36. insulinoterapia

AACE Diabetes Guidelines 2000

ALAD Guia de Dg y Tto DM-2 , 2000

ADA Clinical Practice Recomendations 2001

INSULINO TERAPIAINSULINO TERAPIA

Dr. Freddy Valdivia Fernández-DávilaDr. Freddy Valdivia Fernández-Dávila

NUEVOS

AO e

INSULINAS

HIPOG. ORALESANTIBIOTICOSINSULINA

ORIENTACION

ALIMENTARIA

INSULINO

TERAPIA

MANUAL DE

DIABETES

JOSLIN 1941

ENF. CRONICA

Y ENFERMERIA

CRATE 1965 INTENSIVA

AUTO -

CONTROL

INSULINO

TERAPIA

T E R A P I A M O D E R N A

- 1921 1922 - 1936 1937 - 1949 1950 - 1965 1966 - 1973 1974 - 1990 -

80

100

40

60

20

CA

US

AS

MU

ER

TE

%

COMA

INFECCIONES

COMPLICACIONES

Historia - Insulino TerapiaHistoria - Insulino Terapia

“ At present we are enclined to believe that more successful results can be achieved if normal blood sugar is aimed at “

Banting 1923

Historia - Insulino TerapiaHistoria - Insulino Terapia

“ In general it is recognized that 30 units of insulin divided into three doses in the day are more effective than when given as a single dose “

“ It is sometimes desirable to give insulin late in the evening. By so doing less insulin will be needed in the next 24 hours”

E. P. Joslin 1928

Historia - InsulinoterapiaHistoria - Insulinoterapia

Descubrimiento de la NPHLa filosofia del tratamiento cambióSe redujo el numero de inyecciones

diariasAceptacion de valores altos de

glicemia

Hagedorn H.C. JAMA 1936

Primeros Estudios InsulinoterapiaPrimeros Estudios Insulinoterapia

Se comparó 2 grupos de pacientes– Serie 1 : 1922 – 1925 – Serie 2 : 1936 – 1945 (NPH)

La incidencia de Nefropatía fue 17 veces mayor en la serie 2

Similares resultados para Retinopatía

Malmö Study : Rev. Diabetes 1960

Evidencia PublicadaEvidencia Publicada

Pirart J. Diabetes Care 1978 Steno Study Lancet 1982 Feldt-Rasmusen Lancet 1986 Oslo Study Acta Endocri. 1988 KROC Study JAMA 1988 DCCT N Engl. J Med 1993 UKPDS BMJ

Diabetes 2: ConsideracionesDiabetes 2: Consideraciones

Deterioro de la células beta en el tiempo 30% a 40% de pacientes requerirán insulina Prevalencia incrementada con el incremento de los

factores de riesgo, eg, obesidad Hiperglicemia afecta morbilidad y mortalidad Estricto control glicémico con insulina puede

reducir el costo de las complicaciones Las nuevas insulinas semisintéticas y sistemas de

aplicación pueden mejorar su aceptación y alcanzar mejor control glicémico con menos hipoglicemia

Terapia Farmacólogica para Terapia Farmacólogica para Diabetes Tipo 2Diabetes Tipo 2 Sulfonilureas (gliburide, glipizida,

glimepirida) Biguanidas (metformina) Inhibidores Alfa-glucosidasa (acarbosa,

miglitol, voglibose) Megletinides (nateglinida, repaglinida) Tiazolidinedionas (rosiglitazona,

pioglitazona) Insulina (insulina humana, análogos de

insulina)

Algoritmo de TratamientoAlgoritmo de Tratamiento

Terapia No farmacológica

MonoterapiaSulfonylureas/Benzoic

acid analogueBiguanide

Alpha-glucosidase inhibitors

ThiazolidinedionesInsulin

Terapia Combinación Insulina

Very symptomaticSevere hyperglycemiaKetosisLatent autoimmune diabetesPregnancy

Insulina en DM tipo 2: Insulina en DM tipo 2: IndicacionesIndicaciones

Descompensaciones Agudas Severas Problema intercurrente Medicamentos Cirugía Embarazo Falla de celula Beta

– Inadecuado control glicémico– Pérdida de peso en forma acelerada– Tendencia a la Cetosis– Descartar enfermedades intercurrentes

Insulina Humana: FarmacocinéticaInsulina Humana: Farmacocinética

INSULINA DE ACCION CORTA ( CRISTALINA)

SC IM EV

Inicio de Acción 15-30' Inmediato

Efecto máximo 1-3hr 50-60' 20-30'

Duración de efecto 5-9hr 90' 20-30'

INSULINA DE ACCION INTERMEDIA (NPH)

Inicio de Acción 1hr

Efecto máximo 3-6hr

Duración de efecto 11-16hr

Comparación de Insulinas HumanasComparación de Insulinas Humanas

Inicio de Duración de Tipos de Insulina Acción Pico Acción

Lispro 5 – 15’ 1 -2 hr 4 - 6 hr

Humana Regular 30 – 60’ 2 - 4 hr 6 - 10 hr

Humana NPH 1 - 2 hr 4 - 6 hr 10 - 16 hr

Humana Lenta 1 - 2 hr 4 - 6 hr 10 - 16 hr

Ultralenta 2 - 4 hr Unpredictable <24 hr

* The time course of action of any insulin may vary in different individuals, or at different times in the same individual. Because of thisvariation, time periods indicated here should be considered as general guidelines only.

Insulina en DM tipo 2Insulina en DM tipo 2

Paciente clínicamente estable

Terapia oral + Insulina NPH (noct)

Paciente clínicamente inestable Con tendencia a la cetosis No alcanza metas con terapia

combinada

Manejo exclusivamente con Insulina

Esquemas de InsulinoterapiaEsquemas de Insulinoterapia

DESAYUNO ALMUERZO CENA 10-11pm

A R R R NPH

B R + NPH - R NPH

C R + NPH R R NPH

D R + NPH R + NPH R + NPH NPH

E R R + NPH R NPH

Regímenes con Insulina MixtaRegímenes con Insulina MixtaRegular

B L S HS B

Reg

NPH

Insu

lin

Eff

ect

Meals

NPH

Reg

Insu

lin

Eff

ect

B L S HS B

Meals

Lispro

NPH

Lispro

NPH

Lispro

NPH + RegularNPH + Regular

NPH at HS + Regular ACNPH at AM and HS + Regular AC

B L S HS B

Reg

Insu

lin

Eff

ect

Meals

Reg

NPH NPH

B L S HS B

Reg

Insu

lin

Eff

ect

Meals

Reg Reg

NPH

NPH at HS + Lispro ACNPH at AM and HS + Lispro AC

NPH + LisproNPH + Lispro

B L S HS B

Lispro

Insu

lin

Eff

ect

Meals

Lispro

NPH NPH

B L S HS B

Lispro

Insu

lin

Eff

ect

Meals

Lispro Lispro

NPH

Ultralenta PM + RegularUltralenta PM + Regular

B L S HS B

Insu

lin

Eff

ect

Meals

Reg

Ultralente

Reg Reg

Factores que influyen en la absorción de insulina :– Sitio de inyección– Profundidad de inyección – Tipo de Insulina– Dosis de insulina – Ejercicio físico– Temperatura de la piel

Absorción de Insulina

Insulina Lispro – Insulina aspartInsulina Lispro – Insulina aspart

Empieza acción más rápido, pico de acción más precoz (1hr) y permanece menos tiempo (3-4 hr)

La elevación pos prandial de la glicemia es 1.5-2.5 mmol/L menor durante insulina lispro vs insulina regular

Control a largo plazo: 0.3-0.4% la HbA1c comparado con insulina regular

Tasa de hipoglicemia severa se reduce 30% (4.4% a 3.1%)

Reducir dosis 20-30% si se realiza ejercicios (1-2 hr pos lispro)

La Insulina basal ideal …La Insulina basal ideal …

Imita la secreción de Insulina basal pancreática normal

Efecto prolongado Perfil sin picos Reducida hipoglicemia nocturna Administración una vez al día Efectos farmacodinámicos similar a

bomba de insulina

Insulina GlarginaInsulina GlarginaUn Nuevo Análogo de Acción ProlongadaUn Nuevo Análogo de Acción Prolongada

Modificationes a cadena de insulina humana– Sustitución de glicina en posición A21– Adición de 2 argininas en posición B30– Patrón de liberación gradual del sitio de inyección

1 5 10

15

20

Asp

Gly

Arg

Arg

Substitution

Extension

1 5 10

15

20

Asp

25

30

Insulina Glargina Vs. NPH Insulina Glargina Vs. NPH

Time (h) after S.C. Injection

0

Glargine insulin

NPH insulin

30

0

1

2

3

4

5

6

Glu

cose

Uti

liza

tion

Rat

e (m

g/k

g/h

)

2010

End of observation period

Lepore, et al. Diabetes 1999;48 (Suppl 1):A97.

Aumento Peso Nocturnal Hypo’s

NPH 3.1 lb 40%

Glargine 0.9 lb* 31%†

* P<0.01; † P <0.02

Rosenstock, et al. Diabetes 48(Suppl 1):A100, 1999

Insulina Glargina vs NPHInsulina Glargina vs NPH

Similar mejoría de HbA1c ( 0.4 a 0.6%) con menos hipoglicemia nocturna y menos ganacia de peso con insulina Glargina

Insulina Basal/BolosInsulina Basal/Bolos

Insulina Basal – Requerimiento de Insulina para suprimir la

producción hepática de glucosa entre las comidas

Insulina Bolos (prandial)– Requerimiento de Insulina para mantener el

depósito normal de glucosa después de comer

Terapia IntensivaTerapia Intensiva

Considera la Insulina basal y prandial Auto-monitoreo de la Glucosa Es muy dificil seguir el control exacto en pacientes

con Peptido C Neg Francis (1982) : mostró que una dosis de Insulina

regular despues de la cena y de Insulina intermedia antes de dormir:– Anula la hipoglicemia nocturna– Baja la glicemia en ayunas– Baja la glicemia post-desayuno

Infusión de Insulina continua Subcutanea

Tratamiento Intensivo de DM 2 y Tratamiento Intensivo de DM 2 y complicaciones microvascularescomplicaciones microvasculares

(años)(años)

Pacientes Pacientes con con eventos eventos microvasmicrovascular (%)cular (%)

*Microvascular events = renal failure, death from renal failure, *Microvascular events = renal failure, death from renal failure, retinal photocoagulation or vitreous haemorrhageretinal photocoagulation or vitreous haemorrhage

UK Prospective Diabetes UK Prospective Diabetes Study Group (1998)Study Group (1998)

0

2

4

6

8

10

12

14

16

18

20

0 3 6 9 12 15

Intensive treatment (n=2,729)Conventional treatment (n=1,138)

((pp=0.0099=0.0099))

ADA Treatment GuidelinesADA Treatment Guidelines

Biochemical Index Normal Goal Action Suggested

Preprandial glucose<90 mg/dL 80-120 mg/dL <80 or >140 mg/dL

Bedtime glucose <120 mg/dL 100-140 mg/dL<100 or >160 mg/dL

HbA1c <6%* <7% >8%*Depending on assay norms

El Estudio KumamotoEl Estudio Kumamoto: : Efectos Efectos de Terapia con Insulina Convencional de Terapia con Insulina Convencional vs. Intensivavs. Intensiva

Ohkubo Y, et al. Diabetes Res Clin Pract. 1995;28:103-117.

32%

44%

28%32%

7.7%

19.2%

7.7%11.5%

0

10

20

30

40

50

PrimaryPrevention

SecondaryPrevention

PrimaryPrevention

SecondaryPrevention

Retinopathy Nephropathy

Cum

ulat

ive

Dev

elop

men

t or

Pro

gres

sion

(%)

Conventional

Intensive

UKPDSUKPDS: : Efectos de Terapia Intensiva en Efectos de Terapia Intensiva en la Glicemiala Glicemia

UKPDS Group. Lancet. 1998;352:837-853.

6

7

8

9

10

0 1 3 5 7 9Years

FPG

(mm

ol/L

) or

HbA

1c (%

)

FPG, Conventional (N=1138)

FPG, Sulfonylurea (N=1573) or Insulin (N=1156)

HbA1c, Conventional

HbA1c, Sulfonylurea or Insulin

UKPDS 10-Year Cohort Data: UKPDS 10-Year Cohort Data: Reducciones con Terapia Intensiva Reducciones con Terapia Intensiva vs. Convencionalvs. Convencional

UKPDS Group. Lancet. 1998;352:837-853.

-6%

-10%

-16%(P= 0.052)

-25%(P= 0.0099)

-12%(P= 0.029)

-11%

-30

-20

-10

0

HbA1c All-Cause Mortality Diabetes-RelatedDeath

Any Diabetes-Related

Complication

MyocardialInfarction

MicrovascularComplication

ResumenResumen VA CSDM:

– Control glicémico se alcanza con tratamiento intensivo de insulina: control mantenido >2 a

– Tto Intensivo no asociado con hipoglicemia severa, aumento de peso, HTA o dislipidemia

Kumamoto:– Tratamiento Intensivo con insulina redujo las

complicaciones microvasculares – Estableció un umbral glicémico para prevenir inicio y

progresión de complicaciones UKPDS:

– Tto sólo con dieta fue inadecuado en 2/3– Es necesario Tto farmacológico mas nutrición/ejercicio– Insulina no aumenta la enf. macrovascular

Estrategias para Terapia con Insulina Estrategias para Terapia con Insulina en Pacientes Ancianosen Pacientes Ancianos

Terapia con Insulina es con frecuencia considerada un último recurso en el anciano

Metas terapeúticas:– Alivio de síntomas– Prevenir la hipoglicemia– Prevenir complicaciones agudas de hiperglicemia

Maneras de facilitar terapia con insulina:– Esquemas de dosis simples– Preparaciones Premezcladas – Sistemas de aplicación mejoradas, mas

convenientes

Terapias de Combinación:Terapias de Combinación: Razón

– Combinación de 2 agentes con diferente mecanismos de acción– Mas convenientes y pueden ser mas seguras

Sulfonilurea + Insulina– bedtime insulin/daytime sulfonylurea– En pacientes temprano o inicio de Insulinotto

Metformina + Insulina– Mejora la sensibilidad a la insulina

Acarbosa + Insulina– Disminuye la glicemia postprandial

Tiazolidinedionas + Insulina– Mejora la resistencia a insulina y la acción de insulina en tejidos

peripéricos – Reduce requerimientos de insulina

Meta-Análisis de Terapia con Meta-Análisis de Terapia con Sulfonilurea/InsulinaSulfonilurea/Insulina

Johnson JL, et al. Arch Intern Med. 1996;156:259-264.

* P< 0.05 vs. baseline value

1.4

-0.6-0.25

0.8

-2.5*

-1.1*

-3

-2

-1

0

1

2

Fasting Serum Glucose(mg/dL)

HbA1c (%) Weight (kg)

Cha

nge

From

Bas

elin

e V

alue

s

Sulfonylurea + InsulinInsulin Only

Comparación de Regímenes de Comparación de Regímenes de Insulina en Falla de Terapia Oral Insulina en Falla de Terapia Oral

Yki-Jarvinen H, et al. N Engl J Med. 1992;327:1426-1433.

-0.9-1.7*

2.2*

-1.9*

1.2* †

-1.8*

1.8*

-1.6*

2.9*

-0.5

-4

-2

0

2

4

6

8

10

Change in HbA1c (%) Weight Change (kg)

*P< 0.001 vs. control group†P< 0.05 vs. other insulin treatment groups

Morning NPH (N= 32)Evening NPH (N= 28)Twice-daily injections (N= 29)

Multiple-daily injections (N= 30)Control (N= 30)

Bomba de InsulinaBomba de Insulina

CSII: usa una bomba de infusión portátil conectado a un catéter SC para dar insulina de acción rápida

Significativas ventajas sobre múltiples inyecciones diarias– Reduce variabilidad glicémica,

hipoglicemia clínica, aumento de peso

Insulin PumpInsulin Pump

Pen de InsulinaPen de Insulina

Beneficios– More accurate dosing mechanisms – Faster and easier than conventional syringes– Improved patient attitude and compliance

Advantages of newer insulin pens– LCD display to show dosage setting– Dosage settings change quickly and easily– Safety button automatically resets after drug

delivery

Insulin PenInsulin Pen

Insulina InhaladaInsulina Inhalada

Gelfand RA, et al. Presented at ADA 58th Annual Meeting. 1998:Abstract 0235.

Changes in Glycemic Parameters

-50-45-40-35-30-25-20-15-10

-50

HbA1c 2-hr PG

% C

hang

e Fr

om B

asel

ine

Inhaled human insulin

Subcutaneously injectedinsulin

Continuous Glucose SensorsContinuous Glucose Sensors

When available, may provide only mechanical means of achieving “normal” glucose homeostasis

Will direct insulin delivery automatically on demand (“closed loop”)

One technology uses reverse iontophoresis to noninvasively extract and measure glucose levels

Technical challenge to develop

United Kingdom Prospective United Kingdom Prospective Diabetes StudyDiabetes Study

(UKPDS) (UKPDS)

UKPDS: MetasUKPDS: Metas

Meta Primaria: determinar el efecto de control intensivo de glucosa (terapia farmacológica vs control convencional de glucosa (cambios de estilo de vida) en el desarrollo de complicaciones macrovascular y microvascular en diabetes tipo 2

Meta Secondaria: determinar si una terapia particular para control glicémico (insulina, sulfonilureas o metformina) tiene algunas ventajas o desventajas

UKPDS Group. Lancet. 1998;352:837–853.

UKPDS: RevisiónUKPDS: Revisión

Estudio 20-años, multicéntrico, prospectivo, randomizado, intervención

5102 personas con diabetes 2 recién diagnosticados

FPG >6 mmol/l (108 mg/dl)Seguimiento medio de: 11 años


UKPDS: DesignUKPDS: Design

Metformin treatmentOverweight patients

(n=342)

Conventional management(n=1138)

Sulphonylurea treatment(n=1573)

Insulin treatment(n=1156)

Intensive management(n=2729)

Non-overweight and overweight patients

(n=3867)

Randomisation(n=4209)

3 month run-in period Diet management regimen

(n=5102)


UKPDS: Manejo ConvenUKPDS: Manejo Convenccionalional

Primary management: diet Treatment goal

– near-normal body weight– FPG <15 mmol/l (270 mg/dl)– premeal glucose 4–7 mmol/l (72–126 mg/dl; insulin

only)

Management if hyperglycaemia or hyperglycaemic symptoms develop:– nonintensive pharmacological therapy

(sulphonylurea or insulin; metformin if overweight)


UKPDS: Manejo UKPDS: Manejo ffarmacolarmacolóógicgicoo Primary management

– sulphonylurea (500 mg/day chlorpropamide) or 20 mg/day glibenclamide

– insulin (daily injection with intermediate- or long-acting insulin)– self-monitoring of blood glucose

Treatment goal– FPG<6 mmol/l (108 mg/dl)

– premeal glucose 4–7 mmol/l (72–126 mg/dl; insulin only) Management if hyperglycaemia or hyperglycaemic symptoms

develop– sulphonyureas

• add metformin; switch to insulin therapy if hyperglycaemia recurs

– insulin single bedtime injection • initiate complex insulin regimen


UKPDS: Clinical endpointsUKPDS: Clinical endpoints

Primary outcome measures = 21 clinical endpoints

Diabetes-related endpoints– myocardial infarction, heart failure,

angina, sudden death, stroke, amputation, retinal photocoagulation, renal failure, vitreous haemorrhage

Non-diabetes-related endpoints– death from accident, cancer


UKPDS: Therapy progressionUKPDS: Therapy progression

Years from randomisation

Per

cen

tag

e o

f p

atie

nts

1 2 3 4 5 6 7 8 9 10 11 120

20

40

60

80

100

diet alone

1 2 3 4 5 6 7 8 9 10 11 12

intensivepharmacologicaltherapy

diet aloneadditional non-intensivepharmacological therapy

Intensive Policy (aim for <6 mmol/l)

Conventional Policy (accept <15 mmol/l)

0

20

40

60

80

100


9


0

6

7

8

0 3 6 9 12 15

Hb

A1

c (%

)

Conventional

Intensive

6.2% upper limit of normal range

UKPDS: Effects of management UKPDS: Effects of management on HbAon HbA1c1c


UKPDS: Effects of management UKPDS: Effects of management on fasting plasma glucoseon fasting plasma glucose

0 3 6 9 12 15


Conventional

Intensive7.8

8.9

10.0

11.1

6.7

Me

dia

n F

PG

(m

mo

l/l)


05.6

UKPDS: Effects of management UKPDS: Effects of management onon body weightbody weight

0 3 6 9 12 15

-2.5

0.0

2.5

5.0

7.5

Ch

an

ge

in b

od

y w

eig

ht

(kg

)

Conventional

Intensive



0

10

20

30

0 3 6 9 12 15

Pe

rce

nta

ge

of

pa

tie

nts

wit

h e

ve

nt


Intensive

Conventional p=0.052


UKPDS: Effects of management UKPDS: Effects of management on myocardial infarctionon myocardial infarction

0 3 6 9 12 15

Pe

rce

nta

ge

of

pa

tie

nts

wit

h e

ve

nt


Intensive

p<0.01

Intensive

Conventional

UKPDS Group. 1998;352 Lancet. :837–853.

0

10

20

30

UKPDS: Effects of management UKPDS: Effects of management on microvascular endpointson microvascular endpoints

0

10

20

30

40

50

0 3 6 9 12 15

Pe

rce

nta

ge

of

pa

tie

nts


0

1

2

3

4

5

0 3 6 9 12 15

Any episode Major episodes

UKPDS: Effects of management UKPDS: Effects of management on hypoglycaemiaon hypoglycaemia

Intensive

Conventional

Intensive

Conventional


UKPDS: Risk reductionUKPDS: Risk reduction

Any diabetes-related endpoint 12

Diabetes-related deaths 10

Myocardial infarction 16

Microvascular disease 25Retinopathy progression* 21Cataract extraction 24Microalbuminuria* 33

Risk reduction (%)


* At 12 years

Any Diabetes Related EndpointAny Diabetes Related Endpoint

Updated mean HbA1c

Haz

ard

ratio

UKPDS 35. BMJ 2000; 321: 405-12

0.5

1

5

0 5 6 7 8 9 10 11

21% decrease per 1% decrement in HbA1c

p<0.0001

Diabetes Related DeathsDiabetes Related Deaths


p<0.0001

0.5

1

5

0 5 6 7 8 9 10 11Updated mean HbA1c

Haz

ard

ratio

UKPDS 35. BMJ 2000; 321: 405-12

All Cause MortalityAll Cause Mortality


p<0.0001

0.5

1

5


Haz

ard

ratio

UKPDS 35. BMJ 2000; 321: 405-12

Fatal and Non-Fatal Myocardial Fatal and Non-Fatal Myocardial InfarctionInfarction


p<0.0001

0.5

1

5


Haz

ard

ratio

UKPDS 35. BMJ 2000; 321: 405-12

Fatal and Non-Fatal StrokeFatal and Non-Fatal Stroke

0.5

1

5

0 5 6 7 8 9 10 11


p=0.035

Updated mean HbA1c

Haz

ard

ratio

UKPDS 35. BMJ 2000; 321: 405-12

Microvascular EndpointsMicrovascular Endpoints

0.5

1

10

15

0 5 6 7 8 9 10 11


p<0.0001

Updated mean HbA1c

Haz

ard

ratio

UKPDS 35. BMJ 2000; 321: 405-12

Cataract ExtractionCataract Extraction

0.5

1

5

0 5 6 7 8 9 10 11


p<0.0001

Updated mean HbA1c

Haz

ard

ratio

UKPDS 35. BMJ 2000; 321: 405-12

Amputation or Death from Peripheral Amputation or Death from Peripheral Vascular DiseaseVascular Disease

0.1

1

10

20

0 5 6 7 8 9 10 11


p<0.0001

Updated mean HbA1c

Haz

ard

ratio

UKPDS 35. BMJ 2000; 321: 405-12

Heart FailureHeart Failure

0.5

1

5

0 5 6 7 8 9 10 11


p=0.016

Updated mean HbA1c

Haz

ard

ratio

UKPDS 35. BMJ 2000; 321: 405-12

UKPDS 35. BMJ 2000; 321: 405-12

Myocardial Infarction and Myocardial Infarction and Microvascular DiseaseMicrovascular Disease

0

20

40

60

80

0 5 6 7 8 9 10 11

Myocardialinfarction

Microvasculardisease

Updated mean HbA1c (%)

Inci

denc

e pe

r10

00 p

atie

nt-y

ears

UKPDS 35 SummaryUKPDS 35 Summary• There is a direct relationship between the risk

of complications of diabetes and glycaemia over time

• No threshold of glycaemia was observed for a substantive change in risk for any of the clinical outcomes examined

• The lower the glycaemia the lower the risk for complications

• The rate of increase of risk for microvascular disease with hyperglycaemia is greater than that for macrovascular disease

0

10

20

30

40

50

Incidence Rates of MI and Microvascular Endpoints Incidence Rates of MI and Microvascular Endpoints by Mean Systolic Blood Pressureby Mean Systolic Blood Pressure: : UKPDSUKPDS

110

120 130 140 150 160 170

Inci

dence

per

1000 P

ers

on

Years

(%

)

Adler AI et al. BMJ 2000;321:412-419.

Updated Mean Systolic Blood Pressure (mmHg)Adjusted for age, sex, and ethnic group

Myocardial Infarction

Microvascular Endpoints

0

20

40

60

80

Incidence Rates of MI and Microvascular Incidence Rates of MI and Microvascular

Endpoints by Mean Hemoglobin AEndpoints by Mean Hemoglobin A1c1c: : UKPDSUKPDS

5 6 7 8 9 10 11

Inci

dence

per

1000 P

ers

on

Years

(%

)

Stratton IM et al. BMJ 2000;321:405-412.

Updated Mean Hemoglobin A1c Concentration (%)Adjusted for age, sex, and ethnic group

Myocardial Infarction

Microvascular Endpoints

UKPDS Group. Lancet 1998;352:837-853.

UKPDS 10-Year Follow-up ResultsUKPDS 10-Year Follow-up Results::Glycemic Control, Weight, and Plasma InsulinGlycemic Control, Weight, and Plasma Insulin

Years from Randomization

0 1 2 3 4 5 6 7 8 9 10 11

12

0 1 2 3 4 5 6 7 8 9 10 11

12Years from Randomization

Conventional

Conventional

Intensive

IntensiveConventional

Intensive

Intensive

Conventional

Fasting plasma glucose

Med

ian (

mm

ol/L) Hemoglobin A1c

Weight Plasma insulin

11

10

9

8

7

60

Med

ian (

%)

9

8

7

60

7.5

5

2.5

0

-2.5

Baseline = 75 kgMean C

han

ge (

kg)

40

30

20

10

0

-10

-20Med

ian C

han

ge (

pm

ol/L)

Baseline = 89 pmol/L

UKPDS: Endpoints by Glucose UKPDS: Endpoints by Glucose Treatment GroupTreatment Group

Rate/1000Rate/1000Patient-Patient-YearsYears

Any diabetes-related*

MI

Stroke

PVD**

Microvascular

UKPDS Group. Lancet 1998;352:837-853.

Rate/1000Rate/1000Patient-Patient-YearsYears

PPCauseCause

40.9

14.7

5.6

1.1

8.6

*Combined microvascular and macrovascular events**Amputation or death from PVD

% Risk% RiskReductionReduction

46.0

17.4

5.0

1.6

11.4

0.029

0.052

0.52

0.15

0.009

12

16

–

–

25

ConventionalConventionalIntensiveIntensive

UKPDS: Impact of Glucose-Lowering UKPDS: Impact of Glucose-Lowering Agents on MI and StrokeAgents on MI and Stroke Sulphonylurea or exogenous insulin (n=2729)

MI 16% reduction (P = 0.052)

Stroke 11% increase (P = 0.52)

Metformin in overweight subjects (n = 342)

MI 39% reduction (P = 0.01)

Stroke 41% reduction (P = 0.13)

Adapted from UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:837-853; UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:854-865.

UKPDS Results: Intensive UKPDS Results: Intensive Blood Pressure ControlBlood Pressure Control

Any diabetes-related endpoint

Deaths related to diabetes

Myocardial infarction

Stroke

Microvascular disease

Intensive BloodIntensive BloodPressure ControlPressure Control

24

32

21

44

37

0.0046

0.019

NS

0.013

0.092

Adapted from UK Prospective Diabetes Study Group. BMJ 1998;317:703-713.

ReductionReduction(%)(%) P ValueP Value

Comparison of Glucose Lowering and Blood Comparison of Glucose Lowering and Blood Pressure Lowering in UKPDSPressure Lowering in UKPDS



Stroke


12

16

11

25

Reduction Reduction

%%

= Increase in risk

Adapted from UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:837-853; UK Prospective Diabetes Study Group. BMJ 1998;317:703-713.

PPValueValue

Reduction Reduction %%

PPValueValue

Intensive BloodIntensive BloodGlucose Control (n=2729)Glucose Control (n=2729)

Intensive BloodIntensive BloodPressure Control Pressure Control

(n=758)(n=758)

0.029

0.052

NS

0.0099

24

21

44

37

0.0046

NS

0.013

0.092

UKPDS Group. BMJ 1998;317:703-713.

Effect of Blood Pressure Control in the Effect of Blood Pressure Control in the UKPDS: UKPDS: Tight vs. Less Tight ControlTight vs. Less Tight Control


Diabetes-related deaths

Heart failure

Stroke



Tight Control

1,148 Type 2 patients

Average BP lowered to 144/82 mmHg (controls: 154/87); 9-year follow-up

24

32

56

44

21

37

Risk Reduction (%) P value

0.0046

0.019

0.0043

0.013

NS

0.0092

Diabetes complications associated with poorer quality of life

Intensive insulin treatment regimen had no effect on quality of life

UKPDS: Quality of lifeUKPDS: Quality of life

UKPDS Study Group. Diabetes Care 1999;22:1125–1136.

UKPDS: ConclusionsUKPDS: Conclusions

Glycaemic control deteriorated with time regardlessof initial choice of therapy

Pharmacological glycaemic control (intensive group) reduced HbA1c by 0.9% over 10 years, with a resulting decrease in clinical complications

No significant reduction in macrovascular events with sulphonylureas or insulin therapy

Pharmacological management was associated with significant increase in weight versus lifestyle changes


UKPDS metformin study in UKPDS metformin study in overweight patients: Risk reductionoverweight patients: Risk reduction

Any diabetes-related end-point 32 7

Diabetes-related deaths 42 20

Myocardial infarction 39 21

Microvascular disease 29 16

Risk reduction* (%)


Metformin intensive

Sulphonylurea/insulin intensive

* Compared with conventional therapy

9


0

6

7

8

0 32 4 51

Hb

A1

c (%

)

Conventional

Intensive (insulin alone)

6.2% upper limit of normal range

UKPDS sulphonyurea UKPDS sulphonyurea inadequacy: HbAinadequacy: HbA1c1c

UKPDS Group. Diabetes Care. 2002;25:330–336.

6

5

Intensive (sulphonylurea ± insulin)

UKPDS: ImplicationsUKPDS: Implications

The UKPDS results support the mandate that intensive glycaemic control is required to reduce the risk of microvascular complications in people with Type 2 diabetes

Macrovascular disease prevention requires management of cardiovascular risk factors in addition to hyperglycaemia

No increase in cardiovascular events or death was observed and the risk of atherosclerotic events should not discourage intensive management

The benefits of intensive glycaemic control outweigh the risk of hypoglycaemia

Tight blood pressure control reduces diabetes-related mortality, heart failure and stroke

The phrase ‘intensive’ in this study is somewhat misleading as it corresponds to usual clinical management in many centres

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