Harvesting Healthy Hemogobins: Optimal Management of A1c and Beyond. Carol H. Wysham, M.D Rockwood Clinic Spokane, WA

Transcription

1 Harvesting Healthy Hemogobins: Optimal Management of A1c and Beyond Carol H. Wysham, M.D Rockwood Clinic Spokane, WA

2 Diabetes: 21 Million and Climbing Estimated 15 million diagnosed million undiagnosed Each year over 1,500,000 new cases are diagnosed Over 54 million have prediabetes Diagnosed Cases (Millions) From Centers for Disease Control and Prevention, accessed 8/29/

3 DCCT and UKPDS: No Glycemic Threshold Continuous relationship between HbA 1c and complication risk Lower HbA 1c associated with lower complication risk No glycemic threshold the lower the better Rate/100 Patient Years DCCT (Type 1) 16 Retinopathy Incidence/100 Patient Years UKPDS (Type 2) 8 6 Retinopathy HbA 1c (%) HbA 1c (%) Diabetes 1996,45: Lancet 1998;352:

4 Glycemic Goals of Therapy Goal ADA, 2007 ACE Verbal Target Premeal glucose (mg/dl) <110 ~100 2-h postprandial glucose HbA1c <180* <7%** <140 <6.5% <<200 As low as possible w/o unacceptable AE * Evaluation and treatment of postprandial glucose may be useful in the setting of suspected postprandial hyperglycemia, with the use of agents targeting postprandial hyperglycemia and for suspected hypoglycemia. ** More stringent glycemic goals (i.e. a normal A1C, <6%) may further reduce complications at the cost of increased risk of hypoglycemia Diabetes Care 29:s4-41, 2007

5 Fewer Than 50% of People with Diabetes have Adequate Glycemic Control % of Subjects n = A 1c >8% 7-8% <7% Adults aged years with previously diagnosed diabetes who participated in the interview and examination components of the National Health Examination Survey (NHANES), & Saydah SH et al. JAMA. 2004;291: Resnick HE et al. Diab Care. 2006;29:

6 Fasting and Postprandial Glucose Levels Contribute to the A1c 250 Basal hyperglycemia Mealtime hyperglycemia Plasma Glucose (mg/dl) Type 2 Diabetes Normal Time of Day 0600 Riddle. Diabetes Care. 1990;13:

7 Postprandial Glucose Contribution to A1C 100 FPG (Fasting Plasma Glucose) PPG (Postprandial Plasma Glucose) % Contribution % 70% 50% 50% 55% 45% 60% 40% 70% 30% 0 < >10.2 A1C Range (%) Data from Monnier L, et al. Diabetes Care 2003; 26:

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9 Emerging Evidence of Association Between PPG Elevation & Risk Of CVD The Rancho Bernardo Study Honolulu Heart Program Paris Prospective Study Diabetes Intervention Study Isolated 2-hour PCH alone more than doubles the risk of fatal CVD and heart disease in older adults.. FG alone for diabetes screening or diagnosis may fail to identify most older adults at high risk for CVD. 1-hour PCH was related in a continuously increasing fashion with CHD, CHD mortality and total mortality Death rates for CHD increase with increasing 2-hour post-challenge insulin levels Postprandial, but not FG, is associated with coronary heart disease

10 Risk for Retinopathy with Conventional and Intensive Treatment Risk for Retinopathy in Subgroups of the DCCT Conventional Rate Per Patient Year % 10% 9% 8% 7% Mean HbA1c Time During Study (Years) Intensive Rate Per Patient Year % 8% 7% Time During Study (Years) Mean HbA1c Adapted from Diabetes 1995;44:

11 Two Concerns Glucose Exposure or high blood sugars Measured by A1c or average glucose on meter Glucose Variability or up and down blood sugars Measured by SD, CGM, MAGE, ADRR

12 Exposure And Variability The DCCT proved that exposure to high blood glucose was damaging. New emphasis is on glucose variability. glucose (mg/dl) :00 PM 3:00 PM 4:00 PM 5:00 PM 6:00 PM 7:00 PM 8:00 PM 9:00 PM 10:00 PM 11:00 PM 12 :00 AM Exposure or Average = A1c or avg. BG from meter 1:00 AM 2:00 AM 3:00 AM 4:00 AM 5:00 AM 6:00 AM 7:00 AM 8:00 AM 9:00 AM 10:00 AM 24 hrs Variability or Swing = SD from meter 11:0 0 AM 12 :0 0 PM 1:00 PM 2:00 PM

13 Exposure And Variability Are Different Glucose variability (SD) and A1c in two individuals: Top: A1c = 6.6% SD = 20 mg/dl Bottom: A1c = 6.7% SD = 61 mg/dl R. Derr et al: Diabetes Care, 26: , 2003

14 Variable Blood Glucose: Independent Risk Factor for Mortality Variability of FPG and CV Mortality 10 year survival Survival Probability p < Mean CV FPG I tertile II tertile III tertile Time (years) Muggeo M et al. Diabetes Care 2000;23:45-50

15 Correlation Between Variability in Blood Glucose Response and Incidence of Hypoglycemia Hypoglycemia (episodes/ person/year) Within-patient variability (CV) of fasting blood glucose (%) BG = blood glucose; FBG = fasting blood glucose; CV = coefficient of variation Heller S et al. Diabetologia. 2004;47(s1):A303.

16 Effects of Lower Blood Glucose and Reduced Inter-Day Variability on Quality of Life in Type 2 Diabetes Blood glucose and day-to-day variability as represented by SD (BG) were both negatively correlated with M (QOL) Variability in daily QOL ratings was explained by absolute level and the day-to-day variation in BG Data provide additional evidence for benefits of maintaining a low and stable glucose profile and support conducting further studies of BG variability and QOL Testa M, et al. 2003; ADA 63rd Scientific Sessions, New Orleans

17 What About Long-Term Glycemic Variability? Pittsburgh Epidemiology of Diabetes Complications 16-year follow-up of childhood T1DM, N=408 Results: Risks of coronary disease over time related to A1c and variability of A1c! Diabetes 55 (Supp 1): A1, 2006

18 Variability is a Characteristic of Severe Insulin Deficiency 400 Mean A1C = 6.7% 300 Glucose Concentration (mg/dl) :00 AM 4:00 AM 8:00 AM 12:00 PM 4:00 PM 8:00 PM 12:00 AM 24-hour CGMS glucose sensor data Type 1 diabetes (N=9) Data on file, Amylin Pharmaceuticals, Inc.

19 Significant Glycemic Variability is Found in both Type 1 and Type 2 Diabetes Type 1 Patients 9.6% (2.3 hours) hypoglycemic (<70 mg/dl) 30% (7.2 hours) hyperglycemic (>180 mg/dl) Type 2 Patients 4.2% (1.0 hours) hypoglycemic 28.7% (6.9 hours) hyperglycemic Bode et al: Diabetes Care. 2005; 28:

20 Postprandial hyperglycemia glycemic variability

21 How Does Hyperglycemia Cause Complications? Glucose Peripheral & Autonomic Neuropathy Polyol Pathway AGE Formation Hexosamine Pathway Cellular 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) (Brownlee, 2001)

22 Role of Oxidative Stress in the Complications of Diabetes

23 What Turns On Oxidative Stress, Free Radicals, and Reactive Oxygen Species High blood glucose Science is confirmed on this point Variability in blood glucose Science is highly suggestive on this point

24 Glycemic Variability Induces Greater PKC Activity in Cultured Endothelial Cells Quagliaro, L et al Diabetes 52:2795

25 Glycemic Variability is Associated with Increased Oxidative Stress Quagliaro, L et al Diabetes 52:2795

26 Role of Oxidative Stress in the Complications of Diabetes

27 Reducing Excess Glucose Exposure and Variability Eat healthy, high fiber diet Calculate carbs and insulin accurately Take all insulin injections Treat hypoglycemia appropriately Take alpha-glucosidase inhibitor Add exenatide (type 2) Replace insulin physiologically (pump, RAA) Introduce lag time between insulin and eating Add pramlintide (type 1 or 2) More frequent testing Continuous glucose monitoring

28 Soluble Fiber Blunts Postprandial Glucose Response Blood glucose (mg/dl) Minutes Standard Simple Sugar Soluble Fiber + Sugar Starch

29 Traditional Diabetes Therapies Do Not Control Postprandial Glucose Levels Baseline Glyburide 2 months Baseline Pioglitazone mg/dl mg/dl Meal Meal Meal Time of day Minutes Miyazaki Y et al. Diabetes Care. 2001;24: Shapiro ET et al. J Clin Endocrinol Metab. 1989;69:

30 Postprandial Therapies? Acarbose Nateglinide % above baseline Meal FPG=fasting plasma glucose Baseline FPG 160 mg/dl Kado S et al. Diabetes Res Clin Pract. 1998;41:49-55 mg/dl Meal 0800 Meal Time Baseline FPG 191 mg/dl Hollander PA et al. Diabetes Care. 2001;24:

31 Postprandial Therapies? mg/dl 300 Placebo Repaglinide Injection 0.15u/kg & breakfast Regular Aspart Meal Meal Meal Time of day Minutes Normal Rosenfalck AM et al. Acta Diabetol 2000;37:41-6 Strange P et al. Diabetes Technol Ther. 1999;1:

32 Biphasic Insulin Aspart Does Not Substantially Reduce Postprandial Glucose Excursions Premixed Insulin, Week 0 Premixed Insulin, Week ** Prebreakfast Postbreakfast Prelunch Postlunch Presupper Postsupper ITT sample, mean (SE) shown; significantly lower mean glucose level observed for exenatide * P<0.001, premixed insulin ** P= P= P= Nauck MA, et al. Presented at EASD Annual Meeting, Copenhagen-Malmoe, Denmark-Sweden, September 14-17, AM

33 Addition of Sitagliptin to Metformin Blunts Postprandial Glucose Levels Placebo + Metformin Breakfast Lunch Dinner Sitagliptin + Metformin Glucose (mg/dl) Dose 1 7:30 Dose 2 18:30 Difference in 24-hour weighted LS mean glucose: 32.8 mg/dl (P < 0.001) 100 8:00 Day 1 13:00 19:00 0:00 Day 2 7:30 Karasik A, et al. PN020 (54-week extension). Adapted from Brazg RL, et al. Poster presented: at American Diabetes Association; June 10 14, 2005; San Diego, Calif.

34 Exenatide Almost Eliminates Postprandial Glucose Excursions 13 Exenatide, Week 0 Exenatide, Week Blood Glucose Level (mmol/l) * * Prebreakfast Postbreakfast Prelunch Postlunch Presupper Postsupper ITT sample, mean (SE) shown; significantly lower mean glucose level observed for exenatide * P<0.001, premixed insulin ** P= P= P= Nauck MA, et al. Presented at EASD Annual Meeting, Copenhagen-Malmoe, Denmark-Sweden, September 14-17, AM

35 Pramlintide Reduces Postprandial Glucose: Type 1 Diabetes 180 Glucose (mg/dl) * * Baseline 6 Months 120 pre-bf post-bf pre-lu post-lu pre-di post-di bedtime Clinical Practice Study: all pramlintide doses bf, breakfast; lu, lunch; di, dinner N=265; *P-values <0.5 Guthrie. Diabetes. 2005

36 Excessive Glucose Fluctuations CSII and Continuous Glucose Monitoring 1 Patient Before/On/After Pramlintide 400 Type 1 Diabetes; Baseline A1C=8.4% Glucose Concentration (mg/dl) Baseline Off Pramlintide On 12:00 AM 4:00 AM 8:00 AM 12:00 PM 4:00 PM 8:00 PM 12:00 AM 24-hour CGMS glucose sensor data Levetan. Diabetes Care. 2003:26:1.

37 Pramlintide and Oxidative Stress Randomized, single-blind, placebo-controlled, crossover study, 18 subjects with type 1 DM (age 38±15 y, duration of DM 22±12 y, A1C 9.4±1.7% [mean±sd]) 2 standardized breakfast meal tests; pts -> preprandial regular insulin (7.2±0.9 and 7.5±1.0 U) at t=-30 min and injection of either PRAM (60 µg at t=0 min) or PBO (at t=-15 min). Diabetes Care 28: , 2005

38 Role of Oxidative Stress in the Complications of Diabetes

39 Pramlintide and Oxidative Stress Diabetes Care 28: , 2005

40 Other Factors Affecting Glycemic Exposure and Variability Monitoring No monitoring: ave A1c 9% Testing 8 times per day: ave A1c 6.5% Recording BG Recording 7.4 % Not recording 7.8% Diet practiced Counting carbohydrates: 7.2% Fixed carbohydrate: 7.5% WAG (Wild guess): 8.0% Insulin Pump Therapy?Bolus timing Bode BW, et al. Diabetes.1999;48(suppl 1):264. Bode BW, et al. Diabetes Care. 2002;25:439.

41 Increased SMBG Testing Frequency Associated with Lower A1C A1C Atlanta Diabetes Associates study: 378 patients sorted from a database of 591 Pumps=MM 511 or earlier BG Target=100 C peptide < SMBG Frequency (BG per day)

42 The Value of Frequent Testing 400 (22) 300 (17) 7 opportunities to intervene versus 1! 200 (11) 100 (5.6) Breakfast Lunch Dinner Bed

43 Today s Pumps Can Improve Control BG testing > better results Fewer missed doses Dependable insulin action Accurate carb counting Precise basal adjustment Accurate bolus calculations with carb & correction factors and BOB tracking History enables accurate therapy assessment When SET UP and USED CORRECTLY!

44 Therapy Effectiveness Guidelines TDD Raise when BG is often high Lower when often BG is often low or when low and high Basal/Bolus Balance usually near 50% of TDD Correction Factor = ~ carb factor X 4 (mg/dl), Correction Bolus % if correction boluses make up over 8% of the TDD, move the excess into basals or boluses Average BG < 160 when checking before & after meals, < 140 when checking mainly before meals Standard Deviation (BG variability) Keep less than half of average BG or below 65 mg/dl For tight control, keep less than 1/3 of avg. BG Suspect a Problem when correction boluses make up > 8% of the TDD, basal rates make up < 40-45% or > 60% of TDD, the DIA is< than 4 hours, or the standard deviation is > 65 mg/dl

45 Many Helpful Pump Features Go Unused Reminders and alerts Entry of glucose test results Accurate carb counting or use of a carb database Alternate and temporary basal patterns Tracking and use of BOB Review of therapy: glucose history and insulin use All improve control!

46 Recommended Reading

47 Glycemic Variability Glycemic variability may be an important mechanism increasing oxidative stress and vascular complications So how do we best measure glycemic variability in our patients with diabetes? Meter Downloads Continuous Glucose Monitoring

48 Which Patient Has More Variable Joe: HbA1c = 6.5%; on CSII with insulin aspart Mean = 123 mg% Fasting Glucose Data? Mary: HbA1c = 6.5%; on HS glargine and prandial lispro Mean = 123 mg% SD = 51 SD = 63

49 Standard Deviation A measurement of glycemic variability Can determine both overall and time specific SD Need sufficient data points Minimum 5 but prefer 10

50 Calculation To Determine SD Target Ideally SD X 3 < mean, but extremely difficult with type 1 patients Mean glucose levels should be in target SD X 2 < MEAN

51 Significance of a High SD Insulin deficiency Poor matching of calories (especially carbohydrates) with insulin Gastroparesis Taking insulin after eating Stacking insulin Giving mealtime insulin late (or missing shots completely) For every 2 missed meal boluses/week, A1c increases by 0.5% Erratic snacking Poor matching of basal insulin, need for CSII? Overtreating hyper- &/or hypoglycemia Not logging data

52 Other Significance of a High SD Increased Oxidative Stress!

53 The Future of Glycemic Variability: Measurements For the Future SD: used with SMBG for over a decade with meter downloads; underutilized % of glucose values in each glycemic category MAGE: gold standard (?) but requires continuous glucose sensing. May be more useful as we move into the CGM era ADRR: complicated calculation using meter data. Correlates well with risk for severe hypoglycemia. Should be easy to program GlycoMark: a blood test for postprandial hyperglycemia

54 Summary - 1,5-anhydroglucitol (1,5-AG) 1,5-AG is a monosaccharide from food Reabsorbed very efficiently through kidney (urinary excretion is 1/20 of total amount in body). Competes with glucose Not rapidly metabolized (metabolic turnaround rate at least 3 days) HO HO OH O OH OH Glucose HO O 1,5-AG urinary excretion increases with hyperglycemia 1,5-AG HO OH OH

55 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 ( mg) Glucose Blocks Reabsorption Blood Stream (1,5-AG Level Lower) Tissues Internal Organs ( mg) Kidney Urinary excretion (5-10mg/day) Kidney Urinary excretion (INCREASED)

56 Post-load glucose measurements in OGTTs correlate well with serum 1,5-AG in subjects with IGT R= R=0.281 N = 211 1,5 Anhydroglucitol is a better indicator than A1C of postprandial blood glucose levels in IGT subjects Yamanouchi et al., Clinical Science 2001

57 Glycemic control markers Fructosamine 1,5AG Blood glucose HbA1C Weeks before measurement

58 1,5-AG and Postmeal Glucose Levels GlycoMark (ug/ml) Approximate Mean Postmeal Maximum Blood Glucose (mg/dl) > 12 < < 2 > 290

59 What About Continuous Glucose Monitoring? Glucose Concentration (mg/dl) :00 AM 4:00 AM 8:00 AM 12:00 PM 4:00 PM 8:00 PM Time

60 Sample CGMS Reports Composite 3 day report for comparison

61 Continuous Monitoring Benefits Alarms to prevent lows & highs Security in knowing where you are and where you re going Trends shown by graph, arrows, or predictors Limitations Little insurance coverage yet Lag time: 10 15% different confirm with a fingerstick Data gaps Needs calibration 3-day use

62 Paradigm RT 522/722 A = reading B = high/low alarm C = trend arrow D = BG graph A = pump B = infusion set C = sensor D = radio transmitter Con Mon readout on pump screen

63 Dexcom STS Monitor Approved for 18 and older Readings every 5 min. over 3-7 days, one high and two low alerts Receiver Transmitter 0.8 x 1.5

64 FreeStyle Navigator TheraSense Continuous Glucose Monitor Investigational Device Limited by U.S. Law to Investigational Use

65 Continuous Monitors Reduce Glucose Variability 15 users with Dexcom continuous monitors blind to glucose readout for the first 50 days, then open readout for the next 44 days. hrs/day min + 32 min Blinded Open min -13 min min blood sugar Garg and Jovanovic Presented at 66 th Annual Scientific Sessions of ADA 4.57

66 CGM: Other Results If A1c is >9%, 95% increase in the time spent in with glucose levels in the range of mg/dl If A1c 7%, 46% decrease in time spent with glucose levels < 55 mg/dl 80% of patients reach peak postprandial glucose in less than 90 minutes (mean 72 )

67 Most Carbs Are Faster Than Insulin At 1 hr, 85% of rapid insulin activity remains while over half of the glucose absorption from a typical meal has already occurred Blood sugar after typical meal Insulin action 0 2 hrs 4 hrs 6 hrs Take Home: Bolus 15 to 30 minutes before meals when possible and use extended and square wave boluses sparingly

68 Examples of Applications for RT-CGM Need for insulin pump therapy Continuous vs intermittent Basal testing Testing carb ratios and correction factors Timing of bolus Hyper- or hypoglycemia Gastroparesis Symlin High fat meals Adjustment for special situations

69 Educating Patients on RT-CGM Concepts Interstitial fluid vs blood Lag time About 10-15% difference Does not mean inaccurate FS still required Calibration Verification Use of Device Set up, operation, calibration Use of data Responding to alarms Responding to trends Adjusting insulin RT vs retrospective Need for learning curve When available, treatment algorithms will be valuable

70 CGMS Pearls Pearl # 1: Watching and Staring: Patients who do best are watching their sensor frequently Pearl # 2: Trend trumps insulin on board For an upward trend 2 mg/dl/min, additional insulin will usually be required Pearl #3: Upward trends Greater than 1 mg/dl/min, increase lag time or reduce carbohydrate content of meal Pearl #4: Downward trend Due to lag time, if significant IOB, SMBG is critical Consider snack at high end of target, if trend dropping at 2 mg/dl/min. Consider snack, if at low end of target and trend dropping at 1 mg/dl/min

71 Basal/Bolus Testing Is Easy With Continuous Moniters 120 Basal test Continuous monitors simplify basal and bolus testing pm 2 am 8 am Carb bolus test 300 Correction bolus test pm 8 pm 10 pm 6 pm 8 pm 10 pm Pumping Insulin, 2006

72 Delaying Eating Reduces Glucose Exposure A lower glucose at the start of a meal reduces glucose exposure. Future Pump Feature Rules: Test early Bolus early Don t forget to eat on time Don t forget you ve already bolused

73 Why Manage Glycemic Variability (GV)? Prevent acute and chronic complications Lower A1c Possible independent effect of GV on vascular risk Decrease risk for severe hypoglycemia Improve quality of life

74 Prevention of Vascular Complications of Get A1c to goal Diabetes As close to 6% as safely possible Minimize glycemic variability Monitor and treat postprandial glucose excursions Use meter downloads and statistical measures to evaluate glycemic variability Use CGM to fine-tune glycemic control

75 Conclusions Although there is no definitive proof from a randomized controlled trial, the data suggests that glycemic variability is a risk factor for microvascular complications We have the opportunity to quantitate and minimize GV now with meter downloads and continuous glucose monitors We now have medications with robust postprandial effects to minimize glycemic variability

76 Reducing Excess Glucose Exposure and Variability Eat healthy, high fiber diet Calculate carbs and insulin accurately Take all insulin injections Treat hypoglycemia appropriately Take alpha-glucosidase inhibitor Add exenatide (type 2) Replace insulin physiologically (pump, RAA) Introduce lag time between insulin and eating Add pramlintide (type 1 or 2) More frequent testing Continuous glucose monitoring

77 Thank you! Thanks to: Irl Hirsch, MD John Walsh, PA-C