Predictors for Remission of Major Components of the Metabolic Syndrome After Biliopancreatic Diversion with Duodenal Switch (BPDDS)

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1 DOI.7/s CLINICAL RESEARCH Predictors for of Major Components of the Metabolic Syndrome After Biliopancreatic Diversion with Duodenal Switch (BPDDS) Villy Våge & Roy M. Nilsen & Arnold Berstad & Jan Behme & Nils Sletteskog & Ronny Gåsdal & Camilla Laukeland & Gunnar Mellgren # Springer Science+Business Media, LLC 12 Abstract Background Metabolic surgery causes the remission of type 2 diabetes mellitus (T2DM), hypertension, and hyperlipidemia to varying degrees, depending on the patient characteristics and the surgical procedure. The aim of this study was to find predictors for the remission of T2DM and hypertension after biliopancreatic diversion with duodenal switch (BPDDS). Methods Eighty patients with T2DM were followed up for 2 years or more after BPDDS, and changes in body weight and metabolic status were noted. was defined as fasting glucose <7 mmol/l with HbA1C <6. %, blood pressure <14/9 mmhg, and low-density lipoprotein (LDL) <2.6 mmol without the use of medication. Results Preoperatively, the mean age was 44 years, body mass index (BMI) was 48 kg/m 2, and duration of diabetes was years. Of the 8 patients, 38 patients were using insulin, 48 patients were using antihypertensives, and 38 patients were using a lipid-lowering drug. Five percent of V. Våge (*) : J. Behme : N. Sletteskog : R. Gåsdal : C. Laukeland Department of Surgery, Førde Central Hospital, 687 Førde, Norway villy.vage@helse-forde.no R. M. Nilsen Centre for Clinical Research, Haukeland University Hospital, Bergen, Norway A. Berstad Unger Vetlesen s Institute, Lovisenberg Diakonale Hospital, Oslo, Norway G. Mellgren Hormone Laboratory, Haukeland University Hospital, Bergen, Norway G. Mellgren Institute of Medicine, University of Bergen, Bergen, Norway the patients had recommended levels for HbA1C, blood pressure, and LDL prior to the operation. The remission rate at 2 years was 94 % for T2DM, 4 % for hypertension, and 86 % for LDL hyperlipidemia. Preoperative predictors for nonremission of T2DM were a higher BMI, insulin usage, and low insulin C-peptide, and for hypertension, older age and more severe hypertension. Postoperative weight loss was important for both. Conclusions Surgical intervention with BPDDS is an effective treatment of T2DM, hypertension, and hyperlipidemia. The duration of T2DM and age of the patient are the most important preoperative predictors for the remission of T2DM and hypertension, respectively. Keywords Biliopancreatic diversion with duodenal switch. Type 2 diabetes. Hypertension. Hyperlipidemia.. Predictors. Latent autoimmune diabetes of the adult Introduction The metabolic syndrome is defined by the World Health Organization as a clustering of glucose intolerance, hypertension, hyperlipidemia, and central adiposity [1]. It is increasingly prevalent in humans with an increase in body mass index (BMI) and with a natural tendency to progression [2]. Type 2 diabetes mellitus (T2DM), which is a major component of the metabolic syndrome, is an independent and strong risk factor for heart attack, stroke, renal failure, blindness, lower limb amputation, and premature death. At the beginning of the century, the prevalence of T2DM in Norway was estimated to be 3 4 % of the population above the age of 3, causing suffering and high costs for the individual and society due to health care expenditure, sick leave, and disability pension [3]. Guidelines for the

2 treatment of T2DM include having a sharp focus not only on blood glucose but also on hypertension and hyperlipidemia [4]. Medical treatment, including recommendations for diet, physical activity, oral medications, and insulin, has, however, a high failure rate in obtaining the recommended treatment targets, especially for patients that are morbidly obese []. As it is increasingly recognized that bariatric surgery is the only treatment proven to give sustained weight loss for the morbidly obese, bariatric surgery in general has gained increased acceptance and popularity [6]. When performed by experienced surgeons, it is safe and provides a dramatic improvement or even remission of metabolic disease [7]. It has, therefore, also been named metabolic or diabetic surgery and has recently been recognized as an appropriate treatment of T2DM in patients with a BMI above 3 [8]. For gastric bypass surgery, several studies have identified longstanding diabetes, insulin usage, and lower weight loss as the most important predictors for nonremission of T2DM [9 11]. Different types of biliopancreatic diversion (BPD) have been reported to give different results, depending on the technique performed [12, 13]. However, among the metabolic operations, the biliopancreatic diversion with or without the duodenal switch (BPDDS) is the procedure that gives the highest remission rates for T2DM [7, 14], and the aim of this study was to evaluate the remission rates and predictors for nonremission of T2DM, hypertension, and hyperlipidemia after this procedure. Patients and Methods Our bariatric surgery program started in 1, and all diabetic patients with a minimum of 24 months follow-up were evaluated for inclusion in the study. Among 224 consecutive patients undergoing BPDDS in the time period April 1 Januar, 9 were identified as having diabetes. Ten patients were excluded; one had type 1 diabetes, two had been classified as T2DM but the preoperative fasting glucose and HbA1C were normal, one patient was excluded due to inadequate data to conclude on diabetic status at 2 years, and six patients were found to have latent autoimmune diabetes of the adult (LADA) at follow-up. LADA was diagnosed by the presence of antibodies to glutamic acid decarboxylate, IA2, and/or insulin [1], and these six patients are presented separately. This left us with 8 patients with T2DM with or without concurrent hypertension and/or hyperlipidemia eligible for the study. Data were collected prospectively in a database after having obtained written informed consent from the patients. The database is approved by the Norwegian Data Inspectorate, and the present study is a prospective cohort study with data extracted from the database. T2DM was defined as a fasting blood glucose 7 mmol/l, or independent of blood value if using medication. Diabetic status was subdivided into controlled by diet, controlled by oral medication, or controlled by insulin. Most of the patients using insulin were also taking oral medication. for diabetes was defined as fasting blood glucose <7 mmol/l with an HbA1C <6. % without medication [16]. The blood pressure was measured using a wide-cuff sphygmomanometer after the patient had been sitting in a relaxed position for at least min. Hypertension was defined as a blood pressure 14/9 mmhg, or independent of blood pressure if taking antihypertensive medication. Hypertension status was subdivided into hypertension without medication, hypertension using one medication, or hypertension using two or more medications. Due to some missing data for serum lipids at 24 months, we decided to present lipidemia status as whether the patient was using lipidlowering medication or not, but the remission rate and the percentage of patients having obtained the recommended level for low-density lipoprotein (LDL) were calculated based on the available data. The LDL level was calculated according to Friedewald s formula(ldlchol HDL.4 Trigl), provided that the serum triglyceride level was <4. mmol/l [17]; if not, the patient was categorized as having hyperlipidemia and not having obtained the recommended level. Waist circumference was not measured as this is a useless task in the morbidly obese, measuring as much the subcutaneous fat as the intra-abdominal fat in this patient category [18, 19]. The BPDDS combines a longitudinal gastric resection (creating gastric volume restriction) with a proximal small bowel bypass (creating intestinal malabsorption). Different combinations of restriction and malabsorption can be created, and as we have gained experience with the procedure, the weight loss among our patients has increased without giving more side effects []. The patients were evaluated at the outpatient clinic preoperatively and at 3, 12, and 24 months after the operation. In addition, all patients were encouraged to visit their general practitioner at 6, 9, and 18 months or as often as needed. The program also includes a - and -year follow-up at the hospital, with yearly visits to their general practitioner between these checkups and yearly thereafter. Changes in weight were calculated as percent excess BMI loss (%EBMIL) and percent excess weight loss (%EWL) [21], and an EWL < % was defined as weight loss failure. Standard biochemical analysis including fasting values of glucose, HbA1C, and serum lipids were performed at the Laboratory of Førde Central Hospital. Fasting serum insulin and insulin C-peptide were analyzed at the Hormone Laboratory, Haukeland University Hospital using the Immulite (Siemens, Tarrytown, NY, USA). Data at the 2-year control, for a few patients supplemented with data from the 18- or 36-month control, were

3 used when evaluating disease status and predictors for remission. Difference in distribution of two continuous variables between patients with remission and nonremission for diabetes or hypertension were evaluated by the Mann Whitney U test, while associations between categorical data were evaluated by the Fisher s exact test. The Kruskal Wallis test was used to examine the difference in T2DM duration between the three severity groups of T2DM (controlled by diet, oral medication, or insulin) and hypertension (without medication, using one medication, or using two or more medications), respectively. The Spearman s correlation coefficient (r s ) was estimated to evaluate the relationship between diabetes duration, insulin C-peptide, and HbA1C. Statistical analysis were performed using the Statistical Analysis System (SAS) version 9.2 (SAS Institute, Inc., Cary, NC, USA) and GraphPad Prism for statistics and graphics, respectively. All p values were two-sided, and values <. were considered statistically significant. Results The mean BMI for the 8 patients at operation was 48.9 (Table 1), and there were 3 males and 4 females. Ten of the patients were on a diabetic diet only, 32 patients were taking oral medication, and 38 were using insulin. Prior to the operation, 48 of the diabetic patients were taking medication for hypertension and 38 for hyperlipidemia. Four of the 8 patients ( %) had recommended levels for HbA1C (<7 %), blood pressure (<13/8 mmhg), and LDL (<2.6 mmol/l) as according to recent guidelines [4]. After 2 years, two of the diabetic patients were using medication for T2DM (insulin at reduced dosage), while three had a fasting glucose 7 nmol/l without using medication (Table 1; Fig. 1). The HbA1C for these five patients at follow-up was 4.7,.1, 6.1, 6.3, and 8.7, respectively. All five with nonremission had been using insulin prior to the operation. This gives a remission rate for diabetes of 7 out of 8 (94 %) and a remission rate of 33 out of 38 (87 %) for patients who were using insulin prior to the operation. For hypertension, 31 of the 67 patients who preoperatively were hypertensive still had hypertension, while 36 had become normotensive, giving a remission rate for hypertension of 36 out of 67 (4 %). Three patients who preoperatively were classified as normotensive were, at 24 months, classified with hypertension (one of them was then taking one antihypertensive). Prior to the operation, 29 of 7 patients (39 %) with available data had recommended levels for LDL, while 46 did not. We have data at 24 months for LDL for 36 of the 46 patients, and 31 of the 36 had obtained serum LDL below 2.6, giving a remission rate of 86 %. Altogether, 7 out of 64 (89 %) with available data had obtained recommended levels for LDL. Three of the 38 patients who were taking lipid-lowering drugs prior to the operation were taking lipidlowering medications at 24 months. Two of these three patients had a past medical history of myocardial infarction, while the third patient had a family history of several cardiovascular events. All three patients had obtained serum cholesterol/hdl ratio <4, triglycerides <2 mmol/l, and LDL at 1.8 mmol/l or lower, but the physicians decided to continue treatment, claiming that the lipid-lowering drugs had positive cardioprotective effects besides the lipid-lowering effect. Statistically significant preoperative predictors for nonremission of diabetes were a higher BMI, more severe diabetes (using insulin), and a low level of fasting insulin Table 1 Changes in BMI, diabetes, hypertension, and lipidemia status for 8 type 2 diabetic patients submitted to BPDDS Preoperatively 3 months 12 months 24 months Weight status (n) BMI (mean±sd) 48.9± ± ± ±.3 Diabetes type 2 (n) No diabetes Diabetes, no medication Diabetes, oral medication Diabetes, insulin Hypertension status (n) No hypertension Hypertension, no medication Hypertension, one medication Hypertension, two medications Lipidemia status (n) No treatment Treatment

4 Fig. 1 Fasting blood values for glucose, HbA1C, insulin C- peptide, and insulin (for patients not taking insulin prior to the operation). Horizontal black lines mean, dotted lines level for considering remission of diabetes (glucose7. mmol/ l, HbA1C6. %) or reference values (insulin C-peptide until 8 and from 8, insulin< mie/l) Glucose (mmol/l) 1 n=8/8 n=78/8 n=77/8 HbA1C (%) 1 n=8/8 n=78/8 n=77/8 Insulin C-peptid (nmol/l) n=74/8 n=7/8 n=64/8 Insulin (mie/l) n=39/42 n=4/42 n=33/42 C-peptide (Table 2). Insulin C-peptide below reference level was a particularly strong predictor for nonremission. For hypertension, older age and severity of hypertension (using antihypertensive drugs) were significant predictors. Unfortunately, we did not have data on the duration of hypertension. Lower weight loss at 2 years was significantly related to nonremission both for diabetes and hypertension. Changes in BMI for patients with diabetes remission versus nonremission and hypertension remission versus nonremission are illustrated in Figs. 2 and 3, respectively. When evaluating the influence of the duration of diabetes, we found that both the severity of diabetes and the severity of hypertension were strongly associated with the duration of diabetes (Kruskal Wallis test: p<.1 for diabetes and p.7 for hypertension). Diabetics who were treated with diet and/or oral medication had had diabetes for a median of 2. years, while those who were taking insulin had had diabetes for a median of 7 years. Patients who had hypertension but without using medication had had diabetes for a median of 2 years, while patients taking antihypertensive medication had had diabetes for a median of. years. We found a positive correlation between the duration of diabetes and the age of the patients (r s.234, p.37). Furthermore, the level of preoperative fasting insulin C-peptide and HbA1C were also a function of the duration of T2DM; the longer the duration of diabetes, the lower the insulin C-peptide (r s.214, p <.1; Fig. 4) and the higher the HbA1C (r s.361, p.1; Fig. ). Before the operation, five patients had fasting insulin C- peptide below the reference level, and all five were taking insulin. At 2 years, only two of these five patients had an insulin C-peptide below the reference level, and these were the two patients that still needed medication for T2DM (insulin at reduced dosage). For the three other patients with a low preoperative C-peptide, the C-peptide value had increased to within reference level; two of these three patients were in remission, while one had diabetes that was controlled by diet only. The %EWL for the three patients that remained with T2DM (controlled by diet) despite insulin C-peptide at reference level was 29, 2, and 77 %, respectively. Prior to BPDDS, five of the six patients with LADA were taking insulin and one was taking oral medication. At 2 years, one patient was taking insulin at a reduced dosage; four were on diet only, while one had complete remission of diabetes. There was a considerable improvement in HbA1C, with three of the six patients obtaining a value <6. % (Fig. 6). Discussion In this study, BPDDS showed remission rates of 94 % for T2DM, 4 % for hypertension, and 86 % for LDL hyperlipidemia 2 years after the operation. Predictors for nonremission of T2DM were a higher preoperative BMI, more severe diabetes, low insulin C-peptide, and lower weight

5 Table 2 Variables evaluated as possible predictors for the remission of type 2 diabetes and hypertension 2 years after BPDDS Variables Type 2 diabetes (n8) Hypertension (n67) All T2DM (n7) Nonremission (n) p value (n36) Nonremission (n31) p value Preoperative Age (years) 44 [21 62] 44 [21 62] 6 [3 9] [26 61] 49 [28 62].11 BMI (kg/m 2 ) 48 [3 67] 48 [3 67] 6 [49 6] [3 67] 48 [37 66].628 Duration of T2DM (years) [1 24] [1 ] [4 24].7 [1 ] [1 24].328 Severity of T2DM Diet/tablet/GLP analog Insulin Severity of hypertension One antihypertensives Two antihypertensives Biochemical variables HbA1C 7.8 [ ] 7.7 [ ] 8.9 [6.6.6] [.6 1.1] 8.1 [. 1.4].968 Insulin C-peptide (nmol/l) 1.2 [.2 2.3] 1.2 [.2 2.3].3 [.2.] < [.2 2.3] 1.2 [.3 2.3].68 Insulin C-peptide<reference value a Two years after BPDDS %EBMIL 89 [16 131] 89 [16 131] [31 1] [16 129] 84 [31 131].4 Patients with EWL < % Values are presented as median [range] or n. Statistical analysis with Mann Whitney U test for continuous variables and Fisher s exact test for proportions a Reference value was nmol/l until 8 and nmol/l from 8 loss, while predictors for nonremission of hypertension were older age, more severe hypertension, and lower weight loss. The age of the patients, severity of diabetes and of hypertension, and level of insulin C-peptide were all related to the duration of diabetes. It is, therefore, likely that duration of diabetes and age of the patient are the most important underlying, clinical denominators for remission of T2DM and hypertension, respectively. Preoperative insulin C- peptide is a function of diabetes duration and an excellent predictor for diabetes remission, while postoperative weight loss is important for the remission of both diabetes and hypertension. Since the first observation of amelioration of T2DM following rerouting of the small bowel [22], remission of T2DM and the speed by which it occurs after metabolic surgery continues to fascinate surgeons. Typically, after BPDDS, all medications for T2DM and hyperlipidemia are stopped, and medications for hypertension were greatly reduced or stopped (except beta blockers) already before the patient is discharged. Mechanisms that may explain the early onset of effect includes proximal small bowel exclusion [23], ileal stimulation [24], and after a few weeks, lipid deprivation [2]. In a study by Prachand et al., a stronger weightindependent effect was found for BPDDS than for gastric 6 Non-remission 6 Non-remission BMI 4 BMI Fig. 2 BMI in patients with (n7) and without remission (n) of T2DM presented as means with SD Fig. 3 BMI in patients with (n36) and without remission (n31) of hypertension presented as means with SD

6 Insulin C-peptid (nmol/l) Duration of T2DM (years) Fig. 4 Relationship between preoperative fasting insulin C-peptide and duration of T2DM. Dotted lines reference values ( until 8 and from 8). Paired data; n74, r s.214, p<.1 bypass [14]. A weight-independent mechanism is also illustrated by one of our patients. Prior to BPDDS, this patient was using 9 IU of insulin, two antihypertensives, and lipidlowering medication. Despite only a 16 % EWL at 24 months and % EWL at 36 months, she remained nondiabetic, normotensive, and with normal serum lipids without any medication. In accordance with our observations, Ahmed et al. found that rerouting the small bowel has an immediate effect on lowering the blood pressure even in normotensive patients [26], and Czupryniak et al. found that a normal diurnal blood pressure rhythm was restored within 8 weeks after gastric bypass [27]. It has been postulated that the early effect on blood pressure is mediated through hormonal mechanisms which include normalization of insulin resistance [18, 26, 28]. In the SOS study where most of the patients had restrictive bariatric procedures, the incidence of new cases of hypertension increased with time, and at years, the incidence of new cases in the surgical group was similar to the incidence of new cases in the lifestyle group despite maintenance of significantly lower body weight in the surgical group [29]. This is in contrast to case series for malabsorptive bariatric procedures with long-term follow-up where no new cases of hypertension develops through years, and even 2 years, and the HbA1C (%) Duration T2DM (years) Fig. Relationship between preoperative HbA1C and duration of T2DM. Dotted line level for considering remission of diabetes (HbA1C6. %). Paired data; n8, r s.361, p.1 HbA1C Fig. 6 HbA1C in six patients with LADA. Prior to BPDDS, five of the patients were taking insulin and one oral medication. At 2 years post- BPDDS, one patient was taking insulin at reduced dosage, four were on antidiabetic diet only, while one had complete remission. Horizontal black lines mean, dotted line level for considering remission of diabetes (HbA1C6. %) number of patients with hypertension actually is lowered with time [18, 3]. Interestingly, malabsorption has an increasingly strong effect on the gut hormones with time, which could support a role for the gut hormones [31]. Scopinaro et al. found that predictors for early remission of T2DM after BPD was diabetes duration and treatment prior to the operation, while predictors for long-term remission could not be explored in a statistically meaningful way due to remission in nearly all cases [32]. When evaluating reasons for nonremission of T2DM, we can focus on our patients individually. Five patients did not obtain remission: two remained on reduced dosages of insulin, while three had their diabetes controlled by diet. For the two on insulin, nonremission is explained by inadequate B cell function (C-peptide below the reference value both preoperatively and postoperatively), while inadequate weight loss could explain nonremission in two (29 and 2 % EWL). In one patient, no clear reason for nonremission was found. Prior to BPDDS, she had a low C-peptide (.3 nmol/l), but obtained a C-peptide within reference level (.8 nmol/l) and a 77 % EWL at 24 months. The low preoperative C-peptide could be a signal of B cell dysfunction, which did not adequately recover after the operation, and it could be that this would have become evident if a meal-stimulated C-peptide had been measured. At the -year control, this patient still has T2DM controlled by diet, with a C-peptide of.6 nmol/l. High remission rates for T2DM, hypertension, and hyperlipidemia after BPD/BPDDS are well known, and case series suggest a rather stable weight and remission rates of 9 % for T2DM 6 years after these operations [18, 33 3]. Weight regain is the most important factor for recurrence of T2DM and hypertension after bariatric surgery, and if inadequate weight loss or weight regain should occur after BPDDS a reresection of the gastric remnant can be considered in order to obtain further weight loss. Recently, it has been

7 found that remission of T2DM and hypertension can be obtained through metabolic surgery without rerouting the small bowel, providing short duration of T2DM and young age as predictors [36, 37]. Today we therefore carefully evaluate the patients diabetes, blood pressure and lipidemia status before entering a dialogue with the patient as to whether a gastric sleeve resection or a BPDDS is to be performed. In summary, the duration of T2DM and age of the patient are the most important preoperative predictors for remission of T2DM and hypertension, respectively, while postoperative weight loss is important for both. This underlines the importance of early surgical intervention and adequate weight loss after metabolic surgery. Conflict of Interest The first author had travel expenses for one international conference in covered by Covidien Norway through an educational grant given to the Surgical Department, Unit for Bariatric Surgery, Førde Central Hospital. Roy M. 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