Ueda2015 barriers consensus dr.megahed abuel-magd

Identifying Barriers

to Glucose Control

BY

MEGAHED ABUELMAGD

MANSOURA University

EGYPT

Globalization of Fast Food

American Diabetes

Association

‘Therefore, the results of the UKPDS mandate

that treatment of type 2 diabetes include

aggressive efforts to lower blood glucose levels

as close to normal as possible’

1 American Diabetes Association. Diabetes Care 2004; 27:S15–S35. 2 American Diabetes Association. Diabetes Care 2002; 25:S35–S49.

3 American Association of Clinical Endocrinologists. Endocrine Pract 2002; 8 (Suppl. 1):40–82.4 European Diabetes Policy Group. Diabet Med 1999; 16: 716–730.

NA110–150Bedtime plasma

glucose

< 140< 180Postprandial

plasma glucose

< 11090–130Fasting/preprandial

plasma glucose

Biochemical index AACE3ADA1,2 IDF4

(Europe)

mg/dl mmol/l mg/dl mmol/l mg/dl mmol/l

< 6.05.0–7.2

< 10.0

< 6.5< 7HbA1c (%) < 6.5

< 110< 6.0

NA

NA

6.0–8.3

< 7.8 NA

NANA

ADA, AACE and IDF glycemic

goals

1 Koro CE, et al. Diabetes Care 2004; 27:17–20. 2 Liebl A. Diabetologia 2002; 45:S23–S28.

Majority of type 2 diabetes patients in US

and EU have inadequate glycemic controlP

erc

en

tag

e o

f su

bje

cts

0

20

40

60

80

100

< 7% 7%

HbA1c (%)

US1

36%

64%

Perc

en

tag

e o

f su

bje

cts

0

20

40

60

80

100

6.5% > 6.5%

HbA1c (%)

EU2

31%

69%

What are the barriers to

achieving and sustaining

glycemic goals?

How can these be overcome?

What are the barriers to achieving

and sustaining glycemic goal?

1) Ineffective diet and exercise?

2) Poor compliance.

3) Complexity of pathophysiologic mechanisms of

Type 2 Diabetes.

4) Suboptimal health care system.

5) Ineffective pharmacological agents.

Barriers to goal

• Ineffective diet/exercise initiatives

• Lack of efficacy of pharmacological agents

• Conservative management

• Adverse events

• Poor compliance

• Underlying pathophysiology

• Sub-optimal healthcare systems

Barriers to goal




• Adverse events

• Poor compliance



Lack of active drugs?• Sulfonylureas

– 1st generation

– 2nd generation

– 3rd generation

– Modified release

• Glinides

– Non-sulfonylureic

– Aminoacid derivatives

• Biguanides

– Metformin

• Thiazolidinediones

– Rosiglitazone

– Pioglitazone

• Fixed-dose OHA

combinations

• -glucosidase inhibitors

– acarbose

• Insulin

– Regular

– Long-acting

– Pre-mixed

– Analogs

• Rapid acting

• Long-actin

– Inhaled

• Rapid acting

• Long-actin

• GLP-1

– Analogs

– DPP-IV inhibitors

Barriers to goal




• Adverse events

• Poor compliance



Conservative management of diabetes?

• It is a considerable barrier to good glycemic

control .

• Unacceptable delays in treatment.

• Maximal monotherapy dose may not an optimal

dose.

• Proactive management of glycemia : early

combination approach.

• Traditional stepwise approach is not a

conservative treatment.

Stepped management of type 2

diabetes

7

6

9

8

Hb

A1

c(%

)

10

OAD monotherapy

DietOAD

combinationOAD

+ basal insulin

Conservative management of glycemia:

traditional stepwise approach

OAD monotherapy

uptitration

Duration of diabetes

OAD + multiple dailyinsulin injections

*May include uptitration. Length of time between first HbA1c > 8% and switch/addition in therapy could include periods where patients had subsequent HbA1c test

values below 8%. Based on nonrandomized retrospective database analysis. Data from Kaiser Permanente Northwest 1994–2002. Patients had to be

continuously enrolled for 12 months with HbA1c lab values

Unacceptable delays in

treatment

0

5

10

15

20

25

Metformin only Sulfonylurea only

Month

s

n = 354 n = 2517

14 months

20 months

Length of time between first monotherapy

HbA1c > 8.0%* and switch/addition in therapy*

Adapted from Brown & Nichols. Diabetes 2003; 52 (Suppl 1):A61

These are consideration in pharmacologic

treatment of Type 2 diabetes.

• Maximum dose of one pharmacological agent.

• Effective HbA1c lowering capacity.

• Mechanisms of action of drugs.

• Impact on weight gain.

• Frequency of hypoglycemia.

Maximal monotherapy dose may

not be optimal dose

Adapted from Garber AJ et al. Am J Med 1997; 103:491–497

*

Fasting Plasma Glucose

*P = 0.054; **P<0.01; ***P<0.001 for estimated difference from placebo.

Diffe

ren

ce

fro

m P

lace

bo

(m

g/d

L)

-100

-80

-60

-40

-20

0

500 1000 1500 2000 2500

HbA1c

***

***

*****

-2.5

-2

-1.5

-1

-0.5

500 1000 1500 2000 2500

***

***

***

***

***

Metformin Dosage (mg)D

iffe

ren

ce

fro

m P

lace

bo

% 0

UKPDS 28. Early addition of metformin

in Su treated Type 2 diabetic patients*.

-10

-8

-6

-4

-2

0

2

4

6

8

10

Sulfonylurea SU+Metformin5

6

7

8

9

Sulfonylurea SU+Metformin

P<0.00001

P=0.006

UKPDS Group Diabetes Care 1985;21:87*N= 591; Follow-up= 3 yrs

Change in fasting plasma glucose

(mg/dl)HbA1c (%)

OAD + basal insulin

OAD + multiple daily

insulin injections

Diet

OAD monotherapy

OAD combinations

Proactive management of glycemia:

early combination approach

OADs uptitration

Duration of diabetes

7

6

9

8

Hb

A1

c(%

)

10

Considerations in Pharmacologic

Treatment of Type 2 Diabetes

• Efficacy (HbA1c lowering capacity)

• Mechanisms of action of drugs

• Impact on weight gain

• Complications/tolerability/contra-

indications

• Frequency of hypoglycemia

• Compliance/complexity of regimen

• Cost

These are another barriers for good

glycemic control.

• Reluctance to prescrible new agents.

• Poor compliance.

• Inadequate monitoring of glycemia.

• Complexity of managing hyperglycemia relative to

dyslipidemia and hypertention.

• All of the above.

Barriers to goal




• Adverse events

• Poor compliance



How to correct the barriers to good

glycemic goal.

• Ineffective diet / exercise initiatives.

How to correct?

• Lack of efficacy of pharmacological agents.

• How to correct conservative

treatment?

• How to correct adverse events of

drugs.

• How to improve poor compliance of

patient.

• How can we organize the

suboptimal health care systems.

Metformin dose-response

curve

2.0

1.5

1.0

0.5

00 500 1000 1500 2000 2500

10

20

30

0

Dose

Re

du

cti

on

vs

.

pla

ce

bo

, H

bA

1c

(%

)

GI d

istr

es

s,

pa

tie

nts

(%

)

Reluctance to prescribe new

agents

Nesto RW, et al. Circulation 2003; 108:2941–2948

Nesto RW, et al. Diabetes Care 2004 27:256–263

Ranking of barriers to achieving glycaemic

targets

(1=Most important / 3=Least important)

• Poor patient compliance

• Lack of long-term efficacy of

agents

• Side effects of higher doses

Most important

58%

28%

14%

n=98

Barriers to goal




• Adverse events

• Poor compliance



Percent of health professionals knowing

correct answers to questions about OHA

0

10

20

30

40

50

60

70

80

90

100

Percent

Total Nurses Pharmacists Doctors

Drug timing

Mechanism

Side effects

Browne DL et al; Diab Med 2000; 17:528

Barriers to goal




• Adverse events

• Poor compliance



Barriers to goal




• Adverse events

• Poor compliance



Barriers to goal




• Adverse events

• Poor compliance



Barriers to goal

• Intensify population programs

• Lack of efficacy of pharmacologic agents


• Adverse events

• Poor compliance



Barriers to goal


• Optimize their use, combine them


• Adverse events

• Poor compliance



Barriers to goal



• Adopt an uncompromising insistence on

“treating to target”

• Adverse events

• Poor compliance



Barriers to goal





• Blame yourself before blaming the patient

• Poor compliance



Barriers to goal






• Don’t prescribe, share therapeutic decision



Barriers to goal







• Don’t miss good chances


Barriers to goal







• Don’t miss good chances

• We are the specialists!

What are the barriers to insulin therapy?

• Fear of injection?

• Insulin therapy linked to poor prognosis.

• Insulin leads to weight gain.

• Hypoglycemia.

• Insulin is atherogenic.

• Insulin leads to improving insulin sensitivity.

Patient Barriers to Insulin Therapy

• Fear of injections

Reality: With new needles, injections are well tolerated

• Insulin therapy linked to poor prognosis

Reality: No actual link – poor prognosis because insulin is begun very late in disease progression

• Insulin leads to weight gain

Reality: Weight gain is modest and can be minimized by regulating caloric intake and increasing physical activity

Provider Barriers to Insulin Therapy

• Hypoglycemia

Reality: Rare in patients with type 2 and manageable in patients with type 1 by diet and insulin adjustment

• Insulin is atherogenic

Reality: Data do not support this concern -poorly controlled patients have increased CVD

• Worsening insulin resistance

Reality: Insulin improves insulin sensitivity by reducing glucotoxicity

Health care system barrier to insulin

therapy

• Office can not easily be setup to manage patient

on insulin.

• No diabetes team in office.

• All of the above.

• None of the above.

Health Care System

Barriers to Insulin Therapy

• Offices can not easily be set up to

manage patients on insulin

Reality: Existing systems can easily be modified to manage these patients

• No diabetes team in office

Reality: “Team” can be community resources

Canadian and American

Diabetes Associations

‘Diabetes must be prevented sooner, and diagnosed earlier.

Canadian Diabetes Association, 2003.

American Diabetes Association. Diabetes Care 2003; 26:S28–S32.

And once diagnosed, all types of diabetes must then be managed

much more aggressively’

Barriers to Sulfonylurea

• Weight gain.

• Hypoglycemia.

• Exaggerated pancreatic β-cell failure.

• Possible cardiotoxicity.

• Barriers to Sus:

• 1-Weigt gain.

• 2-hypoglycemia.

• 3-Exaggrated Pancreatic B-cell failure.

• 4-possible cardiotoxicity.

Cardiomyocytes have KATP channels in two

sites:

a) In sacrolemmal membrane.

b) In mitochondrial membrane.

Sulfonylureas differ in their relative

affinities for sacrolemmal and mitochondrial

KATP channels.

Ischemic preconditioning demonstrates

the unique ability of a sub- lethal

period of ischemia to protect the heart

from a subsequent lethal ischemic

insult.

Glimepiride:

Glimepiride has powerful affinity

both the pancreatic SUR1/Kire 6.2 and

myocardial SUR2/Kir6.2 similar to that of

Gb (Song and Aschroft, Br. J pharmacol, 2001,

133-139).

However, the effects of this substance on

the myocardium in animals as compared with

Gb, seem to be far more modest. Several in

vitro and in vivo studies have failed to find

any effect of glimepiride on IPC.

IPC was modeled in the cardiac

catheterization by repeated inflation of an

angioplasty balloon.

In patients receiving a placebo infusion, the

magnitude of ST-depression decreased

progressively with subsequent balloon inflation

IPC.

Following a glimepiride infusion, patients had

similar, progressive decrease in st segment depression

with subsequent balloon inflations, suggesting no

adverse effect of glimepiride on IPC. In contrast,

patients pretreated with glyburide had no change in the

magnitude of st segment depression with subsequent

balloon inflations (Klepzig et al., 1999. Eur Heart H 20: 439-

446).

BARRIERS TO METFORMIN .

1- G ASTERINTESINAL UPSETS

2-INCREASED INCIDENCE OF LACTIC

ACIDOSIS

3-IT IS THE FIRST DRUG TO BE USED IN ALL

GUIDELINES

4-IN EVIDENCE BASED STUDIES METFORMIN

IS THE ONLY ANTIHYPERGLYCEMIC TO

SHOW IMPROVED MACROVASCULAR EVENTS

• METFORMIN IS COTRAINDICATED IN PATINTS

WITH:

ADAVANCED LIVER DISEASE

DIABETIC NEPHROPATHY WITH GFR LESS

THAN 50 ml/min

GESTIONAL DIABETES

NAFLD

HEART FAILURE

RESPIRATORY FAILURE

THANK YOU

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Ueda2015 barriers consensus dr.megahed abuel-magd