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Ten-year duration of type 2 diabetes as prognostic factor for remission after sleeve gastrectomy
Surgery for Obesity and Related Diseases 7 (2011) 697–702
Original article
Ten-year duration of type 2 diabetes as prognostic factor for remission after sleeve gastrectomy Giovanni Casella, M.D.a, Francesca Abbatini, M.D.a, Benedetto Calì, M.D.a, Danila Capoccia, M.D.b, Frida Leonetti, M.D.b, Nicola Basso, M.D.a,* a
Surgical-Medical Department for Digestive Diseases, Policlinico “Umberto I,” “Sapienza” University of Rome, Italy b Department of Clinical Sciences, Policlinico “Umberto I”, “Sapienza” University of Rome, Italy Received February 4, 2011; accepted August 17, 2011
Abstract
Background: Several studies have demonstrated a high rate of type 2 diabetes mellitus (T2DM) resolution after sleeve gastrectomy. Different prognostic factors have been hypothesized for T2DM remission after bariatric surgery. Our objectives were to analyze the role of T2DM duration as an independent prognostic factor for remission. Methods: From January 2008 to September 2010, 56 obese patients with T2DM underwent sleeve gastrectomy. Group A consisted of 16 patients who had lived with T2DM for ⬎10 years (12 women and 4 men, mean body mass index 42.7 kg/m2). Group B included 40 obese patients who had lived with T2DM for ⬍10 years (29 women and 11 men, mean body mass index 44.9 kg/m2). Results: In group A, 43.7% were treated with oral hypoglycemics, 6.3% with insulin, and 50% with oral hypoglycemics and insulin. In group B, 87.5% were treated with oral hypoglycemics, 5% with dietary therapy, and 7.5% with insulin. The preoperative average glycemia, glycosylated hemoglobin, and C-peptide value was 206.2 mg/dL, 9.5%, and 2.8 g/L in group A and 134 mg/dL, 7.1%, and 4.5 g/L in group B, respectively (P ⬍ .05 for all). The T2DM remission rate in all 56 patients was 80.3%. However, in group B, the resolution rate was 100%, but in group A, the resolution rate was 31%. Patients without complete remission were more sensitive to lower doses of antidiabetic drugs. Conclusion: Sleeve gastrectomy is effective in the treatment of obese patients with T2DM. The duration of T2DM seems to be of paramount importance as a prognostic factor, with 10 years representing a cutoff between a 100% rate of remission and significantly lower rates of remission. (Surg Obes Relat Dis 2011;7:697–702.) © 2011 American Society for Metabolic and Bariatric Surgery. All rights reserved.
Keywords:
Sleeve gastrectomy; Diabetes mellitus; Metabolic surgery; Bariatric surgery; Prognostic factors
Obesity is a major risk factor for the development of type 2 diabetes mellitus (T2DM). 57% of obese patients were affected by T2DM, and 90% of patients with T2DM were overweight or obese [1,2]. The prevalence of T2DM associated with obesity is increasing worldwide [3]. T2DM is a chronic disease with a natural history
*Correspondence: Nicola Basso, M.D., Surgical-Medical Department for Digestive Diseases, Policlinico “Umberto I,” “Sapienza” University of Rome, Viale del Policlinico 155, Rome 00161, Italy. E-mail: [email protected]
characterized by progression to micro- and macrovascular complications that can result in cardiovascular disease, neuropathy, nephropathy, erectile dysfunction, and retinopathy. In Western countries, T2DM is the main cause of blindness, kidney failure, and amputations; and 70% of patients with T2DM die of cardiovascular disease [4]. The effectiveness of bariatric surgery in achieving significant weight loss and the resolution of co-morbidities, including T2DM, is well established [5–7]. In a 2009 meta-analysis of 621 studies, T2DM remission after bariatric surgery occurred in 86% of patients [7].
1550-7289/11/$ – see front matter © 2011 American Society for Metabolic and Bariatric Surgery. All rights reserved. doi:10.1016/j.soard.2011.08.014
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G. Casella et al. / Surgery for Obesity and Related Diseases 7 (2011) 697–702
Previously, Schauer et al. [8] and then Kim and Richards [9] identified increasing patient age, diabetes duration, use of insulin, and weight loss after surgery as adverse prognostic factors for T2DM remission after Roux-en-Y gastric bypass (RYGB). Sleeve gastrectomy (SG) as a definitive procedure is gaining popularity for the surgical management of morbid obesity [10 –13]. Several studies have suggested that SG is effective in treating weight loss and co-morbidities and has a low complication rate [14 –16]. In a large series, T2DM resolved in 80 –96% of patients [17–20]. At present, the preoperative factors predicting the successful treatment of T2DM after SG have not yet been established. In a previous study, we showed that SG induced very early normalization of the insulin response after an intravenous glucose tolerance test in 18 obese patients with T2DM with a diabetes duration of ⬍10 years; however, this was not the case for patients who had lived with T2DM for ⬎10 years [21]. The aim of the present study was to ascertain whether a cutoff of 10 years for T2DM duration was of clinical significance and could be considered an independent prognostic factor for the remission of T2DM after SG. Methods From January 2008 to September 2010, 56 obese patients with T2DM, diagnosed according to the American Diabetes Association guidelines, underwent SG with a minimal follow-up of 3 months [22]. The patients were divided in 2 groups according to the T2DM duration. Group A, with a T2DM duration of ⬎10 years, included 16 patients (12 women and 4 men), with a mean age of 52.7 years (range 44–63) and mean body mass index (BMI) 42.7 kg/m2 (range 28–52.3). The mean duration of T2DM was 14.8 years (range 11–25). In addition to T2DM, hypertension was present in 15 patients, severe obstructive sleep apnea syndrome (OSAS) requiring treatment with continuous positive airway pressure in 4, and dyslipidemia in 11 (Table 1). Group B, with a T2DM duration of ⬍10 years, included 40 patients (29 women and 11 men), with a mean age of 50.4 years (range 34 – 64) and a mean BMI of 44.9 kg/m2 (range 32–57.2). The mean T2DM duration was 2.8 years (range 1– 8). In addition, 26 patients had hypertension, 16 had severe OSAS requiring continuous positive airway pressure, and 14 had dyslipidemia (Table 1). All patients underwent laparoscopic SG, according to a previously described technique [13]. The medical therapy was determined by the same T2DM team with identical criteria used for both groups. Glycemia and body weight were measured, and the effects of antidiabetic drug therapy were monitored preoperatively and at 1, 3, 6, 9, 12, and 18 months after surgery in all patients. T2DM remission was defined by a fasting glycemia of ⬍100 mg/dL, glycosylated hemoglobin (HbA1c) ⬍6%, and
Table 1 Patient characteristics Characteristic
Group A (⬎10 yr)
Group B (⬍10 yr)
Patients (n) Gender Men Women Mean follow-up (mo) Mean BMI (kg/m2) Mean age (yr) Mean T2DM duration (yr) Hypertension (n) Severe OSAS (n) Dyslipidemia (n)
16
40
12 4 11 42.7 52.7 14.8 15 4 11
29 11 10 44.9 50.4 2.8 26 16 14
P value
.3 .27 ⬍.001*
BMI ⫽ body mass index; T2DM ⫽ type 2 diabetes mellitus; OSAS ⫽ obstructive sleep apnea syndrome. * Statistically significant.
an unwillingness to pursue medical treatment. HbA1c was determined preoperatively and at 3, 6, 9, and 12 months postoperatively, and the C-peptide level was measured preoperatively. A comparative statistical analysis was performed with the Wilcoxon test using the GraphPad program (GraphPad Software, La Jolla, CA). Binary logistic regression analysis was used to analyze the correlation between T2DM remission and independent variables. P values ⬍.05 were considered statistically significant. The T2DM duration was considered as a continuous variable, and the sensitivity and specificity for the 10-year cutoff were determined. Results Of the 16 patients in group A, 7 were treated with oral hypoglycemic drugs (43.7%), 1 with insulin (6.3%), and 8 with oral hypoglycemic drugs and insulin (50%). The preoperative average glycemia, HbA1c, and C-peptide level was 206.2 mg/dL, 9.5%, and 2.8 ng/mL, respectively. A postoperative major complication (portal vein thrombosis) occurred in 1 patient 2 weeks after surgery. The mortality rate was 0%. The mean BMI at 1, 3, 6, 9, 12, and 18 months after surgery was 36.7, 33.5, 32.2, 31.7, 29.3, and 29.1 kg/m2, respectively. Hypertension, OSAS, and dyslipidemia had remitted or improved in 60%, 100%, and 81.8% of the patients, respectively. Overall, the remission of T2DM was obtained in 45 (80.3%) of 56 patients. In group A, remission occurred in 5 (31%) of the 16 patients, 3 of whom were taking oral hypoglycemic medication and 2 oral hypoglycemic medication and insulin. For the 3 patients taking oral medications who had T2DM resolution, the HbA1c and C-peptide values were 5.8, 6.4, and 10.4 mg/dL and 3.1, 3.2, and 3.7 ng/mL, respectively. In 4 patients, remission occurred during the early postoperative period and in 1 patient 18 months after SG
G. Casella et al. / Surgery for Obesity and Related Diseases 7 (2011) 697–702
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Table 3 Results of binary logistic regression analysis of preoperative factors associated with no type 2 diabetes mellitus remission after sleeve gastrectomy Variable
Odds ratio
95% Confidence interval
P value
T2DM duration C-peptide level Antidiabetic therapy†
3.49 .28 23.24
1.15–10.64 .07–1.08 3.58–151.02
.028* .064 .001*
T2DM ⫽ type 2 diabetes mellitus. * Statistically significant. † Antidiabetic therapy divided by increasing value, with a score of 1 indicating diet and insulin-sensitizing agents; 2, secretagogues; and 3, insulin.
Fig. 1. T2DM remission after SG. Group A, ⬎10-year T2DM duration; group B, ⬍10-year T2DM duration. Diabetic Pts ⫽ diabetic patients.
(Fig. 1). The remaining 11 patients had significant improvement in glycemic control with reduced drug dosages. In group B, 35 patients were in treatment with oral hypoglycemic agents (87.5%), 2 were controlling their T2DM with dietary therapy (5%), and 3 were in treatment with insulin (7.5%). Their preoperative average glycemia, HbA1c, and C-peptide value was 134 mg/dL, 7.1%, and 4.5 ng/mL, respectively (P ⬍ .05 for all values). Postoperative major complications occurred in 2 patients; a suture line leak in 1 patient and portal vein thrombosis in 1 patient. The mortality rate was 0%. The mean BMI at 1, 3, 6, 9, 12, and 18 months after surgery was 39.4, 35.7, 31.6, 29.7, 29.9, and 27.6 kg/m2, respectively. No significant differences were found in the BMI trend between groups A and B. Hypertension, OSAS, and dyslipidemia had remitted or improved in 57.7%, 100%, and 92.8% in group B, respectively. Suspension of T2DM therapy occurred immediately after SG in 30 patients, within 3 postoperative months in 5 patients, at 6 months in 3 patients, and at 1 year in 2
patients. In group B, therefore, T2DM was remitted in 100% of the 40 patients 1 year after surgery. Three of these patients had required insulin therapy preoperatively. The preoperative and postoperative mean values of glycemia and HbA1c are listed in Table 2. In both groups, glycemic control improved, although this change was more pronounced and more prompt in group B. Considering a 10-year duration of T2DM as the cutoff value for remission, the sensitivity was 75% and the specificity was 95.45%. The preoperative factors negatively related to the remission of T2DM are analyzed in Table 3. A longer duration of T2DM and preoperative treatment with secretagogues and insulin appeared to be associated with a low chance of remission. Low preoperative C-peptide levels were a negative prognostic factor for T2DM resolution after SG. Discussion SG, in large series, demonstrated a high rate of T2DM remission [17–19]. In 2006, Cottam et al. [23] reported T2DM remission in 81% of patients with T2DM after SG. Moon Han et al. [24] reported an excess weight loss of 71% and T2DM remission of 100% at 6 months. They also showed that T2DM resolution was not related to weight loss. In patients with remission, in fact, the BMI diminished slightly during the first 4 weeks after surgery and glucose
Table 2 Fasting plasma glucose and glycosylated hemoglobin before and after sleeve gastrectomy Variable
Group A (⬎10 yr) Glycemia (mg/dL) HbA1c (%) Group B (⬍10 yr) Glycemia (mg/dL) HbA1c (%)
Preoperative value
Postoperative value (mo) 1
3
6
9
12
18
206.2 9.5*
166.5 —
134.3 7.2
137.1 6.5
114.1 6.7
135.4 7.1*
128 6.4
134.6 7.1*
109.9 —
100.5 5.6
90.8 5.3
90.5 5.6
85.1 6.0*
77.8 5.2
HbA1c ⫽ glycosylated hemoglobin. * P ⬍.05.
700
G. Casella et al. / Surgery for Obesity and Related Diseases 7 (2011) 697–702
homeostasis improved significantly [24]. In a prospective randomized study, Vidal et al. [17] reported a high percentage of T2DM remission at 4 months after SG and RYGB (51.4% and 62%, respectively, P ⫽ .332). At 12 months, the remission rate was identical for the 2 types of procedures (84.6%, P ⫽ .618) [19]. In a recent, randomized, controlled trial, Lee et al. [25] demonstrated a high remission of T2DM after minigastric bypass versus SG (93% versus 47%) in a moderately obese (BMI 25–35 kg/m2) Asian population of patients with T2DM. However, they concluded that pure restrictive surgery, such as laparoscopic adjustable gastric banding or SG, can be considered for the surgical treatment of T2DM in patients without the metabolic syndrome or hyperlipidemia [25]. All these results confirm the efficacy of SG in resolving T2DM; in a varying percentage of patients, this effect is lacking or not complete. Thus, prognostic criteria would be of great importance to better indicate the need for this type of surgery in patients with T2DM. In a previous study of 17 obese patients with T2DM undergoing SG, we observed, 5 days after surgery, a significant reduction in glycemia, insulinemia, and Homeostasis Model of Assessment–Insulin Resistance. The results were confirmed at 15, 30, and 60 days [26]. In a subsequent work, insulin secretion and insulin sensitivity, as determined using the intravenous glucose tolerance test in 18 obese patients with T2DM, were improved after SG. A significant reduction of ghrelin and an increase in glucagon-like peptide-1 and peptide YY was also observed. However, in the subgroup of patients with a disease duration greater than the median (10.5 yr), the initial insulin response (insulin secretion in response to glucose) did not improve significantly [21]. The results of the present study indicate that a T2DM duration of ⬎10 years is also of clinical significance. When considering the results of SG in the 56 diabetic patients grouped according to the T2DM duration, 100% of all patients with a duration ⬍10 years discontinued drug treatment and exhibited normalized glucose and HbA1c levels, in contrast to 31% of patients with a duration ⬎10 years. The limit of 10 years for T2DM duration effectively differentiated between patients exhibiting early remission and those with a low resolution rate (31%; P ⬍ .001). It is apparent that the 10-year cutoff is an independent and highly significant prognostic factor. This finding was confirmed by the high sensitivity and specificity values achieved using this cutoff (75% and 95.45%, respectively). Previous studies have already shown a correlation between the duration of T2DM and resolution after different types of bariatric surgery. Dixon and O’Brien [27] showed that the excess weight loss and duration of T2DM were independent predictive factors of T2DM remission after laparoscopic adjustable gastric banding. Sugerman et al. [28] instead identified the young age of the patients and the excess weight loss as favorable prognostic factors for the resolution of disease after RYGB. Schauer et al. [8] con-
firmed the high efficacy of RYGB in the treatment of T2DM (83%) and concluded that patients with the shortest duration (⬍5 yr), the mildest form of T2DM (diet controlled), and the greatest weight loss after surgery were most likely to achieve complete resolution of T2DM. In the present study, age and postoperative weight loss were not accurate discriminating prognostic factors for T2DM remission after SG. The 2 groups of patients had a similar preoperative mean age (52.7 versus 50.4 yr, P ⫽ .27), and the postoperative BMI trend curves were perfectly comparable (Table 1). In group B, the remission of patients was not dependent on the type of preoperative therapy, whether insulin or oral hypoglycemic therapy. However, only 3 of 7 patients using oral hypoglycemic agents with a disease duration ⬎10 years achieved T2DM remission. Furthermore, although preoperative treatment with insulin is a negative prognostic factor for T2DM remission, 42% of patients in both groups receiving insulin or insulin plus oral hypoglycemic drugs were normalized, demonstrating a low predictive value (Fig. 2). It appears that patients with a ⬎10-year history of T2DM are more refractory to any type of therapy, medical or surgical. Moreover, the group A medication pattern can be considered to represent worse control of disease owing to a reduction in the functional pancreatic -cell reserve. This was also corroborated by greater Hb1Ac values in group A (9.5% versus 7.1%). These values could also represent the difficulty in achieving patient compliance with the diet and therapy regimens over time. Lee et al. [29] identified the C-peptide value as the most important predictor for successful treatment of T2DM in nonmorbidly obese patients after SG. The T2DM remission rate for patients with a preoperative C-peptide level ⬍3, 3– 6, and ⬎6 ng/mL was 14.3%, 63.6%, and 100%, respectively. In the present study, the low -cell reserve of patients who had lived with T2DM for a long time was confirmed by preoperative C-peptide levels that were significantly lower than in the patients with a recent onset of T2DM (2.8 versus 4.5 ng/mL, P ⬍ .05), and high preoperative values are related to a lower risk of no T2DM remission after SG. The preoperative level of ⬍3 and ⬎6 ng/mL correlated with a 44% and 50% remission rate, respectively, and therefore were not accurate prognostic cutoff values for our patient population. These differences might also have resulted from the small series of patients in both studies (Lee et al. [29], 20 patients) and to the heterogeneous patient characteristics (Asian versus white, not morbidly versus morbidly obese, T2DM duration, antidiabetic therapy). Our results indicate that a ⬍10-year duration of T2DM can be considered an independent and accurate prognostic factor for T2DM remission after SG. In patients with T2DM of ⬍10 years, the effectiveness of SG was 100%, suggesting that early surgical treatment for T2DM is advantageous. In recent years, we have assisted in the transformation of bariatric surgery to “metabolic surgery.” Accurate prognostic
G. Casella et al. / Surgery for Obesity and Related Diseases 7 (2011) 697–702
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Fig. 2. T2DM remission stratified by antidiabetic therapy. OAD ⫽ oral antidiabetic medication; INS ⫽ insulin.
factors and the identification of ideal candidates could better define the role of surgery in the treatment of T2DM and, also, ensure a better assessment of the results after surgery. Conclusion SG is very effective in achieving T2DM remission. The duration of T2DM seems to be of paramount importance as a prognostic factor, with a 10-year duration serving as an informative cutoff between those patients who will achieve 100% remission and those who will achieve significantly less resolution. The amount of postoperative weight loss, patient age, and C-peptide level were less accurate in predicting T2DM resolution after SG. Accurate prognostic factors could allow the identification of ideal candidates, minimize the rate of failure, and ameliorate the risk/benefit ratio after SG for T2DM. Disclosures The authors have no commercial associations that might be a conflict of interest in relation to this article. References [1] Mokdad AH, Bowman BA, Ford ES, Vinicor F, Marks JS, Koplan JP. The continuing epidemics of obesity and diabetes in the United States. JAMA 2001;286:1195–200. [2] North American Association for the Study of Obesity (NAASO) and the National Heart, Lung, and Blood Institute (NHLBI). The Practical Guide: Identification, Evaluation, and Treatment of Overweight and Obesity in Adults. NIH Publication No. 00-4084, Oct 2000. Bethesda: National Institutes of Health; 2000. [3] Hossain P, Kawar B, Nahas ME. Obesity and diabetes in the developing world—a growing challenge. N Engl J Med 2007;356: 213–5.
[4] Nathan DM. Clinical practice: initial management of glycemia in type 2 diabetes mellitus. N Engl J Med 2002;347:1342–9. [5] Buchwald H, Avidor Y, Braunwald E, et al. Bariatric surgery: a systematic review and meta-analysis. JAMA 2004;292:1724 –37. [6] Rubino F, Gagner M. Potential of surgery to curing type 2 diabetes mellitus. Ann Surg 2002;236:554 –9. [7] Buchwald H, Estok R, Fahrbach K, et al. Weight and type 2 diabetes after bariatric surgery: systematic review and meta-analysis. Am J Med 2009;122:248 –56. [8] Schauer PR, Burguera B, Ikramuddin S, et al. Effect of laparoscopic Roux-en Y gastric bypass on type 2 diabetes mellitus. Ann Surg 2003;238:467– 84. [9] Kim S, Richards WO. Long-term follow-up of the metabolic profiles in obese patients with type 2 diabetes mellitus after Roux-en-Y gastric bypass. Ann Surg 2010;251:1049 –55. [10] Tucker ON, Szomstein S, Rosenthal RJ. Indications for sleeve gastrectomy as a primary procedure for weight loss in the morbidly obese. J Gastrointest Surg 2008;12:662–7. [11] Frezza EE. Laparoscopic vertical sleeve gastrectomy for morbid obesity: the future procedure of choice? Surg Today 2007;37:275– 81. [12] Akkary E, Duffy A, Bell R. Deciphering the sleeve: technique, indications, efficacy, and safety of sleeve gastrectomy. Obes Surg 2008;18:1323–9. [13] Basso N, Casella G, Rizzello M, et al. Laparoscopic sleeve gastrectomy as first stage or definitive intent in 300 consecutive cases. Surg Endosc 2010;25:444 –9. [14] Silecchia G, Boru C, Pecchia A, et al. Effectiveness of laparoscopic sleeve gastrectomy (first stage of biliopancreatic diversion with duodenal switch) on co-morbidities in super obese high-risk patients. Obes Surg 2006;16:1138 – 44. [15] Himpens J, Dapri G, Cadière GB. A prospective randomized study between laparoscopic gastric banding and laparoscopic isolated sleeve gastrectomy: results after 1 and 3 years. Obes Surg 2006;16: 1450 – 6. [16] Iannelli A, Dainese R, Piche T, Facchiano E, Gugenheim J. Laparoscopic sleeve gastrectomy for morbid obesity. World J Gastroenterol 2008;14:821–7. [17] Vidal J, Ibarzabal A, Nicolau J, et al. Short-term effects of sleeve gastrectomy on type 2 diabetes mellitus in severely obese subjects. Obes Surg 2007;17:1069 –74.
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[18] Gill RS, Birch DW, Shi X, Sharma AM, Karmali S. Sleeve gastrectomy and type 2 diabetes mellitus: a systematic review. Surg Obes Relat Dis 2010;6:707–13. [19] Abbatini F, Rizzello M, Casella G, et al. Long-term effects of laparoscopic sleeve gastrectomy, gastric bypass, and adjustable gastric banding on type 2 diabetes. Surg Endosc 2010;24:1005–10. [20] Vidal J, Ibarzabal A, Romero F, et al. Type 2 diabetes mellitus and the metabolic syndrome following sleeve gastrectomy in severely obese subjects. Obes Surg 2008;18:1077– 82. [21] Basso N, Capoccia D, Rizzello M, et al. First-phase insulin secretion, insulin sensitivity, ghrelin, GLP-1 and PYY changes 72 hours after sleeve gastrectomy in obese diabetic patients: the gastric hypothesis. Surg Endosc Epub 2011 June 3. [22] American Diabetes Association. Standards of Medical care in Diabetes 2010. Diabetes Care 2010;33:S11– 61. [23] Cottam D, Qureshi FG, Mattar SG, et al. Laparoscopic sleeve gastrectomy as an initial weight-loss procedure for high-risk patients with morbid obesity. Surg Endosc 2006;20:859 – 63.
[24] Moon Han S, Kim WW, Oh JH. Results of laparoscopic sleeve gastrectomy (LSG) at 1 year in morbidly obese Korean patients. Obes Surg 2005;15:1469 –75. [25] Lee WJ, Chong K, Ser KH, et al. Gastric bypass vs sleeve gastrectomy for type 2 diabetes mellitus: a randomized controlled trial. Arch Surg 2011;146:143– 8. [26] Rizzello M, Abbatini F, Casella G, et al. Early postoperative insulinresistance changes after sleeve gastrectomy. Obes Surg 2010;20: 50 –5. [27] Dixon JB, O’Brien PE. Changes in comorbidities and improvements in quality of life after LAP-BAND placement. Am J Surg 2002;184: 51S– 4S. [28] Sugerman HJ, Wolfe LG, Sica DA, Clore JN. Diabetes and hypertension in severe obesity and effects of gastric bypass-induced weight loss. Ann Surg 2003;237:751– 6. [29] Lee WJ, Ser KH, Chong K, et al. Laparoscopic sleeve gastrectomy for diabetes treatment in nonmorbidly obese patients: efficacy and change of insulin secretion. Surgery 2010;147:664 –9.
Original article
Ten-year duration of type 2 diabetes as prognostic factor for remission after sleeve gastrectomy Giovanni Casella, M.D.a, Francesca Abbatini, M.D.a, Benedetto Calì, M.D.a, Danila Capoccia, M.D.b, Frida Leonetti, M.D.b, Nicola Basso, M.D.a,* a
Surgical-Medical Department for Digestive Diseases, Policlinico “Umberto I,” “Sapienza” University of Rome, Italy b Department of Clinical Sciences, Policlinico “Umberto I”, “Sapienza” University of Rome, Italy Received February 4, 2011; accepted August 17, 2011
Abstract
Background: Several studies have demonstrated a high rate of type 2 diabetes mellitus (T2DM) resolution after sleeve gastrectomy. Different prognostic factors have been hypothesized for T2DM remission after bariatric surgery. Our objectives were to analyze the role of T2DM duration as an independent prognostic factor for remission. Methods: From January 2008 to September 2010, 56 obese patients with T2DM underwent sleeve gastrectomy. Group A consisted of 16 patients who had lived with T2DM for ⬎10 years (12 women and 4 men, mean body mass index 42.7 kg/m2). Group B included 40 obese patients who had lived with T2DM for ⬍10 years (29 women and 11 men, mean body mass index 44.9 kg/m2). Results: In group A, 43.7% were treated with oral hypoglycemics, 6.3% with insulin, and 50% with oral hypoglycemics and insulin. In group B, 87.5% were treated with oral hypoglycemics, 5% with dietary therapy, and 7.5% with insulin. The preoperative average glycemia, glycosylated hemoglobin, and C-peptide value was 206.2 mg/dL, 9.5%, and 2.8 g/L in group A and 134 mg/dL, 7.1%, and 4.5 g/L in group B, respectively (P ⬍ .05 for all). The T2DM remission rate in all 56 patients was 80.3%. However, in group B, the resolution rate was 100%, but in group A, the resolution rate was 31%. Patients without complete remission were more sensitive to lower doses of antidiabetic drugs. Conclusion: Sleeve gastrectomy is effective in the treatment of obese patients with T2DM. The duration of T2DM seems to be of paramount importance as a prognostic factor, with 10 years representing a cutoff between a 100% rate of remission and significantly lower rates of remission. (Surg Obes Relat Dis 2011;7:697–702.) © 2011 American Society for Metabolic and Bariatric Surgery. All rights reserved.
Keywords:
Sleeve gastrectomy; Diabetes mellitus; Metabolic surgery; Bariatric surgery; Prognostic factors
Obesity is a major risk factor for the development of type 2 diabetes mellitus (T2DM). 57% of obese patients were affected by T2DM, and 90% of patients with T2DM were overweight or obese [1,2]. The prevalence of T2DM associated with obesity is increasing worldwide [3]. T2DM is a chronic disease with a natural history
*Correspondence: Nicola Basso, M.D., Surgical-Medical Department for Digestive Diseases, Policlinico “Umberto I,” “Sapienza” University of Rome, Viale del Policlinico 155, Rome 00161, Italy. E-mail: [email protected]
characterized by progression to micro- and macrovascular complications that can result in cardiovascular disease, neuropathy, nephropathy, erectile dysfunction, and retinopathy. In Western countries, T2DM is the main cause of blindness, kidney failure, and amputations; and 70% of patients with T2DM die of cardiovascular disease [4]. The effectiveness of bariatric surgery in achieving significant weight loss and the resolution of co-morbidities, including T2DM, is well established [5–7]. In a 2009 meta-analysis of 621 studies, T2DM remission after bariatric surgery occurred in 86% of patients [7].
1550-7289/11/$ – see front matter © 2011 American Society for Metabolic and Bariatric Surgery. All rights reserved. doi:10.1016/j.soard.2011.08.014
698
G. Casella et al. / Surgery for Obesity and Related Diseases 7 (2011) 697–702
Previously, Schauer et al. [8] and then Kim and Richards [9] identified increasing patient age, diabetes duration, use of insulin, and weight loss after surgery as adverse prognostic factors for T2DM remission after Roux-en-Y gastric bypass (RYGB). Sleeve gastrectomy (SG) as a definitive procedure is gaining popularity for the surgical management of morbid obesity [10 –13]. Several studies have suggested that SG is effective in treating weight loss and co-morbidities and has a low complication rate [14 –16]. In a large series, T2DM resolved in 80 –96% of patients [17–20]. At present, the preoperative factors predicting the successful treatment of T2DM after SG have not yet been established. In a previous study, we showed that SG induced very early normalization of the insulin response after an intravenous glucose tolerance test in 18 obese patients with T2DM with a diabetes duration of ⬍10 years; however, this was not the case for patients who had lived with T2DM for ⬎10 years [21]. The aim of the present study was to ascertain whether a cutoff of 10 years for T2DM duration was of clinical significance and could be considered an independent prognostic factor for the remission of T2DM after SG. Methods From January 2008 to September 2010, 56 obese patients with T2DM, diagnosed according to the American Diabetes Association guidelines, underwent SG with a minimal follow-up of 3 months [22]. The patients were divided in 2 groups according to the T2DM duration. Group A, with a T2DM duration of ⬎10 years, included 16 patients (12 women and 4 men), with a mean age of 52.7 years (range 44–63) and mean body mass index (BMI) 42.7 kg/m2 (range 28–52.3). The mean duration of T2DM was 14.8 years (range 11–25). In addition to T2DM, hypertension was present in 15 patients, severe obstructive sleep apnea syndrome (OSAS) requiring treatment with continuous positive airway pressure in 4, and dyslipidemia in 11 (Table 1). Group B, with a T2DM duration of ⬍10 years, included 40 patients (29 women and 11 men), with a mean age of 50.4 years (range 34 – 64) and a mean BMI of 44.9 kg/m2 (range 32–57.2). The mean T2DM duration was 2.8 years (range 1– 8). In addition, 26 patients had hypertension, 16 had severe OSAS requiring continuous positive airway pressure, and 14 had dyslipidemia (Table 1). All patients underwent laparoscopic SG, according to a previously described technique [13]. The medical therapy was determined by the same T2DM team with identical criteria used for both groups. Glycemia and body weight were measured, and the effects of antidiabetic drug therapy were monitored preoperatively and at 1, 3, 6, 9, 12, and 18 months after surgery in all patients. T2DM remission was defined by a fasting glycemia of ⬍100 mg/dL, glycosylated hemoglobin (HbA1c) ⬍6%, and
Table 1 Patient characteristics Characteristic
Group A (⬎10 yr)
Group B (⬍10 yr)
Patients (n) Gender Men Women Mean follow-up (mo) Mean BMI (kg/m2) Mean age (yr) Mean T2DM duration (yr) Hypertension (n) Severe OSAS (n) Dyslipidemia (n)
16
40
12 4 11 42.7 52.7 14.8 15 4 11
29 11 10 44.9 50.4 2.8 26 16 14
P value
.3 .27 ⬍.001*
BMI ⫽ body mass index; T2DM ⫽ type 2 diabetes mellitus; OSAS ⫽ obstructive sleep apnea syndrome. * Statistically significant.
an unwillingness to pursue medical treatment. HbA1c was determined preoperatively and at 3, 6, 9, and 12 months postoperatively, and the C-peptide level was measured preoperatively. A comparative statistical analysis was performed with the Wilcoxon test using the GraphPad program (GraphPad Software, La Jolla, CA). Binary logistic regression analysis was used to analyze the correlation between T2DM remission and independent variables. P values ⬍.05 were considered statistically significant. The T2DM duration was considered as a continuous variable, and the sensitivity and specificity for the 10-year cutoff were determined. Results Of the 16 patients in group A, 7 were treated with oral hypoglycemic drugs (43.7%), 1 with insulin (6.3%), and 8 with oral hypoglycemic drugs and insulin (50%). The preoperative average glycemia, HbA1c, and C-peptide level was 206.2 mg/dL, 9.5%, and 2.8 ng/mL, respectively. A postoperative major complication (portal vein thrombosis) occurred in 1 patient 2 weeks after surgery. The mortality rate was 0%. The mean BMI at 1, 3, 6, 9, 12, and 18 months after surgery was 36.7, 33.5, 32.2, 31.7, 29.3, and 29.1 kg/m2, respectively. Hypertension, OSAS, and dyslipidemia had remitted or improved in 60%, 100%, and 81.8% of the patients, respectively. Overall, the remission of T2DM was obtained in 45 (80.3%) of 56 patients. In group A, remission occurred in 5 (31%) of the 16 patients, 3 of whom were taking oral hypoglycemic medication and 2 oral hypoglycemic medication and insulin. For the 3 patients taking oral medications who had T2DM resolution, the HbA1c and C-peptide values were 5.8, 6.4, and 10.4 mg/dL and 3.1, 3.2, and 3.7 ng/mL, respectively. In 4 patients, remission occurred during the early postoperative period and in 1 patient 18 months after SG
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Table 3 Results of binary logistic regression analysis of preoperative factors associated with no type 2 diabetes mellitus remission after sleeve gastrectomy Variable
Odds ratio
95% Confidence interval
P value
T2DM duration C-peptide level Antidiabetic therapy†
3.49 .28 23.24
1.15–10.64 .07–1.08 3.58–151.02
.028* .064 .001*
T2DM ⫽ type 2 diabetes mellitus. * Statistically significant. † Antidiabetic therapy divided by increasing value, with a score of 1 indicating diet and insulin-sensitizing agents; 2, secretagogues; and 3, insulin.
Fig. 1. T2DM remission after SG. Group A, ⬎10-year T2DM duration; group B, ⬍10-year T2DM duration. Diabetic Pts ⫽ diabetic patients.
(Fig. 1). The remaining 11 patients had significant improvement in glycemic control with reduced drug dosages. In group B, 35 patients were in treatment with oral hypoglycemic agents (87.5%), 2 were controlling their T2DM with dietary therapy (5%), and 3 were in treatment with insulin (7.5%). Their preoperative average glycemia, HbA1c, and C-peptide value was 134 mg/dL, 7.1%, and 4.5 ng/mL, respectively (P ⬍ .05 for all values). Postoperative major complications occurred in 2 patients; a suture line leak in 1 patient and portal vein thrombosis in 1 patient. The mortality rate was 0%. The mean BMI at 1, 3, 6, 9, 12, and 18 months after surgery was 39.4, 35.7, 31.6, 29.7, 29.9, and 27.6 kg/m2, respectively. No significant differences were found in the BMI trend between groups A and B. Hypertension, OSAS, and dyslipidemia had remitted or improved in 57.7%, 100%, and 92.8% in group B, respectively. Suspension of T2DM therapy occurred immediately after SG in 30 patients, within 3 postoperative months in 5 patients, at 6 months in 3 patients, and at 1 year in 2
patients. In group B, therefore, T2DM was remitted in 100% of the 40 patients 1 year after surgery. Three of these patients had required insulin therapy preoperatively. The preoperative and postoperative mean values of glycemia and HbA1c are listed in Table 2. In both groups, glycemic control improved, although this change was more pronounced and more prompt in group B. Considering a 10-year duration of T2DM as the cutoff value for remission, the sensitivity was 75% and the specificity was 95.45%. The preoperative factors negatively related to the remission of T2DM are analyzed in Table 3. A longer duration of T2DM and preoperative treatment with secretagogues and insulin appeared to be associated with a low chance of remission. Low preoperative C-peptide levels were a negative prognostic factor for T2DM resolution after SG. Discussion SG, in large series, demonstrated a high rate of T2DM remission [17–19]. In 2006, Cottam et al. [23] reported T2DM remission in 81% of patients with T2DM after SG. Moon Han et al. [24] reported an excess weight loss of 71% and T2DM remission of 100% at 6 months. They also showed that T2DM resolution was not related to weight loss. In patients with remission, in fact, the BMI diminished slightly during the first 4 weeks after surgery and glucose
Table 2 Fasting plasma glucose and glycosylated hemoglobin before and after sleeve gastrectomy Variable
Group A (⬎10 yr) Glycemia (mg/dL) HbA1c (%) Group B (⬍10 yr) Glycemia (mg/dL) HbA1c (%)
Preoperative value
Postoperative value (mo) 1
3
6
9
12
18
206.2 9.5*
166.5 —
134.3 7.2
137.1 6.5
114.1 6.7
135.4 7.1*
128 6.4
134.6 7.1*
109.9 —
100.5 5.6
90.8 5.3
90.5 5.6
85.1 6.0*
77.8 5.2
HbA1c ⫽ glycosylated hemoglobin. * P ⬍.05.
700
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homeostasis improved significantly [24]. In a prospective randomized study, Vidal et al. [17] reported a high percentage of T2DM remission at 4 months after SG and RYGB (51.4% and 62%, respectively, P ⫽ .332). At 12 months, the remission rate was identical for the 2 types of procedures (84.6%, P ⫽ .618) [19]. In a recent, randomized, controlled trial, Lee et al. [25] demonstrated a high remission of T2DM after minigastric bypass versus SG (93% versus 47%) in a moderately obese (BMI 25–35 kg/m2) Asian population of patients with T2DM. However, they concluded that pure restrictive surgery, such as laparoscopic adjustable gastric banding or SG, can be considered for the surgical treatment of T2DM in patients without the metabolic syndrome or hyperlipidemia [25]. All these results confirm the efficacy of SG in resolving T2DM; in a varying percentage of patients, this effect is lacking or not complete. Thus, prognostic criteria would be of great importance to better indicate the need for this type of surgery in patients with T2DM. In a previous study of 17 obese patients with T2DM undergoing SG, we observed, 5 days after surgery, a significant reduction in glycemia, insulinemia, and Homeostasis Model of Assessment–Insulin Resistance. The results were confirmed at 15, 30, and 60 days [26]. In a subsequent work, insulin secretion and insulin sensitivity, as determined using the intravenous glucose tolerance test in 18 obese patients with T2DM, were improved after SG. A significant reduction of ghrelin and an increase in glucagon-like peptide-1 and peptide YY was also observed. However, in the subgroup of patients with a disease duration greater than the median (10.5 yr), the initial insulin response (insulin secretion in response to glucose) did not improve significantly [21]. The results of the present study indicate that a T2DM duration of ⬎10 years is also of clinical significance. When considering the results of SG in the 56 diabetic patients grouped according to the T2DM duration, 100% of all patients with a duration ⬍10 years discontinued drug treatment and exhibited normalized glucose and HbA1c levels, in contrast to 31% of patients with a duration ⬎10 years. The limit of 10 years for T2DM duration effectively differentiated between patients exhibiting early remission and those with a low resolution rate (31%; P ⬍ .001). It is apparent that the 10-year cutoff is an independent and highly significant prognostic factor. This finding was confirmed by the high sensitivity and specificity values achieved using this cutoff (75% and 95.45%, respectively). Previous studies have already shown a correlation between the duration of T2DM and resolution after different types of bariatric surgery. Dixon and O’Brien [27] showed that the excess weight loss and duration of T2DM were independent predictive factors of T2DM remission after laparoscopic adjustable gastric banding. Sugerman et al. [28] instead identified the young age of the patients and the excess weight loss as favorable prognostic factors for the resolution of disease after RYGB. Schauer et al. [8] con-
firmed the high efficacy of RYGB in the treatment of T2DM (83%) and concluded that patients with the shortest duration (⬍5 yr), the mildest form of T2DM (diet controlled), and the greatest weight loss after surgery were most likely to achieve complete resolution of T2DM. In the present study, age and postoperative weight loss were not accurate discriminating prognostic factors for T2DM remission after SG. The 2 groups of patients had a similar preoperative mean age (52.7 versus 50.4 yr, P ⫽ .27), and the postoperative BMI trend curves were perfectly comparable (Table 1). In group B, the remission of patients was not dependent on the type of preoperative therapy, whether insulin or oral hypoglycemic therapy. However, only 3 of 7 patients using oral hypoglycemic agents with a disease duration ⬎10 years achieved T2DM remission. Furthermore, although preoperative treatment with insulin is a negative prognostic factor for T2DM remission, 42% of patients in both groups receiving insulin or insulin plus oral hypoglycemic drugs were normalized, demonstrating a low predictive value (Fig. 2). It appears that patients with a ⬎10-year history of T2DM are more refractory to any type of therapy, medical or surgical. Moreover, the group A medication pattern can be considered to represent worse control of disease owing to a reduction in the functional pancreatic -cell reserve. This was also corroborated by greater Hb1Ac values in group A (9.5% versus 7.1%). These values could also represent the difficulty in achieving patient compliance with the diet and therapy regimens over time. Lee et al. [29] identified the C-peptide value as the most important predictor for successful treatment of T2DM in nonmorbidly obese patients after SG. The T2DM remission rate for patients with a preoperative C-peptide level ⬍3, 3– 6, and ⬎6 ng/mL was 14.3%, 63.6%, and 100%, respectively. In the present study, the low -cell reserve of patients who had lived with T2DM for a long time was confirmed by preoperative C-peptide levels that were significantly lower than in the patients with a recent onset of T2DM (2.8 versus 4.5 ng/mL, P ⬍ .05), and high preoperative values are related to a lower risk of no T2DM remission after SG. The preoperative level of ⬍3 and ⬎6 ng/mL correlated with a 44% and 50% remission rate, respectively, and therefore were not accurate prognostic cutoff values for our patient population. These differences might also have resulted from the small series of patients in both studies (Lee et al. [29], 20 patients) and to the heterogeneous patient characteristics (Asian versus white, not morbidly versus morbidly obese, T2DM duration, antidiabetic therapy). Our results indicate that a ⬍10-year duration of T2DM can be considered an independent and accurate prognostic factor for T2DM remission after SG. In patients with T2DM of ⬍10 years, the effectiveness of SG was 100%, suggesting that early surgical treatment for T2DM is advantageous. In recent years, we have assisted in the transformation of bariatric surgery to “metabolic surgery.” Accurate prognostic
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Fig. 2. T2DM remission stratified by antidiabetic therapy. OAD ⫽ oral antidiabetic medication; INS ⫽ insulin.
factors and the identification of ideal candidates could better define the role of surgery in the treatment of T2DM and, also, ensure a better assessment of the results after surgery. Conclusion SG is very effective in achieving T2DM remission. The duration of T2DM seems to be of paramount importance as a prognostic factor, with a 10-year duration serving as an informative cutoff between those patients who will achieve 100% remission and those who will achieve significantly less resolution. The amount of postoperative weight loss, patient age, and C-peptide level were less accurate in predicting T2DM resolution after SG. Accurate prognostic factors could allow the identification of ideal candidates, minimize the rate of failure, and ameliorate the risk/benefit ratio after SG for T2DM. Disclosures The authors have no commercial associations that might be a conflict of interest in relation to this article. References [1] Mokdad AH, Bowman BA, Ford ES, Vinicor F, Marks JS, Koplan JP. The continuing epidemics of obesity and diabetes in the United States. JAMA 2001;286:1195–200. [2] North American Association for the Study of Obesity (NAASO) and the National Heart, Lung, and Blood Institute (NHLBI). The Practical Guide: Identification, Evaluation, and Treatment of Overweight and Obesity in Adults. NIH Publication No. 00-4084, Oct 2000. Bethesda: National Institutes of Health; 2000. [3] Hossain P, Kawar B, Nahas ME. Obesity and diabetes in the developing world—a growing challenge. N Engl J Med 2007;356: 213–5.
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