Safety, Effectiveness, and Cost Effectiveness of Metabolic Surgery in the Treatment of Type 2 Diabetes Mellitus

Remission of type 2 diabetes mellitus with metabolic surgery is a field of active investigation and development. The extraordinary results obtained in diabetic patients with BMI > 35 kg/m2 have led investigators to query if similar results could be achieved in patients with BMI < 35 kg/m2. A few studies have been recently conducted to evaluate the safety, effectiveness, and cost effectiveness of bariatric surgery in diabetic patients with BMI BMI < 35 kg/m2. However, stronger evidence would be required before insurance coverage is extended for bariatric surgery to all type 2 diabetic patients, in addition to those with BMI ≥ 35 kg/m2 for whom eligibility is already established. In addition, the hormonal and metabolic mechanisms of diabetes remission after gastrointestinal surgery are yet to be determined. This paper will review the evidence about safety, effectiveness, and cost effectiveness of bariatric surgery in type 2 diabetes mellitus remission and the potential socioeconomic impact of offering bariatric surgery to diabetic patients with BMI BMI < 35 kg/m2.


Introduction
Type 2 Diabetes Mellitus (T2DM) is a major cause of morbidity and mortality around the world. The prevalence of T2DM in the US was 8% in 2008 [1]. According to the American Diabetes Association, the total estimated cost of diabetes in 2007 was $174 billion [2]. The traditional goal for medical treatment of T2DM has been to delay the appearance of end-organ complications. In contrast, surgical treatment for T2DM is currently being evaluated as a potential "cure" for T2DM. Several studies have demonstrated that obese diabetic patients who undergo bariatric surgery experience complete T2DM remission, maintaining euglycemia without medications for more than 10 years [3]. Additionally, following some gastrointestinal (GI) procedures, T2DM resolves within days to weeks, long before the occurrence of major weight loss [4]. Bariatric surgery as a modality to treat obesity in the US is reserved for patients with BMI ≥ 35 kg/m 2 and the presence of serious comorbidities (T2DM, moderate or severe obstructive sleep apnea (OSA), pseudotumor cerebri, and severe steatohepatitis), or BMI > 40 kg/m 2 and minor comorbidities (mild OSA, hypertension (HTN), insulin resistance, glucose intolerance, dyslipidemia, impaired quality of life, or activities of daily living) [5]. However, some recent publications also suggest that conventional bariatric surgery results in remission of T2DM in patients with BMI < 35 kg/m 2 [6,7]. In addition, novel antidiabetic GI procedures have been developed by groups outside the US to treat T2DM patients with BMI < 35 kg/m 2 [8,9]. In view of the growing enthusiasm for surgical interventions to treat T2DM, the 1st diabetes surgery summit (DSS) was held in Rome in March 2007 to develop guidelines for the use of GI surgery to treat T2DM. The DSS position statement included that a surgical approach may be appropriate as a nonprimary alternative to treat inadequately controlled T2DM in suitable surgical candidates with BMI 30-35 kg/m 2 and that novel GI surgical techniques (duodenal-jejunal bypass, ileal interposition, sleeve gastrectomy, and endoluminal sleeves) should be used only in the context of IRB-approved trials [10]. The growing interest in offering surgical therapy to T2DM patients with BMI < 35 kg/m 2 within the world surgical community has not yet spread to the US surgical community. A major limitation for the development of the field of metabolic surgery in the US is the absence of insurance coverage for bariatric procedures in T2DM patients with BMI < 35 kg/m 2 . Several studies have demonstrated that adjustable gastric banding (AGB) and Roux-en-Y gastric bypass (RYGB) are cost effective at 5year followup in comparison to conventional treatment (CT) for T2DM in patients with BMI ≥ 35 kg/m 2 [11][12][13][14]. One study has also shown cost effectiveness of bariatric surgery in patients with T2DM and BMI ≥ 30 and <40 kg/m 2 [15]. The purpose of this paper is to review the existing literature about safety, effectiveness, and cost effectiveness of bariatric surgery in T2DM remission and the potential socioeconomic impact of offering bariatric surgery to diabetic patients with BMI < 35 kg/m 2 .

Morbidity and Mortality of Bariatric Surgery
Trends in mortality in bariatric surgery were reported by Buchwald et al. [16] in 2007. This systematic review and meta-analysis included 360 studies for a total of 85,000 patients with a mean BMI of 47.4 kg/m 2 . In contrast to the popular belief that bariatric surgery is a drastic measure to treat obesity because of its associated risks, this study demonstrates that mortality from laparoscopic RYGB (LRYGB) is comparable to mortality from laparoscopic cholecystectomy, which is considered to be a safe operation by the general public. Mortality rates from LRYGB in this study were 0.16% within 30 days and 0.09% from 30 days to 2 years. Similarly, a 30-day postoperative mortality of 0.3% after RYGB or laparoscopic AGB (LAGB) was reported by the Longitudinal Assessment of Bariatric Surgery (LABS) Consortium, a 10center prospective trial involving 4776 patients undergoing bariatric surgery. This study also reported a composite end point of death or serious complication of 4.1% within 30 days after surgery [17]. Gastric bypass surgery has been associated with decreased long-term total mortality in severely obese patients, as demonstrated by Adams et al. [18] in 2007. This retrospective cohort study compared the long-term mortality of 7925 patients who underwent gastric bypass surgery matched for age, sex, and BMI to severely obese control subjects who applied for driver's licenses, using the National Death Index. During a mean followup of 7.1 years, adjusted long-term mortality from any cause in the surgery group decreased by 40%, as compared with that in the control group (37.6 versus 57.1 deaths per 10,000 person-years, P < .001); cause-specific mortality in the surgery group decreased by 56% for coronary artery disease (2.6 versus 5.9 per 10,000 person-years, P = .006), by 92% for diabetes (0.4 versus 3.4 per 10,000 person-years, P = .005) and by 60% for cancer (5.5 versus 13.3 per 10,000 person-years, P < .001) However, rates of death not caused by disease, such as accidents and suicide, were 58% higher in the surgery group than in the control group (11.1 versus 6.4 per 10,000 person-years, P = .04). Sjöström et al. [19] also reported a survival benefit of bariatric surgery over conventional treatment for obesity. This prospective controlled study compared 2010 patients who underwent bariatric surgery (AGB: 376; RYGB: 265; vertical banded gastroplasty: 1369) to 2037 patients who received conventional treatment (matched control group). The unadjusted overall hazard ratio was 0.76 in the surgery group (P = .04), as compared with the control group, and the hazard ratio adjusted for sex, age, and risk factors was 0.71 (P = .01). The most common causes of death were myocardial infarction and cancer. Perioperative complications were experienced by 13% of patients, which included bleeding (0.9%), thromboembolic events (0.8%), wound complications (1.8%), abdominal infection (2.1%), pulmonary symptoms (6.2%), and miscellaneous (4.8%). Postoperative complications requiring reoperation were experienced by 2.2%.  [21] confirmed that bariatric surgery was highly effective in obtaining weight reduction in morbidly obese patients of up to 60% of the excess weight, along with resolution of preoperative diabetes in more than 75% of the cases.  [12] replicated this model in Austria, Italy, and Spain. In Austria  A similar study was conducted in the US by Ikramuddin et al. [13]. The analysis showed that compared with medical management, RYGB surgery for obese diabetic patients has a cost effectiveness ratio of $22,000 per QALY gained ( Table 2). The authors concluded that, in the US, RYGB surgery is cost-effective from a payer's perspective. From a third-party payer's perspective, Crémieux et al. [14] evaluated the return on investment for bariatric surgery in the United States. Morbidly obese patients aged 18 years or older were identified in an employer claims database of more than 5 million beneficiaries. Each of the 3651 patients who underwent bariatric surgery during this period was matched to a control subject who was morbidly obese and never underwent bariatric surgery. Total healthcare costs for bariatric surgery patients and their controls were recorded for 6 months before surgery through the end of their continuous enrollment. The study suggested that the total cost of laparoscopic bariatric surgery is fully recovered after 25 months. These returns on investment result from reductions in prescription drug costs, physician visit costs, and hospital costs (including emergency department visits and inpatient and outpatient visits). The reduced costs are associated with multiple major diagnosis categories, including diabetes mellitus, coronary artery disease, hypertension, and sleep apnea. Similarly, a review of 15 years of experience in a French university hospital reported that bariatric surgery is cost effective after 3.5 years [22].  [25] also demonstrated that obese patients with a BMI of <35 kg/m 2 and severe comorbidities can benefit from LRYGB. A total of 37 patients (mean BMI 32.5 kg/m 2 ) who had tried to lose weight with no success and had been undergoing clinical treatment with no resolution or improvement of their life-threatening comorbidities (T2DM, HTN, lipid disorder, GERD, and sleep apnea) underwent LRYGB. After extensive explanation and documentation, the Brazilian insurance companies approved the procedure in 3 cases, and international (nonAmerican) insurance companies approved the procedure in 4 cases. The followup range was 6-48 months. The mean excess weight loss was 81%. Thirty-six patients had total remission of their comorbidities. One patient still had mild hypertension, but with a reduction in the number of antihypertensive drugs used. No surgery-related complications were reported.

Effectiveness of Bariatric Surgery in T2DM
Remission of T2DM in patients with BMI < 35 kg/m 2 after LRYGB was also published by Lee et al. [26]. This was a retrospective study of prospectively collected data that included 201 patients with impaired fasting glucose or T2DM. Among the 201 patients, 44 (21.9%) had BMI < 35 kg/m 2 and 157 (78.1%) had BMI ≥ 35 kg/m 2 . One year after surgery, fasting plasma glucose returned to normal in 89.5% of BMI < 35 kg/m 2 T2DM and 98.5% of BMI ≥ 35 kg/m 2 patients (P = .087). The treatment goal of T2DM (HbA 1C < 7.0%, LDL < 150 mg/dl, and triglyceride <150 mg/dl) was met in 76.5% of BMI < 35 kg/m 2 and 92.4% of BMI ≥ 35 kg/m 2 patients (P = .059). Major perioperative complications occurred in 4.5% of patients with BMI < 35 kg/m 2 and no perioperative mortality. The authors concluded that despite a slightly lower response rate of T2DM treatment, patients with include BMI < 35 kg/m 2 still had an acceptable T2DM resolution, and this treatment option can be offered to this group of patients. A recent study demonstrated T2DM remission and reduced cardiovascular risk after gastric bypass in Asian Indians with BMI < 35 kg/m 2 . A total of 15 consecutive patients with T2DM and a BMI of 22-35 kg/m 2 underwent RYGB. The data were prospectively collected before surgery and at 1, 3, 6, and 9 months postoperatively. The BMI decreased postoperatively by 20%, from 28.9 ± 4.0 kg/m 2 to 23.0 ± 3.6 kg/m 2 (P < .001). All antidiabetic medications were discontinued by 1 month after surgery in 80% of the subjects. At 3 months and thereafter, 100% were euglycemic and no longer requiring diabetes medication. The fasting blood glucose level decreased from 233 ± 87 mg/dL to 89 ± 12 mg/dL (P < .001), and the HbA 1C decreased from 10.1% ± 2.0% to 6.1% ± 0.6% (P < .001). Their waist circumference, presence of dyslipidemia, and hypertension improved significantly. The predicted 10-year cardiovascular disease risk (calculated using the United Kingdom Prospective Diabetes Study equations) decreased substantially for fatal and nonfatal coronary heart disease and stroke. No mortality, major surgical morbidity, or excessive weight loss occurred [27].

Cost Effectiveness of Bariatric Surgery in
Patients with T2DM and BMI < 35 kg/m 2 Cost effectiveness of surgically induced weight loss for the management of T2DM has also been demonstrated for patients with BMI >30 and <40 kg/m 2 . Keating et al. [15] published the within-trial cost efficacy of surgical therapy relative to CT for achieving remission of recently diagnosed T2DM in class I and II obese patients. The efficacy results were derived from a 2-year randomized controlled trial conducted by Dixon et al. [24]. Trial intervention costs included LAGB surgery, mitigation of surgical complications, outpatient medical consultation, pathology, medical investigations, weight loss assisted therapies, and medication. During the first 6 months of the trial, mean intervention costs per patient were approximately sevenfold greater for surgical patients than for CT patients. The difference between costs in each intervention group decreased with each subsequent 6-month period until the last 6 months of the trial, when intervention costs were equivalent in both groups. The ICER for surgical therapy (relative to CT, 16,600 Australian dollars) was lower than the comparable ICER for CT (relative to no intervention, 25,500 Australian dollars). Modeling cost effectiveness over a longer time period, Keating et al. [28] concluded that after 10 years the return on investment of surgical therapy is fully recovered through savings in health care costs to treat T2DM in the surgical group.

Discussion
A significant existing body of literature has proven that bariatric surgery is safe, effective, and cost effective as a treatment for T2DM in patients with BMI ≥ 35 kg/m 2 . A rapidly growing body of literature has demonstrated that bariatric surgery is also safe, effective and cost-effective as a treatment for T2DM in patients with BMI > 30 and <35 kg/m 2 . However, most data collection on weight loss surgery has relied on administrative data sets, singleinstitution studies, and other sources that are not weight loss surgery specific. The results from weight loss surgery specific databases, which have been implemented since 2004 (i.e., NIH-sponsored longitudinal assessment of bariatric surgery consortium, the ACS-Bariatric Surgery Center Network, and the ASMBS/SRC Centers of Excellence Program), could identify areas for improvement and optimize outcomes and patient care [29]. There is still controversy in the US health system about extending coverage for bariatric surgery to all obese patients with diabetes, in addition to those with BMI ≥ 35 kg/m 2 for whom eligibility is already established. This approach would result in immediate costs of several hundred billion dollars. There is concern that such expenditures would redirect scarce resources away from prevention efforts [30]. Although the studies quoted above refute this argument, opponents to expanding metabolic surgery argue that at least one recent study suggests that maintenance of weight loss over time may Journal of Obesity 5 be no better in surgical patients than in those who lost weight without surgery [31]. Weight regain may be associated with deceleration in the rate of recovery from comorbidities after bariatric surgery [20].
It is important to promote funding for projects that study the safety, effectiveness, and cost effectiveness of metabolic surgery in T2DM patients. The Surgical Therapy and Medications Potentially Eradicate Diabetes Efficiently (STAMPEDE) trial was designed to evaluate the efficacy of two bariatric surgery procedures (laparoscopic sleeve gastrectomy and RYGB) in comparison to advanced medical therapy in patients with T2DM with modest obesity with BMI of 27-42 kg/m 2 . This single site, prospective, randomized controlled trial will enroll 150 subjects who will be followed. The primary end point will be the rate of biochemical resolution of T2DM at 1 year as measured by HbA1c < 6%. The safety and adverse event rates will also be compared between the three arms of the study [32]. The creation and development of similar parallel trials would help to validate the results derived from STAMPEDE.
It is also important to promote funding for projects that investigate the hormonal and metabolic mechanisms of diabetes remission after gastrointestinal surgery. It appears that other mechanisms besides weight loss contribute to the higher rates of T2DM remission after RYGB in comparison with AGB [33]. Potential mechanisms underlying the direct antidiabetic impact of RYGB include enhanced nutrient stimulation of lower intestinal hormones (e.g., glucagonlike peptide-1), altered physiology from excluding ingested nutrients from the upper intestine, compromised ghrelin secretion, modulations of intestinal nutrient sensing, and regulation of insulin sensitivity, and other changes yet to be fully characterized [34]. Elucidation of the antidiabetic mechanisms of RYGB may help develop more potent and efficacious drugs in the future treatment of T2DM.
Although cost effectiveness of bariatric surgery in patients with T2DM and BMI < 35 kg/m 2 have been reported in at least 2 well-conducted studies, more good quality evidence is required before extending coverage for all T2DM patients. It is unclear if all T2DM would be potential candidates for metabolic surgery or if only patients that meet certain criteria (e.g., duration of T2DM, BMI, established cardiovascular disease, insulin dependency, Cpeptide levels, etc.) would benefit while others would not. The socioeconomic impact of obtaining T2DM remission via metabolic surgery is yet to be determined and should be an area of active investigation.