Importance Controlling glycemia, blood pressure, and cholesterol is important for patients with diabetes. How best to achieve this goal is unknown.
Objective To compare Roux-en-Y gastric bypass with lifestyle and intensive medical management to achieve control of comorbid risk factors.
Design, Setting, and Participants A 12-month, 2-group unblinded randomized trial at 4 teaching hospitals in the United States and Taiwan involving 120 participants who had a hemoglobin A1c (HbA1c) level of 8.0% or higher, body mass index (BMI) between 30.0 and 39.9, C peptide level of more than 1.0 ng/mL, and type 2 diabetes for at least 6 months. The study began in April 2008.
Interventions Lifestyle-intensive medical management intervention and Roux-en-Y gastric bypass surgery. Medications for hyperglycemia, hypertension, and dyslipidemia were prescribed according to protocol and surgical techniques that were standardized.
Main Outcomes and Measures Composite goal of HbA1c less than 7.0%, low-density lipoprotein cholesterol less than 100 mg/dL, and systolic blood pressure less than 130 mm Hg.
Results All 120 patients received the intensive lifestyle-medical management protocol and 60 were randomly assigned to undergo Roux-en-Y gastric bypass. After 12-months, 28 participants (49%; 95% CI, 36%-63%) in the gastric bypass group and 11 (19%; 95% CI, 10%-32%) in the lifestyle-medical management group achieved the primary end points (odds ratio [OR], 4.8; 95% CI, 1.9-11.7). Participants in the gastric bypass group required 3.0 fewer medications (mean, 1.7 vs 4.8; 95% CI for the difference, 2.3-3.6) and lost 26.1% vs 7.9% of their initial body weigh compared with the lifestyle-medical management group (difference, 17.5%; 95% CI, 14.2%-20.7%). Regression analyses indicated that achieving the composite end point was primarily attributable to weight loss. There were 22 serious adverse events in the gastric bypass group, including 1 cardiovascular event, and 15 in the lifestyle-medical management group. There were 4 perioperative complications and 6 late postoperative complications. The gastric bypass group experienced more nutritional deficiency than the lifestyle-medical management group.
Conclusions and Relevance In mild to moderately obese patients with type 2 diabetes, adding gastric bypass surgery to lifestyle and medical management was associated with a greater likelihood of achieving the composite goal. Potential benefits of adding gastric bypass surgery to the best lifestyle and medical management strategies of diabetes must be weighed against the risk of serious adverse events.
Of the patients with suboptimally controlled type II diabetes and a BMI that ranged from 30.0 through 39.9 who underwent Roux-en-Y gastric bypass surgery, 49% achieved established diabetes management goals compared with 19% of patients in the lifestyle-medical management group. Only about half of the participants achieved the composite treatment goal despite surgery and their simultaneous participation in intensive medical and lifestyle therapy; however, the patients in the gastric bypass group who achieved the composite goal took 66% fewer medications than did those in the lifestyle-medical management group.
To our knowledge, this is the first trial comparing Roux-en-Y gastric bypass surgery with intense lifestyle and medical management to treat type 2 diabetes using composite specified therapeutic goals. The rationale for these end points is that achieving a HbA1c of 7.0% or less protects against vascular complications of type 1 diabetes.17– 18 Decreasing LDL cholesterol and blood pressure reduce the risk of macrovascular events in populations of patients with diabetes.1 Previous randomized trials involving patients with diabetes who underwent gastric bypass reported effects on glycemia, and sometimes on blood pressure and lipids, as individual variables but not as a composite end point. The proportion of participants in both groups who achieved the composite goal was greater than the 10.2% cross-sectional rates reported in the National Health and Nutrition Survey database3 and the 10.1% in the baseline Look AHEAD study population.19 The Look AHEAD intensive lifestyle intervention improved achievement of the composite goal from 10.8% to 23.6% of participants at 1 year,16 similar to the 19% (95% CI, 10%-32%) achieved by those participating in the current lifestyle-medical management group. In our trial, the proportion of patients in both groups who achieved the composite goal was less than we projected in our power analysis. This was because of the smaller than expected improvements in systolic blood pressure and serum LDL cholesterol levels. Between-group differences in the triple end point were consistent with our projections.
Glycemic control results are comparable with the experience of other controlled trials testing bariatric surgery treatment of diabetes. In the current study, the mean (SD) HbA1c at baseline was 9.6% (1.1%), substantially greater than the baseline reported in the Look AHEAD trial,16 the gastric band trial of Dixon et al,6 and the bariatric surgery study by Mingrone et al,7 but similar to the trial by Schauer and colleagues.8 The generally greater mean HbA1c likely reflects our entry criteria requiring an HbA1c higher than 8.0% and is relevant to balancing the risks of poorly controlled diabetes with surgical risks. The glycemic goal of an HbA1c lower than 7.0%, achieved by 75% of those in the gastric bypass group cannot be directly compared with the other randomized trials of bariatric surgery involving patients with diabetes because the current study target was different. The mean (SD) HbA1c in our gastric bypass group was 6.3% (0.9%) at 1 year, comparable with 6.4% for those undergoing Roux-en-Y gastric bypass surgery in the Schauer et al study and 6.3% at 2 years in the Mingrone et al study. The lifestyle-medical management group improved its mean HbA1c to 7.8% (1.5%), similar to the 7.2% achieved in the Look AHEAD intense treatment group and the medical treatment groups of the other 3 studies.6– 8,16 Overall, both of the treatment groups in the current study were congruent with our prior hypotheses on glycemic control.
The gastric bypass procedure did not significantly improve LDL cholesterol or blood pressure outcomes with more than 70% of both groups having achieved these goals. The mean (SD) 1-year LDL cholesterol concentration of 89 mg/dL (31 mg/dL) among those in the lifestyle-medical management group was lower than among patients who had participated in the Look AHEAD intense treatment group and the Mingrone et al study medical group. The mean (SD) LDL of 83 mg/dL (25 mg/dL) among patients in the gastric bypass group was similar to what was reported by Mingrone et al. The 84% rates in the gastric bypass and the 79% rates in lifestyle-medical management groups of achieving the blood pressure goal approximate what was achieved in the Look AHEAD and other diabetes-focused bariatric surgery studies.6– 8,16
Compared with previous randomized surgical studies, we pursued optimal medical management including the use of weight-lowering medications. In addition to lifestyle modification, sibutramine (until removed from the market) and orlistat were used to facilitate weight loss. Glucagon-like peptide-1 analog mimetics, known to produce sustained weight loss in this population, were used early in the diabetes treatment algorithm. Weight loss in the lifestyle-medical management group averaged 7.9% at 1 year compared with 5.4% in Schauer et al,6 4.7% at 2 years in Mingrone et al,7and 1.4% at 2 years in Dixon et al.8 Interestingly, all metabolic benefits in the lifestyle-medical management group were realized by 6 months with subsequent decrease in the number meeting composite goal by 12 months. In contrast, treatment benefits continued to increase in the gastric bypass group throughout the year.
The mechanisms responsible for improvement in diabetes and cardiovascular risk factors in this study cannot be determined with certainty. The underlying assumption for the original application of bariatric surgery to treat type 2 diabetes was that greater sustained weight loss would benefit patients. In other studies, weight loss among patients who had gastric band surgery correlated with improvement in type 2 diabetes control,6 but other bariatric surgery studies have not found a correlation with weight loss or reduction of BMI.7– 8,20 Regression analyses of the present data indicate that the effect of gastric bypass on achieving the composite end point is attributable to weight loss. This finding does not preclude the possible contribution of changes in the secretion of gastrointestinal hormones to glucose control improvement,21 nor does it take into account between-group differences in medication use.
There was substantial difference in the frequency of serious adverse events between groups. Patients in the gastric bypass group experienced 50% more serious and 55% more nonserious adverse events than did those in the lifestyle-medical management group (Table 4). The 2 most serious complications of gastric bypass were related to problems with gastrointestinal anastomotic leakage. All surgeons performing gastric bypass in this study were experts, thus the occurrence of serious complications must be factored into the design of larger trials of effectiveness for patients with moderate obesity. Although the published incidence of anastomotic leakage after gastric bypass has decreased from as high as 5%22 to 0.8%,10 even in the hands of experienced surgeons serious complications occur at a modest rate. Our leak rate of 3% is likely a function of random effects, but it is important to emphasize the differences in our patient population compared with other reported complications. The reported complication rates reflect data to 1 year and do not reflect internal hernias, the potential for later development of anastomotic ulcers, suicide, substance addiction, and failure of maintenance of weight loss known to occur beyond the first year after gastric bypass. As expected, the number of nutritional deficiencies was greater in the gastric bypass group despite monitoring of laboratory values and prescription of appropriate nutritional supplements.
Proponents have suggested that bariatric surgery for type 2 diabetes be considered earlier and for patients with lower BMIs, based on evidence of lower mortality, decreased rate of malignancy, and better glycemic control durability.23– 24 Others hesitate to recommend widespread use of a costly surgical procedure with inherent risks without support from large, prospective randomized clinical trials. The American Diabetes Association and the National Institutes of Health have been conservative about application of bariatric surgery in treatment algorithms for type 2 diabetes.1Emerging data suggest that recurrence of type 2 diabetes is associated with weight regain after bariatric surgery.25 This study provides an indication of the potential benefit as well as the risks of adding gastric bypass to best lifestyle and medical management for diabetes. However, to determine the long-term cardiovascular effects of bariatric surgery would require a large-scale, multiinstitutional study.
Strengths of this study include randomized design, multiple sites, surgeons, and an intention-to-treat comparison to a group treated with best practices for lifestyle and pharmacological management, as well as examining gastric bypass in combination with existing best medical practices. A high level of participant follow-up was obtained. Weaknesses include relatively small sample size, use of surrogate end points for cardiovascular disease, and evaluation of the primary outcome at 1 year. Because recruitment emphasized participants with suboptimally controlled diabetes among patients whose BMI ranged from 30 to 40 and who were willing to attend the lifestyle program, generalizability of the study to patients with better control of their diabetes, those in other BMI ranges, or those less able to engage with lifestyle change treatment is uncertain.
It is important to comment that recruitment for the study with 4 participating clinical centers proved to be considerably more difficult than anticipated: for every patient enrolled in the study, an additional 21 potential candidates were screened.
The Diabetes Surgery Study examined Roux-en-Y gastric bypass surgery as an adjunct to intensive behavioral intervention and intensive medical management using a composite primary end point of cardiovascular disease risk factors in the treatment of diabetes. This trial provides data about efficacy and safety for the first year of treatment.
The merit of gastric bypass treatment of moderately obese patients with type 2 diabetes depends on whether potential benefits make risks acceptable. Bariatric surgery can result in dramatic improvements in weight loss and diabetes control in moderately obese patients with type 2 diabetes who are not successful with lifestyle changes or medical management. The benefits of applying bariatric surgery must be weighed against the risk of serious adverse events.