Supplementary Online Content Sjöström L, Peltonen M, Jacobson P, et al. Association bariatric surgery with long-term remission type 2 diabetes and with microvascular and macrovascular complications. JAMA. doi:10.1001/jama.2014.5988. eappendix 1. SOS study design and recruitment efigure 1. SOS: Weight changes over 15 years in the control and surgery groups with diabetes at baseline efigure 2. SOS: Prevalence diabetes remission in controls and the three bariatric surgery subgroups after 2, 10 and 15 years follow up efigure 3. SOS: The cumulative incidence all (microvascular plus macrovascular) diabetes complications in the three surgery groups etable 1. SOS: Nonfatal and fatal diabetes complications according to ICD-9 and ICD-10 and according to Surgical procedures as coded in the National Swedish Patient Register (with inpatient and specialist outpatient care) and Cause Death Register etable 2. Baseline characteristics, weight change by treatment group and participation status at 15-year follow-up etable 3. SOS: Multivariable logistic regression model on diabetes remission at 2 years for surgery and control groups combined etable 4. SOS: Association between bariatric surgery and diabetes remission without and with multiple imputations etable 5. SOS: Multivariable logistic regression models on diabetes remission and relapse in the surgery groups etable 6. Cox proportional hazard regression models treatment and baseline variables on (A) microvascular and (B) macrovascular diabetes complications during up to 25 years This supplementary material has been provided by the authors to give readers additional information about their work.
2 eappendix: SOS study design and recruitment After recruitment campaigns in mass media and at primary health care centers, a matching examination was completed by 6905 patients. Among 5335 eligible individuals, 2010 choosing surgery formed the surgery group. A contemporaneously matched control group 2037 individuals was created using 18 matching variables. The matching variables were sex, age, weight, height, waist and hip circumferences, systolic blood pressure, serum cholesterol and triglyceride levels, smoking status, diabetes, menopausal status and four psychosocial variables with documented associations with the risk death [social support, life events, health perception, psychosocial functioning], and two personality traits related to treatment preferences [monotony avoidance, psychastenia] (Karlsson J, Sjöström L & Sullivan M. J Clin Epidemiol, vol 48:817-823, 1995). According to the method sequential treatment assignment, a matching algorithm selected controls so that the current mean values the matching variables in the control group became as similar as possible to the current mean values in the surgery group (Pocock SJ, Simon R. Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trial. Biometrics 1975;31:103-15.) The two study groups had identical inclusion and exclusion criteria, and all controls were eligible for surgery. The inclusion criteria were aged 37 to 60 years and BMI 34 kg/m2 or more for men and 38 kg/m2 or more for women before or at the matching examination. The exclusion criteria were earlier surgery for gastric or duodenal ulcer, earlier bariatric surgery, gastric ulcer during the past 6 months, ongoing malignancy, active malignancy during the past 5 years, myocardial infarction during the past 6 months, bulimic eating pattern, drug or alcohol abuse, psychiatric or cooperative problems contraindicating bariatric surgery, other contraindicating conditions (such as chronic glucocorticoid or anti-inflammatory treatment). To examine the association between bariatric surgery and diabetes remission and incidence diabetes complications, 603 patients who had diabetes at baseline were included in the analysis.
3 SUPPLEMENTARY FIGURES AND TABLES efigure 1. SOS: Weight changes over 15 years in the control and surgery groups with diabetes at baseline. Bars represent 95% confidence intervals. VBG, vertical banded gastroplasty. GBP, gastric bypass.
4 efigure 2. SOS: Prevalence diabetes remission in controls and the three bariatric surgery subgroups after 2, 10 and 15 years follow up. Diabetes remission was defined as fasting blood glucose levels lower than 110 mg per deciliter and no diabetes medication. 95 percent confidence intervals are indicated. VBG, vertical banded gastroplasty. GBP, gastric bypass. Panel A: Patients were analyzed according to their original treatment allocation. Panel B: Controls who have later obtained surgery and surgery patients who have later been converted to another surgical method were excluded.
5 efigure 3. SOS: The cumulative incidence all (microvascular plus macrovascular) diabetes complications in the three surgery groups. Surgery patients who had been converted to another surgical method after the initial operation at baseline were removed from calculations. Diabetes complications requiring hospital treatment, specialist care or diabetes complications that were associated with death during follow-up were traced by cross-checking against the Swedish National Patient Register (consisting inpatient and specialist outpatient registers) and the Cause Death Registry until December 31, 2012. The ICD codes and surgery procedures used for cross checking are specified in S-Table 1. The x-axis is truncated at 20 years, but all observations after 20 years were included in the statistical analysis. VBG, vertical banded gastroplasty. GBP, gastric bypass.
6 etable 1. SOS. Nonfatal and fatal diabetes complications according to ICD-9 and ICD-10 and according to Surgical procedures as coded in the Patient Register (with inpatient and specialist outpatient care) and Cause Death Register. Registry searches were performed using these codes and any sub-classifications there. Diagnosis ICD-9 ICD-10 Surgical procedures Procedure codes operations,! Ed. 5, 1985 Ed. 6, 1989, both editions including also Procedure codes surgical procedures (KKÅ) 1997 Temporary list procedures (TÅL) 1997. Microvascular diabetes complications, non-fatal or fatal Kidney complications 250D E11.2 E10.2* E14.2 Swedish Classifications Health Interventions (KVÅ) 2007 # including both surgical (KKÅ) and (KMÅ) Kidney transplantation 6070 KAS00 KAS10 KAS20
7 Diagnosis ICD-9 ICD-10 Surgical procedures Procedure codes operations,! Ed. 5, 1985 Ed. 6, 1989, both editions including also Procedure codes surgical procedures (KKÅ) 1997 Temporary list procedures (TÅL) 1997. Diabetes nephropathy N08.3 Kidney biopsy 6080 6081 Swedish Classifications Health Interventions (KVÅ) 2007 # including both surgical (KKÅ) and (KMÅ) KAB00 KAB01 Albuminuria Renal failure Dialysis 791A 584 to 586 V45B R80 N39.1 N17 to N19 Z99.2 Hemodialysis Peritoneal dialysis 9211 9212 9213 9214 DR015 DR016 DR020 V9211 V9212 DR023 DR024
8 Diagnosis ICD-9 ICD-10 Surgical procedures Procedure codes operations,! Ed. 5, 1985 Ed. 6, 1989, both editions including also Procedure codes surgical procedures (KKÅ) 1997 Temporary list procedures (TÅL) 1997. Eye complications V56A V56W 250E Z49 E11.3 E10.3* E14.3 Swedish Classifications Health Interventions (KVÅ) 2007 # including both surgical (KKÅ) and (KMÅ) JAK10 TJA20 TJA33 V9213 V9214 Diabetes retinopathy 250E H36.0 Retinal operations 1630-1638 CKC
9 Diagnosis ICD-9 ICD-10 Surgical procedures Procedure codes operations,! Ed. 5, 1985 Ed. 6, 1989, both editions including also Procedure codes surgical procedures (KKÅ) 1997 Temporary list procedures (TÅL) 1997. Neurological complications Amyotrophy Autonomous (poly)neuropathy Mononeuropathy Polyneuropathy Peripheral, mainly macrovascular diabetes complications, non-fatal and fatal + 250F 357E E11.4 E10.4* E14.4 G73.0 G99.0 G59.0 G63.2 Swedish Classifications Health Interventions (KVÅ) 2007 # including both surgical (KKÅ) and (KMÅ) CKD
10 Diagnosis ICD-9 ICD-10 Surgical procedures Procedure codes operations,! Ed. 5, 1985 Ed. 6, 1989, both editions including also Procedure codes surgical procedures (KKÅ) 1997 Temporary list procedures (TÅL) 1997. Claudication, atherosclerosis arteries extremities Diabetes gangrene, diabetic foot Diabetes gangrene, cont. 443X 440C 250G I70.2 E11.5 E10.5* E14.4 I79.2 Amputations on leg or foot Operations on suprarenal aorta and visceral arteries 8750 8760 8770 8771 8780 8781 0963 0964 0965 Swedish Classifications Health Interventions (KVÅ) 2007 # including both surgical (KKÅ) and (KMÅ) NFQ NGQ NHQ PCE PCF PCG PCH
11 Diagnosis ICD-9 ICD-10 Surgical procedures Procedure codes operations,! Ed. 5, 1985 Ed. 6, 1989, both editions including also Procedure codes surgical procedures (KKÅ) 1997 Temporary list procedures (TÅL) 1997. Operations on renal aorta and iliac arteries 8836 8837 8838 8839 8884 Swedish Classifications Health Interventions (KVÅ) 2007 # including both surgical (KKÅ) and (KMÅ) PCJ PCK PCN PCP PCQ PDE PDF PDG PDH PDN
12 Diagnosis ICD-9 ICD-10 Surgical procedures Procedure codes operations,! Ed. 5, 1985 Ed. 6, 1989, both editions including also 8885 8815 8816 8817 8818 Procedure codes surgical procedures (KKÅ) 1997 Temporary list procedures (TÅL) 1997. Swedish Classifications Health Interventions (KVÅ) 2007 # including both surgical (KKÅ) and (KMÅ) PDP PDQ PDS Operations leg arteries 8861 8862 8865 8866 8868 PEE PEF PEG PEH PEN
13 Diagnosis ICD-9 ICD-10 Surgical procedures Procedure codes operations,! Ed. 5, 1985 Ed. 6, 1989, both editions including also Procedure codes surgical procedures (KKÅ) 1997 Temporary list procedures (TÅL) 1997. Macrovascular centrally located diabetes complications, non-fatal or fatal + 8886 8887 8825 8826 8827 8828 8884 8885 Swedish Classifications Health Interventions (KVÅ) 2007 # including both surgical (KKÅ) and (KMÅ) PEP PEQ PFE PFG PFH PFN PFP PFQ PFS
14 Diagnosis ICD-9 ICD-10 Surgical procedures Procedure codes operations,! Ed. 5, 1985 Ed. 6, 1989, both editions including also Procedure codes surgical procedures (KKÅ) 1997 Temporary list procedures (TÅL) 1997. Angina pectoris Acute myocardial infarction Myocardial reinfarction Complications to myocardial inf. Other ischemic conditions 413 410 411 412 414 I20 I21 I22 I23 I24 I25 Coronary artery operations Heart transplantation 3105 3127 3158 3085 Swedish Classifications Health Interventions (KVÅ) 2007 # including both surgical (KKÅ) and (KMÅ) FNA to FNK FNW FQA FQB Heart failure 428 I50 Subarachnoidal bleeding 430 I60 Aneurysm operations 0190 0191 AAC AAL
15 Diagnosis ICD-9 ICD-10 Surgical procedures Procedure codes operations,! Ed. 5, 1985 Ed. 6, 1989, both editions including also Procedure codes surgical procedures (KKÅ) 1997 Temporary list procedures (TÅL) 1997. Hemorrhagia cerebri Cerebral infarction Unspecified stroke 431 432x 434 436 I61 I62 I63 I64 Swedish Classifications Health Interventions (KVÅ) 2007 # including both surgical (KKÅ) and (KMÅ) Arterial operations 0193 PAF PAG PAH PAJ PAK! First edition Operations (Swedish: Klassifikation av Operationer) was printed by the and Welfare in 1963.
16 # KVÅ is available only on the net (www.socialstyrelsen.se/klassificeringochkoder/atgardskoderkva) and is updated annually since 2007. Older code lists were printed by the and Welfare. * In the Swedish National Patient Registry and the Cause Death Registry, complications some typical type 2 diabetic individuals have erroneously been coded as type 1 diabetes (i.e. with E10# codes), particularly if they have obtained insulin treatment. Since we know that all patients in this report had type 2 diabetes at baseline (see Methods), we have included both E11 (type 2) and E10 (type 1) codes in our searches for complications type 2 diabetes. + Since we know that all patients in this report had type 2 diabetes at the SOS baseline examination, we have considered claudication as well as heart and brain problems as diabetic complications even if diabetes is not a specified diagnosis in the corresponding hospital records.
17 etable 2. Baseline characteristics, weight change by treatment group and participation status at 15-year follow-up. Individuals with diabetes at baseline in the SOS study. Non-participants: did not participate at 15-year follow-up; Participants: did participate at 15-year follow-up. SURGERY Non-participants at 15 year, n=172 Participants at 15 year, n=115 Baseline data: Mean SD Mean SD t- or z-value CONTROL Non-participants at 15 year, n=135 Participants at 15 year, n=62 p- value Mean SD Mean SD Sex, men (%) 71 (41.3) 50 (43.5) -0.4 0.712 50 (37.0) 32 (51.6) -1.9 Age, yr Weight, kg 48.7 6.1 48.7 5.5 0.0 0.974 50.5 6.5 49.6 5.9 1.0 122.8 18.1 123.0 20.5-0.1 0.937 115.9 16.9 116.8 15.6-0.3 BMI, kg/m 2 42.1 4.4 42.1 5.0 0.0 0.967 40.0 4.6 39.4 4.3 1.0 Waist, cm Hip, cm Waist-hip ratio Blood glucose, mg/dl Serum insulin, mu/l 129.4 11.9 128.6 12.2 0.6 0.575 123.1 10.4 122.1 9.6 0.6 126.6 10.8 125.8 10.4 0.6 0.560 121.9 10.4 121.5 9.2 0.3 1.0 0.1 1.0 0.1 0.2 0.870 1.0 0.1 1.0 0.1 0.4 159.9 49.0 148.7 44.6 2.0 0.051 160.2 49.4 150.2 48.1 1.3 29.6 23.9 29.1 14.5 0.2 0.831 26.1 18.5 26.0 18.9 0.0 HOMA-IR 11.5 9.4 10.8 7.1 0.7 0.516 10.2 7.8 9.4 7.3 0.6 Systolic blood pressure, mmhg 151.6 20.0 150.1 16.1 0.6 0.521 142.8 18.6 145.5 20.8-0.9 Diast blood pressure, mmhg 92.6 10.5 93.1 10.9-0.5 0.649 87.3 11.2 87.7 11.5-0.2 Total cholesterol, mg/dl HDL cholesterol, mg/dl 230.5 48.5 234.7 47.5-0.7 0.470 229.2 43.7 219.2 43.9 1.5 48.8 12.0 47.4 11.4 0.9 0.356 48.1 11.2 46.9 10.3 0.7 t- or z- value p- valu e 0.05 6 0.33 2 0.73 6 0.33 9 0.53 3 0.77 9 0.69 1 0.18 7 0.97 4 0.53 5 0.37 0 0.81 2 0.13 7 0.50 9
18 SURGERY Non-participants at 15 year, n=172 Participants at 15 year, n=115 CONTROL Non-participants at 15 year, n=135 Participants at 15 year, n=62 Triglycerides, mg/dl 255.6 187.0 269.7 206.4-0.6 0.550 281.8 250.6 236.5 141.6 1.3 U-albumin excretion, μg/minute, median 15.3 18.4 0.254 13.2 14.8 IQR* (7.6-57.2) (7.2-41.2) (6.0-37.0) (6.8-32.6) Smoking, n (%) 44 (25.7) 26 (22.6) 0.6 0.548 35 (26.5) 9 (14.5) 1.8 Physically active, leisure time, n (%) 84 (49.1) 64 (55.7) -1.1 0.280 80 (61.1) 44 (71.0) -1.3 Total calorie intake, kcal 1655. 2979.8 1299.1 3044.7 7-0.4 0.711 2613.9 1149.1 2569.1 892.0 0.3 Weight change at 2-year, kg -23.7 13.0-27.5 15.3 2.1 0.033-3.1 7.7-4.2 9.7 0.8 95% CI (-25.8 to -21.6) (-30.4 to -24.6) (-4.6 to -1.5) (-6.8 to -1.7) Weight change at 10 yr, kg -20.6 14.9-23.1 16.2 1.1 0.252-3.3 13.4-5.5 11.8 0.9 95% CI (-23.6 to -17.5) (-26.1 to -20.1) (-7.0 to 0.3) (-8.5 to -2.5) 0.18 5 0.83 9 0.06 7 0.18 3 0.78 6 0.40 7 0.36 0 * IQR: Interquartile range.
19 etable 3. SOS: Multivariable logistic regression model on diabetes remission at 2 years for surgery and control groups combined. Surgery plus Control group Remission n=253/n=510 Baseline variables Remission from diabetes at 2 years Multiple imputation analysis # OR 95% CI z p OR 95% CI t p Surgery, yes (219/303) vs. no (34/207) 40.5 21.0-78.2 11.0 <0.001 28.8 15.3-53.9 10.5 <0.001 Sex, men (101/201) vs women (152/309) 1.42 0.83-2.43 1.3 0.199 1.33 0.79-2.34 1.1 0.283 Age, per 6.2 years 1.00 0.77-1.30-0.01 0.992 0.98 0.75-1.27-0.2 0.880 Blood glucose, per 48 mg/dl 0.61 0.44-0.86-2.9 0.004 0.55 0.41-0.75-3.8 <0.001 BMI, per 4.8 kg/m2 1.07 0.80-1.44 0.5 0.628 1.18 0.87-1.60 1.1 0.280 Diabetes duration, per 4.6 years 0.31 0.19-0.50-4.7 <0.001 0.41 0.25-0.69-3.4 0.001 Oral antidiab. medication, yes (67/195) vs. no (177/255) 0.19 Insulin treatment, yes (9/60) vs. no (177/255) 0.24 0.10-0.37 0.07-0.83-4.9 <0.001 0.27-2.3 0.024 0.36 0.14-0.52 0.11-1.13-3.9 <0.001-1.8 0.079 Odds-ratios (OR) are expressed as surgery v.s. control, men v.s. women etc. for dichotomous variables, and per standard deviation increase for continuous variables. OR values greater than 1 indicate higher likelihood for the occurrence outcome. Men coded as 1, women as 0. Yes coded as 1, no as 0. # Multiple Imputation calculations are based on observed plus imputed data. The missing outcome data were imputed using chained equations with Stata (version 12.1). The following variables were used as predictors missing outcome data: age, sex, treatment group (surgery/control), body mass index at baseline, and blood glucose at baseline. The number imputations (complete datasets with imputed values) was set to 30.
20 etable 4. SOS: Association between bariatric surgery and diabetes remission without and with multiple imputations. Observation year Participation rate (adjusted for mortality) Number observations Odds Ratio Surg Contr Surg Contr OR 95% CI P Observed data (no imputations) Baseline 100 100 343 260 - - - 2 years 90 81 303 207 13.3 8.5-20.7 <0.001 10 years 76 58 236 135 5.3 2.9-9.8 <0.001 15 years 47 41 115 62 6.3 2.1-18.9 <0.001 Multiple imputation # 2 years 100 100 343 260 13.3 8.5-20.7 <0.001 10 years 100 100 343 260 5.5 2.9-10.3 <0.001 15 years 100 100 343 260 6.2 2.5-15.5 <0.001 Odds-ratios (OR) are expressed as surgery vs control ; values greater than 1 indicate higher likelihood for remission in the surgery group as compared to control group. # Multiple Imputation calculations are based on observed plus imputed data. The missing outcome data were imputed using chained equations with Stata (version 12.1). The following variables were used as predictors missing outcome data: age, sex, treatment group (surgery/control), body mass index at baseline, and all observed data on blood glucose at baseline and during follow-up. The number imputations (complete datasets with imputed values) was set to 30.
21 etable 5. SOS: Multivariable logistic regression models on diabetes remission and relapse in the surgery group. Odds ratios (OR) for continuous variables are expressed per standard deviation. All variables except weight change 0-2 years refer to baseline conditions. For direction relationships, see foot note. A. Remission from diabetes at 2 years in the surgery group. B. Two to ten-year relapse after remission at 2 years in the surgery group. A. Surgery group only. Remission from type 2 diabetes at 2 years Remission n=84/n=303 Observed data Observed plus imputed data OR# 95% CI z p OR# 95% CI z p Sex, men (88/120) vs. women (131/183) 1.65 0.83-3.31 1.4 0.157 1.43 0.73-2.80 1.1 0.292 Age, per 6.2 years 1.09 0.78-1.52 0.5 0.614 1.07 0.79-1.45 0.4 0.678 Blood glucose, per 48 mg/dl 0.66 0.46-0.96-2.2 0.030 0.59 0.42-0.83-3.0 0.003 BMI, per 4.8 kg/m 2 0.89 0.61-1.31-0.6 0.564 0.98 0.67-1.45-0.1 0.931 Diabetes duration, per 4.6 years 0.32 0.18-0.54-4.2 <0.001 0.39 0.22-0.69-3.3 0.001 Oral antidiab. medication, Yes (66/111) vs. no (145/156) 0.24 0.10-0.53-3.5 <0.001 0.33 0.15-0.71-2.8 0.005 Insulin treatment, Yes (8/36) vs. no (145/156) 0.23 0.06-0.88-2.2 0.031 0.35 0.09-1.30-1.5 0.116 B. Surgery group only. 10-year relapse after 2-year remission from diabetes Relapse n=88/n=169 Observed data Observed plus imputed data OR# 95% CI z p OR# 95% CI z p Sex, men (45/70) vs. women (43/99) 3.60 1.69-7.66 3.3 0.001 3.64 1.72-7.73 3.4 0.001 Age, per 6.2 years 0.90 0.59-1.37-0.5 0.609 0.87 0.60-1.24-0.8 0.433 Blood glucose, per 48 mg/dl 1.50 0.97-2.33 1.8 0.070 1.54 1.04-2.27 2.2 0.029 BMI, per 4.8 kg/m 2 1.37 0.90-2.08 1.5 0.145 1.33 0.89-1.97 1.4 0.159 Diabetes duration, per 4.6 years 3.71 1.14-12.1 2.2 0.029 1.32 0.82-2.12 1.2 0.252 Weight change 0 to 2 yrs, per 16.9 kg 4.52 2.55-8.01 5.2 <0.001 3.85 2.32-6.41 5.2 <0.001 # Odds-ratios (OR) are expressed as men vs women etc. for dichotomous variables, and per standard deviation increase for continuous variables. OR values greater than 1 indicate higher likelihood for the occurrence outcome (remission and relapse, respectively). Men coded as 1, women as 0. Yes coded as 1, no as 0. Multiple Imputation calculations are based on observed plus imputed data. The missing outcome data were imputed using chained equations with Stata (version 12.1). The following variables were used as predictors missing outcome data: age, sex, treatment group (surgery/control), body mass index at baseline, and all observed data on blood glucose at baseline and during follow-up. The number imputations (complete datasets with imputed values) was set to 30.
etable 6. Cox proportional hazard regression models treatment and baseline variables on (A) microvascular and (B) macrovascular diabetes complications during up to 25 years. Hazard ratios (HR) for continuous variables are expressed per standard deviation. The ICD codes and surgery procedures used for cross checking against the Swedish National Inpatient, Specialist Outpatient and Cause Death registries are specified in etable 1. A. Surgery and control groups: Microvascular complications 240 events/ N=603. HR# 95% CI z p Surgery (106/343), vs. control (134/260) 0.43 0.33-0.58-5.8 <0.001 Sex, men (108/245) vs. women (132/358) 1.51 1.16-1.96 3.1 0.002 Age, per 6.2 years 1.15 1.01-1.32 2.1 0.033 Blood glucose, per 48 mg/dl 1.46 1.27-1.67 5.3 <0.001 BMI, per 4.8 kg/m 2 0.91 0.79-1.05-1.3 0.180 Diabetes duration, per 4.6 years 1.47 1.27-1.70 5.1 <0.001 B. Surgery and control groups: Macrovascular complications 293 events/n=603. HR# 95% CI z p Surgery (151/343) vs. control (142/260) 0.74 0.58-0.94-2.5 0.013 Sex, men (146/245) vs. women (147/358) 1.94 1.53-2.47 5.5 <0.001 Age, per 6.2 years 1.42 1.25-1.60 5.5 <0.001 Blood glucose, per 48 mg/dl 1.08 0.95-1.23 1.1 0.268 BMI, per 4.8 kg/m 2 1.03 0.91-1.17 0.5 0.632 Diabetes duration, per 4.6 years 1.31 1.15-1.48 4.2 <0.001 22 # Hazard-ratios (HR) are expressed as surgery vs. control, men vs women etc. for dichotomous variables, and per standard deviation increase for continuous variables. HR values greater than 1 indicate higher likelihood for the occurrence diabetes complications. Men coded as 1, women as 0. Yes coded as 1, no as 0.