*Review* **Factors Related to Weight Loss Maintenance in the Medium–Long Term after Bariatric Surgery: A Review**

**Isabel Cornejo-Pareja 1,2,3, María Molina-Vega 1,2,\*, Ana María Gómez-Pérez 1,2,\*, Miguel Damas-Fuentes 1,2 and Francisco J. Tinahones 1,2,3**


**Abstract:** Despite bariatric surgery being the most effective treatment for obesity, some individuals do not respond adequately, especially in the long term. Identifying the predictors of correct weight maintenance in the medium (from 1 to 3 years after surgery) and long term (from 3 years and above) is of vital importance to reduce failure after bariatric surgery; therefore, we summarize the evidence about certain factors, among which we highlight surgical technique, psychological factors, physical activity, adherence to diet, gastrointestinal hormones or neurological factors related to appetite control. We conducted a search in PubMed focused on the last five years (2015–2021). Main findings are as follows: despite Roux-en-Y gastric bypass being more effective in the long term, sleeve gastrectomy shows a more beneficial effectiveness–complications balance; pre-surgical psychological and behavioral evaluation along with post-surgical treatment improve long-term surgical outcomes; physical activity programs after bariatric surgery, in addition to continuous and comprehensive care interventions regarding diet habits, improve weight loss maintenance, but it is necessary to improve adherence; the impact of bariatric surgery on the gut–brain axis seems to influence weight maintenance. In conclusion, although interesting findings exist, the evidence is contradictory in some places, and long-term clinical trials are necessary to draw more robust conclusions.

**Keywords:** bariatric surgery; weight regain; surgical technique; psychological disorders; physical activity; diet; gut hormones; gut–brain axis

#### **1. Introduction**

Obesity is defined as the pathological increase in adipose tissue associated with chronic low-grade inflammation and an increased risk of many pathological conditions such as type 2 diabetes mellitus (T2DM), cardiovascular disease, or cancer [1,2]. It is considered an epidemic disease and is expected to affect 44% of the adult population of the USA in 2031 and 31% of the adult population of Europe in 2037 [3].

The first-line treatment for obesity is lifestyle intervention, including a healthy diet and physical activity to produce a negative energy balance [2]. In those patients with moderaterisk or high-risk obesity, pharmacological therapy is indicated [2]. A weight loss of 5–10% can be easily attained and maintained for a time by lifestyle modification programs and anti-obesity medications. However, the weight usually recovers progressively from the first year after the intervention onwards [4].

Bariatric surgery is the most effective treatment for weight loss and weight-loss maintenance. Weight loss with bariatric surgery can reach 50–75% of excess body weight

**Citation:** Cornejo-Pareja, I.; Molina-Vega, M.; Gómez-Pérez, A.M.; Damas-Fuentes, M.; Tinahones, F.J. Factors Related to Weight Loss Maintenance in the Medium–Long Term after Bariatric Surgery: A Review. *J. Clin. Med.* **2021**, *10*, 1739. https://doi.org/10.3390/jcm10081739

Academic Editors: David Benaiges Boix and Giuseppe Nisi

Received: 25 February 2021 Accepted: 9 April 2021 Published: 16 April 2021

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**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

(EBW) and can be maintained 10 years later [4]. Nevertheless, the efficacy of bariatric surgery is not uniform between patients, with some of them not obtaining satisfactory weight loss from the beginning (primary non-responders) or regaining weight in the long term (secondary non-responders) [5].

In this review, we will focus on the factors that influence weight loss in the medium– long term after bariatric surgery.

#### **2. Surgical Technique**

Since Edward Mason reported effective weight loss after the first gastric bypass in the mid-1960s, many bariatric procedures such as jejunoileal bypass, vertical banded gastroplasty, and laparoscopic adjustable gastric band (LAGB) have been used and later abandoned because of adverse events or inadequate long-term efficacy [6,7]. In 1994, the first report of the use of the laparoscopic technique was a landmark in bariatric surgical care as laparoscopic surgery reduces postoperative pain, time recovery, wound infection, and late ventral hernia formation in comparison to conventional techniques [6]. Nowadays, the most frequently performed bariatric procedures are laparoscopic Roux-en-Y gastric bypass (RYGB) and, especially, laparoscopic sleeve gastrectomy (SG), which accounts for 61% of primary bariatric procedures in the USA [7]. Therefore, we are going to analyze the evidence (clinical trials and meta-analysis) in the last 5 years comparing RYGB and SG regarding weight loss in the medium–long term.

In a recent meta-analysis, including 7443 patients from 23 studies, Hu et al. [8] found that there was no difference in excess weight loss (EWL)% between RYGB and SG in the short term (3 months–2 years), but RYGB was superior to SG in the mid-term (3 years) and long term (5 years) after surgery. However, RYBG showed more late complications than SG. Previously, Yang et al. [9] found similar results in a meta-analysis of 15 randomized controlled trials (1381 patients), concluding that SG and RYBG were similar regarding weight loss at <3 years but that EWL% was greater with RYBG 5 years after surgery, although with a higher incidence of complications. Other smaller meta-analyses found comparable results [10,11]. Likewise, King et al. [12] reported that weight regain seems to be higher after SG in comparison to RYGB. Conversely, other authors have concluded that there is no difference in weight loss between SG and RYBG at 1 year [13,14] and at 3 years [14,15] after surgery. Data from 10 or more years show that RYGB is able to maintain substantial weight loss, but data on SG are insufficient for a meta-analysis [16].

Results from clinical trials comparing weight loss between SG and RYGB published in the last 5 years are compiled in Table 1.

The Sleeve vs. Bypass (SLEEVEPASS) trial was a multicenter, multisurgeon, openlabel randomized trial whose main aim was to determine if SG and RYGB were equivalent for weight loss in 240 patients. At five years since surgery, it was observed that EWL% after SG was 49% and after RYGB 57%, and this difference was not statistically significant despite that higher weight loss was achieved with RYGB [17]. Similar results were maintained at 7 years after surgery [18]. Regarding obesity co-morbidities, SG and RYGB were similar in T2DM remission and dyslipidemia resolution, where RYGB was better than SG in hypertension resolution at 5 years [17]. At 1 year after surgery, both Hofsø et al. [19] and Murphy et al. [20] reported RYGB to be superior to SG for weight loss (total weight loss 29% vs. 23%; *p* < 0.001 and EWL% 84.2% vs. 70.2%, *p* = 0.002, respectively). However, the primary outcome of these trials was T2DM remission, not weight loss, and although Hofsø et al. [19] found a higher remission of T2DM in RYGB in comparison to SG, Murphy et al. [20] observed both surgical procedures to be similar. In a small clinical trial, Schneider et al. [21] reported a higher EBMIL% (excess body mass index loss) with RYGB in comparison to SG (76.4% vs. 64.4%, *p* = 0.046) after 17 ± 5.6 months of follow-up. However, they also compared both surgical techniques regarding body composition and resting energy expenditure, not finding significant differences. In the Swiss Multicenter Bypass or Sleeve Study (SM-BOSS) trial, Peterli et al. [22,23] reported similar EBMIL% when comparing SG and RYGB at 1, 2, 3, and 5 years after surgery. Similarly, no statistically significant differences were observed between one anastomosis gastric bypass and SG at 1 year [24] and 3 years [25] after surgery. On the contrary, as that reported in the meta-analysis performed by Hu et al. [8], Ignat et al. [26] showed that, although EWL% was similar between SG and RYGB in the short term, a higher EWL% was achieved with RYBG vs. SG in the medium-term (at 3 years: 83% vs. 66.3%, *p* = 0.024) and long-term (at 5 years: 74.8% vs. 65.1%, *p* = 0.045) follow-up.


**Table 1.** Comparative clinical trials: SG vs. RY/OAGB.

SG: sleeve gastrectomy; RYGB: Roux-en-Y gastric bypass; OAGB: one anastomosis gastric bypass; T2DM: type 2 diabetes mellitus; EWL: excess weight loss; TWL: total weight loss; EBMIL: excess body mass index loss. GB > SG: gastric bypass better than sleeve gastrectomy; GB = SG: gastric bypass similar to sleeve gastrectomy.

> In summary, despite many studies concluding that SG and RYGB are comparable at weight loss in the medium and long term, other studies have found RYGB to be better than

SG regarding this outcome and also in obesity-related co-morbidities (such as T2DM or hypertension, between others) resolution. However, SG seems to produce fewer complications than RYGB. Maybe new clinical trials [27] will be able to tip the balance in favor of RYBG or confirm the equivalence of both surgical procedures in weight loss at medium and long term.

#### **3. Psychological Factors**

Psychological difficulties and poorly treated mental health can negatively affect the results of bariatric surgery [28]. Mood, emotional dysregulation, depression, poor health literacy, and deficits in executive functioning, attention, and memory skills, among others, are likely to be important barriers to effective maintenance of weight loss [29], consistently finding deficiencies of these skills in the obese population compared to lean people [30].

A growing body of evidence suggests that deficits in executive function are common in obesity [31,32], finding a constant inverse association between obesity and executive function in children, adolescents, and the adult population [33].

Obese subjects show a pronounced impairment in decision-making and real-life learning in terms of reward and punishment (by the Iowa gambling task (IGT)) [34], and impaired central coherence (processing style centered on the details) that makes it impossible for them to see the "big picture" in a similar way to patients with anorexia nervosa [35,36]. In addition, the obese subject is impulsive and has poor performance on tests of global cognitive function and memory [37]. These deficits in executive function are considered the cause of inappropriate attitudes towards food and represent a trigger for both eating disorders and changes in BMI [38]. Likewise, obese individuals show an unregulated physiological response to intense emotion by tending to increase their food intake during periods of emotional arousal and/or stress, a response known as emotional eating [39]. However, the nature of this obesity-associated cognitive decline is unclear. Different explanations have been proposed including factors driven by inflammation, dopamine dysregulation implicated in hyperphagia, vascular diseases or neuroendocrine changes in ghrelin and leptin [40–42].

#### *3.1. Cognitive Impairment*

The presence of cognitive impairment in the obese subject can be particularly problematic in the population undergoing bariatric surgery, given the many lifestyle changes required after it. Up to 23% of subjects undergoing bariatric surgery have clinically significant cognitive impairment, and approximately 40% have more subtle cognitive deficits [43]. Such deficiencies in executive function have been associated with maladaptive eating behaviors, including uncontrolled or uninhibited eating along with sedentary behaviors, and may contribute to suboptimal weight loss after bariatric surgery [44] Spitznagel et al. found that preoperative baseline cognitive impairment predicted the outcome of weight at one year after bariatric surgery (RYGB) in 84 obese individuals. Poorer initial cognitive function in the domains of executive ability, attention, and memory predicted a lower percentage of weight loss and higher BMI at 12 months after bariatric surgery. Impairments in memory or executive function could interfere with the patient's ability to plan and follow postoperative guidelines for successful maintenance of weight loss [45]. Furthermore, cognition has been shown to improve shortly after bariatric surgery [46], and this initial improvement appears to be of substantial importance in its predictive ability for sustained weight loss. Supporting this notion, Spitznagel and colleagues [47,48] found that early postoperative cognitive dysfunction (at 12 postoperative weeks) predicted progression at 24 and 36 months. Poorer performance on cognitive tests at 12 weeks (lower performance in executive ability, attention, and memory) was indicative of a reduction in weight loss at 2- and 3-year follow-up after bariatric surgery. In this sense, Alosco et al. [49] evaluated 50 obese subjects who underwent RYGB, finding early cognitive benefits (12 weeks) that were generally maintained up to 36 months after surgery. Interestingly, it was observed in this work that the reduction in the domain of attention 24-36 months after the intervention

was associated with weight recovery in this time. Kulendran et al. [50] in a study with 45 patients found that impulsivity measured as an inhibitory control of executive function together with the type of surgery (most effective RYGB vs. SG) were able to predict weight loss 6 months after bariatric surgery. The results found regarding the relationship between weight loss and executive performance in bariatric surgery may suggest that a reduction in body fat favors an improvement in executive function as a consequence of the resolution of metabolic alterations related to obesity. Likewise, a lower cognitive deficit at the beginning would lead to improvements in eating habits linked to a greater reduction in BMI, as we have seen. Similarly, cognitive function seems to be related to the durability of weight loss after bariatric surgery [47,48]. The cognitive skills that seem to best predict the results of weight loss included memory (particularly recognition memory) and executive functions (specifically working memory and generativity), and adherence behaviors could be the likely mechanism by which cognitive dysfunction leads to poorer performance in reducing long-term weight loss in bariatric surgery [33]. However, Bergh et al. [51], after evaluating 230 who underwent RYGB, found that while certain psychological factors such as selfesteem, planning, disposition to change behavior, or depressive symptoms, among others, were related to postoperative adherence to dietary recommendations and physical exercise. However, no associations were found in relation to weight loss one year after surgery.

#### *3.2. Eating Disorders*

Another important point in the failure of weight loss after bariatric surgery is related to the presence of eating disorders (EDs). Recent studies [52,53] have reported a higher prevalence of EDs among patients undergoing bariatric surgery with weight regain, with binge eating disorder especially prevalent in this population [54]. Conceição et al., [53] in a longitudinal study, found that up to 65% of patients who experienced weight regain between 17 and 20 months after surgery (both LAGB or RYGB) suffered from ED postoperatively. Furthermore, other studies have emphasized the role of other ED such as emotional eating, night eating syndrome (NES), or picking and nibling (P&N) in the results of bariatric surgery and how they contribute to suboptimal weight loss [55].

#### *3.3. Depression*

The reciprocal, longitudinal link between depression and obesity has been demonstrated in different studies [56]. Nevertheless, the exact nature of the relationship between depression and maintenance of obesity remains unclear, perhaps because clinical depression is a common exclusion criterion in weight loss intervention trials [57].

A recent meta-analysis [58] provides evidence for bariatric surgery, finding a reduction in depression symptoms at 6, 12, and 24 months after surgery. However, these symptoms increased after 36 months in a similar way to the baseline situation. Similar studies showed that improvements in depressive symptoms after bariatric surgery may not be maintained after 1–3 years after surgery, worsening again as in the starting point [59]. Weight regain and depression after surgery can act as a mutual risk factor. A depressed mood is associated with unhealthy lifestyle habits, emotional eating and loss of eating control [60], and weight regain after bariatric surgery [58,60,61]. Novelli et al. [62] found a higher score on emotional eating in obese women who underwent RYGB with insufficient weight loss 2 years after surgery. Feig et al. [63], in a cross-sectional study of 95 subjects undergoing RYGB and SG mainly, suggested that positive psychological states (positive affect or optimism) could be relevant in the state of well-being after bariatric surgery, finding greater adherence to healthy behaviors, physical activity, and weight loss. However, these associations lost statistical significance when factors such as depression were included.

#### *3.4. Impulsive Behavior*

Loss-of-control (LOC) eating is a common characteristic among subjects undergoing bariatric surgery [64], especially widespread in the adolescent population [65], and is associated with poorer weight outcomes. Goldschmidt et al. [64,66] and White et al. [67] determined that postoperative LOC eating constitutes a phenotype that negatively affects the weight result, being prospectively related to greater long-term weight recovery after RYGB, while pre-surgical eating LOC was not related to changes in post-surgery BMI. The rates of LOC eating decreased in the period immediately after surgery (6 months) compared to baseline; however, these rates increased gradually over time (2–4 years) after surgery.

#### *3.5. Other Psychological Factors*

It has been investigated whether different personality types predict the results of weight after bariatric surgery, without being able to draw clear conclusions. While some showed no influence in this regard [68], Gordon et al. found that they could influence the amount of weight loss at 2 years of RYGB [69].

In conclusion, multiple physicological factors are related to weight loss after bariatric surgery. An integrative and multiple approach that includes pre-surgical psychological and behavioral evaluation along with post-surgical treatment can be corrective for weight regain and persistence of obesity. In addition, addressing depression and executive deficits before and after bariatric surgery is needed to improve long-term surgical outcomes. Future research should further explore the best way to consider cognitive deficits in preoperative detection and follow-up of candidates for bariatric surgery.

#### **4. Physical Activity**

National Institute for Health and Care Excellence (NICE) [70] recommends that the postoperative follow-up of the obese patient should incorporate counseling and support for physical activity.

#### *4.1. Lack of Adherence to Exercise Training in Bariatric Surgery Patients*

People with severe obesity can, generally, safely exercise vigorously [71]; however, candidates for bariatric surgery are generally less active than normal-weight subjects [72]. Additionally, candidates for bariatric surgery are more sedentary than the general obese population. Likewise, of all postoperative recommendations, those related to physical activity are commonly the most non-compliant [73]. King et al. [74] examined the physical activity of 310 patients who underwent bariatric surgery through the use of accelerometers, finding that most of the subjects increased their level of physical activity 1 year after bariatric surgery (RYGB mainly and other techniques included such as LAGB, SG, banded gastric bypass, or biliopancreatic diversion with duodenal switch) compared to baseline. However, most remained with poor physical activity according to the American Diabetes Association and the American College of Sports Medicine (<150 min per week), and some even decreased their activity compared to baseline. Bond et al. [75] compared selfreported estimates of physical activity vs. those based on objective measurements by an accelerometer in 20 patients who underwent bariatric surgery (65% LAGB and 35% RYGB) 6 months after surgery. Although in the postoperative period 55% of the participants self-reported adherence to the physical activity recommendations, only 5% were objectified by accelerometer measurement, with the changes in physical activity of moderate to vigorous intensity being much smaller than the self-reported. Ouellette et al. [76] also found no changes in early postoperative physical activity compared to baseline in subjects undergoing bariatric surgery (29% RYGB and 71% SG), with no correlation between the levels of physical activity self-reported by the patient and those observed by accelerometry. In addition, participants failed to adhere to the minimum recommended physical activity (150 min per week of moderate to vigorous intensity physical activity). Taken together, these data suggest that a high proportion of patients after bariatric surgery do not increase their physical activity, and some even decrease it, identifying a relevant area of intervention.

#### *4.2. Aerobic and Resistance Training*

Increased physical activity has been associated with greater weight loss after bariatric surgery [77–84]. Furthermore, close supervision and monitoring of exercise programs support greater weight loss compared to minimally supervised programs [85]. Egberts et al. [78] in a systematic review of observational studies (on 3852 patients) found a relationship between increased physical exercise (measured by physical activity questionnaires) and weight loss after bariatric surgery (LAGB and RYBG). In addition, the meta-analysis showed an average of 3.62 kg of greater weight loss with the practice of physical activity.

#### 4.2.1. Aerobic Training

Carnero et al. [77] in a study carried out on 96 patients who underwent bariatric surgery (RYGB), monitored physical activity and effects on weight and body composition according to a 6 month structured exercise program, observing greater weight loss and more favorable body composition (less fat mass and greater muscle mass) in patients who performed moderate physical activity and decreased sedentary time. Furthermore, patients in the highest quartiles of physical activity achieved greater reductions in adiposity, reporting a dose–response association between exercise time and adiposity, already revealed by previous studies. In this sense, Woodlief et al. [86] demonstrated that patients who performed a greater amount of exercise (286 ± 40 min per week) after RYGB were those who obtained the greatest loss of weight and body fat compared to those who performed less physical activity. However, other studies have not supported this finding [87–90]. Coen et al. [88] examined the efficacy of a physical exercise program (120 min/week of treadmill walking for 6 months) in severely obese subjects, not observing any additional impact on RYGB-induced weight loss or fat mass. These findings are similar to those of Shah et al. [89] who showed how the prescription of a high-volume exercise program (energy expenditure in exercise > 2000 Kcal/week) with bariatric surgery (70% GB and 30% RYGB) at least 3 months earlier had no impact on the body weight or circumference of waist compared to the control group. The lack of effect of exercise on weight in these studies is probably due to the strong initial influence of surgery; thus, these data do not rule out the possibility that an exercise program may cause additional weight loss and improve body composition or adiposity favorably after surgery. Furthermore, after the initial large loss, weight tends to stabilize, and the long-term sustainability of this weight loss is probably more related to lifestyle changes such as avoiding sedentary behavior and regular physical activity [90].

#### 4.2.2. Combination of Aerobic and Resistance Training

A randomized clinical trial introducing a 12-week structured and supervised physical exercise program in 24 post-bariatric surgery (surgical technique not specified) patients (at 12-24 months later) and 12 controls with the same characteristics demonstrated improvements in capacity/physical function and weight, among other parameters [91]. In this sense, Rothwell and colleagues [79] reported that weight loss after a semi-structured exercise program at 12 months of bariatric surgery (LAGB) improved, without observing this effect at 36 months. Hanvold and colleagues [81] found that patients undergoing RYGB who reported physical activity ≥150 min/week had a lower percentage of weight regain compared to less active participants. However, they found no differences when comparing the diet and physical activity-focused lifestyle intervention group vs. the usual care group at long-term (2 years). Coleman et al. [90] found that a structured post-bariatric exercise program improves the physical capacity of patients (strength, balance, flexibility, mobility, coordination) at 6–24 months post-surgery (GS, RYGB, LAGB), without finding additional effects on weight loss.

A recent meta-analysis [80] of 15 exercise training studies (aerobic training in 5 studies, resistance training in 2 studies, and a combination of aerobic and resistance training in 8 studies) also concluded that physical training programs carried out after bariatric surgery (RYGB and SB mainly) were effective in optimizing the loss of weight and fat mass and improving the physical condition of the patients, although no additional effect on lean mass loss was described.

#### *4.3. Maintenance of Muscle Mass*

The maintenance of muscle mass is vital to optimize physical functioning and preserve energy expenditure at rest. The latter represents 60–70% of total energy expenditure [70], finding greater reductions and less recovery of visceral abdominal fat when it is included physical exercise in weight loss programs [92]. Loss of fat free mass (FFM) can predispose to long-term weight regain. Metcalf et al. [93] found that duodenal switch surgery in patients adhering to an exercise program (30 min per session, with > 3 sessions a week) achieved 28% more loss of fat mass and 8% more gain of lean mass compared to sedentary patients at 18 months postoperatively. A systematic review by Chaston et al. [94] suggests that loss of FFM (skeletal muscle, bone, and organs) represents a weight percentage of 31.3% of weight loss after RYGB. Although the significance of the loss of this FFM is not well known, excessive loss may be undesirable. Specifically, in older patients, the loss of muscle mass and bone mineral density may have a negative impact on their physical function, sarcopenia, and quality of life [95]. Physical exercise, and specifically endurance exercise, is effective in maintaining muscle mass [96].

In summary, despite that physical activity programs after bariatric surgery have been shown to be associated with a higher weight loss and a more beneficial body composition, most patients do not increase, and may even decrease, physical activity. However, most of the papers refer to the early postoperative stages, and the evidence is very limited in the long term. More interventional clinical trials with long-term structured exercise programs are needed to determine whether exercise is important in preventing weight regain in bariatric surgery patients.

#### **5. Dietary Factors**

In the bariatric population in particular, the diet is often poor, and caloric intake often increases progressively after bariatric surgery [97]. Sawer et al. [98] found an increase in caloric intake 2 years after bariatric surgery compared to the first 5 months (1172.9 ± 46.5 Kcal/day vs. 1358.1 ± 60.5 Kcal/day), finding greater weight loss and maintenance in those with greater dietary adherence.

In the National Weight Control Registry (NWCR), a large-scale prospective study to investigate the maintenance of long-term weight loss, among the dietary strategies adopted for the stable maintenance of weight loss, the following stand out: Adherence to a low-calorie and low-fat diet, eating breakfast regularly, and maintaining a consistent eating pattern throughout the week [99]. However, the literature on dietary advice to improve weight after bariatric surgery is limited. In addition, the studies in this regard present a small sample size, as well as heterogeneity of dietary support, settings, times, duration, type of surgery, etc.

The main macronutrients in food (carbohydrates, proteins, and fats) stimulate oxygen consumption in different ways, which can influence changes in body weight and possibly subsequent weight regain. Bray et al. [100] in the POUNDS LOST Study and Grave et al. [101] found no effect of diet composition on body weight or energy expenditure [100]. However, Reid et al. [102] found higher carbohydrate and alcohol consumption in those subjects who had regained weight after an average of 12 years since bariatric surgery, compared to those who had maintained weight loss. Frequent consumption of high-fat and high-sugar snacks can lead to excessive energy intake from carbohydrates, and this behavior may reduce the maintenance of weight loss [103]. Restricting the consumption of soft drinks or carbonated beverages is another important aspect that has been related to the stability of postsurgical weight [104]. Likewise, different studies [105,106] have found that a diet high in protein and with a low glycemic index was the best option to maintain weight loss, and this macronutrient composition could be related to a lower decrease in energy expenditure in the subjects who followed it [105].

Regarding dietary behavior, and more specifically behaviors related to reduced rations and frequency of intake, they have been related to more favorable weight 3 years after bariatric surgery [107]. Similar findings have been described in a cohort of 50 adolescents undergoing bariatric surgery [87].

It is likely that numerous mechanisms contribute to changes in lifestyle after bariatric surgery. Continuous and comprehensive care interventions appear to be the most successful approaches to maintaining weight loss. However, more long-term randomized clinical trials are needed to clarify these issues.

#### **6. Gut Hormones and Neuronal Factors**

#### *6.1. Gut Hormones*

Bariatric surgery produces changes in gastrointestinal anatomy and functionality that may be implicated in different ways in weight loss after the procedure and weight maintenance in the long-term. Regulation of appetite and eating is a complex process that depends on the integration of signals from the digestive tract to the central nervous system (CNS). Specifically, there are regions in the hypothalamus and brainstem that integrate peripheral signals to coordinate orexigenic and anorexigenic responses. Those signals provide information about energy availability depending on nutritional state and energy storage in adipose tissue. There is a very intricate system of signals between the gut, vagal afferents, hypothalamus, brainstem, and reward centers in response to nutrient ingestion to regulate energy homeostasis [108].

The main gut hormones implicated in energy homeostasis are ghrelin, which is orexigenic, peptide tyrosin-tyrosin (PYY), glucagon-like peptide 1 (GLP-1), oxyntomodulin (OXM), glicentin, pancreatic polypeptide (PP), amylin and cholecystokinin (CCK), which are anorexigenic [109]. Ghrelin increases appetite and food intake, accelerates gastric emptying, increases gastric acid secretion, decreases insulin secretion, and stimulates hepatic glucose production. Its levels are higher just before nutrient intake, and there is a ghrelin suppression after a meal; this suppression is greater following a high-carbohydrate meal compared to a high-fat meal [108]. On the contrary, PYY reduces food intake and appetite, increases insulin secretion, and delays gastric emptying. The peak in PYY secretion takes place typically 15–30 min after food intake, and protein and fat-rich foods stimulate greater peaks of this hormone compared to carbohydrates [110]. GLP-1 has a biphasic secretion after nutrients intake with an early phase 15 min after ingestion and a second peak at 30–60 min [111]. Its effects are similar to PYY—suppressing appetite, reducing food intake, and delaying gastric emptying—but it also promotes glucose-dependent insulin secretion [112]. OXM is co-secreted with GLP-1 in response to food ingestion, and it reduces energy intake, increases energy expenditure related to physical activity, delays gastric emptying, and also stimulates glucose-dependent insulin secretion. Glicentin seems to have a role in stimulating insulin secretion, and decreasing gut motility and acid secretion in animals, but its biological role is not fully elucidated yet. PP is secreted after nutrients ingestion depending on caloric load, and its main functions are the inhibition of gastric emptying, pancreatic exocrine secretion, and gallbladder motility. Amylin levels reach a peak one hour after nutrient ingestion and remain high for four hours, slowing gastric emptying, suppressing glucagon postprandial secretion, inhibiting energy intake, and increasing energy expenditure [108]. Finally, CCK promotes gallbladder contraction and pancreatic exocrine secretion favoring food digestion, but it also slows gastric emptying, inhibits acid gastric secretion, decreases energy intake, and stimulates insulin secretion [113].

Some alterations in the normal function of these hormones have been reported in obese patients compared to lean subjects, also in syndromic obesity. Some changes in these hormones have been identified following different weight loss strategies, including bariatric surgery (Table 2). For example, an increase in postprandial levels of GLP-1 in patients after SG and RYGB has been reported in several studies, and this change may persist in the long-term (at least 1–2 years). In the case of GIP (Gastric inhibitory polypeptide), data are more controversial, as some studies have reported an increase in postprandial levels after bariatric surgery, but some others did not find any change, especially after RYGB. Similar effects have been observed in a lot of studies for OXM and PYY, with increases

in postprandial levels after RYGB and for PYY also after SG. Regarding ghrelin, the only orexigenic gut hormone of those previously mentioned, its suppression is usually improved after bariatric surgery. However, the mechanism seems to be different depending on the technique, as in RYGB the effect observed is in postprandial ghrelin, and in SG the effect observed is in fasting ghrelin. Although this is controversy, lower ghrelin levels may have beneficial effects on appetite regulation and in body weight [114].


**Table 2.** Summary of main changes in gut hormones after RYGB and SG.

\* All hormone levels refer to postprandial levels, except for ghrelin, whose changes occurred mainly in fasting levels. RYGB: Roux-en-Y gastric bypass. SG: sleeve gastrectomy. GLP-1: glucagon polypeptide like 1. GIP: glucose-dependent insulinotropic peptide OXM: oxyntomodulin. PYY: polypeptide tyrosine-tyrosine.

Differential behaviors of gut hormones depending on surgical technique could be related with anatomical changes (duodenum exclusion in RYGB and restriction of the gastric fundus in SG) produced in the surgery and with different exposure to carbohydrates and fat. Based on this idea, there are three hypothesis that try to explain weight control. The hindgut hypothesis poses that the accelerated delivery of nutrients to the distal gut increases insulinotropic signals that are mediated, among others, by GLP-1, and that improves postprandial glucose and free fatty acids metabolism, favoring body weight control [115]. Besides, nutrient delivery to the distal intestine also may produce an increase in intestinal gluconeogenesis and may activate a hepato-portal sensor that leads to neural signals for reduced food intake and decreased glucose output from the liver, as the midgut hypothesis proposes [116]. Finally, foregut hypothesis suggests that bypassing the duodenum may reduce some factors that induce insulin resistance and β-cell dysfunction, decreasing diabetogenic signals [117].

Among the studies published in last five years regarding gut hormones and weight maintenance after bariatric surgery, there are some interesting results, though the majority of them are observational studies. Perakakis et al. performed two independent trials to assess circulating levels of gut hormones in response to different types of bariatric surgery and its influence on weight loss after a year of follow up. They compared the fasting and postprandial levels of nine gut hormones after a mixed meal test, before and after bariatric surgery (laparoscopic gastric banding, SG and RYGB), and they related them with weight loss, looking for predictors of long-term weight loss. Their most robust results referred to OXM and glicentin, which showed a significant increase 3 months after the surgery (SG and RYGB) that was maintained at one year. The percentage of weight change was related to this increase at 6 months (OXM: *p* = 0.004; glicentin: *p* = 0.001) and at 12 months (OXM: *p* = 0.053; glicentin: *p* = 0.049). For GLP-1, changes were more profound and significant for SG than for RYGB, in contrast with other studies. For GIP they only found a decrease after RYGB and no changes for SG, and finally for ghrelin there was a significant decrease after SG but no changes after RYGB. They concluded that glicentin increase may predict weight loss at 12 months better than GLP-1, and these effects seemed to be related with better satiety control [118]. In another comparative study, Santo et al. compared postprandial secretion of ghrelin, GIP, GLP-1, and leptin in patients with maintenance of more than 50% of the EWL (group A) versus patients with regain of more than 50% of the EWL (group B), with a follow up of 26 months. Although the sample size was very small and all patients had undergone RYGB, they found some interesting results. There was a decrease in postprandial ghrelin levels in both groups, suggesting better appetite control. GIP showed a relatively larger increase (with respect to baseline) in postprandial levels at 30 min in

group A compared to group B (*p* = 0.01), and GLP-1 also showed a greater increase at 30 min in group A compared to group B (*p* = 0.05) as well as a greater relative increase with respect to baseline (*p* = 0.01). Finally, leptin showed greater basal levels in group B compared to group A (*p* = 0.02), suggesting that energetic reserves could have been larger in group B. Thus, they concluded that the increase in GLP-1 and GIP after nutrient intake may show the influence of these hormones in weight maintenance after RYGB [119]. Another similar prospective observational study led by Alamuddin analyzed postprandial GLP-1, PYY, ghrelin, and leptin levels at 6 and 18 months after bariatric surgery (SG and RYGB), and they compared with a control group. Despite the low number of patients who completed the 18 months of follow up, the results are interesting to understand gut hormone changes in the long term. They reported a decrease in fasting ghrelin levels, especially in the SG group at 6 months (*p* = 0.0199) and 18 months (*p* = 0.0003), and an exaggerated postprandial increase in GLP-1 and PYY at 6 months (RYGB: *p* < 0.0001; SG: *p* = 0.006) that lasted until 18 months only for GLP-1 [120]. With some differences, the results of these studies suggest that the increase in anorexigenic hormones levels and the decrease in orexigenic hormones may be related to weight loss and weight maintenance after bariatric surgery in the short and long-term.

#### Other Hormonal Factors

On the other hand, bile acids also may have a role in weight loss and weight maintenance after bariatric surgery. A lower increase in circulating levels of postprandial bile acids has been reported in obese individuals, and this fact may play a role in energetic metabolism and weight control because they have some hormonal effects, and they stimulate brown adipose tissue activity for thermogenic effects. Some studies have shown an increase in postprandial bile acids levels after RYGB, and this increase seems to be grater in the long-term. The exact mechanism is not known, but it could be related to the nutrient delivery to the distal small intestine [121]. In addition, the alterations in gut microbiota after RYGB could have a role because microbiota are a key regulator of bile acids conjugation and secondary bile acids formation [122]. Bile acid fasting levels correlate with GLP-1 peak levels and stimulate GLP-1 secretion, probably contributing to satiety and ß-cell insulin secretion [123]. Insulin secretion also may be facilitated via farnesoid X receptor (FXR), which directly responds to bile acid increase [124]. Moreover, there are bile acid receptors (TGR5 receptors) in skeletal muscle and brown adipose tissue. Thus, the binding of bile acids to these receptors may increase energy expenditure, facilitating thyroid hormone action. However, data are controversial, and it is not clear if energy expenditure contributes to weight maintenance after bariatric surgery [125].

#### *6.2. Neuronal Factors*

Several studies have suggested that changes in taste preferences after bariatric surgery, especially after RYGB and alterations in the reward system, may have an influence in weight maintenance after surgical treatment of obesity, though data are inconclusive [126].

The mesolimbic reward pathway is a dopaminergic pathway that is key in substance abuse disorders, and there is evidence that it is also important in obesity. Although food intake regulation is a very complex system with many actors implied, dopamine may mediate some aspects of eating behaviors. It is known that food reward and dopamine functions are altered in obesity [127]. Bariatric surgery (SG and RYGB) may increase striatal dopamine transmission, improving reward sensitivity. This improved sensitivity, along with other factors, may help to modify eating behaviors enhancing the preference for non-highly stimulating food. These changes in striatal dopamine transmission seem to be related to changes in gut hormone levels after bariatric surgery, such as the decrease in ghrelin levels and the increase in GLP-1 or PYY levels. Gut hormones are key in the connection of the gut and brain as well as microbiota, as some gut bacteria are also implicated in dopamine release, and the shift in gut microbiota after bariatric procedures may improve dopaminergic signaling. This microbiota–gut–brain axis is an important regulator of weight control, including after bariatric surgery [126].

Finally, another interesting point is the connection between appetite, taste preferences, and eating behavior since some changes in appetite and taste preferences have been reported after bariatric surgery [128]. A recent study by Zhang et al. [129] investigated the association between presurgical taste preferences and postsurgical weight regain. They included patients who underwent RYGB or SG and had at least 2 years of follow up, and they assessed preoperative taste preferences with a multichoice questionnaire. They found that patients with sweet food preferences had 5.5 kg of weight regain (*p* = 0.038), and patients with salty food preferences had 6.1 kg of weight regain (*p* = 0.048) compared to patients with no taste preferences. After adjustment, patients with salty food preferences showed the greater weight regain with 6.8 kg (*p* = 0.027) compared to patients with no preferences. Though these results from just one study do not allow to establish robust evidence, it is a very interesting approach to identify more factors related to weight maintenance in the long-term after bariatric surgery.

In summary, there are very complex and intricate systems connecting gut hormones, microbiota, and the CNS that play an important role in appetite control and energy homeostasis. Thus, the changes produced by SG and RYGB in this complex gut–brain axis seem to influence weight maintenance in the medium- and long-term after surgery.

#### **7. Conclusions**

Bariatric surgery is the most effective intervention for weight loss in obese patients, although it is not exempt from possible long-term failure and weight regain. Multiple factors that may be related to long-term weight maintenance have been described, ranging from the surgical technique itself to anatomical and functional modifications that lead to changes in the microbiota–gut–brain axis through gastrointestinal hormones, bile acids, and FXR-TGR5 influence on skeletal muscle and brown adipose tissue or dopaminergic pathways related to appetite control and energy homeostasis. Similarly, factors such as changes in lifestyle related to diet and physical activity, psychological factors such as executive function disorders, and the coexistence of depressive symptoms and eating disorders can play important roles in maintaining long-term weight loss. Therefore, numerous mechanisms may contribute to changes in lifestyle and weight maintenance after bariatric surgery; thus, continuous and comprehensive care interventions appear to be the most successful approaches to maintaining. However, some data are discordant, and more longterm studies are necessary in order to clearly identify predictive factors of weight regain that allow us to optimize the management and follow-up of the obese patient undergoing bariatric surgery.

**Author Contributions:** Conceptualization, F.J.T. and I.C.-P.; methodology, M.M.-V.; investigation, I.C.-P., A.M.G.-P. and M.M.-V.; resources, M.D.-F. and A.M.G.-P.; writing—original draft preparation, I.C.-P., M.M.-V. and A.M.G.-P.; writing—review and editing, I.C.-P., M.M.-V. and A.M.G.-P.; visualization, M.D.-F.; supervision, F.J.T. All authors have read and agreed to the published version of the manuscript.

**Funding:** ICP was supported by Rio Hortega, and Juan Rodes from the Spanish Ministry of Economy and Competitiveness (ISCIII), and cofounded by Fondo Europeo de Desarrollo Regional-FEDER (CM 17/00169, JR 19/00054). MMV was supported by Rio Hortega from the Spanish Ministry of Economy and Competitiveness (ISCIII) and cofounded by Fondo Europeo de Desarrollo Regional-FEDER (CM18/00120). AMGP was supported by a research contract from Servicio Andaluz de Salud (B-0033-2014). MDF was supported by Rio Hortega from the Spanish Ministry of Economy and Competitiveness (ISCIII) and cofounded by Fondo Europeo de Desarrollo Regional-FEDER (CM20/00183). This study was supported by the "Centros de Investigación Biomédica en Red" (CIBER) of the Institute of Health Carlos III (ISCIII) (CB06/03/0018), research grants from the ISCIII (PI18/01160), and co-financed by the European Regional Development Fund (ERDF). The funders had no role in the manuscript.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**


### *Review* **Bariatric Surgery and Hypertension**

**Elisenda Climent 1,2,3, Anna Oliveras 2,4,5,6, Juan Pedro-Botet 1,2,3, Albert Goday 1,2,3,7 and David Benaiges 1,2,3,8,\***


**Abstract:** A clear pathogenetic association exists between obesity and arterial hypertension, becoming even more evident in subjects with severe obesity. Bariatric surgery has proved to be the most effective treatment for severe obesity, with its benefits going beyond weight loss. The present review aimed to determine the effects of bariatric surgery on arterial hypertension evident in short- and long-term follow-ups. Moreover, the differences between surgical techniques regarding hypertension remission are described as well as the possible pathophysiologic mechanisms involved. In addition, the effects of bariatric surgery beyond blood pressure normalization are also analyzed, including those on target organs and cardiovascular morbidity and mortality.

**Keywords:** bariatric surgery; obesity; severe obesity; hypertension; blood pressure; modifications of structural changes

### **1. Introduction**

Hypertension (HTN) is one of the best known and most widely studied cardiovascular risk factors, and a close correlation between obesity and HTN has been extensively demonstrated [1]. Thus, HTN prevalence in subjects with obesity varies between 60 and 77%, and it is clearly higher than the 34% observed in subjects with normal weight [2]. The mechanisms by which obesity raises the risk of developing HTN are multifactorial, involving structural, functional, and hemodynamic changes in the cardiovascular system [3].

Conventional medical treatment for morbid obesity has previously achieved mild outcomes, which are probably related to limited long-term adherence to lifestyle modifications in some patients [1]. By contrast, bariatric surgery (BS) has proved to be the most effective therapy for these patients when both weight loss and comorbidity remission after surgery, including HTN, were evaluated [2,3].

In this respect, owing to the widely known systematic review published by Buchwald et al. [3] in 2004, which included a total of 22,094 patients, it has been accepted that approximately three of every five subjects undergoing BS achieve HTN remission. However, it must be considered that this meta-analysis mainly included studies with a short-term follow-up, with the surgical procedures performed at that time (gastric bypass (GB), gastric band, and biliopancreatic diversion), and most studies were retrospective and with great heterogeneity regarding HTN remission definition. In recent years, several prospective studies have reported mid- and long-term results after surgery, with laparoscopic sleeve gastrectomy (LSG) emerging as the most used BS technique worldwide [4]. Moreover, the possible underlying mechanisms responsible for HTN improvement after BS have been

**Citation:** Climent, E.; Oliveras, A.; Pedro-Botet, J.; Goday, A.; Benaiges, D. Bariatric Surgery and Hypertension. *J. Clin. Med.* **2021**, *10*, 4049. https://doi.org/10.3390/ jcm10184049

Academic Editor: Emmanuel Andrès

Received: 23 July 2021 Accepted: 7 September 2021 Published: 7 September 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

further evaluated, together with the possible benefits beyond weight loss. The present narrative review aimed to delve into these newly acquired data.

#### **2. Bariatric Surgery Effects on Blood Pressure**

#### *2.1. Short-Term Effects on Blood Pressure*

HTN remission in the short term (<3 years) after BS has been widely analyzed in observational studies, some meta-analyses, and a few randomized controlled trials (RCT) [5–9]. Schiavon et al. [10] in 2018 published the first RCT specifically aimed at evaluating the effect of BS on HTN remission. The GATEWAY (Gastric Bypass to Treat Obese Patients with Steady Hypertension) trial [10] included patients with HTN (using ≥2 medications at maximum doses or >2 at moderate doses) and a body mass index between 30.0 and 39.9 kg/m2. Subjects were randomized to GB plus medical therapy or medical therapy alone. The primary endpoint (≥30% reduction in the total number of antihypertensive medications while maintaining systolic and diastolic blood pressure < 140 and 90 mmHg, respectively, at 12 months) occurred more frequently in the GB group (83.7%) compared to the control group (12.8%). Moreover, HTN remission 1 year after surgery, defined as systolic and diastolic blood pressure < 140 and 90 mmHg, respectively, with previous withdrawal of all medication, occurred in approximately one-half of the patients in the GB group and none in the conventional treatment group. It is noteworthy that the HTN remission rate after BS obtained in the GATEWAY trial [10] was lower than those described in other previous reports [5,6,9], including the Buchwald et al. meta-analysis [3]. This was probably due to the first including patients who required an "aggressive" antihypertensive treatment, in comparison to the other studies where the included patients needed one or no antihypertensive medication. Hence, taking these results into account, if BS were primarily indicated to control refractory HTN, the chance of achieving remission would probably be close to 50% in the short term. In accordance with these data, it has been reported that the number of antihypertensive drugs prior to surgery was associated with a lower remission rate during the first year [9]. Another relevant result obtained from the GATE-WAY study was that no differences in systolic and diastolic blood pressure levels were observed between groups during follow-up. This seems to indicate that if good titration of the medication is made during follow-up considering blood pressure levels, the effects of BS on HTN are mainly reflected in the reduction in the number of antihypertensive medications.

#### *2.2. Mid- and Long-Term Effects*

Less evidence exists on the mid- (3–5 years) and long-term (>5 years) effects of BS on HTN remission compared to other obesity comorbidities such as type 2 diabetes, and this evidence is mainly available from observational studies [2,11,12].

The results obtained in the mid- and long-term after BS were more modest compared to those achieved with a shorter-term follow-up. Regarding this, our group had previously evaluated HTN remission after BS with a 36-month follow-up, observing that 68.1% of hypertensive patients showed HTN remission 1 year after the surgical procedure, 21.9% of whom had relapsed at 3 years [9]. A possible justification for these less favorable results seems to be explained, at least in part, by weight regain after surgery. It must be taken into account that maximum weight loss is achieved during the first 12 months post-surgery, and from this point onwards, weight regain and worsening of certain metabolic parameters usually emerge. This coincides with the results obtained in our cohort, where milder weight loss during the first year was also associated with increased HTN recurrence at 3 years [9].

However, BS still presents more beneficial outcomes in the mid- and long-term followup compared to conventional treatment. In this respect, various RCT [13–15] compared BS to conventional treatment with a 5-year follow-up. Mingrone et al. [13] found that the BS group and conventional treatment maintained similar blood pressure levels 60 months after surgery. Nevertheless, more subjects in the latter group required antihypertensive

medication (73% with conventional treatment versus 58% after GB and 32% after biliopancreatic diversion). Similarly, Ikramuddin et al. [15] also found a favorable trend toward BS. In that study, primary systolic blood pressure < 130 mm Hg at 5 years was obtained in 73% in the GB group versus 49% in the lifestyle and intensive medical management group (odds ratio (OR), 2.71; 95% CI, 0.95–7.78; *p* = 0.06).

The superior results obtained with a surgical approach compared to lifestyle modifications have also been further confirmed with a longer-term follow-up. In this respect, the Swedish Obese Subjects cohort [2] observed a greater reduction in blood pressure levels after GB compared to a non-surgical approach, with a mean follow-up of 10 years. Moreover, the percentage of patients requiring antihypertensive treatment was also lower after BS compared to the control group (35% vs. 53%; *p* < 0.001), with these results being in line with other previous studies [11,16].

Systematic reviews and meta-analyses also confirmed the superiority of BS, which was previously observed with a short-term follow-up. In this respect, Vest et al. [17] in 2012 (including 70 observational studies and three RCT) reported a 63% resolution or improvement in HTN with a mean follow-up of approximately 5 years. Similarly, Wilhelm et al. [8] in 2014 (including 31 prospective and 26 retrospective studies) observed 50% and 63.7% HTN resolution or improvement, respectively, with a mean follow-up varying from 1 week to 7 years post-surgery. Of the 57 studies included, 32 reported HTN improvement (OR, 13.24; 95% CI, 7.73–22.68; *p* < 0.00001) and 46 reported HTN resolution (OR, 1.70; 95% CI, 1.13–2.58; *p* = 0.01).

However, although studies with a longer follow-up confirmed the beneficial outcomes after BS in comparison to conventional treatment regarding HTN evolution, an RCT specifically focused on evaluating HTN remission at mid- and long-term after BS is lacking. Moreover, the possible differences among the most used surgical procedures (including malabsortive, restrictive, or both surgical approaches) must not be ignored, as detailed below.

#### *2.3. Differences among Surgical Procedures*

Considering the different BS procedures, GB has been considered, until recently, the gold standard technique owing to its favorable results in both weight loss and comorbidity remission [18]. However, in recent years, LSG also proved to achieve comparable promising results to GB, hence becoming the most used BS procedure in 2014 [4]. Moreover, LSG is a technically easier procedure compared to GB [19,20], with a presumably lower risk of perioperative complications [18].

In order to shed light on the effects of both BS techniques, our group carried out a meta-analysis to evaluate 1 and 5-year HTN remission after both procedures [21]. Thirtytwo articles were involved, with a higher HTN remission rate being observed with GB compared to LSG both at 1 year (RR, 1.14, 95% CI, 1.06–1.21) and at 5 years (RR, 1.26, 95% CI, 1.07–1.48) after surgery. Blood pressure improvement after surgery was also evaluated. No differences were found between GB and LSG in terms of systolic or diastolic blood pressure changes at both 1 and 5 years. Thus, we could speculate that although patients in the LSG group were less likely to present HTN remission after BS, and hence not all the antihypertensive medication could be withdrawn, overall blood pressure levels in both groups were equivalent after surgery. It is also important to highlight the fact that the superiority of GB over LSG was observed when all studies were included, as well as when only the highest evidence studies (RCT) were evaluated.

Thus, although some studies obtained more promising results regarding HTN remission after GB compared to LSG, the superiority of GB must be further confirmed with longer-term follow-up (>5 years).

#### *2.4. Metabolic Surgery and HTN*

Owing to the favorable results (which go beyond weight loss) of BS in obese subjects, the concept of metabolic surgery has gained importance in recent years [22], with the

focus on the physiologic modifications that occur after surgery, which lead to comorbidity improvement [23]. Moreover, the metabolic effects of the surgical procedure become more evident when obesity comorbidities improve within days after BS and when significant weight loss has not yet been achieved [8].

This fact has opened debate on whether BS should be indicated in patients with body mass index < 35 kg/m<sup>2</sup> for comorbidity improvement, which was addressed in previous observational publications mainly aimed at glycemic improvement after surgery but also at achieving hopeful results regarding HTN remission [24,25].

Five RCT [5,26–29] also assessed the effects of BS in subjects with class I obesity, observing positive results in blood pressure evolution, nearly equivalent to those obtained in patients with body mass index > 35 kg/m2 (Table 1). However, the main limitation when evaluating these data was the heterogeneity of the definitions used for remission or improvement in the different studies, as some considered total withdrawal of antihypertensive medication and others only blood pressure normalization. In order to standardize all studies evaluating comorbidity remission with grade I obesity, the International Federation for the Surgery of Obesity and Metabolic Disorders (IFSO) realized a position statement in 2014 [30] summarizing the scientific background concerning BS in class I obesity. They concluded that a clinical decision of whether to deny BS to these patients should be based on a more comprehensive evaluation of the patient's current global health and on a more reliable prediction of future morbidity and mortality. Hence, future observational studies and RCT with a longer-term follow-up are necessary.


**Table 1.** Randomized trials of bariatric surgery including patients with body mass index <35 kg/m2.

BMI: body mass index; DBP: diastolic blood pressure; EWL: excess weight loss; HTN: hypertension; LABG: laparoscopic adjustable gastric banding; LRYGB: laparoscopic Roux-en Y gastric bypass; LSG: laparoscopic sleeve gastrectomy; SBP: systolic blood pressure; TWL: total weight loss.

#### *2.5. Possible Mechanisms Related to HTN Improvement*

Although weight loss has proved to be a key factor in comorbidity improvement after BS, other underlying factors may also play an important role. With regard to blood pressure improvement after BS, the reasons are probably multifactorial and remain under debate (Figure 1) [31,32].

**Figure 1.** Mechanisms related to HTN remission. RAAS = Renin–angiotensin–aldosterone system; Na = Sodium; SNS = sympathetic nervous system. ↑ = increase; ↓ = decrease.

It has been speculated that a decreased inflammatory response together with an improvement in insulin resistance could reduce arterial stiffness and sodium reabsorption and hence lead to normalization of blood pressure levels [33]. Patients with central obesity are known to have increased activation of the renin–angiotensin–aldosterone system, which may also normalize after surgery [34].

In addition, an increase in gastrointestinal gut hormones such as peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) could also play an important part due to their effects on the gastrointestinal system together with a diuretic and natriuretic effect on the kidney [35]. Furthermore, a possible effect of GLP-1 on the sympathetic nervous system, which may play a part in the blood pressure-lowering effect after BS, has also been described [36]. Ghrelin may also aid in normalizing blood pressure levels, although its levels may raise, fall, or remain unchanged after BS, depending on the surgical procedure [37].

Furthermore, adipokines and other inflammatory cytokines also appear to be related to HTN recovery. In this respect, previous studies observed a decline in leptin levels from 1 week up to 1 year after BS together with increasing adiponectin concentrations [38]. Moreover, as insulin sensitivity increases, C-reactive protein and interleukin-6 levels decrease, thus ameliorating adipocyte inflammation and in turn preventing vascular constriction [39].

Finally, the resolution of other obesity comorbidities (which share pathophysiologic mechanisms with HTN) such as obstructive sleep apnea could also play a part in blood pressure improvement [40,41].

The underlying mechanisms related to the possible superiority of GB over LSG are also worth mentioning. The main accepted hypothesis is that these differences could be explained by the superior weight loss after GB in the mid- and long-term followup. As mentioned previously, the possible role of gastrointestinal hormones in HTN improvement after surgery gains value, as some studies observed a decrease in blood pressure levels within the first week post-BS and when weight loss was minimal [8]. In this respect, a previous study found significant reductions in both systolic (9 mm Hg) and diastolic (7 mm Hg) blood pressure 1 week after GB, and these were maintained 1 year after surgery [42]. Considering the different surgical procedures, GLP-1 and PYY are known to

increase after both, but they increase more intensely after GB [42,43], which may account for the more favorable results after this procedure.

#### **3. Bariatric Surgery Benefits beyond Blood Pressure Improvement**

#### *3.1. Organ Damage Changes*

Patients with morbid obesity have a higher prevalence of target organ damage than patients of normal weight, and HTN is clearly related to its development. These target organ alterations mostly refer to changes in heart, vessels, and kidney structure and function [44].

#### 3.1.1. Cardiac Changes

Regarding cardiac changes, several works reported echocardiographic alterations, both morphologic and functional, in obese patients [45,46]. The main alterations consisted of left ventricular (LV) hypertrophy and impaired LV diastolic function, while LV systolic dysfunction was less common and, on these lines, reports concerning the ejection fraction in obese patients were contradictory [47]. Morphologic LV alterations have been described in patients with morbid obesity, with 56% of LV hypertrophy being reported from a meta-analysis of 22 studies including 5486 obese subjects [45]. Many of these changes are precursors of more overt forms of cardiac dysfunction and heart failure [48]. Indeed, obesity clearly increases the risk of atrial fibrillation, myocardial infarction, heart failure, and sudden death [49]. Beyond findings from observational epidemiology, Larsson et al. [50] recently found evidence that a genetically instrumented 1 kg/m2 higher body mass index is associated with an increased risk of aortic stenosis, heart failure, deep venous thrombosis, HTN, peripheral artery disease, coronary artery disease, atrial fibrillation, and pulmonary embolism (estimates in the range of 6–13% higher risk). The findings for fat mass were broadly consistent. Specifically, the link between obesity and heart failure is known to be stronger than those for other cardiovascular disease subtypes and is uniquely unexplained by traditional risk factors [51]. However, the findings apparently diverged from observational studies for ischemic stroke, and this field merits further investigation [50].

In relation to the mechanisms responsible for cardiac improvement after BS, several authors concur in that the effects of weight-loss surgery on cardiac function and morphology are either hormonally or centrally regulated, probably with an important role for leptin and other adipokines [52], as well as for the renin–angiotensin–aldosterone axis [53]; however, further insight needs to be gained into the mechanisms underlying changes in cardiovascular function after weight loss.

Importantly, these cardiovascular structure and function alterations have also proved to be reversible with weight loss strategies such as BS, resulting in lowered cardiovascular risk [54]. The effects of BS on cardiac structure and function were recorded in a systematic review of 23 studies and meta-analysis [55], showing that in obese patients with preserved LV systolic function, BS induced significant decrements of absolute LV mass and relative wall thickness (RWT), which are all reliable indexes of LV hypertrophy and LV geometry that have been shown to predict cardiovascular outcomes. Furthermore, that meta-analysis showed improvements in LV diastolic function, as reflected by a clear-cut increase in the mitral flow ratio of the early (E) to late (A) ventricular filling velocities (E/A ratio), as well as decreases in left atrium size, which is an indirect marker of chronically elevated LV filling pressure and diastolic dysfunction. As for LV hypertrophy and RWT, similar results were reported by Owan et al. [56] 2 years after BS. Those authors found that the decreases in LV mass index and RWT correlated with body mass index reduction but not with changes in blood pressure. Of note, one of the most salient observations of the BARIHTA study by our group was that even severely-obese patients with strictly normal blood pressure experience an improvement in morphologic and functional LV parameters after BS [53].

#### 3.1.2. Vessel Changes

One of the main manifestations of vessel alteration is the development of arterial stiffness (AS). It is considered to be an independent cardiovascular risk factor [57] and is defined as the diminished ability of an artery to expand and contract in response to a given pressure change [58]. Pulse wave velocity (PWV) is the gold standard for AS measurement [59]. In the last two decades, excess body weight has been found to be associated with greater aortic stiffness in young and older adults [60]. Therefore, increased AS may be one of the mechanisms by which obesity raises cardiovascular risk independently of traditional risk factors. Indeed, high PWV predicts outcomes independent of the Framingham Risk Score, and it is associated with increased cardiovascular disease risk regardless of HTN status [61]. On the same lines, some authors suggested that AS may precede rises in systolic blood pressure and incident HTN in obese individuals [62].

Regarding the effect of BS on AS, several studies reported a significant decrease in both PWV and the augmentation index, another marker of AS, several months after BS [63–65]. The potential mechanisms responsible for the reduction in AS after weight loss are not clear. Some authors [66] found a correlation between weight loss and reduction in PWV independently of changes in established hemodynamic and cardiometabolic risk factors, and other groups [64], but not all [60], suggested that this correlation is mediated by the drop in blood pressure. On the other hand, elevated cardiac volume and output in obese individuals were also noted as possible mediators of AS, more importantly than elevated BP [67].

#### 3.1.3. Renal Changes

Obesity is an independent risk factor for kidney disease, regardless of diabetes and HTN, both of which are driven largely by obesity [68]. Hyperfiltration is the hallmark of obesity-associated kidney dysfunction, and the main proposed mechanisms for this association are hemodynamic factors, inflammatory cytokines, and renal lipotoxicity [68,69]. As regards hemodynamic factors [70], excessive weight initially causes functional renal vasodilation and increases in renal blood flow and glomerular hyperfiltration prior to nephron injury. These changes are later followed by declines in renal blood flow and the glomerular filtration rate (GFR) as a result of kidney injury and gradual loss of nephrons. Increased extracellular fluid volume results from the obesity-associated increase in tubular sodium reabsorption. This may be related to the elevated levels of anti-natriuretic hormones such as angiotensin II and aldosterone, as a consequence of both kidney compression by visceral, perirenal, and renal sinus fat and of the increased renal sympathetic nerve activity. These and other contributors may be linked by the altered macula densa feedback (tubuloglomerular feedback) to the observed afferent arteriola vasodilation. Sodium balance may be re-established despite increased sodium chloride reabsorption in the loop of Henle through compensatory increases in the GFR and blood pressure elevation. Furthermore, mineralocorticoid receptor (MR) activation may also contribute to renal vasodilation. MR expressed on macula densa cells are activated by aldosterone, thereby increasing their production of nitric oxide and leading to renal vasodilation and glomerular hyperfiltration. Despite the adaptative value of glomerular hyperfiltration in offsetting renal sodium reabsorption, this increase in glomerular hydrostatic pressure probably contributes greatly to the renal injury observed in obesity.

Obesity also favors a deleterious adipocytokine pattern [68,69] characterized by the overproduction of angiotensinogen and angiotensin II as well as the upregulation of pro-inflammatory cytokines such as interleukin-6, C-reactive protein, and tumor necrosis factor-α. These factors induce renal fibrosis via the transforming growth factor-β (TGF-β) pathway and via oxidative stress, as shown by experimental models. Moreover, obese individuals are known to have high levels of serum leptin and high expression of leptin receptors in the kidney, which also stimulate cellular proliferation and expression of the prosclerotic TGF-β1 cytokine implicated in the early scarring formation of renal failure. Finally, reduced levels of another adipokine, adiponectin, have been implicated as a mechanism of obesity-related renal impairment through podocyte damage leading to albuminuria. Pathologic changes due to long-lasting hyperfiltration include the development of glomerulomegaly and renal lesions of focal segmental glomerulosclerosis, leading to obesity-related glomerulopathy [71]. Thus, hyperfiltration, i.e., GFR higher than 120 mL/min/1.73 m2, and albuminuria, biomarkers of kidney function and damage, respectively, characterize renal alterations in obese patients.

The gold-standard method to assess the GFR is measurement of the renal clearance of an exogenous filtration tracer (inulin, 51 Cr-EDTA, 125 I-iothalamat, iohexol); however, most studies use GFR (eGFR) estimations derived from prediction equations. These equations were obtained by regression analyses in various populations with body mass index < 30 kg/m2, where the GFR was measured by the gold standard method, but these are not accurate in obesity classes II and III [68]. Thus, it is unclear how reliably creatinine-based eGFR equations perform among those with obesity, especially when faced with results normalized to a body surface area of 1.73 m<sup>2</sup> since, after BS, patients lose not only fat but also muscle mass, which generates creatinine [72]. Furthermore, although body surface area, which is considered in the eGFR equations, is vastly reduced after BS, it is not reflected in the eGFR results routinely available [73]. Cystatin C has been suggested as a potential alternative since, unlike creatinine, it does not come strictly from muscle. However, it has not been validated as a reliable biomarker of GFR in obese patients, nor has its laboratory assay been standardized as for creatinine. On the other hand, measurement of albumin excretion rates via albumin-to-creatinine ratios (ACR) in fresh spot urines or absolute excretion rates in timed urine collection has become a more reliable measurement of renal damage [74].

Overall, patients with complicated obesity will likely benefit from the weight loss after BS [75]. Li et al. [76] reported a systematic review and meta-analysis from 32 studies showing significant reductions in hyperfiltration (measured GFR, eGFR, and creatinine clearance with and without adjustment for body surface area), albuminuria (defined as an ACR of more than 30 mg/g of creatinine), and proteinuria after BS. They reported a reduction in hyperfiltration (RR: 0.46, 95% CI 0.26–0.82, *p* = 0.008) after surgery when analyzed as a dichotomous variable as well as statistically significant decreases. Moreover, drops were observed in the incidences of albuminuria and proteinuria after BS of 58% and 69%, respectively (*p* < 0.0001 for both). Data on the 4047 patients included in the Swedish Obese Subjects study [77], comparing patients undergoing BS and controls followed up for a median time of 18 years, showed a lower incidence of chronic kidney disease (CKD) stages 4 and 5 in patients in the surgery group (adjusted HR = 0.33; 95% CI 0.18–0.62; *p* < 0.001). Similarly, O'Brien et al. [78] in a retrospective analysis reported a 59% lower incidence of nephropathy at 5 years in a cohort of 4000 diabetic patients undergoing BS compared to 11,000 matched non-surgically treated patients. Friedman et al. [75] analyzed 2144 obese patients who underwent BS and found an improvement in CKD risk categories in a large proportion of patients over a 7-year follow-up period. They reported that the reduction in risk was most pronounced in persons with high baseline risk.

As regards renal protective factors, Favre et al. [68] reported that low C-reactive protein levels, high fat mass, lack of HTN, and young age predicted kidney protection in severely obese patients undergoing BS.

The mechanisms behind the improvement in risk factors following BS are not well understood. Glomerular function may be related to restoration in homeostasis of the renin– angiotensin system through better renal perfusion and to the restitution of normal insulin signaling in glomerular podocytes and attenuation of hyperfiltration. Additionally, this improvement may also be secondary to reductions in the pro-inflammatory state related to obesity [74] as measured by urinary monocyte-chemoattractant protein-1/creatinine ratios [73]. It has recently been shown that the glucagon-like peptide 1 (GLP-1), an incretin hormone released by intestinal endocrine L cells, exerts renoprotective effects by inhibiting tubular reabsorption of sodium. These effects increase after BS, suggesting a role in the improvement in glomerular function. As for albuminuria remission, at least in obese

diabetics, the restitution of podocyte health may be a key cellular event contributing to the benefits of BS.

Obese patients who undergo BS may also experience some renal complications. Lieske et al. [72] reported that up to 50% of these patients might be hyperoxaluric one year after surgery, and the risk of new kidney stone events doubled compared with unoperated obese controls. Nevertheless, the net effect on long-term kidney health is potentially positive for most patients.

#### *3.2. Implications in Cardiovascular Morbidity and Mortality*

Moving a step forward, the next question to answer is: what is the real impact of HTN improvement after BS in terms of cardiovascular morbidity and mortality reduction? It has previously been reported that BS reduces the number of cardiovascular events and mortality rates in patients with morbid obesity. For instance, the Swedish Obese Subjects Study Group [79] observed a reduced number of cardiovascular deaths in the surgical group compared to the control group (28 events among 2010 patients vs. 49 events among 2037 patients; adjusted hazard ratio (HR), 0.47; 95% CI, 0.29–0.76; *p* = 0.002) during a median follow-up of 14.7 years. In that same cohort, the number of total fatal or nonfatal cardiovascular events (myocardial infarction or stroke) was also lower in patients undergoing BS. Other studies yielded similar results, thereby confirming the beneficial effects of BS on cardiovascular morbidity and mortality [80,81].

Although the observed reduction in cardiovascular disease prevalence after BS is probably multifactorial, it can be assumed that HTN improvement probably plays a key role, although this remains to be confirmed. In fact, the Swedish Cohort [79] failed to find an association between weight loss and cardiovascular event reduction, thus highlighting the possible role of other factors that could explain the improvement in cardiovascular outcomes. In this respect, the decline in cardiovascular risk following the improvement in blood pressure levels after BS could be related to a reduction in target organ damage (including cardiac, vessel, and renal changes), as described previously in the present review [44,82].

However, the possible "obesity paradox" must also be acknowledged. This refers to a more favorable evolution regarding cardiovascular or renal outcomes in patients with a higher body mass index. This possible paradoxical effect observed in some studies could be explained by increased tumor necrosis factor (TNF-α) receptors in adipose tissue or an earlier diagnosis of cardiovascular events in the obese population, among others. Despite this, the underlying mechanisms of this possible paradox in obese population are still being investigated in order to achieve more solid conclusions [83].

#### **4. Conclusions**

BS has proved to be a highly effective treatment for obesity-associated HTN, achieving HTN remission in more than half of patients. However, a greater need for antihypertensive medication prior to BS and less weight loss during follow-up are both factors that may hinder the achievement of complete HTN remission.

Moreover, a decline in cardiovascular morbidity and mortality has also been observed after BS in morbidly obese subjects. These favorable results regarding cardiovascular outcomes may be mediated by multiple mechanisms that go beyond weight loss, one of which may be improved blood pressure levels together with a decline in target organ damage. However, future studies are required in this field for more solid conclusions to be drawn.

**Author Contributions:** All authors contributed equally to this review. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Acknowledgments:** We thank Christine O'Hara for review of the English version of the manuscript.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**

