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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
DIABETES SPOT LIGHTS
INSULIN initiation benefits/
guidelines
New ultra long basal insulin
analogue benefits
& Summary/home message
:
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
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)
SAUDI ARABIA
1 IN 4
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).
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%
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
CARDIO-METABOLIC RISK
REDUCTION???? 4-stop
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
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*
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
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
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
Barriers to Diabetes Care
Clinical Practice
Therapeutic Regimen
(poly-pharmacy/complex)
Disease Process
Patient Adherence
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
Early initiation of
Basal Insulin
in management of T2DM
is recommended by all
International Guidelines
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
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
Recent Guidelines
2016
But
Insulin considered as
A …………??
For both * patients* doctors
LETHAL
WEAPON
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.
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.
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
Basal Insulin choice
NPH: insulin with protamine,
intermediate:
"Long-acting" insulin analogs
 Glargine:
 Detemir:
Cause of Type 2 DM
► Insulin resistance (genetics)
- aggravated by obesity
- aggravated by lack of exercise
► “Exhaustion” of insulin-producing β-cells
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
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
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.
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.
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
Early insulin treatment prolongs beta-cell
function and promotes metabolic control
Alvarsson et al. Diabetes Care 2003;26:2231–7
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
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
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
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
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.
(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
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
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.
(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.
(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
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.
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
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.
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
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
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
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
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
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
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
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
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
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
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
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
+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
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
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
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
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
When basal insulin alone is not
enough
What is the next step?
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
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
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
Antihyperglycaemic therapy in type 2
diabetes : add-on therapy to metformin
Inzucchi SE et al. Diabetes Care 2015;38:140-149
Metformin
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
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.
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
CHOICES MODULES OF THERAPIES FOR MANAGEMENT
OF TYPE 2 DM
4 RIGHTS MODULE
Institute of Medicine Report, November 2010
Thank you
DR./ ADEL EL NAGGAR

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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
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  • 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)
  • 7.
  • 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).
  • 10.
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  • 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%
  • 13.
  • 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
  • 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
  • 19.
  • 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
  • 27.
  • 29.
  • 30.
  • 31. But Insulin considered as A …………?? For both * patients* doctors
  • 32.
  • 34.
  • 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?
  • 77.
  • 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
  • 86.
  • 87. Institute of Medicine Report, November 2010 Thank you DR./ ADEL EL NAGGAR