FoodSteps Navorming T2DM Anti-hyperglycemic Therapy: General Recommendations Gezonde leefstijl: voeding en beweging

FoodSteps®

Navorming 21-02-2013

Insuline-therapie

Insuline-therapie in type 2 diabetes

C. Mathieu Endocrinologie, UZ Leuven

C. Mathieu Endocrinologie, UZ Leuven

Thuis heb ik nog een ansichtkaart Waarop een kerk een kar met paard Een slagerij J. van der Ven Een kroeg, een juffrouw op de fiets Het zegt u hoogstwaarschijnlijk niets Maar het is waar ik geboren ben Dit dorp, ik weet nog hoe het was De boerenkind'ren in de klas Een kar die ratelt op de keien Het raadhuis met een pomp ervoor Een zandweg tussen koren door Het vee, de boerderijen En langs het tuinpad van m'n vader Zag ik de hoge bomen staan Ik was een kind en wist niet beter Dan dat 't nooit voorbij zou gaan

Basic Steps in the Management of Type 2 Diabetes

+ + +

Insuline starten voor huisartsen, C. Mathieu 2007

T2DM Anti-hyperglycemic Therapy: General Recommendations

Gezonde leefstijl: voeding en beweging SU Glinide

Metformine TZD

DPP-4 inhibitoren

GLP-R agonisten

Insuline Inzucchi et al. Diabetes Care, Diabetologia. 2012

LMN Zuid-West-Vlaanderen

1

FoodSteps®


Type 2 diabetes is a complex disease Insulin resistance

Waarom is er in type 2 diabetes insuline nodig?

Healthy beta-cell

Unhealthy lifestyle and environmental factors

Metabolic syndrome

Increased risk of cardiovascular disease

+

Er is toch hyperinsulinisme?

Type 2 diabetes is a complex disease Environment


Type 2 diabetes is a complex disease Insulin resistance


Metabolic syndrome Inflammation FFA Glucose

Genes

+

+

Increased risk of cardiovascular disease

Hyperglycemia Hyperglycemia Failing beta-cell

Type 2 diabetes Type 2 diabetes

UKPDS HOMA-B: beta-cell function progressively declines

Until we can stop the deterioration of functional betacell mass, most type 2 diabetic patients will eventually need insulin to maintain glucose control 100

Clinical inertia: “Failure to advance therapy when required” Percentage of subjects advancing when HbA1C > 8% 100

80 60 40 20

80 Subjects (%)

Beta-cell function (%, HOMA)

Diabetes diagnosis

At insulin initiation, the average patient had: • 5 years with HbA1C > 8% • 10 years with HbA1C > 7% 66.6%

60

44.6% 35.3%

40

Extrapolation of beta-cell function prior to diagnosis

18.6%

20

0 –12

–10

–8

–6

–4

–2 0 2 Years from diagnosis

4

6

8

0 Diet

UKPDS 16. Diabetes 1995; 44:1249–58


Sulphonylurea Metformin

Combination

Brown et al. Diabetes Care 2004;27:1535–40

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Poor HbA1c levels reflected in clinical practice Before intensification

12

Mean HbA1c %

10

Mean HbA1c by country

After intensification

Finland 8.51%

9,96 9,21

9,04

8

8,16

UK & Ireland 8.84%

8,55

8,04

Sweden 7.54%

Belgium 7.94%

Denmark 8.02%

6

Germany 7.61% 4

Italy 7.88% France 8.42%

2

Spain 7.45%

0 2 OHD

3 OHD

Insulin

Calvert et al. Br J Gen Pract 2007;57:455–60 Coninck et al. J Diabetes 2010;2:168–79



Biggest hurdle?

Inzucchi et al. Diabetes Care, Diabetologia. 2012

Biggest hurdle?

Inzucchi et al. Diabetes Care, Diabetologia. 2012

Physician barriers to initiating insulin Reliance on lifestyle changes

Time constraints Perceived patient incompetence

Insufficient infrastructure

Patient barriers Attitudes among patients willing or unwilling to accept insulin therapy1

Perceptions of insulin therapy among treatmentnaïve/experienced patients2

Willing

Desire to avoid unpleasant confrontation

Insulin experienced

Unwilling

Concerns about outcomes and hypoglycaemia

Potential for weight gain

Insulin naïve

Can never stop insulin Seen as sick

Patient’s care not good enough Not confident with therapy

Lack of confidence in insulin clinical data

Impact on patient QoL and employment

Fear of seeming incompetent to colleagues

Weight gain

Problematic hypoglycaemia Anticipated pain (injecting)

Injection fear

Lack of fairness

Unsure when to initiate insulin

Unsure when and how to intensify therapy

Believe barriers reside mainly with patients

Less flexibility

Life will be restricted My diabetes will be more serious Insulin causes problems like blindness

Diabetes worse 0%

20%

40%

60%

0%

20%

40%

60%

80%

1. Polonsky et al. Diabetes Care 2005;28:2543–5; 2. Snoek et al. Health Qual Life Outcomes 2007;5:69 Kunt and Snoek. Int J Clin Pract 2009;63(Suppl. 164):6–10


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Increased incidence of severe hypoglycaemia with intensive therapy in ACCORD, ADVANCE and VADT ACCORD1

ADVANCE2

Per 100 patients per year

1.0

1.0 0

0.7

0.6 0.4

0.4

0.2 0

Standard Intensive p<0.001


Conventional Chlorpropamide

12.0

12 9 6

Change in weight (kg)

2.0

0.8

Insulin

10. 0

15 Severe hypoglycaemic events

3.1

Severe hypoglycaemic events

Severe hypoglycaemic events

1.0

3.0

Weight gain by treatment

VADT3

Per 100 patients per year Per 100 patients per year

5.0 4.0

Weight gain by treatment in UKPDS

7.5

Glibenclamide Metformin

5.0

2.5

4.0 3

0

0

-2.5

0


1. ACCORD Study Group. N Engl J Med 2008;358:2545–59; 2. ADVANCE Collaborative Group. N Engl J Med 2008;358:2560–72; 3. Duckworth et al. N Engl J Med 2009;360:129–39

3

6

9

12

Years from randomization

UKPDS Group (34). Lancet 1998; 352:854–865.

Weight change in treat-to-target trials Detemir pm Detemir twice daily NPH pm NPH twice daily Glargine pm

3.5 * p < 0.001

Change in weight from baseline (kg)

3 2.5 2

* p = 0.004

1.5 1 0.5 0 Riddle 2003 24 weeks

Hermansen 2006 24 weeks

Philis-Tsimikas 2006 20 weeks

Outcome Reduction with an Initial Glargine INtervention NEJM June 11 2012

Summary of Findings Compared to standard glycemic care of people with early diabetes, IGT &/or IFG … using once daily basal insulin glargine to target a FPG < 95 mg/dl (5.3 mmol/l) for a median of 6.2 years ... • • • • •

Maintains near-normal glycemic control Has a neutral effect on CV outcomes & on cancers Slows progression of dysglycemia Modestly increases hypoglycemia Modestly increases weight


Hypoglycemia & Weight (6 -7 years) Glargine (N=6264)

Standard (N=6273)

P

%

/100py

%

/100py

Any Non-severe 1 or more episodes

57

17

25

5

<0.001

Severe 1 or more episodes

6

1.0

2

0.3

<0.001

Weight Change Since Randomized

Glargine

Standard

P

1.6 kg (3.5 lbs)

-0.5 kg (1 lb)

<0.001

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Higher proportion of patients intensified by specialists (591) vs PCPs (1911)

Methods of overcoming clinical inertia

p=0.009

Adherence to medications

p=NS

Developing quality measures Education (CME)

p=NS

Motivating and supporting patients on selfmanagement

Effective use of information system p<0.001

Recommendations Guidelines

PCP, primary care physician Shah et al. Diabetes Care 2005;28:600–6

Zafar et al. Primary Care Diabetes 2010;4:203–7

Patient-adjusted dosing algorithm vs physician standard of care: 26-week RCT Insulin detemir was started once daily as add-on therapy to any other glucose-lowering regimens or as a replacement for prestudy basal insulin • Insulin dose adjustments* – 303 algorithm sites: patients to adjust dose every 3 days based on mean FPG values, n=2787 FPG (mg/dL)

Basal dose adjustment

<80

Reduce detemir dose by 3 U

80–110 >110

Personal feedback to HCP

Summary • There are many issues contributing to inertia, and consequently many potential solutions • Inertia surrounding insulin initiation and intensification is apparent from clinical trials and real-life practice • Improving education of physicians and patients may address current barriers

No change Increase detemir dose by 3 U

– Standard-of-care sites: physician to adjust dose based on standard of care, n=2817 * Insulin detemir dose titration was not enforced in either group Kunt, Snoek. Int J Clin Pract 2009;63(Suppl. 164):6–10

Meneghini et al. Diabetes Obes Metab 2007;9:902–13

Proportion of patients reaching HbA1c targets is low

% patients with diabetes reaching targets

80 70

60

Praktisch insuline starten

50 40 30

C. Mathieu

20 10 0 Total cholesterol <200 mg/dl

LDL cholesterol Blood pressure <100 mg/dl <130/80 mmHg

Grant et al. Diabetes Care 2005;28:337–442


HbA1c <7%

LDL, low-density lipoprotein

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De challenge van subcutane toediening van insuline

Praktisch • Welke insuline? • Wanneer? • Wie titreert? • Hoe titreren?

70 Normal free insulin levels (Mean)

Insulin (mU/l)

60

Meals

50 40 30 20 10 0 0600

0900

1200

1500

1800

2100

2400

0300

0600

Time of day Breakfast

Lunch

Dinner

Bedtime

Adapted from Polonsky et al. 1988

Wat doet de beta-cel?

Insuline kristallen

Molecular Size Determines the Rate of Subcutaneous Absorption

Effect subcutaan ‘regular insulin’ (mU/l)

Actrapid®, Humuline Regular®, Insuman Rapid®

(pmol/l)

500 Human Actrapid ® (0.2 U/kg)

Subcutaneous tissue Molecular size Insulin

72 kDa Zn2+

36 kDa

6 kDa

Zn2+ Zn2+

Serum insulin

75 400

50

300 200

25 100

Absorption

0

Capillary membrane

Slow Absorption

Rapid Absorption

Werkingsduur: minuten-uren


0 -60

0

60

120 180 240 300 360 420 480 540

600

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

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FoodSteps®


Probleem subcutaan ‘regular insulin’


Om basaal profiel te dekken:

Te kortwerkend Piekwerking

Subcutaneous tissue >5000 kDa

Molecular size

72 kDa

High molecular weight forms

Insulin

Om maaltijden te dekken:

36 kDa

Zn2+

6 kDa

Zn2+ Zn2+

Absorption

Te trage start Te lange duur

Capillary membrane

Slow Absorption

Rapid Absorption

Humand insuline trager maken:


Fysisch: eiwit (of Zn) toevoegen

Fysisch: eiwit (of Zn) toevoegen

NPH insuline: protamine

NPH insuline: protamine

Humuline NPH®, Insulatard®, Insuman Retard®

Humuline NPH®, Insulatard®, Insuman Retard®

NPH insuline: protamine Humuline NPH®, Insulatard®, Insuman Retard®

GIR (mg/kg/min)

7 6 5 4 3 2 1 0

GIR (mg/kg/min)

Noodzaak tot mengen

GIR profiles following four identical NPH insulin injections

7 6 5 4 3 2 1 0

GIR (mg/kg/min)


7 6 5 4 3 2 1 0

Subject no: 202

0

4

8

12

16

20

24

Subject no: 212

0

4

8

12

16

20

24

Subject no: 222

0

4

8

12

16

20

Elapsed time (hours)

24

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


7 6 5 4 3 2 1 0 7 6 5 4 3 2 1 0

7 6 5 4 3 2 1 0

Subject no: 203

0

4

8

12

16

20

24

Subject no: 214

0

4

8

12

16

20

24

Subject no: 224

0

4

8

12

16

20


24

7 6 5 4 3 2 1 0 7 6 5 4 3 2 1 0

7 6 5 4 3 2 1 0

Subject no: 209

0

4

8

12

16

Clamp Clamp Clamp Clamp

20

24

Subject no: 216

0

4

8

12

16

1 2 3 4

Dose at each injection: NPH Insulin 0.4 U/kg, thigh

20

24

Subject no: 228

0

4

8

12

16

20

24


NN304-1450

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FoodSteps®


Probleem fysisch vertraagde insuline

Om basaal profiel te dekken:

Insuline analogen: gewenste eigenschappen • Basale insuline analogen : – Trage en stabiele absorptie – Lange werkingsduur – Weinig fluctuatie in actieprofiel van dag tot dag

Te kortwerkend Piekwerking Variabiliteit +++

Insulin Glargine Mechanism of Action

Oplossing vertraging insuline Lantus®

Injection of an acidic solution (pH 4.0)  Microprecipitation of insulin glargine in subcutaneous tissue (pH 7.4)  Slow dissolution of free insulin glargine hexamers from microprecipitates (stabilised aggregates)  Protracted action

The mechanics of sustained release

1. Lantus® (insulin glargine) EMEA Summary of Product Characteristics. 2002. 2. McKeage K et al. Drugs. 2001;61:1599-1624. 3. Kramer W. Exp Clin Endocrinol Diabetes. 1999;107(suppl 2):S52-S61.

Adapted from Kaarsholm & Ludvigsen. Receptor 1995;5:1–8

Insulin Profiles

Oplossing vertraging insuline Levemir®

Regular (6–8 hr) NPH (12–16 hr)

Plasma Insulin Levels

Phe

Albuminbinding moeity

Phe

Gly

Arg

Tyr

Glu

Thr

Gly

Pro

Cys

Lys

Val

Thr Lys

A21

B29 A1

Asn

Cys

Gly

Asn

Ile

Glargine (~24 hr)

Leu

Tyr

Tyr

Glu

Val Glu Gln

Leu

Leu

Ala

Gln

Glu

Tyr

Cys Cys

Val

Leu Thr

Ser

Ile

Cys

Leu

Ser

His Ser

0

2

4

6

8

12

10

14

16

18

20

22

24

Myristic acid

Gly Cys B1

Phe

Val

Asn

Gln

His

Leu

Hours

Based on Rosenstock J, Wyne K. In: Goldstein BJ, Muller-Wieland D, eds. Textbook of Type 2 Diabetes. 2003. Ch. 11:131-154.


8

FoodSteps®


Oplossing vertraging insuline Levemir®

Potential sites of protraction

Myristic acid binding sites

Albumine

Subcutaneous depot

Delayed absorption through self-association and albumin binding

Delayed delivery to target tissues due to retention by albumin binding

Circulation

Myristic acid binding site

Myristic acid binding sites

(Delayed arrival at insulin receptors due to albumin binding)

Interstitial fluid

Curry S et al. Nature Structural Biology 1998:5:827-35

Insuline analogen: gewenste eigenschappen

Variability in time-action profile of basal insulins*

GIR mg/(kg/min)

68% 8.0

48%

NPH insulin

8.0

Insulin glargine

8.0

6.0

6.0

6.0

4.0

4.0

4.0

2.0

2.0

2.0

0

0

0

6

12

18

24

0

Time (hours)

6

12

• Basale insuline analogen :

27%

18

Time (hours)

24

0

– Trage en stabiele absorptie – Lange werkingsduur – Weinig fluctuatie in actieprofiel van dag tot dag

Insulin detemir

• Maaltijd-gerelateerde analogen : 0

6

12

18

Time (hours)

T. Heise, et al. Diabetes 2004.

24

– Snelle absorptie – Piek actie die samenvalt met de piek van KH absorptie

* 0.4U/kg

Oplossing snellere insulines


Humalog®, Novorapid®, Apidra® (Lispro, Aspart, Glulisine)

Subcutaneous tissue Molecular size Insulin

>5000 kDa High molecular weight forms

72 kDa Zn2+

36 kDa

6 kDa

Zn2+ Zn2+

Absorption

Capillary membrane

Slow Absorption

Rapid Absorption

Adapted from Kaarsholm & Ludvigsen. Receptor 1995;5:1–8


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Insulin profiles and glycemic excursions after a test meal in patients with type 1 diabetes

Bottom line: comparable glucose control- less hypoglycemia

NovoRapid, t = 0 min

(pmol/l)

Soluble human insulin, t = 0 min Soluble human insulin, t = 30 min

NovoRapid Soluble human insulin (0.15 U/kg)

12

Serum insulin

Serum glucose (mmol/l)

Blood glucose (mmol/l)

(0.15 U/kg)

11 p<0.05

10

p<0.05

9 8 7 6 5 0

0

Pre

Time (hours)

Time (hours)

Adapted from Lindholm et al. 1999

Post

Pre

Breakfast

Post

Pre

Lunch

Post

Dinner

Bedtime 2 a.m.

Adapted from Home et al. 1998

Continuous development in insulin therapy

Insulin Profiles

58

Aspart, Lispro, Glulisine (2-4 hr) Next generation insulin

Regular (6–8 hr)

Glargine (~24 hr) Detemir (~20-24 hr)

0

2

4

6

8

12

10

14

16

18

20

22

Advancements


NPH (12–16 hr)

Basal insulin analogues Biphasic insulin analogues

Neutral protamine Isolation Hagedorn of insulin (Banting & Best) (NPH) insulin

24

Recombinant human insulin

Rapid-acting insulin analogues

1990s

1977 1921

Hours

1946

Time



2000s

Correcting Fasting Hyperglycemia… Is Usually the First Task ! 300

Plasma Glucose (mg/dL)

Uncontrolled A1C ~9%

“Controlled” A1C <7%

200

100

Normal A1C 5%–6% 0800

1200

1800

0800

Time of Day Inzucchi et al. Diabetes Care, Diabetologia. 2012


10

FoodSteps®


Insulin Profiles

Current pure insulin preparations and their pharmacokinetics following s.c. injection Onset of action

Peak of action

Duration of action

Soluble

30-60 minutes

2-4 hours

6-8 hours

Lispro/Aspart 5-15 minutes Glulisine NPH 1-2 hours

1-2 hours

4-5 hours

5-7 hours

13-18 hours

Glargine Levemir

peakless 6-8 hours

>24 hours 18-24 hours

1-2 hours 1-2 hours


Insulin

Aspart, Lispro , Glulisin (4–5 hr)

Glargine (~24 hr) Levemir (~20-24 hr)

0

2

4

6

8

10

12

14

16

18

20

22

24

Hours


Adapted from Burge and Schade. 1997

Insulin Profiles

Insulin Profiles

Regular (6–8 hr)

0

2

4

6

8

14

16

18

20

22

24

Hours


Starten met Basale Insuline • Start ZTJ- zorg voor educatie en zelfmonitoring • Hou de orale medicatie als is- als je start met laag HbA1c (<8%), eventueel SU verminderen- Stop TZD, DPP4i, GLP1Ra • • Voeg NPH toe bedtime: 0.1u/kg • Evalueer nuchtere glycemie na paar dagen • Verhoog minstens wekelijks de dosis > 120-140 mg/dL: verhoog dosis met 2 E > 160 mg/dL: verhoog dosis met 4 E > 180 mg/dL: verhoog dosis met 6 E > 200 mg/dL: verhoog dosis met 8 E • Treat to Target (<100 mg/dL) • Verminder insuline als nuchter <72 mg/dL of hypoglycemie ‘s nachtsverminder SU als hypoglycemie overdag


Humuline 30/70

Plasma Insulin Levels 12

10

Novomix 30

0

2

4

6

8

10

12

14

16

18

20

22

24

Hours


Correcting Fasting Hyperglycemia… Is Usually the First Task ! 300

Uncontrolled A1C ~9% Plasma Glucose (mg/dL)


NPH (12–16 hr)

“Controlled” A1C <7%

200

100

Normal A1C 5%–6% 0800

1200

1800

0800

Time of Day

…then Treat Postprandial Hyperglycemia with a Short-Acting Analog at Main Meal if A1C still >7% !

11

FoodSteps®


Wat als basale insuline onvoldoende is? = als HbA1c >7% en NPH kan niet verder opgedreven worden owv hypoglycemie • Switch naar Lantus, dose for dose

Premixes = tussenoplossing die +/- regeling toelaat • Humane: 10

50% Regular/NPH

• Analoog: Novomix 30: 30% Aspart Dosis zoeken

• Bij goed ochtendglycemie, maar vooral overdag oplopen glycemie: voeg maaltijdinsuline toe: -Snelle insuline bij maaltijden (basaal bolus)

= Rekenen

-Pre-mix insulines

75jaar, vrouw, ex-verpleegster

Dit zijn ongenuanceerde casussen bedoeld om te leren spelen met insuline

Huidige therapie:

Amarylle 2 Co Glucophage 2x850mg

HbA1c 9%

De casussen zijn allemaal statine en bloeddruk gecontroleerd

Dagprofiel 140---200---160----136 Wat is uw therapie suggestie als u weet dat patiënt volgende therapie heeft en een HbA1c van 8%

- 32 E Insulatard - Gliclazide 3x 1Co - Glucophage 3x 850mg


Dagprofiel: 225---180---220---190

Dagprofiel 140---200---160----136 Wat is uw therapie suggestie als u weet dat patiënt volgende therapie heeft en een HbA1c van 8%

-35 E Lantus

12

FoodSteps®


65jaar, man, ex-lasser

Dagprofiel 140---200---160----136

Huidige therapie:

Wat is uw therapie suggestie als u weet dat patiënt volgende therapie heeft en een HbA1c van 8%

-16 E Novomix ----20 E Novomix ---- Glucophage 3x850mg

Diamicron 3x1Co Novonorm 3x2mg Glucophage 2x850mg 32E Insulatard voor slapen

HbA1c 8% Dagprofiel: 140---136---120---220

55jaar, vrouw, huisvrouw Huidige therapie:

Erik S., 42jaar

Januvia 100mg Glucophage 3x850mg

• Diabetes type 2, behandeld met Metformine 3x850mg en ‘s morgens 16E Humuline 30/70 en ‘s avonds 32E Humuline 30/70

HbA1c 8% • Hij wordt lid van een wielerclub maar durft er niet aan beginnen- uw advies?

Dagprofiel: 140---136---120---220

Empowerment through motivation

Insulin Profiles


32E Humuline 30/70 16E Humuline 30/70

18

20

22

0

2

4


6

8

10

12

14

16

18

13

FoodSteps®


Primary Care

Podologists

Nurse educators

Endocrino logist

Patient ….


Cardiol ogist

Ophtalmo logists

Dieticians

14

FoodSteps Navorming T2DM Anti-hyperglycemic Therapy: General Recommendations Gezonde leefstijl: voeding en beweging

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