Update on Diabetes Technology

Transcription

1 Update on Diabetes Technology Andrew Ahmann, MD Professor of Medicine Director, Harold Schnitzer Diabetes Health Center OHSU

2 Objectives: Recognize the growing role of technology in assisting patients and providers in diabetes management Identify those tools that readily apply to nonspecialized practice Understand prominent diabetes technology tools that your patient may be using

3 Apps for patient independent use Data management software for diabetes provider and patient decision support Smart Pen Development Glucose monitoring Meters Flash monitoring Continuous Glucose Monitoring (CGM) Pumps Forms of Diabetes Management Technology Tools

4 Tools for Patient Independent Use Dietary assistance Diaries and calorie counters Carb counting apps Digital diaries (for doses, glucose, exercise, etc) Exercise trackers Motivational / behavioral apps Insulin dosing apps Kerr D et al Diabetes Forecast 2017; March pgs 56-59

5 Dosing Apps Many found in app stores: 2015 review found 46 apps for insulin dose calculation None were FDA approved It was determined that 67% carried a high risk of inappropriate dose calculation Only 1 was thought to be issue free Some approved and many in development Basal titration (several FDA approved) Insulia (Voluntis), mydose Coach (Sanofi), isage Rx Bolus calculators Go Dose (Lilly), mysugr, Accu-Chek Connect Huckvale K et al BMC Medicine 2015; 13: 106

6 Insulia: Basal Insulin Dosing App FDA approved Requires prescription Guides patient in basal insulin adjustments Gives feedback to provider

7 Tools for decision support Glucose testing Capillary glucose point testing by meter Interstitial fluid glucose testing Flash glucose testing Continous glucose monitoring Downloaded information for physician or patient review Manufacturer developed Independently developed across brands

8 Diabetes Data Management Systems Clinic Based Has a number of reports that your clinic can customize for upload to media file Has a traditional log that shows daily detail Patient Based Adaptable to multiple meters Information can be transmitted to provider Many of the same vendors are developing apps that are more informative and interactive. Started with meters but progressing to CGM & pumps GLOOKO

9 Tidepool Is A Non-profit Diabetes Management System

10 Tidepool

11 Smart Pens Pens with last dose indicator Pen caps that record last dose time only Devices attaching to pens to record doses, glucose and communicate with cell phone Devices that will replace insulin pumps with dosing calculators

12 Smart Pen: Last dose and time Available.

13 Smart Pen: Pen Cap Records Time Only No prescription required. Available at pharmacies.

14 Smart Pen: Communicates Glucose, Dose and Time Not marketed. May later have AI.

15 Integrated Insulin Pen, Meter, Cell Phone Not approved in US

16 Glucose Testing Options Single point glucose monitors Blinded professional CGM Flash monitoring Continuous glucose monitoring

17 T1D Exchange Clinic Network Large Database on Patients With T1D

18 SMBG Frequency and HbA1c levels in T1D Exchange 20,555 Participants Age >13-<26 y.o. Age >1-<13 y.o. Age >26-<50 y.o. Age >50 y.o. Miller KM et al. Diabetes Care. 36(7): , 2013

19 Relationship Between SMBG and A1C in Type 1 DM Multicenter Analysis of 24,500 Patients in Germany and Austria Patients on Intensive Insulin Therapy Patients on 1-3 Injections per day Schutt M et al Exp Clin Endocrinol Diabetes 2006; 114:384

20 Status of Glucose Point Meters Have become progressively more accurate By 2017 ADA Consumer Guide 88 meters/ 25 companies Inexpensive meters/ strips are generally less accurate but not always May not make a difference in those managed with oral agents but could impact insulin dosing Increasing convenience and speed Smaller sample size Improved decision support software/ apps

21 Dario An all in one system using cell phone

22 Recent Meter Advances Facilitated diaries Incorporation of smart phone reports Share information Dosing calculators Insulin:Carb Correction ratio Require provider involvement

23 BG Monitoring System Surveillance Program 2017 Meter % Compliant CV Contour Next 100% 5.3% Accu-Chek Aviva Plus Walmart ReliOn Confirm CVS Advanced FreeStyle Lite AccuChek Smart View Considered compliant if within 15% of YSI if 100 mg/dl and within 15 mg/dl if < 100 All the other meters were under 95% compliant. The MARD for these meters are generally 5-8% overall and 9-16% for glucose < 70 mg/dl Ekhlaspaur L et al JDST 2016; DOI: /

24 Blood Glucose Meter Accuracy Ekhlaspour et al, JDST meters: MARD=5.6%-20.8% 9 with MARD >10%

25 Future Glucose Point Meters Many different sampling sources considered Infra-red Tears Saliva Others None likely to be available for years if ever Microfilament with flash sensing may dramatically change the future of point sampling

26 Premature Excitement on Google s Contact lens Contact Lens Glucose Sensor Measures glucose in lacrimal fluid Proof of concept Submitted patent Very slow development No evidence for relationship with blood glucose Oregon State U is working on a similar sensor

27 Libre Flash Glucose Monitoring Two versions: Blinded glucose monitoring - - Freestyle Libre Pro Patient controlled flash monitoring - - Approved 9/27/17 in US Freestyle Libre Uses thin filament as a sensor - - interstitial glucose Secured by an adhesive patch - size of a quarter Result transmitted to a reader Used for two weeks Calibrated in the factory (does not require patient calibration) In US it is approved 12 hours after initiation through day 10

28 Freestyle Libre Pro Sensor placed in arm by staff Patient wears device for 2 weeks Does not see results real time Clinic staff downloads results after 1-2 weeks Patient often will be asked to keep a food, dosing and activity diary to compare to tracings

29 Freestyle Libre Pro Report

30 Professional CGM All systems read values mg/dl Medtronic ipro 2 Abbott Flash Libre Pro Dexcom G4 Platinum System Carlson A. et al., Diabetes Technol Therap 19(S2), S4-S12, 2017

31 Ability to: Value of Professional CGM (T1 and T2 DM) Discover unknown hyper-hypoglycemia (silent or symptomatic) Measure glycemic control directly Observation of glycemic variability Percent of time in/out of range Severity of hypo/hyperglycemia during day and night Provide actionable information derived by CGM report Highlight impact of behavioral variances Analyze glycemic effects of new interventions effectively and efficiently Vigersky R, Shrivastav M. J Diabetes Complications31: , 2017

32 Glycemic Patterns Kesavadev et al, Adv Ther DOI /s x 2017

33 Abbott FreeStyle Libre Approved by FDA last week 10-day sensor in U.S. Factory calibrated swipe

34 Flash Monitoring System in Europe Uses Freestyle Libre sensor Wear the sensor up to 14 days Factory calibrated Scan with a cell phone placed against the sensor Present reading Last 8 hour trend Trend arrows

35 Abbott Libre Study: IMPACT (T1D)

36 Abbott Libre: IMPACT Randomized Trial Results Libre usage overall 93% Libre reduced time < 70 mg/dl by 74 min/day (P<0.001) Libre increased TIR, reduced hyperglycemia and variability No difference in HbA1c Severe hypo events: 2 in Libre and 4 in Control Group SMBG testing 0.5 times/day versus 5.6 times/day Mean sensor scans per day 15 High treatment satisfaction and quality of life with Libre

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38 Monitoring: Beyond SMBG 1999: MiniMed CGM was approved - retrospective 2001: The Glucowatch G2 Biographer was released Used reverse iontophoresis Needed to be changed after about 13 hours of use Caused burning/ irritation at site Didn t sell well and was taken off the market 2005: Medtronic approved for Guardian CGM 2006: Dexcom introduced their CGM 2006: Medtronic first integrated CGM with pump SAP

39 Real-time CGMs circa 2008 Dexcom: SEVEN Sensor (FDA approved for adults in 2006) Medtronic: Guardian REAL-Time Sensor (FDA approved for adults/children in 2005) Abbott: FreeStyle Navigator (FDA approved for adults in 2008)

40 Continuous Glucose Monitoring Two brands presently approved in US Increasing accuracy and convenience Interference with acetaminophen Increased evidence of benefit Improved glucose control Less hypoglycemia Primarily used in type 1 DM However high educational/ behavioral potential in type 2 DM. Critical for development of artificial pancreas

41 CGM-measured Mean Glucose Versus Lab-Measured HbA1c 218 mg/dl 155 mg/dl Data from 3 studies with Dexcom sensor N= 387 (315 T1D + 72 T2D)

42 Available CGM in US

43 CGM Accuracy Over Time Medtronic Enlite 3 (10.5%) Abbott Libre (9.7%) Faccinetti A. Sensors 2016

44 Accuracy of Current Sensors Mean Absolute Relative Difference (MARD) Percentage within 20 mg/dl or 20% Dexcom G5 9.0% 93% Medtronic Enlite % 88% Abbott Libre 12.3%* 84% *9.7% after first 12 hrs on day 1 (through 10 days)

45 Sensor Accuracy Needed for Non-Adjunct Use of CGM In-Silico Model CGM for insulin dosing decisions feasible below sensor error in silico at MARD= 10% Kovatchev BP et al, Diab Technol Therap, 17(3) , 2015

46 Coming Soon: Dexcom G6 Sensor 10 Day duration sensor Acetaminophen Blocking 1 Calibration Per Day (after start) 30% Thinner Wearable Simple, Push Button Sensor Applicator

47 Dexcom G6 Sensor Accuracy - Expect Further Accuracy Improvement - Study Results Overall N Mean ARD %20/20 N G6 All Data % 96.1% 161 G6 Adults % 99.4% 95 G5 Adults % 93% subjects (32 Adult, 17 Pediatric) with T1D Accuracy assessed over 10 days with YSI Calibrated once per day after start Day 1 Mean ARD %20/ % 90.1% 7.3% 100% 10.7% 84%

48 Sensionics: Eversense System Implantable Sensor Sensor Mean ARD = 8.8% Smart Transmitter No extra deviceto carry Mobile App ios and Android platform Alarm settings & reports

49 What about outcomes with CGM?

50 JDRF CGM Study: Similar HbA1c Reductions Observed in Pump and MDI Users* Pump (n=43) MDI (n=9) Baseline HbA1c, % 7.5 ± ± 0.6 Change from baseline, % 0.5 ± ± 0.8 *Among patients 25 years old. JDRF CGM Study Group. N Engl J Med. 2008; 2008;359(14): , supplemental Table 2.

51 JDRF Study: CGM Effect In Type 1 Diabetes AGE 25 or older 0.5% Reduction in A1c (p < 0.001) 34% vs 9% reached 7.0% A1c (p = 0.005) AGE No difference from control Age 7-14 A1c reduction 0.15% difference (NS) 27% vs 12% reached 7.0% (p = 0.01) JDRF CGM Study Group NEJM 2008; 358; 2565

52 JDRF CGM Study: Frequency of Use AGE 25 or older AGE Age 7-14 Frequency of use was a predictor of success for all age groups. JDRF CGM Study Group NEJM 2008; 358; 2565

53 STAR 3 Study: SAP Therapy vs MDI A1C at 3, 6, 9, 12 months: Adults 19 years 7.8% 7.3% 7.8% 7.9% 7.3% 7.3% 7.9% 7.3% Values are means ± SE. Asterisks denote P<0.001 for comparisons between SAP group and MDI group at each time point. Bergenstal R et al NEJM 2010; 363: :

54 STAR 3 Study: Relationship of Sensor Use and A1C at 1 year Values are means ± SE. P=0.003 for association between sensor wear and A1C reduction at 1 year. Bergenstal R et al NEJM 2010; 363: :

55 CGM works with pumps What about with MDI?

56 GOLD Trial of CGM in Type 1 with MDI Performed in Sweden at 15 sites Study of 142 patients age 18 years, on MDI Randomized 1:1 to CGM or SMBG alone 17 week washout after 6 months and then crossover to alternate intervention for 6 months Primary outcome was difference in HbA1C Mean age = 44.6 years Initial mean HbA1C = 8.6% GOLD Lind M, et al JAMA. 2017;317(4):

57 AA3 KL2 CGM First With GOLD Baseline HbA1c Reduction with CGM + MDI: 0.8% Between Group HbA1c Reduction with SMBG + MDI and CGM + MDI: 0.4% More severe hypoglycemia in SMBG + MDI group (12 events vs. 1 event) 88% of time CGM worn throughout the study Lind M, et al JAMA. 2017;317(4): Lind M, et al JAMA. 2017;317(4):

58 Slide 57 AA3 KL2 Include A1C change from baseline and A1C difference between groups somewhere on the slide. Also could mention that there was more severe hypoglycemia in the control group and that mean CGM was was 87.8% of the time. Andrew Ahmann, 2/6/2017 Done Keri Leone, 2/13/2017

59 DIAMOND Study: Multiple Daily Injections and Continuous Glucose Monitoring in Diabetes

60 Study Design for Phase 1 of DIAMOND Two Different Cohort in Phase 1 Type 1 Type 2 PHASE 1 (24 weeks) SCREENING RUN-IN Blinded CGM (2 weeks) RANDOMIZE 1:1 T2D 1:2 T1D SMBG Usual Care CGM Beck RW et al., JAMA. 2017;317(4):

61 DIAMOND: SMBG Frequency Beck RW et al., JAMA. 2017;317(4):

62 DIAMOND Trial of CGM in T1DM HbA1c Treatment Group Differences P<.001 P<.001 HbA1c (%) Baseline Adjusted mean difference (95% CI) Week % (-0.7% to -0.3%) Week % (-0.8% to -0.3%) Beck RW et al., JAMA. 2017;317(4):

63 HbA1c Change From Baseline to Week 24 By Baseline HbA1c Beck RW et al., JAMA. 2017;317(4):

64 DIAMOND Type 1: By Age n=83 n=39 N=32 N=23 n=19 n=14 Beck RW et al., JAMA. 2017;317(4):

65 Beck RW et al., JAMA. 2017;317(4): DIAMOND Type 1: By Education

66 DIAMOND Type 1: By Diabetes Numeracy Test Beck RW et al., JAMA. 2017;317(4):

67 CGM-Measured Hypoglycemia 50-70mg/dL ( mmol/l) P=.006 P=.01 Usual Care P=.005 Beck RW et al., JAMA. 2017;317(4): Baseline Week 24 Baseline Week 24 Baseline Week 24 <70 mg/dl <60 mg/dl <50 mg/dl <3.9 mmol/l <3.3 mmol/l <2.8 mmol/l

68 DiaMonD Trial of CGM in T1DM: Glucose Variability Beck RW et al., JAMA. 2017;317(4):

69 Summary: CGM in MDI Users in DIAMOND High adherence to CGM for type 1 and type 2 HbA1c significantly reduced compared with control group Reduced 0.6% in type 1 cohort Reduced 0.3% 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 68

70 T1D Exchange Registry How often insulin dosed based on CGM alone? (data collected prior to change in Dexcom labeling)

71 REPLACE-BG Study Objective: To determine whether the routine use of CGM without BGM confirmation is as safe and effective as CGM used as an adjunct to BGM 226 participants randomly assigned 2:1 to either CGM-only or CGM+BGM group Both groups used Dexcom G4 Platinum CGM System with an enhanced algorithm (software 505) and Contour Next BGM Primary Outcome: Time in range mg/dl, measured with CGM over the full 6 months of the study Aleppo G et al, REPLACE- BG Study Group. Diabetes Care 40 (4): , 2017

72 Primary Outcome: Mean time mg/dl P=0.81 Aleppo G et al, REPLACE- BG Study Group. Diabetes Care 40 (4): , 2017

73 Hypoglycemia CGM+BGM Aleppo G et al, REPLACE- BG Study Group. Diabetes Care 2017; 40 (4):

74 Changes As A Result of Recent CGM Studies FDA approved Dexcom CGM as replacement monitoring for SMBG in December 2016 Still must calibrate Medicare agreed to cover CGM recently For DM treated with intensive insulin therapy No longer any question that CGM benefits both patients on MDI and pumps

75 Can you use CGM rate of change to adjust insulin doses?

76 Recommendations For Using ROC Information to Guide Dosing No proof of benefit. Klonoff D & Kerr D. JDST 2017; pg 1-7

77 T1D Exchange Data: CGM Use Is Increasing But Still Low

78 Various Options Beyond SMBG (cont) Canine Sensor Loved May be highly valuable for patient well being Costly Probably not very reliable

79 Glu

80 Study Design Exploratory, controlled study Inclusion: age 2-80, T1D, have professionally-trained diabetes alert dog 1 week blinded CGM Hypo = CBG <70 mg/dl, CGM <70 x 15 min Detailed event diary correlate any dog alert with CBG Timely dog alert if CBG <70 mg/dl or within -10 to 30 minutes CGM <70 mg/dl Surveys hypo unawareness, subjective dog reliability, motivations for having a dog

81 Dogs vs CGM: Overall Reliability Sensitivity Of all hypo events, timely dog alert to 36% Positive Predictive Value When dog alerts, have hypoglycemia 12% of time False Positive Rate Mean 14.5 false positive alerts per week Los E et al J Diabetes Sci Technol Aug 28. pii:

82 CGM outperforms trained dogs 30 hypoglycemia events detected by both dog and CGM CGM reached hypoglycemia threshold (<70 mg/dl) before dog in 73% of events median 22 minute difference When hypo occurred, what was first sign? symptoms 12%, dog 19%, CGM 70% Los E et al J Diabetes Sci Technol Aug 28. pii:

83 Results: Subject Surveys Question Response mean (range) 1. Overall satisfaction 8.9/10 (7-10) 2. If low, how often will dog alert? (Sensitivity) 79% (70-90) 3. How often is alert first sign of low (added value) 76% (50-95) 4. When alert occurs, how often are you low? (PPV) 83% (50-100) 5. Minimum % of lows detected to be worth it 65% (20-80) 6. Maximum % tolerable incorrect alerts 26% (10-80) 7. If dog detects 80%, what is reasonable cost? $12,313 ($2500- $20,000)

84 Patient from Dogs vs CGM Study: 15 yo sleeps soundly through the night 2311 CGM < asleep CBG 41, treated 1053 Dog alert

85 Medtronic 630G System Animas Vibe Accu-Check Combo T-Slim OmniPod Pumps of Today

86 T1D Exchange Data: Insulin Pump Use Is Increasing Slightly However, general use is < 30% among all patients in non-specialty database.

87 Progress in insulin pumps Improved mechanics Easier programming One available pump is a patch pump (no tubing) Improved decision support and data management - - smart pumps Give patients much more flexibility Customized basal rates and bolus ratios Multiple options for adjusting for exercise, travel, illness, etc.

88 What is more important, the CGM or CSII?

89 Evidence is stronger for CGM than pumps

90 Meta-analysis of newer pump studies (using insulin analogs) **None of these studies used a bolus calculator** Yeh et al. Ann Intern Med. 2012;157:

91 DIaMonD Phase 2 Methodology Phase enrolled and 158 randomized 105 to CGM + MDI 53 to Control (MDI + BGM) 24 Week Phase 1 RCT Phase from CGM + MDI group eligible; 75 enrolled 38 MDI 37 CSII Omnipod pump used Both groups continued with Dexcom G4 with Software 505 Primary endpoint = Time in Target Baseline HbA1c 7.6% Beck RW et al Lancet Diabetes Endocrinol 2017: 5:

92 DIAMOND Phase 2 Results CGM adherence was excellent at 96% wear time of >6 days/week Adding CSII showed the following benefit: Increased time in target (70-180mg/dL) by 78 minutes Decreased time in hyperglycemia by ~ 1 hour Daily insulin dose decreased (but number of boluses increased) However there were some surprises: Time in hypoglycemia increased in CSII group HbA1C reduction was not statistically improved MDI group increased HbA1c by 0.1% CSII group increased by 0.3% Adverse events MDI group 1 severe hypoglycemia episode CSII group 1 DKA episode and 1 hospitalization due to hyperglycemia without DKA Beck RW et al Lancet Diabetes Endocrinol 2017: 5:

93 However, the future of pumps is assured as the automated vehicle for insulin delivery in an artificial pancreas

94 Progress in Insulin Pump-CGM Integration Several pumps share CGM information on the pump display Medtronic has made the most progress Sensor Augmented Pump (SAP) STAR 3 trial showed improved A1C Threshold suspend ASPIRE trial showed reduced hypoglycemia with automated suspend at low glucose Hybrid closed loop system Bolus for meals manually but computer algorithm adjusts basal rates between meals and overnight.

95 Threshold Suspend Download

96 Hybrid Closed Loop System 670G Medtronic step toward artificial pancreas Manual meal bolus with the calculator The pump automatically adjusts basal rates between meals and overnight Requires the constant use of a new CGM Reduced A1C Reduced Hypoglycemia FDA Approved

97 Adult Results From Medtronic 670G Hybrid Closed Loop System Study Parameter Run-in End of Study P Sensor avg Percent Values in Range mg/dl +/ mg/dl +/ mg/dl 1.1 % 0.6 % < mg/dl < mg/dl < > 300 mg/dl CV % < HbA1C % < TDD < % Basal < Garg S et al DTT 2017;

98 Things to Come: Fully automated artificial pancreas Could be: Insulin only Dual hormone Insulin + glucagon Preliminary results are positive ilet - - dual hormone One of several

99 Conclusions Technology is playing a major role in diabetes care Smart phone apps have potential but beware CGM offers much more in patient guidance than does SMBG The evidence now strongly supports use of CGM for MDI patients as well as those on a pump Flash monitoring may have a major impact The immediate future for type 1 will undoubtedly focus on AP technology Monitoring options will continue to evolve, improve and apply to type 2 patients as well