Predicting Remission of Diabetes After RYGB Surgery Following Intensive Management to Optimize Preoperative Glucose Control

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1 DOI /s ORIGINAL CONTRIBUTIONS Predicting Remission of Diabetes After RYGB Surgery Following Intensive Management to Optimize Preoperative Glucose Control Thomas MacAndrew English & Samir Malkani & Rebecca L. Kinney & Abdulkadir Omer & Mary Beth Dziewietin & Richard Perugini # Springer Science+Business Media New York 2014 Abstract Background The purpose of the study is to investigate the association of preoperative glucose optimization prior to a Roux-en-Y gastric bypass (RYGB) and diabetes remission. Methods The study is a retrospective review of 245 patients with a history of diabetes type II and a RYGB from 2008 to 2012 at UMass Memorial Hospital. Results Patients that benefited from glucose optimization prior to RYGB were more likely to achieve diabetes remission 1 year after surgery. The preoperative glucose optimization intervention demonstrated that when patients decreased their HbA1c prior to surgery by 1 %, these individuals were 68 % more likely to remit (p=0.015). Duration of diabetes (p=0.005) and insulin use (p<0.001) were also significant predictors of remission, whereas age, race, and gender were not. Conclusions Our study results indicate that a greater degree of glycemic improvement in response to presurgical medical intervention is associated with higher rates of diabetes remission post-operatively among obese adults with diabetes type II. Conversely, the lack of favorable glycemic response to intensification of medical management predicts a poor glycemic response to bariatric surgery. Further research is needed to determine if this difference is due to physiological factors or is simply an indicator of patient behavior. Keywords Diabetes. Gastric bypass. Remission. Glucose optimization. Medical intervention T. M. English : R. L. Kinney (*) : M. B. Dziewietin Department of Quantitative Health Sciences, University of Massachusetts Medical School, 368 Plantation St, Worcester, MA 01605, USA rebecca.kinney@umassmed.edu T. M. English Thomas.English@umassmed.edu M. B. Dziewietin MaryBeth.Dziewietin@umassmed.edu S. Malkani Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, MA, USA Samir.Malkani@umassmemorial.org A. Omer Endocrinology, University of Massachusetts Medical School, Worcester, MA, USA islet4cure@yahoo.com R. Perugini Department of Surgery, University of Massachusetts Medical School, Worcester, MA, USA Richard.Perugini@umassmemorial.org Introduction/Purpose Recent literature has documented the profound impact of bariatric surgery on the resolution of the clinical manifestations of diabetes type II in obese patients (1,2). A meta-analysis of the 621 studies found that 78.1 % of patients had diabetes type II resolution after the gastric bypass procedure (3). These findings also suggest that diabetes type II remission after bariatric surgery may be associated with weight loss (4,5), body mass index (BMI) (6 8), hemoglobin A1c level (HbA1c) (1,9,10), age (7-9), insulin use (5,9,10), oral anti-diabetics (9), and duration of diabetes type II (6). These findings are compelling in the context of the growing global incidence of both obesity and diabetes type II, which are recognized as major contemporary public health challenges (11). More than 8.3 % of Americans (25.8 million people) have diabetes; this trend will continue upward to 29 million people by the year 2050, an increase of 165 % from the year 2000 (12). Given the growing disease prevalence, strategies that seek to augment the benefits of bariatric surgery in obese, diabetes type II patients need to be further explored.

2 While there is adequate evidence that a substantial proportion of diabetes type II patients achieve remission of the illness after bariatric surgery, trials thus far have compared the efficacy of bariatric surgery with intensive medical management (13,14) or conventional medical management (2,15 17). There are no studies examining the role of maximal intensification of lifestyle interventions and medical management to target HbA1c of 7 % or less prior to bariatric surgery in individuals with diabetes type II. Yet, it is possible that preoperative interventions may increase patient satisfaction (18), clinical indicators, weight loss (19 22), and self-management prior to bariatric surgery, thus impacting both short- and longterm, postoperative health outcomes (22). Two recent studies examined the association between behavioral lifestyle interventions and preoperative weight loss in bariatric surgery candidates; both concluded that the interventions were significantly associated with larger weight loss prior to surgery (20,21). Yet, the impact of such preoperative interventions on other clinical indicators (e.g., HbA1c) still needs to be explored, as does our understanding of how these improved indictors may influence postoperative outcomes. We conducted a retrospective analysis of patient electronic health records (EHRs) to examine the benefits of an intensive, preoperative glucose optimization intervention in diabetes type II, obese patients prior to bariatric surgery. Specifically, we were interested in whether this preoperative intervention would impact postoperative diabetes remission. Materials/Methods From a population of patients who were indicated for bariatric surgery for weight loss, we identified a cohort of all diabetes type II patients who underwent Roux-en-Y gastric bypass (RYGB) at UMass Memorial Medical Center between 2008 and 2012, using a registry and data extracted from EHRs. To be included in our study, patients had to have sufficient data in their EHR (e.g., HbA1c levels, medication list) so that their status could be followed for a minimum of 6 months prior to surgery and 12 months postbariatric surgery. To supplement our data collection methods, we also performed a manual chart audit to confirm variables, such as the duration of disease and insulin dose, that were not easily abstracted from the registry and/or EHR. The study was performed with the approval of the University of Massachusetts Medical School Institutional Review Board (approval #14808) and met all HIPPA requirements. Preoperative Intervention Prior to bariatric surgery for weight loss, the current preoperative surgical standard at the study institution is to have all obese candidates with diabetes type II participate in an intense medical intervention that targets glycemic control in an attempt to achieve a preoperative HbA1c 7.0 % (53 mmol/ mol) and better postoperative outcomes. The emphasis of the intervention was to decrease preoperative HbA1c through diet, exercise, and medication when needed. The preoperative medical intervention incorporated consultations with a nutritionist, psychologist, and exercise physiologist along with adjustments to the patient s diabetes medications, including addition and titration of insulin. The intervention lasted for approximately 6 months prior to surgery. Outcomes Measures Our primary endpoint was diabetes type II remission, defined as an HbA1c measurement of <6.5 % (48 mmol/mol) and the absence of diabetes medication 1 year after RYGB. Statistical Analysis All parametric data were analyzed using Student s t test. We identified significant differences between categorical variables and proportions through chi-squared and z test analyses. We used a logistic regression model to determine which factors were indicative of diabetes type II remission 1 year after RYGB. A p value <0.05 was considered statistically significant. Statistical analyses were performed using the Statistical Package for Social Sciences (SPSS), version 21 (IBM SPSS Inc., Chicago, IL, USA) for Windows. Results Between 2008 and 2012, 656 UMass Memorial Medical Center patients with diabetes type II underwent RYGB, of which 357 (54 %) patients had postoperative information documented in their charts. Our final sample consisted of 245 (38 %) patients who had sufficient information in their charts to assess their diabetes type II at both 6 months prior to surgery and 1 year postoperative. Among the 245 patients, 35 % were male; their mean age was 54 years; and their mean baseline BMI was 47 kg/m 2. In 172 (70.2 %) of the cases, patients achieved diabetes type II remission at 1 year postsurgery. Patients who attained postoperative remission varied significantly by baseline characteristics from patients who did not remit (Table 1). Significant characteristics of patients who remitted include lower HbA1c prior to initiating the glucose optimization intervention (remit, 7.1 vs. no remit, 8.2; p<0.001), a greater decrease in HbA1c from the start of the intervention to surgery (remit, 0.79 % vs. no remit, 0.42 % p= 0.028), lower HbA1c at surgery (remit, 6.7 vs. no remit, 7.4;

3 Table 1 Characteristics of remitters and non-remitters Remit (N=172) Non-remit (N=73) p value HbA1c prior to glucose optimization 7.1 % (54 mmol/mol) 8.2 % (66 mmol/mol) <0.001 HbA1c change prior to surgery 0.79 % 0.42 % HbA1c at surgery 6.7 % (50 mmol/mol) 7.4 % (57 mmol/mol) <0.001 HbA1c 1 year after surgery 5.6 % (38 mmol/mol) 6.9 % (52 mmol/mol) <0.001 BMI Weight Age White 79 % 88 % Male 32 % 44 % Diabetes duration over 2 years 54 % 93 % <0.001 Insulin use at surgery 21 % 84 % <0.001 Insulin use 1 year after surgery 0 % 42 % <0.001 DiaRem score <0.001 p<0.001), younger age (remit, 53 vs. no remit, 56; p=0.005), and shorter duration of type 2 diabetes (2 years or more prior to surgery, 45 % vs. less than two years prior to surgery, 93 %; p<0.001). The group that remitted was less likely to be on insulin prior to surgery (remit 21 % vs. no remit, 84 % p<0.001), less likely to be on insulin after surgery (remit 0% vs. no remit, 42% p<0.001), and had a lower DiaRem (23) score (remit, 6.65 vs. no remit, 14.99; p<0.001). Neither preoperative BMI nor weight was significantly associated with remission. No association was found between percent of excess body weight lost and remission. A logistic regression analysis was used to assess the impact of baseline (as measured at surgery) HbA1c, age, insulin, duration of diabetes type II, gender, and race on postsurgery remission. This model also was utilized to develop an equation that could predict remission. As HbA1c at surgery increased by 1 %, patients were 59 % less likely to remit (p<0.001); patients using insulin were 91 % less likely to remit (p<0.001); and patients that has diabetes for more than 2 years were 81 % (p=0.001) less likely to remit. Patient age, gender, and race did not have statistically significant relationships in the model. This model was able to correctly predict remission status in 82.9 % of study patients. Preoperative Glucose Optimization We developed a second regression model (Table 2) to determine the importance of glucose optimization prior to surgery. We used this model to investigate the association with the changes in HbA1c prior to surgery and diabetes remission. In this model, we utilized two new measures of HbA1c: first, HbA1c as documented at least 6 months prior to surgery and preintervention, and second, the change in HbA1c from preintervention to preoperative. As HbA1c prior to glucose optimization increased by 1 %, patients were 40 % less likely to remit (p<0.001); as HbA1c decreased 1 % prior to surgery, patients were 68 % more likely to remit (p=0.015); and patients using insulin (p<0.001)and who had a duration of diabetes greater than 2 years were significantly less likely to remit (p=0.005). The remaining variables (age, race, and gender) in the model were not were not statistically significant. Discussion Our study results indicate that a greater degree of glycemic optimization, in response to presurgical medical intervention, is associated with higher rates of postoperative diabetes remission among obese adult candidates for RYGB, with diabetes type II. Conversely, the lack of favorable glycemic response to intensification of medical management predicts a poor glycemic response to bariatric surgery. The relationship between obesity, glucose intolerance, and diabetes type II is well established: an increase in BMI has been demonstrated to lead to impaired fasting glucose and diabetes type II. Pharmacotherapy, despite improvements, has resulted in fewer than 50 % of patients with moderate-to-severe diabetes type II achieving and maintaining therapeutic thresholds, particularly for glycemic control (5). We hypothesize that preoperative improvement in HbA1c may be a reflection of better beta cell function at baseline in this cohort, making them more responsive to changes in diet, exercise, and oral agents, which ultimately translates to better postoperative outcomes. Ideally, we would have liked to correlate a direct measure of beta cell function with diabetes type II remission, but clinical practice lacks an easy method of assessment. Our study demonstrated lower remission rates in patients with larger insulin requirements; this finding is not all that surprising given that diminished beta cell reserve is a function

4 Table 2 Predictors of remission with preoperative glucose optimization ** Statistically significant B S.E. p value Exp(B) A1c prior to glucose optimization ** A1c change prior to surgery ** Insulin <0.001** Diabetes duration over 2 years ** Age White Male Constant <0.001** 10, of disease duration. This data suggests that RYGB may have a greater health impact on patients who are early in the course of diabetes type II given that diabetes remission was associated non-insulin use and shorter duration of diabetes. Our study confirms that a prediction model of diabetes type II remission after RYGB is possible using an equation based on variables that typically are available to clinicians. Our formula proved predictive of remission in 82.9 % of our study population. While insulin use to optimize glycemic control is the single most powerful predictive factor, HbA1c, age, and duration of the disease were also variables that were predictive of diabetes type II remission. Patients not requiring insulin achieved remission in 92 % of the cases, while only 40 % of patients on insulin achieved remission. Higher insulin doses and duration of insulin use are other factors that should be further explored in future studies. Gender, race, preoperative BMI, and the degree of postoperative weight loss were not significant predictors of remission. We found that the degree of postoperative weight loss was not an important predictor of diabetes type II remission in our analysis, which may be due to the temporal course of postoperative biological events. One postulated mechanism for diabetes type II remission following bariatric surgery is improved beta cell function related to enhanced secretion of the incretin hormones induced by surgery (24). Moreover, an acute reduction in caloric intake in the immediate postoperative period is probably an important contributor to the rapid improvement in glycemic control (25). The majority of individuals will achieve diabetes type II remission by 6 weeks postoperative, a time when only the weight-loss independent mechanisms are in effect. Yet, RYGB also leads to a reduction in peripheral insulin resistance, which only can be seen about 6 months after surgery and is directly correlated to degree of weight loss (26,27). The later impact of improved peripheral insulin sensitivity may be masked by the more powerful earlier effects. We postulate that these individuals require this late effect on insulin sensitivity to achieve diabetes type II remission; hence, degree of weight loss and long-term weight regain may be more relevant for this population. A strength of our study is the relatively narrow range of preoperative HbA1c, therefore we were able to maximize the impact of lifestyle modifications and medication use. The mean HbA1c at surgery for our study population was 6.9 % (52 mmol/mol), which contrasts with prior studies that report the outcomes of surgical interventions performed on patients with poor glycemic control (28). In our study, most of the subjects manifested adequate glycemic control prior to surgical intervention, which allowed us to study other predictors of remission in a more independent manner. Our second model suggests that it may be more meaningful to look at the change in HbA1c as a result of preoperative interventions as correlated to postoperative remission. Finally, we argue that comparisons of diabetes type II medication requirements before and after bariatric surgery are more robust when medications have been adjusted for optimal and more uniform glycemic control, preoperatively. Future studies should use endpoints that are reflective of the overall glycemic benefit that patients receive from RYGB. While we applied an accepted threshold for diabetes type II remission as our primary study outcome, our analysis demonstrated that many patients had significant benefits from the surgery but did not meet our defined remission criteria. For example, one patient s HbA1c dropped from 8.5 % (69 mmol/ mol) preoperatively to 7.6 % (60 mmol/mol) postoperatively, and the patient s daily insulin dose dropped from 450 units to 60 units; still, the patient did not achieve remission by our study standards. Moreover, 33 % of patients who took insulin preoperatively and did not meet criteria for remission were able to quit taking insulin postoperatively to manage their diabetes type II. Future studies that examine the benefits of bariatric surgery also should consider additional clinical outcomes, such as progression of diabetes type II, complications like renal insufficiency, retinopathy, and cardiovascular morbidity and mortality. Longitudinal studies are needed as well to determine the long-term benefits of gastric bypass surgery in comparison to alternative procedures. Our study had a few limitations. All surgeries were performed at a single institution; therefore, these results may not be generalizable to the larger population. We had to exclude a large portion of the target population because they did not have significant data either before or after surgery. Our second model confirmed that it may be more relevant to define baseline as the time point at which the initial clinical decision for bariatric surgery is made, when exploring predictors of

5 diabetes type II remission. While we did analyze HbA1c several months prior to surgery, we did not have adequate data to assess other predictors that may be relevant over this time frame. Our study also did not focus on long-term outcomes or the sustainability of diabetes type II remission; our focus was remission at 1 year after surgery. Still, in a small sub-sample of our study s patients, we were able to retrospectively explore the impact of a preoperative optimization intervention over a 4-year period. While this data was sparse, it underscores the need to prospectively examine the effectiveness of RYGB in patient populations over time, and it provides us with a foundation on which to begin this exploration. These future studies should aim to capture comprehensive medication, severity, and disease duration data in the populations of interest. Ideally, this data should be captured from the initial time point at which patients consider undergoing RYGB surgery and prospectively thereafter. Despite the limitations, we conclude that preoperative glucose optimization is a useful practice, as patients with diabetes type II who benefit from this intervention prior to surgery are more likely to achieve remission at 1 year postoperative. Further research is needed to determine if this difference is due to physiological factors or is simply an indicator of patient behavior. Conclusion Our study results indicate that a greater degree of glycemic improvement in response to an intensive, preoperative glucose optimization intervention is associated with higher rates of diabetes remission postoperatively among obese adults with diabetes type II. Conversely, the lack of favorable glycemic response to intensification of medical management predicts a poor glycemic response to bariatric surgery. Further research is needed to determine if this difference is due to physiological factors or is simply an indicator of patient behavior. Acknowledgements All authors contributed to the numerous discussions and reviewed and edited the article. TE conducted the data analysis and wrote the initial drafts of the paper. SM, AO, and RP provided clinical insight and wrote a large portion of the discussion. RK and MD shaped the entirety of the text and conducted the final edits. Thomas MacAndrew English had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. None of the authors have any conflicts of interest to report. Research reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under award number UL1TR The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The study was performed with the approval of the University of Massachusetts Medical School Institutional Review Board (approval #14808) and met all HIPPA requirements. Conflict of Interest interest. The authors of this article declare no conflicts of References 1. Schauer PR, Kashyap SR, Wolski K, et al. Bariatric surgery versus intensive medical therapy in obese patients with diabetes. N Engl J Med. 2012;366(17): PMCID: Mingrone G, Panunzi S, De Gaetano A, et al. Bariatric surgery versus conventional medical therapy for type 2 diabetes. N Engl J Med. 2012;366(17): Buchwald H, Estok R, Fahrbach K, et al. Weight and type 2 diabetes after bariatric surgery: systematic review and meta-analysis. 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