glycemic targets in clinical practice postprandial vs preprandial and fasting

Glycemic Targets in Clinical Practice: Postprandial vs Preprandial and Fasting?. The question is not whether to target postprandial, preprandial or fasting glycemia, but when, how, and

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

What are appropriate goals?

 2 hr PPG

 Normalization of Glycemia

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

Adapted from Monnier L Eur J Clin Invest 2000;30(suppl 2):3-11.

Duration of postprandial state

Breakfast Lunch Dinner Midnight 4 AM Breakfast

8 AM 11 AM 2 PM 5 PM

Postprandial Postabsorptive Fasting

Correlation between plasma glucose levels

after OGTT and standard mixed meal

r=0.97

Changes in Postprandial Glucose

Metabolism in Type 2 DM

 Use triple isotope technique and indirect calorimetry

the first 90 min post-prandial

reduced

d.t increased glycogen cycling

Woerle HJ et al Am J Physiol Endocrinol Metab 2006

Relationship between HbA1C, FPG and 2 h PPG

Woerle HJ et al Arch Intern Med 2004;164:1627-1632

Relative Changes in FPG and 2-h PG

as HbA1c Increases

70 160 250

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

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.

Post-Prandial Hyperglycemia Antecedes Fasting Hyperglycemia

Monnier L et al Diabetes Care 30:263-269, 2007

PPG, but not FPG distinguishes patients with

Therefore, the initial HbA1c can be a guide.

Relative risk for death increases with 2-hour blood glucose irrespective of

the FPG level

<6.1 6.1–6.9 ≥7.0

≥11.1 7.8–11.0

<7.8 Fasting plasma glucose (mmol/l) 2- ho

ur p

la sm

a gl

uc os e

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

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.

Normal IGT (2 hr PG 140-200)

Normal IFG (FPG 110-126)

DM (FPG >126)

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%

Relationship Between HbA1c, FPG and PPG in Treated T2DM Patients

So How Can We Assess Post-Prandial

Glucose Control Clinically ??

Postprandial Index vs A1C/1,5-AG Assay Ratio

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 Index is the conglomerate multivariable analysis using AUC-180 and post-meal maximum glucose values as the independent variables

Dungan K et al Diabetes Care; June 2006

Approaches/Agents That Address

Importance of Post-Prandial Control in

Managing Gestational Diabetes

de Veciana M et al NEJM Nov 1995

Davies M et al Tt.Lantus study group; ADA 2006 Abstract

Adding Prandial Insulin to Basal Therapy

Further Improves HbA1C

Inhaled Insulin is Superior to Metformin as

Add-on Therapy to SulfAdd-onylureas !!

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?

Lowering FPG first will lower all PG values throughout the day and thus will also reduce PPG and may be sufficient

Safer Simpler

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

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

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

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

Heine RJ et al Ann Int Med 2005; 143: 559-569

Results: HbA1C reduced by 1.16 and 1.14%

respectively (Mean final HbA1C ~ 7%)

Exenatide vs Glargine in Type 2

Addressing Fasting vs Postprandial First

Fix Fasting First Algorithm

Step 1: If FPG >100 mg/dl (5.5 mM) :

a) drug nạve, 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.

Effects of Intensified Treatment Regimens (N=164)

Cases of Hypoglycemic Episodes before and after Intensification of Treatment (N=164)

Plasma Glucose (mg/dl) Cases

Before Cases After

Diurnal Plasma Glucose Profiles Before and After Intensified Therapy Intervention in Subjects Who Did and Did Not Achieve

HbA1C < 7.0%

100 160

Time (Hours)

200 180

140 120

22 20

16 14

10 8

%

Contribution of Postprandial BG to HbA1C

0 20 40 60 80 100

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

Road map to achieve glycaemic goals1

Combination therapy:

Meglitinide, SU, AGI, metformin, TZD, exenatide, pre-mixed insulin analogs, rapid-acting insulin analogs or basal insulin

Monotherapy:

Meglitinide, SU, AGI, metformin, TZD, pre-mixed insulin analogs or basal insulin

Monotherapy

or combination therapy

Pre-mixed insulin analogs

Pre-mixed insulin analogs, Rapid-acting insulin analogs

*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

Recommendations for Drug Nạve

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 !!

 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

 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

Questions ??

Glycemic Excursions Predict

Oxidative Stress

Monnier L et al JAMA 2006;295:1681-1687

CV = coefficient of variation

*Significant differences in the CV of FPG (p<0.001)

Variability of FPG and cardiovascular mortality

1.0

0.7 0.6 0.5

Lack of Effect of Glucose Variability

1,5 AG as Adjunct to A1C to Reflect Postprandial

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

1,5-AG (ug/ml) Mean

Total AUC-180 Glucose 1

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

Demographic Characteristics and Treatment Regimens Before and

After Three Months

NPH plus short acting insulin 19 (12) 34 (21)

NPH plus short acting insulin

NPH plus Secretagogue plus

Woerle HJ et al in press