SCIENTIFIC SEMINARon

Dr Shahjada SelimAssistant Professor

Department of EndocrinologyBangabandhu Sheikh Mujib Medical

University

ORGANIZED BY:

Rapid acting analog: Use and

Optimization

Diabetes is a huge and growing problem, and the costs to society are high and escalating

382 million people have diabetes

By 2035, this number will rise to 592 million

The worldwide challenge of glycaemic control: mean HbA1C in type 2 diabetes

Canada 7.36–8.7%11

Latin America 7.6%1 US 7.2%7

China 9.5%11

India 8.7–9.6%9,11

Japan 7.05–9.6%11

Korea 7.9–8.7%4

Russia 9.6%11

Spain 9.2%8

Sweden 8.7%3

Turkey 10.6%3

UK 8.510–9.8%2

Germany 8.42–9.2%8

Greece 8.911–9.7%3,8

Italy 8.4%11

Poland 9.0%11

Portugal 9.7%3

Romania 9.9%3

1. Lopez Stewart et al. Rev Panam Salud Publica 2007;22:12–20; 2. Kostev & Rathmann Primary Care Diabetes 2013;7:229–33; 3. Oguz et al. Curr Med Res Opin 2013;29:911–20; 4. Ko et al. Diabet Med 2007;24:55–62; 5. Arai et al. Diabetes Res Clin Prac 2009;83:397–401; 6. Harris et al. Diabetes Res Clin Pract 2005;70:90–7; 7. Hoerger et.al. Diabetes Care 2008;31:81–6; 8. Liebl et al. Diabetes Ther 2012;3:e1–10; 9. Shah et al. Adv Ther 2009;26:325–35; 10. Blak et al. Diabet Med 2012;29:e13–20; 11. Valensi et al. Int J Clin Pract 2008;62:1809–19

Type 2 Diabetes Is Progressive

Diabetes is a progressive disease that requires reassessment to reach target

Europe(CODE-2)3

HbA1c <6.5%

31%

69%

Canada(DICE)2

HbA1c <7%

51%49%

Latin America(DEAL)1

HbA1c <7%

43%

57%

Achieving glycaemic target

Failed to achieve glycaemic target

US(NHANES)4

HbA1c <7%

57%43%

• Diabetes progresses and requires treatment reassessment

• Insulin used to help achieve control

England and Wales(NDA5)

HbA1c <6.5%

25%

75%57%

43% 31%

69%

49% 51% 57%43%

DEAL, Diabetes En America Latina; CODE-2, The Cost of Diabetes in Europe - Type II; DICE, Diabetes in Canada Evaluation; NDA, National Diabetes Audit; NHANES, National Health and Nutrition Examination Survey 1. Lopez Stewart et al. Rev Panam Salud Publica 2007;22:12–20; 2. Harris et al. Diabetes Res Clin Pract 2005;70:90–7;3. Liebl et al. Diabetologia 2002;45:S23–8; 4. Hoerger et.al. Diabetes Care 2008;31:81–6; 5. HSCIC et al. National Diabetes Audit Report, 2011–12

Intensification of glucose-lowering treatment delayed despite OAD failure

Avoidable glycaemic burden = time remaining on therapy after exceeding HbA1c target

Metforminmonotherapy

Sulphonylureamonotherapy

Combination(Metformin + SU)

0

10

20

30

40

50

60

1217

2626

37

51

Mon

ths

7% HbA1c target8% HbA1c target

OAD, oral antidiabetic drug; SU, sulphonylureaBrown et al. Diabetes Care 2004;75:1535–40

Good glycaemic control matters: 20 and 30 year follow-up results

1977–1991Randomisation

2007(30 years)

10-year post-trial follow-up(non-interventional)

UKPS original results:Intensive vs. conventional

treatment

12%*

25%*

16%

1997(20 years)

Any diabetes-related endpoint

Myocardial infarction

Microvascular disease

9%*

24%*

15%*

In T2D, improvements in glycaemic control reduce the risk of

complications

*p<0.05; intensive vs. conventional treatmentT2D, type 2 diabetes; UKPDS, UK Prospective Diabetes StudyAdapted from Holman et al. N Engl J Med 2008;359:1577–89; UKPDS Study Group. Lancet 1998;352:837–53

Treating T2D and its complications creates major economic burdens

€1373 1.3xincrease

€1723

€3355

2.4xincrease

€3436

2.5xincrease

€ 5642

4.1xincrease

All insuredpatients

Diabetes, nocomplications

Diabetes,microvascularcomplications

Diabetes,macrovascularcomplications

Diabetes, micro-and macrovascular

complications

Annual costs per patient3

In 2011, ~11% (~$465B) of the total healthcare expenditure worldwide

was spent on treating diabetes1

In 2007, only 10.6% of US expenditure on managing diabetes was on diabetes

medication2

Based on an exchange rate of 1 Euro = 1.4156 US dollars. Exchange rate as of 30 Oct 20111. IDF Diabetes Atlas, 5th Edition. http://www.idf.org/diabetesatlas/5e/healthcare-expenditures. Accessed November 2013; 2. American Diabetes Association Diabetes Care 2008;31:596–615; 3. Liebl et al. Dtsch Med Wochenschr 2001;126:585–89 (CODE-2 Study)

Hypoglycaemia rates are higher than expectedResults from the HAT study

T1D, type 1 diabetesKhunti et al. Diabetologia 2014;57 (Suppl. 1):S201

Prospective data suggests higher than expected rates of hypoglycaemia in both T1D and T2D, in particular severe events

T2D, retrospective (n=19,563)T2D, prospective (n=19,563)

Any hypoglycaemia Severe hypoglycaemia0

5

10

15

20

25

16.5

0.9

19.3

2.5

Hyp

ogly

caem

ia in

cide

nce,

eve

nts

per

patie

nt y

ear

HAT study• Non-interventional, global,

6-month retrospective and 1-month prospective study of patient self-reported hypoglycaemic events

• n=27,585 (T1D: 8,022; T2D: 19,563)

Hypoglycaemia continues to be a main obstacle for HCPs to treat effectively with insulinResults from the GAPP™ study

GAPP™• A global internet survey of patient and

physician beliefs regarding insulin therapy

• n=1250 physicians

0 10 20 30 40 50 60 70 80 90 100

72%

79%

Percentage

I would treat my patients more aggressively if there was no

concern about hypoglycaemia

p<0.05

Diabetes specialistsPrimary care physicians

GAPP, Global Attitudes of Patients and Physicians; HCP, health care providerPeyrot et al. Diabet Med 2012;29:682–9

50%

24%

34%

0

10

20

30

40

50

3 years 6 years 9 years

Glycemic Control Declines Over Time With Traditional Monotherapy

Adequately controlled and treated with sulfonylureas†

13%

44%

34%

0

10

20

30

40

50

3 years 6 years 9 years

Patie

nts

with

A1C

<7%

(%)

Adequately controlled and treated with metformin*

Turner RC, et al. JAMA. 1999;281:2005-2012.

*Overweight drug-naïve patients. †Normal weight and overweight drug-naïve patients

Patie

nts

with

A1C

<7%

(%)

Most Patients With T2D Will Eventually Need Insulin

Types of insulin

Type of Insulin & Brand Names Onset Peak Duration

Role in Blood Sugar Management

Rapid-Acting

Lispro 15-30 min. 30-90 min 3-5 hours Covers insulin needs for meals eaten at the same time as the injection.Aspart 10-20 min.

40-50 min. 3-5 hours

Glulisine 20-30 min.30-90 min. 1-2½ hours

Short-Acting

Regular 30 min- 60 min

2-5 hours 5-8 hours Covers insulin needs for meals eaten within 30-60 minutes

Intermediate-Acting

NPH (N) 1-2 hours 4-12 hours

18-24 hours

Covers insulin needs for about half the day or overnight.

Types of insulin

Name of Insulin

Onset DurationRole in Blood

Sugar Management

Long-Acting

Long-acting insulin covers insulin needs for about one full day.

Degludec 30-90 min No peak: insulin is

delivered at a steady

level.

Longer than 24 hours

Glargine 30-90 min Up to 24 hours

Detemir 1-120 min 20-24 hours

Types of insulin

Type of Insulin Onset Peak DurationRole in Blood Sugar

Management

Pre-Mixed*

30/70 30 min. 2-4 hours 14-24 hours These products are generally taken two or three times a day before mealtime.

50/50 30 min. 2-5 hours 18-24 hours

25/75 15 min.30 min.-2½

hours 16-20 hours

InhalerExubera  Banned

Afrezza  With in min 12 to 15 min 2-3 hoursPost prandial effects.

*Premixed insulins are a combination of specific proportions of intermediate-acting and short-acting insulin in one bottle or insulin pen (the numbers the brand name indicate the percentage of each type of insulin).

Basal and Bolus Insulin

6-16

The Basal Bolus Insulin Concept

• Basal Insulin– Suppresses glucose production between meals and overnight– Nearly constant levels – 50% of daily needs

• Bolus Insulin (Mealtime or Prandial)– Limits hyperglycemia after meals– Immediate rise and sharp peak at 1 hour – 10% to 20% of total daily insulin requirement at each meal

6-20

Ideally, for insulin replacement therapy, each component should come from a different insulin with

a specific profile

Insulin and Glucose Patterns: Normal and Type 2 Diabetes

Polonsky, et al. N Engl J Med. 1988;318:1231-1239.

100

200

300

400

Glucose Insulin

0600 1000 18001400 02002200 0600

Time of Day

0600 1000 18001400 02002200 0600

Time of Day

20

40

60

80

100

120

B L SB L S

Normal

Type 2 Diabetes

mg/

dL

U/m

L

6-17

Limitations of Human NPH, Lente, and Ultralente

• Do not mimic basal insulin profile– Variable absorption

– Pronounced peaks

– Less than 24-hour duration of action

• Cause unpredictable hypoglycemia– Major factor limiting insulin adjustments

– More weight gain

6-30

Rapid-acting Analogues: Clinical Features

• Insulin profile more closely mimics normal physiology

• Convenient administration immediately prior to meals

• Faster onset of action

• Limit postprandial hyperglycemic peaks

• Shorter duration of activity

– Reduced late postprandial hypoglycemia

– But more frequent late postprandial hyperglycemia

• Need for basal insulin replacement revealed

6-27

Structure of insulin aspart

Glu

Thr

Lys

ThrTyr Phe Phe Gly Arg

GluGly

Cys

Val

Leu

Tyr

Leu

Ala

Val

Leu

His

Ser

GlyCysLeuHisGlnAsnValPheB1

Asn CysTyr

Asn

Glu

Leu

Gln

Tyr

LeuSerCysIleSerThrCys

Cys

Gln

Glu

Val

Ile

Gly

A21B28B30

AspPro

Asp

Insulin aspart: more physiological insulin profile than soluble human insulin

Lindholm et al. Diabetes Care 1999;22:801-5

Plas

ma

insu

lin (p

mol

/l)

Time (hours)

Insulin aspart, t = 0 min

Human insulin, t = 0 min

Human insulin, t = –30 min

(insulin dose 0.15 U/kg)

600

500

400

300

200

100

00 1 2 3 4 5 6

n = 22

Prandial increment isthe mean increase in blood glucose from pre-meal to 90 min post-meal

European trial North American trial

Bloo

d gl

ucos

e in

crem

ent (

mm

ol/l

)

p < 0.001

0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

Insulin aspartHuman insulin

Postprandial blood glucose increment:mean over the three meals at 6 months

Home et al. Diabetic Med 2000;17:762-70, Raskin et al. Diabetes Care 2000;23:583-8

p < 0.001

n = 1070 n = 884

Postprandial glucose control in type 1 diabetes

• Patients with type 1 diabetes (n = 368) were randomised to receive either IAsp or HI as the meal-related part of a basal-bolus regimen

• IAsp reduced postprandial blood glucose levels when compared to HI (at 3 and 15 months)

Post-breakfast

Post-lunch Post-dinner

0123456789

10

IAsp HI

Post

pran

dial

glu

cose

(mm

ol/l

)

DeVries et al. Diabet Med 2003 Apr;20(4):312-8

p = 0.0137 p = 0.0037 p = 0.081

N = 368

At 3 months

Change in HbA1c

-2-10123456789

Baseline End of trial Difference

HbA

1c (%

)

IAspHIBHI

Bretzel et al. Diabetologia 2001;44(Suppl. 1):A209 1197

n = 222

Insulin aspart significantly reduces the rate of severe nocturnal hypoglycaemia

0

0.5

1

1.5

2

2.5

3

Totalevents

Nocturnalevents

Diurnalevents

Hyp

ogly

caem

ia e

vent

rate

(eve

nts

per p

atien

t-ye

ar)

Heller et al. Diabetic Medicine 2004, in press 066

IAspHI

n = 155

72% risk reduction with IAsp

• Insulin Aspart provides improved postprandial glycaemia through a rapid onset, rapid time to maximum effect and a gentle return to baseline insulin levels.

• Insulin Aspart significantly improves and maintains lower HbA1c levels over 3 years without increasing major hypoglycaemia.

Insulin Aspart

• Insulin Aspart is the only analogue to show a 72% reduction in major nocturnal hypoglycaemia

• Insulin Aspart can be administered immediately before or after a meal offering convenience and flexibility

• Insulin Aspart is safe and efficacious in pumps

Insulin Aspart

30

Reduced glucose excursions vs. Insulin Lispro and BHI 30

Hermansen K et al. Diabetes Care 2002;25:883–888

p < 0.05

–10%

p < 0.001

–17%

0

13

14

15

16

17

18

19

20

21

Humalog® Mix 25 BIAsp BHI 30

Bloo

d gl

ucos

e ex

curs

ion

0– 5

h (m

mol

/l h

)

31

Improved postprandial glucose after 3 months

*

Bloo

d gl

ucos

e (m

mol

/l)

*

0Pre-

10

12

Post-

8

6

BIAsp 30

BHI 30 * p < 0.05*

*

LunchPre- Post-Breakfast

Pre- Post-Dinner

Bedtime 0200 h

Boehm B et al. Diabet Med 2002;19(5):393–399

32

Superior glycaemic control with BIAsp+ metformin in poorly controlled patients (HbA1c > 9%)

p = 0.037 p = 0.033

Kvapil M et al. Diabetes 2002;51(Suppl 2):A104

7

7.5

8

8.5

BIAsp BIAsp+met Met+SU

Treatment group

HbA

1c (%

)

0

33

Blood glucose levels did not differ between treatment groups

Warren et al. Diab Res Clin Pract, in press 2004

Preprandial dosing(BIAsp, bid)Postprandial dosing(BIAsp, bid)

0

20

40

60

80

100

120

140

160

180

200

Before breakfast

Before dinner

2 hrs after breakfast

2 hrs afterdinner

Bloo

d gl

ucos

e le

vels

(mg/

dl)

n = 91

p = NS in all cases

• BIAsp provides improved postprandial glycaemic control compared to biphasic human insulin and Insulin Lispro.

• BIAsp provides a superior hypoglycaemic profile to biphasic human insulin

Biphasic Insulin Aspart (BIAsp)

• BIAsp improves HbA1c when used in combination with oral medications

• BIAsp is simple and convenient to use in clinical practice

• BIAsp is effective and well tolerated in adolescents

Biphasic Insulin Aspart (BIAsp)

Thank you

Thank You All