Long-term cancer outcomes after bariatric surgery.

OBJECTIVE: Obesity is associated with increased cancer risk. Because of the substantial and sustained weight loss following bariatric surgery, postsurgical patients are ideal to study the association of weight loss and cancer. METHODS: Retrospectively (1982-2019), 21,837 bariatric surgery patients (surgery, 1982-2018) were matched 1:1 by age, sex, and BMI with a nonsurgical comparison group. Procedures included gastric bypass, gastric banding, sleeve gastrectomy, and duodenal switch. Primary outcomes included cancer incidence and mortality, stratified by obesity- and non-obesity-related cancers, sex, cancer stage, and procedure. RESULTS: Bariatric surgery patients had a 25% lower risk of developing any cancers compared with a nonsurgical comparison group (hazard ratio [HR] 0.75; 95% CI 0.69-0.81; p < 0.001). Cancer incidence was lower among female (HR 0.67; 95% CI 0.62-0.74; p < 0.001) but not male surgery patients, with the HR lower for females than for males (p < 0.001). Female surgery patients had a 41% lower risk for obesity-related cancers (i.e., breast, ovarian, uterine, and colon) compared with nonsurgical females (HR 0.59; 95% CI 0.52-0.66; p < 0.001). Cancer mortality was significantly lower after surgery in females (HR 0.53; 95% CI 0.44-0.64; p < 0.001). CONCLUSIONS: Bariatric surgery was associated with lower all-cancer and obesity-related cancer incidence among female patients. Cancer mortality was significantly lower among females in the surgical group versus the nonsurgical group.

Pre-Operative Substance Use Disorder is Associated with Higher Risk of Long-Term Mortality Following Bariatric Surgery.

PURPOSE: Metabolic and bariatric surgery (MBS) has been associated with reduced all-cause mortality. While the number of subjects with substance use disorders (SUD) before MBS has been documented, the impact of pre-operative SUD on long-term mortality following MBS is unknown. This study assessed long-term mortality of patients with and without pre-operative SUD who underwent MBS. MATERIALS AND METHODS: Two statewide databases were used for this study: Utah Bariatric Surgery Registry (UBSR) and the Utah Population Database. Subjects who underwent MBS between 1997 and 2018 were linked to death records (1997-2021) to identify any death and cause for death following MBS. All deaths (internal, external, and unknown reasons), internal deaths, and external deaths were the primary outcomes of the study. External causes of death included death from injury, poisoning, and suicide. Internal causes of death included deaths that were associated with natural causes such as heart disease, cancer, and infections. A total of 17,215 patients were included in the analysis. Cox regression was used to estimate hazard ratios (HR) of controlled covariates, including the pre-operative SUD. RESULTS: The subjects with pre-operative SUD had a 2.47 times higher risk of death as compared to those without SUD (HR = 2.47, p < 0.01). Those with pre-operative SUD had a higher internal cause of death than those without SUD by 129% (HR = 2.29, p < 0.01) and 216% higher external mortality risk than those without pre-operative SUD (HR = 3.16, p < 0.01). CONCLUSION: Pre-operative SUD was associated with higher hazards of all-cause, internal cause, and external cause mortality in patients who undergo bariatric surgery.

Long-term all-cause and cause-specific mortality for four bariatric surgery procedures.

OBJECTIVE: This retrospective study incorporated long-term mortality results after different bariatric surgery procedures and for multiple age at surgery groups. METHODS: Participants with bariatric surgery (surgery) and without (non-surgery) were matched (1:1) for age, sex, BMI, and surgery date with a driver license application/renewal date. Mortality rates were compared by Cox regression, stratified by sex, surgery type, and age at surgery. RESULTS: Participants included 21,837 matched surgery and non-surgery pairs. Follow-up was up to 40 years (mean [SD], 13.2 [9.5] years). All-cause mortality was 16% lower in surgery compared with non-surgery groups (hazard ratio, 0.84; 95% CI: 0.79-0.90; p < 0.001). Significantly lower mortality after bariatric surgery was observed for both females and males. Mortality after surgery versus non-surgery decreased significantly by 29%, 43%, and 72% for cardiovascular disease, cancer, and diabetes, respectively. The hazard ratio for suicide was 2.4 times higher in surgery compared with non-surgery participants (95% CI: 1.57-3.68; p < 0.001), primarily in participants with ages at surgery between 18 and 34 years. CONCLUSIONS: Reduced all-cause mortality was durable for multiple decades, for multiple bariatric surgical procedures, for females and males, and for greater than age 34 years at surgery. Rate of death from suicide was significantly higher in surgery versus non-surgery participants only in the youngest age at surgery participants.

Association of Pre-operative Arthritis with Long-Term Mortality Following Bariatric Surgery.

BACKGROUND: Metabolic and bariatric surgery (MBS) is an effective treatment for obesity and may reduce mortality. Several factors are associated with higher mortality following MBS. The purpose of this study was to examine whether pre-operative arthritis was associated with long-term mortality following MBS. METHODS: Using a retrospective cohort design, subjects who underwent MBS were identified from the Utah Bariatric Surgery Registry. These subjects were linked to the Utah Population Database. State death records from 1998 through 2021 were used to identify deaths following MBS. ICD-9/10 diagnosis codes were used to identify a pre-operative diagnosis of arthritis and to classify the cause of death. All causes of death, internal cause of death (e.g., diabetes, heart disease), and external cause of death (e.g., suicide) were defined as outcomes. Entropy balancing (EB) was applied to create weights to balance the baseline characteristics of the two groups. Weighted Cox proportional hazards regression was used to evaluate the association of pre-operative arthritis with long-term mortality following MBS. RESULTS: The final sample included 15,112 patients. Among them, 36% had a pre-operative arthritis diagnosis. Average (SD) age was 48(12) years old at surgery, and 75% were female. Patients with pre-operative arthritis had 25% (p < 0.01) and 26% (p < 0.01) higher risk of all cause of death and internal cause of death, respectively, compared to patients without pre-operative arthritis. CONCLUSION: Individuals with arthritis prior to MBS may have higher hazard of long-term mortality than those without pre-operative arthritis.

Development of dementia in patients who underwent bariatric surgery.

BACKGROUND: Dementia, including Alzheimer's disease, interfere with daily function and are one of the major causes of disability, institutionalization, and death. Obesity is associated with an increased risk of dementia. However, the effect of significant and sustained weight loss following bariatric surgery on dementia is not known. The purpose of this study was to assess the long-term risk of dementia following bariatric surgery. METHODS: A surgical cohort was identified from the Utah Bariatric Surgery Registry and was linked to the Utah Population Database that includes electronic medical records, death records, and State Facility data. Adult subjects (≥ 18 years old) at time of surgery (1996-2016) were matched with non-surgical subjects. The final sample included 51,078 subjects (1:2 matching); surgery group n = 17,026; non-surgery subjects n = 34,052). Dementia were identified by ICD-9/10 diagnosis codes following surgery year or matched baseline year. Cox proportional hazard model was used to calculate the hazard ratio in the outcome between the groups. RESULTS: Average (SD) age of the subjects was 42 (12) years old at surgery or matched baseline year, 78% were female and mean follow-up time was 10.5 years. 1.4% of the surgery group and 0.5% of the control group had an incidence of dementia. Controlling the covariates in the Cox regression, the surgery group had a higher risk for dementia incidence than the matched non-surgery subjects (HR = 1.33, p = 0.02). CONCLUSIONS: The study showed an increased hazard for dementia in individuals who underwent bariatric surgery compared to matched non-surgical subjects. Additional long-term data is needed to verify this association.

Following Roux-en-Y gastric bypass surgery, serum ceramides demarcate patients that will fail to achieve normoglycemia and diabetes remission.

BACKGROUND: Obesity is a prevalent health threat and risk factor for type 2 diabetes. In this study, we evaluate the relationship between ceramides, which inhibit insulin secretion and sensitivity, and markers of glucose homeostasis and diabetes remission or recursion in patients who have undergone a Roux-en-Y gastric bypass (RYGB). METHODS: The Utah Obesity Study is a prospective cohort study, with targeted ceramide and dihydroceramide measurements performed on banked serum samples. The Utah Obesity Study consists of 1,156 participants in three groups: a RYGB surgery group, a non-surgery group denied insurance coverage, and severely obese population controls. Clinical examinations and ceramide assessments were performed at baseline and 2 and 12 years after RYGB surgery. FINDINGS: Surgery patients (84% female, 42.2 ± 10.6 years of age at baseline) displayed lower levels of several serum dihydroceramides and ceramides at 2 and 12 years after RYGB. By contrast, neither the control group (77% female, 48.7± 6.4 years of age at baseline) nor the non-surgery group (95% female, 43.0± 11.4 years of age at baseline) experienced significant decreases in any species. Using a linear mixed effect model, we found that multiple dihydroceramides and ceramides positively associated with the glycemic control measures HOMA-IR and HbA1c. In surgery group participants with prevalent diabetes, ceramides inversely predict diabetes remission, independent of changes in weight. CONCLUSIONS: Ceramide decreases may explain the insulin sensitization and diabetes resolution observed in most RYGB surgery patients. FUNDING: Funded by the National Institutes of health (NIH), The Juvenile Diabetes Research Foundation, and the American Heart Association.

Depression and Anxiety Incidence During Pregnancy Between Bariatric Surgery Patients and Matched Control Subjects.

PURPOSE: Obesity is a well-known risk factor for depression and mental illnesses. Metabolic and bariatric surgery (MBS) is a common treatment for individuals with severe obesity. Studies suggest that MBS is associated with increased risk of depression. However, little is known if pregnant women following MBS have greater incidence of depression/anxiety than non-surgical pregnant women with severe obesity. MATERIALS AND METHODS: Utah Bariatric Surgery Registry (UBSR) was used to identify subjects who underwent bariatric surgery between 1996 and 2016 and were matched (1:2 matching) to subjects with severe obesity from the Utah Population Database (UPDB). Depression and anxiety diagnoses during pregnancy were identified from birth records and electronic medical records (EMRs) during 10 months before birth. A multivariate logistic regression with clustering due to same subjects with multiple births was used. RESULTS: Patients included 1427 MBS women (associated 2492 births) and 2854 non-surgical women (associated 4984 births). In the surgical group, 24.4% of the pregnancies had diagnosed depression/anxiety, while 14.3% of the pregnancies in the control group had depression/anxiety (p < 0.01). The surgery group had 1.51 times higher odds of depression and/or anxiety during pregnancy than the control group after controlling for covariates (OR = 1.51, p < 0.01). CONCLUSION: The present study provides evidence that women who previously underwent MBS have higher odds of depression/anxiety during pregnancy than women with obesity who did not undergo MBS.

Association of prenatal substance use disorders with pregnancy and birth outcomes following bariatric surgery.

BACKGROUND/OBJECTIVES: While an increased risk for substance use disorders (SUD) and also for several adverse pregnancy and birth outcomes in patients who have undergone bariatric surgery have been well documented when considered separately, an association between these important risk factors has not been investigated. This study explored the potential dependence of these two bariatric surgery-related risks. SUBJECTS/METHODS: This study was a retrospective cohort study with adult women (18-45) who underwent bariatric surgery between 1996 and 2016 and who gave birth after surgery between 1996 and 2018. The study population consisted of 1849 post-bariatric surgery women with 3010 reported post-surgical births. Subjects with post-surgical, prenatal SUD were identified based on diagnosis codes extracted within the 10 months prior to delivery. Using random-effects logistic regression with retrospective cohort data, preterm birth, low birth weight, macrosomia, Caesarian delivery, congenital anomalies, and neonatal intensive care unit admission were considered as outcomes. RESULTS: About 10% (n = 289) of women had an SUD diagnosis within 10 months prior to child delivery. Women with SUD during pregnancy had significantly more pregnancy and birth complications compared to women without SUD: preterm birth (OR = 2.08, p = 0.03, 95% CI: 1.07-4.03), low birth weight (OR = 3.41, p < 0.01, 95% CI: 1.99-5.84), Caesarian delivery (OR = 9.71, p < 0.01, 95% CI: 2.69-35.05), and neonatal intensive care unit admission (OR = 3.87, p < 0.01, 95% CI: 2.04-7.34). Women with SUD had lower risk for macrosomia than women without SUD (OR = 0.07, p = 0.02, 95% CI: 0.01-0.70). CONCLUSION: Results from this study demonstrated that post-bariatric surgery women who had SUD during pregnancy had significantly more pregnancy- and birth-related complications than post-surgery pregnant women without SUD, despite the reduction in macrosomia. Where possible, greater prenatal surveillance of post-surgery women with SUD should be considered.

Proteome-wide associations with short- and long-term weight loss and regain after Roux-en-Y gastric bypass surgery.

OBJECTIVE: Gastric bypass surgery results in long-term weight loss. Small studies have examined protein changes during rapid weight loss (up to 1 or 2 years post surgery). This study tested whether short-term changes were maintained after 12 years. METHODS: A 12-year follow-up, protein-wide association study of 1,297 SomaLogic aptamer-based plasma proteins compared short- (2-year) and long-term (12-year) protein changes in 234 individuals who had gastric bypass surgery with 144 nonintervened individuals with severe obesity. RESULTS: There were 51 replicated 12-year protein changes that differed between the surgery and nonsurgery groups. Adjusting for change in BMI, only 12 proteins remained significant, suggesting that BMI change was the primary reason for most protein changes and not non-BMI-related surgical effects. Protein changes were related to BMI changes during both weight-loss and weight-regain periods. The significant proteins were associated primarily with lipid, uric acid, or resting energy expenditure clinical variables and metabolic pathways. Eight protein changes were associated with 12-year diabetes remission, including apolipoprotein M, sex hormone binding globulin, and adiponectin (p < 3.5 × 10-5 ). CONCLUSIONS: This study showed that most short-term postsurgical changes in proteins were maintained at 12 years. Systemic protection pathways, including inflammation, complement, lipid, and adipocyte pathways, were related to the long-term benefits of gastric bypass surgery.

Prescriptions for pain medication before and after bariatric surgery.

BACKGROUND: Significant and sustained weight loss resulting from bariatric surgery have demonstrated clinical reduction in severe obesity-related pain. Subsequentially, post-surgical pain reduction may reduce pain medication use. However, clear evidence regarding use of prescribed pain medications before and after bariatric surgery is absent. METHODS: Linking two state-wide databases, patients who underwent bariatric surgery between July 1, 2013 and December 31, 2015 were identified. Proportion tests were used to compare percent of patients with pain medication prescriptions 1 year before and 1 year after bariatric surgery. Logistic regression was used to identify baseline factors that were associated with pain medication use 1-year following surgery. RESULTS: A total of 3535 bariatric surgical patients aged 18-64 years at surgery were identified. Of these patients, 1339 patients met the following study criteria: covered by private insurance; known pre-surgical BMI; and continuous enrollment with health plan(s) from 12-month pre-surgery to 13-month post-surgery. While comparison of average number of overall pain medication prescriptions before and after surgery did not change, from 3.46 to 3.32 prescriptions (p value = 0.26), opioid prescription use increased from 1.62 vs. 2.05 (p value < 0.01). Patients prescribed more types of pain medications before surgery were more likely to have prescribed pain medications after surgery. Patients prescribed benzodiazepines at baseline had higher odds being prescribed post-surgery corticosteroids (OR = 1.89, p value < 0.01), muscle relaxants (OR = 2.18, p value < 0.01), and opioids (OR = 3.06, p value = < 0.01) compared to patients without pre-surgery--prescribed benzodiazepine. CONCLUSION: While comparison of average number of overall pain medication prescriptions before and after bariatric surgery did not decrease, opioid prescription increased post-surgery. Further studies are needed to examine whether post-surgery opioids are prescribed in lieu of or in tandem with other pain medication prescriptions.

Effects of Post-operative Nutritional Disorders Following Bariatric Surgery on Health Care Cost and Use.

PURPOSE: Risk of nutritional disorders (NDs) in bariatric surgical patients has led to guideline recommendations for pre- and post-operative nutrient deficiency screening. The aim of this study was to identify baseline factors associated with incident NDs and, in addition, to explore possible differences in health care spending and use between patients with and without incident NDs following bariatric surgery. MATERIALS AND METHODS: Using data linked with a state-wide bariatric surgical registry and a state-wide claims database, subjects who underwent bariatric surgery between July 1, 2013, and December 31, 2015, were identified. Incident NDs and health care cost and use outcomes following 1 year from surgery were extracted from the claims data. Logistic regression was used to identify baseline factors associated with incident NDs. Zero-inflated negative binomial regression and generalized linear regression were used to estimate health care cost and use outcomes. RESULTS: A total of 3535 patients who underwent bariatric surgery were identified. Of these patients, those without continuous health insurance enrollment (n=1880), having prevalent (pre-surgery) NDs (n=461), and missing baseline BMI (n=41) were excluded. Of patients analyzed (n=1153), about 30% had incident NDs, with a mean (SD) age and BMI at surgery of 46 (12) years and 48 (9.2) kg/m2, respectively. Patients with one incident ND had higher total health care spending (coefficient=$41118, p-value<0.01) and ED visits (IRR=1.86, p-value<0.01). CONCLUSION: Those without pre-operative NDs may have a higher chance of having NDs post-operatively. Taking multivitamins and continues monitoring are necessary to prevent any negative outcomes related to post-operative NDs.

Associations of Visceral, Subcutaneous, Epicardial, and Liver Fat with Metabolic Disorders up to 14 Years After Weight Loss Surgery.

Background: Bariatric surgery leads to long-term remission and reduced incidence of diabetes, hypertension, and dyslipidemia. Short-term studies suggest reduction in specific fat depots may be more predictive of health improvement than reduced body mass index (BMI). Visceral, subcutaneous, epicardial, and liver fat, measured 11 years after bariatric surgery, were associated with long-term remission and incidence of diabetes, dyslipidemia, and hypertension. Methods: Fat depots an average of 11 (maximum 14) years after surgery were quantified by noncontrast computed tomography in subjects who did (N = 261; 86% gastric bypass) or did not (N = 243) have bariatric surgery. Multiple regression related fat depots to disease endpoints with and without adjustment for change in BMI and surgical status. Results: Visceral fat was 42% lower, subcutaneous fat 20% lower, epicardial fat 30% lower, and liver-to-spleen density ratio 9% higher at follow-up in the bariatric surgery group compared with the nonsurgery group (all P < 0.01). Higher visceral fat at follow-up exam was significantly associated with reduced remission and increased incidence of diabetes, hypertension, and dyslipidemia. Subcutaneous fat was not associated with disease. The liver-to-spleen ratio was associated with the remission and incidence of hypertriglyceridemia and not with other fat depots. Epicardial fat was related to incidence of elevated low-density lipoprotein cholesterol and low high-density lipoprotein cholesterol. Conclusions: Whether or not a patient shows greater long-term diabetes, dyslipidemia, or hypertension remission or incidence after bariatric surgery appears dependent on the amount of fat within specific fat depots measured at follow-up. Furthermore, associations of the three disease endpoints with different fat depots suggest varied fat depot pathology.

Longitudinal Changes in Cardiac Structure and Function in Severe Obesity: 11-Year Follow-Up in the Utah Obesity Study.

Background Progressive cardiac remodeling and worsening myocardial function over time have been proposed as potential mediators of heart failure in obesity. Methods and Results We serially assessed cardiac structure and function in 254 subjects participating in a longitudinal study of obesity. Demographic, clinical, laboratory, and echocardiographic features were determined at baseline and 2-, 6-, and 11-year follow-up. We measured body mass index (BMI) exposure as the area under the curve of the BMI at each of the 4 visits. At enrollment, mean age of the subjects was 47 years, 79% were women, mean BMI was 44 kg/m2, 26% had diabetes mellitus, 48% had hypertension, and 53% had hyperlipidemia. Between baseline and 11 years, BMI increased by 1.1 and 0.3 kg/m2 in men and women, respectively. There were modest increases in left ventricular (LV) end-diastolic volume, LV mass, and left atrial volume, and significant decreases in early/late mitral diastolic flow velocity ratio and E wave deceleration time. However, there were no significant changes in LV ejection fraction or ratio of early mitral diastolic flow velocity/early mitral annular velocity, whereas right ventricular fractional area change increased. Significant predictors of the change in LV mass were male sex, baseline BMI, BMI area under the curve, and change in LV stroke volume, but not smoking, hypertension, or diabetes mellitus. Conclusions In long-standing, persistent severe obesity, there was evidence of cardiac remodeling over a period of 11 years, but no clear worsening of systolic or diastolic function. Measures of remodeling were most strongly related to BMI. The observed changes might predispose to heart failure with preserved ejection fraction, but are not classic for an evolving dilated cardiomyopathy.

Gut microbiota differs a decade after bariatric surgery relative to a nonsurgical comparison group.

BACKGROUND: Few studies have assessed differences in the gut microbiota composition after bariatric surgery in the long term or whether differences are correlated with remission of type 2 diabetes. OBJECTIVES: This observational study assessed differences in the gut microbiota between individuals at up to 13 years after surgery and a comparison group of individuals with severe obesity. The relationship between type 2 diabetes remission and the gut microbiota was also assessed. SETTING: University. METHODS: Stool samples were collected from individuals completing bariatric surgery (surgery group; n = 16) and individuals with severe obesity that did not receive surgery (nonsurgery group; n = 19) as part of the 12-year follow-up in the Utah Obesity Study. Metabolic health data were collected at baseline and the follow-up examination. The gut microbiota was quantified by sequencing the V4 region of the 16 S rRNA gene. Significant differences in microbiota composition with surgery and other covariates were determined by Unifrac distance analysis and permutational multivariate analysis of variance. Significant differences in the relative abundance of individual bacterial taxa were assessed using analysis of composition of microbiomes software. RESULTS: The surgery group had higher relative abundances of Verrucomicrobiaceae (5.7 ± 1.3% versus 1.1 ± .3%) and Streptococcaceae (6.3 ± 1.0% versus 3.2 ± .8%), but lower relative abundances of Bacteroidaceae (8.8 ± 1.8% versus 18.6 ± 2.3%) 10.6 years after surgery. In a small subset of 8 individuals, a higher relative abundance of Akkermansia muciniphila was correlated with type 2 diabetes remission. CONCLUSIONS: Differences in the gut microbiota are evident a decade after bariatric surgery compared with individuals with severe obesity that did not undergo surgery. The observed long-term differences are consistent with previous findings.

Healthcare cost and utilization of bariatric surgical patients with and without preoperative mental health diagnoses.

BACKGROUND: Postoperative healthcare cost and use among patients with and without preoperative mental health illness are not well known. OBJECTIVE: This study compared total healthcare spending and use (emergency department [ED] visits and inpatient admissions) after 1 year post operation of those with and without preoperative mental health disorders. SETTING: United States. METHODS: Mental illness disorders were identified using International Classification of Disease-9/10 diagnosis codes in a statewide bariatric surgery registry and in claims databases that were linked to identify the study cohort. Generalized linear regression and zero-inflated negative binomial regression were used for the healthcare cost and use outcomes. RESULTS: Among 3580 registry patients with private insurance, 1610 patients with continuous enrollment and without missing body mass index data were included. Among patients, 56.8% (n = 915) had diagnosed mental health disorders before surgery. Those with mental illness spent more in total cost than those without mental illness (unstandardized coefficient = $18,513, P value < .01) in the first year after surgery. Those with mental illness had a 73% higher rate in ED visits (P value < .01), 83% higher rate in preventable ED use (P value < .01), and a 101% higher rate in hospital admissions (P value < .01) than those without mental illness. CONCLUSIONS: Patients with mental health diagnoses before having bariatric surgery appear to have significant positive association with surgical outcomes relating to postsurgical healthcare cost and utilization. Greater postsurgical surveillance may be warranted for bariatric surgery patients with preoperative mental illness to reduce postoperative ED visits and inpatient admissions.

FGF19 Analog as a Surgical Factor Mimetic That Contributes to Metabolic Effects Beyond Glucose Homeostasis.

Bariatric surgery has proven to be the most effective treatment for controlling hyperglycemia in severely obese patients with diabetes. We show that fibroblast growth factor 19 (FGF19), a gut hormone, is rapidly induced by bariatric surgery in rodents and humans. Administration of FGF19 achieves diabetes remission independent of weight loss in animal models of diabetes, supporting a role for FGF19 in the hormonal remodeling that restores metabolic function after the surgery. Through an unbiased, systematic screen in diabetic mice, we identified selective, safe, and effective FGF19 analogs. Unexpectedly, a lead FGF19 analog, NGM282, did not correct hyperglycemia in patients with type 2 diabetes. In contrast, administration of NGM282 resulted in a rapid, robust, and sustained reduction in liver fat content and an improvement in liver histology in patients with nonalcoholic steatohepatitis, faithfully replicating another key benefit of bariatric surgery. Our work identifies a strategy for replacing the surgery with an equally effective, but less invasive, treatment for nonalcoholic steatohepatitis.