ESPEN Congress Florence 2008

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1 ESPEN Congress Florence 2008 Severe obesity - Session organised in conjunction with ASPEN Long term mortality in cohorts of severely obese subjects D. Mirabelli (Italy)

2 Long-term mortality in cohorts of severely obese subjects Franco Merletti, Dario Mirabelli Cancer Epidemiology, University of Turin and CPO-Piemonte Firenze, 16 September 2008

3 Introduction There is large epidemiological evidence that a U (or J) shaped curve relates general mortality and body weight. Mortality increases both under and above the optimal range of BMI values, which is generally in the range of Recently, it has been suggested that after control for confounding due to pre-existing diseases, a linear relationship exists (Gelber et al, 2007; Zhang et al, 2008). Mortality is very high in morbidly obese persons (BMI 40).

4 Outline We will first report the main findings from international cohort studies presenting results on mortality or morbidity in the subgroup of individuals with BMI 40. For specific cancer morbidity, we will examine the results of a national surveillance system, based on a case-control approach, where the effect of obesity (BMI 30) rather than of morbid obesity are considered. We will then show the findings of a recent Italian cohort study of morbidly obese persons

5 The Dusseldorf cohort study 6193 patients with hospital discharge records for obesity. Follow-up from to 1994 (Bender et al, Am J Epidemiol 1998) Height and weight at enrollment measured General mortality relation with BMI estimated by calculation of Standardised Mortality Ratios (reference regional population): BMI class SMR (men) SMR (women)

6 The American Cancer Society CPS II study More than 1 million volounteers, aged 30, enrolled in Follow-up 14 years (Calle et al, New Engl J Med 1999) Height and weight at enrollment self-reported General mortality relation with BMI estimated by means of Cox regression (reference BMI ): BMI class HR (men) HR (women)

7 The Norwegian study A 2 million persons cohort (Engeland et al. Epidemiology, 2003) was set up Follow-up to Height and weight at enrollment measured General mortality relation with BMI estimated by means of Cox regression (reference BMI ): BMI class HR (men) HR (women)

8 The Nurses Health Study A 120,000 persons cohort (Hu et al. New Engl J Med, 2004) was set up in Follow-up to Height and weight at enrollment self-reported General mortality relation with BMI estimated by means of Cox regression (reference BMI < 21.0): BMI class HR (women)

9 The NIH-American Association of Retired Persons study A 530,000 persons cohort (Adams et al. New Engl J Med, 2006) was set up Follow-up to Height and weight at enrollment self-reported General mortality relation with BMI estimated by means of Cox regression (reference BMI ): BMI class HR (men) HR (women)

10 The Canadian Enhanced Cancer Surveillance System Canada: case-control study of incident cancer cases and population controls (Pan et al. Am J Epidemiol, 2004). Obesity (BMI > 30): Site RR All cancers 1.22 Colon 1.93 Rectum 1.65 Pancreas 1.51 Kidney 2.74 Breast Prostate 1.27 Multiple myeloma 2.06 Leukaemia (postmenopausal women)

11 Other cancers consistently associated with obesity Study Sex RR, esophageal adenocarcinoma Engeland et al, Cancer Causes Control 2004 Men 2.6 Women 2.1 RR, cardia adenocarcinoma Remarks BMI > 30 vs Lagergren et al, Ann Intern Med 1999 Men and women BMI > 30 vs < 22 Chow et al, J Nat Cancer Inst 1998 Men Women BMI > 27.3 vs < 23.1 BMI > 27.4 vs < 22.0

12 The Italian Gruppo di Studio per la Grande Obesità (GSGO) cohort study

13 An Italian cohort of morbidly obese persons Adults (age > 18 at presentation) 4761 persons, who had: BMI 40 kg/m 2 Attended one of the following recruiting centres: Piancavallo 4426 Torino 50 San Donato (Mi) 170 San Luigi (To) 28 Napoli 73 Bari after exclusion of duplicate records and of individuals not fulfilling inclusion criteria

14 Aims of the study To compare general and cause-specific mortality among cohort members and that of the general (Italian) population To identify trends in mortality according to: BMI at recruitment Period of recruitment

15 Methods Vital status ascertainment: follow up at the Registrar Office of the municipality of residence (last known residence), who: Notifies the vital status of residents For former residents who moved, reports their new town of residence End of follow-up: 31/12/2001 Cause of death ascertainment: copy/transcription of the death certificate, provided by the Local Health Authority including the municipality of residence at the time of death Contribution to person-time of observation: from start (date of first visit to a recruiting centre) to stop of observation (date of death, of loss to follow-up or of end of follow-up, whichever the first) Calculation of standardised mortality ratios (SMR), reference the Italian population

16 Follow-up status Cohort members 4681 Lost to follow-up 183 Retained for analysis 4498 Deaths 484

17 General and cause-specific mortality Gender Cause of death Obs SMR 95% CI Men All causes All malignant neoplasms Cardiovascular diseases Respiratory diseases External causes Women All causes All malignant neoplasms Cardiovascular diseases Respiratory diseases External causes

18 General mortality, multivariable analyses Variable Category Cox regression model HR Sex Women % CI Men BMI Recruitment By five-year age-class 2 Reference category

19 Conclusions Few previous studies had comparable potency in investigating the health consequences of severe obesity (BMI 40) Our results on overall mortality are consistent with those of the largest North-American and North-European cohorts For the first time, we could study the shape of the relationship between mortality and BMI in severe obesity: Excess mortality continues to be substantially linearly related with BMI It is highest among men Even moderate reduction in BMI may entail considerable improvements in the risk of death The decrease in excess mortality among most recently recruited individuals may reflect better effectiveness in treatment

20 Acknowledgments This work is a collaborative project of Istituto Auxologico Italiano, Gruppo di Studio Grande Obesità (GSGO), and Unità di Epidemiologia dei Tumori Università di Torino Investigators: Franco Balzola Maria Letizia Petroni Dario Mirabelli Franco Merletti Data management and statistical analysis: Monica Chiusolo We are indebted with all coworkers in the GSGO collaborating centres for their help in data collection

21 General mortality by gender and age Age Men Women group Obs O/E 95% CI Obs O/E 95% CI < Total

22 General mortality, by BMI at first visit Men Women BMI Obs SMR 1 95% CI Obs SMR 2 95% CI Test for homogeneity of SMRs: , p < 0.01 Test for trend of SMRs: , p < Test for homogeneity of SMRs: , p < Test for trend of SMRs: , p < 0.001

23 General mortality, by period of enrolment Calendar period Men Women Obs SMR 1 95% CI Obs SMR 2 95% CI Test for homogeneity of SMRs: , p < 0.05 Test for trend of SMRs: , p < Test for homogeneity of SMRs: , p < 0.01 Test for trend of SMRs: , p < 0.01

24 Study (full reference) Name BMI max cat Wei M et al. Relationship between low cardio-respiratory fitness and morality in normal-weight, overweight, and obese men. JAMA 1999;282: Aerobics Center Longitudinal Study 30 Farrell SW et al. The relation of body mass index, cardio-respiratory fitness, and all-cause mortality in women. Obes Res 2002;10: Aerobics Center Longitudinal Study 30 Corrada MM et al. Association of body mass index and weight change with all-cause mortality in the elderly. Am J Epidemiol 2006;163: Leisure World Cohort Study 30 Gelber RP et al. Body mass index and mortality in men: evaluating the shape of the association. Int J Obes 2007;31: Physicians Health Study 30 Zhang X et al. Body mass index at various ages and mortality in Chinese women : impact of potential methodological biases. Int J Obes 2008;32: Shanghai Women s Health study 26.7 Wei M et al. Relationship between low cardio-respiratory fitness and morality in normal-weight, overweight, and obese men. JAMA 1999;282: Aerobics Center Longitudinal Study 30 Jee SH et al. Body mass index and incident ischemic heart disease in South Korean men and women. Am J Epidemiol 2005;162:42-48 Korean Medical Insurance Corporation Study 30 Samanic C et al. Obesity and cancer risk among white and black United States veterans. Cancer Causes Control 2004;15:35-43 US Veterans cohort study 30 1 Inoue M et al. Impact of body mass index on the risk of total cancer incidence and mortality among middle aged Japanese. Cancer Causes Control 2004;15: Japanese Public Health Center Study 30 Jee SH et al. Body mass index and cancer risk in Korean men and women Korean Cancer Prevention Study 30 Reeves GK et al. Cancer incidence and mortality in relation to body mass index in the Million Women Study. Br Med J 2007;335: The Million Women Study 30 Pischon T et al. Body size and risk of colon and rectal cancer in the European prospective investigation into cancer and nutrition. J Natl Cancer Inst 2006;98: EPIC 28.9 Magnusson PKE at al. Association of body-mass index with suicide mortality: a prospective cohort study of more than one million men. Am J Epidemiol 2006;163:1-8 Swedish (conscription) cohort 30 Stevens J et al. The effect of age on the association between body mass index and mortality ACS-CPS I 32 Jee SH et al. Body mass index and mortality in Korean men and women. New Engl J Med 2006;355: Korean Cancer Prevention Study 32 Moore SC et al. Past body mass index and risk of mortality among women. Int J Obes 2008;32: Breast Cancer Detection Demonstration Project 35 Rapp K et al. Obesity and incidence of cancer: a large cohort study of over adults in Austria. Br J Cancer 2005;93: Voralberg Health Monitoring and Promotion Program 35 Bender R et al. Assessment of excess mortality in obesity. Am J Epidemiol 1998;147:42-8 Dusseldorf Cohort Study 40 Calle E et al. Body mass index and mortality in a prospective cohort of US adults. New Engl I Med 1999;341: ACS-CPS II 40 Engeland A et al. Height and body mass index in relation to total mortality Norwegian study 40 Hu FB et al. Adiposity as compared to physical activity in predicting mortality among women. New Engl J Med 2004;351: Nurses Health Study 40 Adams KF et al. New Engl J Med 2006 ;355 : NIH-AARP Diet and Health Study 40 Mirabelli D et al. Long-term mortality in a cohort of severely obese persons in Italy. Obesity 2008;16: The Italian GSGO cohort study 40 Calle E et al. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of US adults. New Engl J Med 2003; 348: ACS-CPS II 40 1 Presumably: a diagnosis of obesity was present in at least one Veterans Administration Hospital discharge record

25 Short ref Name Sex No. Members Bender et al, AJE 1998 Calle et al, NEJM 1999 Engeland et al, Epidemiology 2003 Hu et al, NEJM 2004 Adams et al, NEJM 2006 Mirabelli et al, Obesity 2008 Dusseldorf Cohort Study ACS-CPS II Norwegian study Nurses Health Study NIH-AARP Diet and Health Study The Italian GSGO cohort study M F M F M F n.a. No. In analysis 6193 n.a n.a F M F M M n.a n.a n.a BMI max cat No. In BMI max Data availability Bw & h (measured) Smoking, phys. act., diseases (at med. exam.) Bw & h (self-rep.) Smoking, phys. act., alcohol cons., diseases (self-rep.) Bw & h (measured) Bw & h (self-rep.) Smoking, phys. act., alcohol cons., diseases (self-rep.) Bw & h (self-rep.) Smoking, phys. act., SES, diseases (self-rep.) Bw & h (measured) Follow-up Cause of death register (municipal) From To 1994 Active From 1982 To 31/12/1996 Cause of death register From To 30/06/2001 US National Death Index, next of kin From 1976 To 01/06/2000 US SSA Death master file From To 31/12/2005 Cause of death register (municipal) From To 31/12/ Number of person-years 2 Number of person-years 3 Number of person-years 4 Number of person-years 5 Exclusion criteria: preexisting cancer or cardiovascular disease 6 Number of person-years

26 Short ref Name Sex Mortality, general Obs RR (CI95%) Bender et al, AJE 1998 Dusseldorf Cohort Study M F n.a. 3.1 ( ) n.a. 2.3 ( ) Calle et al, NEJM 1999 ACS-CPS II M F ( ) ( ) Engeland et al, Epidemiology Norwegian study M F ( ) ( ) 2003 Hu et al, NEJM Nurses Health Study 2004 F ( ) Adams et al, NIH-AARP Diet and M ( ) NEJM 2006 Mirabelli et al, Obesity 2008 Health Study The Italian GSGO cohort study F M F ( ) ( ) ( )

27 Short ref Name Sex Mortality, CVD Obs RR (CI95%) Mirabelli et al, Obesity 2008 The Italian GSGO cohort study M F ( ) ( )

28 Short ref Name Sex Mortality, all cancers Obs RR (CI95%) Calle et al, NEJM 2003 ACS-CPS II M F ( ) ( ) Mirabelli et al, Obesity 2008 The Italian GSGO cohort study M F ( ) ( )

29 2007 Jee et al, Int J Cancer 2008 Gender Cancer site 1 Highest BMI category, Obs, RR (CI95%) Calle et al, New Engl J Med 2003 Samanic et al, Cancer Causes Reeves et al, BMJ Control Men Esophagus ( ) ( ) ( ) Lower esoph ( ) Stomach ( ) ( ) ( ) Cardia ( ) Colon and rectum ( ) Colon ( ) ( ) Rectum ( ) ( ) Liver ( ) ( ) ( ) Gallbladder ( ) ( ) ( ) Pancreas ( ) ( ) ( ) Prostate ( ) ( ) ( ) Kidney ( ) ( ) ( ) NHL ( ) ( ) Breast ( ) Women Esophagus ( ) ( ) ( ) Lower esoph. Stomach ( ) ( ) ( ) Cardia Colon and rectum ( ) ( ) Colon ( ) Rectum ( ) Liver ( ) ( ) Gallbladder ( ) ( ) Pancreas ( ) ( ) ( ) Endometrium ( ) ( ) Kidney ( ) ( ) ( ) NHL ( ) ( ) Breast () ( ) Breast, post-men ( ) 1 In bold fonts: gender/site neoplasms for which a causal association with increased body weight was assessed in the Second Expert Report of the American Institute for Cancer Research Food, nutrition, and the prevention of cancer Washington DC, AICR Only results for white men are included. BMI > 30 is assumed: never measured or self-reported, but a diagnosis of obesity had been done 3 Adenocarcinoma