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Glycemic Targets in Clinical Practice: Postprandial vs Preprandial and Fasting? Steven D Wittlin MD University of Rochester School of Medicine and Dentistry.

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Presentation on theme: "Glycemic Targets in Clinical Practice: Postprandial vs Preprandial and Fasting? Steven D Wittlin MD University of Rochester School of Medicine and Dentistry."— Presentation transcript:

1 Glycemic Targets in Clinical Practice: Postprandial vs Preprandial and Fasting? Steven D Wittlin MD University of Rochester School of Medicine and Dentistry Rochester, New York

2 In all affairs it’s a healthy thing now and then to hang a question mark on the things you have long taken for granted…… Bertrand Russell

3 The question is not whether to target postprandial, preprandial or fasting glycemia, but when, how, and to what goals. The question is not whether to target postprandial, preprandial or fasting glycemia, but when, how, and to what goals.

4 UKPDS Epidemiologic Data in Type 2 Diabetes No A1C Threshold 0% 10% 20% 30% 40% 50% 60% 70% 80% Adjusted incidence per 1000 person- years Myocardial infarction Microvascular endpoints Updated mean A1C (%) Stratton IM, et al. BMJ. 2000;321:

5 What are appropriate goals? HbA 1c HbA 1c FPG FPG 2 hr PPG 2 hr PPG Normalization of Glycemia Normalization of Glycemia

6 Woerle HJ et al. Am J Physiol 290:E67-E77, 2006 What is Normal? HbA 1c <6.0% FPG <100 mg/dl (5.5 mM) 1 hr PPG <162 mg/dl (9.0 mM) 2 hr PPG <126 mg/dl (7.0 mM) (N=15)

7 Hyperglycemia is a continuous risk factor for CVD... Therefore normality should be the goal if it can be safely achieved

8 CDA: HbA1C<7% “ consider targets in the normal range for patients in whom it can be achieved safely..” CDA: HbA1C<7% “ consider targets in the normal range for patients in whom it can be achieved safely..” ADA: “...for patients in general is an A1C<7%....for the individual patient is an A1C as close to normal (<6.0%) as possible without significant hypoglycemia..” ADA: “...for patients in general is an A1C<7%....for the individual patient is an A1C as close to normal (<6.0%) as possible without significant hypoglycemia..” ADA, Diabetes Care 29:S4-S42, CDA, Can J Diabetes 27:S1-S151, 2003

9 To achieve a normal or near normal HbA 1c, both FPG and PPG levels must be normal or near normal. To achieve a normal or near normal HbA 1c, both FPG and PPG levels must be normal or near normal. Thus both FPG and PPG must be targets for therapy Thus both FPG and PPG must be targets for therapy Nevertheless, might there be situations in which it is preferable to treat one or the other first ??? Nevertheless, might there be situations in which it is preferable to treat one or the other first ???

10 Postprandial Hyperglycemia

11 Patients With Type 2 Diabetes May Spend More Than 12 Hours per Day in the Postprandial State Adapted from Monnier L. Eur J Clin Invest. 2000;30(suppl 2):3-11. Duration of postprandial state BreakfastLunchDinnerMidnight4 AM Breakfast 8 AM 11 AM 2 PM 5 PM PostprandialPostabsorptiveFasting

12 Correlation between plasma glucose levels after OGTT and standard mixed meal Wolever TMS et al. Diabetes Care 1998;21:336–40 r=0.97

13 Changes in Postprandial Glucose Metabolism in Type 2 DM Use triple isotope technique and indirect calorimetry Use triple isotope technique and indirect calorimetry DM pts had: DM pts had: increased overall glucose release increased overall glucose release Increased gluconeogenesis and glycogenolysis Increased gluconeogenesis and glycogenolysis ~90% of the increased glucose release occurred in the first 90 min post-prandial ~90% of the increased glucose release occurred in the first 90 min post-prandial In DM glucose clearance and oxidation were reduced In DM glucose clearance and oxidation were reduced Non-oxidative glycolysis was increased Non-oxidative glycolysis was increased Net splanchnic glucose storage was reduced ~ 45% d.t. increased glycogen cycling Net splanchnic glucose storage was reduced ~ 45% d.t. increased glycogen cycling Woerle HJ et al Am J Physiol Endocrinol Metab 2006

14 Relationship between HbA1C, FPG and 2 h. PPG Van Haeften T et al Metabolism 2000

15 Woerle HJ et al Arch Intern Med. 2004;164: Relative Changes in FPG and 2-h PG as HbA 1c Increases Plasma Glucose (mg/dL) = HbA 1c versus 2hppg = HbA 1c versus FPG r = 0.55 y = 47.1 x -109 r = 0.48 y = 12.0 x +30 HbA 1c (%)

16 In Individuals with HbA1C <6.5%, Postload Dysglycemia Predominates Woerle HJ et al Arch Intern Med. 2004;164:

17 As Patients Get Closer to A1C Goal, the Need to Successfully Manage PPG Significantly Increases Adapted from Monnier L, Lapinski H, Collette C. Contributions of fasting and postprandial plasnma glucose increments to the overall diurnal hyper glycemia of Type 2 diabetic patients: variations with increasing levels of HBA(1c). Diabetes Care. 2003;26:

18 Post-Prandial Hyperglycemia Antecedes Fasting Hyperglycemia Monnier L et al Diabetes Care 30: , 2007

19 PPG, but not FPG distinguishes patients with HbA1C Between % Characteristics Characteristics # of patients # of patients Gender Gender Age Age BMI BMI FPG FPG 2hPPG 2hPPG Mean HbA1C Mean HbA1C /23 8/ (p=0.88) (p=0.03) HbA1C Group (%) Woerle HJ et al Arch Intern Med. 2004;164:

20 Therefore, the initial HbA 1c can be a guide.

21 Relative risk for death increases with 2-hour blood glucose irrespective of the FPG level <6.16.1–6.9  7.0  –11.0 <7.8 Fasting plasma glucose (mmol/l) 2-hour plasma glucose (mmol/l) Hazard ratio Adjusted for age, center, sex DECODE Study Group. Lancet 1999;354:617–621

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23 Effect of Acarbose on CVD in Patients with IGT ( STOP-NIDDM) ( Chiasson J - L et al JAMA July 2003 )

24 Controlling Postprandial Glucose Prospective trial of fasting vs pc control in 164 pts w/ Type 2 DM Prospective trial of fasting vs pc control in 164 pts w/ Type 2 DM Forced titration to target either FBS < 100 or 90 min pc < 140 Forced titration to target either FBS < 100 or 90 min pc < 140 Results: Results: HbA1C fell from 8.7 % to 6.5% HbA1C fell from 8.7 % to 6.5% Only 64% of patients achieving FPG < 100 reached HbA1C < 7% Only 64% of patients achieving FPG < 100 reached HbA1C < 7% 94% of patients w/ pc < 140 reached HbA1C < 7% 94% of patients w/ pc < 140 reached HbA1C < 7% Decreased pc BG accounted nearly twice as much as FBS for fall in HbA1C Decreased pc BG accounted nearly twice as much as FBS for fall in HbA1C If HbA1C < 6.2%, pc accounted for ~ 90% If HbA1C < 6.2%, pc accounted for ~ 90% If HbA1C > 8.9%, pc accounted for ~ 40% If HbA1C > 8.9%, pc accounted for ~ 40% Woerle HJ et al in press

25 Relationship Between HbA 1c, FPG and PPG in Treated T2DM Patients Major Major HbA 1c (%) FPG (mM) PPG (mM) Problem PPG PPG PPG PPG FPG+PPG FPG+PPG FPG+PPG FPG+PPG FPG FPG Woerle et al., 2006.

26 So How Can We Assess Post-Prandial Glucose Control Clinically ?? Frequent fingersticks Frequent fingersticks HbA1C HbA1C Fructosamine Fructosamine Continuous Glucose Monitoring Systems Continuous Glucose Monitoring Systems Historical Historical Real-time Real-time 1,5 Anhydroglucitol 1,5 Anhydroglucitol

27 Postprandial Index vs. A1C/1,5-AG Assay Ratio  A1C/1,5-AG Ratio Correlated Better than A1C or 1,5-AG independently to the Postprandial Index  Combination of 1,5-AG and A1C are more predictive of postprandial hyperglycemia Postprandial Index (Multi- variate-PI) N=19 Avg. A1C Avg. 1,5-AG Avg. A1C/Avg. 1,5-AG Ratio R=0.36R=0.58R=0.66 *Postprandial Index is the conglomerate multivariable analysis using AUC-180 and post-meal maximum glucose values as the independent variables. Dungan K et al Diabetes Care; June 2006

28 Approaches/Agents That Address Postprandial Hyperglycemia Meglitinides Meglitinides Alpha-Glucosidase Inhibitors Alpha-Glucosidase Inhibitors Prandial Insulin Prandial Insulin GLP-1 analogues GLP-1 analogues DPP-IV inhibitors DPP-IV inhibitors Pramlintide Pramlintide Glycemic Index/Load Glycemic Index/Load

29 Importance of Post-Prandial Control in Managing Gestational Diabetes de Veciana M et al NEJM Nov 1995

30 Insulin (pmol/L) Time (hr) Glucose (mg/dL) Time (hr) Nateglinide Monotherapy: Effect on Plasma Glucose and Insulin Pretreatment Nateglinide Hollander PA, et al. Diab Care 24: , 2001.

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32 Davies M et al Tt.Lantus study group; ADA 2006 Abstract Adding Prandial Insulin to Basal Therapy Further Improves HbA1C

33 Inhaled Insulin is Superior to Metformin as Add- on Therapy to Sulfonylureas !! Barnett AH et al. Diabetes Care 29: , 2006

34 Fasting Hyperglycemia

35 Fasting Plasma Glucose Reflects Endogenous Glucose Production Dinneen S, Gerich J, Rizza R. N Engl J Med. 1992;327:

36 Why Fix Fasting First? Lowering FPG first will lower all PG values throughout the day and thus will also reduce PPG and may be sufficient. Lowering FPG first will lower all PG values throughout the day and thus will also reduce PPG and may be sufficient. SaferSimpler

37 Effect of Glyburide or NPH Insulin on Glycemia in Type 2 Diabetes Time of day From: Shapiro ET et al. J Clin Endocrinol Metab 69 (1989), pp. 571–576 Cusi K et al Diabetes Care 18 (1995), pp. 843–851

38 Agents that Address Fasting Hyperglycemia Basal Insulin Basal Insulin Metformin Metformin Sulfonylureas Sulfonylureas TZDs?? TZDs??

39 Pioglitazone Affects both FPG and PPG Miyazaki Y et al.Diabetes Care 25: , 2002

40 Insulin Glargine vs NPH Insulin Added to Oral Therapy Patient Demographics 756 insulin-naïve patients with type 2 diabetes 756 insulin-naïve patients with type 2 diabetes Insulin glargine n=367 Insulin glargine n=367 NPH n=389 NPH n=389 Mean age 55 yr Mean age 55 yr BMI 32 kg/m 2 BMI 32 kg/m 2 Duration of diabetes 8-9 yr Duration of diabetes 8-9 yr Baseline A1C 8.6% Baseline A1C 8.6% Riddle MC et al and the Insulin Glargine 4002 Study Investigators. Diabetes Care 2003:26:

41 Insulin Glargine vs NPH Insulin Added to Orals Riddle MC et al and the Insulin Glargine 4002 Study Investigators. Diabetes Care 2003:26:

42 Insulin Glargine vs NPH Insulin Added to Oral Therapy Results ITT AnalysisInsulin Glargine NPH FPG, mg/dL mM mM A1C, % A1C, % Final A1C  7% (% patients) Nocturnal Hypoglycemia Patients,* % Events, † no Severe Hypoglycemia Patients, % *P<0.01; †P<0.002 Riddle et al and the Insulin Glargine 4002 Study Investigators. Diabetes Care 2003:26:

43 Exenatide vs Glargine in Type 2 Diabetes Mellitus 551 patients, multi-site international study 551 patients, multi-site international study Rx w/ Metformin and SU for 3 months prior to screening Rx w/ Metformin and SU for 3 months prior to screening HbA1C % ; BMI HbA1C % ; BMI Randomly assigned exenatide or glargine Randomly assigned exenatide or glargine Exenatide 10 mcg BID Exenatide 10 mcg BID Glargine titrated to FBS< 100mg/dl Glargine titrated to FBS< 100mg/dl Heine RJ et al Ann Int Med 2005; 143: Results: HbA1C reduced by 1.16 and 1.14% respectively (Mean final HbA1C ~ 7%)

44 Exenatide vs Glargine in Type 2 Diabetes Mellitus Heine RJ et al Ann Int Med 2005; 143: glucose Time

45 Addressing Fasting vs Postprandial First Approach Overall Goals: HbA 1c <7 HbA 1c <7 FPG <100 mg/dl (5.5 mM) FPG <100 mg/dl (5.5 mM) PPPG (90 min) <140 mg/dl (7.8 mM) PPPG (90 min) <140 mg/dl (7.8 mM) Woerle HJ et al in press

46 Fix Fasting First Algorithm Step 1: If FPG >100 mg/dl (5.5 mM) : a) drug naïve, start metformin a) drug naïve, start metformin b) if on SU, add metformin b) if on SU, add metformin c) if on SU+Met, DC SU, add HS NPH c) if on SU+Met, DC SU, add HS NPH Step 2: When FPG near goal, but PPPG >140 mg/dl (7.8 mM) : >140 mg/dl (7.8 mM) : a) add repaglinide with meals a) add repaglinide with meals b) if above unsuccessful in achieving b) if above unsuccessful in achieving PPG goal, DC and use regular PPG goal, DC and use regular insulin with meals. insulin with meals. Woerle HJ et al in press

47 Demographic Characteristics Age (years)62.4 ± 0.9 Gender90 men/74 women BMI (kg/m2)28.8 ± 0.6 Diabetes duration HbA 1c (%) 8.4 ± 0.6 y 8.7 ± 0.1 Woerle HJ et al in press

48 Effects of Intensified Treatment Regimens (N=164) PrePostP HbA1c (%)8.7 ± ± 0.1P<0.001 FPG (mg/dl)174 ± 4117 ± 2P<0.001 Post breakfast (mg/dl)233 ± 6159 ± 3P<0.001 Pre lunch (mg/dl)170 ± 6116 ± 2P<0.001 Post lunch (mg/dl)213 ± 5155 ± 4P<0.001 Pre dinner (mg/dl)176 ± 5133 ± 4P<0.001 Post dinner (mg/dl)227 ± 6164 ± 4P<0.001 Bedtime (mg/dl)201 ± 5143 ± 3P<0.001 Average postmeal (mg/dl)224 ± 4159 ± 3P<0.001 Daylong (mg/dl)199 ± 4141 ± 2P<0.001 Weight (Kg)84.0 ± ± 1.5P=0.36 Woerle HJ et al in press

49 Cases of Hypoglycemic Episodes before and after Intensification of Treatment (N=164) Plasma Glucose (mg/dl)Cases Before Cases After ≤4000 Woerle HJ et al in press

50 Diurnal Plasma Glucose Profiles Before and After Intensified Therapy Intervention in Subjects Who Did and Did Not Achieve HbA1C < 7.0% (mg/dL) = HbA 1c > 7% = HbA 1c < 7% Mean ± SEM (N = 164) Time (Hours) % Woerle HJ et al Diabetes Res Clin Pract Jan 19

51 Contribution of Postprandial BG to HbA1C Woerle HJ et al Diabetes Res Clin Pract Jan 19

52 Simpler and Safer Lowering PPG first will require subsequent readjustments in PPG Rx when FPG is treated. Failure to do so may result in hypoglycemia. Lowering PPG first will require subsequent readjustments in PPG Rx when FPG is treated. Failure to do so may result in hypoglycemia.

53 Higher A1C Baseline Level Correlates With Larger A1C Reduction With Pharmacologic Intervention Baseline A1C% 6.0– – – – –11.8 Number of patients enrolled in clinical trials n=410n=1,620n=5,269n=1,228n=266 Adapted from Bloomgarden ZT et al. Diabetes Care. 2006;29:

54 Road map to achieve glycaemic goals 1 Combination therapy: Meglitinide, SU, AGI, metformin, TZD, exenatide, pre-mixed insulin analogs, rapid-acting insulin analogs or basal insulin Target: FPG and PPG Insulin therapy † Target: PPG and FPG 6−7 Target: PPG and FPG 7−8 Target: FPG and PPG 8−9 9−10 >10 Lifestyle modification Monotherapy or combination therapy Monotherapy: Meglitinide, SU, AGI, metformin, TZD, pre-mixed insulin analogs or basal insulin Monotherapy or combination therapy 6– 6.5 >8.5 Naïve to therapy (type 2) Treated patients (type 2) Achieve ACE glycaemic goals* (FPG and PPG) Initial A 1c (%) Current Therapy Current A 1c (%) 6.5− 8.5 Continue lifestyle modification PPG Pre-mixed insulin analogs Pre-mixed insulin analogs, Rapid-acting insulin analogs *ACE glycaemic goals: ≤6.5% HbA 1c, 10%, certain oral agent combinations may be effective AACE. Roadmap for prevention and treatment of type 2 diabetes, 2005

55 Recommendations for Drug Naïve Patients HbA 1c <7.5%, target PPG HbA 1c >7.5%, target FPG, then PPG (Fix the fasting first) (Fix the fasting first)OR……… If HbA1C > 7.5%, use double therapy that addresses BOTH fasting and postprandial hyperglycemia !!

56 Conclusions Hyperglycemia as reflected by HbA 1c is a continuous risk factor for micro- and macrovascular complications. Hyperglycemia as reflected by HbA 1c is a continuous risk factor for micro- and macrovascular complications. HbA 1c includes both fasting and postprandial glycemia. HbA 1c includes both fasting and postprandial glycemia. To minimize glycemic exposure both FPG and PPG need to be addressed, especially if HbA1C > 7.5%. To minimize glycemic exposure both FPG and PPG need to be addressed, especially if HbA1C > 7.5%. If HbA1C < 7.5%, initial therapy should address postprandial glucose, preferentially. If HbA1C < 7.5%, initial therapy should address postprandial glucose, preferentially. In order to achieve normoglycemia, postprandial glucose must be addressed In order to achieve normoglycemia, postprandial glucose must be addressed

57 Reflections Normalization of HbA1C can not be considered the equivalent of normoglycemia in view of our ability to measure other markers, elevated post- challenge glucose, the availability of continuous glucose monitoring and increased CVD in the normal range of HbA1C. Normalization of HbA1C can not be considered the equivalent of normoglycemia in view of our ability to measure other markers, elevated post- challenge glucose, the availability of continuous glucose monitoring and increased CVD in the normal range of HbA1C.

58 Questions ??

59 Glycemic Excursions Predict Oxidative Stress Monnier L et al JAMA. 2006;295:

60 CV = coefficient of variation *Significant differences in the CV of FPG (p<0.001) Muggeo M et al. Diabetes Care. 2000;23: Variability of FPG and cardiovascular mortality 10-year survival Variability in Blood Glucose Is an Independent Risk Factor for Mortality Group 1 (8.5%) Group 2 (14.8%) Group 3 (27.7%) Time (years) Survivalprobability Mean CV of FPG *

61 Lack of Effect of Glucose Variability on Microvascular Complications Assessment of DCCT data using seven-point glucose profiles Assessment of DCCT data using seven-point glucose profiles Performed quarterly Performed quarterly No preferential influence of the following on probability of retinopathy: No preferential influence of the following on probability of retinopathy: BG variability (nor Nephropathy) BG variability (nor Nephropathy) FPG FPG pc BG pc BG Kilpatrick ES et al Diabetes Care 29:

62 1,5 AG as Adjunct to A1C to Reflect Postprandial Hyperglycemia  1,5 AG is indicative of differing postmeal glucose levels in moderately controlled patients – despite similar A1C levels! (1,5-AG) Range 0-6 N=17 A1C (%) Mean 1,5-AG (ug/ml) Mean Total AUC-180 Glucose 1 PostMeal Glucose-Max Mean (mg/dl) BreakfastN=9 LunchN=10 DinnerN=9 Higher Postprandial Variables (1,5-AG) Range 6-18 N=16 A1C (%) Mean 1,5-AG (ug/ml) Mean Total AUC-180 Glucose 1 PostMeal Glucose-Max Mean (mg/dl) Breakfast N=11 PostMeal Glucose-Max Mean (mg/dl) Lunch N=13 N=13 PostMeal Glucose-Max Mean (mg/dl) DinnerN=13 Lower Postprandial Variables Dungan K et al Diabetes Care; June 2006

63 Demographic Characteristics and Treatment Regimens Before and After Three Months Age (years)62.4 ± 0.9 Gender90 men/74 women BMI (kg/m2)28.8 ± 0.6 Diabetes duration (years) HbA 1c (%) 8.4 ± ± 0.1 Initial Treatment (in %)Final Treatment (in %) Diet alone42 (26)7 (4) Metformin alone17 (10) Secretagogue alone32 (20)15 (9) Metformin plus Secretagogue23 (14)11 (7) NPH-insulin alone5 (3)12 (7) NPH plus Metformin6 (4)14 (9) NPH plus Secretagogue13 (8)34 (21) Twice insulin1 (1) NPH plus short acting insulin19 (12)34 (21) NPH plus short acting insulin plus Metformin 2 (1)4 (2) NPH plus Secretagogue plus Metformin 4 (2)15 (9) Woerle HJ et al in press


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