What's Hot in Diabetes Care Fred Toffel, MD, FACP, FACE

Transcription

1 What's Hot in Diabetes Care 2018 Fred Toffel, MD, FACP, FACE

2 Objectives A Taste of Technology Updates on Continuous Glucose Monitoring Smart Insulin Pumps Connected Insulin Pens Getting to the Heart of Type 2 Algorithms Review of the 2018 AACE Algorithm Review of Cardiovascular Outcomes Trials and How these Impact Diabetes Treatment Recommendations

3 History of Glucose Monitoring

4 In 1500 BC Diabetes First Described In Writing Hindu healers wrote that flies and ants were attracted to urine of people with a mysterious disease that caused intense thirst, enormous urine output, and wasting away of the body

5 Monitoring Glycaemic Control : Early History Methodology: Urinalysis for glucose In 1941 Clinitest effervescent urine sugar testing tablets launched by Bayer (formerly Miles Laboratories) Red cuprous oxide 0% 2% Uses alkaline copper sulphate and Na citrate forms colour in re-hydrated state dependent on glucose content non-specific test subject to interference

6 Monitoring Glycaemic Control : Early History Methodology: Urinalysis for glucose In 1954 Glucotest /Testape roll licensed by Eli Lilly to Boehringer Mannheim) During 196Os the dipstix : Diastix, Clinistix, Chemstrip ug available In 1964 Combur-Test (BM) for glucose, protein and ph of urine. Later range extended to include ketones Ketostix/Ketodiastix

7 Early History : Self-Monitoring Blood Glucose (SMBG) Visual Reading: semi-quantitative estimations In 1964 Earnest C Adams developed Dextrostix (Ames Miles Laboratories) Patent No 3,092,465 issued 4 th April 1963) 1st dry-reagent blood sugar teststrip using immobilized glucose oxidase with horseradish peroxidase and a color indicator. Modifications: covering over enzymes and dye with water resistant material on a plastic support Limitations : Large drop of blood required to cover test zone (30μl) Reaction time 60 seconds, Remove blood - wash/blot or wipe, Read result within 1-2 seconds after washing Reliance on color matching Glucose + O 2 gluconic acid + H 2 O 2 H 2 O 2 + dye* reduced colourless Glucose oxidase Peroxidase oxidised dye + H 2 O coloured *chromogen

8 Early History : Self-Monitoring Blood Glucose (SMBG) Automated Evaluation : Reflectance Meters (ARM) (i) photometric (colourimetric) Desk-Top Reflectance Meters 1979 Dextrometer 1968 Haemo-Glukotest developed (improved 1979). Remains the gold standard of accuracy for purely visual blood glucose determination. Bulky Heavy Expensive 1974 Reflomat 1st film-based colorimetric test-strip

9 Early History : Self-Monitoring Blood Glucose (SMBG) Automated Evaluation : Glucose meters - digital read-out (1) photometric test strips Roche (ex Boehringer M) 1983 Reflolux / Accu-chek : from Roche diagnostix 1986 Reflolux II / Accu-chek II 1987 Reflolux II M / Accu-chek II M, memory & PC interface 1990 Reflolux S / Accu-chek III

10 Early History : Self-Monitoring Blood Glucose (SMBG) Second Generation Meters - requirements 1. Recognise blood sample application and time the reaction, 2. Eliminate need for blood removal step by separation of plasma from RBCs, or correct for blood color in colorimetric devices or use electrochemical reactions 4. Incorporate checks to identify defects and user error in procedure 1987 One Touch meter : introduced by LifeScan Automated digital read-out meter using photometric test strips One Touch II Simplify: No timing, wiping, blotting or washing of blood

11 Today s Many Choices

12 The Transformation from Intermittent Self Blood Glucose Monitoring (SMBG) to Continuous Glucose Monitoring (CGM)

13 Cygnus Glucowatch

14 2006 The Year EVERYTHING Changed MiniMed Guardian Real-Time MARD=19.7% (2006) Dexcom STS MARD=26.0% (2006) Abbott Navigator MARD=13% (2006)

15 The Second Generation 2008 Medtronic Paradigm 522/722 System MARD 19.7% 2008 Dexcom Seven 2009 Dexcom Seven Plus MARD 15.9%

16 CGMs 2018 Guardian Connect CGM Eversense Implanted CGM Dexcom G6 CGM (No Calibration) Freestyle Libre CGM (No Calibration)

17

18

19 Trials Comparing CGM to SMBG

20 Study Population Design Key Outcome(s) GOLD Lind M, et al. JAMA 2017; 317(4) : T1D on MDI A1C 7.5% Randomized crossover 1:1 to 26 weeks of CGM before (n=82) or after (n=79) 26 weeks of usual care Between-group difference of 0.43 percentage points in favor of CGM, p<0.001 AND less hypoglycemia COMISAIR Soupal J, et al. Diabetes TechTher ; 18(9): T1D / MDI or CSII A1C 7.0% to 10% 1 year Nonrandomized, controlled: CGM (n=15 SAP, 12 MDI) or SMBG (n= 20 using CSII, 18 MDI) Comparable reductions in A1C and hypoglycemia in CGM/MDI and CGM/CSII groups HypoDE Heinemann L, et al. Lancet 2018; 391: T1D on MDI History of impaired hypo awareness or recent severe hypo Randomized 1:1 to CGM (n=75) or usual care (n=74) for 26 weeks Incidence of hypoglycemic events fell by 72% for CGM group, p<0.0001

21 Studycenter picture on slide Population Design Key Outcome(s) Impact Bolinder J, et al. Lancet 2016; 388: , T1D on MDI or CSII A1C <7.5% Excluded IAH Randomized 1:1 to Flash (n=119) or usual care (n=120) for 24 weeks Reduced hypoglycemia. No between-group difference in A1C change, p= Replace Haak T, et al. Diabetes Ther. 2017; 8(1): T2D on MDI or CSII A1C 7.5% to 12.0% Randomized 2:1 to CGM (n=149) or usual care (n=75) for 6 months No between-group difference in A1C change, p= Reduced hypoglycemia I HART CGM Reddy M, et al. Diabet Med. 2018; 35(4): T1D on MDI Gold score 4 or recent severe hypo Randomized 1:1 to CGM (n=20) or flash glucose monitoring (n=20) for 8 weeks CGM reduces hypoglycemia more effectively than flash glucose monitoring

22

23

24 CMS Will Cover Home CGM for Patients Insured by Medicare If the patient: Has a diagnosis of diabetes and Currently monitors fingerstick glucose four (4) times daily and Injects insulin three (3) times daily Currently only Dexcom G5 and Freestyle Libre are Medicare approved

25 Adding the Other Dimension Follow the Arrow

26 Grams of CHO (CHO to Insulin Ratio) + (Fingerstick Glucose - Target Glucose) Correction + Active Factor Insulin

27

28

29

30

31 Freestyle Report

32 Dexcom Report

33 Combining CGM with CSII Bionic Pancreas 1.0

34 History of BP Under Development for more than 50 years Described in 1974 As a computerized control system closely simulating the endocrine function of the pancreas. 1 Intravascular delivery of dextrose and insulin based on instantaneous glucose readings Only worked on supervised inpatient conditions Peyser et al., 2014, Annals of New York Academy of Science, 1311, Albisser et al., 1974, Diabetes, 23,

35 Biostator: The Artificial Pancreas 1977 Clemens, AH. The development of Biostator, a glucose controlled insulin infusion system (GCIIS), Horm Metab Res 1977.

36 Current Outpatient Conceptual Models Closed Loop Patient is removed from interaction once the system has been initiated Algorithm has total control Open Loop (Hybrid Closed Loop) Varying Degrees of Interaction Meal / Exercise announcement

37 Hormonal Models Uni-Hormonal Only insulin is used Algorithms to reduce risk of hypoglycemia Bi-Hormonal Insulin to lower the blood glucose Glucagon to raise the glucose Algorithms balance the effects of the two hormones Generally doses of glucagon are quite small Peyser et al., 2014, Annals of New York Academy of Science, 1311,

38 Basal Suspend Medtronic 630G Tandem T:Slim X2 with Basal IQ Software

39 Currently Available Hybrid Closed Loop Pump Medtronic 670G

40 670G Data Download

41 Dual Hormone Bionic Pancreas at Camp

42 A Camper s Thoughts I was never hypoglycemic I never felt hypoglycemic I was never worrying about hypoglycemia I was never recovering from hypoglycemia That s already enough of a game changer for me. But there was more If I started veering low, my bionic pancreas figured it out and gave me the perfect amount of glucagon to make sure that hypoglycemia didn t occur I always felt safe during the week at no time did I feel threatened or scared My glucoses were being watched and stayed perfectly in range overnight, every night. Wow. I counted zero carbs I never corrected I never thought about insulin sensitivity and how I couldn t figure that out I never thought about insulin to carb ratios I never bolused I was a nicer and kinder person the entire week with the bionic pancreas

43 Twitter Analysis of #OpenAPS DIY Artificial Pancreas Technology Use Suggests Improved A1C and Quality of Life Background: Patient-driven innovation in diabetes management has resulted in a group of people with type 1 diabetes who choose to build and share knowledge around a do-it-yourself (DIY) open source artificial pancreas systems (OpenAPS). The purpose of this study was to examine Twitter data to understand how patients, caregivers, and care partners perceive OpenAPS, the personal and emotional ramifications of using OpenAPS, and the influence of OpenAPS on daily life. Methods: Qualitative netnography was used to analyze #OpenAPS on Twitter over a two-year period. Results: There were 328 patients, caregivers, and care partners who generated 3347 tweets. One overarching theme, OpenAPS changes lives, and five subthemes emerged from the data: (1) OpenAPS use suggests self-reported A1C and glucose variability improvement, (2) OpenAPS improves sense of diabetes burden and quality of life, (3) OpenAPS is perceived as safe, (4) patient/caregiver provider interaction related to OpenAPS, and (5) technology adaptation for user needs. Conclusions: As users of a patient-driven technology, OpenAPS users are self-reporting improved A1C, day-to-day glucose levels, and quality of life. Safety features important to individuals with diabetes are perceived to be embedded into OpenAPS technology. Twitter analysis provides insight on a patient population driving an innovative solution to improve their quality of diabetes care. Article first published online: September 10,

44 Not Interested in Wearing a Pump?

45 Connected Insulin Pens

46 Pen Based Decision Support Merging Insulin Pen, CGM and Activity data Cloud Based Computi ng Can provide dosing decision support, hypoglycemia predictions, proactive alerts, exercise advice

47 What Does the Future Hold? 1. Bi-Hormonal systems in a single unit. 2. Apps for smart phones to combine CGM, Smart Pen, Smart Watch exercise data and maybe even to estimate nutrient content from food picture to suggest bolus dose. 3. Implantable systems with glucose sensing and insulin delivery to the portal system. 4. In hospital CGM and automated insulin delivery. 5.???? However we need to remember

48 The Dumbest Beta Cells are Still Smarter than Endocrinologists and their Technologies

49 Type 2 Diabetes Treatment Algorithm Changes from Results of CVOTs

50

51

52 ADA Glycemic Control Algorithm

53 Overview of CVOTs of Glucose-lowering Drugs 1 (1 of 2) SAVOR-TIMI 53 3 (n=16,492) P-MACE ORIGIN 6 (n=12,537) 3P-MACE TOSCA IT 20 (n=~3371) 4P-MACE EXAMINE 2 (n=5380) 621 3P-MACE TECOS 4 (n=14,671) P-MACE DEVOTE 11 (n=7637) 3P-MACE CARMELINA 14 (n=~7053) 4P-MACE + renal PIONEER 6 18 (n=~3176) 3P-MACE CAROLINA 21 (n=~6041) 631 4P-MACE ELIXA 5 (n=6068) 805 4P-MACE SUSTAIN-6 9 (n=3297) 3P-MACE CANVAS 12 (n=4330) 420 3P-MACE HARMONY Outcomes 15 (n=~9400) 3P-MACE DECLARE-TIMI (n=~17,150) P-MACE DPP-4i EMPA-REG OUTCOME 7 (n=7028) 691 3P-MACE FREEDOM CVO 10 (n=4156) 4P-MACE CANVAS-R 12 (n=5812) Albuminuria REWIND 16,17 (n=9901) P-MACE CREDENCE 23 (n=~4200) Renal + 5P-MACE SGLT-2i GLP1 RA Oral GLP1 RA LEADER 8 (n=9341) 611 3P-MACE EXSCEL 13 (n=>14,000) P-MACE STELLA-LONG TERM 19 (n=~11,412) 3P-MACE + Tumors VERTIS CV Study 24 (n=~8000) 3P-MACE Insulin TZD Timings represent estimated completion dates as per ClinicalTrials.gov 1. Johansen OE White WB et al Scirica BM et al Green JB et al Pfeffer MA et al ORIGIN Zinman B et al Marso SP et al Marso SP et al NCT Marso SP et al Neal B et al NCT NCT NCT Copyright 2017 Eli Lilly and Company 16. NCT Gerstein HC et al NCT NCT NCT NCT NCT NCT NCT

54 Overview of CVOTs of Glucose-lowering Drugs 1 (2 of 2) SAVOR-TIMI 53 3 (n=16,492) P-MACE ORIGIN 6 (n=12,537) 3P-MACE TOSCA IT 20 (n=~3371) 4P-MACE EXAMINE 2 (n=5380) 621 3P-MACE TECOS 4 (n=14,671) P-MACE DEVOTE 11 (n=7637) 3P-MACE CARMELINA 14 (n=~8300) 4P-MACE + renal PIONEER 6 18 (n=~3176) 3P-MACE CAROLINA 21 (n=~6041) 631 4P-MACE ELIXA 5 (n=6068) 805 4P-MACE SUSTAIN-6 9 (n=3297) 3P-MACE CANVAS 12 (n=4330) 420 3P-MACE HARMONY Outcomes 15 (n=~9400) 3P-MACE DECLARE-TIMI (n=~17,150) P-MACE DPP-4i EMPA-REG OUTCOME 7 (n=7028) 691 3P-MACE FREEDOM CVO 10 (n=4156) 4P-MACE CANVAS-R 12 (n=5812) Albuminuria REWIND 16,17 (n=9901) P-MACE CREDENCE 23 (n=~4200) Renal + 5P-MACE SGLT-2i GLP1 RA Insulin LEADER 8 (n=9341) 611 3P-MACE EXSCEL 13 (n=>14,000) P-MACE STELLA-LONG TERM 19 (n=~11,412) 3P-MACE + Tumors VERTIS CV Study 24 (n=~8000) 3P-MACE Study not yet completed Timings represent estimated completion dates as per ClinicalTrials.gov 1. Johansen OE White WB et al Scirica BM et al Green JB et al Pfeffer MA et al ORIGIN Zinman B et al Marso SP et al Marso SP et al NCT Marso SP et al Neal B et al NCT NCT NCT Copyright 2017 Eli Lilly and Company 16. Gerstein HC et al NCT NCT NCT NCT NCT NCT NCT NCT

55 Cardiovascular Outcome Trials for SGLT-2 Inhibitors Study Identifier No. of Patients Study Design EMPA-REG OUTCOME 1 CVD; HbA1c % 7028 Empagliflozin Placebo Primary Endpoint 3P-MACE Results HR (95% CI) 0.86 (0.74, 0.99) p=.04 a (superiority) CANVAS 2 High risk/history of CV event HbA1c % CANVAS-R 2 High risk/history of CV event HbA1c % Canagliflozin 100 mg Canagliflozin 300 mg Placebo Canagliflozin (100 or 300 mg) Placebo 3P-MACE Progression of albuminuria 0.86 ( ) b p=.02 (superiority) STELLA LONGTERM 3 First ipragliflozin use (July 2014-July 2015) ~11,412 Ipragliflozin (Observational study) CV AEs and malignant tumors 2018 c DECLARE-TIMI 58 4 CVD ~17,150 Dapagliflozin Placebo 3P-MACE 2019 c CREDENCE 5 CKD; HbA1c % ~4200 Canagliflozin Placebo ESRD, doubling of scr, or renal/cv death 2019 c VERTIS CV Study 6 Vascular disease HbA1c % ~8000 Ertugliflozin 5 mg Ertugliflozin 15 mg Placebo 3P-MACE 2019 c a Two-sided tests for superiority were conducted (statistical significance was indicated if p.0498); b Integrated analysis of CANVAS and CANVAS-R studies c Estimated study completion per clinicaltrials.gov Click on the study title to view additional details regarding each study 1. Zinman B et al. N Engl J Med 2015;373: Neal B et al. N Engl J Med 2017;Ahead of print Copyright 2017 Eli Lilly and Company

56 Cardiovascular Outcome Trials for GLP- Study Identifier No. of Patients Study Design ELIXA 1 ACS; FPG >7.0 mmol/l 1 RA (Parenteral) 6068 Lixisenatide Placebo Primary Endpoint 4P-MACE Results HR (95% CI) 1.02 ( ) p=.81 (superiority) LEADER 2 CV risk/cvd; HbA1c 7.0% 9340 Liraglutide Placebo 3P-MACE 0.87 ( ) p=.01 (superiority) SUSTAIN 6 3 CVD; HbA1c 7.0% 3297 Semaglutide Placebo 3P-MACE 0.74 ( ) p=.02 (superiority) FREEDOM CVO 4 CV risk/vascular disease HbA1c % 4156 ITCA 650 Placebo 4P-MACE Trial met its primary endpoint a EXSCEL 5 CV risk/cvd HbA1c % ~14,000 Exenatide Placebo 3P-MACE Trial met its primary endpoint b REWIND 6 High CV risk HbA1c 9.5% HARMONY Outcomes 7 CVD, vascular disease HbA1c >7.0% ~9622 ~9400 Dulaglutide Placebo Albiglutide 30 mg Albiglutide 50 mg Placebo 3P-MACE 3P-MACE 2018 c 2019 c a The primary endpoint was a composite of CV death, nonfatal MI, nonfatal stroke, or hospitalization for unstable angina (4P-MACE); b The primary endpoint was a composite of CV death, nonfatal MI, or nonfatal stroke (3P-MACE); c Estimated study completion per clinicaltrials.gov; Click on the study title to view additional details regarding each study 1. Pfeffer MA et al. N Engl J Med 2015;373: Marso SP et al. N Engl J Med 2016;375(4): Marso SP et al. N Engl J Med 2016;375(19): Copyright 2017 Eli Lilly and Company

57 ADA/EASD Consensus Statement ORLANDO The treatment approach to type 2 diabetes should begin with an assessment of cardiovascular disease (CVD) status, other comorbidities, and patient preferences, according to a draft of the upcoming 2018 joint consensus statement from the American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD). The final version of the 2018 update to the current 2015 ADA/EASD Management of Hyperglycemia in Type 2 Diabetes statement (Diabetes Care. 2015;38: ) will be presented on October 5, 2018 at the EASD annual meeting in Berlin and will be published in Diabetes Care and Diabetologia. The statement will aim to help clinicians navigate the increasingly complex options for management of hyperglycemia in type 2 diabetes, with particular emphasis on data published since 2014, including those suggesting cardiovascular benefit for the sodium-glucose cotransport-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists.

58 ADA Updated Glycemic Control Algorithm

59

60 Remember as Physicians we need to Combine High Tech with High Touch! and Empower Our Patients to Control Their Diabetes and Not Let Diabetes Control Them Thank You! Questions?