Association of bariatric surgery with all-cause mortality and incidence of obesity-related disease at a population level: A systematic review and meta-analysis.

BACKGROUND: Previous clinical trials and institutional studies have demonstrated that surgery for the treatment of obesity (termed bariatric or metabolic surgery) reduces all-cause mortality and the development of obesity-related diseases such as type 2 diabetes mellitus (T2DM), hypertension, and dyslipidaemia. The current study analysed large-scale population studies to assess the association of bariatric surgery with long-term mortality and incidence of new-onset obesity-related disease at a national level. METHODS AND
FINDINGS: A systematic literature search of Medline (via PubMed), Embase, and Web of Science was performed. Articles were included if they were national or regional administrative database cohort studies reporting comparative risk of long-term mortality or incident obesity-related diseases for patients who have undergone any form of bariatric surgery compared with an appropriate control group with a minimum follow-up period of 18 months. Meta-analysis of hazard ratios (HRs) was performed for mortality risk, and pooled odds ratios (PORs) were calculated for discrete variables relating to incident disease. Eighteen studies were identified as suitable for inclusion. There were 1,539,904 patients included in the analysis, with 269,818 receiving bariatric surgery and 1,270,086 control patients. Bariatric surgery was associated with a reduced rate of all-cause mortality (POR 0.62, 95% CI 0.55 to 0.69, p < 0.001) and cardiovascular mortality (POR 0.50, 95% CI 0.35 to 0.71, p < 0.001). Bariatric surgery was strongly associated with reduced incidence of T2DM (POR 0.39, 95% CI 0.18 to 0.83, p = 0.010), hypertension (POR 0.36, 95% CI 0.32 to 0.40, p < 0.001), dyslipidaemia (POR 0.33, 95% CI 0.14 to 0.80, p = 0.010), and ischemic heart disease (POR 0.46, 95% CI 0.29 to 0.73, p = 0.001). Limitations of the study include that it was not possible to account for unmeasured variables, which may not have been equally distributed between patient groups given the non-randomised design of the studies included. There was also heterogeneity between studies in the nature of the control group utilised, and potential adverse outcomes related to bariatric surgery were not specifically examined due to a lack of available data.
CONCLUSIONS: This pooled analysis suggests that bariatric surgery is associated with reduced long-term all-cause mortality and incidence of obesity-related disease in patients with obesity for the whole operated population. The results suggest that broader access to bariatric surgery for people with obesity may reduce the long-term sequelae of this disease and provide population-level benefits.

Introduction

Obesity is a worldwide pandemic, with 39% of the worldwide adult population being considered overweight [1]. Mean worldwide body mass index (BMI) has been steadily increasing since 1975, and current trends predict that 20% of the global population will be classified as having obesity (BMI ≥ 30 kg/m2) by 2030 [1,2]. In the UK, 27% of the population is already classified as having obesity [3]. Billions of dollars are spent annually worldwide to curb this health crisis, alongside the development of government public health initiatives [2,4].

Secondary to smoking, obesity has been identified as the leading cause of preventable premature death in the US [5]. Obesity predisposes individuals to a plethora of adverse conditions and is an established risk factor for overall all-cause mortality, cardiovascular disease, and type 2 diabetes mellitus (T2DM) [6-9]. Although multiple therapeutic options for the treatment of patients with obesity are available, bariatric surgery has been established as the most effective method of achieving sustained weight loss in these patients [10,11]. Bariatric surgery has also been associated with reduced overall mortality rates in patients with obesity [12] and leads to remission of obesity-related disease [10,11,13]. Bariatric surgery has also been associated with an overall reduction in the risk of developing multiple cancer types [14-16].

Current national guidance in the UK recommends that bariatric surgery be considered for patients who have a BMI of 40 kg/m2 or more, or a BMI between 35 kg/m2 and 40 kg/m2 if other significant obesity-related comorbidities are present [17]. Patients with new-onset T2DM may also be considered for surgery at lower BMI (≥30 kg/m2). Despite the presence of these criteria and evidence that patients are healthier and more functional following bariatric surgery, far less than 1% of eligible patients receive bariatric surgery [18,19]. Data from the UK National Bariatric Surgery Registry establish that at the time of primary surgery 53.9% of men and 41.4% of women already have a high level of co-existing disease (defined as 4 or more obesity-related diseases) [20]. Previous studies have also demonstrated that improving pathways to bariatric surgery can reduce the healthcare burden upon individuals and lead to overall healthcare cost savings [21].

Results from previous pooled analyses have demonstrated that bariatric surgery reduces long-term all-cause mortality [22,23]. However, these studies also included data from clinical trials and single-institution studies, which may lack external validity compared to data collected independently in population studies undertaken using administrative datasets. The present study aimed to investigate, in people with severe and complex obesity, the influence of bariatric surgery on overall long-term mortality and prevention of incident obesity-related disease at a population level.

Methods

A systematic literature search of Medline (via PubMed), Embase, and Web of Science was performed using the search criteria as follows: (“Bariatric Surgery”[MeSH] OR bariatric surgery) AND (mortality OR survival OR diabetes OR metabolic OR hypertension OR sleep apnoea OR cardiac OR angina OR heart disease OR myocardial infarction OR dyslipidaemia OR dyslipidemia OR thromboembolism) AND (national OR registry OR population) (S1 Text). Two authors (TW and NG) performed the electronic literature search independently, which was last updated in January 2020. The literature search dates included any studies published between 1 January 2000 and 31 January 2020. Studies published prior to 2000 were excluded to ensure all data were contemporaneous and applicable to present-day bariatric surgical practice. The electronic search was supplemented by a hand-search of published abstracts from relevant specialist conference meetings. Reference lists of all relevant studies were also reviewed to identify potentially relevant studies. The protocol for this study was not prospectively registered in any repository for systematic reviews.

Identified abstracts were independently scrutinised by 2 reviewers (TW and NG) to determine eligibility for inclusion. Any discrepancies regarding study inclusion from the literature search were settled by discussion with a third author (SRM). Studies were included if they were either national or regional administrative database cohort studies reporting comparative risk of long-term mortality or incident obesity-related diseases for patients who have undergone any form of bariatric surgery compared to an appropriate control group (i.e., with a clinical diagnosis of obesity) with a minimum follow-up period of 18 months. For the purposes of this study, obesity-related diseases were defined as T2DM, hypertension, obstructive sleep apnoea, cardiac disease (ischemic heart disease or cardiac failure), dyslipidaemia, and venous thromboembolism. Studies that only provided details on remission of obesity-related diseases existing prior to bariatric surgery (as opposed to new onset) were not included. Any study that was not a population-based study utilising data from an administrative database (including randomised controlled trials and single-institution studies) was excluded. This selection criterion was imposed to ensure that results from all included studies could be directly applied at a population level. This led to randomised controlled studies, and cohort studies that did not utilise a population-registry-based data design, being excluded as results from these studies may be representative of only the highly specialised units participating in such studies and would lack external validity when applied to the general population of patients receiving bariatric surgery. In the situation where 2 studies utilised the same registry data and reported on the same outcome measure, and therefore potentially contained duplicate data, the most recent study was selected for inclusion. Only English-language studies were included.

Data from eligible studies were extracted into a computerised spreadsheet for analysis. Data were collected for overall all-cause long-term mortality and new-onset obesity-related comorbidities. Authors of individual studies were not specifically contacted to obtain more detailed results than those available in the main publication and published appendices. Mortality was evaluated according to reported HRs to minimise the effect of patient dropouts, whereas obesity-related diseases were primarily analysed directly according to event rates in each group. Event rate analysis was used for the primary analysis of obesity-related disease, as a greater proportion of included studies reported these data, but outcomes were also analysed according to adjusted odds ratios (ORs) where these data were available, for confirmatory purposes.

Statistical analysis was performed using StatsDirect 3.2.9. Pooled outcome measures were determined using random effects models as described by DerSimonian and Laird [24]. Heterogeneity amongst the trials was assessed by Cochran Q statistic, a null hypothesis test in which p < 0.05 is taken to indicate the presence of heterogeneity, and the I2 statistic, which describes the percentage of variation across studies due to heterogeneity. The Egger test was used to assess the funnel plot for asymmetry, indicating possible publication or other biases.

Results

The literature search identified 18 studies suitable for inclusion [25-42]. Fig 1 provides details of the PRISMA flowchart for the literature search. In total there were 1,539,904 patients included in the analysis, with 269,818 patients receiving bariatric surgery and 1,270,086 control patients. The types of surgery were gastric bypass (n = 137,578, 51%), sleeve gastrectomy (n = 58,916, 22%), adjustable gastric band (n = 52,973, 20%), vertical banded gastroplasty (n = 6,397, 2%), biliopancreatic diversion (with or without duodenal switch) (n = 1,002, 0.4%), and an alternative procedure or unspecified operation (n = 12,952, 5%) (S1 Table). Median follow-up across all studies was 59 months (range 18 to 144 months).

Fig 1

PRISMA flow chart with details of literature search.

Patient demographic details for all studies are provided in Table 1. Quality assessment of studies was undertaken with the Newcastle–Ottawa Scale (S2 Table) [43]. The majority of studies used patients with a diagnosis of obesity as the control group, although a group of patients without a diagnosis of obesity was utilised as the control group in 1 study [26]. All studies except this one scored 4 stars for patient selection (rated out of 4) [25,27-42]. Studies that did not report BMI for control and surgery groups scored only 1 star for comparability [26,28,29,39-42]. All studies scored the maximum 3 stars for exposure.

Table 1

Patient demographics for the studies included in the pooled analysis.

Study	Nation or region of origin	Included study dates	Median follow-up (months)	Number of patients		Mean ± SD or median (range) age (years)		Female sex, n (%)		Mean BMI ± SD (kg/m2) or n (%) with BMI ≥ 40 kg/m2
				Surgery	Control	Surgery	Control	Surgery	Control	Surgery	Control
Arterburn [25]	US	2000–2011	60	2,500	7,462	52 ± 8.8	53 ± 8.7	651 (26%)	1,920 (26%)	47 ± 7.9	46 ± 7.3
Backman [26]	Sweden	2007–2012	55	18,418	175,138	39 ± 10.5	39 ± 10.5	14,518 (79%)	138,082 (79%)	42.2 ± 5.8	—
Bailly [35]	France	2008–2016	44	102,627	225,882	37.3 ± 10.5	44.0 ± 11.7	88,464 (86%)	151,566 (67%)	47,516 (46.3%)	37,948 (16.8%)
Ceriani [36]	Lombardy region, Italy	1999–2008	144	472	1,405	43.1 ± 10.6	43.5 ± 12.5	354 (75%)	995 (71%)	47.3 ± 7.5	46.8 ± 3.8
Douglas [37]	UK	Up to 2014	36	3,882	3,882	45 ± 11	45 ± 11	3,126 (81%)	3,166 (82%)	44.7 ± 8.8	42.1 ± 6.5
Eliasson [38]	Sweden	2007–2014	60	6,132	6,132	48.5 ± 9.8	50.5 ± 12.7	3,678 (61%)	3,768 (61%)	42.0 ± 5.7	41.4 ± 5.7
Flum [39]	Washington State, US	1987–2001	120	3,328	62,781	43.1 ± 10.1	47.0 ± 6.2	2,679 (81%)	40,368 (64%)	—	—
Johnson [40]	South Carolina, US	1996–2009	60	2,580	13,371	47.5 ± 10.6	52.1 ± 12.8	1,987 (77%)	9,012 (67%)	—	—
Kauppila [41]	Nordic countries	1980–2012	48	49,977	494,842	—	—	37,247 (75%)	334,407 (68%)	—	—
Moussa [42]	UK	Up to 2017	129	3,842	177,973	—	—	—	—	—	—
Moussa [27]	UK	Up to 2017	60	4,073	4,073	50 (42–58)	50 (43–58)	—	—	40.2 (37.0–45.2)	40.4 (36.7–45.6)
Perry [28]	US	2001–2014	18	11,903	11,901	—	—	9,237 (78%)	9,236 (78%)	—	—
Persson [29]	Sweden	1987 onwards	44	22,295	25,564	40.7 ± 10.7	44.3 ± 13.2	16,921 (76%)	17,077 (67%)	—	—
Pontiroli [30]	Lombardy region, Italy	1995–2001	59	385	681	39.2 ± 10.4*	40.2 ± 12.0*	292 (76%)	509 (75%)	41.1 ± 5.4*	40.9 ± 7.3*
Singh [31]	UK	1990–2018	43	5,170	9,995	—	—	4,158 (80%)	8,105 (81%)	3,634 (70.3%)	6,780 (67.8%)
Reges [32]	Israel	2005–2014	48	8,385	25,155	46 (37–54)	46 (37–54)	5,490 (66%)	16,470 (66%)	4,980 (59%)	14,940 (59%)
Thereaux [33]	France	2008–2015	72	15,650	15,650	38.9 ± 11.2	39.4 ± 11.2	13,241 (85%)	13,241 (85%)	9,449 (60%)	9,449 (60%)
Thereaux [34]	France	2009	72	8,199	8,199	39.9 ± 11.5	40.5 ± 11.6	6,728 (82%)	6,728 (82%)	6,092 (74%)	6,092 (74%)

*Study subgroup with no type 2 diabetes at baseline.

All-cause mortality

Eleven studies reported a significant reduction in relative risk of long-term all-cause mortality for patients following bariatric surgery compared to controls [25,28,30-32,36,37,38,39,41,42], with a pooled OR (POR) of 0.62 (95% CI 0.55 to 0.69, p < 0.001). There was some evidence of statistical heterogeneity (Cochran Q = 39.03, p < 0.001; I2 = 71.8%) but no evidence of bias (Egger intercept = −0.31, p = 0.714) (Fig 2).

Fig 2

Forest plot of all-cause mortality (pooled odds ratio 0.62, 95% CI 0.55 to 0.69, p < 0.001).

Cardiovascular mortality

Three studies reported significantly reduced relative risk of cardiovascular mortality for patients following bariatric surgery compared to controls [36,38,41] (POR 0.50, 95% CI 0.35 to 0.71, p < 0.001). There was no evidence of statistical heterogeneity (Cochran Q = 2.82, p = 0.24; I2 = 29.2%), and too few strata to assess for bias.

Data for overall and cardiovascular mortality are presented in Table 2.

Table 2

Outcomes for overall mortality rates relative to controls.

Study	Overall mortality risk		Cardiovascular mortality risk
	Hazard ratio or POR	95% CI	Hazard ratio or POR	95% CI
Arterburn [25]	0.47	0.39–0.56	—	—
Ceriani [36]	0.64	0.29–0.97	0.26	0.09–0.72
Douglas [37]	0.97	0.66–1.43	—	—
Eliasson [38]	0.42	0.30–0.57	0.41	0.19–0.90
Flum [39]	0.67	0.54–0.85	—	—
Kauppila [41]	0.63	0.60–0.66	0.57	0.52–0.63
Moussa [42]	0.49	0.34–0.69	—	—
Perry (age 65 years or over) [28]	0.85	0.65–1.11	—	—
Perry (age under 65 years) [28]	0.72	0.64–0.81	—	—
Pontiroli [30]	0.52	0.33–0.80	—	—
Singh [31]	0.70	0.55–0.89	—	—
Reges [32]	0.50	0.40–0.61	—	—
POR	0.62	0.55–0.69	0.50	0.35–0.71

POR, pooled odds ratio.

Details of incident comorbidities

Details of incident comorbidities in each study are provided in Table 3.

Table 3

Outcomes for incident obesity-related diseases.

Study	T2DM		Hypertension		Obstructive sleep apnoea		Dyslipidaemia		Ischemic heart disease		Cardiac failure		VTE
	Surgery	Control	Surgery	Control	Surgery	Control	Surgery	Control	Surgery	Control	Surgery	Control	Surgery	Control
Arterburn [25]	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Backman [26]	189 (1.0%)	2,319 (1.3%)	—	—	—	—	—	—	—	—	—	—	—	—
Bailly [35]	2,091 (2.0%)	29,855 (13.2%)	—	—	—	—	—	—	—	—	—	—	—	—
Ceriani [36]	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Douglas [37]	158 (6.6%)	237 (9.3%)	79 (3.2%)	219 (8.8%)	36 (1.1%)	71 (2.0%)	—	—	40 (1.2%)	68 (1.9%)	—	—	—	—
Eliasson [38]	—	—	—	—	—	—	—	—	24 (0.4%)	67 (1.1%)	—	—	—	—
Flum [39]	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Johnson [40]	—	—	—	—	—	—	—	—					—	—
Kauppila [41]	—	—	—	—	—	—	—	—	8 (0.3%)	241 (1.8%)	—	—	—	—
Moussa [42]	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Moussa [27]	—	—	—	—	—	—	—	—	—	—	—	—	71 (1.7%)	179 (4.4%)
Perry [28]	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Persson [29]	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Pontiroli [30]	15 (9.7%)	75 (20.8%)	47 (30.5%)	174 (48.3%)	—	—	—	—	—	—	89 (0.4%)	944 (3.7%)	—	—
Singh [31]	—	—	118 (3.3%)	567 (8.0%)	—	—	—	—	14 (9.1%)	52 (14.4%)	—	—	—	—
Reges [32]	265 (3.2%)	2,038 (8.1%)	265 (3.1%)	2038 (8.1%)	—	—	570 (6.8%)	3,100 (12.3%)	49 (1.0%)	123 (1.3%)	19 (0.4%)	71 (0.7%)	—	—
Thereaux [33]	68 (0.4%)	213 (1.4%)	—	—	—	—	—	—	—	—	—	—	—	—
Thereaux [34]	—	—	305 (5.6%)	760 (15.8%)	—	—	144 (2.1%)	565 (9.1%)	—	—	—	—	—	—

Data are given as n (%).

T2DM, type 2 diabetes mellitus; VTE, venous thromboembolism.

New-onset type 2 diabetes

Six studies reported a reduction in incident T2DM after bariatric surgery compared to controls [26,30,32,33,35,37] (POR 0.39, 95% CI 0.18 to 0.83, p = 0.010) (Fig 3). There was significant evidence of statistical heterogeneity (Cochran Q = 824.8, p < 0.001; I2 = 99.4%) but no evidence of bias (Egger intercept = 8.18, p = 0.069).

Fig 3

Forest plot of incident diabetes (pooled odds ratio 0.39, 95% CI 0.183 to 0.831, p = 0.010).

New-onset hypertension

Five studies reported that incident hypertension was reduced after bariatric surgery compared to controls [30-32,34,37] (POR 0.36, 95% CI 0.32 to 0.40, p < 0.001) (Fig 4). There was no evidence of statistical heterogeneity (Cochran Q = 5.90, p = 0.21; I2 = 32.2%) and no evidence of bias (Egger intercept = −0.32, p = 0.92).

Fig 4

Forest plot of new-onset hypertension (pooled odds ratio 0.36, 95% CI 0.32 to 0.40, p < 0.001).

New-onset obstructive sleep apnoea

Only 1 study reported incident obstructive sleep apnoea relative to controls, and therefore it was not possible to do a pooled analysis [37]. This individual study reported a reduced rate of new-onset obstructive sleep apnoea in patients undergoing bariatric surgery (new-onset obstructive sleep apnoea rate of 1.1%) compared to controls (2.0%) (HR 0.55, 95% CI 0.37–0.82, p = 0.004) [37].

New-onset dyslipidaemia

Two studies reported significantly reduced incident dyslipidaemia following bariatric surgery compared to controls [32,34] (POR 0.33, 95% CI 0.14 to 0.80, p = 0.010) (S1 Fig). There was evidence of statistical heterogeneity (Cochran Q = 69.5, p < 0.001; I2 = 98.6%), and too few strata to assess for bias.

New-onset ischemic heart disease

Five studies reported significantly reduced incident ischemic heart disease after bariatric surgery compared to controls [30,31,37,38,40] (POR 0.46, 95% CI 0.29 to 0.73, p = 0.001). There was evidence of statistical heterogeneity (Cochran Q = 18.9, p < 0.001; I2 = 78.8%) but no evidence of bias (Egger intercept = −5.62, p = 0.119) (S2 Fig).

New-onset cardiac failure

Two studies reported the rate of incident cardiac failure [29,31] and found no statistically significant protective association with bariatric surgery (POR 0.23, 95% CI 0.05 to 1.10, p = 0.066). There was significant evidence of statistical heterogeneity (Cochran Q = 32.5, p < 0.001; I2 = 96.9%), and too few strata to assess for bias.

Development of venous thromboembolism

Only 1 study reported incident venous thromboembolism in bariatric surgery patients relative to controls, and therefore it was not possible to undertake a pooled analysis [27]. This individual study demonstrated a reduced incidence of new-onset venous thromboembolism in bariatric surgery patients (1.7%) compared to controls (4.4%) (HR 0.60, 95% CI 0.43 to 0.84, p = 0.003) [27].

Comorbidity analysis by adjusted ORs

Adjusted ORs for incident comorbidities were analysed separately in order to confirm results identified during event rate analysis. These results demonstrated the same patterns identified in the event rate data, with reduced incidence of T2DM (POR 0.28, 95% CI 0.11 to 0.73, p = 0.009), hypertension (POR 0.32, 95% CI 0.21 to 0.47, p < 0.001), ischemic heart disease (POR 0.67, 95% CI 0.49 to 0.90, p = 0.009), and cardiac failure (POR 0.43, 95% CI 0.29 to 0.64, p < 0.001) in bariatric surgical patients compared to controls. These data are presented in S3 Table.

Discussion

The results of the present study suggest that bariatric surgery is associated with reduced all-cause long-term mortality compared to appropriate control patients at a population level. This is consistent with the findings of the Swedish Obese Subjects observational study, which demonstrated decreased overall mortality in patients with obesity who received bariatric surgery [12]. This association was also identified in previous meta-analyses that had included data from non-population-based clinical trials [22,23,44]. The current results establish that these findings are generalisable to the population at large and are not just limited to patients receiving bariatric surgery within specialised centres participating in clinical trials or publishing individual series.

The present study also suggests that bariatric surgery is associated with reduced incidence of obesity-related disease including T2DM, hypertension, and dyslipidaemia. The relative risk reductions associated with bariatric surgery were 61%, 64%, and 77% for the development of T2DM, hypertension, and dyslipidaemia, respectively. These data demonstrate the potential protective association of bariatric surgery with prevention of these obesity-related diseases. Bariatric surgery was also specifically associated with a reduction in cardiovascular mortality and development of ischemic heart disease. Bariatric surgery has previously been associated with a reduction in both macrovascular (including myocardial infarction and cerebrovascular events) and microvascular (including retinal complications, diabetic kidney disease, and peripheral neuropathy) complications relating to T2DM [10,40,45]. The reduction in cardiovascular mortality is likely accounted for by the modification of comorbidities that are known cardiovascular risk factors (T2DM, hypertension, and dyslipidaemia), as suggested in the present study.

In addition to prevention of new-onset disease, bariatric surgery effectively improves pre-existing diseases including T2DM [10,11,46,47], dyslipidaemia [46,47], and hypertension [47]. Some of the included studies also identified improvements in remission of these diseases at a population level. Thereaux et al. [33] established that discontinuation of antidiabetic medications for patients in France with pre-existing T2DM was significantly greater in patients receiving bariatric surgery compared to controls (−49.9% versus −9.0%, p < 0.001) [33]. Population studies from Israel and the UK Clinical Practice Research Datalink have identified similar results [32,37]. In a separate study also included in the present analysis, Thereaux et al. [34] identified that bariatric surgery was significantly associated with discontinuation of therapy for pre-existing hypertension and dyslipidaemia relative to having obesity but not having bariatric surgery [34].

Following surgery, most patients remain in the overweight or class 1 obesity BMI category (BMI 25–35 kg/m2). From data currently available, it is unclear if the overall mortality rate for patients following surgery decreases to that of the general population, decreases to that of the new equivalent BMI category, or is persistently elevated due to the period of time spent at an even higher BMI. In data from 5 Nordic countries, the standardised mortality rate (SMR) of patients receiving bariatric surgery was improved compared to non-operated patients with obesity (SMR 0.63, 95% CI 0.60 to 0.66), although mortality for these patients was still significantly increased relative to the general non-obese population (SMR 1.94, 95% CI 1.83 to 2.05) [41]. Increased BMI class has been strongly associated development of disease and increased mortality risk [48-50]; therefore, elevated mortality relative to the general population may relate to ongoing effects of existing disease before surgery. Determining the ongoing mortality rate of patients following bariatric surgery relative to non-operated individuals within their new BMI classification remains an area for future population-based research.

Data from the UK National Bariatric Surgery Registry indicate that over 80% of patients receiving surgery have several obesity-related diseases [20]. Although most therefore have the chance to improve existing disease with bariatric surgery, our data enable us to quantify the relative risk reduction for developing disease in those disease-free at presentation. Knowledge of the relative risk reductions of 61%, 64%, and 77% for the diagnosis of incident T2DM, hypertension, and dyslipidaemia, respectively, for bariatric surgery patients relative to controls may aid the discussions between healthcare professionals and people with obesity as to whether bariatric surgery should be undertaken.

Strengths and limitations

Our study has limitations that may affect interpretation of the results. All the studies included were large-scale, non-randomised comparative studies based upon registry data. It is therefore not possible to account for potentially important confounding variables, which may not have been equally distributed between patient groups given the non-randomised design of the studies included. One potential example is socioeconomic status, which is known to be an important predictor of all-cause mortality [51]. Previous evidence indicates that patients receiving bariatric surgery may have higher education levels and income than controls, and socioeconomic status may have influenced results [52,53]. Another example would be the higher rate of alcohol abuse disorders and schizophrenia within the control group of the study by Arterburn et al. [25] included in the present analysis. However, these large-scale studies, a strength of the paper, were selected to explore the association of bariatric surgery with long-term mortality and incidence of new obesity-related disease at a population level, with this natural variation in patient factors. The majority of studies compared results from patients receiving bariatric surgery to those of an appropriate control group, with only 1 study unable to select control group patients who also had a diagnosis of obesity [26].

An additional potential source of bias is that patients receiving bariatric surgery would have been managed within a weight loss management pathway including non-surgical treatments for obesity and close monitoring of obesity-related diseases. As the control cohorts for the studies included were taken from the general population, these individuals would likely not have been receiving any non-surgical treatment of obesity, and obesity-related diseases would likely have been less closely monitored, potentially influencing the risk of developing these diseases. It is not possible from the current dataset to evaluate separately the influence of bariatric surgery and non-surgical interventions for treatment of obesity within weight loss management programmes on rates of incident disease, and this may have led to an overestimate of the beneficial effects of bariatric surgery.

This potential source of bias can be reduced by comparing outcomes of patients receiving bariatric surgery to patients seeking treatment for obesity within a specialised medical treatment service including individual- or group-based lifestyle intervention programmes. This approach has been undertaken in a previous study by Jakobsen et al. [54] investigating long-term medical complications in a single-institution cohort of patients receiving bariatric surgery or specialised medical treatment for obesity. However, due to the population-based nature of the studies included in our analysis, it was not possible to identify which patients within the non-surgical control group may have received non-surgical treatment of obesity.

Due to heterogeneity in the definition of pre-existing disease, along with differences in the definition of remission, we did not examine disease remission rates. It was also not possible to perform a specific analysis of outcomes by procedure type in the current analysis. Our study also did not examine specific procedure-related complications or measures of adverse outcomes associated with bariatric surgery. Bariatric surgery is known to be extremely safe, with low peri-operative mortality and complication rates [55-57]. Although other long-term potential complications of bariatric surgery exist (including gastroesophageal reflux [58], internal herniation [59], and trace element malnutrition [60]), these issues are relatively uncommon in modern bariatric surgical practice, and management strategies are available to treat these conditions should they occur. Finally, from the perspective of statistical analysis, the Egger test was utilised to measure for the presence of potential bias. This test is considered to be most reliable when greater than 10 studies are included within the analysis. Due to the limited number of studies included in some of the analyses presented here, some of these bias assessments must be interpreted carefully, although we have chosen to report these results as they still provide an indication of the presence of any potential bias.

To our knowledge, this is the first published study of pooled data from population-based studies of incident disease following bariatric surgery. Our results represent real-world data that may be generalisable to routine clinical practice. As further data accumulate, it may become clearer whether bariatric surgery reduces the incidence of new-onset obstructive sleep apnoea or venous thromboembolism. Another significant strength of the current study is that due to the nature of data collection from administrative datasets, follow-up data (such as mortality and rate of incident obesity-related disease) are externally validated outside each of the individual studies as part of the administrative database collection. This allows for completeness of data collection regarding these aspects and removes the inherent difficulties with patient follow-up data within single-institution-based studies. One method utilised to circumvent this issue within institutional studies has been to link study participants directly to data contained within administrative datasets, and this methodology was utilised successfully by Adams et al. for patients in Utah [47]. This study was not included in the present meta-analysis as all surgical patients had been collected from a single centre, although results were consistent with those identified in the current analysis (OR of incident obesity-related diseases in the surgical cohort 0.08 [95% CI 0.03 to 0.24] for T2DM, 0.23 [95% CI 0.11 to 0.49] for hypertension, and 0.12 [95% CI 0.03 to 0.46] for dyslipidaemia [47]). Results from the Swedish Obese Subjects study were also excluded from the present analysis as this study did not use a population-based design methodology, rather individuals within the control group responded to a nationwide advert [61,62]. However, results from this study also support the findings identified here, with bariatric surgery being associated with reduced long-term mortality (HR 0.71, 95% CI 0.54 to 0.92) [12], decreased development of T2DM (OR 0.17, 95% CI 0.13 to 0.21) [63], and reduced incidence of cardiovascular events (OR 0.67, 95%CI 0.54 to 0.83) [64].

Conclusion

This meta-analysis of large-scale registry studies indicates that patients receiving bariatric surgery have improved long-term mortality rates compared to controls at a population level. They also have significantly reduced incidence of obesity-related disease including T2DM, hypertension, dyslipidaemia, and ischemic heart disease. Healthcare providers may use the data on relative risk reduction as part of the discussion with patients considering bariatric surgery.

Forest plot for development of new-onset dyslipidaemia (POR 0.33, 95% CI 0.14 to 0.80, p = 0.010).

(TIF)

Click here for additional data file.

Forest plot of new-onset ischemic heart disease (POR 0.46, 95% CI 0.29 to 0.73, p = 0.001).

(TIF)

Click here for additional data file.

Details of type of bariatric surgery performed within each study.

BPD, biliopancreatic diversion; DS, duodenal switch; VBG, vertical banded gastroplasty.

(DOCX)

Click here for additional data file.

Newcastle–Ottawa Score for all included studies.

(DOCX)

Click here for additional data file.

Analysis of development of comorbid disease via adjusted OR data.

Data in parentheses represent 95% confidence interval. T2DM, type 2 diabetes; VTE, venous thromboembolism.

(DOCX)

Click here for additional data file.

Additional information for literature search.

(DOCX)

Click here for additional data file.

PRISMA checklist.

(DOC)

Click here for additional data file.

17 Feb 2020

Dear Dr Markar,

Thank you for submitting your manuscript entitled "Effect of bariatric surgery on all-cause mortality and incidence of obesity-related disease at a population level – systematic review and meta-analysis" for consideration by PLOS Medicine.

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26 Apr 2020

Dear Dr. Markar,

Thank you very much for submitting your manuscript "Effect of bariatric surgery on all-cause mortality and incidence of obesity-related disease at a population level – systematic review and meta-analysis" (PMEDICINE-D-20-00372R1) for consideration at PLOS Medicine.

Your paper was evaluated by a senior editor and discussed among all the editors here. It was also discussed with an academic editor with relevant expertise, and sent to independent reviewers, including a statistical reviewer. The reviews are appended at the bottom of this email and any accompanying reviewer attachments can be seen via the link below:

[LINK]

In light of these reviews, I am afraid that we will not be able to accept the manuscript for publication in the journal in its current form, but we would like to consider a revised version that addresses the reviewers' and editors' comments. Obviously we cannot make any decision about publication until we have seen the revised manuscript and your response, and we plan to seek re-review by one or more of the reviewers.

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Requests from the editors:

*Not a request but just to note that this paper was submitted, and is being considered in PLOS Medicine as part of a special issue focussed on the Determinants, Consequences and Management of Obesity

*The authors have appropriately reported the work as per PRISMA guidelines for systematic reviews, but would also be good to state (although this is not compulsory for the journal) whether the protocol for the systematic review was established and either published or registered before the start of the SR conduct - ie, either as a published protocol paper or in the PROSPERO registry (https://www.crd.york.ac.uk/PROSPERO/)

*At this stage, we ask that you include a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract. Please see our author guidelines for more information: https://journals.plos.org/plosmedicine/s/revising-your-manuscript#loc-author-summary

*In the last sentence of the Abstract Methods and Findings section, please describe the main limitation(s) of the study's methodology. One thing to note here (see later) is that the systematic review did not, as far as this reader can tell, aim to assess adverse effects associated with bariatric surgery, only improvements on mortality and obesity-related disease.

*If possible, please change the referencing format to the PLOS Medicine style using square brackets to enclose sequential numbered callouts in the text (rather than superscript numbers) - this should be easy if referencing software was used.

*Main text covering study limitations might also include a point about not covering adverse effects in this review.

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Comments from the reviewers:

Reviewer #1: In this meta-analysis, the methods are correct, and the conclusions are sound.

There are a few details that require attention:

1. under strategy, there is no mention of paper search in PubMed

2. figures should report weight of studies

3. the analysis would be more satisfactory if reporting surgeries separately; only if no difference appears, then the surgeries can be considered together

Reviewer #2: Alex McConnachie, Statistical Review

Wiggins et al present a systematic review and meta-analysis of whole-population studies using administrative datasets, of the association between bariatric surgery and adverse outcomes, confirming the beneficial effects seen in randomised trials in general population settings. This review considers the statistical elements of the paper.

First, to be pedantic, the word "effect" in the title of the paper should perhaps be changed - since this meta-analysis is combining observational studies, the associations observed cannot be interpreted as causal effects, even if few would dispute that they are.

As a whole, the statistical methods used, their presentation, and interpretation are good. My comments are therefore relatively minor.

The literature search was reportedly carried out in January 2020. I assume that is when it was last updated?

In the final sentence of the first paragraph of the methods, the words "formal" and "formally" should maybe be removed. I am not sure what it would mean to say this was done "informally", so better to simply say it was not done.

In the final paragraph of the methods, covering the statistical methods, the word "significant" can be removed (twice). I do not think it adds anything.

For Egger's test, I have read that it is not recommended with fewer than 10 studies. This is only a rule of thumb, so the results can still be reported, but it is perhaps a limitation.

For those outcomes where there was only one study, so that a pooled analysis could not be performed, it would help the reader if the result of that one trial were shown in the text.

One phrase that crops up throughout the paper is that included studies should include an appropriate control group. It was not clear to me what was meant by "appropriate" here. Perhaps this could be expanded upon.

Also, it is stated that whilst mortality was analysed in terms of hazard ratios, the obesity related disease incidence data were analysed as event rates in each group. Did any studies present adjusted odds ratios, or use propensity scores, or other methods to control for confounding? Would it have been better to perform the meta-analysis using these adjusted ORs, rather than the raw event counts?

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Reviewer #3:

* Is the manuscript well organized and written clearly enough to be accessible to non-specialists?

Yes, this an interesting and well written manuscript.

* What are the main claims of the paper and how significant are they for the discipline?

The authors claim:

1. In the abstract (line 55-57) that "This pooled analysis has demonstrated that bariatric surgery can improve long-term all-cause mortality and reduce the incidence of obesity-related disease in patients with obesity for the whole operated population."and that "The results suggest that broader access to bariatric surgery for people with obesity may reduce the long-term sequelae of this disease and provide population-level benefits"

2. In the discussion: "This meta-analysis of large-scale registry studies indicate that patients receiving bariatric surgery have improved long-term mortality rates compared to controls at a population level."

3. In the introduction: "bariatric surgery improves all-cause mortality" (line 34 abstract), "reduces overall risk of developing multiple cancer types" (line 73), "previous pooled analyses have demonstrated that bariatric surgery reduces long-term all-cause mortality" (line86-87). These causal claims about previous research are not supported by any randomised controlled study or clinical study with an appropriate control group.

These main claims may be important for the discipline, but they are generally too optimistic by indicating causality (e.g. by the inappropriate use of the term "effect of") several places in the title, abstract, and manuscript. Importantly, all studies included in the meta-analysis were observational and none could infer causality, only associations, as mentioned in the title of several of the included studies (particularly those published in JAMA). A meta-analysis of "association studies" does not increase the evidence level to infer causation. In view of this, my advice to the authors is to remove or rephrase all undocumented causal claims in the manuscript.

* Are the claims properly placed in the context of the previous literature? Have the authors treated the literature fairly?

Yes

* Do the data and analyses fully support the claims? If not, what other evidence is required?

The claims in the first part of the discussion (lines 209-210, and 218) are partly supported by the data: "bariatric surgery is associated with reduced all-cause long-term mortality" and "reduced incidence of ", but whether the studies had "appropriate control groups" is discussable (see below).

Tthe claims of the beneficial effects (indicating causal effects) of bariatric surgery on all-cause mortality and cardiovascular mortality are overly optimistic and should be modified. Most importantly, the term "Effect" in the title "Effect of bariatric surgery.." should be removed, and may be substituted with "Associations of bariatric surgery …" as in the JAMA-papers referred to. The term "effect" should also be replaced in line 36, because the design of the current meta-analysis is not appropriate to assess any cause-effect relationship.

Regarding other outcomes (e.g. obesity related diseases), the findings are in accordance with previously published randomised and non-randomised controlled studies.

In my view, the main problem with the majority (if not all) of studies included in the meta-analysis is the absence of an appropriate control group, which the authors stated that they aimed to include in the methods sections (line 42 and line 112). Although this limitation is partly addressed in the discussion (lines 263-266), several other limitations with the control groups regarding imbalances in important known and unknown confounding factors in general, and in the included studies in particular, need to be addressed. First, as mentioned by the authors, less than 1% of eligible patients receive bariatric surgery. In general, and as shown in the paper by Reges et al in JAMA (ref 29), these patients probably have higher socioeconomic status (higher education and income) than controls not receiving bariatric surgery. It is well known that socioeconomic status is an important predictor of all-cause mortality. Another example is the higher prevalence of people with schizophrenia in the control group in the study by Arterburn et al. (ref 22) etc. Second, few, if any (?) control groups consisted of treatment seeking patients with obesity who received an adequate non-surgical treatment for obesity? An ethical committee would find it very difficult to accept a control group not receiving any kind of active treatment in a clinical trial, and comparing treatment-groups with no-treatment groups will probably favor the treatment group. FYI, our group has tried to partly overcome this bias by comparing treatment seeking patients with obesity who opted for either bariatric surgery or tertiary care based conservative treatment in an observational cohort study (Jakobsen GS, et al. Association of Bariatric Surgery vs Medical Obesity Treatment With Long-term Medical Complications and Obesity-Related Comorbidities. JAMA 2018;319(3):291-301) regarding remission and incidence of obesity related diseases. Third, several unmeasured confounders in the various studies might have biased the results.

In addition, although beyond the scope of the article, the well-known detrimental long-term effects of bariatric surgery should at least be addressed in the discussion.

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Reviewer #4: Dear Editor,

Thank you for the opportunity to review the manuscript entitled: " Effects of bariatric surgery on all-cause mortality and incidence of obesity-related disease at a population level - systematic review and meta-analysis".

In the manuscript, the authors address the impact of bariatric surgery on all-cause mortality and new onset of metabolic comorbidities in a systematic review of studies published between 2000 and January, 2020.

My general impression of the study is that it is overall well conducted and the manuscript well written. The topic of the study, as well as the conclusion, are already known and accepted by bariatric surgeons and physicians with positive attitudes towards bariatric surgery. Despite the evidence supporting bariatric surgery for many patients with morbid obesity, the results still have a hard time reaching a wide acceptance. Thus, there is a need for further well written papers summarizing the beneficial effects (as well as side-effects and complications) of bariatric surgery, and these papers need to reach a wide audience of readers, such as through PLoS Medicine. Furthermore, the present study included only population-based studies, which is a novel approach.

While I have a few (mostly minor) comments and questions to the authors, it is my opinion that the manuscript should be of interest to a wide readership, and thus should be eligible for publication in PLoS Medicine.

General comments:

My main overall concern with the manuscript is related to the transparency of the presentation, and to some extent to the limitations of the studies included.

First, while all search terms are presented in the first section of the methods section, the description remains unclear in the sense that there are too may possible options for the search terms. For optimal transparency the reader should be able to redo the literature search, and end-up with similar results. I assume that the authors clustered search terms related to study group (i.e. bariatric, obesity, bariatric surgery etc.), outcome, and study level separately. If the authors could present the search-terms more specifically, it would be helpful

I fully agree with the authors that avoiding randomized trials, in particular single-center studies, can be supported by the tendency of these studies to overestimate treatment effects (and the sometimes low external validity). However, I don't fully understand why matched, prospective, multicenter studies (such as the SOS-trial) were not included in the study. Could the authors specify this decision better?

Perhaps some of these issues has been presented already in a study plan, published and registered elsewhere, but I can't find it. Was the systemic review registered before the study was conducted? Perhaps this could be specified with registration number if it was, or with a short comment if not.

Finally, it is likely that intervention groups, in general, are better controlled for comorbid disease, thus identifying more cases with disease and thereby influencing the risk for new onset of disease. Thus, there is a risk that the meta-analyses in the study overestimates the potential beneficial effect on new onset of disease. Providing remission of disease could have added to the overall view of the effect of bariatric surgery on metabolic comorbidities, but the authors have provided a reasonable explanation as to why they did not choose to include this outcome. However, a potential differential bias exists and should be presented in the limitation section.

Minor additional comments:

Abstract: Information on eligibility criteria is incomplete, and should preferably be extended in the methods section. Furthermore, a short section on the major limitations of the study could be informative.

Methods section: Did the authors contact authors from the included studies to obtain or confirm specific data from the included studies? This could have been helpful in order to have more detailed data. For instance, by contacting specific authors, surgical methods known to have inferior results (i.e. the vertical banded gastroplasty, as well as the unknown /miscellaneous group) could have been excluded. It is not a major issue though, since keeping these methods in the study is likely to underestimate the treatment effects of the intervention.

Supplementary Table 1: The studies could be more uniformly presented, preferably with author name and reference number (as raised numbers)

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Any attachments provided with reviews can be seen via the following link:

[LINK]

8 May 2020

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

29 May 2020

Dear Dr. Markar,

Thank you very much for re-submitting your manuscript "Association of bariatric surgery on all-cause mortality and incidence of obesity-related disease at a population level – systematic review and meta-analysis" (PMEDICINE-D-20-00372R2) for review by PLOS Medicine.

I have discussed the paper with my colleagues and the academic editor and it was also seen again by xxx reviewers. I am pleased to say that provided the remaining editorial and production issues are dealt with we are planning to accept the paper for publication in the journal.

The remaining issues that need to be addressed are listed at the end of this email. Any accompanying reviewer attachments can be seen via the link below. Please take these into account before resubmitting your manuscript:

[LINK]

Our publications team (plosmedicine@plos.org) will be in touch shortly about the production requirements for your paper, and the link and deadline for resubmission. DO NOT RESUBMIT BEFORE YOU'VE RECEIVED THE PRODUCTION REQUIREMENTS.

***Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.***

In revising the manuscript for further consideration here, please ensure you address the specific points made by each reviewer and the editors. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments and the changes you have made in the manuscript. Please submit a clean version of the paper as the main article file. A version with changes marked must also be uploaded as a marked up manuscript file.

Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. If you haven't already, we ask that you provide a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract.

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We ask every co-author listed on the manuscript to fill in a contributing author statement. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT.

Please ensure that the paper adheres to the PLOS Data Availability Policy (see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it.

If you have any questions in the meantime, please contact me or the journal staff on plosmedicine@plos.org.

We look forward to receiving the revised manuscript by Jun 05 2020 11:59PM.

Sincerely,

Adya Misra, PhD

Senior Editor

PLOS Medicine

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Requests from Editors:

First sentence- should “surgery” be “bariatric surgery”?

Methods and findings- please state the study designs included for clarity

Please can you provide p-values along with 95% CI as required

Conclusions must be tempered, I suggest using “suggest” instead of “demonstrated” owing to the various limitations cited in the prior section

Author summary

We need these in bullet points and using subheadings. Please see our author guidelines for more information: https://journals.plos.org/plosmedicine/s/revising-your-manuscript#loc-author-summary. We usually suggest 2-3 bullet points per subheading so please do adhere to our guidelines to avoid delays to your manuscript

Through the manuscript can you please add a space between text and the reference brackets

Introduction

Line 91- public health need not be capitalised

Methods

Please provide the full search strategy as per PRISMA guidelines as SI files

You may wish to briefly mention why you restricted studies between 2000 and 2020

Line 207- p values are required for up to three decimal places only

Discussion

Please replace demonstrate with “suggest” or similar to void overreaching conclusions

Line 294-295 please rephrase “obese” to “with obesity” as you have in the rest of the submission

You may wish to rename the limitations section to “strengths and limitations”?

Table 1- please replace gender with sex

Suppl Table 3 VTE column contains line numbers, please correct this

Please remove page numbers from the PRISMA checklist and instead use paragraphs and sections as page numbers are likely to change

Should bariatric-metabolic surgery just be ‘bariatric’?

Line 360 please avoid assertions of primacy by adding ‘to our knowledge’

Comments from Reviewers:

Reviewer #2: Alex McConnachie, Statistical Review

The authors have satisfactorily addressed each of my original observations, and I have no further comments to make.

Reviewer #3: In my opinion, the manuscript has improved considerably after revision. I have no further questions or comments.

Any attachments provided with reviews can be seen via the following link:

[LINK]

22 Jun 2020

Dear Dr. Markar,

On behalf of my colleagues and the academic editor, Dr. Ronald Ching Wan Ma, I am delighted to inform you that your manuscript entitled "Association of bariatric surgery on all-cause mortality and incidence of obesity-related disease at a population level – systematic review and meta-analysis" (PMEDICINE-D-20-00372R3) has been accepted for publication in PLOS Medicine.

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Thank you again for submitting the manuscript to PLOS Medicine. We look forward to publishing it.

Best wishes,

Adya Misra, PhD

Senior Editor

PLOS Medicine

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