Health Evidence™ hosted a 60 minute webinar examining the effects of weight loss interventions for adults who are obese on mortality, cardiovascular disease and cancer. Follow this link to access to the audio recording for this webinar: https://youtu.be/olF1bvaofXE Dr. Alison Avenell, Clinical Chair in Health Services Research, and Sam (Chenhan) Ma, from the Health Services Research Unit at the University of Aberdeen presented an overview of findings from their latest systematic review and meta-analysis: Ma C, Avenell A, Bolland M, Hudson J, Stewart F, Robertson C, et al. (2017). Effects of weight loss interventions for adults who are obese on mortality, cardiovascular disease, and cancer: Systematic review and meta-analysis. BMJ, 359, j4849. Adults with obesity have an increased risk of premature mortality, cardiovascular disease, some cancers, type 2 diabetes, and many other diseases. This review assesses whether weight loss intervention for adults with obesity affect all cause, cardiovascular, and cancer mortality, cardiovascular disease, cancer, and body weight. Fifty-four randomized controlled trials (RCTs) with 30,206 participants were identified in the review. High quality evidence showed that weight loss interventions decrease all cause mortality, with six fewer deaths per 1000 participants. Moderate quality evidence showed an effect on cardiovascular mortality, and very low quality evidence showed an effect on cancer mortality. Weight reducing diets, usually low in fat and saturated fat, with or without exercise advice or programmes, may reduce premature all cause mortality in adults with obesity.

1. Welcome!
Effect of weight loss
interventions for adults
who are obese on
mortality and morbidity:
What’s the evidence?
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3

4. What’s the evidence?
Ma C, Avenell A, Bolland M, Hudson J, Stewart F,
Robertson C, et al. (2017). Effects of weight
loss interventions for adults who are obese on
mortality, cardiovascular disease, and cancer:
Systematic review and meta-analysis. BMJ, 359,
j4849.
https://healthevidence.org/view-
article.aspx?a=effects-weight-loss-
interventions-adults-obese-mortality-
cardiovascular-disease-32978

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11. A Model for Evidence-
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National Collaborating Centre for Methods and Tools. (revised 2012). A
Model for Evidence-Informed Decision-Making in Public Health (Fact
Sheet). [http://www.nccmt.ca/pubs/FactSheet_EIDM_EN_WEB.pdf]

12. Stages in the process of
Evidence-Informed Public Health
National Collaborating Centre for Methods and Tools. Evidence-Informed
Public Health. [http://www.nccmt.ca/eiph/index-eng.html]

13. Poll Question #2
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14. Searchable Questions Think “PICOS”
1.Population (situation)
2.Intervention (exposure)
3.Comparison (other group)
4.Outcomes
5.Setting

15. How often do you use systematic reviews to
inform a program/services?
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E. I don’t know what a systematic review is
is
Poll Question #3

16. Dr. Alison Avenell
MD, MSc, BSc, Clinical Chair in Health
Services Research, Health Services
Research Unit, University of Aberdeen
Sam Ma
Foundation Year 2 Doctor,
University of Aberdeen

17. Effects of Weight Loss Interventions in
Adults with Obesity on Mortality,
Cardiovascular Disease and Cancer
A Systematic Review and Meta-
analysis of Long-term RCTs
BMJ 2017; 359 doi: https://doi.org/10.1136/bmj.j4849
Chenhan Ma, Alison Avenell, Jemma Hudson, Fiona Stewart, Clare Robertson,
Pawana Sharma, Cynthia Fraser, and Graeme MacLennan,
Health Services Research Unit, University of Aberdeen, UK
Mark Bolland, Department of Medicine, University of Auckland, New Zealand

18. Disclosures
None to declare.
The Health Services Research Unit is
funded by the Chief Scientist Office of the
Scottish Government Health and Social
Care Directorate.

19. Background
Obesity = BMI≥30kg/m2
• At least 650 million adults with obesity worldwide
(WHO, 2016)
• in addition to 381 million children with overweight or
obesity under 18 (WHO, 2016).
• In Canada, 1 in 4 obese adults (increased from 13.8%
to 26.4% between 1978 to 2014).
• In UK, 26% adult men and 27% adult women are
obese (Health Survey in England 2016), more are
overweight.
World Health Organisation [Internet]. Obesity and overweight. Available from:
http://www.who.int/mediacentre/factsheets/fs311/en/
Health Survey in England, 2016. Available from: https://files.digital.nhs.uk/publication/m/6/hse2016-adult-obe.pdf

20. Worldwide projected rates of
obesity
OECD. Obesity Update 2017. Organisation for Economic Co-operation and Development. Available at:
https://www.oecd.org/els/health-systems/Obesity-Update-2017.pdf

21. Scottish Data (Scottish Government)
Condition
2003 2030
Total cases
Total cases
attributable to
obesity (%)
Total cases
Total cases
attributable to
obesity (%)
Predicted
increase due to
obesity
Hypertension 1,351,185 488,496 (36%) 1,730,561 867,872 (50%) 379,376
Angina Pectoris 249,909
40,151
(16%)
281,091 71,333 (25%) 31,182
Type 2 diabetes 139,881 87,216 (62%) 207,615 154,950 (75%) 67,734
Myocardial
infarction
133,869
27,111
(20%)
154,924 48,166 (31%) 21,055
Stroke 92,252 6,174 (7%) 97,047 10,969 (11%) 4,795
Increased prevalence of diseases associated with predicted
increases in obesity levels, 2030 assuming no effective obesity
prevention
(Source: Preventing Overweight and Obesity in Scotland, Gov.scot,
http://www.gov.scot/Publications/2010/02/17140721/14 )

22. Obesity and Diseases

23. However…
• Is deliberate weight loss able to reduce premature
mortality, CVD and cancers?
• For any BMI in 18.5-24.9 (normal),25-29.9 (overweight),
30-34.9 (obesity I), ≥35 (obesity II+) (Flegal 2013)?
• For any age group?
• … Obesity paradox
Flegal 2013, JAMA. 2013;309(1):71-82.

24. Global BMI Mortality Collaboration
The Global BMJ Mortality Collaboration. Body-mass index and-all-cause mortality: individual-participant-data
meta-analysis of 239 prospective studies in four continents. Lancet 2016 July 13 http://dx.doi.org/10.1016/S0140-
6736(16)30175-1
Figure 2 Association of body-mass index with all-cause mortality, by baseline age group
The HR per 5 kg/m2 higher body-mass index (BMI) and its 95% CI are calculated only for BMI more than 25·0 kg/m2. Analyses restricted to never-smokers without pre-existing
chronic disease, and excluding the first 5 years of follow-up, and include data from all geographical regions. The reference category is shown with the arrow and is 22·5–<25·0
kg/m2. CIs are from floating variance estimates (reflecting independent variability within each category, including the reference category). Areas of squares are proportional to the
information content. Analyses by baseline age and the three main geographical regions are in the appendix (p 38). HR=hazard ratio.

25. The Global BMJ Mortality Collaboration. Body-mass index and-all-cause mortality: individual-participant-data
meta-analysis of 239 prospective studies in four continents. Lancet 2016 July 13 http://dx.doi.org/10.1016/S0140-
6736(16)30175-1
Figure 3 Association of body-mass index with all-cause mortality, by sex
The HR per 5 kg/m2 higher body-mass index (BMI) and its 95% CI are calculated only for
BMI more than 25·0 kg/m2. Analyses restricted to never-smokers without pre-existing
chronic disease, excluding the first 5 years of follow-up, and include data from all
geographical regions. The reference category is shown with the arrow and is 22·5–<25·0
kg/m2. CIs are from floating variance estimates (reflecting independent variability within
each category, including reference). Areas of squares are proportional to the information
content. Analyses by sex and the three main geographical regions (east Asia, Europe, and
North America) are in the appendix (p 39). HR=hazard ratio.

26. The Global BMJ Mortality Collaboration.
Body-mass index and-all-cause mortality:
individual-participant-data meta-analysis of
239 prospective studies in four continents.
Lancet 2016 July 13
http://dx.doi.org/10.1016/S0140-
6736(16)30175-1
Figure 4 Association of body-mass index with mortality, by major underlying cause
The HR per 5 kg/m2 higher body-mass index (BMI) and its 95% CI are calculated only for BMI more than 25·0 kg/m2. Analyses restricted
to never-smokers without pre-existing chronic disease, excluding the first 5 years of follow-up, and include data from all geographical
regions. The reference category is shown with the arrow and is 22·5–<25·0 kg/m2. CIs are from floating variance estimates (reflecting
independent variability within each category, including reference). Areas of squares are proportional to the information content.
Analyses of cause-specific mortality by three geographical regions (east Asia, Europe, and North America) are in the appendix (pp 41,
42).

27. Systematic Review of RCT
Evidence
Kritchevsky 2015 review of 15 RCTs (overweight and obese)-
• Weight loss vs non-weight loss: RR 0.85 (0.73, 1.00)
• Few studies, not investigated CVD, cancer
Kritchevsky SB, et al. (2015)
Intentional Weight Loss and All-
Cause Mortality: A Meta-
Analysis of Randomized Clinical
Trials. PLoS ONE 10(3):
e0121993.

28. Methods
Question:
Do dietary (+/-exercise) weight loss interventions compared to no
intervention or control affect the risk of mortality, cardiovascular or
cancer outcomes in obese adults?
Primary Outcomes:
• All-cause mortality
• Cardiovascular Mortality
• Cancer Mortality
Secondary Outcomes:
• Participants with any Cardiovascular Events
• Participants with Cancer Events
• Weight Change

29. Subgroup Analysis
Pre-specified Subgroup analyses – these were performed
for
• Effects of Age (<60,≥60),
• Gender (M, F, Both),
• BMI (<35, ≥35),
• Type 2 DM (No/Other, IGT/IFG, Yes),
• Physical Activity (No, Yes-advice only, Yes-facility
provided),
• Ethnicity (Mixed, Caucasian, Black, Asian (post-hoc))

30. Sensitivity Analysis
• Sensitivity analysis – these were performed for
• Effects of Risk of Bias for Allocation Concealment (indication of
study quality/intervention effect) (Low risk, Unclear/High Risk),
• % participant follow-up (<80%, ≥80%)
• CVD Outcomes using JACC definitions (Fatal, Non-fatal, Fatal
and Non-fatal)
JACC = Journal of American
College of Cardiologists
Hicks KA, et al. 2014 ACC/AHA Key data elements and definitions for cardiovascular endpoint events in clinical trials.
J Am Coll Cardiol 2015; 66(4): 403-469. Available from: http://ac.els-cdn.com/S0735109714074841/1-s2.0-
S0735109714074841-main.pdf?_tid=27df2800-8c76-11e5-b1b6-
00000aab0f27&acdnat=1447687660_73fa495cdf0a1e0f4443e826101b30d7

31. Flowchart of Review Process
1174 RCTs reports
identified in
Obesity Database
1174 RCT reports
screened fulltext
5595 Abstracts identified
in Online Database
Medline/Embase Screen
5595 Abstracts screened
4 Abstract papers + 89
RCTs with review
outcomes - Reviewed in-
depth
Excluded Abstracts:
5591 due to non-
RCT, <12mo
duration, BMI<30 or
duplicated.
Excluded RCT
reports: 1088 due
to <12mo duration,
non-dietary
interventions, no
review outcomes or
duplicates.
Excluded:
BMI<30 (9)
BMI<25 Asian (1)
No suitable interventions
(17)
Unsuitable RCT design (4)
Unclear/unsuitable
outcomes (9)
No outcomes (3)
Duplicates (1)
48 studies included in
qualitative and
quantitative syntheses
Obesity Database
Inclusion Criteria:
• Randomised Controlled Trials
≥1yr duration
• Adults ≥ 18yrs old
• Obesity (BMI≥30kg/m2, Asian
BMI≥25kg/m2)
• Dietary Intervention
• +/- Exercise, Behavioural
Exclusion Criteria:
• Pregnancy, Lactation

32. Results
Characteristics of Included Studies:
Participants: 30 206 obese adults participants in 54 RCTs
• Co-morbidities included: DM type 2, hypertension,
osteoarthritis, post-cancer treatment, psychiatric illness
• Length of Follow-up: 1yr-12.7yrs
• Location: USA, Europe, Australia, Asia

33. Weight loss on All-cause
Mortality (34 RCTs)
Figure 1. All-cause Mortality
(Weight Loss Intervention vs
Control)
Overall: Weight Loss Intervention vs
Control
All-cause mortality
RR (95% CI) – 0.82 (0.71, 0.95)
18% relative risk reduction, 6 fewer
deaths per 1000 population
Weight Loss
Weight
Loss

34. Weight loss on Cardiovascular
Mortality (8 RCTs)
Figure 2. Cardiovascular Mortality
CVD Mortality (Weight Loss vs Control):
RR (95% CI) 0.93 (0.67, 1.31)

35. Weight loss on Cancer
Mortality (8 RCTs)
Figure 3. Cancer Mortality
Cancer Mortality (Weight Loss vs Control)
RR (95% CI) 0.58 (0.30, 1.11)
Weight Loss

36. Weight loss on Participants with
Cardiovascular Events (24 RCTs)
Figure 4. Any cardiovascular event Any CVD Event (Weight Loss vs Control)
RR (95% CI) 0.93 (0.83, 1.04)Weight Loss
Weight
Loss

37. Weight Loss on Participants with
Cardiovascular Events (JACC/AHA)
(17 RCTs)
Figure 4.1 Cardiovascular events (JACC/AHA defined)
Cardiovascular Events (JACC/AHA
defined)
(Weight loss vs Control)
RR (0.95% CI) 0.95 (0.84, 1.08)

38. Weight loss on Participants with
Cancer Events (19 RCTs)
Figure 5. Cancer Events
Cancer Event (Weight Loss vs Control)
RR (95% CI) 0.92 (0.63, 1.36)
Weight Loss

39. Weight loss Intervention on Weight changes
at 1 year (44 RCTs)
Figure 6. Weight Change in kg – at 1 year
Weight change in kg (at 1 year) (Weight Loss vs Control)
Mean Difference (95% CI) -3.42 (-4.09, -2.75)
Weight Loss

40. Weight Loss Intervention on Weight change at 2yr
(20 RCTs)
Weight Change in kg (2yr)
(Weight Loss vs Control)
Mean Difference (95% CI) -2.51
(-3.42, -1.60)
Figure 7. Weight change at 2yr FU
Weight
Loss
Weight Loss

41. Weight Loss Intervention on Weight Change at 3 or
more yrs (8 RCTs)
Weight change in kg (3 or
more yrs) (Weight Loss vs
Control)
MD (95% CI)
-2.56 (-3.50, -1.62)
Figure 8. Weight change at 3 or more
yrs FU
Weight Loss

42. Asian Studies Summary
Outcome
Outcome or
Subgroup
No. of
RCTs
Intervention
(Events /
N Randomised)
Control
(Events /
N Randomised)
Statistical
Method
Effect Estimate
Hetero
geneity I2
Test for
Significance of
Overall Effect: Z
value, (p-value)
1.58 All-cause
Mortality
38 326 / 12197 385 / 11392 RR (95% CI) 0.84 [0.73, 0.97] I² = 0%
Z = 2.44 (P =
0.01)
1.59 Cancer
Mortality
9 16 / 1700 21 / 1415 RR (95% CI) 0.65 [0.34, 1.23] I² = 0%
Z = 1.32 (P =
0.19)
1.60
Cardiovascular
Mortality
10 68 / 5053 70 / 5064 RR (95% CI) 0.95 [0.68, 1.32] I² = 0%
Z = 0.31 (P =
0.75)
1.61 Cancer
Event
20 56 / 3669 50 / 3157 RR (95% CI) 0.96 [0.65, 1.40] I² = 0%
Z = 0.23 (P =
0.82)
1.62 Any
Cardiovascular
Event
26 522 / 8334 560 / 7869 RR (95% CI) 0.94 [0.84, 1.06] I² = 0%
Z = 1.00 (P =
0.32)
1.63 Weight
Change
in kg
52 0 / 13328 0 / 11895
Mean
Difference
(95%
CI)
-2.72 [-3.19, -
2.25]
I² = 86%
Z = 11.36 (P <
0.00001)
Figure: Outcomes with Asian RCTs having Obesity defined as BMI≥25

43. Subgroup and Sensitivity
Analyses
• Non-diabetics/non-IGT had lower risks of CVD events
compared to diabetics when following weight loss
interventions (p=0.04)
• Reduction in CVD event incidence in Caucasians when
following weight loss interventions vs other ethnic groups
(p=0.02) and including Asian RCTs (p=0.01)
• *IGT = impaired glucose tolerance

44. Further results
• Additional Bayesian meta-analyses (due to rare events)
consistent with above results
• Consistent effects for age, BMI over and under 35, with
and without physical activity

45. Discussion
• Weight reducing dietary interventions reduces risk ratio
for premature all-cause mortality by 18%, 6 fewer deaths
per 1000 participants
• Appears consistent irrespective of age and BMIs
above 30
• Predominantly low fat/saturated fat weight reducing
diets
• Evidence for reduction in CVD events in Caucasians/non-
diabetics on weight reducing diets, but likely related to many
tests for subgroup differences

46. Discussion
Limitations of study
1) Few data for other outcomes
- Fewer trials with data, reporting of adverse
events in RCTs (CONSORT statement)
2) Lack of power in subgroup/sensitivity analysis
- Role of individual participant data meta-analysis
- Specific studies on other types of diets/patient groups
CONSORT Extension for Harms, Ann Intern Med. 2004;141:781-788 .

47. Acknowledgements
• We’d like to thank the 16 RCT authors whom provided
additional data/clarifications to assist with this study.
• All the HSRU staff for their support and time.

48. Protocol
Prospero registration: CRD42016033217
http://www.crd.york.ac.uk/PROSPERO/display_record.as
p?ID=CRD42016033217

49. References
• World Health Organisation [Internet]. International; 2015. Obesity and overweight; [cited 2015 Aug 23]; [about 3 screen]. Available from:
http://www.who.int/mediacentre/factsheets/fs311/en/
• Bancej C, Jayabalasingham B, Wall RW et al. Trends and projections of obesity among Canadians. Health Promot Chronic Dis Prev Can. 2015 Sep;
35(7): 109–112.
• National Institute for Health and Care Excellence. Obesity. Identification, assessment and management of overweight and obesity in children, young
people and adults [Internet]. UK: National Institute for Health and Care Excellence; 2014 [cited 2015 Aug 23]. Available from:
http://www.nice.org.uk/guidance/cg189/evidence/obesity-update-full-guideline-193342429
• Lavie CJ, McAuley PA, Church TS, Milani RV, Blair SN. Obesity and cardiovascular diseases. Implications regarding fitness, fatness, and severity in
the obesity paradox. J Am Coll Cardiol [Internet]. 2014 [cited 2015 Aug 17]. 63(14): 1345-1354. Available from:
http://dx.doi.org/10.1016/j.jacc.2014.01.022
• Kritchevsky SB, Beavers KM, Miller ME, Shea MK, Houston DK, Kitzman DW et al. Intentional weight loss and all-cause mortality: a meta-analysis of
randomised clinical trials. PLoS ONE [Internet]. 2015 [cited 2015 Aug 17]; 10(3): e0121993.doi:10.1371/journal.pone.0121993 Available from:
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0121993
• Wing RR, Bolin P, Brancati FL, Bray GA, Clark JM, Coday M et al. Cardiovascular effects of intensive lifestyle intervention in Type 2 diabetes. N Engl
J Med [Internet]. 2013 [cited 2015 Sep 5];369:145-54. Available from: http://www.nejm.org/doi/pdf/10.1056/NEJMoa1212914.
• Hicks KA, Tcheng JE, Bozkurt B, Chaitman BR, Cutlip DE, Farb A et al. ACC AHA Clinical data standards. 2014 ACC/AHA Key data elements and
definitions for cardiovascular endpoint events in clinical trials. J Am Coll Cardiol 2015 [cited 2015 Oct 11]; 66(4): 403-469. Available from: http://ac.els-
cdn.com/S0735109714074841/1-s2.0-S0735109714074841-main.pdf?_tid=27df2800-8c76-11e5-b1b6-
00000aab0f27&acdnat=1447687660_73fa495cdf0a1e0f4443e826101b30d7
• Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0 [updated March 2011]. The Cochrane
Collaboration
• Avenell A, Broom J, Brown TJ, Poobalan A, Aucott L, Stearns SC et al. Systematic review of the long-term effects and economic consequences of
treatments for obesity and implications for health improvement. Health Technol Assess 2004; 8(21): 1-458.
• Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analysis. BMJ 2003;327:557–60.

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