Transcript Glycemic Targets in Clinical Practice: Postprandial vs

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
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
The question is not whether to target
postprandial, preprandial or fasting
glycemia, but when, how, and to what
goals.
UKPDS Epidemiologic Data in Type
2 Diabetes
No A1C Threshold
Adjusted incidence
per 1000 person80%
years
Myocardial infarction
Microvascular endpoints
70%
60%
50%
40%
30%
20%
10%
0%
5
6
7
8
9
Updated mean A1C (%)
Stratton IM, et al. BMJ. 2000;321:405-412.
10
11
What are appropriate goals?
 HbA1c
 FPG
2
hr PPG
 Normalization of
Glycemia
What is Normal?
HbA1c
FPG
1 hr PPG
2 hr PPG
<6.0%
<100 mg/dl (5.5 mM)
<162 mg/dl (9.0 mM)
<126 mg/dl (7.0 mM)
(N=15)
Woerle HJ et al . Am J Physiol 290:E67-E77, 2006
Hyperglycemia is a continuous
risk factor for CVD...
Therefore normality should be
the goal if it can be safely
achieved


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, 2006. CDA, Can J Diabetes 27:S1-S151, 2003
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 ???
Postprandial Hyperglycemia
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
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
2 hr after SMM plasma glucose (mmol/l)
Correlation between plasma glucose levels
after OGTT and standard mixed meal
16
14
12
10
8
6
r=0.97
4
2
0
0
5
10
15
2 hr after OGTT plasma glucose (mmol/l)
Wolever TMS et al. Diabetes Care 1998;21:336–40
20
25
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
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
6
HbA1c (%)
Woerle HJ et al Arch Intern Med. 2004;164:1627-1632.
7
In Individuals with HbA1C <6.5%, 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
Increasing Contribution of PPG as A1C Improves
%
Contribution
100%
30%
80%
60%
70%
60%
55%
50%
40%
20%
70%
30%
40%
45%
50%
0%
< 10.2
10.2 to 9.3 9.2 to 8.5 8.4 to 7.3
A1C Range (%)
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;26:881-885.
< 7.3
FPG
PPG
Post-Prandial Hyperglycemia
Antecedes Fasting Hyperglycemia
Monnier L et al Diabetes Care 30:263-269, 2007
PPG, but not FPG distinguishes patients with
HbA1C Between 6.0-7.0%
HbA1C Group (%)

Characteristics



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


# of patients
Gender
Age
BMI
FPG
2hPPG
Mean HbA1C

6.0-6.5







37
14/23
54.6
27.8
111
198
6.26
Woerle HJ et al Arch Intern Med. 2004;164:1627-1632.
6.6-7.0
16
8/8
49.6
27.9
113 (p=0.88)
226 (p=0.03)
6.73
Therefore, the initial HbA1c can be
a guide.
Relative risk for death increases with
2-hour blood glucose irrespective of
the FPG level
2.5
Hazard ratio
2.0
1.5
1.0
11.1
0.5
7.8–11.0
<7.8
0.0
<6.1
6.1–6.9
7.0
Fasting plasma glucose (mmol/l)
Adjusted for age, center, sex
DECODE Study Group. Lancet 1999;354:617–621
THE FUNAGATA DIABETES STUDY
Impaired Glucose Tolerance is a CV Risk Factor
Cumulative Cardiovascular Survival
1.00
1.00
0.99
0.98
0.98
0.97
0.96
0.96
0.94
Normal
IGT (2 hr PG 140-200)
DM (2 hr PG >200)
0.95
0.94
Normal
IFG (FPG 110-126)
DM (FPG >126)
0.92
0
0
0
1
2
3
4
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 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
Relationship Between HbA1c, FPG
and PPG in Treated T2DM Patients
HbA1c (%)
5
6
7
8
9
10
FPG (mM)
5.1
6.3
7.5
8.7
9.9
11.1
Woerle et al., 2006.
PPG (mM)
7.0
8.4
9.8
11.2
12.6
14.0
-
Major
Problem
PPG
PPG
FPG+PPG
FPG+PPG
FPG
So How Can We Assess 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 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
Approaches/Agents That Address
Postprandial Hyperglycemia







Meglitinides
Alpha-Glucosidase Inhibitors
Prandial Insulin
GLP-1 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
300
600
250
500
Insulin (pmol/L)
Glucose (mg/dL)
Pretreatment
200
150
100
50
0
400
300
200
100
0
-1 0
1
2
3
4
5
6
7
8
9 10
Time (hr)
Hollander PA, et al. Diab Care 24:983-988, 2001.
-1 0
1
2
3
4
5
6
Time (hr)
7
8
9 10
Adding Prandial Insulin to Basal Therapy
Further Improves HbA1C
Davies M et al Tt.Lantus study group; 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
reduce PPG and may be sufficient.
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
Agents that Address Fasting
Hyperglycemia




Basal Insulin
Metformin
Sulfonylureas
TZDs??
Pioglitazone Affects both FPG and PPG
Miyazaki Y et al .Diabetes Care 25:517-523, 2002
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
2003:26:3080-3086.
Insulin Glargine vs NPH Insulin Added to Orals
Riddle MC et al and the Insulin Glargine 4002 Study Investigators. Diabetes Care 2003:26:3080-3086.
Insulin Glargine vs NPH Insulin Added to Oral
Therapy
Results
ITT Analysis
Insulin Glargine
FPG, mg/dL
117
mM
6.5
A1C, %
6.96
Final A1C 7% (% patients)
57
Nocturnal Hypoglycemia
Patients,* %
40
Events, † no.
532
Severe Hypoglycemia
Patients, %
2.5
*P<0.01; †P<0.002
NPH
120
6.68
6.97
57
49
886
2.3
Riddle et al and the Insulin Glargine 4002 Study Investigators. Diabetes Care 2003:26:3080-3086.
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 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: 559-569
glucose
Exenatide vs Glargine in Type 2
Diabetes Mellitus
Time
Heine RJ et al Ann Int Med 2005; 143: 559-569
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
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
Demographic Characteristics
Age (years)
Gender
BMI (kg/m2)
Diabetes duration
HbA1c (%)
Woerle HJ et al in press
62.4 ± 0.9
90 men/74
women
28.8 ± 0.6
8.4 ± 0.6 y
8.7 ± 0.1
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
P<0.001
Post breakfast (mg/dl)
233 ± 6
159 ± 3
P<0.001
Pre lunch (mg/dl)
170 ± 6
116 ± 2
P<0.001
Post lunch (mg/dl)
213 ± 5
155 ± 4
P<0.001
Pre dinner (mg/dl)
176 ± 5
133 ± 4
P<0.001
Post dinner (mg/dl)
227 ± 6
164 ± 4
P<0.001
Bedtime (mg/dl)
201 ± 5
143 ± 3
P<0.001
Average postmeal (mg/dl)
224 ± 4
159 ± 3
P<0.001
Daylong (mg/dl)
199 ± 4
141 ± 2
P<0.001
84.0 ± 1.4
82.9 ± 1.5
P=0.36
Weight (Kg)
Woerle HJ et al in press
Cases of Hypoglycemic Episodes before and
after Intensification of Treatment (N=164)
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
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
(mg/dL)
180
160
140
120
Mean ± SEM
(N = 164)
100
6
8
10
12
14
16
18
Time (Hours)
Woerle HJ et al Diabetes Res Clin Pract. 2007 Jan 19
20
22
24
Contribution of Postprandial BG to HbA1C
100
*=p<0.05vs HbA1c <6.2 %
*
80
Contribution (%)
*
*
60
*
*
40
20
0
4.7-6.2
6.2-6.8
6.8-7.3
7.3-7.8
7.8-8.9
HbA1c sixtiles(%)
Woerle HJ et al Diabetes Res Clin Pract. 2007 Jan 19
8.9-15.0
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.
Higher A1C Baseline Level Correlates With Larger A1C
Reduction With Pharmacologic Intervention
Baseline A1C%
Number of patients
enrolled in clinical
trials
0
6.0–6.9
7.0–7.9
8.0–8.9
9.0–9.9
10.0–11.8
n=410
n=1,620
n=5,269
n=1,228
n=266
-0.1
-0.2
A1C Reduction, %
-0.2
-0.4
-0.6
-0.6
-0.8
-1
-1.0
-1.2
Change in A1C from baseline
-1.4
Adapted from Bloomgarden ZT et al. Diabetes Care. 2006;29:2137-2139.
-1.2
Road map to achieve glycaemic goals1
Naïve to therapy (type 2)
Achieve ACE
glycaemic goals*
(FPG and PPG)
6−7
Target: PPG
PPG and FPG
8−9
9−10
>10
Lifestyle modification
7−8
Current
A1c(%)
6–
6.5
Target: PPG
PPG and FPG
Target: FPG and PPG
PPG
6.5−
8.5
Target: FPG and PPG
Insulin therapy†
>8.5
Current Therapy
Continue lifestyle modification
Initial
A1c(%)
Treated patients (type 2)
Monotherapy
or
combination therapy
Monotherapy:
Meglitinide, SU, AGI, metformin, TZD,
pre-mixed
Pre-mixed insulin analogs or basal
insulin
Monotherapy
or
combination therapy
Combination therapy:
Meglitinide, SU, AGI, metformin, TZD,
exenatide, Pre-mixed
pre-mixed insulin analogs,
rapid-acting insulin
Rapid-acting
insulin analogs
analogs or basal
insulin
*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
http://www.aace.com/pub/odimplementation/roadmap.pdf
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 !!
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
Reflections

Normalization of HbA1C can not be
considered the equivalent of
normoglycemia in view of our ability to
measure other markers, elevated postchallenge glucose , the availability of
continuous glucose monitoring and
increased CVD in the normal range of
HbA1C.
Questions ??
Glycemic Excursions Predict
Oxidative Stress
Monnier L et al JAMA. 2006;295:1681-1687
Variability in Blood Glucose Is an
Independent Risk Factor for Mortality
Variability of FPG and cardiovascular mortality
10-year survival
1.0
0.9
Mean CV of FPG*
Survival
probability
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
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.
8
10
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 29:1486-1490.2006
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
PostMeal
Glucose-Max
Mean (mg/dl)
Lunch
N=10
PostMeal
Glucose-Max
Mean (mg/dl)
Dinner
N=9
Higher
Postprandial
Variables
7.36
4.55
16.29
259
224
198
(1,5-AG)
Range 6-18
N=16
A1C
(%)
Mean
1,5-AG
(ug/ml)
Mean
Total AUC-180
Glucose1
PostMeal
Glucose-Max
Mean (mg/dl)
Breakfast
N=11
PostMeal
Glucose-Max
Mean (mg/dl)
Lunch
N=13
PostMeal
Glucose-Max
Mean (mg/dl)
Dinner
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
Demographic Characteristics and Treatment Regimens Before and
After Three Months
Age (years)
Gender
62.4 ± 0.9
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