Glycemic Targets in Clinical Practice:  Postprandial vs Preprandial
Download
1 / 63

Glycemic Targets in Clinical Practice: Postprandial vs ... - PowerPoint PPT Presentation


  • 257 Views
  • Uploaded on

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.

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about 'Glycemic Targets in Clinical Practice: Postprandial vs ...' - Mia_John


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript

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
UKPDS Epidemiologic Data in Type 2 Diabetes preprandial or fasting glycemia, but No 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? preprandial or fasting glycemia, but

  • HbA1c

  • FPG

  • 2 hr PPG

  • Normalization of Glycemia


What is Normal? preprandial or fasting glycemia, but

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


Hyperglycemia is a continuous risk factor for CVD... preprandial or fasting glycemia, but Therefore normality should be the goal if it can be safely achieved


CDA: HbA1C<7% “ preprandial or fasting glycemia, but 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 HbA preprandial or fasting glycemia, but 1c, 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
Postprandial Hyperglycemia preprandial or fasting glycemia, but


Patients With Type 2 Diabetes May Spend More Than preprandial or fasting glycemia, but 12 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.


r=0.97 preprandial or fasting glycemia, but

Correlation between plasma glucose levels after OGTT and standard mixed meal

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


Changes in Postprandial Glucose Metabolism in Type 2 DM preprandial or fasting glycemia, but

  • 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 preprandial or fasting glycemia, but

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 preprandial or fasting glycemia, but 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.


As Patients Get Closer to A1C Goal, Predominatesthe 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 Predominates

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


Ppg but not fpg distinguishes patients with hba1c between 6 0 7 0

Characteristics Predominates

# 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.


Therefore, the initial HbA Predominates1c can be a guide.


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


Effect of Acarbose on CVD in Patients with IGT ( STOP-NIDDM) irrespective of the FPG level

( Chiasson J - L et al JAMA July 2003 )


Controlling Postprandial Glucose irrespective of the FPG level

  • 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 HbA irrespective of the FPG level1c, 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.


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 Clinically ??

*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 Clinically ??

  • 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 Monotherapy: DiabetesEffect 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 hyperglycemia
Fasting Hyperglycemia to Sulfonylureas !!


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? Production

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 Diabetes

  • Basal Insulin

  • Metformin

  • Sulfonylureas

  • TZDs??


Pioglitazone affects both fpg and ppg
Pioglitazone Affects both FPG and PPG Diabetes

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 Diabetes

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 Diabetes

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 Diabetes

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 Diabetes

  • 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


Exenatide vs Glargine in Type 2 Diabetes Mellitus Diabetes

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 Diabetes

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 Diabetes

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 Diabetes

Woerle HJ et al in press


Effects of intensified treatment regimens n 164
Effects of Intensified Treatment Regimens (N=164) Diabetes

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


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 Therapy Intervention in Subjects Who Did and Did Not Achieve HbA1C < 7.0%

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


Simpler and safer
Simpler and Safer Therapy Intervention in Subjects Who Did and Did Not Achieve HbA1C < 7.0%

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 Therapy Intervention in Subjects Who Did and Did Not Achieve HbA1C < 7.0%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) Therapy Intervention in Subjects Who Did and Did Not Achieve HbA1C < 7.0%

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 Therapy Intervention in Subjects Who Did and Did Not Achieve HbA1C < 7.0%

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 HbA Therapy Intervention in Subjects Who Did and Did Not Achieve HbA1C < 7.0%1c 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 Therapy Intervention in Subjects Who Did and Did Not Achieve HbA1C < 7.0%

  • 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 ?? Therapy Intervention in Subjects Who Did and Did Not Achieve HbA1C < 7.0%


Glycemic Excursions Predict Oxidative Stress Therapy Intervention in Subjects Who Did and Did Not Achieve HbA1C < 7.0%

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


Variability in Blood Glucose Is an Therapy Intervention in Subjects Who Did and Did Not Achieve HbA1C < 7.0%

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


1,5 AG as Adjunct to A1C to Reflect Postprandial ComplicationsHyperglycemia

  • 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


ad