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.