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Original Investigation |

Surgical vs Medical Treatments for Type 2 Diabetes Mellitus A Randomized Clinical Trial FREE

Anita P. Courcoulas, MD, MPH1; Bret H. Goodpaster, PhD2,3; Jessie K Eagleton, MPH1; Steven H. Belle, PhD, MScHyg4,5; Melissa A. Kalarchian, PhD6,7; Wei Lang, PhD8; Frederico G. S. Toledo, MD2; John M. Jakicic, PhD9
[+] Author Affiliations
1Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
2Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
3Sanford Burnham Medical Research Institute, Florida Hospital Translational Research Institute, Orlando
4Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania
5Department of Biostatistics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania
6Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
7School of Nursing, Duquesne University, Pittsburgh, Pennsylvania
8Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina
9Department of Health and Physical Activity, University of Pittsburgh, Pittsburgh, Pennsylvania
JAMA Surg. 2014;149(7):707-715. doi:10.1001/jamasurg.2014.467.
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Published online

Importance  Many questions remain unanswered about the role of bariatric surgery for people with type 2 diabetes mellitus (T2DM).

Objective  To determine feasibility of a randomized clinical trial (RCT) and compare initial outcomes of bariatric surgery and a structured weight loss program for treating T2DM in participants with grades I and II obesity.

Design, Setting, and Participants  A 12-month, 3-arm RCT at a single center including 69 participants aged 25 to 55 years with a body mass index (calculated as weight in kilograms divided by height in meters squared) of 30 to 40 and T2DM.

Interventions  Roux-en-Y gastric bypass (RYGB), laparoscopic adjustable gastric banding (LAGB), and an intensive lifestyle weight loss intervention (LWLI).

Main Outcomes and Measures  Primary outcomes in the intention-to-treat cohort were feasibility and effectiveness measured by weight loss and improvements in glycemic control.

Results  Of 667 potential participants who underwent screening, 69 (10.3%) were randomized. Among the randomized participants, 30 (43%) had grade I obesity, and 56 (81%) were women. Mean (SD) age was 47.3 (6.4) years and hemoglobin A1c level, 7.9% (2.0%). After randomization, 7 participants (10%) refused to undergo their allocated intervention (3 RYGB, 1 LAGB, and 3 LWLI), and 1 RYGB participant was excluded for current smoking. Twenty participants underwent RYGB; 21, LAGB; and 20, LWLI, with 12-month retention rates of 90%, 86%, and 70%, respectively. In the intention-to-treat cohort with multiple imputation for missing data, RYGB participants had the greatest mean weight loss from baseline (27.0%; 95% CI, 30.8-23.3) compared with LAGB (17.3%; 95% CI, 21.1-13.5) and LWLI (10.2%; 95% CI, 14.8-5.61) (P < .001). Partial and complete remission of T2DM were 50% and 17%, respectively, in the RYGB group and 27% and 23%, respectively, in the LAGB group (P < .001 and P = .047 between groups for partial and complete remission), with no remission in the LWLI group. Significant reductions in use of antidiabetics occurred in both surgical groups. No deaths were noted. The 3 serious adverse events included 1 ulcer treated medically in the RYGB group and 2 rehospitalizations for dehydration in the LAGB group.

Conclusions and Relevance  This study highlights several potential challenges to successful completion of a larger RCT for treatment of T2DM and obesity in patients with a body mass index of 30 to 40, including the difficulties associated with recruiting and randomizing patients to surgical vs nonsurgical interventions. Preliminary results show that RYGB was the most effective treatment, followed by LAGB for weight loss and T2DM outcomes at 1 year.

Trial Registration  clinicaltrials.gov Identifier: NCT01047735

Figures in this Article

Despite much interest and a growing body of literature, enough level I evidence to support the use of bariatric surgery to treat type 2 diabetes mellitus (T2DM) is lacking.14 Bariatric surgery is effective at inducing weight reduction and controlling obesity-related T2DM in the setting of grade II or III obesity.2,3,59 However, insufficient evidence exists regarding the longer-term outcomes of bariatric surgery, resulting in less than uniform acceptance of these procedures as a primary treatment for T2DM. This issue is especially true for T2DM in the setting of grade I obesity, for which limited evidence addresses even short-term surgical safety and outcomes.10

Several key questions left unanswered about the role of bariatric surgery in the treatment of T2DM include the relative safety and efficacy of treatment options (surgical vs nonsurgical), the modification of the future risk for microvascular and macrovascular complications, and the economic impact of these treatments.4 Answers to such questions could come from a new, large, multicenter randomized clinical trial (RCT) to compare bariatric surgery with the best available medical care, but such a trial would be costly in a difficult funding climate, time-consuming when answers of comparative effectiveness are urgently needed, and potentially difficult to execute, as 2 recent studies1,3 have shown. The National Institutes of Health funded 7 prospective pilot and feasibility studies1118 several years ago, possibly to consider a large multicenter study to address these questions.

This study is one of the first of these to address important feasibility and preliminary effectiveness aims. We report the results of an RCT examining the feasibility of a larger study and comparing the effectiveness of 2 types of bariatric surgery (Roux-en-Y gastric bypass [RYGB] and laparoscopic adjustable gastric banding [LAGB]) and an intensive lifestyle weight loss intervention (LWLI) modeled after the Look AHEAD (Action for Health in Diabetes) trial19 in adults with grades I and II obesity and T2DM.

Study Design

This prospective RCT was conducted at the University of Pittsburgh Medical Center from October 1, 2009, through May 31, 2012. The local institutional review board approved the study protocol, and written informed consent was obtained. Participants were recruited by a variety of advertisement techniques (television, print newspapers, multiple Internet sources, and other local media) followed by an initial telephone screening and an in-person informational group session. Each participant underwent individual evaluation by the surgeon (A.P.C.) and, after successful completion of medical, nutritional, and psychological assessments, random assignment to 1 of 3 treatment arms: RYGB, LAGB, or LWLI (Figure 1). We performed stratified (by sex and body mass index [BMI; calculated as weight in kilograms divided by height in meters squared]) blocked randomization with equal allocation to each arm using computer-generated random numbers. The cost of the surgical procedures was subsidized by the medical center.

Place holder to copy figure label and caption
Figure 1.
CONSORT Diagram of Screening, Randomization, and Follow-up of Study Participants

LAGB indicates laparoscopic adjustable gastric banding; LWLI, lifestyle weight loss intervention; and RYGB, Roux-en-Y gastric bypass.

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Participants

Adults were eligible for enrollment if they were 25 to 55 years of age and had a BMI of 30 to 40 because these characteristics represent a high-priority subgroup for comparative effectiveness studies.11 Diagnosis of T2DM was confirmed by a documented fasting plasma glucose (FPG) level of 126 mg/dL or greater (to convert to millimoles per liter, multiply by 0.0555) and/or treatment with antidiabetics to include a broad spectrum of T2DM severity. For participants with grade I obesity, treatment with antidiabetics and permission from their treating physician were required to participate. Adults were excluded for prior weight loss surgery, impaired mental status, alcohol or other drug addiction, current smoking, pregnancy or planned pregnancy, inability to tolerate general anesthesia owing to poor health, type 1 diabetes mellitus, failed nutritional or psychological assessment, unwillingness to be randomized, inability to provide informed consent, or being deemed unlikely to comply with study visits or procedures.

Treatments

All surgical procedures were performed by one of us (A.P.C.). The RYGB was performed with a standard retrocolic-retrogastric technique using a linear stapled and hand-sewn gastrojejunal anastomosis. The LAGB was performed using 1 of 2 gastric banding devices (Allergan 10 or AP Standard Lap-Band; Allergan, Inc) with sutures to secure the gastric cardia and prevent slippage and placement of the infusion port on the anterior rectus muscle. Surgical participants underwent clinical follow-up assessments consistent with current practice at 2 weeks and 3, 6, 9, and 12 months postoperatively in the RYGB group and at 2 weeks and 2, 4, 6, 8, 10, and 12 months or more frequently, as necessary, for band adjustment in the LAGB group. Those participants undergoing surgical intervention were counseled on a diet program consistent with postbariatric surgery recommendations and were encouraged to exercise a minimum of 3 to 4 times per week and to focus on weight-bearing aerobic activity.

Participants randomized to the LWLI underwent a standard behavioral weight control program delivered using an in-person, individual format based on the intervention developed for the Diabetes Prevention Program20 and the Look AHEAD trial21 and adapted into a 12-month program for subjects with grades I to II obesity. During the initial 6 months of treatment, LWLI participants attended weekly in-person intervention sessions. During months 7 to 12, they attended in-person sessions in the first and third weeks of the month and received brief telephone contacts in the second and fourth weeks. Each session focused on a specific behavioral topic related to weight loss, eating, or exercise behaviors. Participants were provided with supplemental written materials and were asked to self-monitor body weight, eating, and exercise. All LWLI participants were prescribed an energy-restricted diet (1200-1800 kcal/d) and were provided meal plans, meal replacements, and calorie-counter books. Moderate-intensity exercise was prescribed 5 days each week beginning at 20 minutes per day and gradually progressing to at least 60 minutes per day, with bouts of activity encouraged to be longer than 10 minutes.

Outcomes and End Points

The primary study end point was the feasibility of performing an RCT involving surgical and nonsurgical treatments. Feasibility was assessed by recruitment, randomization, and retention rates. Secondary outcomes included effectiveness to induce weight loss and improvements in T2DM. Changes in lipid levels and blood pressure were also reported. All participants underwent assessment at baseline (within 30 days before the start of the intervention) and 12 months (330-390 days) after the intervention. Weight and height were assessed using a digital scale (TBF-300A; Tanita) and a standard stadiometer, and blood pressure was measured twice at each visit. Serum measures of hemoglobin A1c (HbA1c), 12-hour FPG, total cholesterol, triglycerides, and high- and low-density lipoprotein cholesterol levels were obtained. At 12 months, we assessed weight loss (change in weight, percentage of weight loss from baseline, and change in BMI), glycemic control (change in FPG and HbA1c levels), use of antidiabetics (categorized as none, oral/other, or insulin), and partial and complete remission of T2DM according to the American Diabetes Association 2009 definitions.22 Changes in blood pressure and serum lipid levels were also assessed at 12 months. Comorbid health conditions (dyslipidemia/hypercholesterolemia and hypertension) were evaluated using a standardized comorbidity status form at baseline and follow-up. Participants completed a treatment preference questionnaire before but independently of randomization at baseline and follow-up.23 The participants were asked to rate how they felt about each of the 3 treatments on a scale of 1 (strongly prefer) to 6 (strongly do not prefer).

Statistical Analysis

Because of the small sample size of this feasibility trial, some of the analysis is descriptive, and results related to the efficacy outcomes should be considered preliminary. Statistical analysis was performed using commercially available software (SAS, version 9.2; SAS Institute Inc), with the type I error rate fixed at 0.05 (2-tailed). Categorical variables were summarized as frequencies, continuous variables with normal distributions as mean (SD) values, and continuous variables with nonnormal distributions as median values (interquartile range). Differences in baseline characteristics among the RYGB, LAGB, and LWLI groups were examined using the χ2 test or Fisher exact test for categorical variables and analysis of variance or Kruskal-Wallis test for continuous variables.

Changes from baseline to the 12-month assessment were analyzed using separate regression models. Each regression model included covariate adjustment for randomization stratification factors (sex and baseline BMI). Change in weight was further adjusted for baseline weight. Inferences were focused on the overall treatment effect along with 3 pairwise between-group comparisons. Least squares means were obtained from the models along with their 95% confidence intervals. Intention-to-treat analyses were conducted using multiple imputation implemented using procedures from the statistical software (PROC MI and PROC MIANALYZE; SAS Institute Inc). For each outcome, 10 data sets were imputed and results were then combined.

The Treatment Preference Questionnaire scores at baseline were categorized into congruent, no preference, and incongruent (ie, they did not receive their treatment preference) groups.23 Partial remission of T2DM was defined as the absence of any antidiabetics at 12 months after surgery with HbA1c levels of less than 6.5% (to convert to proportion of total hemoglobin, multiply by 0.01) and FPG levels of 125 mg/dL or less. Complete remission of T2DM was defined as the absence of antidiabetics with HbA1c levels of less than 5.7% and FPG levels of 100 mg/dL or less per the American Diabetes Association guidelines.22 For categorical data with missing values (eg, T2DM remission, use of antidiabetics, or history of blood pressure or lipid level abnormalities), we assumed no remission or no improvement of the condition at follow-up.

Feasibility

Of the 667 patients undergoing assessment for eligibility, 463 (69.4%) were determined to be ineligible by way of telephone assessment. The most common reasons for ineligibility during telephone screening were BMI outside the study range (170 participants [36.7%]), lack of T2DM (90 [19.4%]), not meeting age criteria (82 [17.7%]), lack of interest (67 [14.5%]), and no local address (36 [7.8%]). Other reasons for exclusion (18 participants [3.9%]) included participating in another study, previous bariatric surgery, current smoking, inability to exercise, and significant medical conditions precluding general anesthesia. The 204 adults who were deemed eligible through telephone assessment were invited to an informational session, of whom 68 (33.3%) did not attend. Later, 33 participants (16.2%) were excluded by medical assessment results, 15 (7.4%) refused further participation, 12 (5.9%) had a BMI outside the study range, and 7 (3.4%) were unwilling to be randomized (1 after gaining insurance approval for RYGB). As shown in Figure 1 for all screening (telephone and in person), 74.7% of those excluded were ineligible and 25.1% lacked interest or willingness to be randomized. A total of 69 of the 667 potential participants undergoing screening (10.3%) completed all requirements and were successfully randomized.

Of these 69 participants, 7 (10%) (3 RYGB, 1 LAGB, and 3 LWLI participants) refused to undergo their allocated treatment after randomization, and 1 participant was excluded on the day of planned surgery (RYGB) owing to current smoking. Sixty-one participants underwent their allocated treatment with 20 each undergoing RYGB and LWLI and 21 undergoing LAGB. Retention rates (defined as undergoing intervention and returning for the 12-month assessment) in the RYGB, LAGB, and LWLI treatment arms were 18 of 20 (90%), 18 of 21 (86%), and 14 of 20 (70%), respectively. Overall, 10 participants withdrew or were unavailable for follow-up at the time of the 12-month assessment (84% overall retention), and 1 participant completed a partial visit with weight and health outcomes measured. Five of these participants could not be contacted and 5 discontinued their participation in the LWLI (for 3, <1 month into the intervention; for 2, before the 12-month assessment) owing to lack of interest. Vital status was obtained and confirmed on 59 of the 61 treated subjects (97%)

Incongruence of treatment preference by arm was similar, at 4 of 24 in the RYGB group (17%), 4 of 22 in the LAGB group (18%), and 3 of 23 in the LWLI group (13%), and most of the participants were in equipoise before randomization. All 3 participants who refused RYGB and 3 who refused LWLI preferred their respective arm (ie, were congruent), and the 1 who refused LAGB treatment was incongruent. Participants who were incongruent before randomization, but underwent treatment, were as likely to be retained in the study as those who were congruent.

For the entire sample, 56 participants (81%) were women. The mean age was 47.3 (6.4) years and mean BMI, 35.6 (3.0). Mean HbA1c level was 7.9% (2.0%), and the mean duration of T2DM at the time of baseline evaluation was 6.4 (4.8) years. By treatment arm, mean duration was 7.4 (4.5) years for the RYGB group, 6.1 (4.3) years for the LAGB group, and 5.7 (5.6) years for the LWLI group (Table 1).

Table Graphic Jump LocationTable 1.  Characteristics of the Patients at Baselinea
Weight Change

Weight change and BMI differed significantly from zero within all treatment groups (Table 2). Participants in the RYGB group had the greatest weight change from baseline (−27.0%) compared with the LAGB and LWLI groups (−17.3% and −10.2%, respectively) (P < .001).

Table Graphic Jump LocationTable 2.  Measures of Weight Change and T2DM Improvement and Remissiona
Diabetes Remission and Medications

As shown in Figure 2, no participants in the LWLI group experienced partial or complete remission of T2DM at 12 months. For the surgical treatment arms, 12 of 24 participants (50%) undergoing RYGB were classified with partial T2DM remission at 12 months and 4 of 24 (17%) with complete remission compared with 6 of 22 (27%) and 5 of 22 (23%), respectively, undergoing LAGB (P < .001 for partial and P = .047 for complete remission between groups). Pairwise treatment comparisons (Table 2) were significant for RYGB vs LWLI (P < .001) for partial T2DM remission and for LAGB vs LWLI partial and complete T2DM remission (P = .009 and P = .02, respectively). As shown in Table 2, significant reductions were observed in use of antidiabetics at 12 months for RYGB and LAGB compared with LWLI, although no LAGB (n = 8) or LWLI (n = 6) participant receiving insulin at baseline had discontinued use at 12 months. We found significant treatment differences for glycemic control at 12 months with RYGB vs LWLI (P = .002) and LAGB vs LWLI (P = .045) as measured by change in FPG level and RYGB vs LAGB (P = .04) and RYGB vs LWLI (P < .001) measured by change in HbA1c levels. For the LWLI group, no significant improvements in FPG or HbA1c levels were observed during the 12-month period.

Place holder to copy figure label and caption
Figure 2.
Remission of Type 2 Diabetes Mellitus (T2DM) at 12 Months

Partial remission of T2DM indicates no use of antidiabetics, hemoglobin A1c (HbA1c) level of less than 6.5%, and fasting plasma glucose (FPG) level of 125 mg/dL or less; complete remission of T2DM, no use of antidiabetics, HbA1c level of less than 5.7%; and FPG level of 100 mg/dL or less. Missing data at follow-up were assumed to be no remission. LAGB indicates laparoscopic adjustable gastric banding; LWLI, lifestyle weight loss intervention; and RYGB, Roux-en-Y gastric bypass.

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Lipid Levels and Blood Pressure Outcomes

The only change in cholesterol levels that showed a significant treatment effect was a change in high-density lipoprotein cholesterol levels (overall, P = .02; RYGB vs LWLI, P = .002 [eTable in the Supplement]). Dyslipidemia or hypercholesterolemia at baseline was reported in 14 RYGB participants (58%), 16 LAGB participants (73%), and 15 LWLI participants (65%) and at 12 months in 7 (29%), 12 (55%), and 15 (65%), respectively. Hypertension was diagnosed at baseline for 12 RYGB participants (50%), 13 LAGB participants (59%), and 16 LWLI participants (70%) and at 12 months for 9 (38%), 7 (32%), and 17 (74%), respectively. No significant reductions were seen in blood pressure measurements. Among those with hypertension at baseline, antihypertensive medication therapy was reduced or discontinued in 7 participants in the RYGB group (58%), 7 participants in the LAGB group (54%), and 2 participants in the LWLI group (13%).

Safety

Six participants undergoing surgery stayed 1 additional night after their operation for nausea or glucose medication management. One LAGB participant required a second procedure to replace a port that later detached from its position on the muscle, and 3 other participants had mild symptoms requiring clinical attention. No deaths were observed. Three participants experienced serious adverse events, including an ulcer that was treated medically in 1 RYBG participant and hospitalization for dehydration in 2 LAGB participants (Table 3).

This study highlights several potential challenges to successful completion of a larger RCT for treatment of T2DM and obesity in patients with a BMI of 30 to 40 and helps to outline what options would be feasible to answer the important question of comparative effectiveness in this target population. The feasibility aim was achieved, and we show that RYGB was the most effective treatment, followed by LAGB, for weight loss and T2DM outcomes at 1 year in a sample that included more than 40% of participants with a BMI of 30 to 35 (low BMI), for whom data are significantly lacking.10

Although we demonstrate feasibility, the study required considerable effort to recruit (only 10.3% of those undergoing screening were randomized) and retain participants. Recently published RCTs demonstrate variable rates ranging from 4.5% to 83.3%13 of those undergoing screening being randomized, and each required several years to complete that phase. To reduce the number of people undergoing screening to meet recruitment goals, future trials should target recruitment, for example, from weight loss clinics, endocrinology clinics, and other sources as opposed to the widespread advertising methods used for this study.

Retention is also a challenge. Despite our specific efforts to assess the willingness of participants to undergo any of the 3 treatments (clinical equipoise) and, according to measured treatment preference, our achievement of equipoise in most of the participants, 10% of those randomized dropped out after randomization but before intervention. This dropout rate could not be explained by stated treatment preference alone. Although retention efforts were equivalent across all 3 treatment arms, slightly higher rates of unavailability for follow-up in the LWLI arm were observed than in the surgical arms. We found no significant relationship between treatment incongruence and retention status; that is, those participants (16% overall) who were incongruent in undergoing treatment were not less likely to be retained in the study. However, the lower retention in the LWLI arm may have reflected unexpressed or unmeasured disappointment with treatment allocation for those who may have been seeking bariatric surgery. The retention rate in the LWLI arm is lower than that observed in the Look AHEAD trial (94% at 4 years),19 indicating that more effective retention strategies than those used in this trial (frequent contacts, relationship building) need to be adopted. Furthermore, the differential retention by treatment arm and our inability to identify reasons based on our data indicate potential inherent and unidentified differences in motivation to be in a trial among participants willing to undergo a surgical vs a nonsurgical treatment.

Finally, with regard to feasibility, funding for all the surgical procedures was significantly subsidized by the medical center where the study was conducted, and participants with low BMI would not have had their surgery covered by insurance that uses current criteria for bariatric surgery to determine reimbursement eligibility.24 Substantial resources also appear to be necessary to maintain high levels of retention, with some new strategies geared to address dropout before intervention implementation. This study included only 1 year of follow-up. Longer-term follow-up is necessary for more definitive conclusions regarding the relative efficacy of treatments and is likely to require substantial resources.25

In summary, these important feasibility issues—the need for targeted screening, the thorough assessment of clinical equipoise to reduce the likelihood of postrandomization dropout, challenging retention in the LWLI arm, and funding—raise a number of concerns for the scalability of this type of study to a larger multicenter trial. For this reason, pursuing alternative methods to obtain high-order evidence regarding outcomes of surgical vs nonsurgical treatment may be more reasonable for people with a relatively low BMI. One possibility is a pooled analysis of other similar feasibility RCTs1318 before undertaking a new, larger multicenter trial.

With respect to the short-term effectiveness of weight loss and T2DM treatment outcomes, RYGB was the most successful, followed by LAGB, and then LWLI for weight loss outcomes only. In the LWLI arm, despite weight loss of 10.2% from baseline, which was more than that achieved in the Look AHEAD trial for the intensive lifestyle intervention (mean weight loss of 8.6% at 1 year),26 and despite the shortest duration of disease, no significant improvements were observed in HbA1c or FPG levels, use of antidiabetics, or any partial or complete remission of T2DM. Why LWLI participants did not achieve significant T2DM and other health improvements as seen in the Look AHEAD trial, despite comparable weight loss and a similar magnitude of improvement in lipid levels and blood pressure, is unclear. This finding may have to do with the relatively small sample size and variability in response, T2DM severity differences, medication adjustment differences that were performed by nonstudy and different treating physicians, or the impact of fitness changes (not addressed in this study).

Roux-en-Y gastric bypass resulted in a mean weight loss of 27% from baseline and 50% partial and 17% complete remission of T2DM at 1 year, which is fairly consistent other published results for weight loss and T2DM remission depending on the thresholds used for definition.13,8,27 This RCT is the first in the United States to include an LAGB treatment option in this population for these end points and resulted in a mean weight loss of 17% from baseline and 27% partial and 23% complete remission of T2DM. These results are somewhat lower for weight and T2DM outcomes than previous reported studies.7,28,29 An RCT by Dixon et al7 demonstrated a mean initial weight loss of 21% and 73% “remission” of T2DM (using a different definition than current American Diabetes Association guidelines), but the 60 participants had mild diabetes mellitus with disease duration of less than 2 years. The T2DM remission rates for LAGB in this study exceed those for intensive medical management alone in this trial (0%) and in the Look AHEAD trial (11.5%)30 but do not reach those observed with the gastric sleeve (37% in the Surgical Therapy and Medications Potentially Eradicate Diabetes Efficiently [STAMPEDE] trial).3 In the present trial, the complete remission rates for T2DM are comparable between the 2 surgical treatment arms, but the sample sizes are small, the study includes people with a broad range of severity of diabetes mellitus, and follow-up is limited to 1 year, so no definitive conclusions can be drawn. Nevertheless, the LWLI arm had no T2DM remission, so these results suggest that the LAGB procedure—low risk and potentially reversible—may have a place as a treatment option for patients with low BMI and T2DM. Further studies will be needed to confirm these results.

This study has some notable strengths, particularly the comparison of 2 current surgical procedures with an intensive nonsurgical treatment arm that has been standardized and extensively reported in the literature.19,21,26 In addition, this study is the first of 6 RCTs1316,18 funded to be completed that addresses these specific issues of feasibility and comparative effectiveness. Its limitations include the small sample size and the lack of generalizability of single-site results. Nonetheless, the results of this study are intended to be a first step to inform a larger, more comprehensive, and longer-term multicenter trial to address critical unanswered questions. We conclude that the lessons learned here should be combined with those to come in the next 2 years from several other similar pilot studies1316,18 before planning a larger RCT. Such a study would require multiple sites and should compare the 3 most common bariatric surgical procedures in current use (RYGB, LAGB, and the gastric sleeve) with each other with or without an adjunctive lifestyle component or treatment arm during the longer term.

Finally, this trial clearly demonstrates that at 1 year, bariatric surgery is more effective at treating T2DM than nonsurgical weight loss induced by diet and increased physical activity in people with T2DM and grades I and II obesity. What is not yet clear from this trial and others to date is whether the short-term T2DM improvements after bariatric surgery are related to the degree of weight loss, the type of surgical procedure, or other factors.

This study highlights several potential challenges to successfully completing a larger RCT for treatment of T2DM and obesity in patients with a BMI of 30 to 40, including the difficulties associated with recruiting and randomizing patients to surgical vs nonsurgical interventions. Our preliminary results indicate that RYGB was the most effective treatment for weight loss and T2DM outcomes at 1 year, followed by LAGB.

Accepted for Publication: January 16, 2014.

Corresponding Author: Anita P. Courcoulas, MD, MPH, Department of Surgery, University of Pittsburgh Medical Center, 3380 Boulevard of the Allies, Ste 390, Pittsburgh, PA 15213 (courcoulasap@upmc.edu).

Published Online: June 4, 2014. doi:10.1001/jamasurg.2014.467.

Authors Contributions: Dr Courcoulas had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Courcoulas, Goodpaster, Eagleton, Belle, Kalarchian, Toledo, Jakicic.

Acquisition, analysis, or interpretation of data: Courcoulas, Goodpaster, Eagleton, Kalarchian, Lang, Toledo, Jakicic.

Drafting of the manuscript: Courcoulas, Eagleton, Lang, Jakicic.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Eagleton, Belle, Lang.

Obtained funding: Courcoulas, Goodpaster, Eagleton.

Administrative, technical, or material support: Courcoulas, Eagleton, Kalarchian, Jakicic.

Study supervision: Courcoulas, Goodpaster, Toledo, Jakicic.

Conflict of Interest Disclosures: Dr Courcoulas has received research grants from Covidien, EndoGastric Solutions, and Nutrisystem and is on the scientific advisory board of Ethicon J & J Healthcare system. Dr Goodpaster has received honoraria from Merck & Co, Inc. for participation on an advisory panel and was a paid consultant to the Translational Research Institute of the Florida Hospital. Dr Kalarchian has received a research grant from Nutrisystem. Dr Toledo has received research grants from BodyMedia and sanofi-aventis. Dr Jakicic has received a research grant from BodyMedia, Inc; has received payment for lectures for Jenny Craig, Calorie Control Council, and Nestle Nutrition Institute; and has served as a member on the Alere Wellbeing Scientific Advisory Board and the board of ILSI North America. No other disclosures were reported.

Funding/Support: This study was supported by grant 1RC1DK086037-01 from the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIKKD-NIH), and by subsidization of the surgical procedures by Magee Women’s Hospital of the University of Pittsburgh Medical Center. This study was also supported by a successful response to a Request for Application from the NIDDK-NIH that outlined a suggested study design and target population.11

Role of the Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributors: Sheila K. Pierson, BS, BA (Division of Minimally Invasive Bariatric and General Surgery, Department of Surgery, University of Pittsburgh Medical Center), Angela A. Laslavic, MS (Division of Endocrinology and Metabolism, University of Pittsburgh), and Nicole L. Helbling, RN, MS (Division of Endocrinology and Metabolism, University of Pittsburgh), served as study coordinators. Linda Nelson Semler MS, RD, LDN, and Lisa B. Martich, RDN, LDN (Department of Health and Physical Activity, University of Pittsburgh), served as study interventionists. Michael D. McDermott, MS (Department of Health and Physical Activity, University of Pittsburgh), provided data support. These individuals received salary support from this grant-funded study for their contributions.

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Adams  TD, Davidson  LE, Litwin  SE,  et al.  Health benefits of gastric bypass surgery after 6 years. JAMA. 2012;308(11):1122-1131.
PubMed   |  Link to Article
Carlsson  LM, Peltonen  M, Ahlin  S,  et al.  Bariatric surgery and prevention of type 2 diabetes in Swedish obese subjects. N Engl J Med. 2012;367(8):695-704.
PubMed   |  Link to Article
Dixon  JB, O’Brien  PE, Playfair  J,  et al.  Adjustable gastric banding and conventional therapy for type 2 diabetes: a randomized controlled trial. JAMA. 2008;299(3):316-323.
PubMed   |  Link to Article
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(4):467-485.
PubMed
Unger  RH.  Reinventing type 2 diabetes: pathogenesis, treatment, and prevention. JAMA. 2008;299(10):1185-1187.
PubMed   |  Link to Article
Maggard-Gibbons  M, Maglione  M, Livhits  M,  et al.  Bariatric surgery for weight loss and glycemic control in nonmorbidly obese adults with diabetes: a systematic review. JAMA. 2013;309(21):2250-2261.
PubMed   |  Link to Article
National Institutes of Health. Recovery Act limited competition: NIH Challenge Grants in Health and Science Research (RC1).http://grants.nih.gov/grants/guide/rfa-files/rfa-od-09-003.html. Accessed June 17, 2013.
Lautz  D, Halperin  F, Goebel-Fabbri  A, Goldfine  AB.  The great debate: medicine or surgery: what is best for the patient with type 2 diabetes? Diabetes Care. 2011;34(3):763-770.
PubMed   |  Link to Article
ClinicalTrials.gov. Surgery or Lifestyle With Intensive Medical Management in the Treatment of Type 2 Diabetes (SLIMM-T2D). NLM Identifier: NCT01073020. http://clinicaltrials.gov/show/NCT01073020. Accessed June 17, 2013.
ClinicalTrials.gov. Surgery or Lifestyle Intervention for Type 2 DIabetes (SOLID). NLM Identifier: NCT01040468. In: http://clinicaltrials.gov/show/NCT01040468. Accessed July 3, 2013.
ClinicalTrials.gov. Calorie Reduction or Surgery: Seeking Remission for Obesity and Diabetes (CROSSROADS). NLM Identifier: NCT01295229. http://clinicaltrials.gov/show/NCT01295229. Accessed June 17, 2013.
ClinicalTrials.gov. Beth Israel Deaconess Medical Center: Apnea, Bariatric Surgery vs Continuous Positive Airway Pressure (CPAP) Trial (ABC). NLM Identifier: NCT01187771. http://clinicaltrials.gov/show/NCT01187771. July 3, 2013.
ClinicalTrials.gov. Effect of Bariatric Surgery on Mechanisms of Type 2 Diabetes (Stampede II). NLM Identifier: NCT01278823. http://clinicaltrials.gov/show/NCT01278823. Accessed July 3, 2013.
ClinicalTrials.gov. Improving Diabetes Through Lifestyle and Surgery (IDeaLS). NLM Identifier: NCT01667783. http://clinicaltrials.gov/show/NCT01667783. Accessed June 17, 2013.
Wing  RR; Look AHEAD Research Group.  Long-term effects of a lifestyle intervention on weight and cardiovascular risk factors in individuals with type 2 diabetes mellitus: four-year results of the Look AHEAD trial. Arch Intern Med. 2010;170(17):1566-1575.
PubMed
Diabetes Prevention Program (DPP) Research Group.  The Diabetes Prevention Program (DPP): description of lifestyle intervention. Diabetes Care. 2002;25(12):2165-2171.
PubMed   |  Link to Article
Ryan  DH, Espeland  MA, Foster  GD,  et al; Look AHEAD Research Group.  Look AHEAD (Action for Health in Diabetes): design and methods for a clinical trial of weight loss for the prevention of cardiovascular disease in type 2 diabetes. Control Clin Trials. 2003;24(5):610-628.
PubMed   |  Link to Article
Buse  JB, Caprio  S, Cefalu  WT,  et al.  How do we define cure of diabetes? Diabetes Care. 2009;32(11):2133-2135.
PubMed   |  Link to Article
Borradaile  KE, Halpern  SD, Wyatt  HR,  et al.  Relationship between treatment preference and weight loss in the context of a randomized controlled trial. Obesity (Silver Spring). 2012;20(6):1218-1222.
PubMed   |  Link to Article
Consensus Development Conference Panel.  NIH Conference: gastrointestinal surgery for severe obesity. Ann Intern Med. 1991;115(12):956-961.
PubMed   |  Link to Article
Gourash  WF, Ebel  F, Lancaster  K,  et al.  Longitudinal Assessment of Bariatric Surgery (LABS): retention strategy and results at 24 months. Surg Obes Relat Dis. 2013;9(4):514-519.
PubMed   |  Link to Article
Pi-Sunyer  X, Blackburn  G, Brancati  FL,  et al; Look AHEAD Research Group.  Reduction in weight and cardiovascular disease risk factors in individuals with type 2 diabetes: one-year results of the Look AHEAD trial. Diabetes Care. 2007;30(6):1374-1383.
PubMed   |  Link to Article
Pories  WJ, Swanson  MS, MacDonald  KG,  et al.  Who would have thought it? an operation proves to be the most effective therapy for adult-onset diabetes mellitus. Ann Surg. 1995;222(3):339-352.
PubMed   |  Link to Article
O’Brien  PE, Dixon  JB, Laurie  C,  et al.  Treatment of mild to moderate obesity with laparoscopic adjustable gastric banding or an intensive medical program: a randomized trial. Ann Intern Med. 2006;144(9):625-633.
PubMed   |  Link to Article
O’Brien  PE, MacDonald  L, Anderson  M, Brennan  L, Brown  WA.  Long-term outcomes after bariatric surgery: fifteen-year follow-up of adjustable gastric banding and a systematic review of the bariatric surgical literature. Ann Surg. 2013;257(1):87-94.
PubMed   |  Link to Article
Gregg  EW, Chen  H, Wagenknecht  LE,  et al; Look AHEAD Research Group.  Association of an intensive lifestyle intervention with remission of type 2 diabetes. JAMA. 2012;308(23):2489-2496.
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.
CONSORT Diagram of Screening, Randomization, and Follow-up of Study Participants

LAGB indicates laparoscopic adjustable gastric banding; LWLI, lifestyle weight loss intervention; and RYGB, Roux-en-Y gastric bypass.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.
Remission of Type 2 Diabetes Mellitus (T2DM) at 12 Months

Partial remission of T2DM indicates no use of antidiabetics, hemoglobin A1c (HbA1c) level of less than 6.5%, and fasting plasma glucose (FPG) level of 125 mg/dL or less; complete remission of T2DM, no use of antidiabetics, HbA1c level of less than 5.7%; and FPG level of 100 mg/dL or less. Missing data at follow-up were assumed to be no remission. LAGB indicates laparoscopic adjustable gastric banding; LWLI, lifestyle weight loss intervention; and RYGB, Roux-en-Y gastric bypass.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1.  Characteristics of the Patients at Baselinea
Table Graphic Jump LocationTable 2.  Measures of Weight Change and T2DM Improvement and Remissiona

References

Ikramuddin  S, Korner  J, Lee  WJ,  et al.  Roux-en-Y gastric bypass vs intensive medical management for the control of type 2 diabetes, hypertension, and hyperlipidemia: the Diabetes Surgery Study randomized clinical trial. JAMA. 2013;309(21):2240-2249.
PubMed   |  Link to Article
Mingrone  G, Panunzi  S, De Gaetano  A,  et al.  Bariatric surgery versus conventional medical therapy for type 2 diabetes. N Engl J Med. 2012;366(17):1577-1585.
PubMed   |  Link to Article
Schauer  PR, Kashyap  SR, Wolski  K,  et al.  Bariatric surgery versus intensive medical therapy in obese patients with diabetes. N Engl J Med. 2012;366(17):1567-1576.
PubMed   |  Link to Article
Wolfe  BM, Purnell  JQ, Belle  SH.  Treating diabetes with surgery. JAMA. 2013;309(21):2274-2275.
PubMed   |  Link to Article
Adams  TD, Davidson  LE, Litwin  SE,  et al.  Health benefits of gastric bypass surgery after 6 years. JAMA. 2012;308(11):1122-1131.
PubMed   |  Link to Article
Carlsson  LM, Peltonen  M, Ahlin  S,  et al.  Bariatric surgery and prevention of type 2 diabetes in Swedish obese subjects. N Engl J Med. 2012;367(8):695-704.
PubMed   |  Link to Article
Dixon  JB, O’Brien  PE, Playfair  J,  et al.  Adjustable gastric banding and conventional therapy for type 2 diabetes: a randomized controlled trial. JAMA. 2008;299(3):316-323.
PubMed   |  Link to Article
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(4):467-485.
PubMed
Unger  RH.  Reinventing type 2 diabetes: pathogenesis, treatment, and prevention. JAMA. 2008;299(10):1185-1187.
PubMed   |  Link to Article
Maggard-Gibbons  M, Maglione  M, Livhits  M,  et al.  Bariatric surgery for weight loss and glycemic control in nonmorbidly obese adults with diabetes: a systematic review. JAMA. 2013;309(21):2250-2261.
PubMed   |  Link to Article
National Institutes of Health. Recovery Act limited competition: NIH Challenge Grants in Health and Science Research (RC1).http://grants.nih.gov/grants/guide/rfa-files/rfa-od-09-003.html. Accessed June 17, 2013.
Lautz  D, Halperin  F, Goebel-Fabbri  A, Goldfine  AB.  The great debate: medicine or surgery: what is best for the patient with type 2 diabetes? Diabetes Care. 2011;34(3):763-770.
PubMed   |  Link to Article
ClinicalTrials.gov. Surgery or Lifestyle With Intensive Medical Management in the Treatment of Type 2 Diabetes (SLIMM-T2D). NLM Identifier: NCT01073020. http://clinicaltrials.gov/show/NCT01073020. Accessed June 17, 2013.
ClinicalTrials.gov. Surgery or Lifestyle Intervention for Type 2 DIabetes (SOLID). NLM Identifier: NCT01040468. In: http://clinicaltrials.gov/show/NCT01040468. Accessed July 3, 2013.
ClinicalTrials.gov. Calorie Reduction or Surgery: Seeking Remission for Obesity and Diabetes (CROSSROADS). NLM Identifier: NCT01295229. http://clinicaltrials.gov/show/NCT01295229. Accessed June 17, 2013.
ClinicalTrials.gov. Beth Israel Deaconess Medical Center: Apnea, Bariatric Surgery vs Continuous Positive Airway Pressure (CPAP) Trial (ABC). NLM Identifier: NCT01187771. http://clinicaltrials.gov/show/NCT01187771. July 3, 2013.
ClinicalTrials.gov. Effect of Bariatric Surgery on Mechanisms of Type 2 Diabetes (Stampede II). NLM Identifier: NCT01278823. http://clinicaltrials.gov/show/NCT01278823. Accessed July 3, 2013.
ClinicalTrials.gov. Improving Diabetes Through Lifestyle and Surgery (IDeaLS). NLM Identifier: NCT01667783. http://clinicaltrials.gov/show/NCT01667783. Accessed June 17, 2013.
Wing  RR; Look AHEAD Research Group.  Long-term effects of a lifestyle intervention on weight and cardiovascular risk factors in individuals with type 2 diabetes mellitus: four-year results of the Look AHEAD trial. Arch Intern Med. 2010;170(17):1566-1575.
PubMed
Diabetes Prevention Program (DPP) Research Group.  The Diabetes Prevention Program (DPP): description of lifestyle intervention. Diabetes Care. 2002;25(12):2165-2171.
PubMed   |  Link to Article
Ryan  DH, Espeland  MA, Foster  GD,  et al; Look AHEAD Research Group.  Look AHEAD (Action for Health in Diabetes): design and methods for a clinical trial of weight loss for the prevention of cardiovascular disease in type 2 diabetes. Control Clin Trials. 2003;24(5):610-628.
PubMed   |  Link to Article
Buse  JB, Caprio  S, Cefalu  WT,  et al.  How do we define cure of diabetes? Diabetes Care. 2009;32(11):2133-2135.
PubMed   |  Link to Article
Borradaile  KE, Halpern  SD, Wyatt  HR,  et al.  Relationship between treatment preference and weight loss in the context of a randomized controlled trial. Obesity (Silver Spring). 2012;20(6):1218-1222.
PubMed   |  Link to Article
Consensus Development Conference Panel.  NIH Conference: gastrointestinal surgery for severe obesity. Ann Intern Med. 1991;115(12):956-961.
PubMed   |  Link to Article
Gourash  WF, Ebel  F, Lancaster  K,  et al.  Longitudinal Assessment of Bariatric Surgery (LABS): retention strategy and results at 24 months. Surg Obes Relat Dis. 2013;9(4):514-519.
PubMed   |  Link to Article
Pi-Sunyer  X, Blackburn  G, Brancati  FL,  et al; Look AHEAD Research Group.  Reduction in weight and cardiovascular disease risk factors in individuals with type 2 diabetes: one-year results of the Look AHEAD trial. Diabetes Care. 2007;30(6):1374-1383.
PubMed   |  Link to Article
Pories  WJ, Swanson  MS, MacDonald  KG,  et al.  Who would have thought it? an operation proves to be the most effective therapy for adult-onset diabetes mellitus. Ann Surg. 1995;222(3):339-352.
PubMed   |  Link to Article
O’Brien  PE, Dixon  JB, Laurie  C,  et al.  Treatment of mild to moderate obesity with laparoscopic adjustable gastric banding or an intensive medical program: a randomized trial. Ann Intern Med. 2006;144(9):625-633.
PubMed   |  Link to Article
O’Brien  PE, MacDonald  L, Anderson  M, Brennan  L, Brown  WA.  Long-term outcomes after bariatric surgery: fifteen-year follow-up of adjustable gastric banding and a systematic review of the bariatric surgical literature. Ann Surg. 2013;257(1):87-94.
PubMed   |  Link to Article
Gregg  EW, Chen  H, Wagenknecht  LE,  et al; Look AHEAD Research Group.  Association of an intensive lifestyle intervention with remission of type 2 diabetes. JAMA. 2012;308(23):2489-2496.
PubMed   |  Link to Article

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