The Relationship between Metabolically Healthy Obesity and the Risk of Cardiovascular Disease: A Systematic Review and Meta-Analysis

Cardiovascular disease (CVD) risk in individuals with metabolically healthy obesity (MHO) is unclear. We searched databases from inception to May 2019. Data were pooled using a random effects model. Newcastle-Ottawa Scale assessment was performed. Primary and secondary outcomes were CVD risk and all-cause mortality. Forty-three studies involving 4,822,205 cases were included. The median percentage of females, age and duration of follow-up was 52%, 49.9 years and 10.6 years, respectively. The mean Newcastle-Ottawa Scale score of the articles was 7.9 ± 1.0. Compared to individuals with a metabolically healthy normal weight, individuals with MHO had higher adjusted risk of CVD and all-cause mortality. We identified a significant linear dose-response relationship between body mass index (BMI) and CVD risk among metabolically healthy individuals (p < 0.001); every unit increase in BMI increased the CVD risk. Multivariate meta-regression analysis showed that an increased proportion of women and age resulted in the risk of CVD affected by MHO reduction (p = 0.014, p = 0.030, respectively). Age and sex explained the observed heterogeneity and reported the adjusted R2. MHO resulted in a significantly increased risk for CVD; therefore, long-term weight loss should be encouraged.


Rationale
3 Describe the rationale for the review in the context of what is already known. 1-2 Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS).

METHODS
Protocol and registration 5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number.
2 Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale.

2-3
Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.

2-3
Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated.

2-3,
Appendix exclusions at each stage, ideally with a flow diagram.

4-5
Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations. Table S2 Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12). 5-6, Table   S1 Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot.

5-10
Synthesis of results 21 Present the main results of the review. If meta-analyses are done, include for each, confidence intervals and measures of consistency

5-10
Risk of bias across studies 22 Present results of any assessment of risk of bias across studies (see Item 15). 7, 10, Figure S7, S17 Additional analysis 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]).

5-10
DISCUSSION Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers).

10-11
Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias).

11-12
Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research.

FUNDING
Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review.      Each star represents if individual criterion within the subsection was fulfilled. In terms of representativeness, articles were awarded one star if the subpopulation with MHO represented the average adult in community. In terms of selection, one star was given if the non-exposed cohort; i.e., MHNW individuals; was drawn from the same community as MHO. One star was given if MHO was identified from secured records or structured interviews, and one star was given if the outcome of interest was not presented at the start of study or was excluded from analysis. In terms of comparability, one star was given if the article adjusted for the most important risk factor, age and sex. Smoking is a well-known confounding factor of BMI, CVD and all-cause mortality; thus, one star was given if the article adjusted for smoking habits. In terms of outcomes, one star was given if the CVD and mortality outcomes were obtained from independent blind assessment or record linkage. One star was given if follow-up was continued for more than five years [43], which was considered sufficient time for the development of CVD. It was difficult to assess the dropout rate of secondary cohort studies, and so we gave articles one star if all participants completed follow-up, only a small number was lost (<20%) or if the loss of participants was unlikely to introduce bias. If the original cohort was specified and the follow-up process and final results were clearly presented, we concluded that the quality was good.      Egger test, slope=0.13, p = 0.62 Figure S18. Sensitivity analyses of metabolically healthy obesity and risk of all-cause mortality by omitting each study.
confidence interval; OR, odds ratio