Glucose Variability & Pattern Management: Way Beyond Logbooks Irl B. Hirsch, M.D. University of Washington, Seattle, WA

Transcription

1 Glucose Variability & Pattern Management: Way Beyond Logbooks Irl B. Hirsch, M.D. University of Washington, Seattle, WA 1

2 Normal Renal Glucose Handling 180 g of glucose is filtered each day Virtually all glucose reabsorbed in the proximal tubules & reenters the circulation SGLT2 reabsorbs 90% of the glucose SGLT1 reabsorbs 10% of the glucose Virtually no glucose excreted in urine Wright EM. Am J Physiol Renal Physiol. 2001;280:F10-F18. 2

3 Renal Handling of Glucose in a Non-Diabetic Individual S1 segment of proximal tubule Reabsorption Glucose ~90% ~10% SGLT2 S G L T 1 Collecting duct Distal S2 / S3 segment of NO GLUCOSE proximal tubule Wright EM. Am J Physiol Renal Physiol. 2001;280:F10-F18. Thorens B. Am J Physiol. 1996;270:G541-G553. 3

4 SGLT2 Mediates Glucose Reabsorption in the Kidney Na+ and Glucose at 1:1 stoichiometry Na+ Lumen SGLT2 Glucose S1 Proximal Tubule GLUT2 Blood Glucose Glucose Na + K+ Na+ ATPase Adapted from Dr. Robert Henry, New Classes of Pharmacologic Agents for the Treatment of Hyperglycemia on the Horizon: Sodium Glucose Cotransporter (SGLT) - Type 2 Inhibitors, Feb

5 History of 1,5 Anhydroglucitol (1,5 AG) ,5AG was discovered in plant of Polygala Senega Presence in human body was reported Decrease of plasma 1,5AG concentration with uremia and diabetes mellitus was reported Blood 1,5AG was determined in Japan present- research into relationship between 1,5 AG and diabetes control became active. 5

6 Physiology of 1,5-AG Oral Supply 1,5AG (5-10mg/day) Normoglycemia Oral Supply 1,5AG (5-10mg/day) Hyperglycemia Blood stream Tissues Internal Organs Glucose Blocks Reabsorption Blood Stream (1,5-AG Level Lower) Tissues Internal Organs Kidney Urinary excretion (5-10mg/day) Kidney Urinary excretion (INCREASED) 6

7 Frequency (%) Histogram of serum 1,5AG concentrations Healthy (n=539) 24.6±7.2 µg/ml Diabetes (n=808) 7.3±7.1 µg/ml Serum 1,5AG (µg/ml) 7

8 What We Know About 1,5 AG 1,5 AG is a strong marker for glucose variability and is now available via commercial labs 1,5 AG is not a strong marker for glycemia (MBG or GV) for people p with A1C levels > 8% (ADAG) For measures of glycemic variability, for those with A1C levels < 8%, 1,5 AG correlates better with standard deviation than other measures of GV 8

9 What We DON T Know About 1,5 AG How it correlates and predicts diabetes vascular complications How it correlates to different risks and rates of hypoglycemia-likely likely different for T1 vs. T2DM 9

10 When to USE 1,5 AG When A1C is < 8% To better understand the QUALITY of the A1C Initial goal: >

11 Further Thoughts 1,5 AG may be useful but with different interpretations for Pregnancy Maternal/fetal outcomes? MODY Diagnosis? 11

12 Final Thought About the Kidney The kidney was, is, and will be an important part for the diagnosis and treatment of diabetes 12

13 HbA1c (A1C) Our primary and most fundamental research and clinical endpoint in diabetes for the past 3 decades 13

14 Average Glucose vs. A1C A1C AG mg/dl (95% CI) 5% 97 (76-120) 6% 126 ( ) 7% 154 ( ) 8% 183 ( ) 9% 212 ( ) 10% 249 ( ) 282) 11% 269 ( ) 12% 298 ( ) A1c is an average, more weighted over the past 30 days, with large CIs Diabetes Care 31: ,

15 Even More Importantly HbA1c and duration of diabetes (glycemic exposure) explain only ~11% of the variation in retinopathy risk for the entire DCCT study population (table 9, reference 1) so that other factors may presumably explain the remaining 89% of the variation in risk among subjects independent of A1C. HUH? Diabetes 57: ,

16 What Is Fructosamine? Glycated proteins that provide an approximate 21 day history of glycemia Relationship between glycemia and fructosamine not a straight line No correlations between fructosamine and MBG via CGM and more importantly, complications When would it be used? 16

17 So When Would You Use Fructosamine? In those conditions A1C won t work! Most anemias, polycythemia vera Hemoglobinopathies Drugs: epo, dapsone Splenomegly (many etiologies) Reticulocytosis of any etiology Prosthetic heart valves Recent blood transfusion 17

18 Glycemic Control Biomarkers HbA1C 1,5AG Fructosamine Blood glucose Weeks before measurement 18

19 My History With This Started downloading meters in 1995 due to my frustration with logbooks and an available computer/software program Was provided with mean, standard deviation, and testing frequency Eventually provided time-specific statistics What did I see? 19

20 What I Quickly Realized Few patients will keep detailed logbooks for extended periods of time With downloading, one can observe means, patterns, and variability not possible with logbooks 20

21 There are Common Pathways in Diabetes Complications Glucose Peripheral & Autonomic Neuropathy AGE Formation PKC Hexosamine Pathway Cellular l Dysfunction Oxidative Stress ROS ROS Cell Damage Vascular Damage Nephropathy Retinopathy Different complications (eye, kidney, nerve, blood vessels) arise from limited number of triggers perturbing a limited number of metabolic pathway(s) 21

22 But Variability Also Predicts Severe Hypoglycemia! Variability: SD of 7-point glucose profiles Intensive P=0.004 Conventional Diabetologia 50:2553,

23 What s a better way to assess glycemic variability? Meter (and sensor) Downloads! 23

24 Which Patient Has More Variable Fasting Glucose Data? Joe: HbA1c = 6.5%; on CSII with insulin aspart Mean = 123 mg% Mary: HbA1c = 6.5%; on HS glargine and prandial lispro Mean = 123 mg% SD = 51 SD = 77 24

25 Statistics 1 SD is a simple measurement of variability SD = square root of the variance SD is based on a group of measurements that is NORMALLY distributed (measurements which are concentrated in the middle but are symmetrical on both sides) 1 problem: glucose is not normally distributed! 25

26 Normal vs. Non-Normal Curves A B In patients with or without diabetes, which one of these curves is consistent with glucose distribution over time? Which curve is normally distributed? 26

27 Standard Deviation Our clinically ca available a ab measurement e e of glycemic variability Many other statistical analysis are available but correlation will be with CGM and outcomes, not SMBG Can determine both overall and time specific SD Need sufficient data points Minimum 5 but prefer 10 27

28 Calculation To Determine SD Target SD X 2 < MEAN Ideally SD X 3 < mean, but extremely difficult with type 1 patients 28

29 Significance of a High SD Insulin deficiency (especially good with fasting blood glucose) Poor matching of calories (especially carbohydrates) with insulin Giving mealtime insulin late (or missing shots completely) Erratic snacking Poor matching of basal insulin, need for CSII? CGM? 29

30 Other Significance of a High SD Increased Oxidative Stress and Inflammation 30

31 Caveats of the SD Need sufficient SMBG data Low or high averages makes the 2XSD<mean rule irrelevant 31

32 Caveats of the SD: Low Mean Mean = 81; SD =

33 Caveats of SD: High Mean Mean = 217; SD =

34 Enough testing Tricks To Reduce GV It is easy to over-react to too much SMBG data One option to reduce variability 34

35 Other Tricks To Reduce GV Enough testing Don t over-treat the lows! Reduce carbs (duh!) Pramlintide (Symlin) Lag times 35

36 BG Level (mg/d dl) Timing of Rapid-Acting Analog Insulin Injection Alters PPG in Type 1 Diabetes Mellitus Insulin Lispro 72 Injection-Meal Interval (minutes) 30 m 15 m 0 m +15 m BG Level (mg/d dl) Insulin Glulisine Injection-Meal Interval (minutes) 20 m 0 m +20 m kcal/kg breakfast 36 Standardized breakfast Minutes Minutes Rassam AG, et al. Diabetes Care. 1999;22: Cobry E, et al. Diabetes Technol Ther. 2010;12:

37 How To Read a BG Download 59 year-old woman with 41 years T1DM NPDR, HTN, past history microalbuminria, CAD with stent placement 5 years ago A1c on clinic i date: 6.3% 37

38 Read aggregate mean/sd 38

39 Read aggregate mean/sd Read frequency of testing 39

40 Read aggregate mean/sd Read frequency of testing Review time-specific means/sds 40

41 Example 2: 38 y/o woman with LADA 2 years ago, presented with polyuria, polydipsia, A1C = 9.5% Started on insulin day of diagnosis GAD positive Family history significant in that 6 year-old daughter with T1DM Now receiving ing 0.32 units/kg/day Risk for severe hypoglycemia? LOW 41

42 When I see a REALLY High SD The typical type 1 patient comes to me on a first visit with an SD of > 100 (no matter the mean) THIS IS BAD For that typical patient, it simply means: Missing insulin, no lag times, poor food choices For the occasional patient it means GASTROPARESIS SD extremely helpful to help determine if doing a reasonable job in matching food to insulin but overall they are lower in type 2 patients 42

43 Meter Downloads Review aggregate g and time-specific means/sds Assess basal insulin replacement BG change between HS and AM with pump or MDI Basal Test -especially with CSII Assess prandial insulin replacement Best done with frequent pc SMBG Assess correction dose What happens to BG after correction? 43

44 How I Interpret Meter/CSII/CGM Downloads No right or wrong way-we just use the technology provided to us Ideal situation: meter download skimmed, then pump/sensor download reviewed in more detail Downloads in evolution, but they are not equal in ability to assist in patient care 44

45 Where I Start After Reviewing the Meter Download in a Patient Using a Pump/Sensor Insulin action time Basal doses: match chart note? Carb ratios, ISF and targets used for BW CGM Alerts and snooze times 45

46 25 year-old woman, depression, anxiety disorder, past history of eating disorder, planning pregnancy in 1 year CSII X 5 years, CGM X 3 months Rapid A1C today = 7.0% WHERE TO START? BUT, excellent overview of pertinent statistics! 46

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48 Where I Spend My Time 48

49 Hypo and Rx Dr. Hirsch-my glucose was 344! This piece of #!%$# doesn't work! Followed BC advice: NO INSULIN Followd BC advice 49

50 What s the Diagnosis? 51 year-old woman diagnosed with GDM during last pregnancy 18 years ago; insulin d/c ed after pregnancy, mother diagnosed with T2DM in her 70s before death from MI 6 months after pregnancy was admitted to hospital in mild DKA, A1C = 11% Since then has had difficulty in managing glucose levels, most A1C levels 8-9% Started CSII in 2004 with no improvement in A1C levels BMI = 26, + acanthosis; tries to get to gym 3-5X/week, states rarely eats more than 80 grams carb PER DAY! 50

51 What s The Diagnosis? More History No retinopathy, intermittent albuminuria + CAD, s/p stent placement in 2003 (at the age of 45 years) Dyslipidemia with high TGs (300s), low HDL-C (30s), LDL-C ~100 mg/dl when not on therapy Does not tolerate statins due to cramping Developed hypothyroidism in 2004 with strongly positive thyroid peroxidase Ab s now on T4 Rx Has required hearing aid for 15 years WHAT S THE DIAGNOSIS? 51

52 What s The Diagnosis? LAB GAD Ab- negative CK, creatinine, electrolytes, TSH all WNL (on T4 Rx) C-peptide: 1.0 ng/ml with concomitant glucose 210 mg/dl WHAT S THE DIAGNOSIS? 52

53 How To Begin Meter Downloading Pick one family of meters (or at the most two) so that you have the minimal number of software programs; the software you pick could be the meters preferred with the majority of insurance companies I would suggest using a dedicated computer (laptops are fine to move between rooms) For larger practices or once you appreciate the value of downloading for insulin-requiring patients, there are several programs that allow downloading of most meters on the market (we use CliniPro from Numedics.com) Get comfortable with meters before tackling CSII/CGM! 53

54 Summary A1C, 1,5 AG, and fructosamine all have different advantages and challenges; only A1C to date is correlated with diabetes- related complications Glucose variability is clearly related to an increase risk of hypoglycemia for those requiring insulin and may be involved in the vascular complications of diabetes 54

55 Summary Blood glucose meter, CSII, and CGM downloading is a powerful tool which assists all of us identify blood glucose trends Blood glucose meter downloading is underutilized by both physicians and patients The concern that it is too time-consuming is not valid since patients can do this at home. 55