Association between metabolic surgery and cardiovascular outcome in patients with hypertension: A nationwide matched cohort study.

BACKGROUND: Hypertension, together with obesity, is a leading cause of mortality and disability. Whilst metabolic surgery offers remission of several metabolic comorbidities, the effect for patients with hypertension remains controversial. The objective of the present study was to evaluate the effect of metabolic surgery on cardiovascular events and mortality on patients with morbid obesity (body mass index [BMI] ≥ 35 kg/m2) and hypertension. METHODS AND
FINDINGS: We conducted a matched cohort study of 11,863 patients with morbid obesity and pharmacologically treated hypertension operated on with metabolic surgery and a matched non-operated-on control group of 26,199 subjects with hypertension (matched by age, sex, and area of residence) of varied matching ratios from 1:1 to 1:9, using data from the Scandinavian Obesity Surgery Register (SOReg), the Swedish National Patient Registers (NPR) for in-hospital and outpatient care, the Swedish Prescribed Drug Register, and Statistics Sweden. The main outcome was major adverse cardiovascular event (MACE), defined as first occurrence of acute coronary syndrome (ACS) event, cerebrovascular event, fatal cardiovascular event, or unattended sudden cardiac death. The mean age in the study group was 52.1 ± 7.46 years, with 65.8% being women (n = 7,810), and mean BMI was 41.9 ± 5.43 kg/m2. MACEs occurred in 379 operated-on patients (3.2%) and 1,125 subjects in the control group (4.5%). After adjustment for duration of hypertension, comorbidities, and education, a reduction in risk was seen in the metabolic surgery group (adjusted hazard ratio [HR] 0.73, 95% confidence intervals [CIs] 0.64-0.84, P < 0.001). The surgery group had lower risk for ACS events (adjusted HR 0.52, 95% CI 0.41-0.66, P < 0.001) and a tendency towards lower risk for cerebrovascular events (adjusted HR 0.81, 95% CI 0.63-1.01, P = 0.060) compared with controls. The main limitations with the study were the lack of information on BMI and history of smoking in the control group and the nonrandomised study design.
CONCLUSION: Metabolic surgery on patients with morbid obesity and pharmacologically treated hypertension was associated with lower risk for MACEs and all-cause mortality compared with age- and sex-matched controls with hypertension from the general population.

Introduction

Obesity is currently one of the major global health threats [1-3]. More than 700 million people in the world are estimated to have obesity, and in 2025, the worldwide prevalence is estimated to reach 18% amongst adult men and 21% amongst adult women [1, 4]. In several Caribbean and Middle East countries, the prevalence is already close to 50% in women [4]. As part of a metabolic syndrome, morbid obesity is associated with high rates of hypertension, dyslipidaemia, and impaired glucose tolerance, factors causing excess risk for cardiovascular events and premature mortality [1, 2, 5]. Metabolic surgery has been shown to reduce the risk for many serious sequelae of morbid obesity [6], and in many randomised trials and observational studies, there is abundant evidence for treating type 2 diabetes (T2DM) with metabolic surgery [7, 8].

Hypertension, together with high body mass index (BMI), is a leading cause of mortality and disability [3]. A combination of the two may also be associated with resistant hypertension and increased risk for organ damage [9]. Compared to T2DM, the effect of metabolic surgery on hypertension is less well studied. Observational studies suggest that remission rates of hypertension as high as 40% can be expected at midterm follow-up after metabolic surgery [10]. The only randomised trial evaluating the effect of metabolic surgery on hypertension is a small single-centre study demonstrating remission of hypertension in 51% of the surgically treated patients [11]. The effect of metabolic surgery on cardiovascular events and mortality remains unclear in patients with hypertension and morbid obesity.

The aim of the present study was to evaluate the effect of metabolic surgery on cardiovascular events and mortality in patients with morbid obesity and hypertension.

Methods

The Scandinavian Obesity Surgery Register (SOReg) is a nationwide register for bariatric and metabolic surgery, containing virtually all patients operated with metabolic surgery in Sweden since 2007 [12]. Data from this register were used to identify patients operated with primary gastric bypass or sleeve gastrectomy for morbid obesity. Patients younger than 18 years were excluded from the study. A 1:10 matched group of non-operated–on individuals, based on age, sex, and regional area of residence in Sweden, was created using Statistics Sweden by exact matching. Both cohorts (58,007 operated-on patients and 580,070 matched controls) were cross-linked with the Swedish National Patient Registers (NPR, based on ICD-10 diagnoses) for in-hospital and outpatient care [13], the Cause-of-Death Register [14], the Swedish Prescribed Drug Register (based on ATC codes) [15], and Statistics Sweden (https://www.scb.se). All follow-ups and definitions were relative to the date of surgery for both the intervention group and the matched controls. Subjects without hypertension and those with antihypertensive therapy possibly for other reasons were excluded from the study. Other reasons for such therapy included previous diagnosis of heart failure (ICD-10: I50) or cardiomyopathy (ICD-10: I42) treated with loop-diuretics (ATC code: C03C); heart failure treated with a beta-blocker (ATC code: C07AB02; C07AB07; C07AG02), ACE inhibitor (ATC code: C09A; C09B), or angiotensin II inhibitor (ATC code: C09C); and previous diagnosis of atrial fibrillation, flutter, or other tachycardia (ICD-10: I47 and I48) treated with a beta-blocker (ATC code: C07) or calcium antagonist (ATC code: C08D). Patients without at least 1 matched control with hypertension were also excluded from the study. This resulted in a matched cohort study with a varied matching ratio ranging from 1:1 to 1:9, including a group of 11,863 patients with hypertension operated on with metabolic surgery and a non-operated–on control group of 26,199 subjects with hypertension (Fig 1).

Fig 1

Flow chart.

Flow chart describing study inclusion.

Although an original study plan was decided on by the authors, it was not officially documented beforehand. In response to peer review, duration of hypertension was added as a covariate, and higher education was considered as 1 group instead of being divided into 2 categories. Stratified analyses of specific subgroups (any comorbidity, T2DM, previous acute coronary syndrome [ACS], and BMI lower or higher than 40 kg/m2) were also added as post hoc analyses. The STROBE reporting guideline was used to guide reporting in the paper (S1 Table).

Definition of covariates

Hypertension was defined as being prescribed antihypertensive medication (ATC code: C02, C03, C07, C08, or C09) within 18 months prior to surgery. Dyslipidaemia was defined as being prescribed medication for hyperlipidaemia (ATC code: C10) within 18 months prior to surgery. T2DM was defined as being prescribed antidiabetic medication (ATC code: A10) within 18 months prior to surgery. Patients prescribed insulin (ATC code: A10A) and diagnosed with type 1 diabetes (T1DM) in the NPR for in-hospital or outpatient care were considered to have T1DM. Chronic Obstructive Pulmonary Disease (COPD) was defined as admission for COPD or a complication of COPD with COPD as secondary diagnosis in the NPR for in-hospital care (ICD-10: J44) or prescription of an anticholinergic drug (ATC code: R03BB), long-acting beta-2 agonist (ATC codes: R03AC12–R03AC18), or a combination of these (ATC code: R03AL) indicating moderate to severe COPD [16]. Cerebrovascular disease was defined as subarachnoid haemorrhage (ICD-10: I60), intracerebral haemorrhage (ICD-10: I61), ischaemic stroke (ICD-10: I63), or acute cerebral event not specified as haemorrhage or ischaemia (ICD-10: I64) registered in the NPR for in-hospital or outpatient care. Previous ACS was defined as acute myocardial infarction (ICD-10: I21–I22) or unstable angina (ICD-10: I20.0) registered in the NPR for in-hospital care.

Sleep apnoea was defined as registration of sleep apnoea (ICD-10: G47.3) in the NPR for in-hospital or outpatient care.

Level of education was based on data from Statistics Sweden on highest completed education and classified as primary school (up to 9 years), secondary school (10–12 years of completed education), or higher education.

Procedure

The surgical technique for laparoscopic gastric bypass is highly standardised in Sweden, with the majority being an antecolic, antegastric, Roux-en-Y gastric bypass with a small (<25 mL) gastric pouch, an alimentary limb of 100 cm, and a biliopancreatic limb of 50 cm [17]. The sleeve gastrectomy procedure is less standardised but routinely performed using a 32–36 Fr bougie, starting resection no more than 5 cm from the pylorus, and ending 1 cm lateral to the angle of His.

Outcome

The main outcome was a major adverse cardiovascular event (MACE), defined as first occurrence of ACS (unstable angina or myocardial infarction), cerebrovascular event (subarachnoid haemorrhage, intracerebral haemorrhage, ischaemic stroke, or acute cerebrovascular disease not specified as haemorrhage or ischaemia), fatal cardiovascular event (cause of death ICD-10: I01–78, excluding I30), or unattended sudden cardiac death (ICD-10: R96.0, R96.1, R98, and R99) registered in the NPR for in-hospital care or the Cause-of-Death Register.

Secondary outcome measures were specific cardiovascular events defined as first episode of ACS, cerebrovascular event, all-cause mortality, cardiovascular mortality, and remission of hypertension. Remission of hypertension was defined as not being prescribed an antihypertensive between 24 and 48 months after surgery for subjects with follow-up of at least 48 months.

Statistical methods

Categorical values were presented as numbers and percentages, and continuous values as mean ± standard deviation or median with interquartile range (IQR) as appropriate. Time to first episode of MACE and time to death for all-cause mortality were estimated and visualised using the Kaplan–Meier method and presented as cumulative probability (Nelson–Aalen estimate). Cox regression for the matched cohort study was used to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for MACEs, ACS events, acute cerebrovascular events, all-cause mortality, and mortality for cardiovascular events. The chance of reaching remission of hypertension was estimated using both unadjusted and adjusted conditional Poisson regression with incidence rate ratios (IRRs) and 95% CIs as measures of association. All Cox regression and conditional Poisson regression analyses were both unadjusted as well as adjusted for comorbidity (dyslipidaemia, T1DM and T2DM, COPD, previous acute coronary event, previous cerebrovascular event, and sleep apnoea), duration of hypertension, and level of education. Proportional hazards assumption was tested using Schoenfeld residuals for all variables, and no violation was found. Potential risk factors related to remission of hypertension in the metabolic surgery group were also evaluated using a Poisson regression model, further adjusted for age, sex, surgical method, and excess BMI loss [(Initial BMI − postoperative BMI)/(Initial BMI − 25)]. Missing data were handled by listwise deletion.

IBM SPSS version 25 (IBM, Armonk, NY, USA) and Stata version 16.0 (StataCorp, College Station, TX, USA) were used for all statistical analyses.

Ethics

The study was approved by the Regional Ethics committee in Stockholm (ref: 2013/535-31/5, 2017/857-32, and 2018/664-32) and followed the standards of the 1964 Helsinki Declaration and its later amendments. No written consent was obtained from the study participants. However, in accordance with Swedish legislation, all participants were informed of the research and quality registry and that the data would be used in clinical research, giving the patients the right to deny participation.

Results

Compared to the control group, patients with metabolic surgery were slightly younger and more often had dyslipidaemia, diabetes, COPD, and sleep apnoea but a slightly lower incidence of cerebrovascular disease (Table 1).

Table 1

Baseline characteristics.

	Operated-on Group, N = 11,863	Non-Operated–on Control Group, N = 26,199
Age, mean ± SD	52.1 ± 7.46	54.6 ± 7.12
BMI, kg/m2, mean ± SD	41.9 ± 5.43	–
Sex
Male, n (%)	4,053 (34.2%)	9,338 (35.6%)
Female, n (%)	7,810 (65.8%)	16,861 (64.4%)
Education1
Primary education (≤9 years), n (%)	2,237 (18.9%)	4,998 (19.2%)
Secondary education (10–12 years), n (%)	6,795 (57.5%)	13,079 (50.2%)
Higher education, n (%)	2,791 (23.6%)	7,951 (30.5%)
Duration of hypertension
<1 year, n (%)	1,599 (13.5%)	3,090 (11.8%)
1–2 years, n (%)	1,175 (9.9%)	2,859 (10.9%)
>2 years, n (%)	9,089 (76.6%)	20,250 (77.3%)
Comorbidities
Dyslipidaemia, n (%)	4,437 (37.4%)	7,802 (29.8%)
T2DM, n (%)	3,328 (28.1%)	2,690 (10.3%)
T1DM, n (%)	676 (5.7%)	911 (3.5%)
COPD, n (%)	467 (3.9%)	571 (2.2%)
Previous acute coronary event, n (%)	531 (4.5%)	1,209 (4.6%)
Cerebrovascular disease, n (%)	274 (2.3%)	877 (3.3%)
Sleep apnoea, n (%)	1,789 (15.1%)	363 (1.4%)

1Missing information on highest completed education for 40 subjects in the operated-on group and 171 in the non-operated–on control group. There were no missing values for any of the remaining variables. Abbreviations: BMI, body mass index; COPD, Chronic Obstructive Pulmonary Disease; T1DM, type 1 diabetes; T2DM, type 2 diabetes

Amongst operated-on patients, 10,692 (90.1%) underwent a gastric bypass procedure and 1,171 (9.9%) a sleeve gastrectomy. In total, 11,428 operations were completed with laparoscopic technique (96.3%), 301 were primarily open procedures (2.5%), and 134 were converted to open surgery (1.1%). Mean follow-up time was 61.1 ± 30.4 months (1,834 ± 913 days) amongst operated-on patients and 60.7 ± 30.6 months (1,820 ± 918 days) for the non-operated–on group. Mean BMI before surgery was 41.9 ± 5.43 kg/m2 in the surgery group.

MACEs

An ACS event, cerebrovascular event, or cardiovascular death occurred in 379 operated patients (cumulative incidence at 3,000 days, 5.5%), and 1,125 subjects in the control group (cumulative incidence at 3,000 days, 7.3%) during the follow-up period. An MACE occurred for 17 patients operated on with sleeve gastrectomy (cumulative incidence at 3,000 days, 8.9%) and 362 patients operated on with gastric bypass (cumulative incidence at 3,000 days, 5.4%). Compared with the nonsurgical patients, the risk for an MACE was reduced by approximately one-fourth (unadjusted HR = 0.73, 95% CI 0.65–0.82, P < 0.001) in the metabolic surgery group. Cumulative hazard and adjusted risk for an MACE are presented in Fig 2 and Table 2, respectively. In a subgroups analysis, patients with BMI < 40 kg/m2 (unadjusted HR 0.86, 95% CI 0.71–1.04, P = 0.121; adjusted HR 0.73, 95% CI 0.58–0.92, P = 0.007), as well as those with BMI ≥ 40 kg/m2 (unadjusted HR 0.78, 95% CI 0.67–0.92, P = 0.003; adjusted HR 0.71, 95% CI 0.58–0.85, P < 0.001), experienced lower risk for MACEs compared with the control group.

Fig 2

Cumulative hazard for MACEs.

Cumulative hazard for an MACE comparing patients with hypertension operated on with metabolic surgery compared with a matched control group with hypertension from the general population (adjusted HR = 0.73, 95% CI 0.64–0.84, P < 0.001). CI, confidence interval; HR, Hazard ratio; MACE, major adverse cardiovascular event.

Table 2

Adjusted risk for MACEs.

	HR (95% CI)	Adjusted P	P for Trend*
Metabolic surgery	0.73 (0.64–0.84)	<0.001
Dyslipidaemia	0.98 (0.84–1.13)	0.766
T2DM	1.37 (1.15–1.63)	<0.001
T1DM	2.72 (2.12–3.49)	<0.001
COPD	1.88 (1.36–2.60)	<0.001
Previous acute coronary event	2.29 (1.83–2.87)	<0.001
Cerebrovascular disease	2.47 (1.93–3.16)	<0.001
Sleep apnoea	0.92 (0.70–1.21)	0.547
Duration of hypertension			0.154
<1 year	Reference	Reference
1–2 years	1.19 (0.87–1.62)	0.271
>2 years	1.21 (0.95–1.53)	0.122
Education
Primary education (≤9 years)	Reference	Reference
Secondary education (10–12 years)	0.83 (0.72–0.97)	0.020
Higher education	0.66 (0.53–0.83)	<0.001

Conditional Cox regression model evaluating risk for MACEs including all variables presented in the Table. Abbreviations: CI, confidence interval; COPD, Chronic Obstructive Pulmonary Disease; HR, hazard ratio; MACE, major adverse cardiovascular event; T1DM, type 1 diabetes; T2DM, type 2 diabetes

*No linear trend was found for using duration of hypertension as continuous variable. Likelihood ratio test was not statistically significant between the models using duration of hypertension as categorical variable and as continuous variable (P = 0.528).

Metabolic surgery resulted in a significantly reduced risk for an ACS event (HR 0.61, 95% CI 0.50–0.75, P < 0.001; adjusted HR 0.53, 95% CI 0.42–0.67, P < 0.001), whilst the effect of metabolic surgery on cerebrovascular events did not reach significance (HR 0.90, 95% CI 0.75–1.09, P = 0.283; adjusted HR 0.81, 95% CI 0.66–1.01, P = 0.063).

Mortality

In all, 472 patients (cumulative incidence at 3,000 days, 8.0%) in the operated-on group died during the follow-up period and 1,197 in the control group (cumulative incidence at 3,000 days, 8.6%); 108 patients died of a cardiovascular cause in the surgery group (cumulative incidence at 3,000 days, 2.1%) and 283 in the control group (cumulative incidence at 3,000 days, 1.9%). Metabolic surgery was associated with lower risk for all-cause mortality after adjustment for comorbidity and level of education (unadjusted HR 0.98, 95% CI 0.87–1.10, P = 0.760; adjusted HR 0.84, 95% CI 0.73–0.97, P = 0.017). No association was seen in the risk for cardiovascular mortality (unadjusted HR 1.02, 95% CI 0.81–1.29, P = 0.849; adjusted HR 0.94, 95% CI 0.71–1.25, P = 0.682).

Remission of metabolic comorbidity

A total of 10,090 patients and 22,064 controls were available for evaluation of hypertension remission rates. Amongst patients operated on with metabolic surgery, 30.7% (n = 3,096) did not take medication for hypertension at any time 2–4 years after surgery, compared to 9.2% (n = 2,034) in the control group (unadjusted IRR for achieving remission 2.82, 95% CI 2.66–3.98, P < 0.001; IRR for remission after adjustment for age, sex, comorbidity, duration of hypertension, and level of education 3.26, 95% CI 3.04–3.50, adjusted P < 0.001). In a subgroups analysis, patients operated on with metabolic surgery with BMI < 40 kg/m2 (unadjusted IRR 3.04, 95% CI 2.78–3.33, P < 0.001; adjusted IRR 3.72, 95% CI 3.32–4.17, P < 0.001), as well as those with BMI ≥ 40 kg/m2 (unadjusted IRR 2.67, 95% CI 2.47–2.88, P < 0.001; adjusted IRR 2.97, 95% CI 2.71–3.25, P < 0.001), had higher chances of remission of hypertension compared with the control group.

Data on weight trajectories 2 years after surgery were available for 6,594 patients (67.1% of potentially available patients), showing a mean excess BMI loss of 76.3 ± 24.6%, a mean BMI loss of 12.5 ± 4.5 kg/m2, and total weight loss of 29.5 ± 8.9%.

Higher age, dyslipidaemia, T1DM, previous ACS, and longer duration of hypertension were all associated with lower chance of remission of hypertension, whilst higher postoperative excess BMI loss was associated with higher chance of remission (Table 3).

Table 3

Adjusted IRRs for reaching remission of hypertension.

	IRR (95% CI)	P	P for Trend†
Age	0.98 (0.97–0.98)	<0.001
Male sex	0.97 (0.88–1.08)	0.589
Dyslipidaemia	0.80 (0.71–0.90)	<0.001
T2DM	1.04 (0.93–1.17)	0.495
T1DM	0.75 (0.57–0.97)	0.027
COPD	0.83 (0.64–1.07)	0.151
Previous ACS	0.49 (0.33–0.73)	<0.001
Cerebrovascular disease	0.84 (0.56–1.27)	0.406
Sleep apnoea	0.97 (0.84–1.11)	0.688
Duration of hypertension			<0.001
<1 year	Reference	Reference
1–2 years	0.83 (0.72–0.95)	0.008
>2 years	0.44 (0.40–0.50)	<0.001
Education
Primary education (≤9 years)	Reference	Reference
Secondary education (10–12 years)	0.95 (0.84–1.08)	0.439
Higher education	1.02 (0.89–1.18)	0.756
Excess BMI loss	2.15 (1.78–2.58)	<0.001
Surgical method
Gastric bypass	Reference	Reference
Sleeve gastrectomy	0.84 (0.67–1.06)	0.141

Poisson regression model including all variables in the Table. Abbreviations: ACS, acute coronary syndrome; BMI, body mass index; CI, confidence interval; COPD, Chronic Obstructive Pulmonary Disease; IRR, incidence rate ratio; T1DM, type 1 diabetes; T2DM, type 2 diabetes

†A linear trend was found for using duration of hypertension as continuous variable. Likelihood ratio test was not statistically significant between the models using duration of hypertension as categorical variable and as continuous variable (P = 0.080).

Before surgery, median numbers of antihypertensive drugs were 2 (IQR 1–3) in the surgery group (mean numbers of drugs 2.3 ± 1.18) and 2 (IQR 1–2) in the control group (mean numbers of drugs 1.9 ± 1.01). After surgery, the median number of drugs was reduced to 1 (IQR 0–2) in the surgery group (mean number of drugs 1.4 ± 1.29), whilst no major difference was seen in the control group (median number of drugs 2, IQR 1–3, mean 2.0 ± 1.22) (Fig 3).

Fig 3

Stacked histogram of numbers of antihypertensive drugs before and 2–4 years after surgery.

Stacked histogram for numbers of antihypertensive drugs before surgery and 2–4 years after surgery for hypertensive patients operated on with metabolic surgery compared with a matched control group from the general population with hypertension.

In total, 1,571 operated patients at the 4-year follow-up had been able to discontinue pharmacological treatment for dyslipidaemia (41.6%), compared to 827 (12.5%) of control subjects with dyslipidaemia at baseline (P < 0.001). Of those with T2DM at baseline, 1,806 operated patients (63.7%) were able to discontinue their pharmacological treatment, compared with 77 (3.5%) in the control group (P < 0.001) at the 4-year follow-up.

Discussion

Metabolic surgery was associated with lower risk for an MACE and overall mortality amongst patients with hypertension and obesity at baseline compared to a matched control group with hypertension from the general population. The main effect appeared to be a reduction of ACS events.

This reduction in risk is in line with that reported for the metabolic surgery group in general as well as for patients with T2DM [18-21]. A recent publication by Aminian and colleagues reported a reduction in the risk for MACEs and mortality in patients with T2DM that underwent metabolic surgery [20]. Comparison of effects of treatment in different populations and studies should be made with caution. Even so, data in the present study suggest that hypertensive patients in the surgery group experienced slightly lower reduction in the risk for an MACE as well as overall mortality compared to those with T2DM at baseline [20]. Yet, the preventive effect on ACS events appears to be higher in patients with hypertension compared with those with T2DM [20]. In contrast to the small risk reduction for cerebrovascular events reported for patients with T2DM [20], we could only demonstrate a tendency towards reduced risk for cerebrovascular events for the operated hypertensive patients. The major risk reduction for patients with hypertension thus appears to be more cardiovascular than cerebrovascular, which is in agreement with previous reports for patients with T2DM and morbid obesity [22]. Patients who suffer an ischaemic cerebrovascular event may, however, have fewer poststroke complications and better disability status, as demonstrated by Han and colleagues [23]. In addition to well-established risk factors and surgery or not, higher education was also associated with reduced risk for an MACE. This supports the previous findings that the risk for coronary heart disease is increased in patients with a low level of education, which was reported in a large mendelian randomisation study [24].

Because hypertension (in particularly in combination with obesity) is a major risk factor for an acute coronary event, remission of hypertension would seem a likely explanation for this preventive effect. Although the remission rate of hypertension was well in line with the rates reported for similar groups of patients [10, 25, 26], the 31% remission rate at 4 years in the present study was lower than that reported in the only randomised clinical trial to date on the subject, the GATEWAY trial [11]. The GATEWAY trial, however, was conducted on a healthier group of patients with lower BMI compared with the present study. The discontinuation and true remission of hypertension has recently been questioned [27], and indeed, relapse of hypertension amongst patients with early remission has been reported to be high [28]. The main benefit of metabolic surgery for patients with hypertension may thus not be remission of hypertension itself, but rather a combination of protective cardiometabolic effects. The effects of bariatric surgery on glucose metabolism and T2DM are well documented [7, 8, 20, 25], and the high remission rates of T2DM in the present study supports this. Furthermore, metabolic surgery has been reported to reduce the thickness of the media wall and pulse wave velocity, in particularly in patients with dyslipidaemia and hypertension [29]. Although dyslipidaemia was associated with lower chance of achieving remission of hypertension, the improvement in important comorbidities such as dyslipidaemia and T2DM signals a general improvement in overall cardiometabolic control after metabolic surgery. Metabolic surgery has also been reported to reduce general systemic inflammation as well as the development of atherosclerosis [30, 31]. With weight reduction being an important measure to prevent and treat hypertension, metabolic surgery may also transform the situation of the patient with poor response or resistance to pharmacological treatment for hypertension into a more benign situation, reducing the risk for development of organ damage [32, 33]. Many of these protective effects are likely to contribute to the lower risk for cardiovascular events as well as overall mortality seen in the present study.

In contrast to the higher hypertension remission rate seen after gastric bypass compared with sleeve gastrectomy in the SLEEVEPASS study [34] (51% for gastric bypass and 29% for sleeve gastrectomy), no difference was seen in the chance of achieving hypertension remission between gastric bypass and sleeve gastrectomy in the present study. Study groups in randomised clinical trials, however, are often highly selected, providing results that are more impressive than those seen in routine clinical practice [35, 36]. Moreover, the present study was not designed to compare the 2 surgical methods, which is why this result should be viewed with caution. Increasing age, dyslipidaemia, T1DM, and previous acute coronary events were all associated with lower chances of achieving remission of hypertension. As with remission of T2DM, patients with shorter duration of disease and those losing more weight had a higher chance of remission [37].

Metabolic surgery may not be the global solution to the obesity epidemic. However, with high blood pressure and obesity being two of the leading causes of mortality and morbidity worldwide [3], metabolic surgery should be considered an important part of treatment if available.

Strengths and limitations

This study was based on a large, nationwide cohort of patients with hypertensive controls matched by age, sex, and place of residence. Follow-up rates for the major outcomes were very high thanks to excellent registration in the national high-quality registers used. The main limitations, however, were the lack of data on BMI and history of smoking in the control group and the fact that this was not a randomised study. Despite the limitations of BMI as a measure of obesity and predictor of outcome after bariatric surgery [38], it remains an important part in the evaluation of candidates for bariatric surgery and is associated with increased mortality [39]. Although we have compensated for other known risk factors in the statistical evaluations, it is likely that the overall healthier patients in the control group may result in underestimation of treatment effects in the surgery group.

The study relied on pharmaceutical use in the definition of hypertension and comorbid disease, without accurate data on blood pressure levels at follow-up. Although all drugs evaluated in the study are prescribed (and thus included in the registers), we have no data on prescribed drugs not being taken by the patient. Noncompliance with recommended treatment is not uncommon even when treatment for disease such as hypertension is so important [40]. The remission rates (9.2% for hypertension and 12.5% for dyslipidaemia) in the control group may well represent noncompliance with medical treatment. Furthermore, duration of hypertension was introduced in the study as an amendment to the original study plan. We did not have data from a long enough period to evaluate separate, longer durations of hypertension. Although shorter duration was associated with higher chance of remission, the effects of longer duration could thus not be evaluated.

Finally, whilst the Swedish Cause-of-Death Register is generally regarded to be a high-quality register with virtually complete data, the historically low autopsy rates in Sweden may make definite cause of death more difficult to ascertain [14]. This could explain why no difference in cardiovascular mortality was seen between the groups despite the lower incidence of ACS events and all-cause mortality in the surgical group.

Conclusion

Metabolic surgery in patients with morbid obesity and hypertension decreases the risk for MACEs and all-cause mortality compared with age- and sex-matched hypertensive controls from the general population.

STROBE checklist.

STROBE, Strengthening the Reporting of Observational Studies in Epidemiology.

(DOC)

Click here for additional data file.

Cumulative risk for MACEs, stratified by T2DM.

For study participants with T2DM, cumulative incidence at 3,000 days was 6.8% for the surgery group and 10.3% for the control group. For study participants without T2DM, cumulative incidence at 3,000 days was 5.0% for the surgery group and 7.0% for the control group. MACE, major adverse cardiovascular event; T2DM, type 2 diabetes.

(TIF)

Click here for additional data file.

Cumulative risk for MACEs, stratified by presence of comorbidity other than hypertension.

For study participants with comorbidity, cumulative incidence at 3,000 days was 6.7% for the surgery group and 11.2% for the control group. For study participants without comorbidity, cumulative incidence at 3,000 days was 3.7% for the surgery group and 5.0% for the control group. MACE, major adverse cardiovascular event.

(TIF)

Click here for additional data file.

Cumulative risk for MACEs, stratified by preoperative ACS.

For study participants with previous ACS, cumulative incidence at 3,000 days was 18.1% for the surgery group and 18.8% for the control group. For study participants without previous ACS, cumulative incidence at 3,000 days was 4.8% for the surgery group and 6.8% for the control group. ACS, acute coronary syndrome; MACE, major adverse cardiovascular event.

(TIF)

Click here for additional data file.

4 May 2020

Dear Dr Stenberg,

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Kind regards,

Adya Misra, PhD,

Senior Editor

PLOS Medicine

4 Jun 2020

Dear Dr. Stenberg,

Thank you very much for submitting your manuscript "Association between metabolic surgery and cardiovascular outcome in patients with hypertension: a nationwide matched cohort study" (PMEDICINE-D-20-01660R1) 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.

In revising the manuscript for further consideration, your revisions should address the specific points made by each reviewer and the editors. 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. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments, the changes you have made in the manuscript, and include either an excerpt of the revised text or the location (eg: page and line number) where each change can be found. Please submit a clean version of the paper as the main article file; a version with changes marked should be uploaded as a marked up manuscript.

In addition, we request that you upload any figures associated with your paper as individual TIF or EPS files with 300dpi resolution at resubmission; please read our figure guidelines for more information on our requirements: http://journals.plos.org/plosmedicine/s/figures. While revising your submission, please upload your figure files to the PACE digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at PLOSMedicine@plos.org.

We expect to receive your revised manuscript by Jun 25 2020 11:59PM. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

***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.***

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Please use the following link to submit the revised manuscript:

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Your article can be found in the "Submissions Needing Revision" folder.

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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.

We look forward to receiving your revised manuscript.

Sincerely,

Emma Veitch, PhD

PLOS Medicine

On behalf of:

Adya Misra, PhD

Senior Editor

PLOS Medicine

plosmedicine.org

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Requests from the editors:

*In the last sentence of the Abstract Methods and Findings section, please briefly note some of the key limitation(s) of the study's methodology.

*It would be good to clarify in the paper if the analyses reported here were planned out prospectively in a pre-existing protocol or analysis plan? Please state this (either way) early in the Methods section.

a) If a prospective analysis plan (from your funding proposal, IRB or other ethics committee submission, study protocol, or other planning document written before analyzing the data) was used in designing the study, please include the relevant prospectively written document with your revised manuscript as a Supporting Information file to be published alongside your study, and cite it in the Methods section. A legend for this file should be included at the end of your manuscript.

b) If no such document exists, please make sure that the Methods section transparently describes when analyses were planned, and when/why any data-driven changes to analyses took place.

c) In either case, changes in the analysis-- including those made in response to peer review comments-- should be identified as such in the Methods section of the paper, with rationale.

*In the Methods section it would be good to add a note that the STROBE reporting guideline was used to guide reporting in the paper and there to call out the supporting information file that corresponds to the STROBE checklist.

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Comments from the reviewers:

Reviewer #1: Association between metabolic surgery and cardiovascular outcome in patients with hypertension: a nationwide matched cohort study shows not only new, but very interesting data about a controversial issue in Metabolic Surgery, the impact on hypertension.

I have some comments and I hope they can improve your manuscript.

MAJOR

1. Lack of data on BMI is a critical issue about your manuscript. Revising other papers based on Sweden's registers, they showed the control group's BMI. Why do you not have it?

2. Data about smoking would be very important. Do you have it?

MINOR

1. In the abstract, the adjustment was made for more than one comorbidity. You should correct to comorbidities.

2. In methods: "The Scandinavian Obesity Surgery Register (SOReg) is a nationwide register for metabolic surgery" I suggest including Bariatric and Metabolic surgery.

3. When you cite ICD-10 and ATC-codes in the Definition of covariates, you should make clear from which coding system they are.

4. In the Outcome, do you think that it is necessary to include the ICD-10 codes? I suggest deleting them to make the text clearer.

5. Table 1 should include the BMI.

6. The follow-up time should be expressed in months. You can maintain days between parentheses.

7. Table 2 is a little confusing for me. Patients with T2DM submitted to Metabolic Surgery, for example, have more risk of MACE than control groups?

8. Although it is not the objective of your manuscript, can you show the other causes of mortality?

9. After the first appearance of type-1 and type-2 Diabetes Melitus you should use T1DM and T2DM that are frequently used in many manuscripts.

10. References: The 3-years results from GATEWAY were presented at AHA and the abstract is published, and you can include the results:

Schiavon CA, Bhatt DL, Santucci EV, Oliveira JD, Santos RN, Damiani LP, Machado RH, Noujaim PM, Halpern H, Monteiro FJ, Sousa MG, Amodeo C; Bortolotto L, Ikeoka DT, Cavalcanti AB, Berwanger O, Drager LF. Effects of Bariatric Surgery in Patients With Hypertension: 3-Year Outcomes From the Randomized GATEWAY Trial. Circulation. 2019;140:e972. DOI: 10.1161/CIR.0000000000000742.

Sincerely,

Carlos Aurelio Schiavon

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Reviewer #2: Thank you very much for the opportunity to review this manuscript.

Overall, this is an interesting manuscript investigating a relevant topic for many patients, The paper is in line with many prior publications of the Scandinavian Obesity Surgery Register linked with national healthcare databases.

The manuscript is well-written, nicely prepared and clearly presented. It further supports the value of metabolic surgery in the treatment of a variety of comorbidties of metabolic diseases. However, there are some major issues with the underlying data (registry based and linking of many national databases using ICD-codes) which are acknowledged by the authors and can unfortunately not be addressed. Despite these limitations, I support the acceptance of the paper after revisions. The value of this paper is that it investigates for the first time patients specifically with hypertension independent of underlying comorbidities except obesity in a large cohort.

1. Also, if you have a relevant number of patients with a BMI <35kg/m2, could you provide the outcome stratified for these low-BMI patients? This questions would be of interesting to know and provide some answers if metabolic surgery is also of value in patients with BMI <35kg/m2. If you do not have these data, than you may be able to make an analysis comparing patients with BMI > and <40kg/m2. I do think that the notion that excess weight loss is associated with more hypertension remission should be related to with the preoperative BMI because EWL depends on the preoperative weight.

2. Could you provide a subgroup analysis for the following subgroups to better define which patients benefit as outlined below including figures like Fig. 2? It would be interesting to know whether one of the subgroup benefits in particular from metbalic surgery or if all benefit equally.

a. Patients with or without diabetes?

b. Patients with prior cardiac incident (prior MACE)

c. Patients without any known comorbidities

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Reviewer #3: I confine my remarks to statistical aspects of this paper. The general approach is fine but I have some issues to resolve before I can recommend publication.

p. 5 Why was a 1 to 10 matching chosen? How was the matching done? Much more detail is needed. (There are tons of ways to do matching)

p. 6 There is a typo People with 10 years of education don't fall in any category.

Why this division for education? In particular, why < 3 vs. > 3 years of higher ed? Are college degrees usually 3 years in Sweden? Why not degree vs. not?

p 10 Don't categorize years of hypertension. Categorizing continuous variables is nearly always a mistake. In *Regression Modeling Strategies* Frank Harrell lists 11 problems with this and sums up "nothing could be more disastsrous" Instead, leave years as years and use a spline to investigate nonlinearity

The referennce category for education needs to be specified.

In the limitations, you should note the problems with BMI as a measure of obesity., See e.g. this blog post I wrote: https://medium.com/peter-flom-the-blog/why-bmi-is-a-bad-measure-of-obesity-and-what-is-better-f8a62fc9ca49?source=friends_link&sk=4b2ea559ab12853beb577764f83d151a

Figure 3 Don't use stacked bar charts (see the work of William S. Cleveland). I think a mosaic plot might be good here, but it depends on what you are trying to show.

Peter Flom

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

[LINK]

17 Jun 2020

Submitted filename: response_hypertension.docx

Click here for additional data file.

9 Jul 2020

Dear Dr. Stenberg,

Thank you very much for re-submitting your manuscript "Association between metabolic surgery and cardiovascular outcome in patients with hypertension: a nationwide matched cohort study" (PMEDICINE-D-20-01660R2) 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.

We expect to receive your revised manuscript within 1 week. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

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 Jul 16 2020 11:59PM.

Sincerely,

Adya Misra, PhD

Senior Editor

PLOS Medicine

plosmedicine.org

------------------------------------------------------------

Requests from Editors:

Abstract

Background-please add a bit more context to illustrate the importance of this study

Please provide participant demographics

Please change “morbidly obese” to “patients with morbid obesity” in line with the principles of people first language. The same goes for “hypertensive” which should be revised to “with hypertension”

Author summary

Please change hypertensive to patients with hypertension

Line 90 probably doesn’t need a question mark

Comments from Reviewers:

Reviewer #1: Association between metabolic surgery and cardiovascular outcome in patients with

hypertension: a nationwide matched cohort study.

I would like to thank the authors for the responses and the improvement of the manuscript.

I still have some questions to you:

1. I understood that you do not have power to compare the two surgical techniques, but can you show the data about ACS events for each technique?

2. I still have a problem with Table 2. You answered me that it is an analysis of the entire cohort, but the legend says matched cohort, what for me represents the control group. Please revise it.

3. The definition of remission of a comorbidity is a controlled disease without an active treatment. You did not show the data about blood pressure and, because of that, I am a little concerned about the remission rate based only in patients who were not taking medications. If you have the data about blood pressure, you should show it. If not, I think it is better to address this issue in the limitations.

4. I still think that showing the others causes of mortality will enrich your paper, but I understood your point and I will let this decision to the Editor.

5. Unfortunately, I did not find the supplement Figures in the manuscript.

Carlos Aurelio Schiavon

Reviewer #2: Thank you for the revised manuscript. My comments and the other comments have been well addressed in my opinion.

However, there are 2 minor points:

1. I was not able to find the supplemental figures in the files

2. I think there is a labeling mistake in Fig. S4, second paragraph: I think it should be "without previous acute coronary syndrome" instead of type-2-diabetes.

Reviewer #3: The authors have addressed my concerns and I now recommend publication

Peter Flom

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

[LINK]

21 Jul 2020

Submitted filename: rebutal_hypertoni2.docx

Click here for additional data file.

30 Jul 2020

Dear Dr. Stenberg,

On behalf of my colleagues and the academic editor, Dr. Carlos Schiavon, I am delighted to inform you that your manuscript entitled "Association between metabolic surgery and cardiovascular outcome in patients with hypertension: a nationwide matched cohort study" (PMEDICINE-D-20-01660R3) 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

plosmedicine.org