Role of early basal insulin initiation of t2 dm

1. Role of Early Initiation
of
Basal Insulin
in Management of T2DM
CARDIO-METABOLIC RISK REDUCTION
(with WEIGHT CONCERN)
DR./ADEL ELNAGGAR
Endocrinologist
Dr.Erfan & Bagedo General Hospital

2. DIABETES SPOT LIGHTS
INSULIN initiation benefits/
guidelines
New ultra long basal insulin
analogue benefits
& Summary/home message

3. :
A GROUP OF DISEASES
Characterized By High Levels Of Blood Glucose
Resulting From Defects In Insulin Production,
Insulin Action, Or Both
:
Metabolic Disorders
Cardio-metabolic Disorders
Complex Metabolic Disorders
Characterized By Hyperglycemia Due To An Absolute Or Relative
Lack Of Insulin
Or To A Cellular Resistance To Insulin

6. Type 2 diabetes,
the metabolic syndrome and cardiovascular disease in Europe
Visual impairment:
diabetic retinopathy,
cataract and
glaucoma
Kidney disease
(diabetic nephropathy)
Sexual
dysfunction
Sensory impairment
(peripheral neuropathy)
Ulceration
Stroke
(cerebrovascular disease)
Heart disease
(cardiovascular disease)
Bacterial and fungal
infections of the skin
Severe hardening of
the arteries (atherosclerosis) Autonomic neuropathy
(including slow emptying
of the stomach and diarrhea)
Necrobiosis lipidoica
Gangrene
The major diabetic complications
Poor blood supply to lower limbs
(peripheral vascular disease)

8. SAUDI ARABIA
1 IN 4

9. Failure of stop diabetes!!
Why??
(LACK OF DIABETES PYRAMID
STRATEGIES):
BASE: Early detection; diagnosis &
prevention Programs (Health
Education).
BODY: Proper scientific socio-
economic Management (Qualified
Health Care Providers).
TOP: Delay or prevent Diabetic
Complications (Reduce Morbidity &
Mortality).

12. Pre-Diabetes
•Impaired fasting glucose (IFG)
•FPG 100-125mg/dL
•Impaired glucose tolerance (IGT)
•PPBG 140-199mg/dL
•HbA1c 5.8-6 up to 6.5%

14. INSULIN RESISTANCE
METABOLIC SYNDROME
&
ADULT OBESITY
Central obesity (waist circumference)
IGT or IFG
High lipid profile
LDL-HDL/CHOLESTEROL/TRIGLYCERIDES
HIGH BP more than 130/90

15. CARDIO-METABOLIC RISK
REDUCTION???? 4-stop

16. Blood Pressure Reductions as Little as 2 mmHg
Reduce the Risk of Cardiovascular Events by up to
10%
Meta-analysis of 61 prospective, observational studies conducted by
Lewington et al involving one million adults with no previous vascular disease
at baseline.
2 mmHg decrease
in mean SBP
10% reduction in
risk of stroke
mortality
7% reduction in
risk of IHD
mortality
Lewington S, et al. Lancet. 2002;360:1903–1913

17. Every 1% reduction in HbA1c
can reduce long-term
DIABETES COMPLICATIONS1
*p<0.0001
1. Adapted from Stratton IM et al. BMJ 2000;321:405–412.
37%
21%
14%
Microvascular
complications*
Deaths related
to diabetes*
Myocardial
infarction*

18. Benefits of weight neutral/reduction
regimens in management of
type 2 diabetes
1. Anderson and Konz. Obes Res 2001;9(Suppl. 4):326S–334S
2. Anderson et al. J Am Coll Nutr 2003;22:331–9
BP, blood pressure; CV, cardiovascular; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-
density lipoprotein cholesterol; TC, total cholesterol; TG, triglycerides

20. INTERNATIONAL DIABETES FEDERATION (IDF)
2005 and 2011/12
AMERICAN GUIDELINES (ADA)
2006, 2008, 2009, 2012, 2015, 2016 ???
EUROPEAN GUIDELINES (EASD)
2006, 2008, 2009, 2012, 2015
NATIONAL GUIDELINES (KSA –EGYPT)
WE LIVE IN A WORLD OF GUIDELINES
FOR MANAGING T2DM
AACE/ACE GUIDELINES
2009, 2013, 2015

21. GUIDANCE Study 7,597 T2DM patients
Gap exists between
checking HbA1c and achieving target HbA1c <7%
Stone MA et al. Diabetes Care. 2013 ; 36: 2628-38
Percent

22. Barriers to Diabetes Care
Clinical Practice
Therapeutic Regimen
(poly-pharmacy/complex)
Disease Process
Patient Adherence

23. 7
6
Diagnosis +5 yrs +10 yrs + 15 yrs
9
8
Diet +
Metformin
Treatment ApproachesHbA1C%
Failure based treatment
of symptoms approach
HbA1C < 7% approach
Campbell. Br J Cardiol 2000; 7: 625-31
Clinical Practice
OHA 3 INSULIN
COMPLEX
INSULIN

24. Early initiation of
Basal Insulin
in management of T2DM
is recommended by all
International Guidelines

25. ADA. Diabetes Care 2014;37:S14–80
*Usually basal; ADA, American Diabetes Association; DPP-4i, dipeptidyl peptidase-4 inhibitor; Fx; bone fractures; GI,
gastrointestinal; GLP-A RA, glucagon-like peptide-1 receptor agonist; HF; heart failure; SU, sulphonylurea; TZD,
thiazolidinedione
ADA 2014 – guidelines for managing hyperglycaemia

26. Treatment of type 2 diabetes:
IDF guidelines
IDF, International Diabetes Federation
IDF. Global guideline for type 2 diabetes. 2012. www.idf.org/global-guideline-type-2-diabetes-2012

28. Recent Guidelines
2016

31. But
Insulin considered as
A …………??
For both * patients* doctors

33. LETHAL
WEAPON

35. Uncontrolled Type 2 Diabetes with
maximum dose of OADs
According to official guidelines*, the
addition of basal insulin is recommended in
case of oral therapy failure with maximum
dose to target HbA1c <7%
Basal insulin is recommended in
association with OADs
*ADA, Diabetes Care 2004, 27 (Supl1), S15-S35; AH Barnet, Pract Diab Int April 2003 vol 20 N° 3
Recommandations françaises (French Recommendations) HAS 2006
Nathan DM, et al. Diabetes Care 2006.

36. initiating insulin
with
BASAL INSULINS
The guidelines state:
 Basal Insulin is effective for lowering
A1C especially for patients with HbA1c
values of >8.5% when initiated 10 IU or 0.2
IU/kg
Insulin analogs with longer non-peaking
profiles have a low rate of Hypoglycemia.

37. Basal insulin to initiate insulin therapy
in type 2 diabetes
*Efficient:
Direct effect on FBG and lower mean
daily BG levels during the day
*Simple protocol
*Simple education for the patient:
Titration on FBG target
*Less hypos
*Premix insulins are not recommended at
initiation

38. Basal Insulin choice
NPH: insulin with protamine,
intermediate:
"Long-acting" insulin analogs
 Glargine:
 Detemir:

39. Cause of Type 2 DM
► Insulin resistance (genetics)
- aggravated by obesity
- aggravated by lack of exercise
► “Exhaustion” of insulin-producing β-cells

40. Primary Endocrinopathies:
Treating a Moving Target
Insulin
Resistance
Type 2
Diabetes
b-cell
Dysfunction
Insulin
Resistance
Insulin
Concentration
Euglycaemia
b-cell Failure
Normal IGT ± Obesity Diagnosis Of T2DM Progression of T2DM
DISEASE

41. Decline of ß-cells function determines
the progressive nature of T2DM
-12 -10 -8 -6 -4 -2 0 2 4 6
0
20
40
60
80
100
Time of diagnostic
Time (years)
ß-cellfunction(%ofnormalbyHOMA)
?
HOMA=homeostasis model assessment.
UKPDS Group. Diabetes 1995;44:1249-58.
Adapted from Holman RR. Diabetes Res Clin Pract 1998;40(suppl 1):S21-5.
Pancreatic function
= 50% of normal

42. Insulin resistance and -cell dysfunction
are core defects of type 2 diabetes
Insulin
resistance
Genetic susceptibility,
obesity, Western
lifestyle
Type 2 diabetes
IR
-cell
dysfunction
Rhodes CJ & White MF. Eur J Clin Invest 2002; 32 (Suppl. 3):3–13.

43. Why does the -cell fail?
Chronic
hyperglycemia
Oversecretion of
insulin to compensate
for insulin resistance1,2
High circulating
free fatty acids
Glucotoxicity2
Pancreas
Lipotoxicity3
-cell
dysfunction
1Boden G & Shulman GI. Eur J Clin Invest 2002; 32:14–23.
2Kaiser N, et al. J Pediatr Endocrinol Metab 2003; 16:5–22.
3Finegood DT & Topp B. Diabetes Obes Metab 2001; 3 (Suppl. 1):S20–S27.

44. Turner et al. Br Med J 1976;1:1252–4; Owens. Diabetes Technol Ther 2013;15:776–85; Unger & Zhou. Diabetes 2001;50:S118–21
Overcoming glucotoxicity with early
insulin initiation facilitates beta-cell
rest

45. Early insulin treatment prolongs beta-cell
function and promotes metabolic control
Alvarsson et al. Diabetes Care 2003;26:2231–7

46. Early insulin therapy improves
beta-cell function and glycemic
control
Weng et al. Lancet 2008;371:1753–60
CSII, continuous subcutaneous insulin infusion; MDI, multiple daily injection; OHA, oral hypoglycaemic agent

47. Targets for glucose control
The overall aim is to achieve glucose levels as
close to normal as possible
This can minimize development and progression of
micro vascular and macro vascular
complications
1. ADA. Diabetes Care 2014;37:S14–80; 2. Inzucchi et al. Diabetes Care 2012;35:1364–79; 3. IDF. IDF Clinical Guidelines Task Force.
2012
ADA, American Diabetes Association; EASD, European Association for the Study of Diabetes; FPG, fasting plasma
glucose; PPG, postprandial plasma glucose

48. Targeting both PPG and FPG is an important strategy
for achieving optimal glycaemic control1
1. 2011 Guideline for Management of PostMeal Glucose in Diabetes.
Available at: www.idf.org/2011-guideline-management-postmeal-glucose-diabetes (accessed
March 2015). 2. Adapted from Monnier L et al. Diabetes Care 2003;26:881−885.
HbA1c
PPG FPG
Glucose
triad2

49. 49
In T2DM ‘Fix fasting first’ –will lower the
entire plasma glucose through 24 hr
Adapted from Polonsky K. N Engl J Med 1988;318:1231–9 and Hirsch I, et al. Clin Diabetes 2005;23:78–86.
Theoretical simulation of diurnal blood glucose profile
Time of day (hours)
400
300
200
100
0
06:00 06:0010:00 14:00 18:00 22:00 02:00
Plasmaglucose(mg/dL)
Normal
Meal Meal Meal
20
15
10
5
0
Plasmaglucose(mmol/L)
Hyperglycaemia due to an increase in fasting glucose
T2DM

50. Basal Insulin Choice
studies view
1. NPH insulin versus
insulin Glargine
2. NPH insulin versus
insulin Detemir
3. Insulin Glargine versus
insulin Detemir
Treat To Target
Riddle et al. Diabetes Care 2003;
26:3080-3086.
LANMET
Yki-Järvinen H, et al. Diabetologia
2006; 49:442-51.
Hermansen et al. Diabetes Care 2006;
29:1269-1274.
Rosenstock et al. Diabetologia 2008;
51:408-416.

51. (1) Basal Insulin Choice
 Glargine / NPH: Treat To Target. Riddle et al.
 Same HbA1c results with 1 injection
/day at bedtime
 Same dose
 Less hypos with Glargine

52. Percentage of patients with HbA1c
<7 % without nocturnal
hypoglycaemia
 Better response (HbA1c <7% without nocturnal hypoglycaemia)
in the insulin glargine group vs. NPH
NPHglargine
33%
27%
% patients p<0.05

53. LANMET: Insulin glargine or NPH
insulin with metformin
 9-month, comparative study of insulin glargine + metformin
versus NPH + metformin in 110 patients with T2DM
4
8
12
16
Before
breakfast
After
breakfast
Before
lunch
After
lunch
Before
dinner
After
dinner
22:00 04:00
Insulin glargine + metformin
NPH + metformin
Baseline
Weeks 25 - 36
Bloodglucose(mmol/L)
p=0.0003
p=0.0047
p=0.07
Yki-Järvinen H, et al. Diabetologia 2006;49:442-51.

54. (2) Basal Insulin Choice NPH vs. Detemir
 NPH / Detemir 2 injections/day, 6 months
 HbA1c equivalent
 Less hypos
 Less weight gain with Detemir
 Higher insulin dose with Detemir
(65 U/day versus 45U/day)
Hermansen et al. Diabetes Care 2006; 29:1269-1274.

55. (3) Insulin Glargine vs. Insulin
Detemir in DM-2
 52-week multinational, randomized (1:1), open-label, parallel-group,
non-inferiority trial
582 insulin naïve
T2DM patients
HbA1c 8.6%
Detemir
x1 or x2*/day
n=291
glargine
x1/day
n= 291
Titration
Fasting &
pre-dinner
glycemia
≤ 6.0
mmol/L
 Primary endpoint
 Adjusted HbA1C
 Patient characteristics
 ≥12 months disease duration
 ≥18 years of age
 ≤2 oral agents (no TZDs) for ≥4 months
 HbA1C between 7.5-10.0%
 BMI ≤40 kg/m2* If pre-dinner PG >7.0 mmol/L and FPG <7.0 mmol/L
Rosenstock J, et al. Diabetologia 2008 Mar;51(3):408-16.
 Secondary endpoints
 Plasma glucose profiles
 Response rate (HbA1C ≤7%)
 Change in body weight
 Hypoglycaemic episodes
 Adverse events
52 weeks

56. No différence for HbA1c
6
7
8
9
glargine (QD) + OADs
8.62
HbA1C%
7.12
8.64
7.16
-1.5% -1.5%
Baseline 52 weeks Baseline 52 weeks
Detemir (QD or BID) + OADs
p=ns
Rosenstock J, et al. Diabetologia 2008 Mar;51(3):408-16.

57. Dornhorst et al. Diabetes Obes Metab 2008;10:75–81
WEIGHT CONCERN
Insulin detemir’s weight advantage
is also shown in a real-life setting
NPH, neutral protamine Hagedorn

58. INITIATE
50
150
250
350
BB
Basal insulin
BIAsp 70/30
Baseline
Week 28
PlasmaGlucose(mg/dL)
100
200
300
B90 BL L90 BD D90 Bed 3:00 am
*
* *
*
*
* p<0.05
Raskin P, et al. Diabetes Care 2005;28:260-265.

59. FBG results
50
100
150
200
Basal insulin morning
FBG(mg/dL)
133
Inclusion End of
study
PreMix x2
Inclusion End of
study
172
115
171
p<0.001
Janka H.U, et al. Diabetes Care 2005. 28: 254-59

60. Glycaemic control
Fasting
Basal insulin + OADs
Premixed Insulin
Baseline
Endpoint
BloodGlucoseLevel(mg/dL)
100
200
250
150
After
Breakfast
Lunch After
Lunch
Dinner After
dinner
Bedtime 3:00 am
*
*
*
*
*
* p<0.05
Janka H.U, et al. Diabetes Care 2005. 28: 254-59

61. Rate of responding patients
0
5
10
15
20
25
30
35
40
45
50
HbA1c ≤7%
Proportionofpatients
reachingtarget(%)
15.0
FBG ≤100 mg/dL
31.629.0
45.0
PreMix insulin
Basal insulin + OADs
p=0.013
p=0.0002
Janka H.U, et al. Diabetes Care 2005. 28: 254-59

62. 62
Janka HU, et al. Diabetes Care 2005;28(2):254–259
• Randomized study in 371 insulin-naïve subjects with T2DM, who received
Insulin Glargine or premix (70% NPH/30% regular) insulin for 24 weeks
Initiating basal insulin plus OADs is safer and more
effective than beginning with twice daily premix
(70/30)
BASAL
+
OHDs
basal
Premix
Premix

63. Hypoglycaemias
Basal
insulin
plus OADs
Premixed
Insulin
p value
Relative risk
reduction
with basal
insulin (%)
All episodes of
hypoglycaemia per patient
3.0 6.3 <0.0001 -52
Episodes of symptomatic
hypoglycaemia per patient
2.3 4.4 0.0009 -48
Episodes of nocturnal
hypoglycaemia per patient
0.3 0.8 0.0067 -63
Episodes of severe
hypoglycaemia per patient
0.01 0.03 0.13 -67
Janka H.U, et al. Diabetes Care 2005. 28: 254-59

64. Vicious cycle of weight gain and diabetes
1. Weight gain
2. Increased
adiposity
3. Increased
insulin
resistance
4. Higher insulin
requirements
5. Further
weight gain
Vicious cycle
of weight
gain
and diabetes
30% women admitted to
underdosing insulin to
manipulate their weight3
1. Rojas et al. Nutrition and Diabetes 2011;1:e10
2. Purnell et al. JAMA 1998;280:140–146
3. Bryden et al. Diabetes Care 1999;22:1956–1960

65. Main inclusion criteria:
• Patients with type 2
diabetes >6 months
• Receiving metformin
± OADs
• HbA1c 7.5–10 %
• BMI ≤45 kg/m2
Insulin detemir (OD) + sitagliptin + metformin
Sitagliptin + metformin ± sulfonylurea
–2 0 26RandomisationWeek
Screening
(n=111)
(n=111)
TRANSITION study: design
Objective:
Evaluate the efficacy and safety of the combination of once-daily insulin detemir
and sitagliptin vs. sitagliptin ± sulfonylurea, both in combination with metformin
in insulin-naïve patients
OD, once daily; OAD, oral anti-diabetic drug; BMI, body mass index
Hollander et al. Diabetes Obes Metab 2011;13:268–75
Version June 2014

66. 36
15
20
8
0
5
10
15
20
25
30
35
40
Category 1 Category 2
HbA1C(%)
6
7
8
9
0 12 18 26 (weeks)
Insulin detemir (OD) +
sitagliptin + metformin
Sitagliptin + metformin
± sulfonylurea
p<0.001
Estimated mean treatment
difference (95% CI)
−0.55 (–0.77; –0.33); p<0.001
HbA1c ≤7.0 % HbA1c ≤6.5 %
p=0.008
p=NS
Patients reaching HbA1c target
without hypoglycaemia
Change in HbA1c
Insulin detemir (OD) +
sitagliptin + metformin
Sitagliptin + metformin
± sulfonylurea
Percentageofpatientsreaching
targetHbA1c
TRANSITION study: results
OD, once daily; CI, confidence interval; NS, non significant
Hollander et al. Diabetes Obes Metab 2011;13:268–75
Mean insulin dose was 0.59 U/kg at end of trial
Version June 2014

67. Weight benefits of detemir with add-on
therapy: sitagliptin (26 wks)
67
BMI, body mass index; Met, metformin; NS, not significant; SU, sulphonylurea
Hollander et al. Diabetes Obes Metab 2011;13(3):268–75

68. SOLVE®: study design
• Observational, multicentre, open-label prospective study
• Insulin-naϊve patients with type 2 diabetes currently on one or
more OADs
OAD, oral antidiabetic drug; OD, once daily
Khunti et al. Diabetes Obes Metab 2012;14:654–61

69. Once-daily Levemir®
reduced HbA1c
Change in HbA1c
Average HbA1c was reduced by 1.3%
using only modest doses of once-daily
Levemir® (0.27 U/kg)
*p<0.05; **p<0.01; ***p<0.001; ns = not significant.
Khunti et al. Diabetes Obes Metab. 2012.
DOI:10.1111/j.1463-1326.2012.01665.x
8.9
7.5
6.0
7.0
8.0
9.0
10.0
Pre-insulin Final
HbA1c
HbA1c(%)
APROM ID 4351; Approval date: October 2012
-1.3%***
average
HbA1c reduction

70. No weight gain with
once-daily Levemir®
APROM ID 4351; Approval date: October 2012
Global
80.8 80.3
0
10
20
30
40
50
60
70
80
90
100
Meanbodyweight(kg)
-0.6***
N=14830
Pre-insulin Final
*p<0.05; **p<0.01; ***p<0.001; ns = not significant
Vora et al IDF 2011 21st World Congress Abstract Book. IDF:
Dubai, 2011; p 275 and Poster discussion D-0829. Insulin
Treatment: Glucose & Other Outcomes, Dec 6th, 14:00-15:00
<Local Reference>
-0.6Kg
average
Weight
reduction

71. +3
units
–3
units
0
maintain current dose
>6.1 mmol/L (>110 mg/dL)
4.4–6.1 mmol/L
(80–110 mg/dL)
<4.4 mmol/L (<80 mg/dL)
If FPG is
>5.0 mmol/L (>90 mg/dL)
3.9–5.0 mmol/L
(70–90 mg/dL)
<3.9 mmol/L (<70 mg/dL)
If FPG is
Goal: 3.9–5.0 mmol/L
(70–90 mg/dL)1
Goal: 4.4–6.1 mmol/L
(80–110 mg/dL)2
Type 2 diabetes dose titration algorithm of
detemir (Levemir® )
FPG, fasting plasma glucose
1. Blonde et al. Diabetes Obes Metab 2009;11:623–31; 2. Insulin Detemir Summary of Product Characteristics, Feb
2014
Version June 2014

72. Dornhorst et al. Diabetes Obes Metab 2008;10:75–81
Insulin detemir’s weight advantage is
also shown in a real-life setting
(PREDICTIVE™ study)
NPH, neutral protamine Hagedorn

73. Individuals with the highest BMI had the
greatest weight loss with insulin detemir
Dornhorst et al. Int J Clin Pract 2008;62:659–65
BMI, body mass index

74. Insulin degludec (Tresiba®)
 Insulin degludec is an ultra long-acting
insulin formulation with several
advantages:
 Lower risk of hypoglycemia
 True 24 hour insulin
Allows flexibility in dosing; especially with
missed doses
Combination of degludec with insulin aspart
planned to allow effective meal-time coverage

75. Pharmacology – Kinetics2
Insulin degludec
 T1/2 : 25 hours
 Glucose-lowering duration : > 42 hours
 Time to steady-state : 3 days of once-daily dosing
 Peak : peakless

76. 76
When basal insulin alone is not
enough
What is the next step?

78. When basal insulin is not enough
Think first of adjusting the basal insulin
dose
 Often under-dosage +++
 Otherwise:
 Prandial insulin secretion
supplementation must
be started

79. In advanced type 2 diabetes, Basal Bolus therapy
reproduces physiological insulin secretion
Adapted from Kruszynska YT, et al. Diabetologia 1987;30:16–21.
Insulin(mU/L)
06.00 12.00 24.0018.00
0
15
30
45
06.00
Breakfast Lunch Dinner
Time (hours)
Endogenous insulin secretion
Ideal basal insulin
Ideal prandial insulin

80. Matching treatment to disease
progression using a stepwise approach
*As the disease progresses, a second daily injection of glulisine may be added
Adapted from Raccah D, et al. Diabetes Metab Res Rev 2007;23:257–64.
Basal Bolus 1+3
Add prandial insulin before each meal
Basal Plus 1+1
Add prandial insulin at main meal
Basal
Add basal insulin and titrate
Lifestyle changes plus metformin
(± other agents)
Progressive deterioration of -cell function
Basal Plus: once-daily basal insulin glargine
plus once-daily* rapid-acting insulin glulisine

81. Antihyperglycaemic therapy in type 2
diabetes : add-on therapy to metformin
Inzucchi SE et al. Diabetes Care 2015;38:140-149
Metformin

82. Type 2 Diabetes ccc., By
Early Progressive Insulin
Deficiency
Early Glycaemic Control
Reduces Complications; Conversely,
poor glycaemic control
is an important driver for
DIABETES COMPLICATIONS

83. There are BENEFITS associated with
Early INSULIN Initiation
Most GUIDELINES suggest
Initiation with BASAL INSULINS
Randomised controlled trials have
shown that Basal Insulin Analogues
are suitable for Early Initiation and
can effectively manage HbA1c, with
low risk of HYPOGLYCAEMIA.

84. Basal Insulin analogue detemir ( Levemir® )
 Long acting once daily
 used in T1DM & T2DM
 approved in pregnancy
 Insulin Detemir provides less weight gain
compared with insulin glargine & NPH.
 Starting or switching to insulin detemir
has been demonstrated to be effective
and safe in several large global
observational studies.
 If added to OHDs : effective HbA1C
reduction control FBS & PPBS not add
more weight gain concern

85. CHOICES MODULES OF THERAPIES FOR MANAGEMENT
OF TYPE 2 DM
4 RIGHTS MODULE

87. Institute of Medicine Report, November 2010
Thank you
DR./ ADEL EL NAGGAR