Metabolic surgery has become the pathway for acceptance of surgical procedures for dealing with diseases traditionally considered as exclusively medically managed. If we look back in history, the classical example of metabolic surgery has been the Program on the Surgical Control of the Hyperlipidemias (POSCH),1,2 where it was observed that partial ileal bypass was an intervention capable of producing a marked reduction of low-density lipoprotein cholesterol (LDL-c), and was consequently associated with a statistically significant decline in cardiovascular events and increase in life expectancy. In this way, the idea that surgery could be regarded as a valid option for the treatment of metabolic diseases turned out to be true. Buchwald and Varco, in 1978, specified the conception of metabolic surgery by defining it as “the operative manipulation of a normal organ or organ system to achieve a biological result for a potential health gain”.3,4

Another example of metabolic surgery with current clinical relevance is bariatric surgery. This was initially conceived with the aim of achieving sustained and significant weight loss by using restrictive, malabsortive and mixed techniques. The rise in the number of interventions performed for people with morbid obesity during the 1990s, revealed that not only was this goal achieved, but, in fact, other associated comorbidities, including type 2 diabetes (T2D) were also improved.5 In 1995, the provocative title of Pories et al., “Who would have thought it? An operation proves to be the most effective therapy for adult-onset diabetes mellitus”,6 showed that, indeed, bariatric surgery was able to resolve T2D of the adult, and emphasized that there were mechanisms beyond those merely anatomical inherent to the surgical technique responsible for this effect.

Buchwald et al. published in 2004 a systematic review and metaanalysis7 of more than 22,000 patients who underwent bariatric surgery, and described improvement of diabetes in 86.6% of patients and complete resolution in 78.1%. Moreover, hyperlipemia was improved in 70% of cases, hypertension was resolved or improved in 78.5%, and obstructive sleep apnea was resolved in 85.7% of patients. Definitions of resolution and improvement differed across the studies included in this metaanalysis, but, given the results observed, it became evident that metabolic surgery was not used solely to designate procedures for the treatment of T2D, but also to refer to those interventions that aimed at reducing the impact of other cardio-metabolic aspects.

The impact of bariatric surgery beyond its effect on weight loss entailed a change in the way of thinking of scientific societies. In 2007, the executive boards of the so-called American Society for Bariatric Surgery (ASBS) and International Federation for the Surgery of Obesity agreed to include the term metabolic in their designations, advocating the idea that metabolic surgery truly operated on perfectly normal organs or organ systems to achieve a biological result for a potential health gain: the treatment of metabolic illnesses, and not just excess weight. Thus, these societies have become to be known as the American Society for Metabolic and Bariatric Surgery (ASMBS) and the International Federation for the Surgery of Obesity and Metabolic Disorders. This renovation has also been adopted by the homologous Spanish society, which is now named Sociedad Española de Cirugía de la Obesidad Mórbida y Enfermedades Metabólicas.8

Intensive lifestyle intervention, as reported in the LOOK-AHEAD study,9 achieves only modest T2D remission rates of 11.5% and 7.4% after one and four years of follow-up, respectively. These rates prove that an intensive lifestyle intervention is associated with a greater likelihood of partial remission of T2D in comparison with conventional support and educational management. However, intensive management still achieves results way lower than outcomes described after a surgical approach, where even the lowest rates reported were higher than with medical protocols.10 The opinion that surgical interventions may be an alternative option for chronic and progressive medical issues such as obesity and T2D has gained acceptance and popularity, and superiority has been subsequently described in several studies.10,11 Bariatric surgery has become, in this way, the prototype of metabolic surgery, to such extent, that both terms have often been considered synonymous.

But a recent study by Rubino et al.,12 which aimed at investigating the practical clinical consequences of offering two different surgery programs, identified differences in patients’ profiles depending on the denomination used: bariatric or metabolic. This may lead to considering distinctions between both denominations, based on what the foremost target is, i.e., weight reduction or treatment of metabolic illnesses. Nevertheless, once again, the debate may revive: can both problems be regarded on an individual basis, or should they be viewed as a whole?

This review aims to identify and clarify controversies regarding metabolic surgery for T2D and tries to guide the reader to an unbiased interpretation of published data.

There are several national and international guidelines and consensus statements that address the indications for bariatric surgery in patients with T2D.13–17 They all share basic terms and conditions, such as failure of previous weight-loss attempts, no specific contraindications to surgery and the patient's commitment to long-term follow-up and after care. These guidelines used to be based on specific body mass index (BMI) cut-off levels. However, this requisite has been questioned over the last recent years. Table 1 shows current guidelines established by the International Diabetes Federation (IDF),13,14 the American Diabetes Association (ADA),15 the National Institute for Health and Clinical Excellence (NICE)16 and the International Federation for the Surgery of Obesity and Metabolic Disorders – Asian Pacific Chapter (IFSO-APC).17 Only the IDF and the Obesity Work Group from the Sociedad Española de Endocrinología y Nutrición (SEEN)18 contemplate the possibility of bariatric surgery in cases with BMI<35kg/m2. Nevertheless, in spite of these general guidelines, consensus and position statements regarding the management of hyperglycemia in T2D have not included surgical intervention in their step-by-step algorithms.

Distinction between successful treatment and cure may be difficult when talking about T2D, since diabetes is defined by hyperglycemia, which exists on a continuum, unlike other acute diseases. Cure is defined as restoration to good health, while remission is defined as reduction or disappearance of signs and symptoms of a disease.19 Due to the chronicity of T2D, it seems reasonable and more accurate to use the term remission, which will be the one used throughout this review.

The Cochrane Database System Review20 and Buchwald et al.’s review,21 both published in 2009, demonstrated the effectiveness of bariatric surgery for improvement and resolution of T2D. However, remission rates described across different studies have varied widely. In general, T2D remission has been defined as “the return to normal values of fasting glucose (FG) and glycosylated hemoglobin (HbA1c), in the absence of active pharmacologic treatment”. But cut-off levels used for these parameters have not always been homogeneous, and variations in the time of follow-up considered for evaluation have also occurred. Moreover, disparities amongst patients’ baseline characteristics have contributed to this heterogeneity.

In an attempt to overcome this controversy and establish standardized remission criteria, a consensus group comprised of experts in endocrinology, diabetes education, transplantation, metabolism, bariatric/metabolic surgery and hematology-oncology, proposed specific definitions for diabetes remission (Table 2).19 These new definitions rely on more stringent criteria for establishing glycemic control, and, consequently, remission rates have been communicated to be lower than previously reported in the literature.

For instance, in the review by Buchwald et al.,21 T2D remission was reported in 78% of patients after gastric bypass, but its definition was largely based on clinical reports, rather than in specific biochemical parameters, there were few good quality studies with a high level of evidence, and patients’ preoperative information and follow up of most cohorts was not described in detail. Nonetheless, these outstanding results reaffirmed surgeons’ optimism for the treatment of T2D. A low level of quality and evidence has been a common attribute of well-known studies, whose reports have been mostly based on case-series, with no methodological control.6,22–24 The studies by Sjostrom et al.,25 Dixon et al.,26 Schauer et al.10 and Mingrone et al.,11 on the other hand, have been considered of higher quality, given its controlled design. But remission rates still varied due to differences in criteria used and baseline patients’ features. Overall, data from large, adequately powered, long-term randomized controlled trials in bariatric surgery are still lacking, although a trend for an increasing number has been observed in recent years.27

Pournaras et al.28 and Blackstone et al.29 compared remission rates using different models of remission criteria: those previously reported in literature, versus the ones proposed by Buse et al.,19 and observed a significant reduction in remission rates to around 50%. This may be a more realistic approximation of what can be expected after metabolic surgery, taking also into account existing differences between population's features. Table 3 highlights the main characteristics of the most relevant publications over the last recent years regarding T2D remission after bariatric surgery. Fig. 1 represents an estimate of the range of remission rates that would be obtained by using different criteria for the same population. It can be observed that frequencies vary from around 50%, when using the more stringent criteria, to near 90%, if only an adequate metabolic control is considered, defined by HbA1c levels below 7%. It must be noted, however, that these results are generally referred to the period of maximum weight-loss, that is, the first two years after surgery, and long-term evaluation may reveal lower remission rates.

Figure 1.

T2D remission rates according to different criteria (percentages estimated for the same population).

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Given the difficulty of establishing remission of a disease whose definition is based on a continuous variable, we suggest that, for example, ADA's HbA1c cut-off levels for diagnosis of diabetes53 could perhaps be helpful, more straightforward, and clinically practical for doing so (Table 4). A comparison of this model of criteria with the one proposed by the 2009 consensus group was recently published,54 and no significant differences were found.

However, scientific societies have not yet formally accepted any specific criteria and there has been no definitive positioning regarding this matter, so heterogeneity across subsequent publications persists.

Published reports have described a set of predictors of T2D remission:

• 1.

  Previous duration of diabetes. Duration of diabetes has been taken as an estimate of disease severity. The longer this period, the lower remission rates. It is one of the most frequently identified predictors of remission across numerous reports.35,42,52,54,55 Some have proposed different thresholds, ranging between 5 and 10 years, for which the probability of achieving diabetes remission decreases, and it has been proposed that T2D duration longer than 15 years would imply no remission.

• 2.

  Previous insulin treatment. The use of insulin therapy prior to surgery has been associated to lower rates of remission, in comparison to those patients who were treated with oral agents exclusively: 13.5% vs. 53.8% in Blackstone et al.’s report.29 The explanation lies on the assumption that insulin treatment could also be regarded as an estimation of disease severity, duration of diabetes and worse control, presumably due to deterioration of pancreatic beta-cells.

• 3.

  Weight loss. The complex association between obesity and T2D justifies the fact that percentage of weight loss (%WL) and percentage of excess weight loss (%EWL) influence diabetes remission. Insufficient %WL seems to be one of the main reasons for inadequate T2D control, and this may sometimes be linked to a lack of patient's commitment to long-term follow-up, or even to failure of the surgical technique.56 A %EWL of at least 50% (or 30% of %WL) is required to allow a significant improvement or even remission of T2D.57 Nevertheless, improvement of glycemic control after surgery can be observed as early as in the immediate postoperative period, when a significant weight loss has not yet been achieved,58,59 and, consequently, surgeons have promoted the use of metabolic surgery in patients with only mild obesity, or even with mere overweight.39,44,60,61 Several weight-independent mechanisms are involved in the short and mid-term amelioration of glucose metabolism, but, there are no studies that evaluate their efficacy in the long-term, in the absence of an associated fat reduction. The association between T2D and excess adiposity is complex; in fact, it has been observed that up to 80% of individuals classified as overweight (BMI 25.0–29.9kg/m2) and up to 29% of lean subjects (BMI 20.0–24.9kg/m2) have a body fat percentage that could be judged as within the obesity range, when determined by air displacement plethysmography.62 Excess body fat, especially abdominal visceral fat, may explain the development of metabolic disorders such as T2D and atherogenic dyslipemia in patients with BMI<30kg/m2. This circumstance can be remarked in the particular case of Asian populations, in whom and elevated risk of T2D, hypertension and hyperlipemia has been observed at a relatively low level of BMI. As a result, surgical indications have been deliberated and BMI criteria have been adapted for this specific group of patients, as it was described earlier.17 Revaluation of T2D in patients with lower BMI with other alternative assessment tools deems, therefore, necessary to manage these individuals, for which well-designed randomized trials should be carried out.

• 4.

  Preoperative baseline C-peptide. Baseline C-peptide is a surrogate of pancreatic beta-cell mass and insulin secretion. High levels have been identified in obese patients, and significant reductions have been observed after bariatric procedures. Some reports have proposed high preoperative C-peptide levels (around >3ng/mL) as predictors of remission,42,55,63,64 although there is no established agreement on preoperative cut-off values and its clinical relevance has not been thoroughly analyzed, especially because levels may be influenced by hypoglycemic treatment. Stimulated C-peptide levels and evaluation of incretin effects require further investigation.

• 5.

  Age. Older age has been associated to no remission, presumably due to deterioration of pancreatic beta-cells and T2D progression.55 However, not all studies have found differences in age between remitters and non-remitters. Furthermore, the majority of studies include patients under the age of 60, making the distinction between the effect of age itself and T2D duration confusing.

• 6.

  Sex. Some studies suggest male sex as a predictor of remission, although this has not been consistent across all reports.29 However it is worth remarking the fact that, in general, men tend to lose more weight than women, but T2D remission rates adjusted for gender have not been found to be significantly different.

• 7.

  Inadequate diagnosis of T2D. Late autoimmune diabetes of the adult (LADA), type 1 diabetes and some forms of maturity-onset diabetes of the young (MODY) prove lower rates of resolution after bariatric surgery, apparently due to other concomitant pathogenic factors involved. Inclusion of these patients in bariatric series may, therefore, influence remission reports.

Bariatric surgery offers an effective treatment option for glycemic control in patients with T2D and morbid obesity, and numerous papers have reported profound weight loss and amelioration of all obesity-related comorbidities in patients with BMI>35kg/m2.7,21,25 These encouraging results, together with the identification of weight-independent mechanisms responsible for resolution of diabetes, have prompted consideration of bariatric surgery for less obese individuals.

Recent reports have described that bariatric surgery was also effective for diabetes resolution in cases with BMI<35kg/m2,39 a finding with important clinical relevance, since patients with a BMI between 30 and 35kg/m2 constitute the most numerous class of obese people. In this setting, metabolic surgery purely aims at resolving T2D, not so much obesity. However, as it was previously outlined, individuals with BMI 30–35kg/m2 still have an elevated body fat percentage, with visceral preponderance, making reduction of this adipose tissue a perdurable main priority for the amelioration of metabolic disorders. It is, therefore, important that patients with T2D and only “mild” obesity receive correct information regarding the main objectives and what to expect of the surgical procedure. Moreover, reduction of micro and macrovascular complications, as well as of long-term cardiovascular morbidity and mortality, should also be aimed, not only an improved BMI, but data in literature is still scarce.65–67

Additionally, several questions have been set to debate in this context. Firstly, the appropriate time to recommend surgery in these cases is not well established, and there are no agreements in consensus statements, since there is insufficient evidence-based data from large randomized controlled trials in this range of BMI. Also, deliberation regarding risks and benefits of surgery should be contemplated. Furthermore, previous diabetes status should be taken into account, since patients would obtain benefit from surgery mainly due to weight-independent mechanisms, and if pancreatic reserve is downgraded, effectiveness would be diminished.

Due to the above-mentioned issues, metabolic surgery for patients with T2D and BMI<35kg/m2 is contemplated by the IDF13,14 and the Obesity Work Group from the Sociedad Española de Endocrinología y Nutrición (SEEN),18 for patients with poor glycemic control and associated cardio-metabolic risk factors, in whom other alternative treatment strategies have failed. Additionally, the American Association of Clinical Endocrinologists, The Obesity Society, and the American Society for Metabolic and Bariatric Surgery (AACE/TOS/ASMBS) in their recently updated guidelines,81 consider that patients with BMI of 30–34.9kg/m2 with diabetes or metabolic syndrome may also be offered a bariatric procedure. Nevertheless, they acknowledge that current evidence is limited by the number of subjects studied and lack of long-term data demonstrating net benefit, and they also remark that there is insufficient evidence for recommending bariatric surgical procedures specifically for glycemic control alone, lipid lowering alone, or cardiovascular disease risk reduction alone, independent of BMI criteria. The ADA,15 on the other hand, considers that there is not enough safety and efficacy data to be able to recommend metabolic surgery in this group of patients outside clinical trials and research protocols. But the Food and Drug Administration (FDA) has recently approved the use of gastric banding and sleeve gastrectomy also for patients with BMI of 30–34.9kg/m2. Further high-quality long-term studies seem necessary.

Resolution of diabetes following bariatric surgery occurs because of both weight-dependent and independent mechanisms.58,59,68 Therefore, the type of surgical procedure will influence rates of remission. Several studies and reviews have addressed the different approaches and their overall results, reporting T2D remission rates ranging from 7–70% for laparoscopic adjustable gastric banding (LAGB), 38–98% for Roux-en-Y gastric bypass (RYGB), 33–85% for sleeve gastrectomy (SG), and 52–100% for biliopancreatic diversions (BPD) (Fig. 2).

Figure 2.

Type 2 diabetes remission rates according to different bariatric procedures: laparoscopic gastric banding (LAGB), Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG) and biliopancreatic diversion (BPD). Percentages taken and adapted from results from different studies, which include different remission criteria.

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Nevertheless, it is essential to bear in mind that there are few studies that directly compare two different techniques10,11,48–51,69; therefore, it is difficult to reach definitive conclusions about the relative effectiveness of various surgical techniques beyond mere and prudent speculations concerning each individual report. And moreover, once again, the use of arbitrary remission criteria and heterogeneous study populations, mainly regarding differences in BMI and previous insulin use, may bias results and confound our interpretations.

The promising results for the short and mid-term follow up may be jeopardized when patients are evaluated in the long-term. In fact, different case series have reported a rate of T2D recurrence of 50–90% 5 years or more after metabolic surgery.25,33,41,75–78 T2D relapse may be explained by unfavorable preoperative factors, inadequate weight loss and weight regain, lack of patient's commitment to treatment and follow-up, failure of the surgical technique, and inadequate incretin stimulation following surgery.56 It is probable that a publication bias exists, with studies that obtain disappointing results not being reported.

Management of T2D relapse after metabolic surgery may be challenging and has not been thoroughly evaluated. Anatomic modifications determine pathophysiological changes that may alter the effects of oral hypoglycemic medications and increase insulin sensitivity.79 The presence of weight regain may be helpful to rule out pancreatic beta-cell exhaustion, and may guide us into the best treatment alternatives. However, there are no evidence-based data to make clinical recommendations. Increase in the number of metabolic procedures performed and long-term follow-up will provide additional data regarding the best approach in these cases.

As it has been previously outlined, stringent criteria have lowered diabetes remission rates. Furthermore, observational studies with mid and long-term follow-up have shown an increased number of patients who do not strictly fulfill these criteria, or in whom T2D reappears after an initial amelioration. This was observed, for example, in the SOS study, where T2D remission rates went from around 70% at 2 years, to around 30% at 10 years, basically due to weight regain.

However, defining an individual as “non-remitter” of diabetes according to biochemical criteria should not underestimate the role that metabolic surgery plays in cases with poorly controlled and long-standing T2D. Indeed, these patients benefit from significant reductions in FG and HbA1c levels, as well as form decreasing insulin requirements and use of hypoglycemic medications. Likewise, the number of patients who reach an optimum combined metabolic control, as defined by ADA's target recommendations15 (HbA1c<7%, LDLc<100mg/dL, tryglicerides<150mg/dL and HDLc>40mg/dL in male or >50mg/dL in female), significantly increases, with barely any difference between “remitters” and “non-remitters”82. Furthermore, since hypertension is also improved or even resolved after metabolic surgery, ADA's target blood pressure levels15 (<140/80mmHg) may be more easily achieved, yet amelioration of hypertension is less obvious, due to other pathogenic mechanisms involved. And also, preliminary analysis point out that bariatric surgery appears to be cost-effective, although long-term data are still needed.80

For these reasons, even though a patient could be initially considered as a poor candidate for T2D resolution after bariatric surgery owing to, for example, his long diabetes duration, high insulin requirements and previous deficient control, this possibility should not be disregarded. In fact, quite the opposite: indication for surgical procedures should be taken into account, since overall metabolic improvement, which is the foremost goal of bariatric surgery, may be attained, with little surgical risk.21,25,34

The impact of bariatric surgery for the treatment of diabetes and other obesity-associated comorbidities has led to widespread of the term metabolic surgery to describe interventions that aim at improving these diseases. T2D remission rates have varied over a wide range across published studies, mainly due to heterogeneity in criteria used for definition, patients’ baseline characteristics, and the type of procedure performed. A valid estimate would be to establish remission of diabetes in around 50% of patients, yet these observations can only apply in the short-term evaluation (up to 2 years of follow-up).

Even in “non-remitters”, surgery allows and overall benefit regarding combined metabolic control. Thus, T2D remission should not be aimed as the foremost goal, to the extent of developing new types of interventions that would risk nutritional health status. Correct metabolic control using the least number of medications as possible should be thought of as enough, and therefore regarded as the overall core objective if patient's quality of life improves.

In this way, metabolic surgery should not be applied only to those with established T2D diagnosis or a specific BMI cut-off level, but also to patients with further signs of metabolic syndrome, such as insulin resistance, arterial hypertension, hyperlipemia, hyperuricemia, liver steatosis, polycystic ovarian syndrome and endothelial disease, amongst others. These patients benefit as well from the impact of surgery on cardio-metabolic comorbidities.

It would be desirable that scientific societies dealing with T2D and metabolic surgery elaborated a consensus document in which guidelines for eligibility for surgical procedures were addressed for patients with T2D and different BMI categories, and universal criteria for evaluation, both in the short and long-term, were also established.

The authors declare no conflict of interest.