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06-07-2017 | Metabolic surgery | Hot topic review | Article

Metabolic surgery: A powerful solution or a last resort?

medwireNews Hot Topic Reviews provide up-to-date overviews of fast-moving areas of research in order to help healthcare providers keep abreast of the latest developments that may influence patient care.

In June 2016, Diabetes Care published guidelines for metabolic surgery, positioning it as an important treatment option for patients with type 2 diabetes [1]. The guidelines were developed and ratified by the American Diabetes Association (ADA), the International Diabetes Federation, Diabetes UK, the Chinese Diabetes Society, and Diabetes India, and, at the time of publication, had been formally endorsed by an additional 40 diabetes, obesity, and surgical societies.

So what has led to surgery, traditionally seen as a last-ditch strategy for people with severe obesity, becoming a viable treatment option for type 2 diabetes? In this hot topic review, we explain the concept of metabolic surgery (as distinct from bariatric surgery), set out the evidence behind the guidelines, along with more recent key publications, and talk to Medicine Matters diabetes editorial board member John Wilding (University of Liverpool, UK) about how metabolic surgery fits into modern diabetes care.

What is metabolic surgery?

In contrast to bariatric surgery, metabolic surgery is intended to specifically address diabetes that fails to respond to lifestyle and medication changes, rather than obesity per se. Whereas bariatric surgery is generally performed in patients with a body mass index (BMI) of at least 40 kg/m2 (or ≥35 kg/m2 with comorbidities), the STAMPEDE metabolic surgery clinical trial in patients with type 2 diabetes included participants with BMIs as low as 27 kg/m2 [2].

This can result in markedly different patient populations. In a US study, patients undergoing surgery primarily for weight loss were generally relatively young and predominantly female, with few or no cardiometabolic abnormalities, whereas those undergoing surgery primarily to combat diabetes were older, a higher proportion were men, and they had more cardiometabolic comorbidities and even overt cardiovascular disease [3].

Wilding notes, however, that differences may be less marked in countries such as the UK, which have strict criteria limiting access to surgery.

What do the guidelines say?

The recent metabolic surgery guidelines do not drop the BMI threshold as far as the STAMPEDE investigators did, instead opting for 30 kg/m2 (27.5 kg/m2 for Asians). They also advocate a first-line glycemic control strategy of medication and lifestyle intervention for all patients with a BMI below 40 kg/m2. The management algorithm (see figure) advises physicians to consider surgery for patients with class I obesity (30.0–34.9 kg/m2) and poor glycemic control despite nonsurgical interventions, and for class II (35.0–39.9 kg/m2) obese patients even if they have good glycemic control. The ADA adopted the same thresholds in the obesity management section of the 2017 update to the Standards of Care [4] and the UK’s National Institute for Health and Care Excellence has endorsed a similar approach since 2014 [5].

Wilding believes the algorithm to be a reasonable strategy, noting that none of the guidelines mandate surgery for mildly obese patients. “They don’t say if you’ve got a BMI between 30 and 35 and you’ve got diabetes, do bariatric surgery. What they say is: just ask the question. Is it appropriate for this person? And if you come up with the answer ‘no’ you can still carry on with medical management.”

Why is metabolic surgery needed?

Most middle- and high-income countries are in the grip of a “diabesity” crisis. During 2011–2014, 36.5% of adults in the USA were obese [6] and in 2012, 9.3% had diabetes, with nearly a third of these being undiagnosed [7], and recent data show rising diabetes rates in American youths [8].

Obesity is tough to combat using behavioral interventions, with studies such as Look AHEAD and the Diabetes Prevention Program Outcomes Study showing only moderate weight loss and frequent weight regain [9, 10]. Likewise, many diabetes patients struggle to control blood sugar and other metabolic risk factors, despite a wide range of available pharmacologic options. For example, only 65.7% of type 2 diabetes patients in England and Wales achieved a glycated hemoglobin (HbA1c) target of 7.5% (58 mmol/mol) in 2015–2016, and only 40.2% achieved all three of their key HbA1c, blood pressure, and cholesterol treatment targets [11]. Likewise, in the USA data for up to 2010 show just over half of patients achieving the ADA HbA1c goal of 7.0% [12, 13].

But controlling weight in diabetes patients is highly beneficial, with a recent analysis of the Look AHEAD study showing a significantly reduced risk for major cardiovascular disease outcomes among participants who lost weight [14].

What evidence supports metabolic surgery?

Historic studies of bariatric surgery have revealed remission of type 2 diabetes in many patients undergoing the procedure [15, 16], which led to a flurry of trials that specifically recruited patients with diabetes [2, 17–24]. One of the first to appear, in JAMA in 2008, recruited 60 patients with BMIs between 30 and 40 kg/m2 and found 2-year diabetes remission in 73% of those who underwent gastric banding versus 13% of those given conventional treatment [17].

More recent studies include the aforementioned STAMPEDE trial, which included 140 patients with a BMI of 27 to 43 kg/m2 and reported 12-month HbA1c levels of 6.0% or less in around 40% of patients who underwent surgery (gastric bypass or sleeve gastrectomy), compared with 12% of those who received medical therapy [2]. At the same time, between half and three-quarters of the surgical patients did not require diabetes medications, whereas all patients in the medical therapy group required at least one.

Another notable trial, being one of the largest per treatment group, is the Diabetes Surgery Study Randomized Clinical Trial, published in JAMA in 2013 [24]. This targeted patients with BMIs between 30.0 and 39.9 kg/m2 and reported that 49% of the 60 who underwent gastric bypass surgery met all three of the HbA1c (<7.0%), cholesterol, and blood pressure targets at 12 months, compared with 19% of the 60 in the medical management group.

Long-term outcomes

Some of these metabolic surgery trials are beginning to yield longer-term data, with STAMPEDE and another trial that reported its initial results in the same year recently reporting their 5-year outcomes [25, 26]. Although some patients had relapsed by this time, the proportion who still met their glycemic targets, with or without diabetes medications, remained substantially larger for surgical patients than for medical intervention patients, at 23–29% versus 5% in STAMPEDE and 42–68% versus 27% in the other trial (which had a less stringent HbA1c target, of 6.5%).

Although a proportion of patients in these trials did relapse, several studies have described a “legacy effect” of a former period of good glycemic control, including as a result of surgery, with benefits seen for later glycemic and microvascular outcomes [27–29].

What about type 1 diabetes patients?

Metabolic surgery is designed to benefit patients with type 2 diabetes, in whom obesity is often a major underlying factor. However, obesity is also increasingly a problem in type 1 diabetes, with a recent study showing that, even before the age of 18 years, around a third of type 1 diabetes patients are overweight or obese [30].

No randomized trial has yet addressed the benefits of surgery in type 1 diabetes patients, but a number of case series and case reports have been published [31], with most reporting a significant reduction in patients’ insulin needs after surgery; however, it remains to be determined whether this in itself is sufficient justification for surgery in patients without other obesity-related comorbidity.

Which patients might gain the most benefit?

In STAMPEDE, the largest metabolic surgery trial so far to report 5-year outcomes, patients with shorter diabetes duration (<8 years) had a fourfold increased likelihood for achieving the primary outcome, leading the investigators to highlight the importance of early intervention to achieve glycemic control in diabetes patients [25]. Their finding is in line with previous results from bariatric surgery studies, which show a similar pattern for longer-term outcomes, including microvascular complications [32].

What are the drawbacks?

Procedural drawbacks

Complication rates were in fact relatively low in the studies that established efficacy in diabetes patients, but some surgical patients did require reoperation – 6% of the gastric bypass group and 2% of the sleeve gastrectomy group in STAMPEDE, for example [2]. Anemia was common, affecting 28% of the gastric bypass group and 49% of the sleeve gastrectomy group at the 5-year follow-up, compared with 16% of the medical therapy group [25].

Other studies reported similar outcomes, with reoperations and anemia being the most notable complications at short- and long-term follow-up, respectively. In addition, nutritional deficiencies are a well-known consequence of bariatric surgery, with patients usually requiring vitamin and mineral supplementation and lifelong monitoring. Indeed, the 2-year follow-up of the Diabetes Surgery Study reported increased rates of nutritional deficiencies, mainly in iron, albumin, calcium, and vitamin D, among patients in the surgical group, despite mandated supplementation after surgery [33]. This trial also flagged an increased risk for secondary hyperparathyroidism after surgery, seen in 17% of patients.

Debatable comparators

Another factor weighing against surgery is that the control interventions with which it has been compared could be considered less than optimal [34]. The CROSSROADS trial attempted to address this, with a nonsurgical comparator that included at least 45 minutes of aerobic exercise 5 days per week and a dietitian-directed diet, along with optimal medical treatment, which the researchers described as “the most intensive lifestyle–medical approach that could reasonably be considered in practice” [35].

The outcome was no different to that of trials with less intensive comparators, however, with just 5.9% of the 17 participants who undertook this approach achieving an HbA1c below 6.0% without diabetes medications, compared with 60.0% of the 15 participants who underwent gastric bypass surgery.

However, medical management has moved on since these trials were initiated, with Wilding noting that in STAMPEDE, “a relatively low proportion of patients were treated with what we would consider to be the most modern drugs and the most modern drug regimen.”

Research into optimal lifestyle interventions is also ongoing, with, for instance, the current increased focus on weight-loss methods such as supervised low-energy diets or liquid meal replacements. One such study – the in-progress DIRECT trial – is anticipating at least 15 kg of weight loss and remission of diabetes in patients assigned to a 2.5 MJ (600 kcal)/day liquid diet for 12 weeks, followed by food reintroduction and weight maintenance phases [36]. Notably, participants stop all antidiabetic and antihypertensive medications when they start the liquid-diet phase, on the assumption of a rapid response to the diet.

Another factor that can hinder good weight-loss outcomes in the comparator groups is that these patients require more antidiabetic medications than those who have undergone surgery, and several of these medications, particularly insulin, sulfonylureas, and thiazolidinediones, are linked to an increased risk for weight gain [37, 38].

What techniques are used, and are they equally effective?

Although the various surgical techniques have been tested against each other, such studies have largely involved bariatric surgery patients, for whom weight loss rather than glycemic control is the primary goal. However, several of the metabolic surgery trials to date have included more than one surgical approach, including gastric bypass, sleeve gastrectomy, and biliopancreatic diversion. Although no published trial has yet been designed to detect significant differences between surgical groups, some likely differences have emerged.

Despite gastric bypass being associated with more complications than sleeve gastrectomy, the STAMPEDE investigators believe the former to be more effective, because patients assigned to that group had lost more weight and required fewer diabetes medications at the 5-year follow-up [2, 25].

The other study that has so far reported 5-year outcomes found that biliopancreatic diversion resulted in a higher rate of diabetes remission than gastric bypass, but that gastric bypass appeared to have a more favorable risk-to-benefit profile [26].

One study that has reported 3-year outcomes included gastric banding as a reversible, less invasive alternative to gastric bypass. However, patients who underwent bypass surgery lost markedly more weight and achieved better glycemic outcomes than those given a gastric band [22].

The ongoing By-Band-Sleeve study in the UK, is the largest trial to date directly comparing surgical outcomes, aiming to recruit 1341 patients in total. It is designed to assess weight loss efficacy and quality of life, and is therefore not specifically recruiting diabetes patients, although resolution of type 2 diabetes is among its secondary endpoints.

What are the remaining questions about metabolic surgery?

Wilding says that one promising line of continuing research stems from the metabolically beneficial changes that surgery appears to induce in gut hormones – changes that are not necessarily a direct result of weight loss. This raises the question of whether it is possible to develop less drastic interventions that can reproduce the hormonal effects of surgery, but without the major weight loss “and without getting all the side effects that are associated with malabsorption and so on.”

However, Wilding notes that such techniques are still experimental and it remains to be seen whether any will deliver the hoped-for benefits.

Another point that remains unclear is when patients should be referred for surgery. “I think everybody would accept that you don’t wait until the patient has severe complications such as visual loss and kidney failure,” says Wilding. “And you probably don’t need to do surgery on day 1 of diagnosis.

“But at what point in between the risk–benefit changes I think is probably individual, but is certainly something that hasn’t really been properly addressed by the current research.”

Could metabolic surgery become a mainstay treatment for diabetes?

The evidence so far suggests that metabolic surgery is effective and relatively low risk, leading to its endorsement in multiple guidelines, but whether it will become “a mainstream treatment that most people with diabetes would accept is a totally different question,” says Wilding.

One barrier to its wider use is that the patients who can potentially benefit often have a poor opinion of the procedure and are unwilling to consider it. In a survey of 130 patients with diabetes and a BMI of 30–40 kg/m2, only about one in five looked favorably upon the idea of metabolic surgery, with most doubting its safety and efficacy, and a substantial proportion even believing that the procedure carried a moderate-to-high risk for death [39].

Wilding notes that surgery may have “a bad press that it doesn’t really deserve, because most patients do really well.” But on the other hand, he says that considering all possible complications of bariatric surgery, between one in 10 and one in 20 patients will end up with a side effect that adversely affects their quality of life.

He observes that patients willingly accept the risks of surgery for a disease such as cancer, which they know will otherwise be fatal. “Whereas if you get told you’ve got diabetes, you think well I’m going to be treated with tablets for a few years and I might at some point need insulin but I don’t mind taking a few pills – so people will always delay and delay and delay.”

And by the time patients have developed irreversible diabetic complications and have begun to perceive it as a serious disease, Wilding says “it may be too late, because the benefits of surgery are more apparent if you do it early on.”

He stresses that surgery is an excellent treatment for people with severe obesity, for whom there is little alternative. “But I think when your BMI is 32, it’s a different question.”

The guidelines potentially make 1.5 million diabetes patients in the UK eligible for surgery, whereas Wilding says the number actually operated on annually is around 2000, “and most of those would have severe obesity with many other complications that would mean surgery is the best thing for them anyway.”

Bearing in mind poor patient acceptance and barriers within health systems, including underfunding of bariatric surgery, Wilding thinks that a large uptake of metabolic surgery is very unlikely. “I think we have to be realistic,” he says. “I just don’t see it in the foreseeable future becoming a mainstream therapy for everybody.”

By Eleanor McDermid

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