1. Fasting diabetic patientBy
Eman Rushdy

2. ”ياأيها الذين أمنوا كتب عليكم الصيام كما كتب على الذين من قبلكم لعلكم تتقون“
“ 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).

8. Main determinants of glucose metabolism
Insulin and Glucagon
Main determinants of glucose metabolism

9. This is augmented in response to alterations in blood glucose levels .
Insulin&
C-peptide
Proinsulin
Proglucagon
Glucagon
Both cell types release their hormones simultaneously at a basal level. 
This is augmented in response to alterations in blood glucose levels .
Blood glucose<70mg/dl
+++
---
Insulin&
C-peptide
Proinsulin
Proglucagon
Glucagon
---
+++
Blood glucose >90mg/dl

10. Paracrine Actions of Insulin and Glucagon
Glucagon Insulin
Insulin glucagon

11. So, insulin favors anabolic reactions and storing energy
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 < 60 mg/dl
2- Lowered blood glucose ++ secretion
of glucagon& -- insulin
+++
3-Glycogenolysis maintain blood
glucose for 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

16. -- 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

18. 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 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 >15days
Prevalence of fasting in Muslims with DM: EPIDIAR Study
13 Countries, 12,243 people with diabetes
Type 2 DM:
– patients (86.5%)
– mean age: 54 years – Duration: 7.6 years
• Type 1 DM:
– 1070 patients (8.3%)
– mean age: 31 years – Duration: 10 years
• D.M unclassified: 671 (5.2%)
A retrospective study conducted in thirteen countries of 12,914 patients with diabetes
8.7% had type1 and rest type 2 diabetes
Population based survey
Algeria, Bangladesh, Egypt, India, Indonesia, Jordan, Lebanon, Malaysia,
Morocco, Pakistan, Saudi Arabia, Tunisia and Turkey
A population-based study of diabetes and its characteristics during the fasting month of Ramadan in 13 countries: results of the epidemiology of diabetes and Ramadan 1422/2001 (EPIDIAR) study
Diabetes Care, October 2004
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 to3 events/100 people/ m.
A Population-Based Study of Diabetes and Its Characteristics During the Fasting Month of Ramadan in 13 Countries
Investigators recruited 1,070 (8.7%) patients with type 1 diabetes and 11,173 (91.3%) patients with type 2 diabetes
Major risks
Hypoglycaemia
Hyperglycaemia
Dehydration (including thromboembolism)
Many patients with diabetes are passionate about fasting during Ramadan
50-60% of persons who fast maintain their body weight during Ramadan (no data in the UK)
20-25% either gain or lose weight (no data in the UK)
Finch GM et al, Appetite 31:2, 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 Oct;48(10):906-10
Faye J et al, Dakar Med. 2005;50(3):146-51

27. Type 1 diabetes Type 2 diabetes 3 fold increase 5 fold increase
*Hyperglycemia: severe hyperglycemia (requiring hospitalization)
Type 1 diabetes Type 2 diabetes
3 fold increase 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.
Nevertheless, many people with diabetes insist on fasting during Ramadan.
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 : 27:2306–2311

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: 2306–11.
Aslam M, Healey MA. Compliance and drug therapy in Moslem patients. J Clin Hosp Pharm 1986; 11: 321–5.
Aslam M, Assad A. Drug regimens and fasting during Ramadan: a survey in Kuwait. Public Health 1986; 100: 49–53.

34. Results in

35. Sequelae of hypoglycaemia
Mild”: Adrenergic (BG<70)
No direct serious clinical effects
With a rapid decline in blood glucose : tachycardia, tachypnea, vomiting, and diaphoresis
May impair subsequent hypoglycaemia awareness
Severe Neuroglycopenic (BG<50)
Usually associated with slower or prolonged hypoglycemia,
Stroke and transient ischaemic attacks
Memory loss/cognitive impairment
Myocardial infarction
Convulsions
Death
Speaker Notes:
It is not possible to define hypoglycaemia exclusively on the basis of plasma glucose concentrations in people with diabetes. Although glycaemic thresholds have been defined for hypoglycaemia, these thresholds are dynamic rather than static. Despite this, low glucose values must be considered to cause episodes of “clinical” hypoglycaemia.
According to UKPDS research, the mean proportion of patients per year with one or more major hypoglycaemic episodes while taking insulin treatment was 2.3%. The corresponding rate for any hypoglycaemic episode (mild or severe) was 36.5% for patients on insulin.
Source: Turner et al (UKPDS 33), The Lancet; 352:

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)
A proven benefit of intensive glucose control:
1) Lowers risk of new or worsening microvascular complications (damage to small vessels that cause kidney and eye damage) (ADVANCE).
However, results of three major clinical trials (ADVANCE, ACCORD and VA Diabetes Trial) confirmed that intensive glucose control in type 2 diabetes presents significant risks. These are:
1) Intensive glucose control was associated with increased mortality in patients with longstanding DM and known CVD (ACCORD).
2) Intensive control increases risk of severe hypoglycemia (ADVANCE, ACCORD and VADT).
Reference:
Action to Control Cardiovascular Risk in Diabetes (ACCORD) N Engl J Med 2008; 358(24):
Action in Diabetes and Vascular Disease: PreterAx and DiamicroN MR Controlled Evaluation (ADVANCE) N Engl J Med 2008; 358 (24):
Veterans Affairs Diabetes Trial (VDAT): J Diabetes Complications 2003; 17 (6):
ACCORD: N Engl J Med 2008; 358(24): ADVANCE: N Engl J Med 2008; 358 (24): VADT: J Diabetes Complications 2003; 17 (6):

37. Hypoglycaemia and CV Disease
Desouza C et al Diabetes Care 26: , 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 Hours Hours
Diabetes *
Control ND *
*p < 0.04 vs. Baseline
Galloway P et al Diabetes Care 23: , 2000

40. Hypoglycaemia and CV Disease
Hemodynamic
Hypoglycaemia
Thrombotic
Ischaemia
Inflammatory
Wright R et al Diabetes/ Metabolism Research and Reviews , 2008

41. Hypoglycemia Unawareness
Type 1 DM
DURATION
50% of type 1 patients lose the autonomic warning symptoms of hypoglycemia and may recognize the condition only when somatic neurologic function becomes impaired.
Usually associated with duration of diabetes and autonomic neuropathy
The introduction of intensified treatment regimens can lower the glucose level that triggers epinephrine release and adrenergic symptoms.
The DCCT trial showed that even brief periods of antecedent hypoglycemia can suppress counter-regulatory responses during subsequent hypoglycemic episodes.
Autonomic neuropathy
Recurrent hypoglycemia

42. MIMICKING NATURE WITH INSULIN THERAPY
All persons need
both basal and mealtime insulin
to control glucose
Slide 6-19
MIMICKING NATURE WITH INSULIN THERAPY
Over time, most patients will need both basal and mealtime insulin to control glucose
Since both fasting and postprandial glucose levels are abnormal in type 2 diabetes and the underlying insulin deficiency typically progresses, most patients will need both basal insulin and mealtime insulin if excellent glucose control is to be maintained. The goal of intensive insulin therapy is to delay the onset of microvascular complications and retard their progression once they occur.
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
Na+
KIR K+ K+ Vm K+
Voltage-gated Ca2+ channel
Ca2+
Ca2+
Pancreatic ß cell
Ca2+
Ca2+
Mature insulin granules contracts by exposure to high intracellular Ca.
Ca2+
Insulin granules

45. Post prandial insulin secretion
Glucose
Glucokinase Ca K

46. Physiologic Insulin Secretion: Basal/Prandial Concept
Nutritional (Prandial) Insulin 50
Insulin
(µU/mL)
Basal Insulin
*Suppresses Glucose Production Between Meals & Overnight 25
Basal Insulin
Breakfast Lunch Supper
150
*Nearly constant levels
40- 50% of daily needs
Nutritional Glucose
Glucose
(mg/dL)
100
Maintain necessary levels of basal insulin to remedy the prevailing relative deficiency and to overcome the existing insulin resistance.
Suppress hepatic glucose output to near-physiologic levels during the fasting period.
Careful use of intermediate- or long-acting insulin preparations plus a short-acting insulin administered before meals would be an effective strategy.
This slide shows a normal insulin profile and a normal glucose profile over the course of a day for a person without diabetes who is eating 3 meals (meal = red arrow). Notice that there is always a basal level of circulating insulin, which serves to suppress glucose and ketone production in periods of fasting. This component of insulin is referred to as “basal insulin,” and it is relatively constant. Next, notice that glucose levels rise, as expected, when the person eats a meal. When this occurs, the physiologic response is to rapidly increase insulin levels, and this figure shows how closely the curves for glucose levels and insulin levels match, after a meal. This rise in the insulin level above the “basal” level that occurs in response to nutritional intake is referred to as “nutritional insulin.”
The goal of insulin therapy in patients with diabetes is to mimic normal physiologic insulin secretion as closely as possible. This slide illustrates the typical 24-hour insulin secretion pattern in response to three meals in individuals without diabetes. The insulin secretory response is pulsatile, with two to four pulses observed after each meal. Insulin concentrations rise rapidly during the first and second hours following the meal. Following breakfast, nearly 67% of the 4-hour secretory response occurs during the first 2 hours, compared with 33% during the third and fourth hours. A similar temporal distribution is seen after lunch and dinner. Between meals and overnight, a lower rate of insulin secretion maintains basal insulin concentrations.
In type 2 diabetes, this pattern of insulin secretion is disrupted in three ways: Patients have an absent or blunted first-phase insulin response to glucose, as well as decreased overall insulin secretion, particularly when diabetes is severe. In addition, there is decreased sensitivity of the insulin response to glucose. Both basal and postprandial glucose levels fail to trigger normal insulin secretion; these defects result in postprandial and fasting hyperglycemia.2 To be fully successful, insulin therapy in patients with type 1 diabetes or long-duration type 2 diabetes must provide for both basal and meal-related insulin requirements. The following slides examine insulin regimens that have been developed to address these issues.
A “normal” human (who does not have significant insulin resistance) secretes a total of about units of insulin per day. About ½ of this is secreted as basal insulin, and about ½ of this is secreted as nutritional insulin. Understanding this bit of physiology is very helpful for creating flexible insulin regimens in hospitalized patients.
In acute illness, the total daily insulin requirement may actually increase, even if the patient’s caloric intake decreases. This increase in physiologic insulin requirement in illness reverts to baseline as recovery takes place. 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 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9
A.M.
P.M.
Time of Day 12

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 evening…e.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

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 2008;114(1): 3 – 10. 49 49

50. Ideal Basal Insulin:
Safe
Effective
Less glucose excurtions

51. Why Glargine

52. Insulin Glargine Peakless with 24hour Release6 5 4 3 2 1
Glucose utilization rate mg/kg/min
NPH
Insulin Glargine
Time
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
Description
In the LAPTOP study carried out by Janka et al, the efficacy and safety of adding once-daily basal Insulin Glargine versus switching to twice-daily premix (70% human insulin/30% regular insulin [70/30]) in patients with T2DM uncontrolled on OADs was determined
In this 24-week trial, 371 insulin-naïve patients were randomized to either once-daily Insulin Glargine plus glimepiride and metformin or to 70/30 premix twice-daily without OADs
Mean adjusted HbA1c improvement was greater with Insulin Glargine plus OAD than with 70/30 premix, with the adjusted mean between-treatment difference of 0.34% significantly favouring the Insulin Glargine plus OAD group (p=0.0003)1
Significantly more patients in the Insulin Glargine plus OAD group achieved HbA1c ≤7% without an episode of confirmed nocturnal hypoglycaemia than in the 70/30 premix group (45.5 and 28.6%, respectively; p= for the between-treatment difference)
The reduction from baseline in blood glucose levels was significantly greater in the Insulin Glargine group than in the premix group for values obtained at the fasting, post-lunch, dinner, post-dinner and 3am timepoints (p<0.05 for all comparisons)
During treatment, the rate of confirmed hypoglycaemic events was approximately 50% lower with Insulin Glargine plus OAD than with premix for the overall (4.07 vs 9.87, respectively, p<0.0001), symptomatic (2.62 vs 5.73, respectively, p=0.0009) and nocturnal categories (0.51 vs 1.04, respectively, p=0.0449)
This study showed that initiating insulin treatment by adding basal Insulin Glargine once daily to patients failing on OADs was significantly more effective than beginning twice-daily premix and discontinuing OAD therapy
Study summary
Aim: To compare the efficacy and safety of adding once-daily basal insulin to OADs versus switching to twice-daily premix in patients insufficiently controlled by OADs
Study design: 24-week, randomized, multinational, multicentre, open-label, parallel group study
Outcomes
Primary: Change in HbA1c from baseline to endpoint
Population: Insulin-naïve patients with poorly controlled T2DM using sulfonylurea and metformin (N=371; aged 35–75 years, BMI ≤35 kg/m2, FBG ≥120 mg/dL and HbA1c 7.5–10.5%)
Treatment received: During screening, sulfonylurea was replaced with glimepiride (3 or 4 mg), while metformin treatment was continued. Patients were treated with either once-daily Insulin Glargine (n=177), given in the morning, plus OADs or twice-daily premix (70% NPH/30% regular; n=187) given before breakfast and dinner, without OADs
Reference
Janka HU, Plewe G, Riddle MC et al. Comparison of basal insulin added to oral agents versus twice-daily premixed insulin as initial insulin therapy for Type 2 diabetes. Diabetes Care 2005;28(2):254–259
Janka HU, et al. Diabetes Care 2005;28(2):254–259 53

54. Less hypoglycemia with glargine vs NPH
Meta-Regression Analysis
Less hypoglycemia with glargine vs NPH
11 randomized controlled trials; n=3,083
200
p=0.021
150
NPH insulin
(Events/100 Patient-Years)
Rate of Hypoglycemia
100
Key Points
In a recent meta-regression analysis, patient-level data from 11 randomized Phase III/IV clinical trials comparing glargine and NPH were evaluated.
Associations between end-of-study HbA1c, with last observation carried forward, and rates of hypoglycemia in patients with type 2 diabetes show consistently lower rates of hypoglycemia with insulin glargine (p=0.021 between treatments).
The curves are derived from the complete data set using the negative binomial regression model, with adjustment for covariates. 50
Insulin glargine 6 7 8 9 10
HbA1c (%) 54
Adapted from Mullins P, et al. Clin Ther 2007;29: 54 54

55. Insulin glargine consistently achieves HbA1C ≤ 7%
Baseline
Study end
9.5
9.0
8.7
8.8
8.7
8.6
8.6
8.5
HbA1C (%)
8.0
7.5
7.0
7.0
7.0
6.8
7.0
7.0
6.5
6.0
5.5
Schreiber5 (n = 12,216)
T-T-T1 (n = 367)
INSIGHT2 (n = 206)
APOLLO3 (n = 174)
INITIATE4 (n = 58)
1. Riddle M, et al. Diabetes Care 2003;26:3080–6. 2. Gerstein HC, et al. Diabetes Med 2006;23:736– Bretzel RG, et al. Lancet 2008;371:1073– Yki-Järvinen H, et al. Diabetes Care 2007;30:1364–9. 5. Schreiber SA, et al. Diabetes Obes Metab 2007;9:31–8. 55 55 55

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
Description
In the LAPTOP study carried out by Janka et al, the efficacy and safety of adding once-daily basal Insulin Glargine versus switching to twice-daily premix (70% human insulin/30% regular insulin [70/30]) in patients with T2DM uncontrolled on OADs was determined
In this 24-week trial, 371 insulin-naïve patients were randomized to either once-daily Insulin Glargine plus glimepiride and metformin or to 70/30 premix twice-daily without OADs
Mean adjusted HbA1c improvement was greater with Insulin Glargine plus OAD than with 70/30 premix, with the adjusted mean between-treatment difference of 0.34% significantly favouring the Insulin Glargine plus OAD group (p=0.0003)1
Significantly more patients in the Insulin Glargine plus OAD group achieved HbA1c ≤7% without an episode of confirmed nocturnal hypoglycaemia than in the 70/30 premix group (45.5 and 28.6%, respectively; p= for the between-treatment difference)
The reduction from baseline in blood glucose levels was significantly greater in the Insulin Glargine group than in the premix group for values obtained at the fasting, post-lunch, dinner, post-dinner and 3am timepoints (p<0.05 for all comparisons)
During treatment, the rate of confirmed hypoglycaemic events was approximately 50% lower with Insulin Glargine plus OAD than with premix for the overall (4.07 vs 9.87, respectively, p<0.0001), symptomatic (2.62 vs 5.73, respectively, p=0.0009) and nocturnal categories (0.51 vs 1.04, respectively, p=0.0449)
This study showed that initiating insulin treatment by adding basal Insulin Glargine once daily to patients failing on OADs was significantly more effective than beginning twice-daily premix and discontinuing OAD therapy
Study summary
Aim: To compare the efficacy and safety of adding once-daily basal insulin to OADs versus switching to twice-daily premix in patients insufficiently controlled by OADs
Study design: 24-week, randomized, multinational, multicentre, open-label, parallel group study
Outcomes
Primary: Change in HbA1c from baseline to endpoint
Population: Insulin-naïve patients with poorly controlled T2DM using sulfonylurea and metformin (N=371; aged 35–75 years, BMI ≤35 kg/m2, FBG ≥120 mg/dL and HbA1c 7.5–10.5%)
Treatment received: During screening, sulfonylurea was replaced with glimepiride (3 or 4 mg), while metformin treatment was continued. Patients were treated with either once-daily Insulin Glargine (n=177), given in the morning, plus OADs or twice-daily premix (70% NPH/30% regular; n=187) given before breakfast and dinner, without OADs
Reference
Janka HU, Plewe G, Riddle MC et al. Comparison of basal insulin added to oral agents versus twice-daily premixed insulin as initial insulin therapy for Type 2 diabetes. Diabetes Care 2005;28(2):254–259
Janka HU, et al. Diabetes Care 2005;28(2):254–259

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 2007;30(10):2447–2452

58. The need for prandial insulin despite
optimal titration of basal insulin is indicated by:
FBG at or close to target (90–130 mg/dl) but HbA1c ≥7%1
FBG controlled but PPBG consistently high
Basal insulin dose > 0.5U/Kg
Basal insulin dose increases are linearly correlated with reductions in HbA1c levels up to 0.5–0.7 IU/kg.
Further dose titration of basal insulin depends on the individual, and is a balance between benefits in glycaemic control and risk of hypoglycaemia and weight gain.
Reference
Raccah D, et al. Diabetes Metab Res Rev 2007 (in press).

59. Fasting and Insulin Glargine in Individuals With Type 1 Diabetes

61. Fasting during Ramadan in T2DM patients with insulin Glargine

63. 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

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.
The basal-bolus regimen involves the greatest number of injections, but offers the best glycaemic control and the most flexible regimen for patients with busy lifestyles. Pre-meal short-acting insulin (fast-acting human insulin or rapid-acting insulin analogues) is combined with once or twice daily long-acting insulin. When a rapid-acting insulin analogue is used the faster absorption of the analogue allows better control of postprandial glucose, and the shorter duration of action reduces the drive to hypoglycaemia during the night. The independent replacement of all basal insulin (daytime as well as night-time) prevents running out of insulin between meals. Patients do not usually need to eat snacks between meals.

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 person’s 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-cell dysfunction
Sulfonylureas
Muscle and fat
Meglitinides
Liver
DPP-4 inhibitors
GLP-1
↓Glucose level
Hepatic glucose overproduction
Major Targeted Sites of Various Oral Drug Classes
Speaker Notes
The various therapeutic agents available for the treatment of type 2 diabetes act on different pathways to control hyperglycemia.1,2
Sulfonylureas act in the pancreas, stimulating insulin release by binding to the sulfonylurea receptor of beta-cell membranes.1
Meglitinides, another class of short-acting insulin secretagogues, also act in the pancreas, stimulating insulin release by binding to several sites on the beta cells. They are used to control postprandial hyperglycemia.1
TZDs (thiazolidinediones) are selective peroxisome proliferator-activated receptor gamma agonists and act in the muscle. They also exert effects in the liver and adipose tissue. These agents reduce insulin resistance and decrease hepatic glucose output.1,2
Alpha-glucosidase inhibitors lower postprandial blood glucose concentrations by inhibiting disaccharidase enzymes in the gut, thereby delaying carbohydrate absorption. This action retards glucose entry into the systemic circulation.1
Biguanides (metformin) act primarily in the liver by decreasing hepatic glucose output through a mechanism that has not been fully elucidated. Metformin also enhances insulin sensitivity in muscle and decreases intestinal absorption of glucose.1,3,4
Based on their different mechanisms of action, these drugs may be used in combination, as noted in the prescribing information for each product.
The dipeptidyl peptidase-4 (DPP-4) inhibitors are a new class of treatment for type 2 diabetes. These agents prevent the enzyme DPP-4 from degrading and inactivating GLP-1 and GIP, incretin hormones that are produced in the gut and help regulate insulin production and secretion.5
This glucose-dependent mechanism targets 2 key defects: insulin release and hepatic glucose production.
Insulin resistance
Purpose:
To provide a broad overview of the key mechanisms and targeted sites of available antihyperglycemic classes and to introduce the concept that DPP-4 inhibitors have an effect on both the pancreas and the liver.
Takeaway:
Different drug classes with different but complementary mechanisms may be suitable for combination therapy to address multiple pathophysiologies and improve A1C control. The glucose-dependent mechanism of DPP-4 inhibitors targets 2 key defects: insulin release and unsuppressed hepatic glucose production.
Biguanides
Gut
TZDs
TZDs
Biguanides
Alpha-glucosidase inhibitors
DPP-4 inhibitors
Glucose absorption
Biguanides
DPP-4=dipeptidyl peptidase-4; TZDs=thiazolidinediones.
DeFronzo RA. Ann Intern Med. 1999;131:281–303.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483.
References:
1. DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med. 1999;131:281–303.
2. Actos [package insert]. Lincolnshire, Ill: Takeda Pharmaceuticals America, Inc; 2004.
3. Buse JB, Polonsky KS, Burant CF. Type 2 diabetes mellitus. In: Larsen PR et al, eds. Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483.
4. Glucophage [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2004.
5. Herman GA, Bergman A, Stevens C, et al. Effect of single oral doses of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on incretin and plasma glucose levels after an oral glucose tolerance test in patient with type 2 diabetes. J Clin Endocrinol Metab. 2006;9:4612–4619. 71

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 73

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-cell dysfunction
Sulfonylureas
Muscle and fat
Meglitinides
Liver
DPP-4 inhibitors
GLP-1
↓Glucose level
Hepatic glucose overproduction
Major Targeted Sites of Various Oral Drug Classes
Speaker Notes
The various therapeutic agents available for the treatment of type 2 diabetes act on different pathways to control hyperglycemia.1,2
Sulfonylureas act in the pancreas, stimulating insulin release by binding to the sulfonylurea receptor of beta-cell membranes.1
Meglitinides, another class of short-acting insulin secretagogues, also act in the pancreas, stimulating insulin release by binding to several sites on the beta cells. They are used to control postprandial hyperglycemia.1
TZDs (thiazolidinediones) are selective peroxisome proliferator-activated receptor gamma agonists and act in the muscle. They also exert effects in the liver and adipose tissue. These agents reduce insulin resistance and decrease hepatic glucose output.1,2
Alpha-glucosidase inhibitors lower postprandial blood glucose concentrations by inhibiting disaccharidase enzymes in the gut, thereby delaying carbohydrate absorption. This action retards glucose entry into the systemic circulation.1
Biguanides (metformin) act primarily in the liver by decreasing hepatic glucose output through a mechanism that has not been fully elucidated. Metformin also enhances insulin sensitivity in muscle and decreases intestinal absorption of glucose.1,3,4
Based on their different mechanisms of action, these drugs may be used in combination, as noted in the prescribing information for each product.
The dipeptidyl peptidase-4 (DPP-4) inhibitors are a new class of treatment for type 2 diabetes. These agents prevent the enzyme DPP-4 from degrading and inactivating GLP-1 and GIP, incretin hormones that are produced in the gut and help regulate insulin production and secretion.5
This glucose-dependent mechanism targets 2 key defects: insulin release and hepatic glucose production.
Insulin resistance
Purpose:
To provide a broad overview of the key mechanisms and targeted sites of available antihyperglycemic classes and to introduce the concept that DPP-4 inhibitors have an effect on both the pancreas and the liver.
Takeaway:
Different drug classes with different but complementary mechanisms may be suitable for combination therapy to address multiple pathophysiologies and improve A1C control. The glucose-dependent mechanism of DPP-4 inhibitors targets 2 key defects: insulin release and unsuppressed hepatic glucose production.
Biguanides
Gut
TZDs
TZDs
Biguanides
Alpha-glucosidase inhibitors
DPP-4 inhibitors
Glucose absorption
Biguanides
DPP-4=dipeptidyl peptidase-4; TZDs=thiazolidinediones.
DeFronzo RA. Ann Intern Med. 1999;131:281–303.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483.
References:
1. DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med. 1999;131:281–303.
2. Actos [package insert]. Lincolnshire, Ill: Takeda Pharmaceuticals America, Inc; 2004.
3. Buse JB, Polonsky KS, Burant CF. Type 2 diabetes mellitus. In: Larsen PR et al, eds. Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483.
4. Glucophage [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2004.
5. Herman GA, Bergman A, Stevens C, et al. Effect of single oral doses of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on incretin and plasma glucose levels after an oral glucose tolerance test in patient with type 2 diabetes. J Clin Endocrinol Metab. 2006;9:4612–4619. 74

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: , 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 79

80. Shift to Insulin Sensitizers
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 81

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 people’s 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 person’s 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.