glycemic targets in clinical practice postprandial vs preprandial and fasting

Glycemic Targets in Clinical Practice: Glycemic Targets in Clinical Practice: Postprandial vs Preprandial Postprandial vs Preprandial and Fasting? and Fasting? Steven D Wittlin MD Steven D Wittlin MD University of Rochester School of Medicine and University of Rochester School of Medicine and Dentistry Dentistry Rochester, New York Rochester, New York In all affairs it’s a healthy In all affairs it’s a healthy thing now and then to hang a thing now and then to hang a question mark on the things question mark on the things you have long taken for you have long taken for granted…… granted…… Bertrand Russell Bertrand Russell The question is not whether to target postprandial, The question is not whether to target postprandial, preprandial or fasting glycemia, but preprandial or fasting glycemia, but when when , , how how , and to , and to what what goals goals . . UKPDS Epidemiologic Data in Type UKPDS Epidemiologic Data in Type 2 Diabetes 2 Diabetes No A1C Threshold No A1C Threshold 0% 10% 20% 30% 40% 50% 60% 70% 80% 5 6 7 8 9 10 11 Adjusted incidence per 1000 person-years Myocardial infarction Microvascular endpoints Updated mean A1C (%) Stratton IM, et al. BMJ. 2000;321:405-412. What are appropriate goals? What are appropriate goals?  HbA HbA 1c 1c  FPG FPG  2 hr PPG 2 hr PPG  Normalization of Normalization of Glycemia Glycemia Woerle HJ et al . Am J Physiol 290:E67-E77, 2006 Woerle HJ et al . Am J Physiol 290:E67-E77, 2006 What is Normal? What is Normal? HbA HbA 1c 1c <6.0% <6.0% FPG FPG <100 mg/dl (5.5 mM) <100 mg/dl (5.5 mM) 1 hr PPG 1 hr PPG <162 mg/dl (9.0 mM) <162 mg/dl (9.0 mM) 2 hr PPG <126 mg/dl (7.0 mM) 2 hr PPG <126 mg/dl (7.0 mM) (N=15) Hyperglycemia is a continuous Hyperglycemia is a continuous risk factor for CVD risk factor for CVD Therefore normality should be Therefore normality should be the goal if it can be safely the goal if it can be safely achieved achieved  CDA: HbA1C<7% “ CDA: HbA1C<7% “ consider targets in the normal range consider targets in the normal range for patients in whom it can be achieved safely ” for patients in whom it can be achieved safely ”  ADA: “ for patients in general is an A1C<7% ADA: “ for patients in general is an A1C<7% for the for the individual patient is an A1C as close to normal (<6.0%) individual patient is an A1C as close to normal (<6.0%) as possible as possible without significant hypoglycemia ” without significant hypoglycemia ” ADA, Diabetes Care 29:S4-S42, 2006. CDA, Can J Diabetes 27:S1-S151, 2003 ADA, Diabetes Care 29:S4-S42, 2006. CDA, Can J Diabetes 27:S1-S151, 2003 To achieve a normal or near normal HbA To achieve a normal or near normal HbA 1c 1c , both FPG and , both FPG and PPG levels must be normal or near normal. 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 Nevertheless, might there be situations in which it is preferable to treat one or the other first ??? preferable to treat one or the other first ??? Postprandial Hyperglycemia Postprandial Hyperglycemia [...]... Post-Prandial Glucose Control Clinically ??     Frequent fingersticks HbA1C Fructosamine Continuous Glucose Monitoring Systems    Historical Real-time 1,5 Anhydroglucitol Postprandial Index vs A1C/1,5-AG Assay Ratio Postprandial Avg A1C Index (Multivariate-PI) N=19 R=0.36 Avg 1,5-AG Avg A1C/Avg 1,5-AG Ratio R=0.58 R=0.66 *Postprandial Index is the conglomerate multivariable analysis using AUC-180 and. .. Day in the Postprandial State Postprandial Postabsorptive Fasting Duration of postprandial state Breakfast 8 AM Lunch 11 AM 2 PM Dinner 5 PM Adapted from Monnier L Eur J Clin Invest 2000;30(suppl 2):3-11 Midnight 4 AM Breakfast Correlation between plasma glucose levels after OGTT and standard mixed meal r=0.97 Wolever TMS et al Diabetes Care 1998;21:336–40 Changes in Postprandial Glucose Metabolism in. .. analogues  DPP-IV inhibitors Pramlintide  Glycemic Index/Load  Importance of Post-Prandial Control in Managing Gestational Diabetes de Veciana M et al NEJM Nov 1995 Nateglinide Monotherapy: Effect on Plasma Glucose and Insulin Nateglinide Insulin (pmol/L) Glucose (mg/dL) Pretreatment Time (hr) Hollander PA, et al Diab Care 24:983-988, 2001 Time (hr) Adding Prandial Insulin to Basal Therapy Further Improves... 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 Approaches/Agents That Address Postprandial Hyperglycemia     Meglitinides Alpha-Glucosidase Inhibitors Prandial Insulin GLP-1 analogues  DPP-IV inhibitors... 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... ADA 2006 Abstract Inhaled Insulin is Superior to Metformin as Addon Therapy to Sulfonylureas !! Barnett AH et al Diabetes Care 29:1282-1287, 2006 Fasting Hyperglycemia Fasting Plasma Glucose Reflects Endogenous Glucose Production Dinneen S, Gerich J, Rizza R N Engl J Med 1992;327:707-713 Why Fix Fasting First? Safer Simpler Lowering FPG first will lower all PG values throughout the day and thus will also... Postload Dysglycemia Predominates Woerle HJ et al Arch Intern Med 2004;164:1627-1632 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)... Year 5 6 7 0 1 2 3 4 5 6 7 Year Tominaga M, et al Impaired glucose tolerance is a risk factor for cardiovascular disease, but not impaired fasting glucose Diabetes Care 1999;22:920-4 Effect of Acarbose on CVD in Patients with IGT ( STOP-NIDDM) ( Chiasson J - L et al JAMA July 2003 ) Controlling Postprandial Glucose    Prospective trial of fasting vs pc control in 164 pts w/ Type 2 DM Forced titration... HJ et al Am J Physiol Endocrinol Metab 2006 Relationship between HbA1C, FPG and 2 h PPG Van Haeften T et al Metabolism 2000 Relative Changes in FPG and 2-h PG as HbA1c Increases Plasma Glucose (mg/dL) 250 = HbA1c versus 2hppg = HbA1c versus FPG 160 r = 0.55 y = 47.1 x -109 r = 0.48 y = 12.0 x +30 70 4 5 HbA1c (%) 6 Woerle HJ et al Arch Intern Med 2004;164:1627-1632 7 In Individuals with HbA1C 8.9%, pc accounted for ~ 40% Woerle HJ et al in press Relationship Between HbA1c, FPG and PPG in Treated . Glycemic Targets in Clinical Practice: Glycemic Targets in Clinical Practice: Postprandial vs Preprandial Postprandial vs Preprandial and Fasting? and Fasting? Steven D Wittlin MD Steven. granted…… granted…… Bertrand Russell Bertrand Russell The question is not whether to target postprandial, The question is not whether to target postprandial, preprandial or fasting glycemia, but preprandial. 1998;21:336–40 r=0.97 r=0.97 Changes in Postprandial Glucose Changes in Postprandial Glucose Metabolism in Type 2 DM Metabolism in Type 2 DM  Use triple isotope technique and indirect calorimetry Use