Eman Rushdy

1
Fasting diabetic patient
By Eman Rushdy
2
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• O you who believe! Fasting has been prescribed
  to you as it was prescribed to those before you
  so that you attain Taqwa

3

• Fasting is not meant to create excessive hardship
  on the Muslim individuals. The Quran specifically
  exempts the sick from the duty of fasting.
• The Prophet Mohammad said, God likes his
  permission to be fulfilled, as he likes his will
  to be executed.

4
Things Happened During Ramadan

• During Ramadan, Muslims must fast from dawn to
  sunset.
• This will involve a sudden change in the daily
  meals.
• Two meals named Iftar and Sahur.
• Ramadan is a lunar-based month. Its timing
  changes with respect to seasons.
• Depending on the geographical location and
  season, the duration of the daily fast may range
  from a few to more than 20 h.

5
Uniqueness of Ramadan Fasting

• It is a voluntary undertaking rather than being
  ordered by a physician
• There is no selective food intake i.e. protein
  only, juice only, fruit only , water only etc
• There is no total calorie malnutrition
• An exercise in self discipline i.e. from constant
  nibbling , drinking, smoking etc

6
Physiological Effects of Fasting

• On Calorie intake
• On fluid /water intake
• Effects on Digestive System
• - Kidneys
• - Endocrine glands
• - Lipid Metabolism
• - Respiratory system
• - Neurological System

7
Some Facts

• The most important metabolic fuels are glucose
  and fatty acids.
• In normal circumstances, glucose is the only fuel
  the brain uses.
• To ensure the continuous provision of glucose to
  the brain and other tissues, metabolic fuels are
  stored.
• Carbohydrates are stored as glycogen - the amount
  of available glycogen stored is not large - about
  75g in the liver and little amounts in the
  muscles. Liver glycogen can supply glucose for
  no longer than 16h.
• To provide glucose over longer periods, the body
  transforms non-carbohydrate compounds into
  glucose (Gluconeogenesis).

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Insulin and Glucagon Main determinants of
glucose metabolism
9
Insulin C-peptide
Glucagon
Proglucagon
Proinsulin
Both cell types release their hormones
simultaneously at a basal level.  This is
augmented in response to alterations in blood
glucose levels .
Blood glucoselt70mg/dl

Insulin C-peptide
---
Proinsulin
Glucagon
Proglucagon
---

Blood glucose gt90mg/dl
10
Paracrine Actions of Insulin and Glucagon
Glucagon Insulin
Insulin - glucagon
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glycogenesis
glycogenolysis
gluconeogenesis from aa
Protein synthesis
Glucagon
Insulin
lipogenesis
lipolysis
So, insulin favors anabolic reactions and
storing energy glucagon, catabolic reactions
and release of stored energy  
12
1- 6 hours blood glucose lt 60 mg/dl
2- Lowered blood glucose secretion of
glucagon -- insulin

3-Glycogenolysis maintain blood glucose for
12-16 hours
Alanin lactate glycerol
Fuel reserves are Triacylglycerols tissue
proteins
4- Then stimulates gluconeogenesis
5- Ketone bodies
FFA
13
So, Effects of Fasting on Carbohydrate Metabolism

• 1. Slight fall in serum glucose from 9 to 11 am,
  but not from 11 am to 6 pm.
• Serum Insulin
  Serum glucagon
  
  
  Growth
  hormone
  
  Catecholamine
• 2-Slight decrease blood glucose in the first week
  then normalization by day 20 rise in the last
  week

14
Fasting and Lipid Metabolism

• Decrease in Total Cholesterol ,LDL and
  Triglycerides in first few days then rise to pre
  fasting levels (quality and quantity of food
  consumed at Iftaar and Sahur)
• Increase in HDL-C

15
Endocrine functions in Fasting

• Fall in free T3 but rise in rT3
• Slight fall in total T4 (due to fall in TBG) but
  normal freeT4 and TSH
• Serum Testosterone, LH, FSH may be normal or
  slightly low with change of circadian pattern

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-- Sexual desire during fasting hours

• Altered circadian patterns of cortisol and
  testosterone, with sharper decreases of these
  hormones in the morning and later rises at night

17

• Decrease in appetite due to ketosis and increase
  in Beta-endorphins

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Decreased and delayed melatonin peak

• Decreased Nocturnal sleep
• Daytime alertness
• Psychomotor performance
  

19
Renal Function in Fasting

• Urinary volume
• Osmolality
• Shift of fluids intracellularly
• Slight increase in BUN (insignificant)
• Increase in Uric acid (less in Ramadan fasting
  than in prolonged fasting)

Dehydration
20
Other Effects of Fasting

• Weight loss of 1.7 - 3.8 Kg (obese lose more
  weight than non obese)
• Fewer suicide in Ramadan than in other months
  (reported in Jordan)

21
Benefits of fasting

• Muslims do not fast because of medical benefits
  but because they are ordered to.
• 1- Self -regulation and self-training
• 2- Concentration of all fluids within the tissues
  and plasma.
• 3-Lower of blood sugar
• 4-Lowering of LDL and elevation of HDL
• 5-Lowering of the systolic blood pressure.
• 6-Lowering of body weight
• 7-Psychological sense of inner peace and
  tranquility
• (Fasting Muslims realize that anger may take
  away the blessings of fasting) (stress elevate
  blood sugar via catecolamines)
• Ramadan fasting would be an ideal recommendation
  for treatment of mild to moderate stable NIDDM,
  obesity and essential hypertension. 

22
What will happen in diabetic patient ?????????
23
In patients with diabetes
Glucagon secretion
may fail to increase
Epinephrine secretion is also defective
due to a autonomic
neuropathy .
Hypoglycemia
Insulin replacement
Hyperglycemia Ketosis

• Excessive Glycogenolysis
  Gluconeogenesis
• Ketogenesis

Insulin replacement
24
EPIDIAR STUDY-T2DM 78.2 fasted gt15days
Salti et al Diabetes Care Vol 27 10 Oct 2
25
Risks associated with fasting in diabetic
patient???
26
Risks associated with fasting in patients with
diabetes

• Hypoglycemia Severe hypoglycemia
• Type 1 diabetes Type 2
  diabetes
• 3 to14 events/100 people/ m 0.4 to3
  events/100 people/ m.

• Finch GM et al, Appetite 312, 1998
• Ghaznawi H I. et al. "The Effect of Ramadan
  Fasting on Body Weight." Joumalfo the IMA, 1993
• Al-Hurani HM etal, Singapore Med J. 2007
  Oct48(10)906-10
• Faye J et al, Dakar Med. 200550(3)146-51

27

• Hyperglycemia severe hyperglycemia (requiring
  hospitalization)
• Type 1 diabetes
  Type 2 diabetes
• 3 fold increase
  5 fold increase
• Ketoacidosis
• due to excessive reduction in dosages
  of medications
• to prevent
  hypoglycemia

28

• Dehydration and thrombosis
• if prolonged fasting
• In hot and humid climates
• Among individuals who perform hard physical labor
  
• Hyperglycemia
• Might lead hypovolemia and orthostatic
  hypotension , however, hospitalizations due to
  coronary events or stroke were not increased

29
Taking the decision

• The decision to fast is usually taken by three
  people the patient , the physician and a
  religious advisor.

Ibrahim M. A. Managing diabetes during Ramadan
Diabetes Voice June 2007 Volume 52 Issue 2
30
Thank You
31
Insulin Glargine during Ramadan

• Eman Rushdy

32
Epidemiology of Diabetes and Ramadan 1422/2001
(EPIDIAR) study
12,243 people with diabetes from 13 Islamic
countries about 43 of patients with type
1 diabetes and 78 of patients with type 2
diabetes fast during Ramadan.
Diabetes Care2004 2723062311
33

• During Ramadan about 60 of patients change their
  antidiabetic drug intake.
• 35 stop treatment
• 8 change the dosage
• Importantly, this is done at the patients own
  initiative without medical supervision.

Salti I, Benard E, Detournay B et al. A
population-based study of diabetes and its
characteristics during the fasting month of
Ramadan in 13 countries. Diabetes Care 2004 27
230611. Aslam M, Healey MA. Compliance and drug
therapy in Moslem patients. J Clin Hosp Pharm
1986 11 3215. Aslam M, Assad A. Drug regimens
and fasting during Ramadan a survey in Kuwait.
Public Health 1986 100 4953.
34
Results in
35
Sequelae of hypoglycaemia

• Mild Adrenergic (BGlt70)
• No direct serious clinical effects
• With a rapid decline in blood glucose
  tachycardia, tachypnea, vomiting, and diaphoresis
  
• May impair subsequent hypoglycaemia awareness
• Severe Neuroglycopenic (BGlt50)
• Usually associated with slower or prolonged
  hypoglycemia,
• Stroke and transient ischaemic attacks
• Memory loss/cognitive impairment
• Myocardial infarction
• Convulsions
• Death

36
Recent Clinical Trial Findings

• Intensive glucose control in type 2 diabetes
• Was associated with increased mortality in
  patients with longstanding DM and known CVD
  (ACCORD)
• Increases risk of severe hypoglycemia (ADVANCE,
  ACCORD and VADT)

ACCORD N Engl J Med 2008 358(24)2545-59.
ADVANCE N Engl J Med 2008 358 (24)
2560-72.VADT J Diabetes Complications 2003 17
(6) 314-22
37
Hypoglycaemia and CV Disease
Desouza C et al Diabetes Care 26 1485-1489, 2003
38
Hypoglycaemia and CV Disease

• Haematologic Responses To Hypoglycaemia

Increased RBCs Leading To Increased Blood
Viscosity Enhanced Platelet Aggregation
Increased Platelet Factor 4 Increased
Thromboglobulin Increased Coagulation Factor
VIII Increased Von Willebrand Factor
Increased Thrombin Generation
Wright R et al Diabetes/ Metabolism Research and
Reviews , 2008
39
Hypoglycaemia and CV Disease

• Inflammatory Responses To Hypoglycaemia

CRP (mg/L)
Baseline 4 Hours 24
Hours
Diabetes 0.77
0.84 2.31
Control 0.32
ND 0.96
p lt 0.04 vs. Baseline
Galloway P et al Diabetes Care 23 861-862, 2000
40
Hypoglycaemia and CV Disease
Hemodynamic
Thrombotic
Hypoglycaemia
Ischaemia
Inflammatory
Wright R et al Diabetes/ Metabolism Research and
Reviews , 2008
41
Hypoglycemia Unawareness

Type 1 DM
DURATION
Autonomic neuropathy
Recurrent hypoglycemia
42
MIMICKING NATURE WITH INSULIN THERAPY

• All persons need
• both basal and mealtime insulin
• to control glucose

6-19
43

• The normal human pancreas has a basal insulin
  secretory rate of 1-2 U per hr, with post
  prandial rates increasing to 4-6 U / hr.
• in two phases (early Late phase).
• Insulin secreted into portal circulation where
  50 of it extracted by liver without reaching
  systemic circulation.
• Insulin catabolized by insulinase in Liver,
  Kidney, placenta.

44
Regulation of Basal insulin secretion
Pacemaker ß cells
Na
GLUT2
K
Signal
K
KIR
Na
K
Vm
K
Voltage-gated Ca2 channel
Ca2
Ca2
Ca2
Pancreatic ß cell
Mature insulin granules contracts by exposure to
high intracellular Ca.
Ca2
Ca2
Insulin granules
45
Post prandial insulin secretion
46
Physiologic Insulin Secretion Basal/Prandial
Concept
Nutritional (Prandial) Insulin
50
Insulin (µU/mL)
Basal Insulin Suppresses Glucose
Production Between Meals Overnight
25
0
Basal Insulin
Breakfast Lunch Supper
Nearly constant levels 40- 50 of daily needs
150
Nutritional Glucose
100
Glucose (mg/dL)
50
Prandial Insulin Limits hyperglycemia
after meals Immediate rise and sharp peak
10 to 20 of total daily insulin
requirement at each meal
Basal Glucose
0
7
8
9
10
11
1
2
3
4
5
6
7
8
9
12
A.M.
P.M.
Time of Day
47
Good

• 70/30 premixed insulin twice daily, .Use the
  usual morning dose at the sunset meal (Iftar) and
  half the usual evening dose at predawn (Suhur),
• e.g., 30 units in morning and 20 units in
  eveninge.g., 70/30 premixed insulin, 30 units in
  Iftar and 10 units in Suhur .

48
The best

• Consider changing premixed insulin preparations
  to Glargine or Dtemir plus Lispro, Glulisine or
  Aspart .

Diabetes Care September 2005 , pages 2305-11
49
Types of basal insulin
Intermediate-Acting (e.g. NPH, lente) Long-Acting Analogues (glargine, detemir)
Onset 1-3 hr(s) 1.5-3 hrs
Peak 5-8 hrs No peak with glargine, dose-dependent peak with detemir
Duration Up to 18 hrs 9-24 hrs (detemir) 20-24 hrs (glargine)
49
Rossetti P, et al. Arch Physiol Biochem
2008114(1) 3 10.
50
Ideal Basal Insulin

• Safe
• Effective
• Less glucose excurtions

51
Why Glargine
52
Insulin Glargine Peakless with 24hour Release
6 5 4 3 2 1 0
Glucose utilization rate mg/kg/min
Time
0 8 16
24

• Insulin Glargine has less intra-patient variation
  has a relatively constant, longer action
  profile with no pronounced peak in contrast to
  the peak and intermediate activity of NPH insulin

53
LAPTOP lower incidence of hypoglycaemia with
Insulin Glargine versus premix
Janka HU, et al. Diabetes Care 200528(2)254259
54
Less hypoglycemia with glargine vs NPH
Meta-Regression Analysis
11 randomized controlled trials n3,083
200
p0.021
150
NPH insulin
Rate of Hypoglycemia (Events/100 Patient-Years)
100
50
Insulin glargine
0
6
7
8
9
10
HbA1c ()
54
Adapted from Mullins P, et al. Clin Ther
2007291607-1619.
55
Insulin glargine consistently achieves HbA1C 7
Baseline
Study end
9.5
8.8
9.0
8.7
8.7
8.6
8.6
8.5
8.0
HbA1C ()
7.5
7.0
7.0
7.0
7.0
6.8
7.0
6.5
6.0
5.5
Schreiber5(n 12,216)
APOLLO3(n 174)
T-T-T1(n 367)
INSIGHT2 (n 206)
INITIATE4(n 58)
1. Riddle M, et al. Diabetes Care 20032630806.
2. Gerstein HC, et al. Diabetes Med
20062373642. 3. Bretzel RG, et al. Lancet
2008371107384. 4. Yki-Järvinen H, et al.
Diabetes Care 20073013649. 5. Schreiber SA, et
al. Diabetes Obes Metab 20079318.
56
LAPTOP once-daily Insulin Glargine oral
antidiabetic drug therapy is better than two
premixes when initiating insulin in Type 2
diabetes

• Randomized study in 371 insulin-naïve subjects
  with T2DM, who received Insulin Glargine or
  premix (70 NPH/30 regular) insulin for 24 weeks
• Insulin Glargine OADs is more efficient in
  lowering HbA1c, with less hypoglycaemia

Janka HU, et al. Diabetes Care 200528(2)254259
57
PK/PD Insulin Glargine has a longer duration of
action than detemir

• Randomized study comparing the pharmacokinetics
  and pharmacodynamics of Insulin Glargine with
  that of detemir in 24 subjects with T1DM who
  were naïve to Insulin Glargine and detemir

Porcellati F, et al. Diabetes Care
200730(10)24472452
58
The need for prandial insulin despite optimal
titration of basal insulin is indicated by

• FBG at or close to target (90130 mg/dl) but
  HbA1c 71
• FBG controlled but PPBG consistently high
• Basal insulin dose gt 0.5U/Kg

59
Fasting and Insulin Glargine inIndividuals With
Type 1 Diabetes
60
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61
Fasting during Ramadan in T2DM patients with
insulin Glargine
62
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Breaking the fast

• Diabetic patients must end their fast
  immediately in the following cases
• if blood glucose levels drop dramatically to 60
  mg/dl or lower
• if blood glucose reaches 70 mg/dl in the first
  few hours after the start of the fast, especially
  if insulin, sulfonylureas, or meglitinides are
  taken at the pre-dawn meal
• if blood glucose levels rise excessively to 300
  mg/dl.

Ibrahim M. A. Managing diabetes during Ramadan
Diabetes Voice June 2007 Volume 52 Issue 2
64
Ramadan in Egypt
65
THANK YOU
66
Management

• People with type 1 diabetes
• In general, people with type 1 diabetes are at
  very high risk of developing severe
  complications, and should be strongly advised to
  not fast during Ramadan.

Ibrahim M. A. Managing diabetes during Ramadan
Diabetes Voice June 2007 Volume 52 Issue 2
67
Management

• To be Discussed later in the following sessions

68
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69

• Two daily injections of NPH intermediate-acting
  insulin in combination with a short-acting
  insulin
• administered the usual dose before Iftar and
  half the dose before Sahour, However, there is an
  increased risk of hypoglycaemia around midday
• Another option use one daily injection of the
  long-acting insulin analogue, glargine or
  detemir along with pre-meal rapid-acting insulin
  analogues.

70
Management

• People with type 2 diabetes
• Lifestyle and nutrition
• In people who manage their diabetes with diet and
  physical activity, the risks associated with
  fasting are quite low.
• However, if people eat excessively, a potential
  risk of post-meal hyperglycaemia .
• Distributing energy intake over two to three
  smaller meals during the non-fasting interval may
  help.
• A persons regular daily exercise programme
  should be modified in its intensity and timing to
  avoid episodes of hypoglycaemia.

Ibrahim M. A. Managing diabetes during Ramadan
Diabetes Voice June 2007 Volume 52 Issue 2
71
Major Targeted Sites of Oral Drug Classes
Pancreas
The glucose-dependent mechanism of DPP-4
inhibitors targets 2 key defects insulin release
and unsuppressed hepatic glucose production.
Beta-celldysfunction
Sulfonylureas
Muscle and fat
Meglitinides
Liver
DPP-4 inhibitors GLP-1
?Glucose level
Hepatic glucoseoverproduction
Insulinresistance
Gut
Biguanides
TZDs
TZDs
Biguanides
Alpha-glucosidase inhibitors
DPP-4 inhibitors
Glucose absorption
Biguanides
DPP-4dipeptidyl peptidase-4 TZDsthiazolidinedio
nes. DeFronzo RA. Ann Intern Med.
1999131281303. Buse JB et al. In Williams
Textbook of Endocrinology. 10th ed. Philadelphia
WB Saunders 200314271483.
72

• Source of hyperglycemia during fasting hours
• 1- Dietary
• 2- Insulin deficiency
• 3- Hepatic glucose output
• 4- Non of the above.

73
An Ideal Oral Agent Should You Select during
fasting..?

• Achieve A1c Target
• Has lower hypoglycemic events
• Promotes weight loss

• In general, medications that act by increasing
  insulin sensitivity
• are associated with a significantly lower risk of
  hypoglycaemia
• than insulin secretagogues

74
Major Targeted Sites of Oral Drug Classes
Pancreas
The glucose-dependent mechanism of DPP-4
inhibitors targets 2 key defects insulin release
and unsuppressed hepatic glucose production.
Beta-celldysfunction
Sulfonylureas
Muscle and fat
Meglitinides
Liver
DPP-4 inhibitors GLP-1
?Glucose level
Hepatic glucoseoverproduction
Insulinresistance
Gut
Biguanides
TZDs
TZDs
Biguanides
Alpha-glucosidase inhibitors
DPP-4 inhibitors
Glucose absorption
Biguanides
DPP-4dipeptidyl peptidase-4 TZDsthiazolidinedio
nes. DeFronzo RA. Ann Intern Med.
1999131281303. Buse JB et al. In Williams
Textbook of Endocrinology. 10th ed. Philadelphia
WB Saunders 200314271483.
75
Management

• Oral medications
• Metformine two thirds of the total daily dose to
  be taken after the sunset meal, with the other
  third taken after the pre-dawn meal.
• Rosiglitazone and Pioglitazone have a low risk
  of hypoglycemia. Usually no change in dose is
  required.

Ibrahim M. A. Managing diabetes during Ramadan
Diabetes Voice June 2007 Volume 52 Issue 2
76

• Sulfonylureas are believed to be unsuitable for
  use during fasting because of the inherent risk
  of hypoglycemia they should be used with caution
  and select the safest SU (glimipride).
• Meglitinides are superior to SU as long as they
  could control hyperglycemia.
• Chlorpropamide is absolutely contraindicated
  during Ramadan because of the high possibility of
  prolonged and unpredictable hypoglycemia.

Ibrahim M. A. Managing diabetes during Ramadan
Diabetes Voice June 2007 Volume 52 Issue 2
77

• Insulin
• The aim should be to maintain necessary levels of
  basal insulin to suppress output of glucose from
  the liver to near-normal levels during fasting.
• Careful use of intermediate or long-acting
  insulins plus a short-acting insulin administered
  before meals would be an effective strategy.

Ibrahim M. A. Managing diabetes during Ramadan
Diabetes Voice June 2007 Volume 52 Issue 2
78
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
79
Case 1

• 47 years old male , accountant
• Sedentary lifestyle
• BMI 32
• Diabetic 5 years on Glimipride 4 mg /day and
  metformin 500 mg 3 times daily

Glimipride adjusted dose (2 or 3 mg) before Iftar
and metformin 1000 mg after Iftar and 500mg after
Sahour
80
Case 2

• 51 year old male
• Type 2 diabetes currently treated with Metformin
  1500 mg
• Serum creatinin 1.9 mg/dl

Not to fast Shift to Insulin Sensitizers
81
Case 1

• 48 years old male
• BMI 28
• Diabetic 11 years controlled on mixed Insulin 60
  U breakfast 40 U dinner and metformin 850mg
  after lunch

60 U Iftar and 20 U Sahour
Basal Insulin 40 U Short acing (better ultra
short analogues) 30 U Iftar 10 U Sahour
82
Patient Care and Management !!!

• Frequent monitoring
• This is especially critical in people who require
  insulin
• Medical assessment
• This should take place one to two months before
  Ramadan.
• Specific attention should be paid to peoples
  overall well-being and to the control of their
  blood glucose levels, blood pressure, and lipids.
  

Ibrahim M. A. Managing diabetes during Ramadan
Diabetes Voice June 2007 Volume 52 Issue 2
83
Nutrition

• People should maintain a healthy and balanced
  diet during Ramadan.
• The common practice of ingesting large amounts of
  foods that are high in fat and carbohydrates,
  should be avoided
• It is recommended that non-caloric fluid intake
  be increased during the non-fasting hours.
• The Sahour meal should be taken as late as
  possible before the start of the daily fast.

x
Ibrahim M. A. Managing diabetes during Ramadan
Diabetes Voice June 2007 Volume 52 Issue 2
84
Physical activity

• Normal levels of physical activity can be
  maintained.
• However, excessive physical activity may lead to
  higher risk of hypoglycaemia and should be
  avoided. x
• If Tarawih prayers (multiple prayers after the
  sunset meal) are performed, they should be
  considered a part of a persons daily physical
  activity programme.

Ibrahim M. A. Managing diabetes during Ramadan
Diabetes Voice June 2007 Volume 52 Issue 2
85
Diabetics should not fast if

• Uncontrolled (no defined figure)
• Recurrent hypoglycemic attacks
• Hypoglycemia unawareness.
• A history of Diabetic Ketoacidosis
• Recent infections
• Kidney disease
• Unstable ischemic heart disease.