Glycemic Targets in Clinical Practice: Postprandial vs Preprandial and Fasting?

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 its 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 DiabetesNo
A1C Threshold
Adjusted incidence per 1000 person-years
80
Myocardial infarction
70
Microvascular endpoints
60
50
40
30
20
10
0
5
6
7
8
9
10
11
Updated mean A1C ()
Stratton IM, et al. BMJ. 2000321405-412.
5
What are appropriate goals?

• HbA1c
• FPG
• 2 hr PPG
• Normalization of Glycemia

6
What is Normal?
HbA1c lt6.0 FPG lt100 mg/dl (5.5 mM) 1 hr PPG
lt162 mg/dl (9.0 mM) 2 hr PPG lt126 mg/dl (7.0
mM)
(N15)
Woerle HJ et al . Am J Physiol 290E67-E77, 2006
7
Hyperglycemia is a continuous risk factor for
CVD... Therefore normality should be the goal
if it can be safely achieved
8

• CDA HbA1Clt7 consider targets in the normal
  range for patients in whom it can be achieved
  safely..
• ADA ...for patients in general is an
  A1Clt7....for the individual patient is an A1C as
  close to normal (lt6.0) as possible without
  significant hypoglycemia..

ADA, Diabetes Care 29S4-S42, 2006. CDA, Can J
Diabetes 27S1-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
Patients With Type 2 Diabetes May Spend More
Than12 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.
200030(suppl 2)3-11.
12
Correlation between plasma glucose levels after
OGTT and standard mixed meal
Wolever TMS et al. Diabetes Care 19982133640
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. 20041641627-16
32.
16
In Individuals with HbA1C lt6.5, Postload
Dysglycemia Predominates
Woerle HJ et al Arch Intern Med. 20041641627-16
32.
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. 200326881-885.
18
Post-Prandial Hyperglycemia Antecedes Fasting
Hyperglycemia
Monnier L et al Diabetes Care 30263-269, 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

• 6.0-6.5 6.6-7.0
• 37 16
• 14/23 8/8
• 54.6 49.6
• 27.8 27.9
• 111 113 (p0.88)
• 198 226 (p0.03)
• 6.26 6.73

Woerle HJ et al Arch Intern Med. 20041641627-16
32.
20

• Therefore, the initial HbA1c can be a guide.

21
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
7.811.0
2-hour plasma glucose(mmol/l)
lt7.8
lt6.1 6.16.9 ³7.0
Fasting plasma glucose (mmol/l)
Adjusted for age, center, sex DECODE Study Group.
Lancet 1999354617621
22
(No Transcript)
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 lt 100 or 90
  min pc lt 140
• Results
• HbA1C fell from 8.7 to 6.5
• Only 64 of patients achieving FPG lt 100 reached
  HbA1C lt 7
• 94 of patients w/ pc lt 140 reached HbA1C lt 7
• Decreased pc BG accounted nearly twice as much as
  FBS for fall in HbA1C
• If HbA1C lt 6.2 , pc accounted for 90
• If HbA1C gt 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
• 5 5.1 7.0 -
• 6 6.3 8.4 PPG
• 7 7.5 9.8 PPG
• 8 8.7 11.2 FPGPPG
• 9 9.9 12.6 FPGPPG
• 10 11.1 14.0 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) N19 Avg. A1C Avg. 1,5-AG Avg. A1C/Avg. 1,5-AG Ratio
Postprandial Index (Multi-variate-PI) N19 R0.36 R0.58 R0.66
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
Insulin (pmol/L)
Glucose (mg/dL)
Time (hr)
Time (hr)
Hollander PA, et al. Diab Care 24983-988, 2001.
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(No Transcript)
32
Adding Prandial Insulin to Basal Therapy Further
Improves HbA1C
Davies M et al Tt.Lantus study group ADA 2006
Abstract
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Inhaled Insulin is Superior to Metformin as
Add-on Therapy to Sulfonylureas !!
Barnett AH et al. Diabetes Care
291282-1287, 2006
34
Fasting Hyperglycemia
35
Fasting Plasma Glucose Reflects Endogenous
Glucose Production
Dinneen S, Gerich J, Rizza R. N Engl J Med.
1992327707-713
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. 571576
Cusi K et al Diabetes Care 18 (1995), pp. 843851
38
Agents that Address Fasting Hyperglycemia

• Basal Insulin
• Metformin
• Sulfonylureas
• TZDs??

39
Pioglitazone Affects both FPG and PPG
Miyazaki Y et al .Diabetes Care 25517-523, 2002
40
Insulin Glargine vs NPH Insulin Added to Oral
Therapy

• Patient Demographics
• 756 insulin-naïve patients with type 2 diabetes
• Insulin glargine n367
• NPH n389
• 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
  2003263080-3086.

41
Insulin Glargine vs NPH Insulin Added to Orals
Riddle MC et al and the Insulin Glargine 4002
Study Investigators. Diabetes Care
2003263080-3086.
42
Insulin Glargine vs NPH Insulin Added to Oral
Therapy

• Results
• ITT Analysis Insulin Glargine
  NPH
• FPG, mg/dL 117 120
• mM 6.5 6.68
• A1C, 6.96 6.97
• Final A1C ?7 ( patients) 57 57
• Nocturnal Hypoglycemia
• Patients, 40 49
• Events, no. 532 886
• Severe Hypoglycemia
• Patients, 2.5 2.3
• Plt0.01 Plt0.002
• Riddle et al and the Insulin Glargine 4002 Study
  Investigators. Diabetes Care 2003263080-3086.

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 7.0-10.0 BMI 25-45
• Randomly assigned exenatide or glargine
• Exenatide 10 mcg BID
• Glargine titrated to FBSlt 100mg/dl

Results HbA1C reduced by 1.16 and 1.14
respectively (Mean final HbA1C 7)
Heine RJ et al Ann Int Med 2005 143 559-569
44
Exenatide vs Glargine in Type 2 Diabetes Mellitus
glucose
Time
Heine RJ et al Ann Int Med 2005 143 559-569
45
Addressing Fasting vs Postprandial First Approach

• Overall Goals
• HbA1c lt7
• FPG lt100 mg/dl (5.5 mM)
• PPPG (90 min) lt140 mg/dl (7.8 mM)

Woerle HJ et al in press
46
Fix Fasting First Algorithm

• Step 1 If FPG gt100 mg/dl (5.5 mM)
• a) drug naïve, start metformin
• b) if on SU, add metformin
• c) if on SUMet, DC SU, add HS NPH
• Step 2 When FPG near goal, but PPPG
• gt140 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 (N164)
Pre Post P
HbA1c () 8.7 0.1 6.5 0.1 Plt0.001
FPG (mg/dl) 174 4 117 2 Plt0.001
Post breakfast (mg/dl) 233 6 159 3 Plt0.001
Pre lunch (mg/dl) 170 6 116 2 Plt0.001
Post lunch (mg/dl) 213 5 155 4 Plt0.001
Pre dinner (mg/dl) 176 5 133 4 Plt0.001
Post dinner (mg/dl) 227 6 164 4 Plt0.001
Bedtime (mg/dl) 201 5 143 3 Plt0.001
Average postmeal (mg/dl) 224 4 159 3 Plt0.001
Daylong (mg/dl) 199 4 141 2 Plt0.001
Weight (Kg) 84.0 1.4 82.9 1.5 P0.36
Woerle HJ et al in press
49
Cases of Hypoglycemic Episodes before and after
Intensification of Treatment (N164)
Plasma Glucose (mg/dl) Cases Before Cases After
70-61 4 10
60-51 1 1
50-41 0 1
40 0 0
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 lt 7.0

220
HbA1c gt 7 HbA1c lt 7
200
180
160
(mg/dL)
140
120
Mean SEM (N 164)
100
6
12
18
24
22
20
16
14
10
8
Time (Hours)
Woerle HJ et al Diabetes Res Clin Pract. 2007 Jan
19
51
Contribution of Postprandial BG to HbA1C
Woerle HJ et al Diabetes Res Clin Pract. 2007 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 6.06.9 7.07.9 8.08.9 9.09.9 10.011.8
Number of patients enrolled in clinical trials n410 n1,620 n5,269 n1,228 n266
Adapted from Bloomgarden ZT et al. Diabetes Care.
2006292137-2139.
54
Road map to achieve glycaemic goals1

ACE glycaemic goals 6.5 HbA1c, lt110 mg/dL
FPG, lt140 mg/dL 2 h PPG For selected patients
presenting with HbA1c gt10, certain oral agent
combinations may be effective
AACE. Roadmap for prevention and treatment of
type 2 diabetes, 2005 http//www.aace.com/pub
/odimplementation/roadmap.pdf
55
Recommendations for Drug Naïve Patients

• HbA1c lt7.5 , target PPG
• HbA1c gt7.5 , target FPG, then PPG
• (Fix the fasting first)
• OR
• If HbA1C gt 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 gt 7.5
  .
• If HbA1C lt 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. 20062951681-1687
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
0
0
2
4
6
8
10
Time (years)
CV coefficient of variation Significant
differences in the CV of FPG (plt0.001) Muggeo M
et al. Diabetes Care. 20002345-50.
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
291486-1490.2006
62
1,5 AG as Adjunct to A1C to Reflect Postprandial
Hyperglycemia
(1,5-AG) Range 0-6 N17 A1C () Mean 1,5-AG (ug/ml) Mean Total AUC-180 Glucose 1 PostMeal Glucose-Max Mean (mg/dl) Breakfast N9 PostMeal Glucose-Max Mean (mg/dl) Lunch N10 PostMeal Glucose-Max Mean (mg/dl) Dinner N9
Higher Postprandial Variables 7.36 4.55 16.29 259 224 198
(1,5-AG) Range 6-18 N16 A1C () Mean 1,5-AG (ug/ml) Mean Total AUC-180 Glucose1 PostMeal Glucose-Max Mean (mg/dl) Breakfast N11 PostMeal Glucose-Max Mean (mg/dl) Lunch N13 PostMeal Glucose-Max Mean (mg/dl) Dinner N13
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
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) 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) 1 (1)
NPH plus short acting insulin 19 (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