Modern Insulins: Evolution For Better Glycemic Control

Modern Insulins: Evolution for Better Glycemic Control

Topics to discuss… Physiological Insulin Profile Available Human Insulins Limitation of Human Insulins Modern Insulins: Do they answer the limitations? Available Modern Insulins – Rapid-acting – Long-acting – Premixed • Summary • • • • •

Insulin First hormone to be • Discovered-oldest hypoglycemic agent • Introduced in clinical practice • Structurally characterized • Synthesized – chemically • Biosynthesized – by rDNA technology ‘one of the most extensively studied proteins’

Insulin

The Most Powerful Agent We Have to Control Glucose

30th July 1921 Experiments in Toronto University F Banting, surgeon C Best, medical college student Banting & Best- extracted insulin from dog & proved that it controls symptoms of diabetes in dogs – 1921

Banting & MacleodNobel Prize for Medicine & Physiology in 1923

Milestones In Development 0f Insulin •

1921 – Discovery of insulin. Following which Eli Lilly and Novo Nordisk start industrial production.

•

1936 – First long-acting insulin (PZI), 1946-NPH, 1953-IZS

•

1960s – First neutral soluble insulin; pre-mixed preparations

•

1973 – Monocomponent insulin, new standard in purity, by Novo

•

1981 - Semi-synthetic human insulin produced

•

1987 – Human insulin (recombinant DNA-Novo)

•

1996 – First insulin analogue

Types of insulin •

Based on SPECIES of origin: Bovine, Porcine & Human

•

Based PURITY: Early preparations, Highly purified & Monocomponent

•

Based on ACTION profile: Short, Intermediate, Long-acting; Mixed

•

Based on STRENGTH of preparation: 40 i.u./ml & 100 i.u. /ml

Targets for Glycemic Control*

• ADA Target

A1c < 7.0%

• Eur IDF and AACE Targets

A1c < 6.5%

• Normal

A1c < 6.0%

• Realistic Target --- Lowest A1c possible without unacceptable adverse effects

*DCCT-referenced assays- Normal Range 4-6%

So, Why Modern Insulins ?

"In using insulin it would of course be ideal if it could be supplied so as to imitate the natural process" Macleod and Campbell 1925 (co-discoverers of insulin with Banting and Best)

Insulin Analogues -Rationale (1) Limitations of conventional soluble human insulin • Inability of s.c. injected soluble insulin to mimic the physiological pattern  Delayed onset of action (30-60 min after injection) i.e. should be injected 30-60 min prior to a meal  Prolonged duration of action (6-8 hrs after injection) • Inadequate insulin when in need • Insulin when not needed • Fitting lifestyle - No

Insulin Analogues -Rationale (2) • Postprandial glucose – Due to variable absorption soluble human insulin does not limit postprandial glucose excursions effectively, which could be an important clinical failing

Contribution of Fasting & Post-Prandial Glycemia to A1C in T2DM Fasting

Post-Prandial

Contribution (%)

100 80 60 40 20 0

< 7.3

7.3-8.4

8.5-9.2

9.3-10.2

A1C (%) quintiles Monnier L et al. Diabetes Care 2003;26:881

>10.2

The shortcomings of conventional Actrapid •

Physiological insulin profile: basal component meal-related peaks

•

Human Actrapid fails to match normal insulin peak

Fails to match the physiology

Insulin Analogues -Rationale (3) • Variability of human insulin Action – Leads to UNPREDICTABILITY in Insulin Action • PREDICTABILITY in insulin action means : To get a blood glucose control which is least variable (or fluctuating) from day to day With the same insulin dose

CGMS plots for one patient on three successive days of once-daily NPH insulin Day 1

Day 2

Glucose concentration (mmol/l)

20.0

Day 3

15.0 10.0 Blood Glucose level is highly Variable with same insulin in the same patient Due to UNPREDICTABLE insulin action

5.0 0.0

CGMS : Continuous Glucose Monitoring System -5.0 12:00 am

4:00 am

8:00 am

12:00 pm

Time Data from David Russel-Jones,2000

4:00 pm

8:00 pm

12:00 am

Variability : So what ? • “ I took the same insulin and the same meal, but woke up in the night with an RBS of 45 mg/dl” • “ Some days, I get ‘hypo’ at 6pm and have to eat something” • “ Doctor, I hate snacking as I become fat, but what to do about the low sugars ?”

Doctor, meri sugar kyon badalti rehti hain?

Variability : So what ? • “ I took the same insulin and the same meal, but woke up in the night with an RBS of 25 mg/dl” • “ Some days, I get ‘hypo’ at 6pm and have to eat something” • “ Doctor, I hate snacking as I become fat, but what to do about the low sugars ?”

Doctor, meri sugar kyon badalti rehti hain?

Patients’ experience

Unpredictable BG

Periods of poor control

Hypoglycaemia

DEMOTIVATION Suspicion

Inability to titrate Can we have a more predictable insulin?

Shortcomings of human insulin •

Physiological insulin profile: basal component meal-related peaks

Period of unwanted hyperglycemia Period of unwanted hypoglycemia

•

Mixtard fails to recreate the physiological insulin profile

Human Human Insulin Insulin in in the the subcutaneous subcutaneous space space

(Brange J et al. Diabetes Care 1990;13:923)

Modern Insulins: Definition • Modified or ‘Modern insulins’ or Newer Insulins • Molecules – differ by one or a few amino acids from primary structure of insulin • Developed – to provide more physiologic replacement after s.c injection than human insulin • Made possible by the advent of BiotechnologyrDNA technology • Provide more optimal time-action profiles

Engineering insulin analogues s

s

A1 s s

A-chain

s

s

A21 B-chain

B1

B30

Light blue: residues preserved in naturally occurring insulins Red: residues involved in receptor binding

Kaarsholm & Ludvigsen. Receptor 1995;5:1-8.

Safety of Modern Insulins IGF-1 R affinity

IGF-1 : IR

= 100

Mitogenic potency (Saos/B10 cells)

1

= 100

587 ± 50

2.9

Insulin aspart

81 ± 9

0.9

58 ± 22

Insulin lispro

156 ± 16

1.9

66 ± 10

Insulin glargine 641 ± 51

7.5

783 ± 13

0.9

~ 11

Human insulin Insulin X10

Insulin detemir

16 ± 1

Kurtzhals P, et al. Diabetes 2000; 49: 999

975 ± 173

Modern Insulins: Addressing the limitations with human insulins • Mimics the physiological insulin secretion • Better time-action profile than human insulins • Have more predictable action • Superior PPG reduction  more cardiovascular benefits • More safety  less hypoglycaemia • Less undesired weight gain • Meal-time flexibility  can be taken just before/after food • Convenient to use  available in simple-to-use pens with painless needles

Modern Insulins: Classification Rapid-acting

Insulin aspart (NovoRapid) Insulin lispro Insulin glulisine

Long-acting

Insulin detemir (Levemir) Insulin glargine

Premix

Biphasic Insulin Aspart (NovoMix 30) Lispro Mix 25

Rapid-Acting Modern Insulins

NovoRapid (Insulin Aspart) Pro Asp

B30 A1

Thr

Tyr

Asp B28

Lys Thr

Phe

Phe

Gly

Arg

Glu

B20

Gly

Cys

A21

Asn

Cys

Val

Tyr

Gly

Leu

Asn

Ile

Glu

Val

Leu

Glu

Gln

Gln Cys

Tyr Leu Ala Glu

Tyr Cys

Thr

Ser

Ile

Cys

Ser

Val

Leu

Leu His Ser

B1

Phe

Val

Asn

Gln

His

Leu

Cys

Gly

NovoRapid vs Actrapid Better Pharmacokinetics Human ActrapidTM Onset of action Duration of action

NovoRapidTM

30-60 minutes

10-15 minutes

6-8 hours

3-5 hours

NovoRapidTM has a faster onset , earlier peak and sharp return to baseline

Twice as Rapid onset & as High peak Doubleblind, cross-over, single dose study in healthy volunteers, n=24 (mU/l) (pmol/l)

Serum insulin

500 7 5

50 min/ 400 pmol/l

400

5 0 2 5 0

NovoRapid

Human Actrapid (0.2 U/kg)

300

100 min/ 200 pmol/l

200 100 0

-60

®

0

60 120 180 240 300 360 420 480 540 600

Time (minutes)

(Heinemann L et al. Diabetes Med 1996;13:683)

®

Mealtime Flexibility Just Before / After Food… Plasma glucose (mmol/l)

15

HI(–15min) HI(0min)

14 13

NovoRapid®(0min) NovoRapid®(+15min)

12

n = 20

11 10 9 8 7 6 0 -30

0

30

Test meal

60

90

120

150

180

210

240

270

Brunner et al. Diabet Med. 2000 May;17(5):371-5.

Superior Postprandial blood glucose Reduction Type 1 diabetes

p < 0.001

p < 0.001

Mean values after 6 months

Blood glucose increment (mmol/l)

1.8 1.6

NovoRapid®

1.4

Human insulin

1.2 1.0

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

0.8 0.6 0.4 0.2 0

European trial

North American trial

n = 1070

n = 884 Home et al. Diabetic Med 2000;17:762-70 Raskin et al. Diabetes Care 2000;23:583-8

Less risk of hypoglycemia

Episodes per patient per year

Double-blind, crossover comparison in T1DM on basal-bolus, duration 4 months, n = 155 1.4

NovoRapid ®

1.2

Human Actrapid ®

1

** * 72%

0.8 0.6 0.4

*** p < 0.005

0.2 0

Total

Nocturnal 24:00 – 6:00 4 months

Heller et al. Diabetes 2001;50(2):A137

Modern Insulin of choice in special situations • Approved in children above 2 years • Safe for use in patients with Liver & Kidney dysfunction • Preferred for use in Insulin pumps • Ideal for managing hyperglycaemic emergencies

Only Modern Insulin approved in Pregnancy by EMEA & FDA after RCTs • Pettit et al. Diabetes Care 2003 – NovoRapid safe & effective as human insulin • 3 studies from 65th ADA, 2005 NovoRapid got EU approval – US study (Jovanovic et al.) for use in pregnancy on – Indian study: Seshaiah et al. 31st July 2006 & FDA on – Ireland study (Kinsley et al) 7th feB 2007 • 2 Studies from 66th ADA, 2006 – Multicentric study (Hod M et al). Published Am J Obstet Gynecol. 2007 Sep 29; [Epub ahead of print] – Multicentric study (Mathiesen et al). Published Diabetes Care.2007;30 (4):771-776.

Long-Acting Modern Insulins Glargine

21

30

Detemir

29

Design of Insulin detemir -Levemir LysB29(N-tetradecanoyl)des(threonine)human insulin C1 4f a (M tty a yri sti cid ch ca cid ain )

Lys

Thr Lys A1

Pro

Thr

Tyr

Phe Phe

Gly Arg

A21 Asn Cys

B29

Gly

Glu

Gly Cys Val Leu

Tyr Asn

Tyr

Ile

Glu

Leu

Val

Leu

Ala

Gln

Glu

Glu Gln Cys

Tyr Cys

Thr

Ser

Ile

Cys

Ser

Val

Leu

Leu His Gly

B1

Phe

Val

Asn Gln

His

Leu

Ser

Cys

Des-threonine myristic(mir) acid

Levemir vs Glargine Similar time action profile Randomized, double-blind, parallel trial; 27 insulin-treated male subjects with T2DM. Levemir shows significantly less within-subject variability than Glargine

Presented at ADA 2006. Klein D et al. Diabetes 2006; June (Suppl):A494

Levemir: more predictable than glargine & NPH Glucose infusion rates

NPH

Heise T et al. Diabetes June 2004;53:1614-1620

Glar

Det

Levemir vs. insulin glargine p < 0.05

Insulin detemir + IAsp

7

Insulin glargine + IAsp

6

p < 0.05

5

0.4

4

0.3

Episodes per subject-year

Episodes per subject-ye 3

0.2

2 1

0.1

0

0

Nocturnal Hypoglycemia

Major episodes

72% lesser major hypoglycemic events 32% lesser nocturnal hypoglycemic events

Pieber et al Diabetologia 2005;48(Suppl. 1):A92

Less undesired weight gain n = patient numbers in each BMI category

Mean weight change (kg)

3.5

36

37 39

3.0 2.5

Insulin detemir NPH insulin

50

76

35 34

2.0 1.5

55 69

1.0 42

0.5 0.0 -0.5

≤ 25

>25-27

>27-29

>29-31

>31

Baseline BMI K. Hermansen et al. Diabetes 2005;54(suppl 1):A67

Levemir once daily • with OADs for type 2 diabetes • with NovoRapid as basal-bolus therapy for both type 1 & 2 diabetes

Premixed modern insulin

• Biphasic Insulin Aspart (NovoMix 30) • Lispro Mix 25

Biphasic insulin aspart

70% protaminated

30

30% soluble, rapidinsulin aspart, which acting insulin aspart is intermediate-acting

NovoMix® 30

Serum insulin (mU/L)

NovoMix® 30- pharmacokinetics 35

Healthy Volunteers NovoMix® 30 Human Insulin 30/70 Premix

25 15 5 0 Injection

4

8

12

16

Time (hour) Weyer, Diabetes Care 1997;10:1612-1614

20

24

Mean plasma glucose (mg/dl)

Meal-time flexibility Just before/After food… After preprandial injection (63.0 ± 28.9 U)

240

After postprandial injection (64.6 ± 29.2 U)

220

n = 93

200

type 2 diabetes patients

180 160 140 120 100

-15

60

120

180

240

Time (minutes) Warren ML, et al. Diabetes Res Clin Pract 2004;66:23–29

INITIATE Trial Study Design

N = 233 T2DM patients Continue OAD* + glargine 10-12u at HS

A1C > 8% (insulin naïve) OAD failures on MET ≥ 1000 mg/d

Continue OAD* + Biphasic Aspart 70/30 5-6u BID 4 wk run-in & 28 wks of treatment with insulin adjustments titration

Target FPG: < 110 mg/dL * Secretagogues and carbohydrate inhibitors discontinued; rosiglitazone switched to pioglitazone 30 mg/d Raskin P, et al. Diabetes Care 2005;28:260-265

INITIATE Trial

Primary Endpoint (A1C) P = 0.478

11

A1C (%)

10

9.7

9.8

Biphasic Aspart 70/30 Glargine P = 0.001

9 8

6.9

7

7.4

6 5 Baseline

28-weeks Raskin P, et al. Diabetes Care 2005;28:260-265

INITIATE Trial

Achieving A1C Goal % Reaching Goals

70

Biphasic Aspart 70/30 Glargine

60 50

P = 0.0002

40 P = 0.036

30 20 10 0

ADA: A1C < 7%

AACE: A1C < 6.5%

Baseline A1C was 9.7% for Biphasic Aspart 70/30 & 9.8% for Glargine Raskin P, et al. Diabetes Care 2005;28:260-265

INITIATE Trial

8-point BG Profiles Blood Glucose (mg/dL)

350 300

Baseline

250 200

*

150

*

*

+

*

Week 28

100

BB

Biphasic Aspart Glargine

B90

BL

L90

BD

D90 Bed 3am

∗ Biphasic Aspart 70/30 lower BG vs glargine P < 0.05 + Glargine lower BG vs Biphasic Aspart 70/30, P < 0.05 Raskin P, et al. Diabetes Care 2005;28:260-265

INITIATE Trial

Additional Outcomes Weight Gain in kilograms P = 0.001

5.4

5 4 3 2 1 0

P = 0.03

3.5

Events/patient/year

Weight Change (kg)

6

All Hypoglycemia (median) 10 9 8 7 6 5 4 3 2 1 0

9.4

5.6

Biphasic Aspart 70/30 Glargine Raskin P, et al. Diabetes Care 2005;28:260-265

The 1 – 2 – 3 Study using Biphasic Insulin Aspart 30/70 Phase 1

QD

Pre-dinner x 16 wk Start with 12 U at dinner

A1C ≤ 6.5%

End of Study

If A1C > 6.5%, go to BID, d/c secretagogues Phase 2

BID

Pre-breakfast & dinner x 16 wk Add 3 U at breakfast if FPG ≤ 110 Add 6 U at breakfast if FPG > 110

A1C ≤ 6.5%

End of Study

If A1C>6.5%, go to TID Phase 3

TID

TID x 16 wk Add 3 U at lunch

Titrate according to schedule every 3 days. N = 100 Type 2 DM ≥ 12 months with A1C ≥ 7.5 ≤ 10%, ≥ 2 OADs or ≥ 1 OAD plus basal insulin OD (max 6 0U). Jain R, et al. Diabetes. 2005 ;54(suppl 1):A69

1-2-3: Cumulative proportion of patients achieving targets 1. Start with NovoMix 30, once a day 41% reached Target

2. Add a second NovoMix 30 dose if needed

77% on on target target 70% 41% 3. Add a third NovoMix 30 dose if needed

(HbA1c ≤ 7.0%)

Garber et al. Diabetes Obes Metab 2006;8:58–66

The 1 – 2 – 3 Study Achievement of A1c Targets A1C ≤ 6.5%

100

A1C < 7.0%

87.8

100 77.0

80

66.2

% of Patients 60

40

80 60

45.9

40 28.4

20

20 0

78.4

QD

BID

TID

0

QD

Jain R, et al. Diabetes. 2005;54(suppl 1): A69.

BID

TID

Switching to Modern Insulins from other insulins From < 30 U premixed or basal insulin:

Transfer units

1:1, titrate according to titration schedule

From > 30 U premixed or basal insulin From a once-daily regimen Transfer units

1:1, titrate according to titration schedule

From a twice-daily regimen Transfer units

1:1, titrate according to titration schedule

Christiansen et al. Diab Obes Metab 2003;5:445-452 McSorley et al. Clin Ther 2002;24:530-539

Insulin Analogs Fulfilling the Promise of Recombinant DNA Technology: Better Basal Better Bolus Better Premix Better Glucose control

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