8/5/217 The Diamond Study: Continuous Glucose Monitoring In Patients on Mulitple Daily Insulin Injections Richard M. Bergenstal, MD Executive Director International Diabetes Center at Park Nicollet Minneapolis, MN Disclosure Statement RMB has Richard participated M. Bergenstal, in clinical research, MD a scientific advisory board or served as a consultant for: Eli Lilly Novo Nordisk Sanofi Hygieia T1D Exchange (Helmsley Charitable Trust) Roche Diabetes Care J&J Abbott Diabetes Care Bayer Diabetes Medtronic Diabetes Care DexCom Astra Zeneca Merck Takeda RMB inherited Merck stock and is a volunteer for ADA & JDRF RMB s employer, non-profit Park Nicollet Institute, contracts for his services and he receives no personal income from these activities How About Patients using MDI There are 6 million adult insulin users in the United States and > 5 million have T2D few are on pumps 6 7% of adults with T1D use MDI Here is what we know Will injectors use a wearable technology? Will they be willing/able to make changes to obtain glycemic benefit? CDC National Diabetes Statistics Report, 214 4 Background on Insulin Treatment of Diabetes & Most insulin treated patients with T1D & T2D have glucose levels above the target goal offers improved glucose control as well as reduction of hypoglycemia and glucose variability Globally, most basal/bolus insulin is delivered by multiple daily injections Most previous clinic research has addressed T1D patients using insulin pumps Information is needed to identify the patients who benefit from including those on MDI Benefits Diverse Users JDRF JDRF well controlled EU Hypo reduction study STAR 3 SWITCH Study Gold Diamond T1D cohort Diamond T2D cohort Predominantly Pump Users MDI 1
The image part with relationship ID 8/5/217 Users Have Lower HbA1c Regardless of Insulin Delivery Method Mean HbA1c % 9.5% 9.% 8.5% 8.% 7.5% 7.% 8.7% 8.3% 7.9% 7.8% Miller KM, et al. Diabetes Care. 215;38:971 978. 9.3% 8.6% 8.1% 8.% 7.8% 7.6% <13 Age (years) 13-25 26 7.2% Injection only Pump only Injection + Pump + 7.2% Study Design for DIaMonD (phase 1) T1D Study Age > 25 A1C 7.5 1% SCREENING A1c 8.6% Duration 21 yrs. RUN IN Blinded (2 weeks) RANDOMIZE 2:1 PHASE 1 (24 weeks) SMBG (n=53) (n=13) Primary outcome difference in mean HbA1c between treatment groups Study Designed to Limit Encounters to Allow Translation into Clinical Practice Weeks 1 3: Device Initiation group: clinic visit at Week 1 to troubleshoot device/use issues Both groups: phone calls at Weeks 2 & 3 Weeks 4 & 12: Diabetes Management Visits Both groups: clinicians review glucose data & insulin adjustments per usual care group: clinic visits for blinded placement at Weeks 11 & 23 Week 24: End of Phase 1 29 clinical sites from across North America. 9 DIaMonD JDRF STAR 3 Encounter Frequency DIaMonD vs JDRF & STAR 3 1 2 3 4/5 6 8 1 13 16 19 22 24/26 Weeks Bergenstal RM, et al. N Engl J Med. 21;363:311 32. JDRF Study Group. N Engl J Med. 28;359:1464 1476. Phone call Visit Usage 6 Days/Week 1 DIaMond Type 1 Phase 1 Results % of Participants 8 6 4 2 94 96 93 1 2 Week 4 Week 12 Week 24 6 days/wk days/wk 2
8/5/217 SMBG Frequency HbA1c Treatment Group Differences Mean No. of Daily SMBG Checks 6 5 4 3 2 1 5.1 5.1 P<.1 4.8 3.7 3.6 P<.1 4.6 Baseline Week 12 Week 24 Mean HbA1c % 8.5 8. 7.5 7. 8.6% 8.6% Baseline Adjusted mean difference (95% CI) P<.1 8.1% 7.6% Week 12.5% (.7% to.3%) P<.1 7.7% 8.2% Week 24.6% (.8% to.3%) % % of of Subjects 6 5 4 3 2 1 HbA1c Secondary Outcomes Week 24 P=.2 P<.1 P<.1 HbA1c <7.% HbA1c <7.5% HbA1c Reduction of 1% Mean HbA1c Change From Baseline, % HbA1c Change From Baseline to Week 24 By Baseline HbA1c..2.4.6.8 1. 1.2 1.4 HbA1c <8.5%.6%.2% HbA1c 8.5% n=46 n=24 n=56 n=29 1.3%.5% By Age By Education Mean HbA1c Change From Baseline, %.2.4.6.8 1 1.2 25 to <6 y 6 y n=83 n=39 n=19 n=14.4%.4% 1.% 1.% Mean HbA1c Change From Baseline, %.2.4.6.8 1 1.2 <Bachelor s Degree Bachelor s Degree n=44 n=22 n=53 n=29.4%.5% 1.% 1.% 3
8/5/217 Mean HbA1c Change From Baseline, %.2.4.6.8 1 1.2 By Diabetes Numeracy Test 6% Correct >6% Correct n=28 n=15 n=73 n=38.6% 1.1%.9%.3% Measured Time in Range 7 18 mg/dl (3.9 1mmol/L) 76 74 734 P=.6 72 7 68 662 66 648 64 633 62 6 58 Baseline Week 24 : 1 hr 12 min more TIR / day than baseline : 15 min less TIR / day than baseline Measured Hypoglycemia <5 to <7mg/dL (2.8 3.9 mmol/l) 1 8 6 4 2 P=.6 9 76 53 75 P=.1 56 44 43 26 P=.5 29 22 23 11 Baseline Week 24 Baseline Week 24 Baseline Week 24 <7 mg/dl <6 mg/dl <5 mg/dl <3.9 mmol/l <3.3 mmol/l <2.8 mmol/l 8 7 6 5 4 3 2 1 Measured Hyperglycemia >18 to >3 mg/dl (1 16.7 mmol/l) P=.4 725 734 687 64 Baseline Week 24 P<.1 352 31 269 28 129 19 Baseline Week 24 Baseline Week 24 >18 mg/dl >25 mg/dl >3 mg/dl >1 mmol/l >13.9 mmol/l >16.7 mmol/l 71 P<.1 171 Median Coefficient of Variation, % 5 45 4 35 3 25 Glucose Variability 42% P<.1 42% 42% 38% Baseline Week 24 DIaMonD Trial Phase 2 Extension: Adding CSII A Randomized Trial Comparing: CSII vs MDI in T1D Patients Beck RW et al. Initiation of Insulin Pump in Adults with T1D on MDI Lancet Diabetes and Endocrinology July 12, 217 epub ahead of print 4
8/5/217 DIaMonD Phase 2 Methodology Phase 1 168 enrolled and 158 randomized Measured Time in Range 7 18 mg/dl (3.9 1mmol/L) Phase 2 15 to + MDI 53 to Control (MDI + BGM) 24 Week Phase 1 RCT; results in JAMA 217; 31(4): 371-378. Phase 2 12 from + MDI group eligible; 75 enrolled 38 MDI 37 CSII Omnipod pump used Both groups continued with Dexcom G4 with Software 55 Primary endpoint = Time in Target Baseline HbA1c 7.6% 8 78 76 74 72 7 68 66 P=.2 762 78 Phase 2 Baseline 741 791 Pooled Followup MDI CSII Measured Hypoglycemia 5 7mg/dL (2.8 3.9 mmol/l) Phase 2 6 5 P<.1 MDI 49 41 CSII 4 34 32 P<.1 3 23 P=.1 2 16 14 12 1 4 4 4 9 Phase 2 Baseline Pooled Followup Phase 2 Baseline Pooled Followup Phase 2 Baseline Pooled Followup <7 mg/dl <3.9 mmol/l <6 mg/dl <3.3 mmol/l <5 mg/dl <2.8 mmol/l DIaMonD Phase 2 Results adherence was excellent at 96% wear time of >6 days/week Time in target (7 18mg/dL) increased by 78 minutes with CSII Time in hyperglycemia decreased in CSII group by ~ 1 hour Time in hypoglycemia increased in CSII group HbA1c change was not statistically different between groups MDI group increased HbA1c by.1% and CSII group by.3% Daily insulin dose decreased with CSII, yet increase in boluses/day Adverse events MDI group 1 severe hypoglycemia episode CSII group 1 DKA episode and 1 hospitalization due to hyperglycemia without DKA DIaMonD Study: Multiple Daily Injections and Continuous Glucose Monitoring in Type 2 Diabetes Beck RW et al. vs in T2D Patients on MDI: A Randomized Trial In Press: Annals Internal Medicine 217 5
The image part with relationship ID The image part with relationship ID The image part with relationship ID The image part with relationship ID 8/5/217 Baseline Characteristics Typical of T2D Population Usage 6 Days/Week In T2 MDI Subjects Characteristic Baseline HbA1c Mean age Mean T2D duration Mean SMBG All Patients (n=158) 8.5% 6 ± 1 years 18 years 3/day Mean BMI 36 > 1 severe hypo / DKA in past 12 months 2% / % 97 94 93 1 1 93% were using 6 days a week in month 6 C-Peptide.2 ng/ml 92% 31 32 % of Participants 1 8 6 4 2 Week 4 Week 12 Week 24 6 days/wk days/wk Mean HbA1c, % 8.5 8. 7.5 7. HbA1c Treatment Group Differences T2 Subjects on MDI 8.5% 8.5% Baseline 7.5% P<.5 7.9% Week 12.5% (.7% to.3%) P<.2 7.7% 8.% Week 24.6% (.8% to.3%) 33 HbA1c Outcomes T2 Subjects on MDI Secondary Outcomes Reduction in HbA1c >.5% Reduction in HbA1c >1% Relative reduction in HbA1c >1% Group (N=79) n (%) 24 Weeks Control Group (N=79) n (%) 56 (73%) 37 (49%) 3 (39%) 21 (28%) 4 (52%) 24 (32%) Adjusted Odds Ratio (95% Confidence Interval) [P value] 2.7 (1.3 to 5.5) [.9] 1.6 (.7 to 3.4) [.23] 2.2 (1.1 to 4.4) [.3] 34 Effect of Baseline HbA1c on Benefit with T2 MDI Subjects Baseline HbA1c Change in HbA1c From Baseline P value Group Group 7.5%.9% (n=79).5% (n=79).2 8.%.9% (n=63).6% (n=57).5 8.5% 1.1% (n=39 ).7% (n=39).2 9.% 1.4% (n=17).7% (n=21).4 Diamond Study Similar HbA1c Reduction Observed in T2 Subsets Mean HbA1c Change from Baseline (%).%.2%.4%.6%.8% 1.% 1.2% 3 out of 5 correct 4 out of 5 correct 25 to <6 years old p=.39 p=.89 p=.84 6 years old <BA Degree BA Degree Numeracy Age Education 46 6
The image part with relationship ID 8/5/217 1 8 6 4 2 Glycemic Results with T2D MDI and Subjects: Minutes/Day P=.1 855 86 87 798 7 18 mg/dl P=.2 11 12 4 12 P=.2 612 67 549 571 Baseline Week 24 Baseline Week 24 Baseline Week 24 <7 mg/dl >18 mg/dl 3.9 1 mmol/l <3.9 mmol/l >1 mmol/l 37 Insulin and Medication Changes Group (N=79) Baseline Group (N=79) Group (N=77) 24 Weeks Group (N=75) P value Total Daily Insulin Dose units/kg/day (mean ± SD) 1.2 ±.6 1. ±.5 1.3 ±.7 1.1 ±.5 Change in Total Daily Insulin Dose (mean ± SD) +.1 ±.3. ±.3.6 % Using Non insulin Glucose Lowering Meds 71% 66% 65% 64% N of Participants Adding Non insulin Glucose Lowering Meds 2 2 4 patients with T1D on MDI HbA1c at a central lab of 8.% 14 days of (AGP) just prior to the HbA1c HbA1c 8% HbA1c 8% HbA1c 8% HbA1c 8% 39 T2D on Metformin A1c 9.9% Added Lantus (titrated to.5 u/kg) A1c 8.2% DIaMonD Trial In Older Adults with T1D or T2D Added Exenatide Bid A1c 6.7% 41 7
The image part with relationship ID The image part with relationship ID 8/5/217 In Older Adults, Use of Significantly Improved HbA1c, Time Spent in Target and Glycemic Variability 97% of the 61 older adults patients wore > 6 days/week in 6 months. Summary: in MDI Users in DIaMonD High adherence to for type 1 and type 2 HbA1c significantly reduced compared with control group Reduced.6% in type 1 cohort Reduced.3% in type 2 cohort Consistent reduction in all sub groups Benefit appeared larger at highest HbA1c In T1DM time in range increased, time hypoglycemic or hyperglycemic decreased In T2DM time in range increased and time hyperglycemic decreased Ruedy K et al. Journal of Diabetes Science and Technology. May, 217. 44 Conclusions and Comments Regarding What the DIaMonD Study Has Shown Us T1D & T2D patients on MDI who have not been exposed to technology: o Will embrace and use consistently o Gain significant benefit from These trials demonstrate basic expectations o Individualization of provider involvement is likely to improve results o Optimal incorporation of education in this process warrants added clinical research Expanded indication for the use of CMG may become more widely used following the Medicare approval of a new category called: Therapeutic CMG which applies if: The beneficiary has diabetes mellitus; and, The beneficiary has been using a home blood glucose monitor (BGM) and performing frequent (four or more times a day) BGM testing; and, The beneficiary is insulin treated with multiple daily injections (MDI) of insulin or a continuous subcutaneous insulin infusion (CSII) pump; and, The beneficiary's insulin treatment regimen requires frequent adjustment by the beneficiary on the basis of therapeutic testing results. Steering Committee Katrina Ruedy, MPSH & Roy Beck, MD, PhD Jaeb Center for Health Research Stacie K. Haller, RD, CDE Diabetes & Glandular Disease Clinic Andy Ahmann, MD OHSU Richard Bergenstal, MD International Diabetes Center Howard Wolpert, MD Joslin Diabetes Center Bill Polonsky, PhD Behavioral Diabetes Institute Acknowledgments Sponsor Members Claudia Graham, PhD; Eileen Casal, RN David Price MD Dexcom Coordinating Center & Data Management Jaeb Center for Health Research HbA1c Central Lab Santica Marcovina, PhD, ScD & Jessica Harting NW Lipid Research Laboratories 29 clinical study sites TO ALL STUDY PARTICIPANTS!! 47 8