Juan P. Frias, MD
Clinical Assistant Professor of Medicine
University of California
San Diego, California
Chief Medical Officer
National Research Institute
Los Angeles, California
What aspects of the overall design and implementation of the LEADER trial do you think deserve the greatest emphasis? What metabolic target goals and CV outcomes achieved by liraglutide do you think were most significant?
Can you describe the kinds of patients evaluated in the LEADER trial and, based on the results, what CV risk groups and clinical profiles with T2D would be most amenable to treatment with liraglutide?
Based on the results of the LEADER trial, where would you likely position liraglutide in the framework of individualized ADA/EASD guidelines?
What do you speculate might be the most important mechanistic explanations for the reduction in CV events reported with liraglutide in the LEADER trial?
How effective was the glycemic control achieved in the GLP-1 RA treatment arm of the LEADER trial?
How effective was the glycemic control achieved in the GLP-1 RA treatment arm of the LEADER trial?
Can you provide some background, including dosing and units of each component, for the two fixed ratio, combination, insulin-plus-GLP-1 receptor agonist formulations that have been investigated and are likely to be approved?
From a front lines translational perspective, where are combination insulin-plus-GLP-1 RA regimens likely to fit into the sequencing algorithm for care of patients with T2D?
What markers and strategies do you recommend for titrating fixed-dose combination regimens? What dosing considerations apply to ensure optimal HA1c control?
Are there significant clinical differences—pharmacokinetic, safety, weight loss, control of PPG—between the two combination formulations, i.e. glargine insulin plus lixisenatide (iGlarLixi) vs. degludec insulin plus liraglutide (iDegLira)?
Given the established use of metformin and SGLT2 inhibitors as oral foundation agents, where do you believe the GLP-1 RA/insulin combination regimens, which are injectable, are likely to play the most important role in guideline-directed care?
How would deploy the fixed ratio combination agents in an obese patient who was not meeting HA1c target goals on metformin alone, or a second oral agent?
How would you deploy the fixed ratio combination regimens in patients who had documented postprandial hyperglycemia? Would one combination offer an advantage over the other, based on pharmacokinetic properties of the GLP-1 RA?
What is the appropriate way to add fixed ratio combination GLP-1 RA/insulin regimens to oral foundational therapy? Are these drugs added sequentially? Should the oral agents be discontinued?
What are the withdrawal and regimen adherence rates with the GLP-1 RA/insulin regimens, and how do the fixed ratio combination formulations affect GI side effects sometimes encountered with GLP-1 RAs? Is the incidence of side effects lower?
What was the physiological, safety, and compliance-focused rationale for combining basal insulin plus GLP-1 RA into a fixed ratio formulation? How would this approach achieve pan-glycemic (FBG and PPG) control?