Obesidad y comorbilidades - SEEDO · 2017-11-24 · De la obesidad a la DM2 Esteatosis hepática y dislipemiaaterogénica. LookAheadTrial and HepaticSteatosis DM2 ... •Diabetes

Obesidad y comorbilidades

asociadasEsteban Jódar Gimeno

Head Department of Endocrinology and Clinical Nutrition.University Hospitals Quiron Salud Madrid (Pozuelo, Ruber Juan Bravo, San José)

Professor of Endocrinology, School of Health Sciences, Universidad Europea de MadridMadrid, Spain

@estebanjodar @estebanjodar https://es.linkedin.com/in/esteban-jodar-gimeno-11285628

• Ninguna relevante para esta actividad

Conflictos de interés

La información aquí aportada se basa en artículos científicos disponiblessobre efectos de distintas moléculas.Algunas de estas podrían no estar aprobadas por la EMA y sobre otras, lasindicaciones son limitadas.La siguiente ponencia incluye información que expresa las opinionespersonales del presentador y no las del promotor de este evento; parte delcontenido puede ser no referenciado.

Consultor: Abbott, AMGEN, BMS/AZ, FAES, Italfármaco, Janssen, Lilly,MSD, NovoNordisk, Takeda.Investigador Clinico: AMGEN, Boehringuer, BMS/AZ, Janssen, Lilly, MSD,Novartis, NovoNordisk, Pfizer, Sanofi.Ponente: AMGEN, Boehringer, BMS/AZ, FAES, Ferrer, Lilly, MSD,NovoNordisk.

@estebanjodar @estebanjodar https://es.linkedin.com/in/esteban-jodar-gimeno-11285628

• Efecto en mortalidad– Efecto de obesidad– Controversias– Otros

• Efecto en morbilidad– Miscelánea– Cáncer– Gastrointestinales– Musculo-esqueléticos– Cardiovasculares– Metabólicos

• Conclusiones

Agenda



• Conclusiones

Agenda

Obesidad y mortalidad

n engl j med 352;11 www.nejm.org march 17, 2005

Individuals who are both obese and smoke have a substantially greaterreduction in life expectancy thannonobese smokers or obesenonsmokers

• Obesidad: – (meta-analysis to date of 230 cohort studies, 30 million

individuals), obesity and overweight associated with anincreased risk of all-cause mortality (nadir BMI 20 to 22 kg/m2 in studies of healthy, never-smokers) BMJ. 2016;353:i2156

• Sobrepeso– Overweight also appears to increase mortality in some, but not

all, studies. – The BMI range associated with the lowest mortality has been

increasing (increased from 23.7 kg/m2 in a 1976 to 1978 cohort to 27.0 kg/m2 in a 2003 to 2013 cohort)

Exceso de peso y mortalidad

BMJ. 2016;353:i2156



• Conclusiones

Agenda

• The term refers to individuals who do not haveadiposity-associated cardiometabolic abnormalities(hypertension, hypertriglyceridemia, low high-densitylipoprotein [HDL] cholesterol, impaired fastingglucose and/or evidence of insulin resistance, abnormal C-reactive protein)

• In a pooled analysis (4 studies, 10-year follow-up), "metabolically healthy obese" had a significantlyincreased risk of mortality compared withmetabolically healthy normal-weight individuals.

– However, in metabolically healthy overweightindividuals, the increased risk of mortality did notreach statistical significance, even when the analysiswas restricted to studies with at least 10 years of follow-up (relative risk [RR] 1.21, 95% CI 0.91-1.61).

Obesos metabólicamente sanos

Arch Intern Med. 2008;168(15):1617-1624

Ann Intern Med. 2013;159:758-769.

Sobr

epes

oO

besi

dad

<10

años

>10

años

<10

años

>10

años

La paradoja de la obesidad

• May elevated BMI improve survival in individuals with CVD, primarily congestiveheart failure?, a phenomenon called the"obesity paradox”

• BUT, have not considered body fatdistribution.

– Abdominal (versus gluteal) fat mass is stronglypredictive of metabolic disease and mortalitywhen measured by dual-energy x-rayabsorptiometry (DXA), waist-to-hip ratio, or waistcircumference.

• Thus, people with BMI <25 kg/m2 but withcentral obesity appear to have anincreased mortality risk and should be targeted for lifestyle modificationstrategies.

The American Journal of Medicine (2009) 122, 1106-1114

Bray Up to Date 2017

Controversias



• Conclusiones

Agenda

Causas de mortalidad en obesos

• 25 to 50 kg/m2, each5 kg/m2 increase in BMI wasassociated with a significantincrease in mortality fromcoronary heart disease (CHD), stroke, diabetes mellitus, chronic kidneydisease, and cancer (liver, kidney, breast, endometrial, prostate, and colon).

• 30 and 35 kg/m2, median survival was reduced by two to four years

• 40 to 45 kg/m2, it was reducedby 8 to 10 years (similar to theeffects of smoking).

Lancet 2009; 373: 1083–96

Disfunción tejido adiposo(patrón secreción adipoquinas alterado)

De la obesidad a la ECVInflamación tejido adiposo como base

Jung RT. Obesity as a disease. Br Med Bull 1997;53:307-21

Beneficios de la pérdida de peso moderada en la historia natural de la DM2

Mortalidad

• Mortalidad total 20-25%.

• Muertes por DM 30-40%.

• Muertes CV por exceso de peso 40-50%.

Diabetes

• Riesgo de diabetes >50%.• Glucemia basal del 30-50%.• HbA1c del 15%.• Reducción medicación antidiabética.

Presión arterial

• Sistólica y diastólica ~10 mmHg.

• Reducción medicación HTA.

Lípidos

• Colesterol total de 10%.

• LDL del 15%, HDL del 8% triglicéridos del 30%.

Efecto del ejercicio • Compared with normal-weight-fitindividuals, unfit individuals hadtwice the risk of mortality regardlessof BMI.

– Overweight- and obese-fitindividuals had similar mortalityrisks as normal-weight-fitindividuals.

• In contrast, in the Lipids ResearchClinics and the Nurses' HealthStudies, both physical fitness and adiposity were independentpredictors of mortality, and higherlevels of physical activity did notnegate the association betweenobesity and mortality

Prog Cardiovasc Dis. 2014 Jan;56(4):382-90.



• Conclusiones

Agenda

(ATP-III)Mujeres >88 cmHombres> 102 cmSon posibles otros puntos de corte según etnia

Distribución androideDistribución ginoide Circunferencia cintura

Puntos de cortemás usados:

Adaptado de: Yusuf S et al. Obesity and the risk of myocardial infarction in 27.000 participants from 52 countries: a case-control study. Lancet 2005, 5;366(9497):1640-9

Obesidad y Smde metabólico

Valoración obesidad abdominal



• Conclusiones

Agenda

Han et al. Eur J Endocrinol 2011;164:1003–11

*Physical function assessed by Short Form-36 (SF-36); psychological function assessed by SF-36 and Beck’s Depression Inventory; sexual function assessed by European Male Ageing Study sexual function questionnaire. n=3369 males; complete data concerning frequency of sexual activities and erectile function were availablein 2734 (92%) and 3193 (95%) of the participants, respectively

6%

10%

19%

6%

10%

22%

12%15%

27%

0

5

10

15

20

25

30

Physical Psychological Sexual

<25

≥25–<30

≥30

Obesity negatively affects health-related quality of lifePr

eval

ence

of im

pairm

ent

(%) BMI

Comorbilidades, Misc• Reproductor:

– Alts regla, anovulación, subfertilidad, alts perinatal y maternal.

– Alteraciones sexualidad y anorgasmia, difon erectil

• Genitourinario:– IRC: ¿FdeR indepte? Alts

Glomerulares– Otros: litiasis,

incontinencia…

• Psicológicas:– Estigma– Depresión – Demencia

• Infecciones– PostQca, nosocomial,

cutánea y tej blandos

• Piel:– Estrías, acantosis

nigricans, hirsutismo




• Conclusiones

Agenda

Cáncer & Obesidad

• Obesity causes 20 % of allcancers.

• Increases the likelihood of dying from cancer.

– (meta-analysis, 141 studies), a 5 kg/m2 increase in BMI in menwas associated with esophageal, thyroid, colon, and renal cancers(RR 1.52, 1.33, 1.24, and 1.24, respectively).

– In women, a 5 kg/m2 increasewas associated with endometrial, gallbladder, esophageal, and renal cancers (RR 1.59, 1.59, 1.51, and 1.34, respectively).

BMJ 2017;356:j477

Suppl Appendix to: Bhaskaran et al. Lancet 2014;384:755–65

0,0

1,0

2,0

3,0

4,0

5,0

6,0

The risk for certain types of cancer increase with BMIRel

ativ

e risk

RR=1

Normal weight (BMI 18.5–24.9)Overweight (BMI 25.0–29.9)

Moderately obese (BMI 30.0–34.9)Severely obese (BMI ≥35.0)

BMI is associated with cancer risk, with substantial population-level effects. The heterogeneity in the effectssuggests that different mechanisms are associated with different cancer sites and different patient subgroups.

Cáncer: causas

Endocr Relat Cancer. 2015 Dec; 22(6): R365–R386.



• Conclusiones

Agenda

Gastrointestinales

• Enfermedad Hepatobiliar– Increased risk of

gallbladder disease and nonalcoholic fatty liverdisease. – (meta-analysis of 17

studies; n=55,670), the riskof gallbladder diseaseincreased even within thenormal BMI range

• Enf por reflujo, Ca Esofago y estómago:


Cusi K et al. Gastroenterology 2012

De la obesidad a la DM2Esteatosis hepática y dislipemia aterogénica

LookAhead Trial and Hepatic SteatosisDM2 (n=96), valoración por 1H-MRS, edad 61.6 años

Lanzo M et al; Diab Care 2010

Weight Change (% relative to baseline)

Cha

nge

in li

ver

fat

+>1% +1,-1% -1,-5% -5.1,-10% ->10.1%

Mejora de esteatosis



• Conclusiones

Agenda

Musculo-esquelético

• Artrosis– increased incidence, is a

major component of thecost of obesity.

– Weight loss is associatedwith a decreased risk of osteoarthritis.

• Hiperuricemia y gota:– Increased risk with body

weight and with the amountof weight gain duringadulthood.




• Conclusiones

Agenda

Based on data from the NHANES III survey; n=7689 (women)BMI, body mass index

Must et al. JAMA 1999;282:1523–9

The prevalence of hypertension increases with increasingBMI

<25.0 30.0–34.9 35.0–39.9 ≥40.025.0–29.9

Hyp

erte

nsio

n pr

eval

ence

(%)

23

39

4855

63

0

10

20

30

40

50

60

70

BMI (kg/m2)

Cardiovascular• HTA:

– Greatest risk in upper body and abdominal obesity.

– Weight loss in obese subjects isassociated with a decline in bloodpressure.

• Enf Cardiaca:– CAD: frequent coexistence of

other CHD risk factors, & independent risk factor

– Fallo Cardiaco: – Esteatosis miocárdica: – Alts EKG– FA

• ACVA Increased risk, mitigated byweight loss.

• ETE Increased risk of deep veinthrombosis and pulmonary embolus.


Relación causal Ob Abdominal-DMt2/CAD

Emdin CA et al. JAMA 2017; 317: 626

0 6 12 18 24 30 36 42 48 540

5

10

15

20

P la ce b o

Pat

ien

ts w

ith

an

eve

nt

(%)

Time from randomisation (months)

LEADER Primary outcomeCV death, non-fatal myocardial infarction, or non-fatal stroke

Patients at riskLiraglutidePlacebo

46684672

45934588

44964473

44004352

42804237

41724123

40724010

39823914

15621543

424407

HR=0.8795% CI (0.78 ; 0.97)

p<0.001 for non-inferiorityp=0.01 for superiority

The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes, non-fatal myocardial infarction, or non-fatal stroke. The cumulative incidences were estimated with the use of the Kaplan–Meier method, and the hazard ratios with the use of the Cox-proportional hazard regression model. The data analyses are truncated at 54 months, because less than 10% of the patients had an observation time beyond 54 months. CI, confidence interval; CV, cardiovascular; HR, hazard ratio.Marso SP et al. N Engl J Med 2016; 375:311-322.

0 6 12 18 24 30 36 42 48 540

5

10

15

20

L ira g lu t id e

0 6 12 18 24 30 36 42 48 540

5

10

15

20

N Engl J Med 2016; 375:311-322July 28, 2016DOI: 10.1056/NEJMoa1603827

BMI, kg/m2 LIRA 32.5 ± 6.3 PCB 32.5 ± 6.3

Relación entre cambio peso y cambio Índice AH

Foster GD et al; Arch Intern Med 2009

Sleep apnea. Sleep AHEAD Trial

Liraglutida en apnea del sueño



• Conclusiones

Agenda

Metabólicos

• Diabetes tipo 2.• Main comorb. >80% of cases can

be attributed to obesity

• Weight gain after 18-20 alsoincreases the risk.

– Weight loss is associated with a decreased risk.

– The risk is also be associatedwith specific dietary patterns.

– Insulin resistance withhyperinsulinemia is characteristic

• Dislipemia:• High serum concentrations LDL &

VLDL & TG and a reduction in HDL of approximately 5 percent


Diabetes

Obesidad

Tendencia a padecer diabetes en EEUU(Incluye diabetes gestacional)

BRFSS 1990Tendencia a padecer diabetes en EEUU

(Incluye diabetes gestacional)BRFSS 1995-96

Tendencia a padecer diabetes en EEUU(Incluye diabetes gestacional)

BRFSS 2001

Evolución de la prevalencia de Obesidad y DM en EEUU en los últimos años

Una epidemia de diabetes que sigue a la de obesidad

15%-19%Sin datos 10%–14%<10% ≥20% ≥25%

Diabesidad: Pandemia del siglo XXI

Tejido adiposo

Adaptado de: Hotamisligil GS. JCI 2003

Gananciapeso

Médula ósea

Estrés REEstrés oxidativo

MCP-1

AGL

Citoquinas pro-inflamatorias

MCP-1

AGL

Obesidad abdominal Grasa intra-abdominal Respuesta inflamatoria

Citoquinas pro-inflamatorias

De la obesidad a la DM2: Adiposopatía



• Conclusiones

Agenda

Knowler WC, N Engl J Med 2002; 346: 393-403.

Tiempo (meses)

Placebo Metformina Estilo de vida

Inci

denc

ia a

cum

ulad

ade

dia

bete

s (%

)

- 58%

40

30

20

10

0 0 6 12 18 24 30 36 42 48

p<0.001para cada

comparación

DPP: Incidencia acumulada diabetes en cada grupo de estudio

Beneficios pérdida peso moderada en DM2Pre-Diabetes

47

31

13 4

7 810

15

19

2527

32

3840

43

1 3 5 7

9 11 12 13 17

19 20 2224

29

0

2

4

6

8

10

12

0 16 32 48 64 80 96 112 128 144 160

Scale: Pacientes diagnosticados de DMT2 en el tiempoCurva de Kaplan–Meier: 0–160 semanas

504

205

Semanas

160

1472 1313 1204 1135 1060 977 910 830 799863738 636 569 523 468 422 376 328 310350

n=

n=776

296

172

46

26

Seguimiento sin fármaco Seguimiento sin fármaco

Liraglutida 3.0 mg Placebo

Paci

ente

s(%

)

Placebo: 11%Liraglutida 3.0 mg: 3%

Grupo total del análisis. Los números del gráfico corresponden al número de pacientes diagnosticados.

Incidencia anual (0–160 semanas)Placebo: 3.2/100 PYE Liraglutida 3.0 mg: 0.8/100 PYE

le Roux et al; Lancet. 2017;389(10077):1399-1409

The Look Ahead Research Group, N Engl J Med 2013

Look AHEAD TrialEvolución HbA1c

-8,6%

-6,0%

-3,5%

-0,7%Pero en grupo Intervenciónmenor uso de:

•Biguanidas•Exenatide•Insulina

Centrados en el peso, ¿”olvidaron” intensificar tto?

Diferencias HbA1c entre grupos,

¿menores por mayor uso fármacos?

Beneficios pérdida peso moderada en DMDiabetes Establecida

OrlistatDM2+Metformina: Dieta hipocalórica + ORLISTAT O PLACEBO

Durante 52 semanas

Cambio en peso corporal Cambio en HbA1c

Berne C, Diab Med 2005

7.6%7.4%

6.5%

Beneficios pérdida peso moderada en DMDiabetes Establecida

SOS Study

SOS Study

Cáncer

Eventos CV

DMt2

Documents

Obesidad y comorbilidades - SEEDO · 2017-11-24 · De la obesidad a la DM2 Esteatosis hepática y dislipemiaaterogénica. LookAheadTrial and HepaticSteatosis DM2 ... •Diabetes