This column highlights recent diabetes clinical trial data and landmark trials to provide relevant information and links for obtaining trial data and articles to facilitate discussion with patients and other providers. Each trial will be identified by its acronym, its ClinicalTrials.gov Identifier (NCT Number) and its journal reference.
Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results—A Long-Term Evaluation (LEADER®)
ClinicalTrials.gov Identifier: NCT01179048
References (related): 1. Marso SP, Poulter NR, Nissen SE, Nauck MA, Zinman B, Daniels GH, Pocock S, Steinberg WM, Bergenstal RM, Mann JF, Ravn LS, Frandsen KB, Moses AC, Buse JB. Design of the liraglutide effect and action in diabetes: evaluation of cardiovascular outcome results (LEADER) trial. Am Heart J. 2013 Nov;166(5):823-30.e5. PMID: 24176437
- Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, Nissen SE, Pocock S, Poulter NR, Ravn LS, Steinberg WM, Stockner M, Zinman B, Bergenstal RM, Buse JB; LEADER Steering Committee on behalf of the LEADER Trial Investigators. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016 Jun 13. PMID: 27295427
Sponsor: Novo Nordisk A/S
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Primary Outcome Measure: Time from randomization to first occurrence of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke (a composite cardiovascular outcome).
Results: 9,340 patients were randomized with median follow up of 3.8 years. The primary outcome occurred in significantly fewer patients in the liraglutide group (608 of 4,668 patients [13%]) than in the placebo group (694 of 4,672 [14.9%]) (hazard ratio, 0.87; 95% confidence interval [CI], 0.78 to 0.97; P<0.001 for noninferiority; P=0.01 for superiority).
Fewer patients died from CV causes in the liraglutide group (219 patients [4.7%]) than in the placebo group (278 [6.0%]) (hazard ratio, 0.78; 95% CI, 0.66 to 0.93; P=0.007). The rate of death from any cause was lower in the liraglutide group (381 patients [8.2%]) than in the placebo group (447 [9.6%]) (hazard ratio, 0.85; 95% CI, 0.74 to 0.97; P=0.02). The rates of nonfatal myocardial infarction, nonfatal stroke and hospitalization for heart failure were nonsignificantly lower in the liraglutide group than in the placebo group. The most common adverse events leading to the discontinuation of liraglutide were gastrointestinal events. The incidence of pancreatitis was non-significantly lower in the liraglutide group than in the placebo group.
Summary: This is the second diabetes drug, and the first of the specific class referred to as “GLP-1s,” much less of the overall group referred to as “incretins,” to demonstrate a CV benefit. The question will be whether this is a class effect. What differentiates these data from the EMPA-REG Outcomes trial is that liraglutide met significance for superiority on the primary outcome. Importantly, these benefits suggest liraglutide and empagliflozin need to be part of any diabetes regimen, or at least for anyone with Type 2 over age 50 who has had diabetes for at least five years and has additional CV risk factors.
American Diabetes Association, New Orleans, June 2016
Session LB-01—Late Breaking Poster Session
99-LB / 99—Pivotal Trial of a Hybrid Closed-Loop System in Type 1 Diabetes (T1D)
Authors: Richard Bergenstal, Bruce Buckingham, Satish Garg, Stuart Weinzimer, Ronald Brazg, Jacob Ilany, Bruce Bode, Timothy Bailey, Stacey M. Anderson, Robert Slover, John Shin, Scott Lee, Francine R. Kaufman, Minneapolis, MN, Palo Alto, CA, Aurora, CO, New Haven, CT, Renton, WA, Ramat Gan, Israel, Atlanta, GA, Escondido, CA, Charlottesville, VA, Northridge, CA
Abstract: A hybrid, closed-loop (HCL) insulin delivery system was evaluated to establish its safety for unsupervised use in patients ≥14 years. The system included the Medtronic MiniMed 670G pump, 4th-generation sensors and a control algorithm. Patients calibrated the sensor periodically and gave mealtime and correction boluses as needed. A two-week run-in (baseline) phase was followed by a three-month study phase of HCL at home and supervised hotel settings for five nights followed by an optional continued-access program. Data were available from 124 patients with Type 1 (55 male) with mean (±SD) age, 37.8±16.46 years (30 age ≤21) and duration of diabetes 21.7±13.65 years. Sensor glucose (SG) and A1c values from baseline and study phases were compared. HCL mode was used for a median 87.2% (IQR, 75.0% to 91.7%) of the time after first start. There were higher percentages of SG 71-180 mg/dL, lower percentages of SG ≤70 mg/dL and lower percentages of SG ≤50 mg/dL during 24 hours and at night (p<.001 for each) in the study phase compared to baseline. Mean A1c decreased from 7.4±0.9% to 6.9±0.6% (p<.001). SG variability measured by coefficient of variation decreased from 0.38 to 0.35 (p<.001). There was no DKA, severe hypoglycemia or serious device-related adverse event during 12,389 patient-days. At study’s end, 99 patients entered the continued-access program. The HCL system was safe, acceptable and associated with improved glucose control.
Summary: These data demonstrate the hybrid closed loop system has the ability to be used by adults safely at home without DKA or severe hypoglycemia.
349-OR / 349—Risk Assessment of Using the New Continuous Glucose Monitoring (CGM) System for Treatment Decisions (Patients 2 YO+)
Authors: Tomas Walker, David A. Price, Katherine Nakamura, Andy Balo, San Diego, CA
Abstract: Retrospective analyses were performed to assess accuracy and risk of using the Dexcom Mobile G5 for CGM-based treatment decisions. The assessment included youth (ages 2-17) and adults (ages 18+) across the glycemic spectrum. 130 subjects (51A, 79Y) enrolled at eight U.S. centers. 52% Male; 57% used CSII. To assess the CGM-based decisions, we considered erroneously high CGM values as posing risk for determining an insulin dose or failing to detect hypoglycemia: 20%-30% or >30% higher of the YSI values when CGM ≥ 100 mg/dL and 20-30 mg/dL or >30 mg/dL when CGM <100 mg/dL. CGM readings lower than YSI or < 20% higher than YSI would pose a minimal risk. When CGM read ≥ 100 mg/dL, the risk of overcorrecting was 2.3% for youth, and 3.6% for adults when CGM read within 20-30% higher than YSIs; risk was 1.8% for youth and 2.5% for adults when CGM read >30% higher than YSI. When CGM read <100 mg/dL, the risk was less than 2% for all cases. When CGM read ≥ 200 mg/dL , the risk of overcorrecting were 2%-3% for both. Despite differences in the glycemic characteristics between adults and youth, the risk assessment for dosing using the new CGM device was as small as 2%-4% for overcorrection incidences. This study suggests the CGM system is accurate enough to dose insulin without the need for SMBG confirmation and with minimal increased risk of overcorrection to patients.
Summary: This raises the question of whether the CGM is now accurate enough to be used for planning insulin dosing and/or correcting high glucose levels. While we know that some patients are already doing this, it is reassuring to see data regarding safety in real-life situations.
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About our expert: Kathleen Wyne, MD, PhD, FACE, FNLA, Associate Professor, Division of Endocrinology, Diabetes and Metabolism, The Ohio State University, Wexner Medical Center, Columbus