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Basal Bolus Regimen in T2DM
Prof. Dr. Hala Aly Gamal El DinProfessor Of internal medicine
Faculty of Medicine - Cairo University
Targets for glycemic (blood sugar) control
• Implementation Conference for ACE Outpatient Diabetes Mellitus Consensus Conference Recommendations: Position Statement at http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf. Accessed January 6, 2006.
• AACE Diabetes Guidelines – 2002 Update. Endocr Pract. 2002;8(suppl 1):40-82. • American Diabetes Association. Diabetes Care. 2009;32(suppl 1)
ADA AACE
A1c (%) <7* ≤6.5
Fasting (preprandial) plasma glucose 70-130 mg/dL <110 mg/dL
Postprandial (after meal) plasma glucose <180 mg/dL <140 mg/dL
*<6 for certain individuals
Goals of Glucose Management
4
Relation between PPG control & Relation between PPG control & Achieving A1C GoalAchieving A1C Goal
Increasing Contribution of PPG as A1C Improves
30% 40% 45% 50%70%
60% 55% 50%30%
70%
0%
20%
40%
60%
80%
100%
< 10.2 10.2 to9.3
9.2 to8.5
8.4 to7.3
< 7.3
A1C Range (% )
%
Contr
ibuti
on
FPGPPG
Adapted from Monnier L, Lapinski H, Collette C. Contributions of fasting and postprandial plasnma glucose increments to the overall diurnal hyper glycemia of Type 2 diabetic patients: variations with increasing levels of HBA(1c).Diabetes Care. 2003;26:881-885.
• 20-25% of Patients Have A1Cs between 8.0% and 7.0%
• Moving from A1C 8.0% to 7.0% - Reduces Serious Complications
UKPDS Study Results
– Reduced microvascular complications (kidney, eye, etc.) by 17-33%
– Reduced risk of heart attack by 16%
– Reduced diabetes-related deaths by 21%
• Challenge: More difficult to make improvements as A1C gets closer to 7.0%
Moving from A1C 8.0% to 7.0% Difficult and Important!!
Every 1% drop in HbA1c can reduce long-term diabetes complications
43%
Lower extremity amputation or fatal peripheral
vascular disease
37%
Microvascular disease
19%
Cataract extraction
14%
Myocardial infarction
16%
Heart failure
12%
Stroke
UKPDS: Stratton et al. BMJ 2000;32:405–12
Improving control reduces risks of long term complications
A1C reduction with glucose – lowering medications
Oral agents A1C (%)*Sulfonylureas 1.5Biguanides (metformin) 1.5Glinides 1.0–1.5Thiazolidinediones 0.8–1.0DPP-IV inhibitors 0.5–0.9α-Glucosidase inhibitors 0.5–0.8
Parenteral/inhaled agentsInsulin ≥2.5Inhaled insulin 1.5GLP analogues 0.6Amylin analogues 0.6
*MonotherapyDPP = dipeptidyl peptidase; GLP = glucagon-like peptideNathan DM. N Engl J Med. 2007;356:437-40.
Nathan DM. N Engl J Med. 2007;356:437-40.
Insulin is the most effective anti diabetic agent
•Significant hyperglycemia at presentation
•Hyperglycemia on maximal doses of oral agents
•Decompensation– Acute injury, stress, infection, myocardial ischemia– Severe hyperglycemia with ketonemia and/or ketonuria– Uncontrolled weight loss– Use of diabetogenic medications (eg, corticosteroids)
• Surgery
• Pregnancy
Insulin therapy in T2DM indications
A clinical fact
Most Patients with T2DM will eventually need exogenous insulin to maintain recommended targets for glycaemic control
Starting insulin treatment in adults with Type 2 diabetesRCN guidance for nurses 2004
When to Start Insulin First
ADA-EASD Consensus
•SEVERELY CATABOLIC PATIENT•Hemoglobin A1C > 10%•FBS > 250 mg/dl (13.9 mmol/l)•Random consistently > 300 mg/dl (16.7 mmol/l)
Nathan et al. Diabetes Care 2006;29: 1963-1972
Insulin 7%
7% 8% 9% 10%
Combination oral agents
MonotherapyDiet and exercise
T2DM treatment
Old paradigm by A1C level
At diagnosis:
Lifestyle+
Metformin
Lifestyle + Metformin+
Basal insulin
Lifestyle + Metformin+
Sulfonylureaa
Lifestyle + Metformin+
Intensive insulin
Lifestyle + Metformin+
PioglitazoneNo hypoglycaemiaOedema/CHFBone loss
Lifestyle + Metformin+
Pioglitazone+
Sulfonylureaa
Tier 1: Well validated core therapies
Tier 2: Less well validated therapies
STEP 1 STEP 2 STEP 3
Lifestyle + Metformin+
GLP-1 agonistb
No hypoglycaemiaWeight lossNausea/vomiting
Lifestyle + Metformin+
Basal insulin
New ADA/EASD treatment New ADA/EASD treatment algorithm for Type 2 diabetesalgorithm for Type 2 diabetes
Reinforce lifestyle interventions at every visit and check HbA1c every 3 months until HbA1c is <7 % and then at least every 6 months. The interventions should be changed if HbA1c is ≥7 %
aSulfonylureas other than glibenclamide (glyburide) or chlorpropamidebInsufficient clinical use to be confident regarding safety
Nathan DM, Buse JB, Davidson MB, et al. Diabetologia. 2009;52:17-30
The Ideal Basal Insulin
• Mimics normal pancreatic basal insulin secretion
• Long-lasting effect – 24 hours• Smooth, peakless profile• Reproducible and predictable effects• Reduced risk of nocturnal hypoglycemia• Once-daily administration
Levemir® FlexPen® ?
LysB29(N-tetradecanoyl)des(B30)human insulin
Thr
Glu
Lys
ValPhe
Asn
Glu
LeuGln
TyrLeu
SerCysIleSerCysCys
GlnGluValIle
GlyTyr
CysAsnLys
ProThr
TyrPhePhe ArgGly
GluGly
CysVal
Leu
TyrLeu
Ala
ValLeu
HisSer
GlyCys
AsnGln LeuHisB1
A21
A1
B29
C14 fatty acid chain
(Myristic acid)
Thr
Detemir Properties:
Neutral pH Albumin binding Long extended action More within patient
consistency Less hypoglycemia Less weight gain
Insulin Detemir (Levemir®)
Hormone
Blood TissueInjection site
CarrierProtein
CarrierProtein
HormoneHormone
Hormone
Receptor
Receptor
Mode of Action
Use of Serum Carrier Protein (e.g. Albumin) to Extend time of action
CarrierProtein
Levemir® FlexPen®
•Designed to bind specifically to albumin •Albumin binding protracts:
– Absorption of insulin detemir from the subcutaneous depot
– Residency of insulin detemir in the circulation•Albumin binding buffers variability of action of insulin
detemir•There are no safety concerns with albumin binding of
insulin detemir or with changes to its insulin structure
Albumin binding of Levemir®
• Myristic acid binds at fatty-acid binding sites of albumin
• 98.8% binding in human plasma
Safety of albumin binding
At therapeutic doses, insulin detemir occupies a tiny fraction of available albumin binding sites, with more than 60,000-fold excess albumin over insulin
•Self association (hexameric)•Fatty acid side chains bind to albumin in
injection depot
•Albumin binding in circulation
Protracted absorption
‘Buffering’ effect and minor contribution to protraction
Mode of prolonging action
Why do we say Levemir™ is “predictable”?
Precipitation
Glargine
Precipitation
Levemir™
Solution, acid pH, pain
Precipitation & de-precipitation is the mechanism of
protraction: so factors of precipitation and
absorption remain
Solution, neutral pH, no pain
No precipitation mechanism of protraction depends on
increased self -association
No absorption factor – albumin binding buffers absorption
GIR profiles following four non-consecutive injections of identical doses (0.4U/kg, thigh) in three patients
Heise T et al. Diabetes 2004;53: 1614-20
Variability in time-action profile of basal insulin
Blonde L et al; Diabetes Obes Metab. 2009 Jun;11(6):623-31
• Levemir® was initiated at 0.1 to 0.2 unit/kg or 10 units once daily at dinner or bedtime
• Dose titration was based on the PREDICTIVE® 303 patient-directed self-titration algorithm
• Patients continued on OAD therapy
Levemir® once dailySelf-adjusted target FPG 70-90 mg/dl
Levemir® once dailySelf-adjusted target FPG 80-110 mg/dl
Prior OADtherapy
Screening period
(n=122)
(n=122)
Main inclusion criteria:• Type 2 diabetes, ≥3 months
• 7%≤HbA1c≤9%
• BMI ≤45 kg/m2
• Age ≥18 years
• Insulin naïve
TITRATE™Study
Time (study week)
FPG 70-90 mg/dl
FPG 80-110 mg/dl
Baseline 12 20
Mean H
bA
1c (%
)
8.0
7.8
7.6
7.4
7.2
7.0
6.8
6.6
6.4
6.2
6.0
8.2
7.94
7.04
7.00*
7.99
6.93 6.77*
*Change in both groups , p=0.019 at 20 weeks Blonde L et al; Diabetes Obes Metab. 2009 Jun;11(6):623-31
-0.94% reduction in HbA1C
-1.22% reduction in HbA1C
HbA1C Improvement
Events
per
sub
ject
/year
Hypoglycaemic events
p=NS
p=NS
One major hypoglycaemic event was reported by subject in the 70-90 mg/dl target group
Low rates of hypoglycaemia with once-daily Levemir®
FPG 80-110 mg/dl
FPG 70-90 mg/dl
Blonde L et al; Diabetes Obes Metab. 2009 Jun;11(6):623-31
Hypoglycaemic Events
Change in weight
Insulin detemir
NPH insulin
Baseline BMI
25 >25-30
>30-35
>35
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
Philis-Tsimikas et al. Clin Ther 2006 Dornhorst et al. Int J Clin Pract 2008
0.55
-0.06
-0.56-0.96
-1.51-2
-1
0
1
n= 270 395 374 341 640<25 25–<27 27–<29 29–<31 ≥31
Baseline BMI
303 Titration:
Patients who experienced hypoglycaemia reduced their daily dose by 3 units
Titration at a once-daily dose
70-90 mg/dLor 80-110 mg/dL
FPG Targetrange
Below target
Above target
Mean 3-day FPG
3 Units
3 Units
no adjustmentMaintain dose
3 unitsIncrease
dose
Decrease dose
3 units
0
3
0
3
Insulin analogues compared
Insulin receptor affinity
IGF-1R affinity
Insulin receptor off rate
Metabolic potency
Mitogenic potency
Human insulin
=100 =100 =100 =100 =100
Insulin aspart
92 ± 6 81 ± 9 81 ± 8 101 ± 2 58 ± 22
Insulin detemir
18 ± 3 16 ± 1 204 ± 9 27 11
Kurtzhals P, et al. Diabetes 2000; 49: 999
Insulin analogues compared
Insulin receptor affinity
IGF-1R affinity
Insulin receptor off rate
Metabolic potency
Mitogenic potency
Human insulin
=100 =100 =100 =100 =100
Insulin aspart
92 ± 6 81 ± 9 81 ± 8 101 ± 2 58 ± 22
Insulin lispro 84 ± 6 156 ± 16 100 ± 11 82 ± 3 66 ± 10
Insulin glargine
86 ± 3 641 ± 51 152 ± 13 60 ± 3 783 ± 13
Insulin detemir
18 ± 3 16 ± 1 204 ± 9 27 11
Kurtzhals P, et al. Diabetes 2000; 49: 999
ONCE-DAILY DOSING1,3
OPTIMALHbA1cControl1,2
LOW RISK OF HYPOS3,
4
LESSWEIGHTGAIN4,5
FlexPen® TRUSTED BY MILLIONS6,7
Summary
• Treatment with basal analogues enables patients to reach HbA1c
target with low rate of hypoglycaemia
• HbA1c improves but some patients need more
• Levemir® + OD is associated with:
– reduced hypoglycemia in comparison to NPH, and
– reduced weight gain in comparison to any other basal insulin.
• Initiation of Levemir® + OD with 3-0-3 algorithm is effective, simple and safe.
Bolus Insulin
Physiologic Insulin Secretion: 24-hour Profile
Prandial glucose
150
Time of day
Glucose(mg/dL)
100
50
07 8 9 10 11 12 1 2 3 4 5 6 7 8 9
AM PM
Basal glucose
Prandial insulinInsulin(µU/mL)
Basal insulin
Breakfast Lunch Dinner
50
25
0
Limitations of Human Regular Insulin
•Slow onset of action–Requires inconvenient administration:
20 to 40 minutes prior to meal –Risk of hypoglycemia if meal is further
delayed–Mismatch with postprandial
hyperglycemic peak
35
Structure of insulin aspart (NovoRapid®)
NovoRapid® is designed for low self-association
to allow rapid absorption
Absorption: human insulin vs. Insulin aspart
Insulin aspart
Insulinconcentration (M)
Absorption
Monomer
Capillary membrane
T-typehexamer
Dimer
R-typehexamer
10–3
10–4
10–6
10–8
Human insulin
This is purely schematic to illustrate absorption of molecules
37
NovoRapid® is designed for rapid, flexible control
1. Rapid absorption
Meal time flexibility
2. Rapid time to maximum effect
Efficacy
3. Rapid return to baseline insulin level
Safety (Less Hypos)
BI Yu- fang, ZHAO Lie-bin et al. Compare efficacy and safety of insulin aspart and Novolin R delivered withCSII in 21 Chinese diabetic patients.Chin Med 2007;120(19):1700-1703
Barnett AH, Owens DR. Lancet. 1997;349:97-51. White JR, et al. Postgrad Med. 1997;101:58-70. Kahn CR, Schechter Y. In: Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 1990:1463-1495. Coates PA, et al. Diabetes. 1995;44(Suppl 1):130A.
Estimated Pharmacokinetics of Current Insulin Preparations
Onset PeakEffective Duration
Rapid acting analog
<15 min 0.5-1.5 hr 3 hr
Human Regular Insulin
0.5-1 hr 2-3 hr 3-6 hr
Bolus Insulin for Pre-prandial Administration
Predictable, reproducible time-action profile
Rapid onsetof action
Short durationof action
Desirable KineticCharacteristics Clinical Benefits
Precise dosing
Optimal glucodynamics
Reduced risk of hypoglycemia (day and night)
NovoRapid® FlexPen®
Insulin Aspart vs. Regular Human Insulin: Effect on A1C
A1C
(%
)
Time (months)
Data represent mean ± SEM* P < 0.05
0 3 6
8.5
8.0
7.5
0
*•
Insulin AspartRegular Insulin
Effect of NovoRapid® versus Actrapid® on PP myocardial perfusion in type 2
diabetes
Myo-cardialBlood-Flow
Scognamiglio R et. al. Diab Care 2006;29:95–100
T2D PatientsHealthy group people
Fasting Posprandial
Nippon ultrarapid Insulin and diabetic Complication Evaluation (NICE) Studie
Cumulative CV events in 374 Japanese T2 patients after 4.5 years
Nishimura M et al. Diabetologia 2008;51(Suppl1):S5432008;51(Suppl1):S543
44
NovoRapid®: approved for every stage of life,from children aged 2 years to the elderly2
Approved for use in abroad range of patients
For patients with Type 1 diabetes2
For patients with Type 2 diabetes2
For patients using an insulin pump2
Even patients requiring special consideration
For use in pregnancy- can be used during lactation2
For use in the elderly2
For use in children aged 2 years and above2
For use in special population with renal or hepatic imparement2,3
45
NovoRapid® : helps T2DM patients attain and maintain their HbA1c goals4
• 1.2% reduction in HbA1c from baseline4
• 63% of patients achieved ADA target <7% over 3 years4
Reduced mean PPG levels4
• The addition of NovoRapid® significantly reduced the mean
• PPG level by 67 mg/dL (3.72 mmol/L)4
6.9% median HbA1cachieved by patients at 3 years
46
NovoRapid® : Reduced rate of nocturnal hypoglycaemia
• 24% Lower risk of nocturnal hypoglycaemia was confirmed by a meta-analysis of 3,727 T1DM patients in randomized, controlled trials conducted over 10 years of clinical experience with NovoRapid®7
Reduced rates of hypoglycaemia, even in pregnant women8
• Initiation of NovoRapid® preconception may result in lower risk of severe hypoglycaemia in pregnant women with type 1 diabetes8
Nocturnal events
72% less major nocturnalhypoglycaemia in patients withtype 1 diabetes6
47
NovoRapid® :pre and post meal dosing allows patients to treat according to
lifestyle9
Depending on their lifestyle and eating habits, some patients require more treatment flexibility10-12
• NovoRapid® enabled an overall improved quality of life with increased flexibility compared with regular human insulin T1DM10
• Since children may have unpredictable eating habits, parents preferred NovoRapid® over regular human insulin11
• Pregnant women with T1DM preferred NovoRapid® for more flexibility12 in their treatment9
48
FlexPen® : trusted by millions worldwide13,14
Next Generation FlexPen® from Novo Nordisk offers
New features of FlexPen
Approved shelf-life: aspart vs. glulisine
• The approved shelf-life is greater for NovoRapid® than for Apidra® in both the Europe and US
• Furthermore, once in use NovoRapid® remain stable for 28 days at 30°C while Apidra® must be stored at no greater than 25°C
Glulisine “zinc-free” counter - what data do we have?
European Label US Label
Shelf-life (2-8°C)
In-use Shelf-life (2-8°C)
In-use
NovoRapid®/NovoLog® 30 months 28 days <30°C
30 months 28 days <30°C
Insulin glulisine 24 months 28 days <25°C
24 months 28 days <25°C
Glulisine US label April 07, European label July 05NovoRapid Core Data Sheet, version 10, 2007
51
After 10 years of study and use2, no other rapid- acting insulin is part of so many
lives1
• Approved for every stage of life, from children aged 2 years to the elderly2
• Helps patients attain and maintain their HbA1c goals4
• NovoRapid® significantly reduced major nocturnal hypoglycaemia versus regular human insulin by 72%6,7
• Pre- and post-meal dosing allows patients to treat according to lifestyle10
• FlexPen®: trusted by millions worldwide14,15
Summary
• Timely addition of prandial insulin reflects a meal plus basal insulin coverage
• Tight glycaemic control can be achieved and maintained with low rates of hypoglycaemia and minimal weight gain, using insulin Detemir (Levemir®) OD first, then adding short acting analogue insulin (insulin Aspart, NovoRapid®), stepwise or with all meals according to 1-0-1
• Initiation and intensification of insulin therapy in type 2 diabetes can be done safely, effectively and conveniently
References:
1. IMS Health Inc. IMS MIDAS (MATQ209). 2. NovoRapid [summary of product characteristics]. Bagsværd, Denmark: Novo Nordisk A/S; 2009. 3. Holmes G, Galitz L, Hu P, Lyness W. Pharmacokinetics of insulin aspart in obesity, renal impairment, or hepatic impairment. Br J Clin Pharmacol. 2005;60(5):469-476. 4. Holman RR, Farmer AJ, Davies MJ, et al, for the 4-T Study Group. Three-year efficacy of complex insulin regimens in type 2 diabetes. N Engl J Med. 2009;361(18):1736-1747. 5. Holman RR, Thorne KI, Farmer AJ, et al, for the 4-T Study Group. Addition of biphasic, prandial, or basal insulin to oral therapy in type 2 diabetes. N Engl J Med. 2007;357(17):1716-1730. 6. Heller SR, Colagiuri S, Vaaler S, et al. Hypoglycaemia with insulin aspart: a double-blind, randomised, crossover trial in subjects with type 1 diabetes. Diabet Med. 2004;21(7):769-775. 7. Heller S, Bode BW, Kozlovski P, Svendsen A. Examining the glycaemic and hypoglycaemic benefits with rapid-acting insulin analogues: a meta versus regular human insulin in randomised controlled trials [poster 916]. Diabetologia . 2009;52(suppl 1):S359-S360. 8. Heller S, Damm P, Mersebach H, et al. Hypoglycemia in type 1 diabetic pregnancy: role of preconception insulin aspart treatment in a randomized study. Diabetes Care. 2010;33(3):473-477. 9. Brunner GA, Hirschberger S, Sendlhofer G, et al. Post-prandial administration of the insulin analogue insulin aspart in patients with type 1 diabetes mellitus. Diabet Med. 2000;17(5):371-375. 10. Bott U, Ebrahim S, Hirschberger S, Skovlund SE. Effect of the rapid-acting insulin analogue insulin aspart on quality of life and treatment satisfaction in patients with type 1 diabetes. Diabet Med. 2003;20(8):626-634. 11. Danne T, Råstam J, Odendahl R, et al. Parental preference of prandial insulin aspart compared with preprandial human insulin in a basal-bolus scheme with NPH insulin in a 12-wk crossover study of preschool children with type 1 diabetes. Pediatr Diabetes. 2007;8(5):278-285. 12. Mathiesen ER, Kinsley B, Amiel SA, et al, on behalf of the Insulin Aspart Pregnancy Study Group. Maternal glycemic control and hypoglycemia in type 1 diabetic pregnancy: a randomized trial of insulin aspart versus human insulin in 322 pregnant women. Diabetes Care. 2007;30(4):771-776. 13. IMS Health Inc. IMS MIDAS (12 months ending September 2009). 14. Reimer T, Hohberg C, Pfützner AH, Jørgensen C, Jensen KH, Pfützner A. Intuitiveness, instruction time, and patient acceptance of a prefilled insulin delivery device and a reusable insulin delivery device in a randomized, open-label, crossover handling study in patients with type 2 diabetes. Clin Ther. 2008;30(12):2252-2262. 15. Asakura T, Seino H, Kageyama M, Yohkoh N. Evaluation of injection force of three insulin delivery pens. Expert Opin Pharmacother. 2009;10(9):1389-1393. 16. Rissler J, Jørgensen C, Rye Hansen M, Hansen N-A. Evaluation of the injection force dynamics of a modified prefilled insulin pen. Expert Opin Pharmacother. 2008;9(13):2217-2222.17. Sommavilla B, Jørgensen C, Jensen KH. Safety, simplicity and convenience of a modified prefilled insulin pen. Expert Opin Pharmacother. 2008;9(13):2223-2232. 18. Weise A, Pfützner JW, Borig J, et al. Comparison of the dose accuracy of prefilled insulin pens. J Diabetes Sci Technol.2009;3(1):149-153.
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