Estudios Advance, Accord,

VADT,

UKPDS, DCCT, Steno..…

¿Que nos enseñan? Alfonso L. Calle Pascual

Servicio de Endocrinología y Nutrición

HCSC, Madrid

Actualización en Endocrinología 2009

FJD 27 de Febrero de 2009

CONTEXTO 2000

Diabetes y riesgo microvascular

Diabetes y riesgo macrovascular

Aggregate clinical end points

conventional

0.5 1 2

0.88

0.90

0.94

0.84

1.11

0.75

0.029

0.34

0.44

0.052

0.52

0.0099

Any diabetes-related end point

Diabetes-related deaths

All-cause mortality

Myocardial infarction

Stroke

Microvascular

RR P

Favors Intensive

Relative Risk & 95% CI

UKPDS,Lancet 1998.

Glycemic threshold for

microvascular/cardiovascular risk

Relative

risk

3

2

1

Fasting Plasma glucose

(mmol/L) 4 5 6 7 8

Microvascular Cardiovascular

4 6 8 10 12 14 2-hour

- Glucose

- Blood pressure

- Lipids

- Antiplatelet agents

- COMBINED INTERVENTIONS

Multiple risk factors in T2DM

GAEDE P, et al. NEJM. 2003;348:383-393.

160 Danish type 2 diabetic patients with

persistent microalbuminuria

One example of a multifactorial strategy:

the STENO 2 study

Results of multifactorial intervention on primary end point (7.8

years’ follow-up)

Link between blood glucose and CV risk:

Association or causality?

Good diabetes control reduces CV risk in type

1 diabetes:

Convincing evidence in type 1 diabetes:

The DCCT/EDIC study

NEJM. 2005;353:2643.

Some comments on the DCCT/EDIC study:

– Good news for type 1 diabetic subjects!

– A major relative risk reduction: ~ 50%

– An illustration of the glucose memory effect

HbA1c during DCCT/EDIC:

- 1983: 9.1% // 9.1%

- 1993: 7.4% // 9.0%

- 2004: 8.0% // 7.9%

Glucose & CV events: meta-regression

RR RR

NB: 2 h G=140: RR=1.58 (1.19-2.10) Fasting G=110: RR=1.33 (1.06-1.67)

After removal of any DM: P=0.0006 for 2 h G

P=0.06 for FPG

Coutinho M, Gerstein HC, et al. Diabetes Care. 1999;22:233-240.

72 108 144 180 198 72 90 108 126 144 163

2 h glucose Fasting glucose

Glucose-lowering and CV risk - IGT Ambulatory IGT: STOP NIDDM analysis: Chiasson, et al. JAMA. 2003;290:486.

HR 0.51 (0.28-0.95) (ie, 32/686 vs 15/682 MI, angina, revasc, CV death, CHF, stroke, or PVD)

ESTRATEGIAS

FARMACOLOGICAS

• Farmacos que corrijan los defectos en la

acción y secreción de la insulina

• Seguros: HIPOGLUCEMIA

• Eficaces sobre el control glucémico

• Otros efectos sobre el control metabólico

What about intensified glucose control in

dysglycemia/type 2 diabetes?

• ADVANCE

• ACCORD

• VADT

• ORIGIN

• NAVIGATOR

.......

Trials ongoing:

Diseño Experimental

• Criterios inclusión: TTO dosis máximas

HO/insulina y HbA1c >7.5%. HbA1c

B>9%

• BMI <27 Kg.m-2: GlimeP+ Rosi Dosis

Max (1/2 Control)

• Antes de cualquier cambios en dosis oral se

suministra Insulina (HbA1c >6%)

Algunas características

Relevantes • Entre 2000-3 hasta 2008

• Edad >60 a Tev >11 años

– 72% HTA y 40% ECV;

– 52% insulina 42% HO dosis Max

• Exclusión:

– 34% HbA1c

– 16% no recibían Dosis Max HO/Insulina

• Seguimiento:

– Ganancia de peso >Intensivo (+4Kg)

– LDL < 80 mg/dl

Tamaño muestral

• Infraestima Tiempo

• Sobreestima riesgo

• Ocurrieron 499

eventos CV

• (264 vs 235 C vs Int)

• Podría esperarse una

reducción no

significativa

Muertes

Muertes (Inten vs Conv)

• CV: 40 vs 33

• Súbitas 11 vs 4; p=0.08

Efectos 2º (Inten vs Conv)

• Hipoglucemias severas:

24 % vs 18% p=0.05

• Disnea: Intensivo

p<0.006

• Neuropatia Autonómica

p=0.07

The Oxford Centre for Diabetes, Endocrinology and Metabolism

PRECAUCIONES • Aquellos que dicen que disminuir

la glucemia no es costo-eficaz

• Aquellos que dicen que el objetivo de 7.5% es “mas” adecuado, sin decir el motivo

• Aquellos que dicen que es suficiente bajar el colesterol y la TA

• Aquellos que quieren hacerse famosos diciendo cualquier cosa ruidosamente

STENO 2

HISTORIA: Reflexiones

• ACCORD: NO VALE TODO

• VADT: ESPERADO

• UKPDS (1998): microangiopatia (2008) macroangiopatia

• Steno 2003. Multifactorial; 2008 Macrovascular Objetivos óptimos. NUNCA ES TARDE

• ADVANCE Objetivos óptimos. Y ESTRATEGIAS

• No todos fármacos pueden ser idénticos (metformin vs SUs; TZDs pueden tener efectos adversos CV

• HIPOGLUCEMIAS ¿ARMAS?

___________________________

Krinsley. Crit Care Med 2008; 36:3008–3013

Retrospective review of 3252 medical surgical ICU patients excluding cardiac surgery. GV, assessed by SD of mean BG levels

Glycemic variability: A strong independent predictor of mortality in critically ill patients

Each of the increments of mean glucose level was subdivided into four quartiles of glycemic variability. Q1= lowest; Q4 =highest quartile

Hypoglycemia-associated Hospital

Mortality Relates to Comorbidities

Retrospective cohort of 31,970 patients admitted to the general wards

aimed to determine inhospital mortality (<70 mg/dL) -spontaneous and

drug-associated hypoglycemia.

RESULTS:

• A total of 10.5% of patients had ≥ episode of hypoglycemia. Patients

with hypoglycemia were older, had more comorbidities, and received

more antidiabetic agents.

• Hypoglycemia was associated with increased in-hospital mortality

(HR, 1.67; 95% CI, 1.33-2.09; P.001).

• Mortality risk was limited to patients with spontaneous hypoglycemia

(HR, 2.62; 95% CI, 1.97-3.47; P.001) and not to patients with drug-

associated hypoglycemia (HR, 1.06; 95% CI, 0.74-1.52; P.749).

• After adjustment for patient comorbidities, the association between

spontaneous hypoglycemia and mortality was eliminated (HR, 1.11;

95% CI, 0.76-1.64; P.582).

Boucai et al. Am J Med 124, 1028-1035, 2011

Number of Hypoglycemic Episodes and In-

Hospital Mortality

Boucai et al. Am J Med 124, 1028-1035, 2011

Mean Glucose & In-Hospital Mortality in 16,871 Patients with AMI

(Reference: Mean BG 100-110 mg/dl)

Kosiborod M et al. Circulation 2008:117:1018

BUENAS NOTICIAS

ORIGIN