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University of Rochester School of Medicine and Dentistry

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1 University of Rochester School of Medicine and Dentistry
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.

4 UKPDS Epidemiologic Data in Type 2 Diabetes No A1C Threshold
Adjusted incidence per 1000 person-years 80% Myocardial infarction 70% Microvascular endpoints 60% 50% 40% UKPDS Epidemiologic Data in Type 2 Diabetes No HbA1c Threshold! This chart shows patients’ risk of myocardial infarction and microvascular endpoints, correlated with updated mean HbA1c levels, with an adjusted incidence per 1000 person-years.1 In this study, exposure to glycemia was measured first at baseline as HbA1c and then over time as an updated mean of annual measurements of HbA1c; for each individual, this value was calculated from baseline to each year of follow-up. Previous epidemiologic studies on the role of glycemia in diabetes complications tended to take measurements on only a single occasion.1 This model shows that both myocardial infarction and microvascular endpoints are strongly associated with increased HbA1c. Even at HbA1c levels between 5% and 6%, the risk of myocardial infarction is 16%, or about 1 in 6. Over the range of updated mean hemoglobin measurements (from <6% to 10%), incidence rates for any complication related to diabetes more than triple. At the highest levels of HbA1c measured (10%), the risk for microvascular disease continues to grow exponentially (up to nearly 60% when HbA1c 10%), while the risk for macrovascular disease flattens but does not drop off (approximately 40%).1 An additional goal of this study was to determine whether a threshold of glycemia exists—that is, a concentration above which the risk of complications markedly increases. These data demonstrate a direct relationship between the risk of diabetes complications and glycemia over time. This analysis indicates no threshold of glycemia for a substantive change in risk for either microvascular or macrovascular complications associated with diabetes.1 Reference 1. Stratton IM, Adler AI, Neil HAW, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321: 30% 20% 10% 0% 5 6 7 8 9 10 11 Updated mean A1C (%) Stratton IM, et al. BMJ. 2000;321:

5 What are appropriate goals?
HbA1c FPG 2 hr PPG Normalization of Glycemia

6 What is Normal? HbA1c <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) Woerle HJ et al . Am J Physiol 290:E67-E77, 2006

7 Hyperglycemia is a continuous risk factor for CVD
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..” 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 HbA1c, both FPG and PPG levels must be normal or near normal.
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 ???

10 Postprandial Hyperglycemia

11 Duration of postprandial state
Patients With Type 2 Diabetes May Spend More Than 12 Hours per Day in the Postprandial State Postprandial Postabsorptive Fasting Duration of postprandial state Breakfast Lunch Dinner Midnight 4 AM Breakfast 8 AM 11 AM 2 PM 5 PM Adapted from Monnier L. Eur J Clin Invest. 2000;30(suppl 2):3-11.

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

13 Changes in Postprandial Glucose Metabolism in Type 2 DM
Use triple isotope technique and indirect calorimetry DM pts had: increased overall glucose release Increased gluconeogenesis and glycogenolysis ~90% of the increased glucose release occurred in the first 90 min post-prandial In DM glucose clearance and oxidation were reduced Non-oxidative glycolysis was increased 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 Relative Changes in FPG and 2-h PG as HbA1c Increases
250 = HbA1c versus 2hppg = HbA1c versus FPG Plasma Glucose (mg/dL) 160 r = 0.55 y = 47.1 x -109 r = 0.48 y = 12.0 x +30 70 4 5 6 7 HbA1c (%) Woerle HJ et al Arch Intern Med. 2004;164:

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 6.0-7.0%
HbA1C Group (%) Characteristics # of patients Gender Age BMI FPG 2hPPG Mean HbA1C 14/ /8 (p=0.88) (p=0.03) Woerle HJ et al Arch Intern Med. 2004;164:

20 Therefore, the initial HbA1c can be a guide.

21 2-hour plasma glucose (mmol/l) Fasting plasma glucose (mmol/l)
Relative risk for death increases with 2-hour blood glucose irrespective of the FPG level 2.5 2.0 1.5 1.0 0.5 0.0 Hazard ratio ³11.1 7.8–11.0 2-hour plasma glucose (mmol/l) <7.8 < –6.9 ³7.0 Fasting plasma glucose (mmol/l) 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 Forced titration to target either FBS < 100 or 90 min pc < 140 Results: HbA1C fell from 8.7 % to 6.5% Only 64% of patients achieving FPG < 100 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 If HbA1C < 6.2% , pc accounted for ~ 90% If HbA1C > 8.9%, pc accounted for ~ 40% Woerle HJ et al in press

25 Relationship Between HbA1c, FPG and PPG in Treated T2DM Patients
Major HbA1c (%) FPG (mM) PPG (mM) Problem PPG PPG FPG+PPG FPG+PPG FPG Woerle et al., 2006.

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

27 Postprandial Index vs. A1C/1,5-AG Assay Ratio
Postprandial Index (Multi-variate-PI) N=19 Avg. A1C Avg. 1,5-AG Avg. A1C/Avg. 1,5-AG Ratio R=0.36 R=0.58 R=0.66 *Postprandial Index is the conglomerate multivariable analysis using AUC-180 and post-meal maximum glucose values as the independent variables. 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 Dungan K et al Diabetes Care; June 2006

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

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

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

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

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? Safer Simpler Lowering FPG first will lower all PG values throughout the day and thus will also reduce PPG and may be sufficient.

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 Metformin Sulfonylureas 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 Insulin glargine n=367 NPH n=389 Mean age 55 yr BMI 32 kg/m2 Duration of diabetes 8-9 yr 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 Analysis Insulin Glargine NPH FPG, mg/dL mM 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 Rx w/ Metformin and SU for 3 months prior to screening HbA1C % ; BMI 25-45 Randomly assigned exenatide or glargine Exenatide 10 mcg BID Glargine titrated to FBS< 100mg/dl Results: HbA1C reduced by 1.16 and 1.14% respectively (Mean final HbA1C ~ 7%) Heine RJ et al Ann Int Med 2005; 143:

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

45 Addressing Fasting vs Postprandial First Approach
Overall Goals: HbA1c <7 FPG <100 mg/dl (5.5 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 b) if on SU, add metformin c) if on SU+Met, DC SU, add HS NPH Step 2: When FPG near goal, but PPPG >140 mg/dl (7.8 mM) : a) add repaglinide with meals b) if above unsuccessful in achieving PPG goal, DC and use regular insulin with meals. Woerle HJ et al in press

47 Demographic Characteristics
Age (years) 62.4 ± 0.9 Gender 90 men/74 women BMI (kg/m2) 28.8 ± 0.6 Diabetes duration HbA1c (%) 8.4 ± 0.6 y 8.7 ± 0.1 Woerle HJ et al in press

48 Effects of Intensified Treatment Regimens (N=164)
Pre Post P HbA1c (%) 8.7 ± 0.1 6.5 ± 0.1 P<0.001 FPG (mg/dl) 174 ± 4 117 ± 2 Post breakfast (mg/dl) 233 ± 6 159 ± 3 Pre lunch (mg/dl) 170 ± 6 116 ± 2 Post lunch (mg/dl) 213 ± 5 155 ± 4 Pre dinner (mg/dl) 176 ± 5 133 ± 4 Post dinner (mg/dl) 227 ± 6 164 ± 4 Bedtime (mg/dl) 201 ± 5 143 ± 3 Average postmeal (mg/dl) 224 ± 4 Daylong (mg/dl) 199 ± 4 141 ± 2 Weight (Kg) 84.0 ± 1.4 82.9 ± 1.5 P=0.36 Woerle HJ et al in press

49 Plasma Glucose (mg/dl)
Cases of Hypoglycemic Episodes before and after Intensification of Treatment (N=164) Plasma Glucose (mg/dl) Cases Before After 70-61 4 10 60-51 1 50-41 ≤40 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% % 220 = HbA1c > 7% = HbA1c < 7% 200 180 (mg/dL) 160 140 120 Mean ± SEM (N = 164) 100 6 8 10 12 14 16 18 20 22 24 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.

53 Higher A1C Baseline Level Correlates With Larger A1C Reduction With Pharmacologic Intervention
Baseline A1C% 6.0–6.9 7.0–7.9 8.0–8.9 9.0–9.9 10.0–11.8 Number of patients enrolled in clinical trials n=410 n=1,620 n=5,269 n=1,228 n=266 Adapted from Bloomgarden ZT et al. Diabetes Care. 2006;29:

54 Road map to achieve glycaemic goals1
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 7−8 8−9 9−10 >10 Lifestyle modification Monotherapy or combination therapy Monotherapy: Meglitinide, SU, AGI, metformin, TZD, pre-mixed insulin analogs or basal insulin 6–6.5 >8.5 Naïve to therapy (type 2) Treated patients (type 2) Achieve ACE glycaemic goals* (FPG and PPG) Initial A1c(%) Current Therapy Current A1c(%) 6.5−8.5 Continue lifestyle modification PPG Pre-mixed insulin analogs Pre-mixed insulin analogs, Rapid-acting insulin analogs In September 2005, the AACE published a treatment algorithm or ‘road map’ for care of patients who have or are developing type 2 diabetes.1 The road map emphasises targeting PPG in patients at all stages in disease progression, but especially for individuals with moderate hyperglycaemia. It sets ambitious targets for controlling all glycaemic parameters, and it suggests suitable treatment regimens for different levels of HbA1c, including the safe use of insulin mixes and prandial insulins, as appropriate. According to this road map: PPG should be a primary target for control in treatment-naïve patients with HbA1c in the range of 6–8% PPG remains an important target at higher HbA1c For individuals already receiving treatment, insulin and insulin analogues may be appropriate at HbA1c values as low as 6.5% 1. AACE. Roadmap for prevention and treatment of type 2 diabetes, 2005 *ACE glycaemic goals: ≤6.5% HbA1c, <110 mg/dL FPG, <140 mg/dL 2 h PPG † For selected patients presenting with HbA1c >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
HbA1c <7.5% , target PPG HbA1c >7.5% , target FPG, then PPG (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 HbA1c is a continuous risk factor for micro- and macrovascular complications. HbA1c includes both fasting and postprandial glycemia. 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. 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.

58 Questions ??

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

60 Variability in Blood Glucose Is an
Independent Risk Factor for Mortality Variability of FPG and cardiovascular mortality 10-year survival 1.0 0.9 Survival probability Mean CV of FPG* 0.8 Group 1 (8.5%) 0.7 Group 2 (14.8%) 0.6 Group 3 (27.7%) 0.5 2 4 6 8 10 Time (years) CV = coefficient of variation *Significant differences in the CV of FPG (p<0.001) Muggeo M et al. Diabetes Care. 2000;23:45-50.

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

62 1,5 AG as Adjunct to A1C to Reflect Postprandial Hyperglycemia
(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) Breakfast N=9 Lunch N=10 Dinner Higher Postprandial Variables 7.36 4.55 16.29 259 224 198 (1,5-AG) Range 6-18 N=16 Total AUC-180 Glucose1 Breakfast N=11 N=13 Lower Postprandial Variables 7.12 9.29 10.75 228 196 162 1,5 AG is indicative of differing postmeal glucose levels in moderately controlled patients – despite similar A1C levels! Dungan K et al Diabetes Care; June 2006

63 Initial Treatment (in %)
Demographic Characteristics and Treatment Regimens Before and After Three Months Age (years) 62.4 ± 0.9 Gender 90 men/74 women BMI (kg/m2) 28.8 ± 0.6 Diabetes duration (years) HbA1c (%) 8.4 ± 0.6 8.7 ± 0.1 Initial Treatment (in %) Final Treatment (in %) Diet alone 42 (26) 7 (4) Metformin alone 17 (10) Secretagogue alone 32 (20) 15 (9) Metformin plus Secretagogue 23 (14) 11 (7) NPH-insulin alone 5 (3) 12 (7) NPH plus Metformin 6 (4) 14 (9) NPH plus Secretagogue 13 (8) 34 (21) Twice insulin 1 (1) NPH plus short acting insulin 19 (12) plus Metformin 2 (1) 4 (2) NPH plus Secretagogue plus Metformin Woerle HJ et al in press


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