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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.

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slide1

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

slide2

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

slide3
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
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. 2000;321:405-412.

what are appropriate goals
What are appropriate goals?
  • HbA1c
  • FPG
  • 2 hr PPG
  • Normalization of Glycemia
slide6

What is Normal?

HbA1c <6.0%

FPG <100 mg/dl (5.5 mM)

1 hr PPG <162 mg/dl (9.0 mM)

2 hr PPG <126 mg/dl (7.0 mM)

(N=15)

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

slide7
Hyperglycemia is a continuous risk factor for CVD... Therefore normality should be the goal if it can be safely achieved
slide8
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

slide9
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 ???

slide11

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. 2000;30(suppl 2):3-11.

slide12

r=0.97

Correlation between plasma glucose levels after OGTT and standard mixed meal

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

slide13

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

slide14

Relationship between HbA1C, FPG and 2 h. PPG

Van Haeften T et al Metabolism 2000

relative changes in fpg and 2 h pg as hba 1c increases
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. 2004;164:1627-1632.

in individuals with hba1c 6 5 postload dysglycemia predominates
In Individuals with HbA1C <6.5%, Postload Dysglycemia Predominates

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

slide17

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
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
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 (p=0.88)

198 226 (p=0.03)

6.26 6.73

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

HbA1C Group (%)

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

slide21

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

7.8–11.0

2-hour plasma glucose(mmol/l)

<7.8

<6.1 6.1–6.9 ³7.0

Fasting plasma glucose (mmol/l)

Adjusted for age, center, sex

DECODE Study Group. Lancet 1999;354:617–621

slide24

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 hba 1c fpg and ppg in treated t2dm patients
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 FPG+PPG

9 9.9 12.6 FPG+PPG

10 11.1 14.0 FPG

Woerle et al., 2006.

slide26

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

  • Frequent fingersticks
  • HbA1C
  • Fructosamine
  • Continuous Glucose Monitoring Systems
    • Historical
    • Real-time
  • 1,5 Anhydroglucitol
slide27

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

*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
Approaches/Agents That Address Postprandial Hyperglycemia
  • Meglitinides
  • Alpha-Glucosidase Inhibitors
  • Prandial Insulin
  • GLP-1 analogues
  • DPP-IV inhibitors
  • Pramlintide
  • Glycemic Index/Load
slide29

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 Monotherapy: Effect on Plasma Glucose and Insulin

Pretreatment Nateglinide

Glucose (mg/dL)

Insulin (pmol/L)

Time (hr)

Time (hr)

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

adding prandial insulin to basal therapy further improves hba1c
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 add on therapy to sulfonylureas
Inhaled Insulin is Superior to Metformin as Add-on Therapy to Sulfonylureas !!

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

fasting plasma glucose reflects endogenous glucose production
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
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
Effect of Glyburide or NPH Insulin on Glycemia in Type 2 Diabetes

Time of day

From: Shapiro ET et al. J Clin Endocrinol Metab69 (1989), pp. 571–576

Cusi K et al Diabetes Care18 (1995), pp. 843–851

agents that address fasting hyperglycemia
Agents that Address Fasting Hyperglycemia
  • Basal Insulin
  • Metformin
  • Sulfonylureas
  • TZDs??
pioglitazone affects both fpg and ppg
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 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. DiabetesCare 2003:26:3080-3086.

insulin glargine vs nph insulin added to orals
Insulin Glargine vs NPH Insulin Added to Orals

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

insulin glargine vs nph insulin added to oral therapy1
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

*P<0.01; †P<0.002

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

exenatide vs glargine in type 2 diabetes mellitus
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

slide44

Exenatide vs Glargine in Type 2 Diabetes Mellitus

glucose

Time

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

addressing fasting vs postprandial first approach
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
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
Demographic Characteristics

Woerle HJ et al in press

cases of hypoglycemic episodes before and after intensification of treatment n 164
Cases of Hypoglycemic Episodes before and after Intensification of Treatment (N=164)

Woerle HJ et al in press

slide50
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

180

160

(mg/dL)

140

120

Mean ± SEM

(N = 164)

100

6

8

10

12

14

16

18

20

22

24

Time (Hours)

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

contribution of postprandial bg to hba1c
Contribution of Postprandial BG to HbA1C

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

simpler and safer
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.

slide53

Higher A1C Baseline Level Correlates With Larger A1C Reduction With Pharmacologic Intervention

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

road map to achieve glycaemic goals 1

Naïve to therapy (type 2)

Treated patients (type 2)

Achieve ACE glycaemic goals* (FPG and PPG)

Pre-mixed insulin analogs

CurrentA1c(%)

Initial A1c(%)

PPG

PPG

Current Therapy

6−7

6–6.5

Monotherapy or combination therapy

Target: PPG and FPG

7−8

Target: PPG and FPG

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

6.5−8.5

PPG

PPG

Continue lifestyle modification

Lifestyle modification

Target: FPG and PPG

8−9

Monotherapy or combination therapy

9−10

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

Target: FPG and PPG

Pre-mixed insulin analogs,Rapid-acting insulin analogs

>8.5

Insulin therapy†

>10

Road map to achieve glycaemic goals1

*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 na ve patients
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

Conclusions
reflections
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.
slide59

Glycemic Excursions Predict Oxidative Stress

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

slide60

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 (p<0.001)

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

lack of effect of glucose variability on microvascular complications
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

slide62

1,5 AG as Adjunct to A1C to Reflect PostprandialHyperglycemia

  • 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
Demographic Characteristics and Treatment Regimens Before and After Three Months

Woerle HJ et al in press

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