- Email: [email protected]
Roux-en-Y gastric bypass decreases serum inflammatory markers and cardiovascular risk factors in obese diabetics
Surgery xxx (2020) 1e4
Contents lists available at ScienceDirect
Surgery journal homepage: www.elsevier.com/locate/surg
Roux-en-Y gastric bypass decreases serum inflammatory markers and cardiovascular risk factors in obese diabetics Isolina Rossi, MDa, Philip Omotosho, MDb, Jennifer Poirier, PhDb, Anna Spagnoli, MDc, Alfonso Torquati, MD, MSCI, FACSb,* a
Department of Surgery, Carolinas Medical Center, Charlotte, NC Department of Surgery, Rush University Medical Center, Chicago, IL c Department of Orthopedic Surgery, Rush University Medical Center, Chicago, IL b
a r t i c l e i n f o
a b s t r a c t
Article history: Accepted 28 September 2020 Available online xxx
Background: Obesity and type 2 diabetes mellitus are associated with elevated levels of inflammatory markers. This chronic inflammation is known to contribute to increased risk of cardiovascular disease in these populations. Laparoscopic Roux-en-Y gastric bypass is associated with a high rate of diabetes remission. We hypothesize that laparoscopic Roux-en-Y gastric bypass decreases systemic inflammatory markers and cardiovascular disease risk factors in obese diabetics. Methods: This was a single-institution prospective cohort study of 61 obese patients with type 2 diabetes mellitus. A total of 30 patients underwent laparoscopic Roux-en-Y gastric bypass surgery, and 31 patients underwent standard medical therapy with diabetes support and education. Collected data included preoperative and postoperative inflammatory biomarkers and clinical parameters. Results: Twelve months after undergoing laparoscopic Roux-en-Y gastric bypass, controlling for sex and age, there was a significant correlation between a change in interleukin-6 and a change in systolic blood pressure (Spearman r ¼ 0.41, P ¼ .03). Similarly, when sex and age were controlled for in the laparoscopic Roux-en-Y gastric bypass group, a statistically significant relationship remained between percent excess weight loss and change in interleukin-6 (P ¼ .001). Conclusion: A significant relationship exists between decreased systemic interleukin-6 levels and both excess weight loss and lowered systolic blood pressure after laparoscopic Roux-en-Y gastric bypass in obese patients with diabetes mellitus. These correlations may explain the decreased risk of cardiovascular disease after surgical weight reduction in this patient population. © 2020 Elsevier Inc. All rights reserved.
Introduction Obesity is an important risk factor for cardiovascular disease (CVD) and is associated with a premature development of atherosclerosis and an increased risk of cardiac ischemia and stroke.1 The increasing prevalence of obesity and, with it, type 2 diabetes mellitus (T2DM) is now the greatest threat to reducing the prevalence of CVD.2 Prospective studies have demonstrated that persons with T2DM have twice the risk of myocardial infarction and ischemic stroke and 2 to 4 times the risk of myocardial infarction and stroke mortality compared
Presented at the 2020 annual meeting of the Central Surgical Association. * Reprint requests: Alfonso Torquati, MD, 1750 W Harrison, Jelke Building, Suite 789, Chicago, IL 60612, USA. E-mail address: [email protected] (A. Torquati). https://doi.org/10.1016/j.surg.2020.09.039 0039-6060/© 2020 Elsevier Inc. All rights reserved.
with their counterparts without diabetes.3 Strong epidemiologic evidence indicates that abdominal adiposity poses a greater CVD risk than observed in other forms of obesity.4 Abdominal adiposity significantly contributes to the inflammatory process in patients with obesity in both vascular and nonvascular tissues. This effect is mediated by pro-inflammatory mediators released by stressed adipose cells. Adipose tissue from obese individuals contains activated macrophages that together with adipocytes produce inflammatory adipokines such as tumor necrosis factor (TNF), interleukin-1 (IL-1), and interleukin-6 (IL-6).5 The chronic state of inflammation is known to contribute to an increased risk of CVD in these populations.6 A loss of 5%e10% of initial weight is sufficient to produce significant, clinically relevant improvements in CVD risk factors in overweight and obese patients with T2DM . However, greater weight loss is associated with greater improvements in risk factors.7 Currently, bariatric surgery procedures appear to be the only interventional modality that results
2
I. Rossi et al. / Surgery xxx (2020) 1e4
in sustained and significant weight loss along with the reversal of T2DM and with improvements in cholesterol biosynthesis, lipoprotein metabolism, and overall decreased CVD risk factors.8 We hypothesized that, in an obese diabetic population, laparoscopic Roux-en-Y gastric bypass (LRYGB) would lead to reduced inflammatory biomarker levels and decreased CVD risk when compared with a matched control medical intervention group. The hypothesis was tested by determining the relationship between circulating cytokines and CVD risk factors in the interventional and control groups.
Methods This was a prospective cohort study aimed to enroll class 2 and 3 patients who are obese (body mass index [BMI] >35 kg/m2) and have T2DM. Patients thus eligible and approved for surgical weight loss treatment by their health insurance carrier were recruited into the LRYGB group (interventional group). Participants who were eligible for LRYGB but did not undergo surgery attributable to insurance coverage denials were enrolled into the Diabetes Support and Education (DSE) Program (control group). The LRYGB group was matched with the DSE group, using a matching algorithm according to age, sex, and body weight. The matching process was verified every 10 enrollments in the LRYGB group to allow targeted recruitment in the DSE group. We collected data and serum samples for analysis before and 12 months after surgical or non-surgical intervention. T2DM was diagnosed based on any one of the following: current regular use of insulin, current regular use of oral hypoglycemic medication, or documented diabetes by American Diabetes Association criteria. Throughout the study, all patients received the standard medical care and management of T2DM and CVD risk factors. The goal for glycemic control was to maintain a glycated hemoglobin (HbA1c) of 7% or less. Height and weight were used to calculate BMI, percentage of excess weight loss (EWL) was calculated using the following formula: (weight loss/excess weight) 100. A more detailed study protocol, including the DSE has been described elsewhere.9 The surgical procedure consisted of a laparoscopic approach with two 10-mm ports and four 5-mm ports. The technique included the creation of an isolated 10e15 mL proximal gastric pouch, an ante-colic Roux-en-Y gastrojejunostomy with linear stapler technique, a 100-cm Roux-limb, a 50-cm biliopancreatic limb, and a stapled end-side enteroenterostomy. The study was registered at ClinicalTrials.gov (NCT00787670). An institutional review board approved the protocol for the study before data collection. Informed consent was obtained from all patients who enrolled in the study. Serum samples were stored at 80 C until assayed. All samples were analyzed at the same time. Cytokines were assayed by a Milliplex human adipokine panel assay (EMD Millipore, Darmstadt, Germany). Descriptive statistics were calculated on sex and age. Paired t test and independent t tests were used to compare pre- and postintervention normally distributed quantitative variables to determine significant differences between the 2 groups. To determine whether there were relationships between predictive variables (change in circulating inflammatory markers) and outcome variables (percent change in systolic blood pressure [SBP] over time, change in BMI over time, change in resting heart rate [HR], and percent excess weight loss), nested multiple regressions were created and compared with likelihood ratio tests. All statistical analyses were conducted RStudio v 1.25 (RStudio, Inc, Boston, MA, USA). All values were given as means ± standard deviation unless otherwise stated.
Results The study enrolled 61 obese participants with T2DM. A total of 30 participants approved for surgical weight loss treatment by their health insurance carrier were recruited for LRYGB. The other 31 participants were enrolled in the DSE group. For the entire cohort, the mean age was 48.5 ± 7.8 y and the mean body weight was 117.2 ± 17.2 kg. As described elsewhere,9 patients in the 2 groups were successfully matched at baseline for age, sex, weight, SBP, serum cholesterol, triglyceride levels, percent on oral antidiabetic medications, and percent on insulin therapy. Although there was no significant difference in the body weight, participants in the LRYGB group had significantly greater BMI than those in the DSE group (43.4 ± 4.4 vs 40.1 ± 5.0; P ¼ .006). In the LRYGB group, 27 patients (90%) had a diagnosis of hypertension and received antihypertensive medications. Hypertension was present in 26 patients (84%) in the DSE group. After the intervention, the remission rate of hypertension (SBP <150 mm Hg, diastolic blood pressure <90mm Hg, and off antihypertensive medications) was 70.4% in the LRYGB and 4% in the DSE groups (P ¼ .001). Table I presents the magnitude change in excess weight, BMI, blood pressure, heart rate, waist circumference, and inflammatory markers from baseline to 12-month follow-up for both groups. The
Table I Measured data at baseline (0 months) and at 12 months after the interventions Baseline BMI (Kg/m2) DSE 40.1 ± 4.8 LRYGB 43.4 ± 4.2 EWL (%) DSE d LRYGB d Waist circumference (cm) DSE 123.0 ± 12.6 LRYGB 130.3 ± 12.1 SBP (mm Hg) DSE 135.4 ± 17.1 LRYGB 138.9 ± 18.9 Diastolic blood pressure (mm Hg) DSE 77.1 ± 8.8 LRYGB 76.1 ± 12.1 HR (BPM) DSE 76.4 ± 12.6 LRYGB 84.8 ± 12.8 GM-CSF (pg/mL) DSE 59.4 ± 42.8 LRYGB 63.1 ± 49.9 Interferon-g (pg/mL) DSE 1.6 ± 1.4 LRYGB 1.8 ± 1.0 IL-6 (pg/mL) DSE 1.6 ± 1.0 LRYGB 2.3 ± 3.9 IL-10 (pg/mL) DSE 4.3 ± 10.1 LRYGB 2.6 ± 3.1 IL-12 (pg/mL) DSE 3.3 ± 5.3 LRYGB 2.8 ± 4.8 IL-2 (pg/mL) DSE 0.6 ± 0.3 LRYGB 0.5 ± 0.3 IL-8 (pg/mL) DSE 10.7 ± 9.8 LRYGB 10.5 ± 7.8 TNF-a (pg/mL) DSE 6.5 ± 2.3 LRYGB 6.7 ± 2.2
12 months
P value
40.4 ± 5.3 31.2 ± 4.6
.332 <.001
0.6 ± 5.6 .551 e33.6 ± 11.0 <.001 121.9 ± 13.7 103.7 ± 12.8
.422 <.001
130.0 ± 16.0 125.6 ± 15.3
.020 <.001
76.2 ± 8.4 76.9 ± 9.1
.513 .693
76.4 ± 10.9 67.1 ± 12.2
.921 <.001
67.5 ± 50.1 52.9 ± 29.1
.580 .781
2.1 ± 1.4 2.2 ± 0.8
.175 .477
1.5 ± 0.7 1.2 ± 2.3
.580 .002
8.6 ± 20.9 2.5 ± 1.3
.337 .803
19.0 ± 76.1 2.2 ± 2.2
.278 .275
0.6 ± 0.4 0.5 ± 0.3
.731 .580
11.0 ± 10.2 10.9 ± 4.6
.901 .782
7.1 ± 1.6 6.7 ± 1.6
.163 .932
I. Rossi et al. / Surgery xxx (2020) 1e4
3
Table II Spearman correlation calculations for change in statically significant variable from baseline to 12 months after LRYGB Delta change (%) 1: 2: 3: 4: 5: 6: *
0e12 0e12 0e12 0e12 0e12 0e12
months months months months months months
BMI EWL waist circumference heart rate SBP IL-6
Mean
Standard deviation
1
2
3
4
5
e27.9 e55.5 e20.3 e20.3 e8.6 e41.7
9.2 15.1 7.7 12.3 12.6 26.9
0.89* 0.80* 0.15 0.10 0.13
0.70* 0.10 0.13 0.25
0.01 e0.20 0.01
0.03 e0.05
0.49*
P <.01
12-month longitudinal changes in BMI, EWL, SBP, heart HR, and IL6 were statistically significant in the LRYGB group; only SBP was significantly changed in the DSE group. In the LRYGB, the mean percent change in IL-6 was e46.5% in patients that went into hypertension remission and e27.9% in patients who did not achieve remission (P ¼ .12). Table II presents Spearman correlation calculations for percent change in statically significant variables from baseline to 12 months after LRYGB. Using nested multiple regressions, when sex and age were controlled for in the LRYGB group, a statistically significant relationship remained between percent change in SBP and percent change in IL-6 (P ¼ .03). In contrast, within the DSE group, when sex and age were controlled for, there was no significant relationship between percent change in SBP and percent change in IL-6 (P ¼ .63). Similarly, when sex and age were controlled for in the LRYGB group, a statistically significant relationship remained between percent EWL and change in IL-6 (P ¼ .001). Discussion The association of obesity with increased morbidity and mortality is well-documented.10 The increasing prevalence of T2DM in the obese population has further confounded such negative effects. Obesity and diabetes are both associated with elevated levels of serum inflammatory markers that create a chronic low-grade inflammatory state. Some of the proinflammatory markers that are most commonly associated with elevated BMI are TNF alpha, C-reactive protein, leptin, and IL-6.11 Adipose tissue is metabolically active by secreting many pro-inflammatory chemokines, as well as the anti-inflammatory marker adiponectin. Our laboratory has investigated adiponectin in the context of bariatric surgery.12 Adiponectin levels are inversely correlated with mass of adipose tissue. Furthermore, adiponectin is associated with increased insulin sensitivity, which is consistent with studies demonstrating that weight loss leads to increased levels measured in obese patients and subsequent T2DM remission.12 LRYGB is superior to sleeve gastrectomy in the associated rates of T2DM remission. A recent 5-y follow-up of a randomized study confirmed that, among patients who underwent bariatric surgery, those who received LRYGB used fewer diabetic medications compared with patients who received a sleeve gastrectomy.8 CVD is particularly prevalent in obese patients with T2DM. Countless studies suggest that the pro-inflammatory state and endothelial cell activation increase the risk for CVD in this population.13,14 Chronic hyperglycemia, as observed in diabetes, causes non-enzymatic glycation of proteins and is associated with comorbidities. Advanced glycation end-products bind to advanced glycation end-product receptors on endothelial cells, which induce the release of pro-inflammatory cytokines.15 The correlation between high advanced glycation end-product levels and severity of coronary artery disease in T2DM has been acknowledged for more than 2 decades.16 IL-6 has also been independently
associated with T2DM and cardiovascular disease.6 Although the exact role of IL-6 in T2DM has been debated, it has been consistently noted that elevated levels of IL-6 precede the development of insulin resistance.17 Long-term reduction in serum IL-6 has been demonstrated after bariatric surgery.18 During the past few years there has been increasing research acknowledging the correlation between IL-6 and blood pressure.19 Various parameters have been evaluated to determine whether LRYGB impacts clinical measurements beyond weight loss. In 2018 the Gastric Bypass to Treat Obese Patients With Steady Hypertension study 20 was published with the primary end point focused on the effect of LRYGB on hypertension in obese patients (most without diabetes). The remission rate was 51% at 12 months for patients who underwent LRYGB. These data were reviewed to meet the Systolic Blood Pressure Intervention Trial levels, which had 22.4% of patients achieving appropriate SBP range without antihypertensive medication.20 The Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy trial involved obese patients with T2DM who underwent LRYGB. Although this study did not demonstrate a significant difference in systolic blood pressure, it did note a significant reduction in total number of cardiovascular medications at the 12-month follow-up.8 The physical and metabolic benefits of gastric bypass procedures are well documented. The LRYGB has repeatedly been associated with diabetes remission.8,21,24 Bariatric operations have been shown to alter inflammatory biomarkers and metabolism in both the immediate and long-term postoperative period. As has been previously observed by our group, patients with obesity and T2DM who undergo LRYGB may have a lower incidence of both microvascular and macrovascular complications as compared with those managed medically.22 We investigated inflammatory cytokines known to be increased in obesity and T2DM in association with increased risk of cardiovascular disease. We hypothesized that in diabetic populations LRYGB will lead to reduced inflammatory biomarker levels and decreased CVD risk. A multivariate regression analysis of our data suggests that a significant relationship exists between the change in inflammatory cytokine IL6 and the reduction in SBP in morbidly obese diabetic patients who undergo LRYGB. Limitations of our study include short duration of follow-up (12 months), lack of randomization, data collection at a single center, and analysis of secondary end points. Although the single-center trial may limit the external validity of the study, we emphasize that all patients were classified at least as class II obesity (BMI 35 or greater), which is the majority of the bariatric surgery population. We believe that this increases its external validity, as many studies reporting on effects of bariatric surgery use BMI of 30 as the sample minimum. Another weakness is that, ideally, baseline levels should also have been measured in additional control groups such as nonobese non-diabetics and obese non-diabetics. In conclusion, LRYGB appears to offer hypertensive control for morbidly obese patients with T2DM. Our study suggests that a
4
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reduction in the chronic inflammatory state (represented by an IL-6 reduction) is associated with a sustained reduction in SBP. Hypertension is a known cardiovascular risk factor. A reduction in hypertension may contribute to the overall decline in morbidity and mortality in morbidly obese patients with T2DM who undergo LRYGB. additional trials with larger sample sizes and longer followups are needed to confirm these findings. Conflict of interest/Disclosure The authors have no conflicts of interest or financial disclosures. Funding/Support This study was supported by the National Institutes of Health (USA) with Grant K23 DK075907 to A.T. References 1. He J, Ogden LG, Bazzano LA, Vupputuri S, Loria C, Whelton PK. Risk factors for congestive heart failure in US men and women: NHANES I epidemiologic follow-up study. Arch Intern Med. 2001;161:996e1002. 2. Ortega FB, Lavie CJ, Blair SN. Obesity and cardiovascular disease. Circ Res. 2016;118:1752e1770. 3. Raghavan S, Vassy JL, Ho Y-L, et al. Diabetes mellitus-related all-cause and cardiovascular mortality in a national cohort of adults. J Am Heart Assoc. 2019;8: e011295. 4. Goldberg RB. Cytokine and cytokine-like inflammation markers, endothelial dysfunction, and imbalanced coagulation in development of diabetes and its complications. J Clin Endocrinol Metab. 2009;94:3171e3182. 5. Zatterale F, Longo M, Naderi J, et al. Chronic Adipose Tissue Inflammation Linking Obesity to Insulin Resistance and Type 2 Diabetes. Front Physiol. 2019;10:1607. 6. Lowe G, Woodward M, Hillis G, et al. Circulating inflammatory markers and the risk of vascular complications and mortality in people with type 2 diabetes and cardiovascular disease or risk factors: the ADVANCE study. Diabetes. 2014;63: 1115e1123. 7. Wing RR, Lang W, Wadden TA, et al. Benefits of modest weight loss in improving cardiovascular risk factors in overweight and obese individuals with type 2 diabetes. Diabetes Care. 2011;34:1481e1486. 8. Schauer PR, Bhatt DL, Kirwan JP, et al. Bariatric surgery versus intensive medical therapy for diabetesd5-year outcomes. N Engl J Med. 2017;376: 641e651. 9. Khoo CM, Chen J, Pamuklar Z, Torquati A. Effects of Roux-en-Y gastric bypass or diabetes support and education on insulin sensitivity and insulin secretion in morbidly obese patients with type 2 diabetes. Ann Surg. 2014;259:494e501.
10. Mora S, Yanek LR, Moy TF, Fallin MD, Becker LC, Becker DM. Interaction of body mass index and framingham risk score in predicting incident coronary disease in families. Circulation. 2005;111:1871e1876. 11. Netto BD, Bettini SC, Clemente AP, et al. Roux-en-Y gastric bypass decreases pro-inflammatory and thrombotic biomarkers in individuals with extreme obesity. Obes Surg. 2015;25:1010e1018. 12. Chen J, Spagnoli A, Torquati A. Omental gene expression of adiponectin correlates with degree of insulin sensitivity before and after gastric bypass surgery. Obes Surg. 2012;22:472e477. 13. Nijhuis J, van Dielen FM, Fouraschen SM, et al. Endothelial activation markers and their key regulators after restrictive bariatric surgery. Obesity (Silver Spring). 2007;15:1395e1399. 14. Nathan DM, Cleary PA, Backlund JY, et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005;353: 2643e2653. 15. Piarulli F, Sartore G, Lapolla A. Glyco-oxidation and cardiovascular complications in type 2 diabetes: a clinical update. Acta Diabetol. 2013;50: 101e110. 16. Nakamura Y, Horii Y, Nishino T, et al. Immunohistochemical localization of advanced glycosylation end products in coronary atheroma and cardiac tissue in diabetes mellitus. Am J Pathol. 1993;143:1649e1656. 17. Spranger J, Kroke A, Mohlig M, et al. Inflammatory cytokines and the risk to develop type 2 diabetes: results of the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study. Diabetes. 2003;52:812e817. 18. Lindegaard KK, Jorgensen NB, Just R, Heegaard PM, Madsbad S. Effects of Rouxen-Y gastric bypass on fasting and postprandial inflammation-related parameters in obese subjects with normal glucose tolerance and in obese subjects with type 2 diabetes. Diabetol Metab Syndr. 2015;7:12. 19. Zhang B, Li XL, Zhao CR, Pan CL, Zhang Z. Interleukin-6 as a predictor of the risk of cardiovascular disease: a meta-analysis of prospective epidemiological studies. Immunol Invest. 2018;47:689e699. 20. Schiavon CA, Bersch-Ferreira AC, Santucci EV, et al. Effects of bariatric surgery in obese patients with hypertension: the GATEWAY Randomized Trial (Gastric Bypass to Treat Obese Patients With Steady Hypertension). Circulation. 2018;137:1132e1142. 21. Halperin F, Ding SA, Simonson DC, et al. Roux-en-Y gastric bypass surgery or lifestyle with intensive medical management in patients with type 2 diabetes: feasibility and 1-year results of a randomized clinical trial. JAMA Surg. 2014;149:716e726. 22. Chen Y, Corsino L, Shantavasinkul PC, et al. Gastric bypass surgery leads to long-term remission or improvement of type 2 diabetes and significant decrease of microvascular and macrovascular complications. Ann Surg. 2016;263:1138e1142. 23. Liang Z, Wu Q, Chen B, Yu P, Zhao H, Ouyang X. Effect of laparoscopic Roux-en-Y gastric bypass surgery on type 2 diabetes mellitus with hypertension: a randomized controlled trial. Diabetes Res Clin Pract. 2013;101: 50e56. 24. Ikramuddin S, Korner J, Lee WJ, et al. Durability of addition of Roux-en-Y Gastric bypass to lifestyle intervention and medical management in achieving primary treatment goals for uncontrolled type 2 diabetes in mild to moderate obesity: a randomized control trial. Diabetes Care. 2016;39: 1510e1518.
Contents lists available at ScienceDirect
Surgery journal homepage: www.elsevier.com/locate/surg
Roux-en-Y gastric bypass decreases serum inflammatory markers and cardiovascular risk factors in obese diabetics Isolina Rossi, MDa, Philip Omotosho, MDb, Jennifer Poirier, PhDb, Anna Spagnoli, MDc, Alfonso Torquati, MD, MSCI, FACSb,* a
Department of Surgery, Carolinas Medical Center, Charlotte, NC Department of Surgery, Rush University Medical Center, Chicago, IL c Department of Orthopedic Surgery, Rush University Medical Center, Chicago, IL b
a r t i c l e i n f o
a b s t r a c t
Article history: Accepted 28 September 2020 Available online xxx
Background: Obesity and type 2 diabetes mellitus are associated with elevated levels of inflammatory markers. This chronic inflammation is known to contribute to increased risk of cardiovascular disease in these populations. Laparoscopic Roux-en-Y gastric bypass is associated with a high rate of diabetes remission. We hypothesize that laparoscopic Roux-en-Y gastric bypass decreases systemic inflammatory markers and cardiovascular disease risk factors in obese diabetics. Methods: This was a single-institution prospective cohort study of 61 obese patients with type 2 diabetes mellitus. A total of 30 patients underwent laparoscopic Roux-en-Y gastric bypass surgery, and 31 patients underwent standard medical therapy with diabetes support and education. Collected data included preoperative and postoperative inflammatory biomarkers and clinical parameters. Results: Twelve months after undergoing laparoscopic Roux-en-Y gastric bypass, controlling for sex and age, there was a significant correlation between a change in interleukin-6 and a change in systolic blood pressure (Spearman r ¼ 0.41, P ¼ .03). Similarly, when sex and age were controlled for in the laparoscopic Roux-en-Y gastric bypass group, a statistically significant relationship remained between percent excess weight loss and change in interleukin-6 (P ¼ .001). Conclusion: A significant relationship exists between decreased systemic interleukin-6 levels and both excess weight loss and lowered systolic blood pressure after laparoscopic Roux-en-Y gastric bypass in obese patients with diabetes mellitus. These correlations may explain the decreased risk of cardiovascular disease after surgical weight reduction in this patient population. © 2020 Elsevier Inc. All rights reserved.
Introduction Obesity is an important risk factor for cardiovascular disease (CVD) and is associated with a premature development of atherosclerosis and an increased risk of cardiac ischemia and stroke.1 The increasing prevalence of obesity and, with it, type 2 diabetes mellitus (T2DM) is now the greatest threat to reducing the prevalence of CVD.2 Prospective studies have demonstrated that persons with T2DM have twice the risk of myocardial infarction and ischemic stroke and 2 to 4 times the risk of myocardial infarction and stroke mortality compared
Presented at the 2020 annual meeting of the Central Surgical Association. * Reprint requests: Alfonso Torquati, MD, 1750 W Harrison, Jelke Building, Suite 789, Chicago, IL 60612, USA. E-mail address: [email protected] (A. Torquati). https://doi.org/10.1016/j.surg.2020.09.039 0039-6060/© 2020 Elsevier Inc. All rights reserved.
with their counterparts without diabetes.3 Strong epidemiologic evidence indicates that abdominal adiposity poses a greater CVD risk than observed in other forms of obesity.4 Abdominal adiposity significantly contributes to the inflammatory process in patients with obesity in both vascular and nonvascular tissues. This effect is mediated by pro-inflammatory mediators released by stressed adipose cells. Adipose tissue from obese individuals contains activated macrophages that together with adipocytes produce inflammatory adipokines such as tumor necrosis factor (TNF), interleukin-1 (IL-1), and interleukin-6 (IL-6).5 The chronic state of inflammation is known to contribute to an increased risk of CVD in these populations.6 A loss of 5%e10% of initial weight is sufficient to produce significant, clinically relevant improvements in CVD risk factors in overweight and obese patients with T2DM . However, greater weight loss is associated with greater improvements in risk factors.7 Currently, bariatric surgery procedures appear to be the only interventional modality that results
2
I. Rossi et al. / Surgery xxx (2020) 1e4
in sustained and significant weight loss along with the reversal of T2DM and with improvements in cholesterol biosynthesis, lipoprotein metabolism, and overall decreased CVD risk factors.8 We hypothesized that, in an obese diabetic population, laparoscopic Roux-en-Y gastric bypass (LRYGB) would lead to reduced inflammatory biomarker levels and decreased CVD risk when compared with a matched control medical intervention group. The hypothesis was tested by determining the relationship between circulating cytokines and CVD risk factors in the interventional and control groups.
Methods This was a prospective cohort study aimed to enroll class 2 and 3 patients who are obese (body mass index [BMI] >35 kg/m2) and have T2DM. Patients thus eligible and approved for surgical weight loss treatment by their health insurance carrier were recruited into the LRYGB group (interventional group). Participants who were eligible for LRYGB but did not undergo surgery attributable to insurance coverage denials were enrolled into the Diabetes Support and Education (DSE) Program (control group). The LRYGB group was matched with the DSE group, using a matching algorithm according to age, sex, and body weight. The matching process was verified every 10 enrollments in the LRYGB group to allow targeted recruitment in the DSE group. We collected data and serum samples for analysis before and 12 months after surgical or non-surgical intervention. T2DM was diagnosed based on any one of the following: current regular use of insulin, current regular use of oral hypoglycemic medication, or documented diabetes by American Diabetes Association criteria. Throughout the study, all patients received the standard medical care and management of T2DM and CVD risk factors. The goal for glycemic control was to maintain a glycated hemoglobin (HbA1c) of 7% or less. Height and weight were used to calculate BMI, percentage of excess weight loss (EWL) was calculated using the following formula: (weight loss/excess weight) 100. A more detailed study protocol, including the DSE has been described elsewhere.9 The surgical procedure consisted of a laparoscopic approach with two 10-mm ports and four 5-mm ports. The technique included the creation of an isolated 10e15 mL proximal gastric pouch, an ante-colic Roux-en-Y gastrojejunostomy with linear stapler technique, a 100-cm Roux-limb, a 50-cm biliopancreatic limb, and a stapled end-side enteroenterostomy. The study was registered at ClinicalTrials.gov (NCT00787670). An institutional review board approved the protocol for the study before data collection. Informed consent was obtained from all patients who enrolled in the study. Serum samples were stored at 80 C until assayed. All samples were analyzed at the same time. Cytokines were assayed by a Milliplex human adipokine panel assay (EMD Millipore, Darmstadt, Germany). Descriptive statistics were calculated on sex and age. Paired t test and independent t tests were used to compare pre- and postintervention normally distributed quantitative variables to determine significant differences between the 2 groups. To determine whether there were relationships between predictive variables (change in circulating inflammatory markers) and outcome variables (percent change in systolic blood pressure [SBP] over time, change in BMI over time, change in resting heart rate [HR], and percent excess weight loss), nested multiple regressions were created and compared with likelihood ratio tests. All statistical analyses were conducted RStudio v 1.25 (RStudio, Inc, Boston, MA, USA). All values were given as means ± standard deviation unless otherwise stated.
Results The study enrolled 61 obese participants with T2DM. A total of 30 participants approved for surgical weight loss treatment by their health insurance carrier were recruited for LRYGB. The other 31 participants were enrolled in the DSE group. For the entire cohort, the mean age was 48.5 ± 7.8 y and the mean body weight was 117.2 ± 17.2 kg. As described elsewhere,9 patients in the 2 groups were successfully matched at baseline for age, sex, weight, SBP, serum cholesterol, triglyceride levels, percent on oral antidiabetic medications, and percent on insulin therapy. Although there was no significant difference in the body weight, participants in the LRYGB group had significantly greater BMI than those in the DSE group (43.4 ± 4.4 vs 40.1 ± 5.0; P ¼ .006). In the LRYGB group, 27 patients (90%) had a diagnosis of hypertension and received antihypertensive medications. Hypertension was present in 26 patients (84%) in the DSE group. After the intervention, the remission rate of hypertension (SBP <150 mm Hg, diastolic blood pressure <90mm Hg, and off antihypertensive medications) was 70.4% in the LRYGB and 4% in the DSE groups (P ¼ .001). Table I presents the magnitude change in excess weight, BMI, blood pressure, heart rate, waist circumference, and inflammatory markers from baseline to 12-month follow-up for both groups. The
Table I Measured data at baseline (0 months) and at 12 months after the interventions Baseline BMI (Kg/m2) DSE 40.1 ± 4.8 LRYGB 43.4 ± 4.2 EWL (%) DSE d LRYGB d Waist circumference (cm) DSE 123.0 ± 12.6 LRYGB 130.3 ± 12.1 SBP (mm Hg) DSE 135.4 ± 17.1 LRYGB 138.9 ± 18.9 Diastolic blood pressure (mm Hg) DSE 77.1 ± 8.8 LRYGB 76.1 ± 12.1 HR (BPM) DSE 76.4 ± 12.6 LRYGB 84.8 ± 12.8 GM-CSF (pg/mL) DSE 59.4 ± 42.8 LRYGB 63.1 ± 49.9 Interferon-g (pg/mL) DSE 1.6 ± 1.4 LRYGB 1.8 ± 1.0 IL-6 (pg/mL) DSE 1.6 ± 1.0 LRYGB 2.3 ± 3.9 IL-10 (pg/mL) DSE 4.3 ± 10.1 LRYGB 2.6 ± 3.1 IL-12 (pg/mL) DSE 3.3 ± 5.3 LRYGB 2.8 ± 4.8 IL-2 (pg/mL) DSE 0.6 ± 0.3 LRYGB 0.5 ± 0.3 IL-8 (pg/mL) DSE 10.7 ± 9.8 LRYGB 10.5 ± 7.8 TNF-a (pg/mL) DSE 6.5 ± 2.3 LRYGB 6.7 ± 2.2
12 months
P value
40.4 ± 5.3 31.2 ± 4.6
.332 <.001
0.6 ± 5.6 .551 e33.6 ± 11.0 <.001 121.9 ± 13.7 103.7 ± 12.8
.422 <.001
130.0 ± 16.0 125.6 ± 15.3
.020 <.001
76.2 ± 8.4 76.9 ± 9.1
.513 .693
76.4 ± 10.9 67.1 ± 12.2
.921 <.001
67.5 ± 50.1 52.9 ± 29.1
.580 .781
2.1 ± 1.4 2.2 ± 0.8
.175 .477
1.5 ± 0.7 1.2 ± 2.3
.580 .002
8.6 ± 20.9 2.5 ± 1.3
.337 .803
19.0 ± 76.1 2.2 ± 2.2
.278 .275
0.6 ± 0.4 0.5 ± 0.3
.731 .580
11.0 ± 10.2 10.9 ± 4.6
.901 .782
7.1 ± 1.6 6.7 ± 1.6
.163 .932
I. Rossi et al. / Surgery xxx (2020) 1e4
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Table II Spearman correlation calculations for change in statically significant variable from baseline to 12 months after LRYGB Delta change (%) 1: 2: 3: 4: 5: 6: *
0e12 0e12 0e12 0e12 0e12 0e12
months months months months months months
BMI EWL waist circumference heart rate SBP IL-6
Mean
Standard deviation
1
2
3
4
5
e27.9 e55.5 e20.3 e20.3 e8.6 e41.7
9.2 15.1 7.7 12.3 12.6 26.9
0.89* 0.80* 0.15 0.10 0.13
0.70* 0.10 0.13 0.25
0.01 e0.20 0.01
0.03 e0.05
0.49*
P <.01
12-month longitudinal changes in BMI, EWL, SBP, heart HR, and IL6 were statistically significant in the LRYGB group; only SBP was significantly changed in the DSE group. In the LRYGB, the mean percent change in IL-6 was e46.5% in patients that went into hypertension remission and e27.9% in patients who did not achieve remission (P ¼ .12). Table II presents Spearman correlation calculations for percent change in statically significant variables from baseline to 12 months after LRYGB. Using nested multiple regressions, when sex and age were controlled for in the LRYGB group, a statistically significant relationship remained between percent change in SBP and percent change in IL-6 (P ¼ .03). In contrast, within the DSE group, when sex and age were controlled for, there was no significant relationship between percent change in SBP and percent change in IL-6 (P ¼ .63). Similarly, when sex and age were controlled for in the LRYGB group, a statistically significant relationship remained between percent EWL and change in IL-6 (P ¼ .001). Discussion The association of obesity with increased morbidity and mortality is well-documented.10 The increasing prevalence of T2DM in the obese population has further confounded such negative effects. Obesity and diabetes are both associated with elevated levels of serum inflammatory markers that create a chronic low-grade inflammatory state. Some of the proinflammatory markers that are most commonly associated with elevated BMI are TNF alpha, C-reactive protein, leptin, and IL-6.11 Adipose tissue is metabolically active by secreting many pro-inflammatory chemokines, as well as the anti-inflammatory marker adiponectin. Our laboratory has investigated adiponectin in the context of bariatric surgery.12 Adiponectin levels are inversely correlated with mass of adipose tissue. Furthermore, adiponectin is associated with increased insulin sensitivity, which is consistent with studies demonstrating that weight loss leads to increased levels measured in obese patients and subsequent T2DM remission.12 LRYGB is superior to sleeve gastrectomy in the associated rates of T2DM remission. A recent 5-y follow-up of a randomized study confirmed that, among patients who underwent bariatric surgery, those who received LRYGB used fewer diabetic medications compared with patients who received a sleeve gastrectomy.8 CVD is particularly prevalent in obese patients with T2DM. Countless studies suggest that the pro-inflammatory state and endothelial cell activation increase the risk for CVD in this population.13,14 Chronic hyperglycemia, as observed in diabetes, causes non-enzymatic glycation of proteins and is associated with comorbidities. Advanced glycation end-products bind to advanced glycation end-product receptors on endothelial cells, which induce the release of pro-inflammatory cytokines.15 The correlation between high advanced glycation end-product levels and severity of coronary artery disease in T2DM has been acknowledged for more than 2 decades.16 IL-6 has also been independently
associated with T2DM and cardiovascular disease.6 Although the exact role of IL-6 in T2DM has been debated, it has been consistently noted that elevated levels of IL-6 precede the development of insulin resistance.17 Long-term reduction in serum IL-6 has been demonstrated after bariatric surgery.18 During the past few years there has been increasing research acknowledging the correlation between IL-6 and blood pressure.19 Various parameters have been evaluated to determine whether LRYGB impacts clinical measurements beyond weight loss. In 2018 the Gastric Bypass to Treat Obese Patients With Steady Hypertension study 20 was published with the primary end point focused on the effect of LRYGB on hypertension in obese patients (most without diabetes). The remission rate was 51% at 12 months for patients who underwent LRYGB. These data were reviewed to meet the Systolic Blood Pressure Intervention Trial levels, which had 22.4% of patients achieving appropriate SBP range without antihypertensive medication.20 The Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy trial involved obese patients with T2DM who underwent LRYGB. Although this study did not demonstrate a significant difference in systolic blood pressure, it did note a significant reduction in total number of cardiovascular medications at the 12-month follow-up.8 The physical and metabolic benefits of gastric bypass procedures are well documented. The LRYGB has repeatedly been associated with diabetes remission.8,21,24 Bariatric operations have been shown to alter inflammatory biomarkers and metabolism in both the immediate and long-term postoperative period. As has been previously observed by our group, patients with obesity and T2DM who undergo LRYGB may have a lower incidence of both microvascular and macrovascular complications as compared with those managed medically.22 We investigated inflammatory cytokines known to be increased in obesity and T2DM in association with increased risk of cardiovascular disease. We hypothesized that in diabetic populations LRYGB will lead to reduced inflammatory biomarker levels and decreased CVD risk. A multivariate regression analysis of our data suggests that a significant relationship exists between the change in inflammatory cytokine IL6 and the reduction in SBP in morbidly obese diabetic patients who undergo LRYGB. Limitations of our study include short duration of follow-up (12 months), lack of randomization, data collection at a single center, and analysis of secondary end points. Although the single-center trial may limit the external validity of the study, we emphasize that all patients were classified at least as class II obesity (BMI 35 or greater), which is the majority of the bariatric surgery population. We believe that this increases its external validity, as many studies reporting on effects of bariatric surgery use BMI of 30 as the sample minimum. Another weakness is that, ideally, baseline levels should also have been measured in additional control groups such as nonobese non-diabetics and obese non-diabetics. In conclusion, LRYGB appears to offer hypertensive control for morbidly obese patients with T2DM. Our study suggests that a
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reduction in the chronic inflammatory state (represented by an IL-6 reduction) is associated with a sustained reduction in SBP. Hypertension is a known cardiovascular risk factor. A reduction in hypertension may contribute to the overall decline in morbidity and mortality in morbidly obese patients with T2DM who undergo LRYGB. additional trials with larger sample sizes and longer followups are needed to confirm these findings. Conflict of interest/Disclosure The authors have no conflicts of interest or financial disclosures. Funding/Support This study was supported by the National Institutes of Health (USA) with Grant K23 DK075907 to A.T. References 1. He J, Ogden LG, Bazzano LA, Vupputuri S, Loria C, Whelton PK. Risk factors for congestive heart failure in US men and women: NHANES I epidemiologic follow-up study. Arch Intern Med. 2001;161:996e1002. 2. Ortega FB, Lavie CJ, Blair SN. Obesity and cardiovascular disease. Circ Res. 2016;118:1752e1770. 3. Raghavan S, Vassy JL, Ho Y-L, et al. Diabetes mellitus-related all-cause and cardiovascular mortality in a national cohort of adults. J Am Heart Assoc. 2019;8: e011295. 4. Goldberg RB. Cytokine and cytokine-like inflammation markers, endothelial dysfunction, and imbalanced coagulation in development of diabetes and its complications. J Clin Endocrinol Metab. 2009;94:3171e3182. 5. Zatterale F, Longo M, Naderi J, et al. Chronic Adipose Tissue Inflammation Linking Obesity to Insulin Resistance and Type 2 Diabetes. Front Physiol. 2019;10:1607. 6. Lowe G, Woodward M, Hillis G, et al. Circulating inflammatory markers and the risk of vascular complications and mortality in people with type 2 diabetes and cardiovascular disease or risk factors: the ADVANCE study. Diabetes. 2014;63: 1115e1123. 7. Wing RR, Lang W, Wadden TA, et al. Benefits of modest weight loss in improving cardiovascular risk factors in overweight and obese individuals with type 2 diabetes. Diabetes Care. 2011;34:1481e1486. 8. Schauer PR, Bhatt DL, Kirwan JP, et al. Bariatric surgery versus intensive medical therapy for diabetesd5-year outcomes. N Engl J Med. 2017;376: 641e651. 9. Khoo CM, Chen J, Pamuklar Z, Torquati A. Effects of Roux-en-Y gastric bypass or diabetes support and education on insulin sensitivity and insulin secretion in morbidly obese patients with type 2 diabetes. Ann Surg. 2014;259:494e501.
10. Mora S, Yanek LR, Moy TF, Fallin MD, Becker LC, Becker DM. Interaction of body mass index and framingham risk score in predicting incident coronary disease in families. Circulation. 2005;111:1871e1876. 11. Netto BD, Bettini SC, Clemente AP, et al. Roux-en-Y gastric bypass decreases pro-inflammatory and thrombotic biomarkers in individuals with extreme obesity. Obes Surg. 2015;25:1010e1018. 12. Chen J, Spagnoli A, Torquati A. Omental gene expression of adiponectin correlates with degree of insulin sensitivity before and after gastric bypass surgery. Obes Surg. 2012;22:472e477. 13. Nijhuis J, van Dielen FM, Fouraschen SM, et al. Endothelial activation markers and their key regulators after restrictive bariatric surgery. Obesity (Silver Spring). 2007;15:1395e1399. 14. Nathan DM, Cleary PA, Backlund JY, et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005;353: 2643e2653. 15. Piarulli F, Sartore G, Lapolla A. Glyco-oxidation and cardiovascular complications in type 2 diabetes: a clinical update. Acta Diabetol. 2013;50: 101e110. 16. Nakamura Y, Horii Y, Nishino T, et al. Immunohistochemical localization of advanced glycosylation end products in coronary atheroma and cardiac tissue in diabetes mellitus. Am J Pathol. 1993;143:1649e1656. 17. Spranger J, Kroke A, Mohlig M, et al. Inflammatory cytokines and the risk to develop type 2 diabetes: results of the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study. Diabetes. 2003;52:812e817. 18. Lindegaard KK, Jorgensen NB, Just R, Heegaard PM, Madsbad S. Effects of Rouxen-Y gastric bypass on fasting and postprandial inflammation-related parameters in obese subjects with normal glucose tolerance and in obese subjects with type 2 diabetes. Diabetol Metab Syndr. 2015;7:12. 19. Zhang B, Li XL, Zhao CR, Pan CL, Zhang Z. Interleukin-6 as a predictor of the risk of cardiovascular disease: a meta-analysis of prospective epidemiological studies. Immunol Invest. 2018;47:689e699. 20. Schiavon CA, Bersch-Ferreira AC, Santucci EV, et al. Effects of bariatric surgery in obese patients with hypertension: the GATEWAY Randomized Trial (Gastric Bypass to Treat Obese Patients With Steady Hypertension). Circulation. 2018;137:1132e1142. 21. Halperin F, Ding SA, Simonson DC, et al. Roux-en-Y gastric bypass surgery or lifestyle with intensive medical management in patients with type 2 diabetes: feasibility and 1-year results of a randomized clinical trial. JAMA Surg. 2014;149:716e726. 22. Chen Y, Corsino L, Shantavasinkul PC, et al. Gastric bypass surgery leads to long-term remission or improvement of type 2 diabetes and significant decrease of microvascular and macrovascular complications. Ann Surg. 2016;263:1138e1142. 23. Liang Z, Wu Q, Chen B, Yu P, Zhao H, Ouyang X. Effect of laparoscopic Roux-en-Y gastric bypass surgery on type 2 diabetes mellitus with hypertension: a randomized controlled trial. Diabetes Res Clin Pract. 2013;101: 50e56. 24. Ikramuddin S, Korner J, Lee WJ, et al. Durability of addition of Roux-en-Y Gastric bypass to lifestyle intervention and medical management in achieving primary treatment goals for uncontrolled type 2 diabetes in mild to moderate obesity: a randomized control trial. Diabetes Care. 2016;39: 1510e1518.