Rebecca O'Brien, MD; Eric Johnson, MS; Sebastien Haneuse, PhD; Karen J. Coleman, PhD; Patrick J. O'Connor, MD, MA, MPH; David P. Fisher, MD; Stephen Sidney, MD, MPH; Andy Bogart, MS; Mary Kay Theis, MA, MS; Jane Anau, BS; Emily B. Schroeder, MD, PhD; David Arterburn, MD, MPH
Disclaimer: Drs. O'Brien and Arterburn take full responsibility for the contents of the article.
Acknowledgment: The authors thank Mike Sorel, Terese Defor, and Jessica Liu for their efforts in creating the study database.
Financial Support: By award 5R01DK092317-04 from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Dr. Schroeder was supported by award 1K23DK099237-01 from the National Institutes of Health, and Dr. O'Connor was supported in part by award P30DK092928 from the National Institutes of Health.
Disclosures: Dr. O' Brien reports grants from the NIDDK during the conduct of the study. Mr. Johnson reports grants from the National Institutes of Health during the conduct of the study. Dr. Sidney reports grants from the NIDDK during the conduct of the study and grants from the National Heart, Lung, and Blood Institute; National Institute of Neurological Disorders and Stroke; and National Institute on Aging outside the submitted work. Mr. Bogart reports grants from the National Institutes of Health during the conduct of the study. Ms. Anau reports grants from the NIDDK during the conduct of the study. Dr. Schroeder reports grants from the NIDDK during the conduct of the study. Dr. Arterburn reports grants from Patient-Centered Outcomes Research Institute during the conduct of the study, grants from the National Institutes of Health outside the submitted work, and personal fees and nonfinancial support from the Michigan Bariatric Surgery Collaborative outside the submitted work. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M17-2383.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that her spouse has stock options/holdings with Targeted Diagnostics and Therapeutics. Darren B. Taichman, MD, PhD, Executive Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer and Johnson & Johnson.
Reproducible Research Statement:Study protocol: See the . Statistical code: Available from Dr. Arterburn (e-mail, email@example.com). Data set: Our data access committee will review any requests for access to data and make a determination. Please contact Dr. Arterburn for details on making a request (e-mail, firstname.lastname@example.org).
Corresponding Author: David Arterburn, MD, MPH, Kaiser Permanente Washington Health Research Institute, 1730 Minor Avenue, Suite 1600, Seattle, WA 98101; e-mail, email@example.com.
Current Author Addresses: Dr. O'Brien: Kaiser Permanente Medical Center, 39400 Paseo Padre Parkway, Fremont, CA 94538.
Mr. Johnson, Ms. Theis, Ms. Anau, and Dr. Arterburn: Kaiser Permanente Washington Health Research Institute, 1730 Minor Avenue, Suite 1600, Seattle, WA 98101.
Dr. Haneuse: Harvard School of Public Health, Department of Biostatistics, 655 Huntington Avenue, Building II, Boston, MA 02115.
Dr. Coleman: Kaiser Permanente Southern California, 100 South Los Robles Avenue, Pasadena, CA 91101.
Dr. O'Connor: HealthPartners Research Foundation, 8170 33rd Avenue South, MS23301A, Minneapolis, MN 55425.
Dr. Fisher: The Permanente Medical Group, 1950 Franklin Avenue, Oakland, CA 94612.
Dr. Sidney: Kaiser Permanente Division of Research, 2000 Broadway, Oakland, PA 94612.
Mr. Bogart: RAND Corporation, 1776 Main Street, Santa Monica, CA 90407.
Dr. Schroeder: Kaiser Permanente Colorado, 2550 South Parker Road, Suite 200, Aurora, CO 80014.
Author Contributions: Conception and design: S. Haneuse, K.J. Coleman, P.J. O'Connor, E.B. Schroeder, D. Arterburn.
Analysis and interpretation of the data: R. O'Brien, E. Johnson, S. Haneuse, P.J. O'Connor, D.P. Fisher, S. Sidney, A. Bogart, J. Anau, E.B. Schroeder, D. Arterburn.
Drafting of the article: R. O'Brien, S. Haneuse, K.J. Coleman, A. Bogart, E.B. Schroeder, D. Arterburn.
Critical revision of the article for important intellectual content: R. O'Brien, E. Johnson, S. Haneuse, K.J. Coleman, P.J. O'Connor, D.P. Fisher, S. Sidney, E.B. Schroeder, D. Arterburn.
Final approval of the article: R. O'Brien, E. Johnson, S. Haneuse, K.J. Coleman, P.J. O'Connor, D.P. Fisher, S. Sidney, A. Bogart, M.K. Theis, J. Anau, E.B. Schroeder, D. Arterburn.
Provision of study materials or patients: P.J. O'Connor, S. Sidney.
Statistical expertise: E. Johnson, S. Haneuse, A. Bogart.
Obtaining of funding: S. Haneuse, K.J. Coleman, D. Arterburn.
Administrative, technical, or logistic support: S. Sidney, J. Anau, D. Arterburn.
Collection and assembly of data: K.J. Coleman, S. Sidney, M.K. Theis, J. Anau, D. Arterburn.
Bariatric surgery improves glycemic control in patients with type 2 diabetes mellitus (T2DM), but less is known about microvascular outcomes.
To investigate the relationship between bariatric surgery and incident microvascular complications of T2DM.
Retrospective matched cohort study from 2005 to 2011 with follow-up through September 2015.
4 integrated health systems in the United States.
Patients aged 19 to 79 years with T2DM who had bariatric surgery (n = 4024) were matched on age, sex, body mass index, hemoglobin A1c level, insulin use, diabetes duration, and intensity of health care use up to 3 nonsurgical participants (n = 11 059).
Bariatric procedures (76% gastric bypass, 17% sleeve gastrectomy, and 7% adjustable gastric banding) compared with usual care.
Adjusted Cox regression analysis investigated time to incident microvascular disease, defined as first occurrence of diabetic retinopathy, neuropathy, or nephropathy.
Median follow-up was 4.3 years for both surgical and nonsurgical patients. Bariatric surgery was associated with significantly lower risk for incident microvascular disease at 5 years (16.9% for surgical vs. 34.7% for nonsurgical patients; adjusted hazard ratio [HR], 0.41 [95% CI, 0.34 to 0.48]). Bariatric surgery was associated with lower cumulative incidence at 5 years of diabetic neuropathy (7.2% for surgical vs. 21.4% for nonsurgical patients; HR, 0.37 [CI, 0.30 to 0.47]), nephropathy (4.9% for surgical vs. 10.0% for nonsurgical patients; HR, 0.41 [CI, 0.29 to 0.58]), and retinopathy (7.2% for surgical vs. 11.2% for nonsurgical patients; HR, 0.55 [CI, 0.42 to 0.73]).
Electronic health record databases could misclassify microvascular disease status for some patients.
In this large, multicenter study of adults with T2DM, bariatric surgery was associated with lower overall incidence of microvascular disease (including lower risk for neuropathy, nephropathy, and retinopathy) than usual care.
National Institute of Diabetes and Digestive and Kidney Diseases.
Flow diagram for identification of eligible patients with T2DM and no history of microvascular disease who had bariatric surgery.
BMI = body mass index; EHR = electronic health record; HbA1c = hemoglobin A1c; T2DM = type 2 diabetes mellitus.
* Adults aged 20–79 y who had a primary (first observed) bariatric surgical procedure between 1 January 2005 and 31 December 2011. Bariatric procedures were identified using a combination of bariatric registries; review of medical records; International Classification of Diseases, Ninth Revision, codes (43.89, 44.31, 44.38, 44.39, 44.68, 44.69, and 44.95); and Current Procedural Terminology codes (43633, 43644, 43645, 43659, 43770, 43775, 43842, 43843, 43844, 43845, 43846, and 43847). We excluded patients with any of the following: <1 y of continuous enrollment; history of gastrointestinal surgery for cancer; pregnancy in the year before surgery; gestational diabetes as the sole diabetes diagnosis; preexisting neuropathy, nephropathy, or retinopathy; metformin as the sole indicator of possible T2DM (no other T2DM medications, laboratory values, or diagnoses); or maximum BMI <35 kg/m2.
† Patients may have >1 type of missing data (BMI, creatinine concentration, or HbA1c level) or have no follow-up time after surgery.
‡ 98 surgical patients could not be matched to a nonsurgical patient on site, age, BMI, insulin use, HbA1c level, and sex.
Appendix Table 1. Comparison of Characteristics of Surgical Patients Who Were Missing Values for BMI, HbA1c, or Serum Creatinine at Baseline Versus Those Who Had Complete Information on These Values at Baseline
Appendix Table 2. Retinopathy Procedure Codes Used to Indicate Diabetic Retinopathy in Patients With ICD-9 Diagnosis Code 250.5x, “Diabetes With Ophthalmic Manifestations”
Appendix Table 3. Reasons for Censoring for Surgical and Nonsurgical Populations*
Table 1. Baseline Characteristics of Patients With Type 2 Diabetes Who Had Bariatric Surgery and Matched Nonsurgical Patients, 2005–2011*
Kaplan–Meier–derived estimates of the cumulative incidence of microvascular disease (A–D) and time-varying HR comparing the risk for incident microvascular disease (E–H).
Separate estimates for neuropathy (B, F), nephropathy (C, G), and retinopathy (D, H) are shown, as well as a composite estimate for incident microvascular disease due to any of the 3 (A, E). Shaded areas represent 95% CIs. HR = hazard ratio.
* Defined as estimated glomerular filtration rate <60 mL/min/1.73 m2 on 2 separate measures separated by 90 d with no interim measures ≥60 mL/min/1.73 m2.
Table 2. Cumulative Incidence Rates and 95% CIs for Microvascular Disease Outcomes in Surgical and Matched Nonsurgical Patients*
Table 3. Results of Matched, Fully Adjusted Cox Proportional Hazards Model Comparing Risk for Incident Microvascular Disease Outcomes in Surgical Versus Matched Nonsurgical Patients*
Appendix Table 4. Fully Adjusted Cox Proportional Hazards Models of Time to Any Incident Microvascular Disease Event, as Well as Incident Retinopathy, Nephropathy, and Neuropathy Separately
Sensitivity analyses comparing the time-varying HR for all microvascular events (composite end point) in the main analysis (fully adjusted) versus a matched, unadjusted analysis.
HR = hazard ratio.
Sensitivity analyses comparing the time-varying HR for all microvascular events (composite end point) in the main analysis (3:1 matching) versus alternative 10:1 and 1:1 matching approaches.
Appendix Table 5. Differences Between Groups in the Number of Key Measures/Contacts*
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In this video, David Arterburn, MD, MPH, and Rebecca O'Brien, MD, offer additional insight into the article, "Microvascular Outcomes in Patients With Diabetes After Bariatric Surgery Versus Usual Care. A Matched Cohort Study."
Lena Carlsson, Björn Carlsson, Markku Peltonen
University of Gothenburg(LC, BC), IMED Biotech Unit AstraZeneca R&D (BC), National Institute for Health and Welfare (MP)
September 19, 2018
Conflict of Interest:
Potential conflicts of interest: LC has obtained lecture fees from AstraZeneca, Johnson&Johnson and MSD. BC is employed by AstraZeneca and holds stock in the same company.
Bariatric surgery and prevention of microvascular disease
In a matched retrospective cohort study, O’Brien et al demonstrate that bariatric surgery is associated with reduced incidence of microvascular disease in patients with type 2 diabetes (1) and thereby confirm our observations in the prospective Swedish Obese Subjects (SOS) study with median follow-up time of 19 years (2, 3). The authors statement that the SOS study did not examine retinopathy independent of other microvascular outcomes is, however, incorrect. In our report from 2017 (3), we showed that bariatric surgery is associated with reduced incidence of retinopathy in patients with established type 2 diabetes (supplementary figure 2: HR= 0·51 (0·37–0·70); p<0·001). However, even greater relative risk reductions were observed in those with screen detected diabetes and prediabetes both for retinopathy and for overall microvascular outcomes (test of interaction p<0.05 for both retinopathy and overall microvascular outcomes, respectively). The number needed to treat to prevent one incidence of microvascular disease was similar in subgroups with prediabetes, screen-detected diabetes, and established type 2 diabetes (<10 for 10-year follow-up). Thus, our results indicate that early treatment might be beneficial for prevention microvascular complications. In the future this may become more important with the trend of earlier onset of type 2 diabetes with a longer lifetime exposure to hyperglycemia (4). In the study by O’Brien, data are available on diabetes duration, and we therefore wonder if there was any difference in risk reduction between the subgroups with short and long duration of diabetes?References1. O'Brien R, Johnson E, Haneuse S, Coleman KJ, O'Connor PJ, Fisher DP, et al. Microvascular Outcomes in Patients with Diabetes After Bariatric Surgery Versus Usual Care: A Matched Cohort Study. Ann Intern Med. 2018;169:300-10. [PMID:30083761] Doi:7326/M17-23832. Sjostrom L, Peltonen M, Jacobson P, Ahlin S, Andersson-Assarsson J, Anveden A, et al. Association of bariatric surgery with long-term remission of type 2 diabetes and with microvascular and macrovascular complications. JAMA. 2014;311:2297-304. [PMID:24915261] doi:10.1001/jama.2014.5988.3. Carlsson LMS, Sjoholm K, Karlsson C, Jacobson P, Andersson-Assarsson JC, Svensson PA, et al. Long-term incidence of microvascular disease after bariatric surgery or usual care in patients with obesity, stratified by baseline glycaemic status: a post-hoc analysis of participants from the Swedish Obese Subjects study. Lancet Diabetes Endocrinol. 2017;5(4):271-9 [PMID:28237791] doi:10.1016/S2213-8587(17)30061-X.4. Lascar N, Brown J, Pattison H, Barnett AH, Bailey CJ, Bellary S. Type 2 diabetes in adolescents and young adults. Lancet Diabetes Endocrinol. 2018;6(1):69-80. [PMID:28847479] doi:10.1016/S2213-8587(17)30186-9
David Arterburn, on behalf of the PROMISE project team
Kaiser Permanente Washington Health Research Institute
September 27, 2018
Respnose to Carlsson and colleagues
We thank Dr. Carlsson and colleagues for their comment. We stand corrected on our statement about the SOS study and retinopathy outcomes. We had reviewed and referenced your work from 2014 and not your paper that was published in 2017. Regarding your question about diabetes duration as a potential effect modifier, we agree that this is an important question. We note that the question is similar to the analysis that you performed in your 2017 publication where you stratified by baseline glycemic status. Overall, we agree that your results suggest that people with earlier stage diabetes may benefit more from bariatric surgery than patients with later stage diabetes. This is consistent with the findings from our prior publication that suggest shorter duration of diabetes is associated with increased likelihood of and longer duration of diabetes remission, which is a possible mechanism that is related to decreased microvascular complications (1). While we didn’t conduct the analysis you propose, we do hope to address this question in a future manuscript.1. Arterburn D, Bogart A, Coleman KJ, Haneuse S, Selby JV, Sherwood NE, Sidney S, Theis MK, Campos GM, McCulloch D and O’Connor PJ. A Multisite Study of Long-Term Remission and Relapse of Type 2 Diabetes Mellitus following Gastric Bypass. Obesity Surgery. 2013 Jan;23(1):93-102.
Yeongkeun Kwon, Sungsoo Park
Korea University College of Medicine, Seoul, Korea
October 1, 2018
Diabetic nephropathy in the early postoperative period after bariatric surgery
O’Brien et al. reported that bariatric surgery reduces the risk of microvascular diseases in patients with types 2 diabetes. The findings of the present study will help healthcare professionals and patients who are considering bariatric surgery to make decisions based on more accurate information. However, the cubic spline plot presented in the study shows that unlike other microvascular diseases, the risk of diabetic nephropathy is increased immediately after bariatric surgery compared to the control group, but the authors did not adequately discuss this matter. Currently, our research team is undertaking a systematic review of the changes of renal functions or renal injuries after bariatric surgery. From four studies that measured proteinuria in the early postoperative period, two studies reported that proteinuria concentration is consistent or is actually increased from that before surgery.(1, 2) These two studies include results of a one-month follow-up after sleeve gastrectomy and Roux-en-Y gastric bypass in obese patients without diabetes. The early postoperative period until six months after bariatric surgery is a period characterized by rapid weight loss as well as rapid changes of inflammatory activities and hemodynamics in the kidney which are known as potential mechanisms of obesity induced kidney injury.(3, 4) It is suspected that these particular conditions may increase the risk of proteinuria immediately after bariatric surgery in some patients with or without type 2 diabetes with indications for bariatric surgery. If a specific group clearly shows an increased risk for diabetic nephropathy immediately after bariatric surgery, as shown in O’Brien et al.’s study, authors should present appropriate data and discussion of the said group. References1. Fenske WK, Dubb S, Bueter M, Seyfried F, Patel K, Tam FW, et al. Effect of bariatric surgery-induced weight loss on renal and systemic inflammation and blood pressure: a 12-month prospective study. Surg Obes Relat Dis. 2013;9(4):559-68.2. Mohan S, Tan J, Gorantla S, Ahmed L, Park CM. Early improvement in albuminuria in non-diabetic patients after Roux-en-Y bariatric surgery. Obes Surg. 2012;22(3):375-80.3. Tsuboi N, Okabayashi Y, Shimizu A, Yokoo T. The Renal Pathology of Obesity. Kidney Int Rep. 2017;2(2):251-60.4. Reilly SM, Saltiel AR. Adapting to obesity with adipose tissue inflammation. Nat Rev Endocrinol. 2017;13(11):633-43.
David Arterburn, MD, MPH, FACP
December 26, 2018
We thank Dr. Kwon and colleagues for their comment. They correctly point out that Figure 2.G. in our study shows the risk of nephropathy was significantly increased immediately after bariatric surgery compared to the control group (based on shaded 95% confidence intervals). Notably, this small increase in post-operative nephropathy risk did not have a significant impact on the long-term cumulative incidence of nephropathy (Figure 2.C.). Table 2 shows that the overall cumulative incidence rates of nephropathy were similar among surgical and nonsurgical patients (2.7% and 2.8%) at the end of year one, and rates of incident nephropathy at 3, 5, and 7 years were 3.6%, 4.9% and 6.4% respectively after bariatric surgery compared with 6.8%, 10% and 14% among nonsurgical patients. This suggests that any potential early negative effect of bariatric surgery on renal function is small compared to the long-term potential benefits of surgery on nephropathy risk among patients with diabetes. Because our study was focused primarily on long-term endpoints, we did not discuss the evidence of early post-operative increased incidence of nephropathy following bariatric surgery. It is unclear if this finding is due to worsening diabetic nephropathy or other renal injury, as we did not pull data looking for potential explanations, such as admissions for post-operative dehydration, use of nephrotoxic medications to treat infections, use of imaging contrast, etc. Acute kidney injury occurs in ~13% of patients who undergo major abdominal surgery (range 3-35% across studies),(1,2) although acute kidney injury rates after bariatric surgery may be lower at 5-10%.(2,3) We are not aware of any bariatric-specific risks for acute kidney injury. Nevertheless, there are gaps in the understanding of the incidence and risk factors for deterioration in renal function in post-bariatric patients, and we welcome future studies in this area. 1. O'Connor ME, Kirwan CJ, Pearse RM, Prowle JR. Incidence and associations of acute kidney injury after major abdominal surgery. Intensive Care Med. 2016 Apr;42(4):521-530.2. Gameiro J, Fonseca JA, Neves M, Jorge S, Lopes JA. Acute kidney injury in major abdominal surgery: incidence, risk factors, pathogenesis and outcomes: Annals of Intensive Care 2018 Feb 9;8(1):22.3. Thakar CV, Kharat V, Blanck S, Leonard AC. Acute Kidney Injury after Gastric Bypass Surgery: CJASN. 2007, 2(3) 426-430.
O'Brien R, Johnson E, Haneuse S, Coleman KJ, O'Connor PJ, Fisher DP, et al. Microvascular Outcomes in Patients With Diabetes After Bariatric Surgery Versus Usual Care: A Matched Cohort Study. Ann Intern Med. ;169:300–310. doi: 10.7326/M17-2383
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Published: Ann Intern Med. 2018;169(5):300-310.
Published at www.annals.org on 7 August 2018
Cardiology, Coronary Risk Factors, Diabetes, Diabetic Nephropathy, Endocrine and Metabolism.
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