Current Atherosclerosis Reports

, 15:366

The Role of Bariatric Surgery in the Treatment of Type 2 Diabetes: Current Evidence and Clinical Guidelines

Authors

    • Division of Endocrinology and MetabolismBeth Israel Medical Center, Albert Einstein College of Medicine
  • Jeffrey I. Mechanick
    • Division of Endocrinology, Diabetes and Bone DiseaseIcahn School of Medicine at Mount Sinai
Lipid and Metabolic Effects of Gastrointestinal Surgery (F Rubino, Section Editor)

DOI: 10.1007/s11883-013-0366-0

Cite this article as:
Via, M.A. & Mechanick, J.I. Curr Atheroscler Rep (2013) 15: 366. doi:10.1007/s11883-013-0366-0
Part of the following topical collections:
  1. Topical Collection on Lipid and Metabolic Effects of Gastrointestinal Surgery

Abstract

The incidence of type 2 diabetes (T2D) continues to rise worldwide. The management of T2D is challenging and therefore amenable to multimodality treatment options. Many published observations of obese individuals with T2D that have undergone bariatric surgery consistently demonstrate remarkable improvement and short-term remission of T2D. Recently published randomized trials confirm these findings and demonstrate significantly improved glycemic control following bariatric procedures, especially Roux-en-Y gastric bypass and laparoscopic sleeve gastrectomy. However, the question of long-term remission remains uncertain. Clinicians may consider the use of bariatric surgery as a treatment option for certain obese patients with T2D who have failed intensive lifestyle intervention and conventional pharmacotherapy.

Keywords

Bariatric surgeryRoux-en-Y gastric bypassLaparoscopic adjustable gastric bandLaparoscopic sleeve gastrectomyType 2 diabetes remission

The worldwide rise in prevalence of type 2 diabetes (T2D) parallels recent trends in obesity. This poses enormous societal costs from direct medical treatment, reduced productivity, and potential reduction in life expectancy [1]. T2D is currently diagnosed in adults and younger individuals with increasing frequency [1]. The progressive nature of T2D, coupled with a responsibility of individuals to modify their lifestyle, present treatment challenges. Over time, the effectiveness of medical treatment regimens for T2D commonly declines [2]. The current T2D treatment strategy is to control blood glucose levels and comprehensively address other metabolic aspects associated with T2D including hypercholesterolemia, hypertension in order reduce associated risks and complications [3, 4].

T2D represents an endpoint of disordered glucose metabolism resulting from genetic, epigenetic, and environmental factors [5]. At-risk individuals can prevent the onset of T2D with weight loss resulting from significant lifestyle change [6], but this strategy alone may not modify rates of cardiovascular complications and other outcomes in patients that have progressed to frank T2D [7].

A surgical approach for the treatment of obesity has been refined over the past 2 decades and yields significantly greater weight reduction in obese individuals than lifestyle modification alone [8]. Medical conditions associated with obesity, including T2D, significantly improve following bariatric surgery [8, 9].

The two most commonly performed bariatric surgical procedures include the Roux-en-Y gastric bypass (RYGB) and the laparoscopic adjustable gastric band (LAGB) [10]. The use of laparoscopic sleeve gastrectomy (LSG) as a bariatric procedure continues to rise in frequency, while the biliopancreatic diversion either with or without duodenal switch (BPD) is performed less often due to high postoperative rates of malabsorption and protein-calorie malnutrition [10, 11]. Generally, in comparison to the conventional BPD procedure, the BPD with duodenal switch has lower rates of dumping syndrome due to preservation of the pylorus, which is anastamosed to the distal ileum [12].

These bariatric surgical procedures mechanistically induce weight loss through restriction of stomach capacity (RYGB, LAGB, LSG, BPD), reduction of intestinal absorptive capacity (RYGB, BPD) and heightened activation of energy hormone signaling pathways that yield improvements in metabolism (RYGB, LSG, BPD). As a consequence of surgically induced changes in energy physiology, T2D improves and reportedly resolves in many individuals that undergo bariatric surgery [13•]. This article reviews the utility of bariatric surgical procedures for the treatment of T2D.

Clinical Evidence

RYGB

One of the earliest published clinical studies linking resolution of T2D and bariatric surgery is an observational trial published nearly two decades ago [14]. Within a cohort of 608 consecutive patients that underwent RYGB surgery at a single center, complete follow-up data was available for 146 subjects that had T2D and another 152 subjects that had impaired glucose tolerance (IGT). After a median follow up of 5 years, 121 (89 %) of those with T2D and 150 (99 %) of those with IGT maintained euglycemia. The high rate of success for treatment of T2D in this trial was surprising, considering the difficulty to achieve long term control of T2D with conventional medical therapy.

Subsequently, a series of observational trials and meta-analyses have been published that demonstrate consistent improvement of T2D following RYGB [1519]. Criteria for resolution generally include cessation of diabetic medications in the setting of normalized blood glucose and glycated hemoglobin (A1c) levels. In many of the published trials, follow up is approximately 2 years or less, with only a subset of patients observed for longer periods after surgery. A pooled analysis of 621 trials published between 1990 and 2006 demonstrates that in patients with greater than 2 years of follow up after RYGB, 71 % meet criteria for remission of T2D (Table 1) [15]. A slightly greater remission rate of 82 % was noted in trials that had follow up for less than 2 years, suggesting that this rate may decline over time.
Table 1

Remission of T2D after surgery >2 years follow up [15, 26]

 

Remission of T2D

Only in clinical trials

LAGB

58 %

RYGB

71 %

LSG

50–80 %a

BPD

96 %

aThe longest follow up data for LSG is 18 months

In one observational trial in which a combined group of patients that underwent either RYBG, LAGB or vertical gastroplasty procedures, the prevalence of T2D increased from a nadir of 1 % at 2 years postoperatively to 7 % at 10 years postoperatively, again demonstrating diminishing rates of remission over time [9].

Another retrospective trial of diabetic patient undergoing RYGB at a single institution showed that although all subjects had initial improvement in T2D following RYGB, 10 of 42 patients had recurrence or worsening of T2D after an average of 5 years of follow up [20]. Significant weight regain was noted in the group in which T2D worsened, while those that had continued improvement or remission of T2D were able to maintain their initial weight loss.

In an observational trial of 32 severely obese (body mass index >40 kg/m2) subjects with T2D, 75 g oral glucose tolerance testing was performed at baseline, 45 days, and 1 year following RYGB [21]. An additional 11 severely obese subjects without T2D that underwent RYGB served as controls. Over the 1-year course of the trial, all patients lost weight and showed improvement in insulin sensitivity and in β-cell function. The patients with T2D showed significant improvement in glycemic control. However, even though there was improvement in oral glucose tolerance at 1 year following surgery, patients with T2D prior to the start of the study continued to have elevated blood glucose levels at 2 hours following OGTT. These findings suggest that while RYGB may achieve remission of T2D, these patients continue to exhibit signs of insulin resistance and may remain at risk for the re-development of T2D.

LAGB

LAGB surgery may also induce remission of T2D, though at a lower rate than RYGB. Moreover, the improvement in T2D follows weight loss in patients that undergo LAGB in contrast to RYGB, LSG and BPD procedures, in which postoperative improvement in T2D often precedes surgically induced weight loss [22].

Several comparison trials demonstrated consistently greater rates of improvement of T2D following RYGB compared to LAGB [9, 23]. Still, glycemic control following LAGB is superior to conventional medical therapy after 2 years of follow up [24]. Pooled analysis of trials with greater than 2 years of follow-up demonstrated remission of T2D in 58 % of patients after LAGB [15].

LSG

As with RYGB surgery, results from trials of LSG surgery in patients with T2D also show significant improvement in the immediate postoperative phase [2529]. In observational cohorts, reported remission rates of T2D range from 50–80 % at 12–18 months of follow up [2628]. In head-to-head comparison trials, similar improvements in T2D and oral glucose tolerance testing are noted at 1 year following either RYGB or LSG procedures [25, 29, 30]. Longer-term outcome data with regard to T2D are not yet available following LSG.

Randomized Clinical Trials

The above studies are generally uncontrolled or they use either matched or historic controls as comparators. In recent years, several randomized comparison trials studying the effectiveness of bariatric surgery in T2D have been conducted. Mingrone et al. performed a trial in which obese diabetic adults were randomized to intensive medical therapy, RYGB, or conventional BPD [31•]. All subjects had T2D for greater than 5 years with baseline A1c levels greater than 7 %. After 2 years of follow up, remission of T2D—defined by fasting blood glucose less than 100 mg/dL and A1c less than 6.5 % without any glucose-lowering medication for 1 year—was observed in 15 of 20 subjects and 19 of 20 subjects randomized to RYGB and BPD, respectively. As expected, none of the medically treated subjects achieved remission. Significant improvements in lipid profile, A1c, and fasting glucose were noted in the surgical groups. An obvious limitation of the study is the relatively short duration of follow up.

A second randomized clinical trial studied 150 obese diabetic adults (A1c >7 %) given either intensive medical therapy, RYGB, or LSG procedures and followed for 1 year [32•]. The primary endpoint, improvement of A1c to less than 6 % was achieved in 12 % of the intensive medical therapy group, compared to 42 % and 37 % of the RYGB and SG groups, respectively. As with the previous study, patients with T2D that undergo bariatric surgery demonstrated superior glycemic control to conventional therapy after relatively short follow up.

A third recently published randomized trial compared RYGB and intensive medical therapy in 120 enrolled diabetic subjects [33•]. The primary endpoint was control of T2D: A1c less than 7 %, low density lipoprotein cholesterol less than 100 mg/d, and systolic blood pressure less than 130 mmHg. The use of medications to achieve these goals was allowed in the RYGB group. At 1 year follow up, 49 % of the RYGB group achieved the triple endpoint compared to 19 % of the intensive medication therapy group.

Dixon et al. report the findings of a randomized trial in which 60 obese diabetics were randomized to conventional medical therapy or LAGB surgery [24]. The primary endpoint was remission of T2D, defined as fasting blood glucose less than 126 mg/dL and A1c less than 6.2 % without the use of glucose lowering medication. At 2 years of follow up remission was achieved in 73 % of the LAGB group compared to only 13 % of the conventional treatment group.

All four of these randomized studies have similar findings that include substantial improvement of T2D over the short term, consistent with previous uncontrolled observations [15, 19]. The results highlight the promise of bariatric surgery to considerably improve the health of patients with T2D.

Pathophysiology

T2D generally occurs in individuals with longstanding insulin resistance syndrome, systemic inflammation, reduced incretin hormone function, impaired pancreatic β-cell function, and altered central control of glucose homeostasis [5]. These factors are associated with obesity—specifically, with a redistribution of adipose tissue in visceral organs. Weight loss can reverse some of these factors and improve glucose homeostasis, however the question of cure or complete reversibility in patients with T2D remains largely unanswered [34].

Aside from weight loss, significant changes in energy regulatory hormone signaling occur following bariatric surgery, which contribute to the rapid improvement of T2D [35]. Following RYGB and BPD, postprandial levels of incretin hormones including GLP-1, rise substantially [36, 37]. Circulating levels of GLP-1 as well as the appetite regulatory hormone PYY, which is also released by the L-cells of the distal ileum increase following RYGB and BPD procedures. The insulin sensitizing and β-cell stimulatory effects of this set of hormones has led some authors to postulate rising incretin activity as the main factor in remission of T2D following RYGB and BPD [23, 3537].

Pournaras et al. [23] compared patients with T2D treated with either RYGB or LAGB in a non-randomized trial. In the RYGB group with T2D, postprandial levels of GLP-1 nearly doubled following bariatric surgery, as early as postoperative day 2. The homeostasis model of insulin resistance (HOMA-IR) also demonstrated rapid improvement following RYGB, corresponding to rise in GLP-1. At 1 year of follow up resolution of T2D was observed in 72 % of RYGB patients and 17 % of LAGB patients. The correlation of rise in GLP-1, reduction in HOMA-IR and resolution of T2D supports the incretin-based model of T2D resolution.

The importance of GLP-1 in postprandial insulin production following RYGB is illustrated further in a comparison trial in which subjects without T2D that either had undergone RYGB or nonsurgical controls were studied for insulin response after several test meals [38]. As with previous studies, subjects with T2D undergoing RYGB demonstrated a larger postprandial insulin response, consistent with an improvement of β-cell function after surgery. Before a second test meal, both groups received exendin (9–39), a GLP-1 receptor antagonist. Postprandial insulin levels declined in both groups, but to a greater extent in the RYGB group, demonstrating the association of GLP-1 activity and improved β-cell function after RYGB surgery.

A recently published clinical trial evaluated the incretin response of diabetic RYGB patients 5 years after surgery. Subjects were divided into three groups: those that sustained a remission of T2D, those that had relapse of T2D, and those that never achieved remission of T2D. Following a test meal, similar levels of GLP-1 were noted in all three groups, suggesting that perhaps the incretin hormones are not the only driver for remission of T2D [39].

In this trial, the group of subjects with remission of T2D showed a higher postprandial insulin response, reduced insulin resistance and higher glucose disposal than the other two groups. Intermediate levels of postprandial insulin secretion was noted in the group of subjects with initial improvement in T2D but subsequently relapsed. The third group, which never achieved remission of T2D after RYGB, had the lowest levels of postprandial insulin. These findings indicate that pancreatic β-cell function may be an important driver of long term remission of T2D following RYGB independent of incretin function [39].

A separate mechanism of improved glycemic control following malabsorptive bariatric procedures may involve circulating bile salts. Approximately 95 % of the bile salts secreted during digestion are absorbed in the distal ileum and recycled via the enteral–portal circulation [40]. A portion of the absorbed bile salts remains in systemic circulation and regulates metabolic pathways through the activation of specific bile salt receptors, including the farsenoid X receptor, which modulates lipid and glucose homeostasis [41]. For poorly understood reasons, patients with T2D have lower circulating levels of bile acids [42]. Following RYGB, LSG, and BPD procedures, circulating bile salt concentrations increase, possibly contributing to the reduction in insulin resistance after these surgeries [4345].

Following LSG, circulating levels of the orexigenic hormone ghrelin significantly decline. This may be an important effect of this surgery that leads to weight loss [46]. Ghrelin is released mainly from the P/D1 cells of the stomach and stimulates appetite centrally, within the arcuate nucleus of the hypothalamus [35]. In addition to appetite stimulation, ghrelin functions to induce hepatic insulin resistance, suppress the release of adiponectin, an insulin-sensitizing hormone, and inhibit β-cell insulin release [47]. These effects of ghrelin on major pathways in the development of T2D has led to the hypothesis that ghrelin is the main mechanism behind the rapid improvement of T2D following LSG surgery [48, 49].

Predictors of Remission

Patient factors that contribute to the successful remission of T2D following bariatric surgery include shorter duration of T2D, lower fasting blood glucose and A1c levels preoperatively, younger age at time of surgery, and higher BMI [18, 5052]. The preoperative use of insulin or the use of high amounts of oral hypoglycemic agents reduce the chance of remission postoperatively [18, 51]. Female patients also have lower rates of remission of T2D [18, 52]. Interestingly, the amount of weight loss following surgery has only a small association with remission of T2D [18].

Many of the above factors are associated with residual β-cell function prior to surgery. Indeed, preoperative fasting C-peptide levels correlate strongly with remission of T2D following bariatric surgery [50].

Risks of Surgery

Since the designation of surgical centers of excellence and the utilization of laparoscopic technique, immediate surgical risks to the patient remain small [22, 53]. Mortality of bariatric surgery is reported to be 0.25–0.5 % [54]. Surgical morbidity is relatively low for bariatric procedures. The need for hospital readmission in approximately 6-9 % for RYGB, 2 % for LAGB, and 5 % for LSG and the need for reoperation is 5 % for RYGB, 1 % for LAGB, and 2.5 % for LSG [11].

Long-term metabolic risks (Table 2) of bariatric surgical procedures should be addressed with regular follow up. Patients that undergo malabsorptive procedures including RYGB, LSG and BPD are at risk for micronutrient deficiencies, especially vitamins D, B1, B6, and B12, as well as folate and iron [55]. High rates of lipid soluble vitamin deficiencies are present following BPD [56]. Metabolic bone disease and secondary hyperparathyroidism may develop due to reduced calcium absorption that generally occurs after all bariatric procedures, including LAGB [57]. Regular screening and supplementation can prevent and treat these potential deficiencies [58].
Table 2

Long-term risks following surgery

LAGB

Calcium malabsorption

RYGB

Calcium malabsorption

Micronutrient deficiencies

Protein-calorie malnutrition

Nephrolithiasis

Alcoholism

LSG

Calcium malabsorption

Micronutrient deficiencies

BPD

Calcium malabsorption

Micronutrient deficiencies

Lipid-soluble vitamin deficiencies

High risk of protein-calorie malnutrition

Severe protein calorie malnutrition may develop in approximately 5 % of RYGB and 22–30 % of BPD patients necessitating nutritional support with tube feeds, parenteral nutrition, or surgical revision [59].

Other long term risks of bariatric procedures include a higher rate of alcohol consumption related disorders thought to be due to enhanced absorption of ethyl alcohol after RYGB [60]. An increased rate of oxalate nephrolithiasis is also noted following RYGB [61].

Current Guidelines

In light of the mounting clinical evidence that demonstrates a clear benefit in the use of bariatric surgery for T2D, several position statements and clinical practice guidelines have been published on this topic. These include recommendations by the Diabetes Surgery Summit of 2007 (DSS 2007), the International Diabetes Federation (IDF), the American Diabetes Association (ADA) and the American Association of Clinical Endocrinologists in conjunction with the American Society for Metabolic and Bariatric Surgery and The Obesity Society (AACE/ASMBS/TOS) [58, 6264].

Among these diverse organizations, there is general agreement regarding the potential use of bariatric surgery as a treatment for T2D in obese individuals with body mass index of 35 kg/m2 or greater (Table 3). The IDF and AACE/ASBMS/TOS go a step further to suggest that diabetic individuals with BMI between 30 and 35 kg/m2 may be considered for bariatric surgery in certain circumstances under the direction of a diabetic specialist. All of these organizations recognize the careful selection of obese diabetic patients that stand to benefit the most from bariatric surgical procedures with clear discussion of the risks and surgical options.
Table 3

Current recommendations for bariatric surgery in published guidelines given by individual body mass index (bmi)

 

DSS 2007

ADA 2013

IDF 2011

AACE/ASMBS/TOS 2013

BMI >40 and T2D

YES

YES

YES

YES

BMI 35–40 and T2D

YES

YES

YES

YES

BMI 30–35 and T2D

Conditionala

Insufficient data to support

Conditionala

Conditionala

BMI < 30 and T2D

Only in clinical trials

Only in clinical trials

Only in clinical trials

Only in clinical trials

aConditional: bariatric surgery may be considered on individual basis in patients with poorly controlled T2D who do not respond to appropriate medical therapy and have other cardiovascular risk factors that may improve from surgical intervention, such as dyslipidemia or hypertension

Conclusion

Recently published studies continue to demonstrate the utility of bariatric surgery in the treatment of T2D. The consistency of these studies is striking. Although the mechanisms are not fully understood, many patients with T2D stand to benefit from improvement in glucose metabolism that typically follows bariatric surgery. Of the published studies, longer periods of postoperative observation are needed to substantiate claims of a durable resolution of T2D, especially given the findings of continued impairment of β-cell function and glucose tolerance 1 year after bariatric surgery [21].

As with any medical recommendation, the risks of the surgery must be weighed against the potential benefits and treatment options. Bariatric surgery is an excellent option for obese patients that are unable to meet their goals for diabetic control. Though, an improved understanding of the biochemical mechanisms underlying observed T2D resolution may ultimately lead to novel pharmacologic targets in the treatment of this disease.

Patients that may benefit the most include those with greater BMI (>35 kg/m2), younger age, and shorter duration of T2D. Current clinical practice guidelines do not support the use of bariatric surgery solely for the treatment of T2D; rather, these procedures should be considered in the context of severe obesity and to address other comorbid conditions associated with obesity, such as obstructive sleep apnea, hypertension, and hypercholesterolemia [58, 6264]. Moreover, studies in non-obese diabetic patients may identify a broader range of patients for these procedures.

Conflict of Interest

Jeffrey I. Mechanick and Michael A. Via declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Copyright information

© Springer Science+Business Media New York 2013