Dr Sander Zwart MD, FACP, ECNU Arizona-AACE 2016 Annual Meeting

Transcription

1 Dr Sander Zwart MD, FACP, ECNU Arizona-AACE 2016 Annual Meeting

2 Disclaimers None Except products and software discussed are all proprietary, so if I mention a brand product it is because there is no other option

3 Introduction Roughly 20% - 30% of patients with T1DM and fewer than 1% of insulintreated patients with T2DM use an insulin pump In 2007, the US FDA estimated that the number of patients with T1DM using CSII was ~375,000 By 2050, up to one-third of US residents may have T2DM; many of these individuals will be insulin-requiring, some of them by pump Insulin pumps and glucose sensors have allowed for better control Therefore, more clinicians must develop a comprehensive understanding of these devices

4 Pumps then in very near future Decades ago

5 Advances have led to a multitude of meters, pumps, sensors, software, USB cables

6 Endocrine office Dedicated workstation for downloads of meters, CGMS, pumps Limit software use, ie Glooko/Diasend (Medtronic s carelink, DEXCOM s Clarity; Freestyle Libre and OmniPod and Tandem work with Diasend/ Glooko) Reporting/ viewing via the LAN or the cloud Billing: No CPT code except for CGMS 95250, 95251

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8 Outline Problems with FS glucose meters and with CGMS Some statistics and facts of use to us when evaluating FS/ CGMS Benefits of CGMS with examples New and coming CGMS and pumps

9 Glucometrics, why and what A1c, great for population, not always so great for individual Standard Deviation, average glucose, rate of change Meter error: Precision Accuracy MARD Clarke error grid analysis Goal 1: Pattern recognition Goal 2 : Apply treatment/ insulin algorithm

10 A1c unreliability Several anemias due to low Hb values or altered Hb ( sickle cell, hemolytic,..) CKD itself, on erythropoetin-analogue therapies Pregnancy Splenectomy s/p BMT Some ethnic groups ie Blacks (NHANES data, Diabetes Care 2009 May; 32(5): ) run higher A1c Intra-person stability > inter-person

11 Most FS/ CGMS downloads give avg, SD SD, 68% of the distribution lies within one standard deviation of the mean (average) CLINICALLY useful : target blood glucoses download SD to be less then 3 x the mean blood glucose Or : subtract one SD from the mean, and keep that number above 80, which means you are avoiding hypoglycemia most of time Home FS meters do not show all the trends, nor rate of change

12 Example of use of Average (194) and SD (64)

13 Sensors: Why is CGM better then FS

14 CGMS, FDA approval criteria Accuracy test clinically (MARD, Clarke EGA) Address human factors in understanding how to use CGMS safely In silico testing, iow what physiologic factors to consider Post marketing surveillance

15 Accurate or precise

16 MARD The best single measure of both accuracy and precision is the mean absolute relative error (MARE) (also called mean absolute relative deviation or MARD and mean absolute error or MAE). MARD is calculated by taking the average for the set of individual absolute errors relative to its reference value So, for example, with a reference value of 100 mg/dl, measured values of both 90 and 110 are in error by 10%

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18 MARD is created by taking the absolute value of the deviation from the reference value. Thus a value that is 100 points too high has a deviation of +100 and a value that is 100 points too low is also Each value is calculated as a percent of the reference and then averaged. On the right, if the reference values are 100, 200, 300, and 400mg/dl, the individual errors would be 100%, 50%, 33%, and 25%, respectively, making the MARD 53.3% (the sum, 213, divided by 4, the number of values). Problem : in hypoglycemic range we need more then the MARD

19 Error Grid Analysis (Clarke) Region A are those values within 20% of the reference sensor, Region B contains points that are outside of 20% but would not lead to inappropriate treatment, Region C are those points leading to unnecessary treatment, Region D are those points indicating a potentially dangerous failure to detect hypoglycemia or hyperglycemia and Region E are those points that would confuse treatment of hypoglycemia for hyperglycemia and vice versa

20 Error Grid, Clarke

21 Error Grid, Clarke

22 FS meter problems FDA guidance +/- 15% for OTC self-monitoring devices +/- 10% for clinical use meters ISO standard 15197: in 2013 Within 20% of glucose values above 75 mg/dl Within 15 mg of glucose values below 75 mg/dl After 10/1/2016: 95% of all measured values must be within 15% of the true value 99% of meter values must be within 20% of the true value

23 Problems with FS vs Plasma value correction how accurate Alternate site use delay, partly venous blood at times Coding most now recognize Anemia Altitude Interfering substances CGMS meters Physiologic changes of interstitial fluids Interfering substances?oxygenation

24 FS meter accuracy in setting of anemia

25 FS meter accuracy in setting of altitude

26 Hypo s and A1c improve with use of CGMS Leinung M, et al Endocr Pract :371-5

27 Sensor studies Sensor augmented pump (SAP) and MDI with real time sensor led to lower A1c (from 8.3 to 7.1) and less hypoglycemia; at 1 year the MDI group caught up with the CSII group (!) Diabetes Tech and Ther, Vol 18(9)2016;1-7 The IN CONTROL study confirmed significant less hypoglycemia, but did not abolish hypo-unawareness (again, CSII and MDI patients were enrolled) Lancet, Diabetes and Endocrinology, Vol 4(11)2016; Several trials show better hypoglycemia-control post trial

28 How does a sensor work

29 FS calibration reveals accuracy

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31 CGMS can help address basal rate

32 CGMS, effects in gastroparesis

33 CGMS can analyze per meal

34 CGMS shows too much basal

35 Or too little

36 Or, confusingly, take a different week

37 Postprandial peaks now well known

38 CGMS can help patient learn

39 Patient learning in CGMS

40 Advances in technology Pumps : threshold suspend, sensor augmented pump, hybrid closed loop systems, bionic, bihormonal systems CGMS : accuracy, calibration, patient comfort, and software analysis

41 2013, Threshold suspend Feature allowing pump to suspend basal rate during CGMS recorded Hypoglycemia Diabetes Technol Ther May 1; 17(5): : Retrospective Analysis of the Real-World Use of the Threshold Suspend Feature of Sensor-Augmented Insulin Pumps It reduces overnight hypoglycemia and reduces overcorrective hyperglycemia

42 Medtronic 670 G Hybrid closed loop 2 week run in Meal FS and CHO required, Exercise notification MARD 10.3% Glucose goal set at 120, or possibly 150

43 670 G continued Single arm, non randomized, 3 months N = 124 (n=94 adults, 30 adolescents) Baseline A1C 7.4%; mean reduction 0.5% Those with baseline > 7.5% reduction by 1.0% Time < 70 mg/dl reduced by 44%, < 50 mg/dl by 40% Time in range increased 72% 1.4 kg weight increase in adults, 1.0 kg weight gain in adolescents

44 Results of the 670 G Medtronic pump

45 Future Medtronics is working on sensor with MARD <10%, sensor is part of infusion set : one site for insulin and CGMS ilet no screen dual insulin glucagon pump DreaMed MD Logic (Fuzzy Logic): incorporate automatic correction doses: This product will be called Medtronic 690G Medtronic IBM Watson, better past-future predictive analysis, intertwine with personal assistant Sugar.IQ

46 Future UVA collaberation with TypeZero, producing incontrolap which provides interactive insulin algorithms for pumps, MDI, working on open and closed loop systems incontrol alos developing tools for clinicians to optimize insulin therapy remotely, based on several weeks of typical data (FS or CGMS, carbs) More phone apps More connectivity ie cloud based systems

47 ilet Mean (SD) of venous PG (A), CGMG (B), insulin and glucagon doses (C), plasma insulin levels (D), and glucagon levels (E) for all experiments. Steven J. Russell et al. Dia Care 2012;35: by American Diabetes Association

48 What about a second hormone from pump Bihormonal attractive option Glucagon Pramlintide GLP1a N = 10; CL, then 4 weeks 60 mcg PRAM ac Mean age 20 years, 9 years T1D, A1C 7.2% N = 11: CL, then 4 weeks 1.8 mg daily LIRA Mean age 22 years, 10.5 years T1D, A1C 7.5% Diabetes Care 2016;39: Improvements in PC pattern, but Pramlintide would require insulin adjustments

49 Freestyle Libre Pro Patch/ filament sensor last 2 weeks Water resistent 1 m Factory calibrated Pro version, the patch is all, scan at end of 2 weeks, one scanner for all patients Records every 15 min 40% error in hypoglycemia

50 Freestyle Libre Consumer Similar but records FS every min No FS replacement claim Not real time, no alarms, sleeps overnight REPLACE and IMPACT studies showed reduced hypoglycemia but not A1c, patients significantly reduced FS usage Cost lower then other CGMS, could be game changer if cutting FS frequency

51 MARD of the Freestyle Libre

52 Libre s EGA

53 CGMS software analysis

54 Dexcom s cloud based system Return of Modal Day/Overlay Chart and Standard Deviation

55 CGMS Improved Accuracy over time Accuracy (Mean ARD) for Dexcom Product Generations 26% 17% 15.9% Mean ARD (%) Home Use SMBG Meters 13.2% 9% 4 STS 3-day Seven Seven Plus G4 Gen Platinum 4 Pt G5 Gen & G4 4 Pt SW

56 Few CGMS comparison studies Head-to-head comparison between flash and continuous glucose monitoring systems in outpatients with type 1 diabetes. J Endocrinol Invest Jun 10 DEXCOM and Freestyle Libre comparable (no true gold standard ref) Disagreements in the clinically important ranges, iow One may be wrong this time The other may be wrong the next time

57 Accuracy and Longevity of an Implantable Continuous Glucose Sensor - Eversense Eversense (Senseonics Inc.) implantable CGM sensor RESULTS The MARD value against reference glucose values >4.2 mmol/l was 11.1% (95% CI 10.5, 11.7). Clarke Error Grid Analysis showed 99.2% of samples in the clinically acceptable error zones A and B. Eighty-one percent of hypoglycemic events were detected by the CGM system within 30 min. care.diabetesjournals.org/content/early/2016/11/03/dc

58 Glucose sensor as a tattoo, contact lens Peel, Stick, Check: Glucose-Sensing "Tattoo" Could One Day Replace Finger-Prick Testing Tattoo-based noninvasive glucose monitoring: a proof-of-concept study, by Bandodkar and colleagues. Analytical Chemistry 2015;87: See more at: Google Secures Patent for Glucose-Sensing Contact Lens - See more at:

59 Questions about the new technology For the larger public? Elderly? Caregivers? Who educates the caregivers? Will there be behavior change, ie the population of hypo unaware type 1 s in low A1c pursuit? Disadvantages as smartphone as device screen in sunlight, Bystander access, alarm bypassing mute, lost phone

60 questions 2 Interfering substances, APAP, Vit C, ASA, high TG, bilirubin, Uric acid, other drugs, icodextrin Insulin dosing are we ready? Reliable in hypo range? Day 1 tends to be less good then days 2+ Calibration needs? How to predict an alert, ie how to use a rate of change Does good precision indeed lead to good pattern recognition

61 Other thoughts Hassle factor in clinic, Hacker safe? $$$$ factor for patients T1DM pump with CGM or MDI with CGM Outcome studies still scarce Re-appraisal of the A1c Re-appraisal of Nice-SUGAR study, ACCORD, as we can now better avoid hypoglycemia (hypo-interstiti-glucose-humora (HIGH))

62 We need more analytical tools Software to support analysis of Exercise Non carb food Stress To help us out in this jungle