Abstract
Several bariatric operations originally designed to promote weight loss have been found to powerfully treat type 2 diabetes, causing remission in most cases, through diverse mechanisms additional to the secondary consequences of weight loss. These observations have prompted consideration of such operations as ‘metabolic surgery’, used expressly to treat diabetes, including among patients who are only mildly obese or merely overweight. Large, long-term observational studies consistently demonstrate that bariatric/metabolic surgery is associated with reductions in all cardiovascular risk factors, actual cardiovascular events, microvascular diabetes complications, cancer and death. Numerous recent randomised clinical trials, directly comparing various surgical vs non-surgical interventions for diabetes, uniformly demonstrate the former to be superior for improvements in all glycaemic variables, as well as other metabolic endpoints. These benefits are similar among individuals with type 2 diabetes and a preoperative BMI of 30–35 kg/m2 compared with traditional bariatric surgery patients with a BMI >35 kg/m2 . The safety profiles of modern laparoscopic bariatric/metabolic operations are similar to those of elective laparoscopic hysterectomy and knee arthroplasty. However, more evidence regarding the risks, benefits and costs of surgery is needed from very long-term (>5 year) randomised clinical trials powered to observe ‘hard’ clinical endpoints following the operations most commonly used today. Given the efficacy, safety and cost-effectiveness of metabolic surgery, the second Diabetes Surgery Summit (DSS-II) consensus conference recently placed surgery squarely within the overall diabetes treatment algorithm, recommending consideration of this approach for patients with inadequately controlled diabetes and a BMI as low as 30 kg/m2 , or 27.5 kg/m2 for Asian individuals. These new guidelines have been formally ratified by 53 leading diabetes and surgery societies worldwide. Given this broad level of endorsement, we feel that the DSS-II recommendations should now replace the outdated National Institutes of Health (NIH) suggestions that have governed bariatric surgery practice and insurance compensation worldwide since 1991.
Introduction
Type 2 diabetes is an expanding pandemic afflicting more than 400 million people, with estimates of 650 million cases by 2040. Despite ever-increasing options for pharmaceutical and lifestyle interventions, including medications recently shown to reduce cardiovascular events, many patients with diabetes fail to achieve glycaemic/metabolic treatment goals designed to reduce micro- and macrovascular complications. In the USA, only 52% of patients with type 2 diabetes maintain HbA1c < 53 mmol/mol (< 7%), and only 19% reach this target along with LDL < 5.6 mmol/l and blood pressure < 130/ 80 mmHg, as recommended to minimise cardiovascular morbidity and mortality [1]. Implementing more effective strategies to prevent and treat diabetes has become a top priority in 21st century medicine.
Recently, the second Diabetes Surgery Summit (DSS-II), an international consensus conference, developed global guidelines that recommend inclusion of bariatric/metabolic surgery among glucose-lowering interventions for selected patients with type 2 diabetes and obesity [2]. Endorsed thus far by 53 organisations worldwide, including major national diabetes and surgical societies, DSS-II guidelines were incorporated into the ADA Standards of Diabetes Care in 2017 [3]. This new guidance proposes that ‘metabolic surgery’ (involving procedures initially developed to treat obesity and dubbed ‘bariatric surgery’) should be considered as standard diabetes treatment options for appropriate candidates with inadequately controlled type 2 diabetes and a BMI >30 kg/m2 , or >27.5 kg/m2 for Asian individuals. This conclusion is based on biological and clinical rationales. For example, mechanistic studies demonstrate that surgical manipulation of the gastrointestinal tract can exert powerful, beneficial effects on various facets of glucose homeostasis, independent of weight loss [4]. Moreover, a large body of clinical evidence, including numerous randomised clinical trials, documents that surgery improves blood glucose levels more effectively than any lifestyle and/or pharmaceutical intervention, often yielding longterm diabetes remission [5].
Inclusion of surgery among standard diabetes therapies represents a significant step forward in diabetes care and research. The mechanisms of metabolic surgery, albeit incompletely understood, underscore important roles for the gut in glucose homeostasis. Elucidating these mechanisms provides opportunities to clarify type 2 diabetes pathogenesis, potentially identifying targets for novel pharmacotherapeutics. Leveraging insights provided by metabolic surgery, however, requires addressing practical and conceptual barriers, including widespread misconceptions about bariatric surgery. Despite compelling evidence of safety, efficacy and cost-effectiveness, using surgery as a diabetes intervention remained controversial until very recently.
Herein we review evidence regarding the effects of metabolic surgery in patients with obesity and type 2 diabetes, discussing the clinical, biological and economic rationales that support expanding its use as part of modern multidisciplinary approaches to diabetes care.
Biological rationale for considering bariatric/metabolic surgery to treat type 2 diabetes
It has become clear that certain operations initially designed to promote weight loss also powerfully improve glucose homeostasis, leading to type 2 diabetes remission in most cases, especially after procedures with intestinal bypass components [5]. Although approximately one-third of patients who initially achieve diabetes remission after Roux-en-Y gastric bypass (RYGB) later experience relapse, the median disease-free period for these individuals is 8.3 years [6]. Given the known benefits of tight vs standard glycaemic control in early diabetes on long-term cardiovascular disease (‘legacy effect’) [7, 8], even among people whose diabetes relapses several years after metabolic surgery, it is possible that this disease-free interval will also yield long-term cardiovascular benefits in relapsed individuals, especially in cases where initial diabetes duration is relatively short. Although this has not yet been proven in randomised clinical trials, very large, rigorously matched, non-randomised studies have shown that metabolic surgery is associated with long-term reductions in all cardiovascular risk factors, actual cardiovascular events, cancer and death [5, 9–12].
It is also clear that many diabetes-associated benefits of intestinal bypass operations, such as RYGB, result not only from known effects of weight loss on glucose homeostasis but also from diverse weight-independent glucose-lowering mechanisms. Several large bodies of evidence demonstrate this [13]. First, diabetes commonly remits very fast after surgery, before significant weight loss. Second, for a given amount of weight loss achieved with intestinal bypass surgery, larger improvements in glucose homeostasis and diabetes occur than with equivalent weight loss achieved by dieting, exercise or purely gastric-restrictive operations. Third, there is an inconsistent relationship between the amount of weight lost after intestinal bypass operations and the degree of diabetes remission, prevention and relapse after initial remission, as well as with rates of improvement in hard outcomes, such as heart attacks, strokes, cancer and death. Fourth, experimental operations and devices that replicate some of the intestinal physiology of metabolic operations, such as RYGB, without compromising gastric capacity, can powerfully improve or eliminate type 2 diabetes with little or no weight loss, disengaging the weightreducing and glucose-lowering effects of surgery. Finally, rare but illuminating cases of profound, late-onset hyperinsulinaemic hypoglycaemia (occurring 1–26 years postoperatively, typically at 2–4 years), sometimes requiring pancreatectomy, suggest long-term post-surgical stimulation of beta cell function and, possibly, mass. This latter point demonstrates that, occasionally, the effectiveness of surgery for the treatment of diabetes can be ‘too powerful’, something that would never occur with non-surgical weight loss.
A partial list of mechanisms mediating weight-independent glucose-lowering effects of gastrointestinal surgery is shown in the text box below. Although many of these specific mechanisms have only been demonstrated thus far in animals, compelling evidence indicates that metabolic surgery engages weight-independent glucose-lowering processes in humans [4]. This has important clinical implications because, although individuals with a lower BMI lose less weight postoperatively than do the severely obese, they still experience these weightindependent glucose-lowering effects. Accordingly, the benefits of bariatric/metabolic surgery for type 2 diabetes appear to be similar among people with a preoperative BMI < 35 kg/m2 to those with a BMI ≥35 kg/m2 [14], the traditional cut-off for bariatric surgery in patients with diabetes (see below). Admittedly, evidence for this assertion is limited for patients with a preoperative BMI < 30 kg/m2.
