bariatric (metabolic) surgery for life-long weight control and mortality risk reduction first...

Bariatric (Metabolic) Surgery for Life-Long Bariatric (Metabolic) Surgery for Life-Long Weight Control and Mortality Risk ReductionWeight Control and Mortality Risk Reduction

First Canadian Summit on Surgery for T2DMFirst Canadian Summit on Surgery for T2DMMay 6, 2010May 6, 2010

Montreal, CanadaMontreal, Canada

Ted Adams, Ph.D., MPHUniversity of Utah School of Medicine, Salt Lake City, Utah

Editorial, NEJM 2007;357:818Editorial, NEJM 2007;357:818

George A. Bray, M.D. George A. Bray, M.D.

“The Missing Link – Lose “The Missing Link – Lose Weight, Live Longer”Weight, Live Longer”

Editorial, NEJM 2007;357:818Editorial, NEJM 2007;357:818

George A. Bray, M.D. George A. Bray, M.D.

“The Missing Link – Lose “The Missing Link – Lose Weight, Live LongerWeight, Live Longer????””

Does Weight Loss = Does Weight Loss = Improved Mortatity?Improved Mortatity?

Observational studies reporting mortality of obese subjects who have lost weight without bariatric surgery are inconclusive, with studies reporting no change, increased, or reduced mortality.

Solomon CG & Dluhy. NEJM 2004;351:2751Hu FB, et al. NEJM 2004;351:2694Yaari S & Goldbourt U. Am J Epidemiol 1998;148:546Gregg EW, et al. Ann Intern Med 2003;138:383

“ “The Missing Link – The Missing Link – Have Have Bariatric SurgeryBariatric Surgery, Lose , Lose

Weight (Weight (??), Live Longer” ), Live Longer”

“ “The Missing Link – The Missing Link – Have Have Bariatric SurgeryBariatric Surgery,,

Lose Weight,Lose Weight,Keep Weight OffKeep Weight Off,,

Live Longer” Live Longer”

Long-term Effect of Gastric Bypass Long-term Effect of Gastric Bypass Surgery on Body WeightSurgery on Body Weight

Pories et al. Ann Surg 1995;222:339.

BMI (kg/m2): 50 34 35 35

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Years After Surgery

0

20

40

60

80

1000 2 4 6 8 10 12 14

Change in BMI Over Time for Change in BMI Over Time for Patients Followed for >10 Patients Followed for >10

YearsYears

BM

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Figure 3, Christou et al. Ann Surg 2006;244:737.

Sjöström, L. NEJM 2004;351:2683-2693.

13% GBP; 19% LAGB & LGB; 68% VBG

Maintenance of weight loss Maintenance of weight loss after gastric bypass surgeryafter gastric bypass surgery

% o

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Lose Weight,Lose Weight,Keep Weight OffKeep Weight Off,,Improve HealthImprove Health,,


Improvement in obesity associated diseases with Improvement in obesity associated diseases with bariatric surgery – McGill Databariatric surgery – McGill Data

*

*

*

*

*

* p<0.001

Christou et al Ann. Surg. 240:416-424, 2004

Prevalence, Incidence andPrevalence, Incidence andResolution of Diabetes (2 years)Resolution of Diabetes (2 years)

Group Prevalence Incidence Remission

GBP Surgery

20% 0% 79%

Seeking GBP – No Surgery

22% 6% 0%

Population Controls

23% 10% 5%

Adams, T. et al. Obesity 2009;17:796-802

Mortality FollowingMortality FollowingBariatric SurgeryBariatric Surgery

11 published studies Methods vary by: surgery type, follow-

up time, control group selection, BMI When severely obese control groups

are included, all studies report improved mortality for bariatric surgery groups

Bariatric Surgery & Reduced Mortality (%) Bariatric Surgery & Reduced Mortality (%)

Study Reference % Reduction

MacDonald, KG. J Gastrointest Surg 1997;1:213-220 88

Flum, DR. J Am Coll Surg 2004;199:543-551 33

Christou, NV. Ann Surg 2004;240:416-424 89

Sowemino, OA. Surg Obes Relat Dis 2007;3:73-77 63

Sjöström, L. NEJM 2007;357:741-752 29

Adams. T. NEJM 2007;357:753-761 40

Busetto, L. Surg Ob Rel Dis 2007;3:496-502 60

Peeters, A. Ann Surg 2007;246:1028-1033 72

Christou, et al. (2004)Christou, et al. (2004)

Mean Follow-up 7.1 years (total 18 years)

Cases 2.5 y Cases; 2.6 y controls

Controls 1,035 (81% GBP; 19% VBG), 66% female, 45 y, BMI 50

% Deaths 5,746 non-bariatric surgery, 64% female, 47 y, BMI unknown

% Death Reduction 0.68% cases, 6.2% controls

Christou, NV. Ann Surg;2004:416-424.

Sjöström et al. SOS (2007)Sjöström et al. SOS (2007)

Mean Follow-up 10.9 years

Cases2,010 (13% GBP; 68% VB; 19% GB), 67% female, 47 y, BMI 41

Controls 2,037 no bariatric surgery, 67% female, 47 y, BMI 41

% Deaths 5% cases, 6% controls

% Death Reduction Unadjusted, 24%

Adjusted, 29%

Sjöström, L. NEJM 2007;357:741-752.

Adams et al. (2007)Adams et al. (2007)

Mean Follow-up 7.1 years (total 18 years)

Cases 7,925 (100% GBP), 84% female, 39.5 y, BMI 45.3

Controls 7,925 no bariatric surgery, 84% female, 39.3 y, BMI 46.7

% Deaths 2.7% cases, 4.1% controls

% Death Reduction Unadjusted, 34%

Adjusted, 40%

Adams, et al. NEJM 2007;357:753-761.

Results: % Difference (based on mortality Results: % Difference (based on mortality HR) Matched GroupsHR) Matched Groups

Cause of Death GBP Patients vs DL Applicants

Total Mortality 40% decrease (p<0.001)

All CVD 49% decrease (p<0.001)

CAD 59% decrease (p=0.006)

Heart Failure 41% decrease (p=0. 54)

All Strokes 57% decrease (p=0.14)

Diabetes 92% decrease (p=0.005)

All Cancers 60% decrease (p<0.001)

All Diseases 52% decrease (p<0.001)

Adams, et al. NEJM 2007;357:753-761.

Results: % Difference (based on mortality Results: % Difference (based on mortality HR) Matched Groups (cont.)HR) Matched Groups (cont.)

Cause of Death GBP Patients vs. DL Applicants

Accident unrelated to drugs

22% increase (p=0.56)

Poisoning of undetermined intent

82% increase (p=0.36)

Suicides 103% increase (p=0.22)

All non-disease causes 58% increase (p=0.04)

Adams, et al. NEJM 2007;357:753-761.

Christou, N. et al. Ann Surg Christou, N. et al. Ann Surg 2006;244:734-7402006;244:734-740

272 post-gastric bypass patients followed (4.7 to 14.9 years) = 7 deaths

(1) suicide at 4.8 years (1) suicide at 5.7 years (1) liver failure at 6.6 years (1) Unknown cause at 8 years (1) Pulmonary embolus at 8.8 years (1) Cardiac failure at 8.8 years (1) Cardiovascular accident at 13 years

Results: First Year DeathsResults: First Year Deathsby Matched Groups by Matched Groups

GBP Patients 42 deaths (0.53% mortality for first year)

DL Applicants 41 deaths (0.52% mortality for first year)

Adams, et al. NEJM 2007;357:753-761.

An An UnexpectedUnexpected Finding! Finding!

Sjöström, L. NEJM 2007;357:741-752Adams et al. NEJM 2007;357:753

The SOS study on mortality revealed a strong effect from cancer (control group, 47 deaths; surgery group, 29 deaths)

The Utah study on mortality reported a 60% reduction in cancer deaths following bariatric surgery when compared to severely obese controls

Well Known FindingWell Known Finding

Increased BMI Increased CA Risk

Association Between BMI and Cancer RiskAssociation Between BMI and Cancer RiskWorld Cancer Research Fund (WCRF)World Cancer Research Fund (WCRF)

Body fatness associated with increased cancer risk for:

Oesphageal adenocarcinoma Pancreas Colorectum Postmenopausal breast Endometrium Kidney And probable association for gallbladder

WCRF. Food, Nutrition, Physical Activity, and Prevention of Cancer: A Global Perspective, 2nd ed. Washington, D.C.: American Institute for Cancer Research, 2007.

Association Between BMI and Cancer RiskAssociation Between BMI and Cancer RiskRenehah, et al. Lancet 2008;371:569Renehah, et al. Lancet 2008;371:569

221 data sets analyzed

282,137 incident cases

5 kg/m2 increase in BMIassociated with the following cancers:

Renehah, et al. Lancet 2008;371:569

Association Between BMI and Cancer RiskAssociation Between BMI and Cancer Risk

Male CancersRelative Risk

(p value)Female Cancers

Relative Risk (p value)

Oesophageal adenocarcinoma

1.52 (<0.0001) Endometrial 1.59 (0.0001)

Thyroid 1.33 (=0.02) Gallbladder 1.59 (0.0001)

Colon 1.24 (<0.0001)Oesophageal adenocarcinoma

1.51 (=0.04)

Renal 1.24 (<0.0001) Renal 1.34 (0.0001)

Renehah, et al. Lancet 2008;371:569

Possible ReasonsPossible ReasonsWhy Obesity Increases Cancer Why Obesity Increases Cancer RiskRisk

1. Chronic inflammation adipocyte release of inflammatory promoters

• Tumor nucrosis factor-alpha interleukin-6 (TNF-IN-6)• C-reactive protein• Leptin – shown to increase in inflammatory states

Calle, et al. Obesity and Cancer. Oxford University Press, Oxford, pp. 196.Renehan, et al. Arch Physiol Biochem 2008;114(1):71.WCRF. Food, Nutrition, Physical Activity, and Prevention of Cancer: A Global Perspective, 2nd ed. Washington, D.C.: American Institute for Cancer Research, 2007.

Possible ReasonsPossible ReasonsWhy Obesity Increases Cancer Why Obesity Increases Cancer Risk (cont.)Risk (cont.)

2. Increased release of sex-steroid hormones• Estrogens• Androgens• Progesterone• Adipocyte primary point for synthesis of

estrogen for men and postmenopausal women• Increased body fat increase in insulin-like

growth factor 1 (IGF-1) rise in estradiol in men and women and potential increase in testosterone in women


Possible ReasonsPossible ReasonsWhy Obesity Increases Cancer Why Obesity Increases Cancer Risk (cont.)Risk (cont.)

3. Insulin related mechanisms• Increased body fatness (in particular, abdominal

or central obesity) increased insulin resistance

• Subsequent increased insulin production by the pancreas

• Hyperinsulinemia in the face of insulin resistance increases risk of colon and endometrial cancer with potential increased risk of pancreatic and kidney cancer


Important QuestionImportant Question??????

Increased BMI Increased CA Risk

but does

Decreasing BMI Decrease CA Risk??

To Date – Four Cancer & To Date – Four Cancer & Bariatric Surgery StudiesBariatric Surgery Studies

1 Prospective Sjöström, L. et al. Lancet Oncol

2009;10:653-62

3 Retrospective Christou, N. et al. Surg Obes Relat Dis

2008;4:691-95 McCawley, G. et al.J Am Coll Surg

2009;208:1093-98 Adams, T. et al. Obesity 2009;17:796-802

SjSjöström, L. et al. öström, L. et al. Lancet Lancet OncolOncol 2009;10:653-62 2009;10:653-62

Unique First prospective, controlled intervention study Weight loss follow-up compare weight loss to cancer incidence Medical and lifestyle history followed over time

2010 bariatric surgery patients; 2037 well-matched controls 1st time cancers: 117 surgery group;169 control group (HR

0.67, p=0.0009) 1st CAs in women: 79 surgery group; 130 control group (HR

0.58, p=0.0001) No effect in men: 38 surgery group; 39 control group (HR

0.97, p=0.90)

SjSjöström, L. et al. öström, L. et al. Lancet Lancet OncolOncol 2009;10:653-62 2009;10:653-62

Similar results after CAs in the first 3 years of study excluded

Sagittal trunk diameter strong multiple CA predictor

Body weight, BMI and reduced energy intake were not CA incidence predictors

The Canadian Bariatric The Canadian Bariatric Cohort StudyCohort Study

Restrospecitve, observational 2-cohort 1035 post-bariatric surgery patients; 5746 severely

obese controls (ICD-9 codes) without surgery CA diagnosis within 6 months prior to study onset

excluded Physician/hospital visits for all CA-related diagnosis Follow-up for a maximum of 5 years Cancer-related visits: 2% (21 visits) surgery group; 8.5%

(487 visits) control group (RR 0.22, p=0.0001)

Christou, N. et al. Surg Obes Relat Dis 2008;4:691-95

Five-Year Incidence of Overall Cancer Risk

Diagnosis:

Cohort

Bariatric Controls Relative Risk

P-valueN % N % Estimate 95% CI

Any Cancer 21 2.0% 487 8.5% 0.22 0.14 0.35 0.001

The Canadian BariatricCohort Study

78% Reduction in Overall Cancer Risk

The Canadian BariatricThe Canadian BariatricCohort StudyCohort Study

(p=0.001)

83%68%

(p=0.063)

Adams, T. et al. Adams, T. et al. ObesityObesity 2009;17:796-8022009;17:796-802

Retrospective, 2-cohort Compared incidence, case-fatality, and mortality of total

and stage-specific cancer Surgical Group: From 9949 GBP patients all non-Utah

residents excluded leaving 6709 patients (surgery 1984 through 2002)

Comparative Group: 9609 severely obese (Utah driver’s license applicants – 1984 through 2002)

In previous study, comparative group matched to represent the gender, age, and body mass index (BMI) distribution of the surgical patients

MethodsMethods

Subjects linked to Utah Cancer Registry for years 1984 through 2007 (24 year follow-up; mean of 12.5 years)

Type of cancer (CA), stage of CA, date of diagnosis, vital status, and death date (SEER standards used)

SEER standards: 0 = in situ; 1 = localized; 2-5 = regional; 7 = distant; and unstaged

Prevalent CA (1.9% surgery group; 2.0% comparative group) was excluded


Incidence (Rates/1,000 PY)Incidence (Rates/1,000 PY)

Cancer Site Surgery GroupComparative

GroupHazard Ratio (P)

All cancers 3.1 4.3 0.76 (0.0006)

All cancers, male

3.7 3.8 1.02 (0.91)

All cancers, female

3.0 4.4 0.73 (0.0004)

Obesity-related 1.3 2.3 0.62 (0.0001)

Non obesity-related

1.9 2.0 0.91 (0.37)


HR for Incident Cancer – HR for Incident Cancer – Surgery versus ComparativeSurgery versus Comparative

Cancer Stage Hazard Ratio P Value

0 (In Situ) 0.86 0.44

1 (Local) 0.86 0.17

2-5 (Regional) 0.61 0.009

7 (Distant) 0.61 0.03

Unstaged 0.40 0.07


Mean Time to Diagnosis by Mean Time to Diagnosis by Cancer Stage, yearsCancer Stage, years

Cancer Stage Surgery GroupComparative

Group

0 (In Situ) 9.2 9.10

1 (Local) 8.4 9.0

2-5 (Regional) 9.3 8.9

7 (Distant) 9.5 9.0

Unstaged 6.2 8.9


Mortality (Rates/1,000 PY)Mortality (Rates/1,000 PY)

Cancer Site Surgery GroupComparative

GroupHazard Ratio (P)

All cancers (males & females)

0.50 0.94 0.54 (0.001)

All cancers, male 0.12 0.21 0.70 (0.35)

All cancers, female 0.38 0.73 0.38 (0.0003)

Obesity-related 0.24 0.48 0.54 (0.02)

Non obesity-related 0.25 0.46 0.53 (0.02)


Opportunity for Discovery!Opportunity for Discovery!(Similar to diabetes remission (Similar to diabetes remission

following bariatric surgery)following bariatric surgery)

What are the causes for reduced cancer incidence? Weight loss (or not) Change in central adiposity Reduced energy intake Other mechanisms??

How rapid are the effects that influence cancer incidence reduction – what is the timeline?

Does cancer incidence vary in relation to bariatric surgical procedures (i.e., GBP vs. banding)?

Does bariatric surgery influence cancer remission (if yes, does this vary by surgery type)?

Opportunity for Discovery (cont.)Opportunity for Discovery (cont.)

Do protective cancer effects (physiological mechanisms) following bariatric surgery vary based upon gender?

Do protective cancer effects (physiological mechanisms) following bariatric surgery vary based upon cancer type?

If larger data sets representing male bariatric surgery data were available, would reduced cancer incidence appear?

Can robust animal models of obesity and cancer risk be explored and combined with human bariatric surgical outcomes?

Final Perspective –Final Perspective –Thought #1Thought #1

It would appear that recent national guidelines recommending weight loss to reduce future cancer risk are supported by results from these bariatric surgery

cancer-related studies.


“… to put this risk reduction (HR 0.58) into perspective, it might be helpful to compare it with statin treatment, where the HR for reduction in incidence of fatal plus non-fatal myocardial infarction (vs placebo) has been in the order of 0.80.”

Sjöström, L. Lancet Oncol 2009;10:653-62


“As the obesity epidemic shows few signs of abating, incidences of obesity-related cancers may rise; however, the establishment that the development of these cancers is reversible brings about an encouraging new paradigm in cancer prevention.”

Andrew G. RenehanLancet Oncology 2009;10:640

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