Ueda2015 fasting diabetics is it a real challenge-dr.lobna el-toony

Moving Beyond Glycaemia

Fasting Diabetics .... Is It A Real Challenge !?!

Prof. Lobna ElToony

Head of Internal Medicine & Diabetes

Assuit University

.االسالم دين اليسر.

.ن أي ومن كان مريضا أو على سفر ام فعدة م

بكم اليسر ر وال يريد بكم العس أخر يريد الل

Ramadan Between Diabetes

and Fasting

Although the Koran exempts

sick people from the duty of

fasting, many Muslims with

diabetes may not perceive

themselves as sick and are

keen to fast.

43% of patients with type 1

and 86% of those with type 2

diabetes fasted during

Ramadan. EPIDIAR* study

1-IBRAHIM SALTI, et al . Diabetes Care 27:2306–2311, 2004

2-E Hui et al , BMJ, 26 june 2010 , Volume 340

Frequently asked questions during Ramadan

Can a diabetic patient fast?

What about diet and exercise?

How to adjust drugs?

Can a patient monitor blood sugar while fasting?

Can a diabetic patient fastduring Ramadan?

The Risks of Fasting Include:

Hypoglycemia

Hyperglycemia

Diabetic ketoacidosis

Dehydration and thrombosis

M. al-Arouj et al, “Recommendations for management of diabetes during Ramadan,” Diabetes Care, 28(2005), 2305-2311.

Ramadan Fasting and Diabetes Mellitus

The bulk of literature indicates that fasting

in Ramadan is safe for the majority of

diabetic patients, but…

Patient needs-

1. Pre-Ramadan assessment

2. Proper education

3. Management

Pre-Ramadan Medical Assessment

Management of Diabetic Patients During Ramadan

Safer Fasting

High

Moderate

Low risk of adverse events

•Poor glycemic control, Severe and recurrent

episodes of hypoglycemia.

• Experience ketoacidosis three months

before Ramadan.

• Elderly and Pregnant women

• Advanced complications

• Well controlled patients treated with short

acting insulin secretogogue,

sulphonylurea, insulin, or taking

combination oral or oral plus insulin

• Well controlled patients treated with

Metformin, Dipeptidyl peptidase-4 inhibitors, or thiazolidinediones who are

otherwise healthy

Pre-Ramadan Medical

Assessment

E Hui et al , BMJ 2010;340:c3053; Al-Arouj M. et al, Recommendations for management of diabetes during Ramadan. Diabetes Care. 2010;33: 1895-1902.

Patients classed as

high risk are advised

not to fast

Before Ramadan they must

make necessary changes to

their diabetes treatment

Those at low risk can

fast without healthcare

advice.

Salti E, et al. Diabetes Care 27:2306–2311, 2004

T2DM fasting during Ramadan are exposed to !?!

5 folds Increase in sever hyperglycemia with Ketoacidosis that required hospital admission

7.5 Folds Increase in the risk of sever hypoglycemia during Ramadan

2% Of fasting patients experienced at least one episode of sever hypoglycemia requiring hospitalization

Salti E, et al. Diabetes Care 27:2306–2311, 2004

(4.7 fold)

(7.5 fold)

Potential Complications and Effects of

Severe Hypoglycemia

15

Plasma glucose level

10

20

30

40

50

60

70

80

90

100

110

1

2

3

4

5

6

mg/dL

mmol/L

1. Landstedt-Hallin L et al. J Intern Med. 1999;246:299–307.

2. Cryer PE. J Clin Invest. 2007;117:868–870.

Arrythmia1 Neuroglycopenia2

Abnormal prolonged

cardiac

repolarization — ↑

QTc and QT

dispersion

Sudden death

Cognitive impairment

Unusual behavior

Seizure

Coma

Brain death

Severe Hypoglycemia Causes QT

Prolongation

P=NS

P=0.0003

Landstedt-Hallin L et al. J Intern Med. 1999;246:299–307.

Euglycemic clamp(n=8)

Hypoglycemic clamp

2 weeks afterglibenclamide withdrawal

(n=13)

0

360

370

380

390

400

410

420

430

440

450

Me

an

QT

in

terv

al,

ms

Baseline (t=0)

End of clamp (t=150 min)

Significant QT prolongation

During hypoglycemic attacks

Summary of Hypoglycemia Results From

Major Clinical Trials: ACCORD,

ADVANCE, and VADT1–3

No benefit of intensive vs standard glycemic

control on macrovascular outcomes at the

end of the prospective study

Higher incidences of severe hypoglycemia in

the intensive therapy arms

Role of hypoglycemia in study outcomes is

uncertain

17

1. ACCORD Study Group. N Engl J Med. 2008;358:2545–2559.

2. Duckworth W et al. N Engl J Med. 2009;360:129–139.

3. ADVANCE Collaborative Group et al. N Engl J Med. 2008;358:2560–2572.

The Occurrence of Hypoglycemia Was

Associated With Negative Consequences

Decreased adherence1

Increased worry/fear of hypoglycemia2,3

Lower quality of life4

Lower health-related quality of life5

Decreased work productivity6

1. Álvarez Guisasola FA et al. Diab Obes Metab. 2008;10 (suppl 1):25–32.

2. Mohamed M. Curr Med Res Opin. 2008;24:507–514.

3. Leiter LA et al. Can J Diabetes. 2005;29:186–192.

4. Pettersson B et al. Diabetes Res Clin Pract. 2011;92:19-25.

5. Álvarez Guisasola F et al. Health Qual Life Outcomes 2010;8:86–93.

6. Brod M et al. Value Health. 2011;14:665–671.

18

Dehydration and Thrombosis

Limitation of fluid intake

Hot and humid

climates

Hard physical labor

Excessive perspiration.

Hyperglycemia•Osmotic

diuresis

&

•Volume and

electrolyte

depletion.

Adapted from : M. al-Arouj et al, “Recommendations for management of diabetes during Ramadan,” Diabetes Care, 28(2005), 2305-2311.

Dehydration and Thrombosis

• Patients with diabetes exhibit a hypercoagulable state

due to an increase in clotting factors, a decrease in

endogenous anticoagulants, and impaired fibrinolysis.

• Increased blood viscosity secondary to dehydration may

enhance the risk of thrombosis.

• A report from Saudi Arabia suggested an increased

incidence of retinal vein occlusion in patients who fasted

during Ramadan

M. al-Arouj et al, “Recommendations for management of diabetes during Ramadan,” Diabetes Care, 28(2005), 2305-2311.

DIABETES CARE, VOLUME 33, NUMBER 8, AUGUST 2010

Management of Diabetic Patients

During Ramadan

Patients Education

T2DM Pharmaceutical Management in

Ramadan

Four key areas in Ramadan

focused education

1-Meal planning and dietary advice

2-Exercise

3-Blood glucose monitoring

4-Recognizing and managing complications

E Hui et al , BMJ 2010;340:c3053;

Special precautions are recommended

to avoid hypoglycemic events

To take Suhur close to Suhur time

To change in the schedule, amount and composition of meals

To reduce physical activity during the day time. However

physical exercise can be performed about one hour after Iftar

To keep the same calorie during Ramadan as before

Management of diabetes during

Ramadan

1. All patients should understand that they will need to

break the fast if blood glucose is <3.3 mmol/L

(59.4mg/dL) or exceeds 16.7 mmol/L (300mg/dL).

They should be advised to break the fast if blood

glucose is <3.9mmol/L in the morning if the patient

is taking sulfonylurea or insulin

2. Nutrition: In terms of calori and composition diet

should remain same healthy and balanced as before

Ramadan.

3. Ingestion of large amount of foods rich in

carbohydrate , fried food and fats during ifter

should be avoided.

Nutrition

At IFTARI. ,a date or water is the first thing to be eaten .

A complex carbohydrate that delays in digestion and absorption is

good choice for sheuri and while food with more simple

carbohydrate may be taken during ifter.

Eat fibre rich foods including whole grain carbohydrates , fruits and

vegetables with skins.

.

Exercise

Avoid any physical activity that requires effort during the fasting hours

especially the last few hours before “Iftar” because that could lead

to hypoglycemia.

Praying 5 times a day and the

additional special night prayers

(Taraweeh , which can last anything

from 1-2 hours each night) is physical

activity. It is advised that you test

before and after prayers.

Benefits of Education & Counselingaccording to the READ study

REA

D

Adjustment of Drugs

Before Ramadan During Ramadan

Patients on “diet and exercise” - No change is needed - Modify time & intensity of exercise- Ensure adequate fluid intake

Treatment Recommendations


Sulfonylurea Once Daily: Morning dose.e.g., Gliclazide MR

Glimepiride

Iftar: Full Morning Dose

Sulfonylurea Twice Daily: Morning & Evening dose.e.g., Gliclazide

Glibenclamide

Iftar: Full Morning DoseSuhur: ½ Evening Dose


Majority of our type 2 diabetic patients are treated

with Sulfonylurea & Metformin


Metformin 500 mg thrice daily Iftar: 1,000 mg,Suhur: 500 mg



DPP4 inhibitor As usual at night

Glitazone As usual at night

Glinide As usual at night



Premixed insulin 30 Morning: (30 U)Dinner: (20 U)

Iftar: Full Morning Dose (30 U)Suhur: ½ Dinner Dose (10 U)

Basal Analogue At the same time 20-30% dose reduction

Split Mixed (R+N)R+0+RN+0+N

R+0+50%of RN+0+50%of N

R+R+R0+0+N

R+R+50% of R0+0+50% of N


Oral hypoglycemic agents

Short actinginsulin SUs

Take twice daily at suhur and iftar

TZDsNo treatment adjustment required 2–4 weeks to exert substantial antihyperglycemic effects

DPP4 inhibitorsThe best tolerated drugs,

Consider DPP4i as an alternative to SUs if the risk of

hypoglycemia is high

SUsUnsuitable for use during fasting because of the

inherent risk ofHypoglycemia, use with caution. Consider dose

adjustment.

MetforminModify timing of doses:

Two thirds of dose at iftar

• One third at suhur.

E Hui et al , BMJ, 26 june 2010 , Volume 340; Al-Arouj M. et al, Recommendations for management of diabetes during Ramadan. Diabetes Care. 2010;33: 1895-1902.

ADA Recomedndation for T2DM Pharmaceutical

Management in Ramadan

Recommended changes to treatment regimen in

patients with type 2 diabetes who fast during

Ramadan

(MONIRA AL-AROUJ, MD. RADHIA BOUGUERRA, MD. JOHN BUSE, MD, PHD. SHERIF HAFEZ, MD, FACP. MOHAMED HASSANEIN, FRCP. MAHMOUD ASHRAF IBRAHIM, MD.

FARAMARZ ISMAIL-BEIGI, MD, PHD. IMAD EL-KEBBI, MD. OUSSAMA KHATIB, MD, PHD. SUHAIL KISHAWI, MD. ABDULRAZZAQ AL-MADANI, MD. ALY A. MISHAL, MD, FACP.

MASOUD AL-MASKARI, MD, PHD. ABDALLA BEN NAKHI, MD. KHALED AL-RUBEAN, MD)

Recommendations for Management of Diabetes During Ramadan; Reviews / Commentaries / ADA Statements ADA WORK GROUP REPORT; DIABETES CARE, VOLUME 28, NUMBER

9: 2305-2311, SEPTEMBER 2005

DPP-4 Inhibitors:

Smart Mode of Action

DPP4 I Enhances Active Incretin Levels

Through Inhibition of DPP-41–4

By increasing and prolonging active incretin levels,

sitagliptin increases insulin release and decreases

glucagon levels in the circulation in a glucose-

dependent manner.

Release of

active incretins

GLP-1 and GIPa

Blood glucose

in fasting and

postprandial

states

Ingesti

on of

food

Glucagon

from alpha

cells

(GLP-1)

Hepatic

glucose

production

GI

tract

DPP-4

enzym

e

Inactive

GLP-1

XVildagliptin

(DPP-4

inhibitor)

Insulin from

beta cells

(GLP-1 and GIP)

Glucose-

dependent

Glucose-

dependent

Pancreas

Inactive

GIP

Beta cells

Alpha cells

Peripheral

glucose

uptake

DPP-4=dipeptidyl peptidase 4; GI=gastrointestinal; GIP=glucose-dependent insulinotropic peptide; GLP-1=glucagon-like peptide-1.aIncretin hormones GLP-1 and GIP are released by the intestine throughout the day, and their levels increase in response to a meal. 1. Kieffer TJ et al. Endocr Rev. 1999;20(6):876–913. 2. Ahrén B. Curr Diab Rep. 2003;3(5):365–372. 3. Drucker DJ. Diabetes Care. 2003;26(10):2929–2940, 4. Holst JJ. Diabetes Metab Res Rev. 2002;18(6):430–441.

The goal remains......but

The

is

glycaemic

control

“how?” and “whether we reach or not” is the question?

The challenge of blood glucose control in

diabetes mellitus

Hypoglycaemia/

weight gain

HbA1c

Jacob AN, et al. Diabetes Obes Metab 2007;9:386–93;

Kahn SE, et al. N Engl J Med 2006;355:2427–43;

Wright AD, et al. J Diabetes Complications 2006;20:395–401

Moving beyond glycaemia

Challenges to reach target HbA1c goals

Targeting beyond glycaemia: challenges

Sustainability

Hypoglycaemia

Confused

Shaking

Sweating

Feels hungry

Feels weak

Adherence to therapy

Helping

patients stick

to their

therapy!

Weight gain/obesity

Diabesity: The new epidemic

Vildagliptin in Ramanda

Does it add any benefits over Sulphonylurea !?!

A multinational non-interventional study to assess the effects of

vildagliptin relative to sulphonylurea as dual therapy with metformin

(or as monotherapy*) in Muslim patients with type 2 diabetes fasting

during Ramadan

*in countries with approved monotherapy

Al-Arouj M, et al. Int J Clin Pract. 2013 Oct;67(10):957-63. Epub 2013 Sep 3

The VIRTUE study

VildagliptIn expeRience compared wiTh sulfonylUreas

obsErved during Ramadan

Egypt

Bangladesh

Pakistan

Oman

Lebanon

Saudi

Arabia

Indonesia

India

Kuwait

T2DM = Type 2 diabetes mellitus


†single pill combination allowed when available

*if applicable, as per local approved prescribing information

SU=sulphonylurea

vildagliptin plus metformin† or vildagliptin monotherapy*

SU plus metformin† or SU monotherapy*

End of fasting

period

Start of fasting

period6 weeks before

fasting

6 weeks after

fasting

Data collection

opportunity 1

-6 weeks to day prior

to start of fasting

Data collection

opportunity 2

End of study Fasting period

approx. 4 weeks

Observational period of approximately 16 weeks

Two patient cohorts:

Patients on

stable diabetes

treatment (1:1)


0

20

40

60

80

100

120

140

Pa

tie

nts

(n

) w

ith

≥1

hyp

og

lyc

ae

mic

eve

nt

Vildagliptin (n=669†) SU (n=621†)

~3.5

-fold

P<0.001‡

†Number of patients with a post baseline assessment of hypoglycaemic events. Hypoglycaemia defined as grade 1 (mild): reported symptoms by the patient

and/or blood glucose measurement of <3.9 mmol/L (70 mg/dL) or grade 2 (severe): need for third party assistance ‡Fisher’s exact test

Patients with ≥1 hypoglycaemic event Patients with grade 2

hypoglycaemic events

SU = sulphonylurea

123

(19.8%)

36

(5.4%)

Pa

tie

nts

(n

) w

ith

gra

de

2

hyp

og

lyc

ae

mic

eve

nt

0

20

40

4

P=0.053‡

0


†The within and between treatment differences were based only on patients with HbA1c levels

assessed at both baseline and end of study. ‡Two-sample t test

–1

Me

an

ch

an

ge

in

Hb

A1c

fro

m b

as

eli

ne

(%

)

SUs (n=417†)Vildagliptin (n=485†) Between-treatment

difference

–0.24

0.02

–0.26

P<0.001‡

Mean change in HbA1c (%) pre- to post-Ramadan

SU = sulphonylurea; HbA1c = haemoglobin A1c

–0.5

0

0.5


M. Hassanein, et al. Curr Med Res Opin 2011; 27:1367–74

Metformin 2000 + Gliclazide 80 mg* per daily n 36

Ramadan

Metformin 2000 + Vildagliptin 50 mg bid daily n23

• Observational, two-cohort study, Conducted in the UK.

• Primary objectives: The incidence of hypoglycemic events.

• Secondary objectives: The change in HbA1c levels; The

change in weight; and The treatment adherence during

Ramadan.

• The average duration of fasting in this study was 16 hours

6 weeks post Ramadan 6weeks pre Ramadan

*Different formulations were used for gliclazide therefore the following conversion factor was used:

80 mg standard formulation 30 mg modified release formulation.


0

34

Number of Hypoglycemic Events

Vildagliptin

SU

0

1

Number of Severe Hypoglycemic Events

Vildagliptin

SU

N=23 N=36


Me

an

ch

an

ge

in

Hb

A1

c

pre

-to

po

st-

Ram

ada

n

–0.5; P=0.0262

–0.4 (NS)

0.2

0.0

–0.2

–0.4

–0.6

0.1 (NS)

Vildagliptin

(n=20)

SU‡

(n=32)

Between-group

difference

HbA1c reduction for vildagliptin vs. gliclazide pre- to post Ramadan;

between-group difference −0.5% (P=0.0262)

Prospective observational study of up to 16 weeks duration in 72 fasting Muslim patients with T2DM observed in UK clinical practice, receiving vildagliptin or

SU as an add-on treatment to metformin; per protocol set with pre- and post Ramadan HbA1c assessments, HbA1c; safety set, AEs and SAEs. ‡ SU = Sulfonylurea (gliclazide); VECTOR= Vildagliptin Experience Compared To gliclazide Observed during Ramadan; AE = adverse event; SAE = severe

adverse event; NS = non-significant difference pre- to post Ramadan

Hassanein M et al. Curr Med Res Opin 2011;27:1367–74

• Mean number of missed doses was lower with vildagliptin (mean between-group difference –7.4;

P=0.0204)

• Body weight remained unchanged in both groups

1

Patient with

vildagliptin

10

Patient with

SU

Significant difference in treatment adherence

during Ramadan between the 2 groups

(Number of patients missed at least one dose)

Vs


Safety of Vildagliptin is Well Established

• In meta – analysis of 38 clinical trials include more than 14.000 patients vildagliptin shows no increased risk of:

• Pancreatitis-related AEs

• ALT / AST or Bilirubin elevation

• Renal AEs and SAEs in patients with normal renal function and mild renal impairment patients

• Infection and skin related adverse events

vs. comparators (placebo, insulin and other OAD)

Ligueros-Saylan et al. DIABETES, OBESITY AND METABOLISM Volume 12 No. 6 June 2010

Today's Conclusion:

Regardless The Stage of Diabetes, or Medical

Condition, Vildagliptin Is Favorite Option For Better

Glycemic Control

Last but not least...

ADA considers DPP4 inhibitors as the best tolerated drugs in Ramadan

Vildagliptin is well studied in Muslim

patients during Ramadan supported

by huge evidence for its efficacy and

safety making it a very good option

during fasting

Knowing is not enough

We must APPLY!

Willing is not enough

We must DO!

Safe Fast

LOBNA

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Ueda2015 fasting diabetics is it a real challenge-dr.lobna el-toony