Obesity Management in Cardiometabolic Disease: State of the Art

Abstract

Purpose of Review

To summarize research from the last 5 years on the effects of weight loss treatments, including lifestyle changes, anti-obesity medications, and bariatric procedures on cardiovascular disease (CVD) risk factors and CVD outcomes in adults.

Recent Findings

This narrative review includes and summarizes the contemporary evidence of the effects of these different weight loss approaches individually. A literature search was performed using the key words obesity, weight loss, CVD, cardiometabolic, and risk factors and included key clinical trials from the past 5 years. Obesity management through weight loss is associated with improvements in CVD risk factors, such as improved blood pressure, lipid profiles, and glycemic control, with greater weight loss leading to greater improvements in CVD risk factors. Bariatric surgery is associated with greater weight loss than the other procedures and treatments for obesity, and for this, and possibly for other reasons, it is associated with greater reductions in CVD outcomes and mortality.

Summary

Obesity is an independent risk factor and modulator of other CVD risk factors, and thus, treatment of obesity should be an integral part of management strategies to reduce CVD risk. Future trials and real-world studies of longer duration are needed to inform providers and patients on how to individualize the approach to modifying risks of cardiometabolic disorders through obesity management.

Introduction

The prevalence of obesity continues to rise in the USA and across the world [1, 2]. Obesity is associated with serious comorbidities, affecting essentially every organ system in the body. The impact of obesity on cardiometabolic comorbidities is especially serious [3], and obesity has been shown to be associated with a significantly higher risk for cardiovascular disease (CVD) independent from other CVD risk factors [4]. Treatments for obesity, including lifestyle modification, pharmacotherapy, and bariatric procedures, are all associated with weight loss and improvements in cardiometabolic risk factors (CVD risk factors). The amount of weight loss, though, appears to be an important factor for seeing reductions in CVD outcomes and mortality. The recent Scientific Statement from the American Heart Association, Obesity and Cardiovascular Disease, summarizes the impact of obesity on CVD outcomes, diagnosis, and management [5]. In this narrative review, we summarize the contemporary data examining in detail the impact of the different obesity management approaches on CVD risk factors and CVD outcomes and mortality.

Lifestyle Modification

Lifestyle modification is the cornerstone to weight loss intervention [6]. Comprehensive lifestyle modification includes three components: dietary change, physical activity, and behavior modification. Behavioral modification, including goal-setting and self-monitoring, is helpful in implementing dietary and physical activity change [7]. Implementing a comprehensive approach has been shown to lead to weight loss, as well as reduction in CVD risk factors. In the Look AHEAD trial, participants with type 2 diabetes and overweight or obesity who underwent intensive lifestyle intervention (caloric restriction, 175 min of moderate-intensity exercise weekly, and frequent individual and group counseling sessions) had significantly more mean weight loss (6% vs. 3.5%, p < 0.05), better hemoglobin A1c (HbA1c) (7.33% vs. 7.44%, p < 0.05) despite less insulin use, reduced use of antihypertensive medications, and higher fitness level (5.38 vs. 5.02 metabolic equivalents, p < 0.05) than the control group who only received diabetes education and support [8]. While the trial did not show a reduction in CVD outcomes overall, those who lost at least 10% of their body weight with the intensive lifestyle intervention did have a reduction in CVD events [8, 9].

Diet

Dietary pattern change has been shown to induce weight loss as well as attenuate CVD risk factors and reduce CVD mortality. Plant-based diets have been associated with lower incident CVD, CVD mortality, and all-cause mortality [10]. In the multicenter randomized control trial, PREDIMED, participants at high CVD risk who were assigned to the Mediterranean diet (supplemented with extra virgin olive oil and nuts) had lower incidence of major cardiovascular events, or MACE (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke), within the follow-up period (median of 4.8 years) compared to those on low-fat diet. However, weight change was not an endpoint of this study [11••]. In the DIRECT trial, however, those on a Mediterranean diet or low-carbohydrate diet lost significantly more weight than the low-fat diet group over 24 months, despite similar caloric reduction. All diet groups had a rise in HDL-C, with the greatest rise in the low-carbohydrate group, which also had a significant decrease in triglyceride (TG) levels. At the same time, there was no significant difference in LDL-C levels or change in LDL-C levels between the three diet patterns [12]. In the DIETFITS trial, there was no significant difference in weight loss at 12 months between those adults on a healthy low-fat diet and those on a low-carbohydrate diet, yet there was a significant rise in HDL-C and a significant decrease in TG levels in the low-carbohydrate diet participants compared to those on low-fat diet. However, those on a low-fat diet had a significantly lower LDL-C level [13]. This finding was also seen in a recent meta-analysis of randomized diet trials where low-fat and low-carbohydrate diets had similar weight loss and blood pressure-lowering effect, but low-fat diets had more LDL-C decreases at 6 months. At the same time, these improvements in blood pressure and blood lipids occurring with these macronutrient diets were no longer present at 12 months when weight loss effect was also lower. Of note, weight loss and CVD risk factor improvements persisted at 12 months for the Mediterranean diet [14]. A similar effect was seen in a study on alternate day fasting where HDL-C levels were significantly increased at 6 months compared to daily caloric restriction, but not at 12 months. Interestingly, participants in the alternate day fasting group had significantly elevated LDL-C levels at 12 months compared to those on daily caloric restriction. There were no differences in other CVD risk factors, including blood pressure, TG levels, fasting insulin and glucose, insulin resistance, heart rate, or inflammatory markers (C-reactive protein or homocysteine concentrations) [15]. Overall, while diets of differing macronutrients and alternate day fasting paradigms may have benefits on CVD risk factors in the short term, the Mediterranean diet appears to be an effective treatment for weight loss and carries the best evidence for primary prevention of CVD in the long term.

Exercise

Physical activity programs or exercise training are associated with improvement in cardiovascular fitness and thereby reduction in cardiovascular risk. For this reason, the Physical Activity Guidelines for Americans, 2nd edition, recommend that adults engage in at least 150 to 300 min of moderate-intensity physical activity [16]. Physical activity without dietary change, however, often induces only modest weight loss (< 5% weight loss) if following minimum physical activity recommendations (150 min of moderate-intensity exercise per week to improve health) [17]. In 2009, the American College of Sports Medicine Position Stand reported that > 250 min of physical activity per week is associated with clinically significant weight loss and prevention of weight regain [18]. However, further analysis of the Look AHEAD trial showed that increasing fitness through physical activity improved CVD risk factors, including diastolic blood pressure, HDL-C, and TG, even without the effect of weight loss [19]. This improvement in CVD risk factors may be related to changes in body composition with exercise training (decreased fat mass and increased lean body mass) [20]. In a meta-analysis on the effects of exercise training compared to daily caloric restriction on body weight and composition, daily caloric restriction induced more weight loss. However, in the absence of weight loss, exercise training showed a greater effect on decrease in visceral adipose tissue (−6.1% vs. −1.1% with diet) [21•]. This is significant as in the Framingham Heart Study, visceral adipose tissue had a stronger correlation to a worse cardiometabolic health profile (hypertension, metabolic syndrome, impaired fasting glucose) than subcutaneous adipose tissue [22]. Therefore, exercise and increased physical activity improve cardiovascular health beyond effects seen on total body weight. Regardless, exercise has a role in weight loss management and should be undertaken in combination with dietary changes to induce the greatest benefit [20].

Anti-obesity Medications

Anti-obesity medications are indicated for patients with a body mass index (BMI) of ≥ 30 kg/m² or in those with a BMI ≥ 27 kg/m² and obesity-related comorbidities. We discuss currently available FDA-approved medications for the treatment of obesity that show clinically meaningful and sustained weight loss: phentermine, phentermine/topiramate extended release (ER), liraglutide, naltrexone-bupropion ER, and orlistat. While lorcaserin was voluntarily withdrawn in 2020 due to concerns about cancer risk, we include a summary of it here since it was available within the last 5 years. It is important to note that the high costs of anti-obesity medications and lack of coverage by commercial insurances can hinder the sustained use needed for weight loss and weight loss maintenance [23]. However, studies have demonstrated that compliant patients have a net decrease in pharmaceutical costs compared to treating obesity-related comorbid conditions [24].

Phentermine and Phentermine/Topiramate ER

Phentermine hydrochloride (HCl) is a sympathomimetic appetite suppressant that was originally approved in the USA in 1959 as a short-term (up to 12 weeks) adjunct therapy to exercise, caloric restriction, and behavioral modification for weight loss. This drug is available in 4 doses: 8 mg (Lomira®), 15 mg (generic), 30 mg (generic), and 37.5 mg (Adipex P®). The majority of the data for phentermine use and CVD outcomes is based on the FDA-approved 3-month use of the medication. Though phentermine fell out of favor in the 1990s due to its association with fenfluramine (and risk of valvular heart disease and pulmonary hypertension), it remains the most commonly prescribed anti-obesity medication today due to its low cost [23]. Yet, no randomized controlled trials or prospective studies have sufficiently determined associated CVD risks and benefits [25-27]. This is partially due to the short-term FDA approval for its use. Interestingly, phentermine is routinely prescribed off-label by providers for longer than 12 weeks. A recent 2019 study by Lewis et al. reviewed electronic health records of nearly 14,000 adults with a BMI > 27 kg/m² between 2010 and 2015 who were prescribed phentermine for up to 24 months. The control group consisted of short-term, on-label phentermine users versus comparison groups of individuals using phentermine off-label (≥ 12 weeks) for up to 24 months. The patients in this cohort overall lost more weight without an increased risk of incident CVD or death, supporting longer-term use of phentermine for lower-risk individuals [28].

The most significant cardiovascular concern with phentermine use is that it may increase blood pressure (systolic BP by approximately 11 mmHg) and heart rate (by approximately 7 bpm) given its pharmacological similarity to amphetamines [29]. For this reason, prescribing phentermine to patients with a history of CVD (e.g., coronary artery disease, stroke, arrythmias, congestive heart failure, uncontrolled hypertension) is cautioned [30, 31]. Despite this concern, older studies have shown neutral changes to decreases in blood pressure and heart rate within the first few weeks of treatment while weight loss was still occurring [32-34]. However, it is difficult to separate these effects on cardiovascular parameters from weight loss with phentermine as these studies did not include patients with CVD [25, 31]. The vast majority of the literature on cardiovascular safety and phentermine is in the context of fixed-dose phentermine/topiramate combination use.

Phentermine was approved in 2012 for long-term use in combination with topiramate ER (Qsymia®). Topiramate is an anti-epileptic medication that has suppressed appetite as a side effect [35]. The safety profile of phentermine/topiramate ER is similar to that of phentermine alone with regard to blood pressure effects and heart rate [36]. A 2014 review of over 3500 patients from the EQUIP and CONQUER trials found that heart rate increased by an average 1 bpm in approximately 900 patients taking higher doses of phentermine/topiramate ER (7.5/46 mg and 15/92 mg) at 56 weeks. There were low rates of serious adverse events of cardiac disorders [36]. A retrospective database evaluated MACE outcomes in more than 500,000 patients either currently using or previously exposed to either phentermine alone, topiramate alone, or combination phentermine/topiramate ER [37]. This study ultimately found that patients on phentermine/topiramate ER were not at an increased risk of MACE, although considerable uncertainty remains due to the overall small number of events and the observational nature of this study. A review of the U.S. FDA Adverse Event Reporting System database assessed cardiovascular safety of the current anti-obesity medications, including 3960 patients on phentermine or phentermine/topiramate ER, and found non-significant event rates for valvulopathy, pulmonary hypertension, and other CVD events when adjusted for age, weight, and gender [38]. Finally, in assessing the effects of various anti-obesity medications on blood pressure in patients with overweight/obesity and hypertension, phentermine/topiramate lowered both systolic and diastolic blood pressure [39]. Serious cardiac adverse events occurred in 6 hypertensive patients and serious adverse vascular events occurred in 2 hypertensive patients within the phentermine/topiramate ER study, but the treatment groups (intervention or placebo) of these individuals were not reported.

The majority of cardiometabolic outcomes data for both phentermine and phentermine/topiramate ER have mainly focused on the blood pressure, heart rate, and CVD outcomes discussed above. Older studies have looked at outcomes in both parameters of lipids and glycemic control and have shown favorable outcomes in HDL-C, LDL-C, TG, HbA1c, and HOMA-IR [33, 40, 41•]. Overall, both phentermine and phentermine/topiramate ER have shown positive profiles in improving cardiometabolic outcomes, though this is most likely related to the robust weight loss that can be attributable to these medications.

Liraglutide 3.0 mg

Liraglutide is a glucagon-like peptide-1 analog used for treatment of type 2 diabetes when used at a dose of 1.8 mg daily (Victoza®); it was also shown to have a dose-dependent effect on weight loss (−4.7% at 1.8 mg daily vs. −6% at 3.0 mg daily) [42] and was therefore FDA-approved for the treatment of obesity at a dose of 3.0 mg daily (Saxenda®) [43-45]. In a randomized controlled trial of liraglutide at various doses (1.2, 1.8, 2.4, or 3.0 mg daily) compared to orlistat or placebo in adults with obesity done to assess safety, tolerability, and efficacy up to 2 years, there were significantly greater decreases in body weight, body fat percentage, and mean systolic and diastolic blood pressure with liraglutide 3.0 mg daily at 1 year and with liraglutide 2.4/3.0 mg daily at 2 years [44]. In the SCALE Maintenance randomized study, those on liraglutide 3.0 mg had greater weight loss and had significant improvement in CVD risk factors (blood pressure, TG, HbA1c) over 56 weeks compared to placebo [46]. In the SCALE Obesity and Prediabetes trial, participants without diabetes in the liraglutide group had reductions in blood pressure (−4.2/ −2.6 mmHg vs. −1.5/ −1.9 mmHg), fasting lipid levels (LDL-C of −3.1% vs. −1.0%), and high-sensitivity CRP (−37.8% vs. −10.1%) and improvement in adiponectin levels (+ 11.5% vs. 3%) when compared to placebo. However, there was also a greater increase in heart rate and higher incidence of tachycardia compared to placebo, though there was no difference in cardiac arrhythmia incidence [43]. Cardiovascular safety was further evaluated in the liraglutide CVD outcome trial in type 2 diabetes (LEADER); participants with type 2 diabetes and at least one cardiovascular coexisting condition (mean baseline BMI of 32.5 kg/m²) who were on maximum of liraglutide 1.8 mg daily had lower risk of first occurrence of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. Of note, those on liraglutide had 2.3 kg greater weight loss than placebo [47]. In a post hoc analysis of the LEADER trial, patients with type 2 diabetes at high CVD risk with either a history of myocardial infarction or stroke or established ASCVD had decreased CVD outcomes; those patients with type 2 diabetes at high CVD risk due to CVD risk factors alone did not have a similar risk reduction while on liraglutide [48]. Additionally, in a recent meta-analysis of trials comparing liraglutide to placebo in adults with type 2 diabetes, those on liraglutide treatment had lower risk of major adverse cardiovascular events (MACE; death from cardiovascular causes, nonfatal [including silent] myocardial infarction, or nonfatal stroke); it is unclear if these studies included or excluded those with pre-existing cardiac disease [49]. Overall, liraglutide is an effective weight loss agent that shows persistent improvement in CVD risk factors; its secondary prevention of CVD events has only been demonstrated at a 1.8-mg dose in patients with type 2 diabetes but has not been specifically studied at a 3.0-mg dose in patients with obesity without type 2 diabetes.

Naltrexone-Bupropion ER

Naltrexone-bupropion ER (Contrave®) is a combination weight loss medication that blocks opioid-mediated inhibition of the proopiomelanocortin system with naltrexone while simultaneously acting to stimulate neurons within the hypothalamic proopiomelanocortin system with bupropion [50]. The COR-I phase 3 randomized controlled trial of naltrexone-bupropion ER compared to placebo showed clinically significant weight loss (−6.1% vs. −1.3%) [50]. In COR-II phase 3 randomized control trial, there were significant improvements with lower TG (−9.8% vs. −0.5%), lower LDL-C (−6.2 mg/dL vs. −2.1 mg/dL), lower fasting insulin (−11.4% vs. + 3.5%%), less insulin resistance (−13.8% vs. + 1.2%), and lower waist circumference (−6.7 cm vs. −2.1 cm), in addition to weight loss (−8.2% vs. −1.4%) at 56 weeks when compared to placebo; however, systolic blood pressure was significantly higher in the naltrexone-bupropion group at 56 weeks compared to placebo (+ 0.6 mmHg vs. −0.5 mmHg) [51]. These findings raised concerns for the cardiovascular safety of naltrexone-bupropion and the FDA deferred approval until a cardiovascular outcome trial was completed. Nissen et al. presented results of an interim analysis of 25% and 50% planned cardiac events in a randomized noninferiority CVD outcome trial and found that in patients with overweight or obesity at high CVD risk, the hazard ratio for MACE while on naltrexone-bupropion ER was not higher than 2.0, as specified by the FDA, and was in fact 0.59 and 0.88 at 25% and 50% analyses, respectively. However, the trial was terminated early due to the sponsor publicly releasing the confidential interim data analysis of 25% of planned cardiac events [52]. Naltrexone-buproprion ER was ultimately FDA-approved for weight loss in September 2014 as it met the pre-specified interim result boundary set for the outcome trial with data collected prior to the analysis leak [53]. At the same time, the FDA did recommend a new CVD outcome trial to show that after 100% of CVD events the hazard ratio for MACE while on naltrexone-bupropion ER was not higher than 1.4, indicating noninferiority to placebo. They also required a “Limitations of Use” statement that notes that the CVD morbidity and mortality effect is not yet known [54]. Further research on naltrexone-bupropion ER’s effects on MACE to show noninferiority to placebo is ongoing.

Orlistat

Orlistat was FDA-approved as a prescription medication (Xenical® 120 mg three times daily) in 1999 and for over-the-counter use (alli® 60 mg three times daily) in 2007 [55]. Orlistat acts through peripheral, irreversible pancreatic and gastric lipase inhibition, which impairs intestinal fat absorption [56]. Orlistat has the best long-term safety record among FDA-approved anti-obesity medications and may be preferentially preferred in patients with obesity who have CVD or psychiatric illnesses [31, 57]. However, factors such as significant gastrointestinal adverse effects and modest placebo-subtracted weight loss (~ 2–4% after 12–18 months) likely contribute to orlistat not being widely prescribed [57]. Nonetheless, recent studies continue to show significant cardiometabolic improvements with orlistat.

In 2017, Sahebkar et al. [58] conducted a systematic review and meta-analysis of 33 randomized controlled trials of orlistat versus placebo (n = 9,732) on lipid profiles and body weight (all studies testing a total of 360 mg/day, with 6 studies including lower doses; 28 studies targeted patients with obesity; range of treatment duration: 3 months to 3 years). They found that compared to control groups, orlistat significantly reduced weighted mean differences in body weight (−2.12 kg [95% CI: −2.51, −1.74], p < 0.001), total cholesterol (−11.6 mg/dL [95% CI: −13.1, −9.7], p < 0.001), LDL-C (−7.7 mg/dL [95% CI: −12.4, −8.5], p < 0.001), HDL-C (−1.3 mg/dL [95% CI: −1.5, −0.7], p < 0.001), and TG (−8.0 mg/dL [95% CI: −10.6, −5.3], p < 0.001). A 2018 systematic review and meta-analysis of the effects of weight loss medications on cardiometabolic risk profiles in adults with overweight or obesity by Khera et al. [59] analyzed 17 trials of orlistat versus placebo (n = 10,702) ranging from 6 months to 1 year in duration. They found that orlistat led to significantly reduced weighted mean differences in fasting glucose (−8.0 mg/dL [95% CI: −12.2, −3.7]), HbA1c (−0.4% [95% CI: −0.6, −0.2]), HDL (−1.1 mg/dL [95% CI: −1.9, −0.4]), waist circumference (−2.26 cm [95% CI: −2.82, −1.69]), systolic blood pressure (−1.67 mmHg [95% CI: −2.45, −0.88]), and diastolic blood pressure (−1.59 mmHg [95% CI: −2.04, −1.13]) compared to placebo.

Orlistat has recently been examined from a pragmatic perspective. In a 2019 retrospective, observational cohort study of adults (n = 400, mean age 47.3 ± 12.3 years, 75% women) with overweight (1.8%) or obesity (98.2%) who had failed to lose at least 5% body weight after a 6-month lifestyle modification program in Spain, Gorgojo-Martínez et al. [60] found that orlistat treatment (up to 360 mg three times daily) in this “real-world study” significantly reduced weight (mean weight reduction −3.3 kg [95% CI: −4.0, −2.5], p < 0.001) over a median follow-up of 7.5 months. In a subset of patients on orlistat with BMI < 35 kg/m², fasting plasma glucose (−4.3 mg/dL ± standard error [SE] 1.4, p = 0.003), systolic blood pressure (−4.4 mmHg ± 1.1, p < 0.001), diastolic blood pressure (−3.0 mmHg ± 0.7, p < 0.001), and LDL-C (−8.9 mg/dL ± 2.0, p < 0.001) all decreased during the follow-up period. Additionally, 27.4% and 11.7% of patients had > 5% and > 10% weight loss at the end of follow-up, respectively. In Grabarczyk’s 2018 retrospective analyses of US veterans participating in the VA’s MOVE! weight-management program who took orlistat (n = 6,153, mean age 58.4 ± 11.5 years, mean BMI 39.5 ± 7.6 kg/m², 75% men) in this type of “real-world clinical practice,” there was a −2.1 ± 12.7% weight change after at least 20 weeks, with 27.1% and 12.8% achieving at least 5% and 10% weight loss, but no clinically significant changes in blood pressure, lipids, or A1c at 24 weeks compared to baseline [61].

Lorcaserin

Lorcaserin (Belviq®) was FDA-approved in 2012 but voluntarily withdrawn by its manufacturer in February 2020 due to the U.S. FDA’s concerns of increased cancer risk, particularly with pancreatic, colorectal, and lung cancers [62]. A selective serotonin receptor 2C agonist, lorcaserin, stimulated only the proopiomelanocortin receptors in the hypothalamus to decrease appetite and was the most well-tolerated anti-obesity medication available [57, 63]. Three phase III randomized, double-blind, placebo-controlled trials with patients with overweight and obesity (one study in patients with diabetes) demonstrated significantly greater weight loss and higher percentage of patients losing ≥ 5% weight in the lorcaserin groups compared to placebo after 1 year [64-66]. These studies also had inconsistent significant differences in blood pressure, lipid parameters, and glycemic control depending on the study and analysis. In 2018, the phase IV trial showed that patients with overweight or obesity and atherosclerotic CVD or multiple CVD risk factors who took lorcaserin for a year had decreased incident diabetes and risk of microvascular complications compared to placebo [67].

Endoscopic Bariatric and Metabolic Therapies

Modes of weight loss action for endoscopic bariatric and metabolic therapies include gastric restriction by space-occupying devices (e.g., single or multiple intragastric balloons), gastric restriction by sutures (e.g., primary obesity surgery endoluminal [POSE] procedure), malabsorption (e.g., aspiration therapy, duodenal-jejunal bypass liner [DJBL]), and other mechanisms (e.g., botulinum toxin injection to the stomach). A 2020 comparative effectiveness systematic review by Jung et al. revealed that most endoscopic procedures demonstrated clinically significant mean differences in percent weight loss compared to controls in a network meta-analysis: aspiration therapy for 12 months, 10.4%; fluid-filled balloon for 3–6 months, 5.3%; POSE for 6 months, 4.9%; and DJBL for 3–6 months, 4.5% [68•]. However, duration of the procedures ranged from 3 to 12 months and inclusion BMI in the studies ranged significantly. The meta-analysis did not find significant mean differences in percent weight loss for the air-filled balloon or botulinum toxin. Only one randomized, double-blind, sham-controlled trial demonstrated significant total weight loss after 6 months with the swallowable gas-filled intragastric balloon system compared to control in the completer analysis (7.1 ± 5% vs. 3.6 ± 5.1%, respectively; P = 0.0085) and with 88.5% of the treatment group maintaining the weight loss at 48 weeks [69]. We will summarize a few of the studies of endoscopic bariatric and metabolic therapies from the last 5 years that examined cardiometabolic changes aside from weight loss.

Gastric Restriction by Space-Occupying Devices

Fluid-Filled Intragastric Balloons

In a 2018 investigator-initiated, post-FDA regulatory approval, multicenter study using prospectively collected data, Vargas et al. found that a single fluid-filled intragastric balloon placed in adults with obesity (n = 321, mean age 48.1 ± 11.9 years, mean BMI 37.6 ± 6.9 kg/m², 80% female) resulted in mean body weight loss of 8.5 ± 4.9% (n = 204), 11.8 ± 7.5% (n = 199), and 13.3 ± 10% (n = 47) at 3, 6, and 9 months, respectively [70]. Very few participants had cardiometabolic measurements, but significant reductions were seen in total cholesterol (167.1 ± SD 33 vs. 181 ± 39 mg/dL, p = 0.02), TG (129.8 ± 87 vs. 174.6 ± 157 mg/dL, p = 0.02), LDL-C (94.9 ± 23.3 vs. 101.6 ± 32.8 mg/dL, p = 0.045), HbA1c (6.1 ± 1.3 vs. 6.97 ± 1.6%, p = 0.01), systolic blood pressure (128.7 ± 15 vs. 133.4 ± 19.9 mmHg, p = 0.003), and diastolic blood pressure (75.6 ± 10.9 vs. 77.3 ± 11.8 mmHg, p = 0.03), between 6 months and baseline.

A 2019 prospective observational cohort study by Guedes et al. looked at 6-month outcomes in adults with obesity (n = 42, mean age 37.6 ± SE 1.28 years, mean BMI 35.15 ± 0.41 kg/m², 76% female) who used adjustable or non-adjustable fluid-filled intragastric balloons [71]. Results revealed a significant 15.88 ± 1.42% reduction in body weight and 12.07 ± 1.18% reduction in waist circumference (p < 0.0001 for both compared to baseline). They also found significant reductions in HOMA-IR (0.97 [IQR: 0.56–1.27] vs. 2.36 [IQR: 1.41–3.51], p < 0.0001), TG (90 [IQR: 72–115] vs. 113 [IQR: 83–157] mg/dL, p < 0.0001), leptin (16.42 [IQR: 8.38–27.05] vs. 60.21 [29.76–100] ng/mL, p < 0.0001), and high-sensitivity (hs) CRP (0.26 [IQR: 0.12–0.46] vs. 0.58 [0.31–1.21] mg/dL, p < 0.0001) but not in total cholesterol, HDL-C, or LDL-C, post- versus preballoon placement, respectively.

In 2020, Wojciechowska-Kulik et al. found that fluid-filled intragastric balloon therapy in adults with metabolic syndrome (n = 30, median BMI 38.9 [IQR: 34.3, 44.1] kg/m², 56% female) resulted in a significant 13.6% weight loss and 11.9% decrease in BMI compared to baseline. They also demonstrated significant decreases in TG (−36.3%, [IQR: −54.8, −15.8], p < 0.0001), glucose (−15.5% [IQR: −28, −3], p < 0.001), leptin (−35.5% [IQR: −65.9, −22.6]), p < 0.04), and hsCRP (−40.9% [IQR: −53.8, −23.3]) after 6 months, but all were still elevated compared to the control group, and no significant changes in total cholesterol, LDL-C, and HDL-C [72].

Malabsorption Procedures

Aspiration Therapy

Aspiration therapy utilizes a percutaneous device that decreases the amount of calories the body processes by removing carefully chewed food from the stomach. In a 1-year US-based, multicenter, randomized controlled trial (PATHWAY) comparing aspiration therapy plus lifestyle therapy to lifestyle therapy-alone, the aspiration therapy group lost significantly more weight than the lifestyle group (12.1 ± 9.6 vs. 3.5 ± 6.0%, respectively; P < 0.001) [73]. In a modified intent-to-treat analysis, while aspiration therapy was associated with significant improvements in HbA1c, TG, and HDL-C, these were not statistically different than the lifestyle group. Four-year follow-up data on the aspiration therapy participants who continued the trial showed that 69% of the participants maintained ≥ 10% weight loss [74]. Furthermore, there were significant reductions compared to baseline in blood pressure, HbA1c, and ALT and increases in HDL-C over that time of follow-up.

Duodenal-Jejunal Bypass Liner

The DJBL is placed endoscopically within the duodenum and proximal jejunum, acting as a physical barrier between food and digestive enzymes within the foregut. A 2018 case–control study in patients with obesity and type 2 diabetes (DJBL n = 111; control n = 222) found that DJBL (mean treatment time 47.5 ± 12.2 weeks) was associated with higher odds of BMI reduction ≥ 5 kg/m² (OR 17.59; 95% CI 8.98–34.36),;HbA1c improvement > 1% (OR 3.37; 95% CI 2.09–5.4); LDL-C reduction ≥ 10 mg/dL (OR 3.37; 95% CI 1.83–6.18); and total cholesterol reduction ≥ 20 mg/dL (OR 2.17; 95% CI 1.20–4.02), compared to routine care (unspecified lifestyle changes and glucose-lowering medications) [75]. No significant effects were seen on HDL-C, triglycerides, or blood pressures.

In 2020, a UK group published results on the impact of DJBL on weight loss and cardiometabolic profiles from a multicenter, open-label, randomized control trial of adults with obesity and type 2 diabetes mellitus. According to Ruban et al., the DJBL cohort (n = 85, mean age 51.6 ± SD 7.9 years, mean BMI 36.8 ± 5.0 kg/m², 45.9% female) had significantly more patients who lost > 15% of their total body weight (OR 8.33 [95% CI: 1.78, 39.0], p = 0.0007) and achieved blood pressure targets of < 135/85 (OR 2.57 [95% CI 1.21, 5.48], p = 0.014) at 12 months compared to controls who underwent intensive lifestyle modification alone, but there was no difference between groups at 24 months [76]. The proportion achieving glycemic targets (HbA1c < 6%) at 12 and 24 months was not significantly different between groups. From a sub-group of the main study population, Glaysher et al. reported that the DJBL group (n = 70, mean age 51.6 ± SD 7.8 years, mean BMI 37.0 ± 5.0 kg/m², 45.7% female) had greater weight loss (11.3 ± 5.3% vs. 6.0 ± 5.7%, p < 0.001), lower total cholesterol (4.10 ± 0.96 vs. 4.36 ± 0.96 mmol/L, p < 0.05), and lower HDL-C (1.15 ± 0.30 vs. 1.29 ± 0.32 mmol/L, p < 0.05), but no significant differences in BMI, LDL-C, or triglycerides, after 11.5 months compared to control, respectively [77]. Given these results and economic analyses, the study team concluded that DJBL was not cost-effective for weight loss or glycemic control in this UK population [76].

Bariatric Surgery

Bariatric surgery has proven to be the most effective tool for weight loss in patients with obesity who qualify for surgery. Of the 256,000 bariatric surgery cases annually, sleeve gastrectomy (SG, 59%) and Roux-en-Y gastric bypass (RYGB, 18%) are the most common procedures performed at present. Other surgical weight loss procedures, including gastric banding (GB) and vertical banded gastroplasty (VBG), have waned in popularity due to complication rates and limited weight loss benefit [78]. SG is performed by removing 80% of the stomach, with the remaining stomach forming a small pouch. RYGB divides the first section of the intestine and brings the distal end to meet a small stomach pouch created and separated from the remainder of the stomach. Both procedures reduce the amount of food which can enter the stomach and trigger changes in gut hormones which reduce hunger and increase satiety [79]. Candidates for surgery typically have a body mass index (BMI) above 40 or a BMI greater than 35 with one or more obesity-related condition such as type 2 diabetes, hypertension, sleep apnea, non-alcoholic fatty liver disease, lipid abnormalities, or cardiovascular disease. Typical post-surgical weight loss varies by study type, with observational data from the PCORnet Bariatric Study showing 5-year mean percent total weight loss of 25.5% for RYGB and 18.8% for sleeve gastrectomy, while randomized trials of RYGB versus sleeve gastrectomy show no significant difference in BMI reduction between procedures at 5-year follow-up [80].

Despite the variance among measured outcomes, the resulting weight loss has been shown to improve multiple weight-related comorbidities that offer cardiometabolic benefit, including diabetes [81]. Courcoulas et al. showed 70% of patients with diabetes went into remission at 1 year after Roux-en-Y gastric bypass surgery (RYGB), with 10% recurring at 7 years; hypertension resolved in 45% at 1 year (10% recurred by 7 years) and approximately 90% of high TG levels, 80% of low HDL-C levels, and 60% of high LDL-C levels resolved by 7 years [82]. Similarly, Adams et al. demonstrated greater remission of multiple metabolic conditions 12 years after RYGB relative to two non-surgical control groups: diabetes remitted in 51% of RYGB cases versus 10% and 5% of controls; hypertension resolved in 36% of RYGB cases versus 10% and 14% of controls; improvements in high LDL-C and low HDL-C levels were also noted. New diabetes diagnoses occurred in 3% of RYGB cases, whereas 26% of both control groups developed diabetes in 12-year follow-up [83]. The Diabetes Surgical Study assessed for a primary outcome at 5 years of the American Diabetes Association triple endpoint of HbA1c < 7.0%, LDL cholesterol < 100 mg/dL, and systolic blood pressure < 130 mmHg, finding 23% of patients after RYGB plus intensive lifestyle intervention (ILI) hit all three targets compared to 4% receiving ILI alone [84]. Furthermore, bariatric surgery has also been shown to reduce atherosclerosis as seen with reductions in intima-media thickness after RYGB [85].

In addition to reducing overall risk of premature death [86, 87], bariatric surgery also demonstrates benefit in reducing CVD outcomes. Fisher et al. showed in a multicenter retrospective cohort of patients who had undergone bariatric surgery (76% RYGB, 17% SG) versus matched controls that surgery reduced the rate of coronary artery and cerebrovascular events by 50% over 10 years [88]. Aminian et al. also showed in a single-center (Cleveland Clinic Health System) retrospective cohort study (63% RYGB, 32% SG) that metabolic surgery was associated with a significant 39% reduction in MACE and 41% in all-cause mortality [89]. The Swedish Obese Subjects study (66% VBG, 16% RYGB, 17% GB) also found that bariatric surgery reduced CVD events in all subjects and in a sub-analysis of patients with diabetes [90], while a national cohort in Sweden of RYGB patients with diabetes exhibited similar benefit compared to matched controls [91, 92]. A single-center RYGB cohort of patients compared to matched controls without CVD similarly showed reduction in cardiovascular events (myocardial infarction and stroke) as well as lower long-term risk of congestive heart failure [93]. A more recent nested cohort study within the Clinical Practice Research Datalink (38% RYGB, 35% GB, 14% SG) showed that patients who underwent bariatric surgery had significant reductions in long-term risk of CVD, heart failure, and death [94•]. Data from bariatric surgery patients (45% SG, 42% RYGB, 13% GB) in the U.S. Renal Data System registry showed that bariatric surgery was associated with 31% reduction in all-cause mortality as compared to usual care and that this was driven by reduction in CVD outcomes [95]. In summary, bariatric surgery has been shown to lead to significant improvements in CVD risk factors and CVD outcomes.

Summary and Conclusion

Obesity is associated with significantly increased risk for CVD events and death. Treatment of obesity with lifestyle/behavioral change, anti-obesity medications, endoscopic bariatric procedures, and bariatric surgery all improve CVD risk factors in a dose-dependent manner. Lifestyle changes with diet and increased physical activity benefit CVD risk factors and reduce CVD events beyond and independent of weight loss. While anti-obesity medications improve all CVD risk factors due to their benefits on adiposity, these treatments have not been associated with reduced CVD events. Studies on endoscopic bariatric procedures have had short follow-up, revealing significant weight loss and improvement in CVD risk factors, but insufficient study duration to evaluate CVD events. Bariatric surgery is associated with the greatest sustained weight loss and has been shown to improve CVD outcomes and death. Obesity is an independent risk factor and modulator of other CVD risk factors, and thus, treatment of obesity should be an integral part of management strategies to reduce CVD risk. Future trials and real-world studies of longer duration are needed to inform providers and patients on how to individualize the approach to modifying risks of cardiometabolic disorders through obesity management.