Diabetes Control and Complication Trial (DCCT) involving type 1 diabetic U.K. Prospective Diabetes Study (UKPDS), the fasting blood glucose …
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Targeting Plasma Glucose: Preprandial Versus Postprandial
Richard J Schrot, MD, CDE
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ver the past decade, a major interest in postprandial glucose PPG has emerged, in part because of a plethora of new medications that specifically target PPG These include insulin analogs lispro and aspart, insulin secretagogues repaglinide and nateglinide, alpha-glucosidase inhibitors miglitol and acarbose, and injectable amylin analogs and glucagonlike peptide receptor agonists Targeting plasma glucose has been an accepted practice For example, in the Diabetes Control and Complication Trial DCCT involving type 1 diabetic patients, pattern analysis of pre-meal glucose values was targeted first In the UK Prospective Diabetes Study UKPDS, the fasting blood glucose FBG was targeted, and medications were titrated based on FBG1 Considering there are potentially seven points within a 24-hour glucose profile premeals, post-meals, and at bedtime, the question of which glucose values to target first and which will have the most impact on hemoglobin A1c A1C, is an important one for both patients and busy practitioners
practice of counting the grams of carbohydrate to be consumed, and
administrating supplemental insulin before the meal to cover the expected carbohydrate load3,4 In type 2 diabetic individuals, peak PPG occurs at about 2 hours after a meal and relates to inadequate glucose disposal1 The pathogenesis of PPG elevation in type 2 diabetic patients results from loss of first-phase insulin secretion, failure to control hepatic glucose production, and resistance of muscle to glucose uptake5 In addition, postprandial hyperglycemia is driven by a lack of suppression of glucagon hence, the interest in agents that antagonize glucagon6 Normally, fasting glucose maintenance mostly depends on glucose production by the liver In the progression of type 2 diabetes, insulin output is able to
IN BRIEF
increase with the increasing glucose level until the FBG reaches about 140 mg/dl, at which point the -cell insulin output cannot keep pace with the increased glucose load, and the fasting insulin concentration decreases This is sometimes referred to as Starlings curve of the pancreas7 At this time, hepatic glucose production begins to increase because insufficient insulin is available for suppression This process is the major determinant of the FBG level7 Mean Plasma
Glucose Most practitioners agree that A1C is the gold standard for glycemic control and that it best correlates with mean plasma glucose MPG Both pre- and post-meal glucose values are important because they both contribute to A1C, but the contribution of each has been debated Rohlfing et al8 calculated the MPG for 1,439 type 1 diabetic patients in the DCCT by using a 7-point capillary glucose database pre- and post-meal and bedtime The importance of this association of MPG and A1C has been recognized by the American Diabetes Association ADA in its position statement Standards of Medical Care in Diabetes9 Table 1 The MPG, while providing general information about control, is not specific enough to allow practitioners to target glucose excursions during a specific time of day The Fasting Glucose Story The ADA has recognized the fasting plasma glucose FPG, instead of the 2hour oral glucose tolerance test GTT, as the diagnostic test of choice9 The
Normal and Abnormal Glucose Physiology In people without diabetes, peak PPG occurs about 1 hour after a meal and generally does not exceed 140 mg/dl1 PPG values can change as a result of a multitude of variables, such as activity, insulin
sensitivity, gastric emptying rate, and meal composition2 For example, carbohydrates contribute significantly more to PPG than do fats or protein Hence, there is an accepted
Considering there are potentially seven points within a 24-hour glucose profile pre-meals, post-meals, and at bedtime, the question of which of these values to target is important to both patients and busy practitioners Appropriate targeting of plasma glucose may lead to less expense and less unnecessary testing for patients and may help patients and practitioners achieve glucose goals more expeditiously This article suggests that targeting fasting plasma glucose is more beneficial when hemoglobin A1c A1C results are very high, whereas targeting postprandial glucose is more effective when A1C results are lower
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Table 1 Correlation Between A1C Level and MPG Levels A1C 6 7 8 9 10 11 12 MPG mg/dl mmol/l 135 170 205 240 275 310 345 75 95 115 135 155 175 195
Reprinted with permission from Ref 9 FPG is more consistent and reproducible than PPG because there are more variables in the latter, such as timing and carbohydrate load10 Likewise, FPG may
be easier to control with medication than PPG The variables of food intake and exercise, for example, are much less of a factor at night preceding measurement of the FPG, and this may enable a more consistent pattern of values for FPG It has been pointed out, however, that targeting FPG alone does not provide as good a degree of control as does targeting all pre-meal glucose values11 For example, the UKPDS, targeting just FPG, lowered A1C an average of 1, whereas the DCCT, targeting pre-meal lunch and supper values in addition to FPG, lowered A1C an average of 2 DeFronzo has noted that, in type 2 diabetic individuals, fasting glucose contributes approximately three-fourths and postprandial glucose approximately onefourth of mean glycemia12 Therefore, the phrase fix the fasting first has become an axiom of care for some practitioners, with the recommendation to use metformin and sulfonylureas first because they each lower the FPG by 6070 mg/dl, whereas thiazolidinediones lower FPG by only 4555 mg/dl, and alpha-glucosidase inhibitors lower FPG by 2030 mg/dl12 Carroll et al13 evaluated the relationship of FPG to PPG and concluded that the FPG level predicts the degree of postmeal
hyperglycemia and the magnitude
of the post-meal excursion from baseline The authors noted a direct relationship between FPG and PPG elevation and concluded that, because FPG is a determinant of PPG excursion, fixing the fasting should precede PPG correction In a study of 371 type 2 diabetic patients, Bonora et al11 concluded that preprandial glucose measurements are more closely related to A1C than are PPG, but that the strongest correlation of A1C was to MPG However, it was noted that many patients whose A1C indicated good control A1C 7 still had PPG values 160 mg/dl This study suggests that treating to goal by attaining A1C 7 may not ensure that PPG goals are also achieved The contribution of FPG to A1C was found to be dominant in patients with poorly controlled type 2 diabetes in a study by Monier et al14 In this study of 290 patients, the contribution of FPG approached 70 as A1C neared 10 It was also noted that, as glucose improves, PPG contribution dominates, so that with A1C values approaching 7, the PPG contribution is about 70 The Postprandial Glucose Story First written about in 1922,10 the GTT was described as currently used in 1979 by the National Diabetes Data
Group It is considered the gold standard for diagnosis of diabetes,15 in part because changes in PPG often precede FPG changes in the natural history of type 2 disease In fact, the World Health Organization retains the 2-hour GTT as the diagnostic test of choice16 Data from the Third National Health and Nutrition Examination Survey suggest that in about 10 of type 2 diabetic patients, the 2-hour value was 200 mg/dl, when the FPG was 126 mg/dl5 In agreement with Monier et al,14 Erlinger and Brancati5 showed that PPG elevations 200 mg/dl occurred generally in 39 of patients whose A1C was optimal 7 Looking at patients who were using oral agents, PPG elevation occurred in 63 of those with A1C results 7 Likewise, Soonthornpun et
al17 noted that with normal or near-normal FPG and an A1C that remained high, the 2-hour PPG becomes a good index of glycemic control Thus, PPG elevation is a frequent finding when optimal control is achieved It follows that controlling PPG at this time would likely lead to an A1C reduction further below 7 In a study by Bastyr et al,18 135 type 2 diabetic patients whose baseline mean A1C was 10 were all prescribed glyburide They were then divided into
three groups depending on whether they received additionally lispro targeting PPG, bedtime NPH targeting FPG, or metformin targeting pre-meal values It was shown that the lispro group targeting PPG had the greatest A1C reduction However, it was the FPG and pre-meal glucose values–not PPG values–that dictated dose titration2,18 This study shows that FPG and pre-meal glucose values in patients with poorly controlled type 2 diabetes can successfully dictate titration of an agent specifically targeting PPG lispro Supporters of PPG control laud its importance by noting that it is an independent risk factor for cardiovascular disease, over and above FBG, as demonstrated in the Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe DECODE study16 In the DECODE study, the plasma glucose value that defined increased risk was 140 mg/dl, 2 hours after a 75-g glucose load This is the rationale for the American College of Endocrinology adopting this number 140 mg/dl as its 2-hour PPG goal2 PPG targets have been established in gestational diabetes with favorable reports By monitoring and controlling PPG at 1 hour, DeVeciana et al19 showed beneficial outcomes, such as
reduced levels of macrosomia, in neonates ADA Consensus Statement In January 2001, the ADA convened a consensus development conference, which led to publication of the consensus
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Table 2 ADA-Recommended Glycemic Goals A1C Preprandial glucose PPG 70 normal range 46 90130 mg/dl 180 mg/dl value, and PPG contributes the remaining 3014 Figure 1 Conclusion The roles of FPG and PPG continue to be debated Table 3 lists various reasons to target each of these values Because the FPG and pre-meal glucose levels are reflected in the PPG, it seems most practical to routinely control pre-meal glucose first, since it will likewise lower post-meal glucose levels, as well When pre-meal glucose and A1C are markedly uncontrolled, the additional financial and personal burden of having patients check their PPG levels does not appear warranted at this time5 Table 4 offers a targeting sequence that can help avoid unnecessary self80 a,b
statement Postprandial Blood Glucose in April of that year1 One of the outgrowths of this conference was the establishment of a 2-hour PPG goal of 180 mg/dl This goal was chosen because it was
associated with an A1C of 72 In the DCCT, average post-breakfast values of 220 mg/dl and post-lunch and postsupper values of 180 mg/dl correlated with an A1C of about 720 In contrast, the American College of Endocrinology has recommended a PPG goal of 140 mg/dl12,21 A post-meal glucose of 140 mg/dl would correlate with an A1C of 49592,20 Achievement of such a goal would be rare and limited by the harmful effects of hypoglycemia, particularly in type 1 diabetic patients, as demonstrated in the DCCT Proponents of the PPG goal of 140 mg/dl, however, point out that in a GTT, the ADA does recognize a 2-hour value between 140199 mg/dl as an impaired state and a cardiovascular risk Thus, 140 mg/dl would be a laudable goal, assuming side effects could be curtailed Under the ADA recommendations, preprandial glucose is targeted first Only when preprandial glucose is at goal, but A1C is not, is PPG targeted1 However, PPG can be measured earlier when postprandial hypoglycemia is suspected The goals for glycemic control, as recommended by the ADA, are listed in Table 29 A Unifying Concept Despite seemingly contradictory studies, there may be a unifying concept as proposed by Monier et
al14,22 This is the notion that the contribution of a given glucose value varies depending on the A1C results For example, with A1C results 73, PPG contributes 70 of the A1C However, with A1C results 102, FPG contributes 70 of the
monitoring of blood glucose by type 2 diabetic patients Various studies have suggested that PPG is an independent risk factor for cardiovascular disease Because impaired glucose tolerance 2-hour values of 140199 mg/dl and impaired fasting glucose FBG of 100125 mg/dl are associated with macrovascular disease, whereas micovascular disease appears to be more related to the FPG of 126 mg/dl,9 it is suggested that a lower glycemic threshold may exist for macrovascular disease Thus, there is adequate rationale to attempt to lower the A1C even further below 7 REFERENCES
1 American Diabetes Association: Postprandial blood glucose Consensus Statement Diabetes Care 24:775778, 2001 2 Buse J: Should postprandial glucose be routinely measured and treated to a particular target? No Diabetes Care 26:16151618, 2003 3 Hirsch I, Farkas-Hirsch R: View 2: Fine-tuning control: pattern management versus supple-
60 Contribution
c
c a
40 b a
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0 1 73 2 3 4 7384
8592 93102 A1C quintiles 5 102
Figure 1 Relative contributions of postprandial and fasting hyperglycemia to the overall diurnal hyperglycemia over quintiles of A1C Reprinted with permission from Ref 14
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Table 3 Reasons to Target FPG or PPG Values FPG Contributes to A1C A determinant of PPG13 PPG Contributes to A1C Preprandial glucose,but not A1C, at goal1 Better glucose control A1C 8414 Contributes 70 when A1C 7314
Endocrinologists meeting, May, 2002 Diabetes Care 25:16441649, 2002
13 Carroll M, Izard A, Riboni K, Burge M, Schade D: Fasting hyperglycemia predicts the magnitude of postprandial hyperglycemia Diabetes Care 25:12471248, 2002 14 Monnier L, Lapinski H, Colette C: Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetes patients Diabetes Care 26:881885, 2003 15 Gerstein H: Fasting versus postload glucose levels Diabetes Care 24:18551857, 2001 16 The DECODE Study Group: Glucose tolerance and mortality: comparison of WHO and American Diabetes Association diagnostic criteria Lancet 354:617621, 1999 17 Soonthornpun S, Rattarasarn
C, Leelawattana R, Setasuban W: Postprandial plasma glucose: a good index of glycemic control in type 2 diabetic patients having near-normal fasting glucose levels Diabetes Res Clin Pract 46:2327, 1999 18 Bastyr E, Stuart C, Brodows R, Schwartz S, Graf C, Zagar A, Robertson K: Therapy focused on lowering postprandial glucose, not fasting glucose, may be superior for lowering HbA1c Diabetes Care 23:12361241, 2000 19 DeVeciana M, Major C, Morgan M, Asrat T, Toohey J, Lien J, Evans A : Postprandial versus preprandial blood glucose monitoring in women with gestational diabetes mellitus requiring insulin therapy N Engl J Med 333:12391241, 1995 20 Buse J: Evolution in the American Diabetes Association standards of care Clinical Diabetes 21:2426, 2003 21 Bloomgarden Z: Cardiovascular disease and diabetes Diabetes Care 26:230237, 2003 22 The International PGR Study Group: Resolving a controversy: new findings show that postprandial glucose is an important contributor to HbA1c and a major player in moderately controlled diabetes PGR Update 1:15, 2003
Poor glucose control A1C 8414 Contributes 70 when A1C 10214 More reproducible Is frequently the earliest abnormality of type 2
diabetes May represent an independent risk for cardiovascular disease17,22 Gestational diabetes19 For patients using medications targeting PPG1 If postprandial hypoglycemia is suspected1 Table 4 Suggested Glucose Targeting Sequence for Type 2 Diabetes 1 With poor glucose control A1C in the 910 range or greater, titrate medication according to FPG 2 With improving control of the FPG A1C in the range of 89, look for patterns for pre-lunch, pre-supper, and bedtime glucose levels, and target these 3 With pre-meal glucose values coming into target range A1C 78 or even less but A1C results still not optimal, look for patterns of PPG elevation, and target these
mentation Diabetes Spectrum 14:7981, 2001
4 Pearson J, Bergenstal R: View 1: Fine-tuning control: pattern management versus supplementation Diabetes Spectrum 14:7578, 2001
Rohlfing C, Wiedmeyer H, Little R, England J, Tennill A, Goldstein D: Defining the relationship between plasma glucose and HbA1c Diabetes Care 25:275278, 2002
9 American Diabetes Association: Standards of medical care in diabetes Position Statement Diabetes Care 27 Suppl 1:S15S35, 2004 10 Barr R, Nathan D, Meigs J, Singer D: Tests of glycemia for diagnosis
of type 2 diabetes mellitus Ann Intern Med 137:263272, 2002 11 Bonora E, Calcaterra F, Lombardi S, Bonfante N, Formentini G, Bonadonna R, Muggeo M: Plasma glucose levels throughout the day and HbA1c interrelationships in type 2 diabetes Diabetes Care 24:20232028, 2001 12 Bloomgarden Z: Treatment of type 2 diabetes: the American Association of Clinical
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Erlinger T, Brancati F: Postchallenge hyperglycemia in a national sample of US adults with type 2 diabetes Diabetes Care 24:17341738, 2001
6 Shah P, Vella A, Basu A, Basu R, Schwenk W, Rizza R: Lack of suppression of glucagon contributes to postprandial hyperglycemia in subjects with type 2 diabetes mellitus J Clin Endocrinol Metab 85:40534059, 2000 7 DeFronzo R, Mandarino L: Pathogenesis of type 2 diabetes mellitus EndotextCom, 2003 Available online at wwwendotextcom/diabetes/ diabetes6/diabetes6htm
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Richard J Schrot, MD, CDE, is an associate professor in the Department of Family Medicine and a member of the research working group of the Pre-Diabetes Treatment and Research Center at the University of South Florida School of Medicine in Tampa
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