Glycemic Targets in Clinical Practice: Postprandial vs Preprandial and Fasting? Steven D Wittlin MD...

Glycemic Targets in Clinical Glycemic Targets in Clinical Practice: Postprandial vs Practice: Postprandial vs

Preprandial Preprandial and Fasting?and Fasting?

Steven D Wittlin MDSteven D Wittlin MD

University of Rochester School of University of Rochester School of Medicine and DentistryMedicine and Dentistry

Rochester, New YorkRochester, New York

http://www.jci.org/content/vol112/issue11/images/large/JCI0320448.f1.jpeg

In all affairs it’s a healthy In all affairs it’s a healthy thing now and then to thing now and then to

hang a question mark on hang a question mark on the things you have long the things you have long

taken for granted……taken for granted……

Bertrand RussellBertrand Russell

The question is not whether to target The question is not whether to target postprandial, preprandial or fasting postprandial, preprandial or fasting glycemia, but glycemia, but whenwhen, , howhow, and to , and to what what goalsgoals..

UKPDS Epidemiologic Data in UKPDS Epidemiologic Data in Type 2 DiabetesType 2 DiabetesNo A1C ThresholdNo 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?

HbAHbA1c1c

FPGFPG2 hr PPG2 hr PPGNormalization of Normalization of GlycemiaGlycemia

Woerle HJ et al . Am J Physiol 290:E67-E77, 2006Woerle HJ et al . Am J Physiol 290:E67-E77, 2006

What is Normal?What is Normal?

HbAHbA1c1c <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 Hyperglycemia is a continuous risk factor for continuous risk factor for

CVD...CVD... Therefore normality Therefore normality

should be the goal if it can should be the goal if it can be safely achievedbe safely achieved

CDA: HbA1C<7% “ CDA: HbA1C<7% “ consider targets consider targets in the normal rangein the normal range for patients in for patients in whom it can be achieved safely..”whom it can be achieved safely..”

ADA: “...for patients in general is an ADA: “...for patients in general is an A1C<7%....A1C<7%....for the individual patient for the individual patient is an A1C as close to normal (<6.0%) is an A1C as close to normal (<6.0%) as possibleas possible without significant without significant hypoglycemia..”hypoglycemia..”

ADA, Diabetes Care 29:S4-S42, 2006. CDA, Can J Diabetes 27:S1-S151, 2003ADA, Diabetes Care 29:S4-S42, 2006. CDA, Can J Diabetes 27:S1-S151, 2003

To achieve a normal or near normal To achieve a normal or near normal HbAHbA1c1c, both FPG and PPG levels must , both FPG and PPG levels must be normal or near normal.be normal or near normal.

Thus both FPG and PPG must be Thus both FPG and PPG must be targets for therapytargets for therapy

Nevertheless, might there be Nevertheless, might there be situations in which it is preferable to situations in which it is preferable to treat one or the other first ???treat one or the other first ???

Postprandial HyperglycemiaPostprandial Hyperglycemia

Patients With Type 2 Diabetes May Spend More Patients With Type 2 Diabetes May Spend More ThanThan

12 Hours per Day in the Postprandial State12 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

0

2

4

6

8

10

12

14

16

0 5 10 15 20 25

2 hr af ter OGTT plasma glucose (mmol/ l)

2 h

r af

ter

SM

M p

lasm

a gl

ucos

e (m

mol

/l)

0

2

4

6

8

10

12

14

16

0 5 10 15 20 25

2 hr af ter OGTT plasma glucose (mmol/ l)

2 h

r af

ter

SM

M p

lasm

a gl

ucos

e (m

mol

/l)

Correlation between plasma glucose Correlation between plasma glucose levels after OGTT and standard mixed levels after OGTT and standard mixed

mealmeal

Wolever TMS et al. Diabetes Care 1998;21:336–40

r=0.97r=0.97

Changes in Postprandial Glucose Changes in Postprandial Glucose Metabolism in Type 2 DMMetabolism in Type 2 DM

Use triple isotope technique and indirect calorimetryUse triple isotope technique and indirect calorimetry

DM pts had: DM pts had: increased overall glucose releaseincreased overall glucose release Increased gluconeogenesis and glycogenolysisIncreased gluconeogenesis and glycogenolysis ~90% of the increased glucose release ~90% of the increased glucose release

occurred in the first 90 min post-prandialoccurred in the first 90 min post-prandial In DM glucose clearance and oxidation were In DM glucose clearance and oxidation were

reducedreduced Non-oxidative glycolysis was increasedNon-oxidative glycolysis was increased Net splanchnic glucose storage was reduced Net splanchnic glucose storage was reduced

~ 45% d.t. increased glycogen cycling~ 45% d.t. increased glycogen cycling

Woerle HJ et al Am J Physiol Endocrinol Metab 2006

Relationship between HbA1C, FPG and 2 h. Relationship between HbA1C, FPG and 2 h. PPGPPG

Van Haeften T et al Metabolism 2000Van Haeften T et al Metabolism 2000

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

Relative Changes in FPG and 2-h Relative Changes in FPG and 2-h PG PG

as HbAas HbA1c1c Increases Increases

4 5 6 7

70

160

250

Pla

sma

Glu

cose

(mg

/dL

)

= HbA1c versus 2hppg= HbA1c versus FPG

r = 0.55y = 47.1 x -109

r = 0.48y = 12.0 x +30

HbA1c (%)

In Individuals with HbA1C <6.5%, In Individuals with HbA1C <6.5%, Postload Dysglycemia PredominatesPostload Dysglycemia Predominates


As Patients Get Closer to A1C Goal, As Patients Get Closer to A1C Goal, the Need to Successfully the Need to Successfully

Manage PPG Significantly IncreasesManage PPG Significantly IncreasesIncreasing Contribution of PPG as A1C Improves

30%40% 45% 50%

70%

60% 55% 50%30%

70%

0%

20%

40%

60%

80%

100%

< 10.2 10.2 to 9.3 9.2 to 8.5 8.4 to 7.3 < 7.3

A1C Range (%)

%

Co

ntr

ibu

tio

n

FPGPPG

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 Post-Prandial Hyperglycemia Antecedes Fasting Antecedes Fasting

HyperglycemiaHyperglycemia

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

http://care.diabetesjournals.org/content/vol30/issue2/images/large/zdc0020759440001.jpeg

PPG, but not FPG distinguishes PPG, but not FPG distinguishes patients with HbA1C Between 6.0-7.0%patients with HbA1C Between 6.0-7.0%

CharacteristicsCharacteristics # of patients# of patients GenderGender AgeAge BMIBMI FPGFPG 2hPPG2hPPG Mean HbA1CMean HbA1C

6.0-6.5 6.0-6.5 6.6-6.6-7.07.0 37 1637 16 14/23 8/814/23 8/8 54.6 49.654.6 49.6 27.8 27.927.8 27.9 111 113 111 113 (p=0.88)(p=0.88)

198 226 198 226 (p=0.03)(p=0.03)

6.26 6.73 6.26 6.73

HbA1C Group (%)


Therefore, the initial HbATherefore, the initial HbA1c1c can can be a guide.be a guide.

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

irrespective of the FPG levelirrespective 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

lasm

a gl

ucos

e

(mm

ol/l)

2.5

2.0

1.5

1.0

0.5

0.0

Haz

ard

rat

io

Adjusted for age, center, sexDECODE 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 Care1999;22:920-4.

NormalIGT (2 hr PG 140-200)DM (2 hr PG >200)

1.00

Cumulative Cardiovascular Survival

0.99

0.98

0.97

0.96

0.95

0.94

0

1.00

0.98

0.96

0.94

0.92

0

NormalIFG (FPG 110-126)DM (FPG >126)

0 1 2 3 4 5 6 7 0 1 2 3 4 5 6 7

Year Year

Effect of Acarbose on CVD in Effect of Acarbose on CVD in Patients with IGT ( STOP-NIDDM)Patients with IGT ( STOP-NIDDM)

( Chiasson J - L et al JAMA July 2003 )( Chiasson J - L et al JAMA July 2003 )

Controlling Postprandial GlucoseControlling Postprandial Glucose Prospective trial of fasting vs pc control in 164 pts Prospective trial of fasting vs pc control in 164 pts

w/ Type 2 DMw/ Type 2 DM Forced titration to target either FBS < 100 or 90 Forced titration to target either FBS < 100 or 90

min pc < 140min pc < 140 Results:Results:

HbA1C fell from 8.7 % to 6.5%HbA1C fell from 8.7 % to 6.5% Only 64% of patients achieving FPG < 100 reached Only 64% of patients achieving FPG < 100 reached

HbA1C < 7%HbA1C < 7% 94% of patients w/ pc < 140 reached HbA1C < 7%94% of patients w/ pc < 140 reached HbA1C < 7% Decreased pc BG accounted nearly twice as much as FBS Decreased pc BG accounted nearly twice as much as FBS

for fall in HbA1Cfor fall in HbA1C If HbA1C < 6.2% , pc accounted for ~ 90%If HbA1C < 6.2% , pc accounted for ~ 90% If HbA1C > 8.9%, pc accounted for ~ 40%If HbA1C > 8.9%, pc accounted for ~ 40%

Woerle HJ et al in press

Relationship Between HbARelationship Between HbA1c1c, , FPG and PPG in Treated T2DM FPG and PPG in Treated T2DM

PatientsPatients MajorMajor

HbAHbA1c1c (%) (%) FPG (mM) PPG (mM) Problem FPG (mM) PPG (mM) Problem 55 5.1 5.1 7.0 7.0 -- 66 6.3 6.3 8.4 8.4 PPGPPG 77 7.5 7.5 9.8 9.8 PPGPPG 88 8.7 8.7 11.2 11.2

FPG+PPGFPG+PPG 99 9.9 9.9 12.6 12.6

FPG+PPGFPG+PPG 1010 11.1 11.1 14.0 14.0 FPGFPG

Woerle et al., 2006.Woerle et al., 2006.

So How Can We Assess Post-So How Can We Assess Post-Prandial Glucose Control Prandial Glucose Control

Clinically ??Clinically ?? Frequent fingersticksFrequent fingersticks HbA1C HbA1C FructosamineFructosamine Continuous Glucose Continuous Glucose

Monitoring SystemsMonitoring Systems HistoricalHistorical Real-timeReal-time

1,5 Anhydroglucitol1,5 Anhydroglucitol

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 hyperglycemia

PostprandiPostprandial Index al Index (Multi-(Multi-variate-PI) variate-PI) N=19N=19

Avg. A1C Avg. A1C Avg. 1,5-Avg. 1,5-AG AG

Avg. Avg. A1C/Avg. A1C/Avg. 1,5-AG 1,5-AG RatioRatio

R=0.36R=0.36 R=0.58R=0.58 R=0.66R=0.66

*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 Approaches/Agents That Address Postprandial Address Postprandial

HyperglycemiaHyperglycemia MeglitinidesMeglitinides Alpha-Glucosidase InhibitorsAlpha-Glucosidase Inhibitors Prandial InsulinPrandial Insulin GLP-1 analoguesGLP-1 analogues DPP-IV inhibitorsDPP-IV inhibitors PramlintidePramlintide Glycemic Index/LoadGlycemic Index/Load

Importance of Post-Prandial Control in Importance of Post-Prandial Control in Managing Gestational DiabetesManaging Gestational Diabetes

de Veciana M et al NEJM Nov 1995

0

100

200

300

400

500

600

-1 0 1 2 3 4 5 6 7 8 9 10In

suli

n (

pm

ol/

L)

Time (hr)

0

50

100

150

200

250

300

-1 0 1 2 3 4 5 6 7 8 9 10

Glu

cose

(m

g/d

L)

Time (hr)

Nateglinide Monotherapy: Nateglinide Monotherapy: Effect on Plasma Glucose and InsulinEffect on Plasma Glucose and Insulin

Pretreatment Nateglinide

Hollander PA, et al. Diab Care 24:983-988, 2001.

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

Adding Prandial Insulin to Basal Adding Prandial Insulin to Basal Therapy Further Improves HbA1CTherapy Further Improves HbA1C

Inhaled Insulin is Superior to Metformin as Inhaled Insulin is Superior to Metformin as Add-on Therapy to Sulfonylureas !!Add-on Therapy to Sulfonylureas !!

Barnett AH et al. Diabetes Care 29:1282-1287, 2006


Fasting HyperglycemiaFasting Hyperglycemia

Fasting Plasma Glucose Fasting Plasma Glucose Reflects Endogenous Glucose Reflects Endogenous Glucose

ProductionProduction

Dinneen S, Gerich J, Rizza R. N Engl J Med. 1992;327:707-713

Why Fix Fasting First?Why Fix Fasting First?

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

SaferSaferSimplerSimpler

Effect of Glyburide or NPH Insulin Effect of Glyburide or NPH Insulin on Glycemia in Type 2 Diabeteson 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 Agents that Address Fasting HyperglycemiaHyperglycemia

Basal InsulinBasal Insulin MetforminMetformin SulfonylureasSulfonylureas TZDs??TZDs??

Pioglitazone Affects both FPG and Pioglitazone Affects both FPG and PPGPPG

Miyazaki Y et al .Diabetes Care 25:517-523, 2002

Insulin Glargine vs NPH Insulin Insulin Glargine vs NPH Insulin Added to Oral TherapyAdded to Oral Therapy

Patient DemographicsPatient Demographics 756 insulin-naïve patients with type 2 756 insulin-naïve patients with type 2

diabetesdiabetes Insulin glargine n=367Insulin glargine n=367 NPH n=389NPH n=389

Mean age 55 yrMean age 55 yr BMI 32 kg/mBMI 32 kg/m22

Duration of diabetes 8-9 yrDuration of diabetes 8-9 yr Baseline A1C 8.6%Baseline A1C 8.6%

Riddle MC et al and the Insulin Glargine 4002 Study Investigators. Riddle MC et al and the Insulin Glargine 4002 Study Investigators. DiabetesDiabetes Care Care 2003:26:3080-3086.2003:26:3080-3086.

Insulin Glargine vs NPH Insulin Added to Insulin Glargine vs NPH Insulin Added to OralsOrals

Riddle MC et al and the Insulin Glargine 4002 Study Investigators. Riddle MC et al and the Insulin Glargine 4002 Study Investigators. DiabetesDiabetes Care Care 2003:26:3080-30862003:26:3080-3086..

Insulin Glargine vs NPH Insulin Added to Oral Insulin Glargine vs NPH Insulin Added to Oral TherapyTherapy

ResultsResultsITT AnalysisITT Analysis Insulin GlargineInsulin Glargine NPH NPHFPG, mg/dLFPG, mg/dL 117 117 120120

mMmM 6.5 6.5 6.68 6.68 A1C, %A1C, % 6.96 6.96 6.97 6.97

Final A1C Final A1C 7% (% patients)7% (% patients) 57 57 57 57Nocturnal HypoglycemiaNocturnal Hypoglycemia

Patients,* %Patients,* % 40 40 49 49Events, Events, † no.† no. 532 532 886886

Severe HypoglycemiaSevere HypoglycemiaPatients, %Patients, % 2.5 2.5 2.32.3

**PP<0.01; <0.01; ††PP<0.002<0.002Riddle et al and the Insulin Glargine 4002 Study Investigators. Diabetes Care 2003:26:3080-Riddle et al and the Insulin Glargine 4002 Study Investigators. Diabetes Care 2003:26:3080-

3086.3086.

Exenatide vs Glargine in Type 2 Diabetes Exenatide vs Glargine in Type 2 Diabetes MellitusMellitus

551 patients, multi-site international 551 patients, multi-site international studystudy

Rx w/ Metformin and SU for 3 months Rx w/ Metformin and SU for 3 months prior to screeningprior to screening

HbA1C 7.0-10.0 % ; BMI 25-45HbA1C 7.0-10.0 % ; BMI 25-45 Randomly assigned exenatide or glargineRandomly assigned exenatide or glargine

Exenatide 10 mcg BIDExenatide 10 mcg BID Glargine titrated to FBS< 100mg/dl 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% Results: HbA1C reduced by 1.16 and 1.14% respectively respectively (Mean final HbA1C ~ 7%)(Mean final HbA1C ~ 7%)

Exenatide vs Glargine in Type 2 Exenatide vs Glargine in Type 2 Diabetes MellitusDiabetes Mellitus

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

glu

cose

Time

http://www.annals.org/content/vol143/issue8/images/large/6FF3.jpeg

Addressing Fasting vs Postprandial Addressing Fasting vs Postprandial First ApproachFirst Approach

Overall Goals:Overall Goals:

HbAHbA1c1c <7 <7 FPG <100 mg/dl (5.5 mM)FPG <100 mg/dl (5.5 mM) PPPG (90 min) <140 mg/dl (7.8 PPPG (90 min) <140 mg/dl (7.8

mM)mM)


Fix Fasting First AlgorithmFix Fasting First Algorithm Step 1Step 1: If FPG >100 mg/dl (5.5 mM) :: If FPG >100 mg/dl (5.5 mM) :

a) drug naïve, start metformina) drug naïve, start metformin

b) if on SU, add metforminb) if on SU, add metformin

c) if on SU+Met, DC SU, add HS NPHc) if on SU+Met, DC SU, add HS NPH

Step 2Step 2: When FPG near goal, but PPPG : When FPG near goal, but PPPG >140 mg/dl (7.8 mM) :>140 mg/dl (7.8 mM) :

a) add repaglinide with mealsa) add repaglinide with meals

b) if above unsuccessful in achieving b) if above unsuccessful in achieving PPG goal, DC and use regular PPG goal, DC and use regular insulin with meals.insulin with meals.


Demographic CharacteristicsDemographic Characteristics

Age (years) 62.4 ± 0.9

Gender 90 men/74 women

BMI (kg/m2) 28.8 ± 0.6

Diabetes durationHbA1c (%)

8.4 ± 0.6 y8.7 ± 0.1


Effects of Intensified Treatment Regimens Effects of Intensified Treatment Regimens (N=164)(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

Weight (Kg) 84.0 ± 1.4 82.9 ± 1.5 P=0.36


Cases of Hypoglycemic Episodes before Cases of Hypoglycemic Episodes before and after Intensification of Treatment and after Intensification of Treatment

(N=164)(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


Diurnal Plasma Glucose Profiles Before and After Diurnal Plasma Glucose Profiles Before and After Intensified Therapy Intervention in Subjects Who Did and Intensified Therapy Intervention in Subjects Who Did and

Did Not Achieve HbA1C < 7.0%Did Not Achieve HbA1C < 7.0%

6 12 18 24

100

160

220

(mg

/dL

)

= HbA1c > 7%= HbA1c < 7%

Mean ± SEM(N = 164)

Time (Hours)

200

180

140

120

22201614108

%

Woerle HJ et al Diabetes Res Clin Pract. 2007 Jan 19

Contribution of Postprandial BG to Contribution of Postprandial BG to HbA1CHbA1C

0

20

40

60

80

100

4.7-6.2 6.2-6.8 6.8-7.3 7.3-7.8 7.8-8.9 8.9-15.0HbA1c sixtiles(%)

Con

trib

utio

n (%

)

*=p<0.05vs HbA1c <6.2 %

*

*

*

**

Woerle HJ et al Diabetes Res Clin Pract. 2007 Jan 19

Simpler and SaferSimpler and Safer

Lowering PPG first will require Lowering PPG first will require subsequent readjustments in PPG Rx subsequent readjustments in PPG Rx when FPG is treated. Failure to do so when FPG is treated. Failure to do so may result in hypoglycemia.may result in hypoglycemia.

-0.2

-0.1

-0.6

-1.0

-1.2

-1.4

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

A1

C R

ed

uc

tio

n, %

Change in A1C from baseline

Higher A1C Baseline Level Correlates With Larger Higher A1C Baseline Level Correlates With Larger A1C A1C

Reduction With Pharmacologic InterventionReduction With Pharmacologic InterventionBaseline A1C%Baseline A1C% 6.06.0––6.96.9 7.07.0––7.97.9 8.08.0––8.98.9 9.09.0––9.99.9 10.010.0––

11.811.8Number of patients Number of patients enrolled in clinical enrolled in clinical trialstrials

n=410n=410 n=1,620n=1,620 n=5,269n=5,269 n=1,228n=1,228 n=266n=266

Adapted from Bloomgarden ZT et al. Diabetes Care. 2006;29:2137-2139.

Road map to achieve glycaemic Road map to achieve glycaemic goalsgoals11

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

Target: FPG and PPG

Insulin therapy†

Target: PPG and FPG6−7

Target: PPG and FPG7−8

Target: FPG and PPG8−9

9−10

>10

Life

sty

le m

od

ificatio

n

Monotherapy or

combination therapy

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

Monotherapy or

combination therapy

6–6.5

>8.5

Naïve to therapy (type 2) Treated patients (type 2)Achieve ACE glycaemic goals* (FPG and PPG)

Initial A1c(%) Current Therapy

CurrentA1c(%)

6.5−8.5

Con

tinu

e life

sty

le m

od

ificatio

n

PPG

PPG

PPG

PPG

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 http://www.aace.com/pub/odimplementation/roadmap.pdf

Recommendations for Drug Recommendations for Drug Naïve PatientsNaïve Patients

HbAHbA1c1c <7.5% , target PPG <7.5% , target PPG

HbAHbA1c1c >7.5% , target FPG, then PPG >7.5% , target FPG, then PPG

(Fix the fasting first)(Fix the fasting first)

OR………OR………

If HbA1C > 7.5%, use double If HbA1C > 7.5%, use double therapy that addresses BOTH therapy that addresses BOTH fasting and postprandial fasting and postprandial hyperglycemia !!hyperglycemia !!

ConclusionsConclusions Hyperglycemia as reflected by HbAHyperglycemia as reflected by HbA1c1c is a continuous risk is a continuous risk

factor for micro- and macrovascular complications. factor for micro- and macrovascular complications.

HbAHbA1c1c includes both fasting and postprandial glycemia. includes both fasting and postprandial glycemia.

To minimize glycemic exposure both FPG and PPG need To minimize glycemic exposure both FPG and PPG need to be addressed, especially if HbA1C > 7.5% .to be addressed, especially if HbA1C > 7.5% .

If HbA1C < 7.5%, initial therapy should address If HbA1C < 7.5%, initial therapy should address postprandial glucose, preferentially.postprandial glucose, preferentially.

In order to achieve normoglycemia, postprandial In order to achieve normoglycemia, postprandial glucose must be addressedglucose must be addressed

ReflectionsReflections

Normalization of HbA1C can not be Normalization of HbA1C can not be considered the equivalent of considered the equivalent of normoglycemia in view of our ability normoglycemia in view of our ability to measure other markers, elevated to measure other markers, elevated post-challenge glucose , the post-challenge glucose , the availability of continuous glucose availability of continuous glucose monitoring and increased CVD in the monitoring and increased CVD in the normal range of HbA1C.normal range of HbA1C.

Questions ??Questions ??

Glycemic Excursions Predict Glycemic Excursions Predict Oxidative StressOxidative Stress

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

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

Muggeo M et al. Diabetes Care. 2000;23:45-50.

Variability of FPG and cardiovascular mortality10-year survival

Variability in Blood Glucose Is anIndependent Risk Factor for Mortality

Group 1 (8.5%)

Group 2 (14.8%)

Group 3 (27.7%)

1.0

0.7

0.6

0.5

0

0 2 4 6 8 10Time (years)

0.8

0.9

Survival probability

Mean CV of FPG*

Lack of Effect of Glucose Lack of Effect of Glucose Variability on Microvascular Variability on Microvascular

ComplicationsComplications Assessment of DCCT data Assessment of DCCT data

using seven-point glucose using seven-point glucose profiles profiles

Performed quarterlyPerformed quarterly No preferential influence of No preferential influence of

the following on probability the following on probability of retinopathy:of retinopathy: BG variability (nor BG variability (nor

Nephropathy)Nephropathy) FPGFPG pc BGpc 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 is indicative of differing postmeal glucose levels in moderately controlled patients – despite similar A1C levels!

(1,5-AG) (1,5-AG) Range 0-6Range 0-6N=17N=17

A1C A1C (%) (%)

MeanMean

1,5-AG 1,5-AG (ug/ml) (ug/ml) MeanMean

Total AUC-180 Total AUC-180 Glucose Glucose 11

PostMeal PostMeal Glucose-Max Glucose-Max Mean (mg/dl)Mean (mg/dl)

BreakfastBreakfastN=9N=9


LunchLunchN=10N=10


Dinner Dinner N=9N=9

Higher Higher Postprandial Postprandial VariablesVariables

7.367.36 4.554.55 16.2916.29 259259 224224 198198

(1,5-AG) (1,5-AG) Range 6-18Range 6-18N=16N=16

A1C A1C (%) (%)

MeanMean

1,5-AG 1,5-AG (ug/ml) (ug/ml) MeanMean

Total AUC-180 Total AUC-180 GlucoseGlucose11


Breakfast Breakfast N=11N=11


LunchLunch N=13N=13


Dinner Dinner N=13N=13

Lower Lower Postprandial Postprandial VariablesVariables

7.127.12 9.299.29 10.7510.75 228228 196196 162162

Dungan K et al Diabetes Care; June 2006

Demographic Characteristics and Treatment Regimens Demographic Characteristics and Treatment Regimens Before and After Three MonthsBefore 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 ± 0.68.7 ± 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)


Glycemic Targets in Clinical Practice: Postprandial vs Preprandial and Fasting? Steven D Wittlin MD...

Documents

Transcript of Glycemic Targets in Clinical Practice: Postprandial vs Preprandial and Fasting? Steven D Wittlin MD...