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1University of Rochester School of Medicine and Dentistry Glycemic Targets in Clinical Practice: Postprandial vs Preprandial and Fasting?Steven D Wittlin MDUniversity of Rochester School of Medicine and DentistryRochester, New York
2In 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
3The question is not whether to target postprandial, preprandial or fasting glycemia, but when, how, and to what goals.
4UKPDS Epidemiologic Data in Type 2 Diabetes No A1C Threshold Adjusted incidence per 1000 person-years80%Myocardial infarction70%Microvascular endpoints60%50%40%UKPDS Epidemiologic Data in Type 2 DiabetesNo 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.1In 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.1This 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%).1An 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.1Reference1. 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%567891011Updated mean A1C (%)Stratton IM, et al. BMJ. 2000;321:
5What are appropriate goals? HbA1cFPG2 hr PPGNormalization of Glycemia
6What 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
7Hyperglycemia 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
8CDA: 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
9To 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 therapyNevertheless, might there be situations in which it is preferable to treat one or the other first ???
11Duration of postprandial state Patients With Type 2 Diabetes May Spend More Than 12 Hours per Day in the Postprandial StatePostprandialPostabsorptiveFastingDuration of postprandial stateBreakfastLunchDinnerMidnight4 AMBreakfast8 AM11 AM2 PM5 PMAdapted from Monnier L. Eur J Clin Invest. 2000;30(suppl 2):3-11.
12Correlation between plasma glucose levels after OGTT and standard mixed meal Wolever TMS et al. Diabetes Care 1998;21:336–40
13Changes in Postprandial Glucose Metabolism in Type 2 DM Use triple isotope technique and indirect calorimetryDM pts had:increased overall glucose releaseIncreased gluconeogenesis and glycogenolysis~90% of the increased glucose release occurred in the first 90 min post-prandialIn DM glucose clearance and oxidation were reducedNon-oxidative glycolysis was increasedNet splanchnic glucose storage was reduced ~ 45% d.t. increased glycogen cyclingWoerle HJ et al Am J Physiol Endocrinol Metab 2006
14Relationship between HbA1C, FPG and 2 h. PPG Van Haeften T et al Metabolism 2000
15Relative Changes in FPG and 2-h PG as HbA1c Increases 250= HbA1c versus 2hppg= HbA1c versus FPGPlasma Glucose(mg/dL)160r = 0.55y = 47.1 x -109r = 0.48y = 12.0 x +30704567HbA1c (%)Woerle HJ et al Arch Intern Med. 2004;164:
16In Individuals with HbA1C <6.5%, Postload Dysglycemia Predominates Woerle HJ et al Arch Intern Med. 2004;164:
17As 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:
18Post-Prandial Hyperglycemia Antecedes Fasting Hyperglycemia Monnier L et al Diabetes Care 30: , 2007
19PPG, but not FPG distinguishes patients with HbA1C Between 6.0-7.0% HbA1C Group (%)Characteristics# of patientsGenderAgeBMIFPG2hPPGMean HbA1C14/ /8(p=0.88)(p=0.03)Woerle HJ et al Arch Intern Med. 2004;164:
212-hour plasma glucose (mmol/l) Fasting plasma glucose (mmol/l) Relative risk for death increases with 2-hour blood glucose irrespective of the FPG level2.52.01.51.00.50.0Hazard ratio³11.17.8–11.02-hour plasma glucose (mmol/l)<7.8< –6.9 ³7.0Fasting plasma glucose (mmol/l)Adjusted for age, center, sexDECODE Study Group. Lancet 1999;354:617–621
23Effect of Acarbose on CVD in Patients with IGT ( STOP-NIDDM) ( Chiasson J - L et al JAMA July 2003 )
24Controlling Postprandial Glucose Prospective trial of fasting vs pc control in 164 pts w/ Type 2 DMForced titration to target either FBS < 100 or 90 min pc < 140Results: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 HbA1CIf HbA1C < 6.2% , pc accounted for ~ 90%If HbA1C > 8.9%, pc accounted for ~ 40%Woerle HJ et al in press
25Relationship Between HbA1c, FPG and PPG in Treated T2DM Patients MajorHbA1c (%) FPG (mM) PPG (mM) ProblemPPGPPGFPG+PPGFPG+PPGFPGWoerle et al., 2006.
26So How Can We Assess Post-Prandial Glucose Control Clinically ?? Frequent fingersticksHbA1CFructosamineContinuous Glucose Monitoring SystemsHistoricalReal-time1,5 Anhydroglucitol
27Postprandial Index vs. A1C/1,5-AG Assay Ratio Postprandial Index (Multi-variate-PI) N=19Avg. A1CAvg. 1,5-AGAvg. A1C/Avg. 1,5-AG RatioR=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.A1C/1,5-AG Ratio Correlated Better than A1C or 1,5-AG independently to the Postprandial IndexCombination of 1,5-AG and A1C are more predictive of postprandial hyperglycemiaDungan K et al Diabetes Care; June 2006
35Fasting Plasma Glucose Reflects Endogenous Glucose Production Dinneen S, Gerich J, Rizza R. N Engl J Med. 1992;327:
36Why Fix Fasting First?SaferSimplerLowering FPG first will lower all PG values throughout the day and thus will also reduce PPG and may be sufficient.
37Effect of Glyburide or NPH Insulin on Glycemia in Type 2 Diabetes Time of dayFrom: Shapiro ET et al. J Clin Endocrinol Metab 69 (1989), pp. 571–576Cusi K et al Diabetes Care 18 (1995), pp. 843–851
38Agents that Address Fasting Hyperglycemia Basal InsulinMetforminSulfonylureasTZDs??
39Pioglitazone Affects both FPG and PPG Miyazaki Y et al .Diabetes Care 25: , 2002
40Insulin Glargine vs NPH Insulin Added to Oral Therapy Patient Demographics756 insulin-naïve patients with type 2 diabetesInsulin glargine n=367NPH n=389Mean age 55 yrBMI 32 kg/m2Duration of diabetes 8-9 yrBaseline A1C 8.6%Riddle MC et al and the Insulin Glargine 4002 Study Investigators. Diabetes Care 2003:26:
41Insulin Glargine vs NPH Insulin Added to Orals Riddle MC et al and the Insulin Glargine 4002 Study Investigators. Diabetes Care 2003:26:
42Insulin Glargine vs NPH Insulin Added to Oral Therapy ResultsITT Analysis Insulin Glargine NPHFPG, mg/dLmMA1C, %Final A1C 7% (% patients)Nocturnal HypoglycemiaPatients,* %Events, † noSevere HypoglycemiaPatients, %*P<0.01; †P<0.002Riddle et al and the Insulin Glargine 4002 Study Investigators. Diabetes Care 2003:26:
43Exenatide vs Glargine in Type 2 Diabetes Mellitus 551 patients, multi-site international studyRx w/ Metformin and SU for 3 months prior to screeningHbA1C % ; BMI 25-45Randomly assigned exenatide or glargineExenatide 10 mcg BIDGlargine titrated to FBS< 100mg/dlResults: HbA1C reduced by 1.16 and 1.14% respectively (Mean final HbA1C ~ 7%)Heine RJ et al Ann Int Med 2005; 143:
44Exenatide vs Glargine in Type 2 Diabetes Mellitus glucoseTimeHeine RJ et al Ann Int Med 2005; 143:
45Addressing Fasting vs Postprandial First Approach Overall Goals:HbA1c <7FPG <100 mg/dl (5.5 mM)PPPG (90 min) <140 mg/dl (7.8 mM)Woerle HJ et al in press
46Fix Fasting First Algorithm Step 1: If FPG >100 mg/dl (5.5 mM) :a) drug naïve, start metforminb) if on SU, add metforminc) if on SU+Met, DC SU, add HS NPHStep 2: When FPG near goal, but PPPG>140 mg/dl (7.8 mM) :a) add repaglinide with mealsb) if above unsuccessful in achievingPPG goal, DC and use regularinsulin with meals.Woerle HJ et al in press
47Demographic Characteristics Age (years)62.4 ± 0.9Gender90 men/74 womenBMI (kg/m2)28.8 ± 0.6Diabetes durationHbA1c (%)8.4 ± 0.6 y8.7 ± 0.1Woerle HJ et al in press
49Plasma Glucose (mg/dl) Cases of Hypoglycemic Episodes before and after Intensification of Treatment (N=164)Plasma Glucose (mg/dl)CasesBeforeAfter70-6141060-51150-41≤40Woerle HJ et al in press
50Diurnal 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%200180(mg/dL)160140120Mean ± SEM(N = 164)100681012141618202224Time (Hours)Woerle HJ et al Diabetes Res Clin Pract Jan 19
51Contribution of Postprandial BG to HbA1C Woerle HJ et al Diabetes Res Clin Pract Jan 19
52Simpler and SaferLowering PPG first will require subsequent readjustments in PPG Rx when FPG is treated. Failure to do so may result in hypoglycemia.
53Higher A1C Baseline Level Correlates With Larger A1C Reduction With Pharmacologic Intervention Baseline A1C%6.0–6.97.0–7.98.0–8.99.0–9.910.0–11.8Number of patients enrolled in clinical trialsn=410n=1,620n=5,269n=1,228n=266Adapted from Bloomgarden ZT et al. Diabetes Care. 2006;29:
54Road map to achieve glycaemic goals1 Combination therapy: Meglitinide, SU, AGI, metformin, TZD, exenatide, pre-mixed insulin analogs, rapid-acting insulin analogs or basal insulinTarget: FPG and PPGInsulin therapy†Target: PPG and FPG6−77−88−99−10>10Lifestyle modificationMonotherapy or combination therapyMonotherapy: Meglitinide, SU, AGI, metformin, TZD, pre-mixed insulin analogs or basal insulin6–6.5>8.5Naïve to therapy (type 2)Treated patients (type 2)Achieve ACE glycaemic goals* (FPG and PPG)Initial A1c(%)Current TherapyCurrent A1c(%)6.5−8.5Continue lifestyle modificationPPGPre-mixed insulin analogsPre-mixed insulin analogs, Rapid-acting insulin analogsIn September 2005, the AACE published a treatment algorithm or ‘road map’ for care of patients who have or are developing type 2 diabetes.1The 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 HbA1cFor 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 effectiveAACE. Roadmap for prevention and treatment of type 2 diabetes, 2005
55Recommendations for Drug Naïve Patients HbA1c <7.5% , target PPGHbA1c >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 !!
56ConclusionsHyperglycemia 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
57ReflectionsNormalization 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.
59Glycemic Excursions Predict Oxidative Stress Monnier L et al JAMA. 2006;295:
60Variability in Blood Glucose Is an Independent Risk Factor for MortalityVariability of FPG and cardiovascular mortality10-year survival1.00.9Survival probabilityMean CV of FPG*0.8Group 1 (8.5%)0.7Group 2 (14.8%)0.6Group 3 (27.7%)0.5246810Time (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.
61Lack of Effect of Glucose Variability on Microvascular Complications Assessment of DCCT data using seven-point glucose profilesPerformed quarterlyNo preferential influence of the following on probability of retinopathy:BG variability (nor Nephropathy)FPGpc BGKilpatrick ES et al Diabetes Care 29:
621,5 AG as Adjunct to A1C to Reflect Postprandial Hyperglycemia (1,5-AG) Range 0-6N=17A1C (%) Mean1,5-AG (ug/ml) MeanTotal AUC-180 Glucose 1PostMeal Glucose-Max Mean (mg/dl)BreakfastN=9LunchN=10DinnerHigher Postprandial Variables7.364.5516.29259224198(1,5-AG) Range 6-18N=16Total AUC-180 Glucose1Breakfast N=11N=13Lower Postprandial Variables7.129.2910.752281961621,5 AG is indicative of differing postmeal glucose levels in moderately controlled patients – despite similar A1C levels!Dungan K et al Diabetes Care; June 2006
63Initial Treatment (in %) Demographic Characteristics and Treatment Regimens Before and After Three MonthsAge (years)62.4 ± 0.9Gender90 men/74 womenBMI (kg/m2)28.8 ± 0.6Diabetes duration (years)HbA1c (%)8.4 ± 0.68.7 ± 0.1Initial 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)plus Metformin2 (1)4 (2)NPH plus Secretagogue plusMetforminWoerle HJ et al in press