a primary regulator of glucose homeostasis in T2D? Question # 102: How do the SGLT2 inhibitors influence primary CV risk factors, such as weight and blood pressure? By what mechanism do they accomplish this? How would these effects translate into CV outcomes? Question # 103: Should such agents as dapagliflozin and canagliflozin be used as monotherapy or in combination with other glucose-lowering agents for T2D? How flexible are they? How widespread is their application? Question # 104: What is the durability dimension of SGLT2 inhibitors? How long do they produce sustained reductions of blood glucose over time? Are their effects transient or consistent over time? Question # 105: Are there any off-target effects associated with SGLT2 inhibitors? Question # 106: What trial-based findings suggest that SGLT2 inhibitors may have properties that are consistent with improving CV outcomes in patients with T2D? Question # 107: Are there significant differences as far as glycemic control and side effect profiles among the SGLT2 inhibitors approved in Europe or the U.S.? Lawrence A. Leiter, MD, FRCP(C), FACP Professor, Departments of Medicine and Nutritional Sciences Head of the Division of Endocrinology and Metabolism Director of the Lipid Clinic Associate Director, Clinical Nutrition and Risk Factor Modification Centre St. Michael s Hospital University of Toronto Toronto, Ontario, Canada Question # 108: Can SGLT2 inhibitors be used at any stage of diabetes? In combination with any of the other glycemia-lowering agents? Question # 109: Although not formally included in the Year 2012 ADA/EASD guidelines, how would you position the use of such agents as dapagliflozin and canagliflozin within the framework of ADA guidelines? Question # 110: Can you review the effects of SGLT2 inhibitors on key cardiometabolic biomarkers and clinical effects, including HA1c reduction, weight, BP control, and risk of severe hypoglycemia? Question # 111: how should we ideally sequence SGLT2 inhibitors such as dapagliflozin or canagliflozin? Question # 112: Is the weight loss that is observed with the SGLT2 inhibitors clinically meaningful? Question # 113: What advantages does the insulin-independence mechanism of SGLT2 inhibition offer with respect to combined use with other agents and reduced risk of hypoglycemia? Question # 114: What makes SGLT2 inhibition of glucose reabsorption at the level of the kidney unique as compared to other glycemiaregulating mechanisms or therapies? Clifford J. Bailey, PhD, FRCP, FRCPath UK Diabetes Research Aston Pharmacy School School of Life and Health Sciences Triangle Aston University Birmingham, UK Question # 115: What advances are being made in the area of SGLT2 inhibition that may offer new therapeutic strategies for optimizing target goal attainment in T2D, and how do these agents work? Question # 116: What are the side effects and safety signals, including cancer, that have emerged in clinical trials evaluating the effectiveness and safety of SGLT2 inhibitors such as dapagliflozin for patients with T2D? Question # 117: How does the presence of renal disease and/or lowered egfr affect the action, efficacy and/or side effects of agents working through SGLT2 inhibition? And are certain levels of GFR incompatible with these agents? YOUR CLINICAL CASES EXPERT STRATEGIES

7 Question # 118: What is the importance of the role of the kidney in glucose homeostasis and what are the implications of renal-mediated metabolic interfaces for glycemic control in normal individuals and those with T2D? Question # 119: How might SGLT2 inhibition with agents such as dapagliflozin play a foundation or adjunctive role in HA1c target goal attainment in patients with T2D? Question # 120: Can you compare and contrast the different SGLT transporters in the body and which ones are of special relevance in patients with T2D? Professor Bernard H. Charbonnel, MD Professor of Endocrinology and Metabolic Diseases University of Nantes Nantes, France Question # 121: Based on the mechanism of action for SGLT2 inhibitors such as dapagliflozin and others, how useful or advantageous are these agents when used as adjuncts to incretin-targeted therapies (DPP-4 inhibitors and GLP-1 agonists) deployed for glucose-lowering in T2D? Question # 122: What are the implications of shifting the kidney-based, glucose reabsorption curve and renal threshold to the left with SGLT2 inhibitors? Can you clarify the pathophysiology and mechanism-of-action for this class; and the practical implications? Question # 123: Although not formally included in the Year 2012 ADA/EASD practice statement with its emphasis on individualization of HA1 levels how would you position the use of such SGLT2 agents as dapagliflozin and canagliflozin within the framework of ADA guidelines? Question # 124: how should we ideally sequence SGLT2 inhibitors such as dapagliflozin or canagliflozin? Should they be used as substitutes for sulfonylureas? Question # 125: Can you clarify the role of HA1c-lowering as a strategy for improving microvascular and/or macrovascular disease outcomes in T2D? Question # 126: How will renal function (and GFR) affect the efficacy (HA1c reduction) of SLGT2 transport-targeting agents acting on the kidney? What is the relationship between GFR and blood glucose as determinants for SGLT2 efficacy? Question # 127: Based on reports from Europe, where dapagliflozin is currently available, and within the U.S., where canagliflozin is approved, what is your experience and your perspective on the role of these agents in the current and future T2D treatment algorithm? Dr. Juris J. Meier, MD St Josef-Hospital Klinikum der Ruhr-Universität Bochum Bochum, Germany Question # 128: To what extent is daily urine volume increased with the use of SGLT2 inhibitors? Is there any clinical impact? Question # 129: What side effects should practitioners be aware of when using SGLT2 inhibitors? Is this a class effect? And what are the comparative side effects of the other oral agents used for SGLT2? Question # 130: Are there any specific considerations when using SGLT2 inhibitors in the elderly population? Question # 131: How long can agents such as dapagliflozin and canagliflozin be used to treat T2D? Does their action plateau over time? How does their independence from beta cell function enhance their durability? Question # 132: Based on your experience in Europe, where dapagliflozin is currently available, what is the role of this agent in the current and future T2D treatment algorithm? What special insights and observations can you share? Question # 133: Based on the clinical and biomarker profiles of SLGT2 inhibitors, where might SGLT2 inhibitors fit into the CV outcome story for T2D? Question # 124: How would you approach a T2D patient on metformin and a DPP-4 inhibitor who also has HBP and obesity, and is failing to meet HA1c target goals? What would be role of an SGLT2 inhibitor? Jaime Davidson, MD, FACP, MACE Clinical Professor of Medicine Division of Endocrinology, Diabetes and Metabolism University of Texas Southwestern Medical School Dallas, Texas, USA Question # 135: Do SGLT2 inhibitors have any impact on beta-cell function? Question # 136: For what HA1c levels are SGLT2 inhibitors most effective? And in what patient groups do we see the greatest efficacy? Question # 137: What are the pharmacokinetic and pharmacodynamics properties of SGLT2 inhibitors? How quickly do they produce glucose lowering? Question # 138: Can you review the effects of SGLT2 inhibitors on key cardiometabolic biomarkers and the associated clinical effects, including HA1c reduction, weight, and BP? YOUR CLINICAL CASES EXPERT STRATEGIES

8 Question # 139: How do dapagliflozin and canagliflozin compare to metformin as far as HA1c level, titration strategies, and other important clinical markers? Question # 140: What is your perspective on the role of these agents in the current and future T2D treatment algorithm? Silvio E. Inzucchi, MD Professor of Medicine (Endocrinology) Clinical Director, Section of Endocrinology Director, Yale Diabetes Center Director, Endocrinology & Metabolism Fellowship Director, Yale Affiliated Hospitals Program New Haven, Connecticut, USA Question # 141: Based on the epidemiology of T2D, and therapeutic options currently available, is there an unmet need for new oral therapies for T2D? Question # 142: What strategies have been shown to be effective for reducing the risk of CVD in patients with T2D? Question # 143: What are the fundamental goals and strategies of the so-called individualized therapeutic approach advocated by the ADA/ EASD position statement for T2D management? Where might SGLT2 inhibitors fit into this framework? Question # 144: how should we ideally sequence SGLT2 inhibitors such as dapagliflozin or canagliflozin? Question # 145: Can you clarify the role of HA1c-lowering as a strategy for improving microvascular and/or macrovascular disease outcomes in T2D? Question # 146: What are the factors that go into the complex calculus of establishing a specific HA1c target in patients with T2D? Question # 147: Is there anything about SGLT2 inhibitors and their effects on CV risk factors that suggest they may produce the hoped-for impact on CV outcomes in patients with T2D? 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 # 148: What are the pleiotropic CV effects associated with SGLT2 inhibitor use that we should factor into our clinical decisionmaking when selecting agents to lower blood glucose? Question # 149: What is the role of multifactorial risk control in achieving reduction in CV events in patients with T2D? What is the role of achieving HA1c control? What is the impact of the duration of diabetes? Question # 150: What might be role of SGLT2 inhibitors in patients with cardiometabolic syndrome? Is this an opportunity for their use? Question # 151: What is the effect of such SGLT2 inhibitors as dapagliflozin and canagliflozin on weight loss? And is the weight loss sustained? Question # 152: What is the likelihood that glucosuric agents will result in reduction of microvascular complications of diabetes? Question # 153: What is the role of SGLT2 inhibitors such as dapagliflozin or canagliflozin as part of combination therapy with metformin? What might be their role as a dominant strategy in patients with metformin intolerance? Question # 154: In a patient with T2D and elevated BP, who is failing initial therapy with metformin and lifestyle changes, how do you select among the other oral agents to optimize and individualize glucose control? Interactive Diabetes Intelligence Zone Global Diabetes Experts Address Kidney-Mediated Glycemic Control and SGLT2 Inhibition YOUR QUESTIONS EXPERT DISCUSSION