Abstract
Several gastrointestinal operations under the name of bariatric-metabolic surgery that were originally designed to achieve and maintain body weight loss, can cause dramatic improvement of related metabolic comorbidities, especially, type 2 diabetes. A growing body of clinical long-term evidence shows that metabolic surgery is more effective than medical and/or lifestyle interventions in producing diabetes mellitus remission, glycemic control and body weight loss in obese patients. Also, it significantly reduces diabetes-related major complications and all-cause of mortality, in obese patients with type 2 diabetes. The new therapeutic algorithm for type 2 diabetes, supported by the American Diabetes Association and the American and European Societies of Bariatric-Metabolic Surgery, includes metabolic surgery as a treatment option for patients with diabetes mellitus even with a body mass index as low as 30 kg/m2. Therefore, access to surgery should be adequately prioritized and offered as therapeutic approach to eligible patients by diabetes care providers.
Diabetes: a silent global epidemic
Diabetes is considered as one of the greatest public health threats of the 21st century. The numbers related to the incidence of diabetes are alarming! According to the most recent global predictions of the International Diabetes Federation, there are 537 million people suffering from diabetes worldwide, a number that is predicted to reach 643 million by 2030 and 783 million by 2045! (1). About 90% of these people have type 2 diabetes. Although diet, exercise and medications remain the cornerstones of type 2 diabetes therapy, the long- term success rates of lifestyle modifications have been disappointing. Fewer than 50% of patients with type 2 diabetes control their blood-sugar levels adequately by changing their diet or exercise regime, or by taking medication.
Metabolic surgery, in the fight of the cure of diabetes.
Obesity is a major independent risk factor for developing type 2 diabetes. About 90% of people with type 2 diabetes have obesity or are overweight. Several gastrointestinal operations, under the name of bariatric-metabolic surgery, originally designed to achieve and maintain body weight loss, can cause dramatic improvement of related metabolic comorbidities, especially, diabetes.
Although diabetes is considered a chronic, progressive disease, in which delay of end-organ complications is the major treatment goal, gastrointestinal surgery offers a novel endpoint: complete long term diabetes remission. Dr Fransesco Rubino, a pioneer in the specialty of metabolic surgery, writes: “The ability of several types of gastrointestinal surgeries to improve blood sugar levels and or even to lead to long-term remission of type 2 diabetes, gives us hope in finding a cure for diabetes” (2). However, the history of the emergence of metabolic surgery began in 1925, when we had the first report of diabetes remission after a gastrointestinal procedure (3). The authors of the article , intitled ‘Diabetes and Operation’, commented: ‘This observation proved that the patient’s carbohydrate metabolism had been depressed by the operation’. Who could have imagined the plethora of observations and clinical research studies that would follow regarding the improvement of diabetes after gastrointestinal surgeries!
Is Type 2 diabetes an operable disease?
The results of randomized clinical trials showed that metabolic surgery, particularly gastric bypass, leeds to complete remission or improvement of diabetes within two years for more than 90% of patients, in some cases at the time of hospital discharge and even before significant body weight loss occurs! These remarkable results, known from previous decades, are consistent with those of meta-analyses. A meta-analysis of more than 135.000 metabolic surgery of obese patients included in 621 studies, found that 87% of patients with type 2 diabetes experienced improvement or remission of the disease and an average overall reduction in excess weight by 60% (4). In JAMA Surgery, meta-analysis of 162.000 patients with obesity, among a total of 164 randomized controlled trials and observentional studies, showed that those with type 2 diabetes who had metabolic surgery experienced improvement or remission of the disease at a rate of 92% and 86%, respectively (5).
Is Metabolic Surgery superior to pharmacological treatment in obese patients with type 2 diabetes?
Several observational studies and randomized clinical trials indicate that metabolic surgery is more effective than medical and/or lifestyle interventions including pharmacological therapy in producing diabetes remission, glycemic control and weight loss. Five-year results of the Surgical Treatment and Medications Potentially Eradicate Diabetes Efficiency (STAMPEDE) Study showed that, in patients with uncontrolled type 2 diabetes and an average Body Mass Index (BMI) of 37 kg/m2, metabolic surgery plus intensive medical therapy was more effective than intensive medical therapy alone in achieving and maintaining glycemic control, medication reduction and body weight loss (6). In another randomized clinical trial, the remission of diabetes was achieved in 85% of the patients who underwent surgery, compared to none of those who received medical therapy (7). In the same study, 50% of the surgical patients maintained diabetes remission at a 5 year follow-up compared to none of the medically treated patients (8).
What are the long-term results of type 2 diabetes remission after metabolic surgery?
Metabolic surgery is more effective than conventional medical therapy even in the long-term control of diabetes. In a randomized clinical study, 37.5 % of obese patients in the metabolic surgery group, compared to 5.5% of obese patients in the medical therapy group, maintained diabetes remission, during 10 years of follow-up (9).
In the prospective ‘Swedish Obese Subjects’ study, the rates of diabetes remission were 72% for the surgical patients, compared to 16% for the control group at a two year of follow-up. At 15 years of follow-up, the rates of diabetes remission decreased to 30% in the surgical group and 6% in the control group (10). In a recently published randomized clinical trial, diabetes remission was greater in patients who underwent metabolic surgery than those who received only medical/lifestyle intervention therapy, both at 7 and 12 years of follow-up (18.2% in the metabolic surgery group vs. 6.2% in the medical/lifestyle group at 7 years and 12.7% in the metabolic surgery group vs. 0.0% in the medical/lifestyle group at 12 years, respectively) (11).
Long-term survival benefit after metabolic surgery. Is it true?
Diabetes is associated with a high risk of multiple end-organ damage, which leads to an increased incidence of cardiovascular disease, heart failure, and stroke; it is also the leading cause of kidney failure, lower-limb amputation, and blindness. Unfortunately, the death rates from diabetes are continuously increasing. According to the statistical data of the Institute for Health Metrics and Evaluation, diabetes mellitus was the direct cause of 1.5 million deaths in 2019! Diabetes was also the cause of 460.000 deaths from kidney disease. Furthermore, raised blood glucose caused around 20% of cardiovascular deaths (12)!
Metabolic surgery significantly reduces diabetes-related major adverse events and all-cause of mortality in patients with type 2 diabetes and obesity! In a retrospective study, Adams et al. compared the long-term mortality of severely obese patients who underwent surgery with that of severely obese patients from the general population during 7 years of follow-up. Interestingly, they found that the long-term mortality from any cause decreased by 40% in the surgery group as compared to the control group! More specifically, the cause-specific mortality in the surgery group decreased by 56% for coronary artery disease (P=0.006), by 92% for diabetes ( P=0.005), and by 60% for cancer (P<0.001), as compared to that of the general population (13).
A Swedish observational study found a 58% reduction in relative overall mortality risk in obese patients with type 2 diabetes who underwent gastric by-pass, compared to controls after 3.5 years of follow-up (p<0·0001). The risk of fatal or non-fatal myocardial infarction was 49% lower (p=0·021) and that of cardiovascular death 59% lower (p=0·026) in the gastric by-pass group than in the control group (14).
A Canadian retrospective study showed that the overall mortality rate was halved in the metabolic surgical group of obese patients with diabetes type 2 compared to that of a matched control group, after five years of follow-up. The surgical patients had 68% lower cardiovascular mortality rates (p = .002) and a 34% lower rate of composite cardiac events (P < .001) than non-surgical patients. Also, the rate of nonfatal renal complications was 42% lower in the surgery group (p = 0.03) than that of the control group (15). In the same population, there was a 46% reduction in cancer mortality in the surgery group (16). A retrospective study focused on comparing the incidence and mortality rates from cancer between 10,000 obese patients who underwent gastric bypass and an equal number of patients in a control group over 24 years of follow-up. They found that both incidence of and mortality from cancer were significanly lower in the surgical group than the controls (p= 0.0006 and p = 0.001, respectively. Cancer mortality was 46% lower in the surgery patients (17).
Is metabolic surgery effective in less obese patients with type 2 diabetes?
Mounting evidence from prospective and large retrospective studies revealed that metabolic surgery is an effective treatment option for patients with type 2 diabetes with a BMI lower than 35 kg/m2. A Chinese retrospective study compared the 5-year efficacy between gastrointestinal metabolic surgery and medical treatment on glycemic control and diabetes remission in patients with type 2 diabetes and a BMI lower than 35 kg/m2. The surgically treated group had a 36% complete and 28% partial diabetes remission rate, while the medically treated group had only 1.2% and 1.6%, respectively, at 5 years of follow-up (18). In a clinical randomized controlled trial, diabetes remission in patients with a BMI between 24 and 30 kg/m2 was achieved in 93% of those who underwent gastric bypass and in 45% of those who underwent sleeve gastrectomy (19).
A recent systematic review and meta-analysis, found that metabolic surgery is more effective than non-surgical treatment to reach diabetes remission and significant reduction of glycosylated hemoglobin in patients with diabetes type 2 and a BMI lower than 35 kg/m2 (20). Two randomized control trials by Ikramudin and Schauer, respectively, highlighted the comparative significant advantage of metabolic surgery over medical therapy in achieving partial or complete remission of type 2 diabetes, in populations with a lower BMI down to 27 kg/m2 (6, 21).
The transition from metabolic surgery to diabetes surgery and the design of dedicated anti-diabetes surgical procedures
In our randomized controlled clinical trial, named VagusSx, we compare the diabetes remission rates in patients with a BMI >30kg/m2, who undergo a gastric bypass plus truncal vagotomy versus those who undergo gastric bypass alone. In our recent publication in one of the top specialty journals “Metabolism” entitled: ‘Metabolic effects of truncal vagotomy when combined with bariatric-metabolic surgery’, we describe the reasons why we should add truncal vagotomy to gastric bypass in order to achieve higher and longer-lasting rates of diabetes remission (22).
This type of gastrointestinal procedure has been extensively used in peptic ulcer therapy in the previous century and is still employed in the therapy of gastric cancer. However, it has not been used in the treatment of diabetes until now. To the best of our knowledge, the clinical trial VagusSx is the first study to use the addition of vagotomy to gastric bypass as an anti-diabetic surgical approach. As we detail in our article, the remission rates of type 2 diabetes in patients with concurrent gastric cancer and type 2 diabetes are impressive. They range between 50% and 90% in patients who are obese, but they include also lean diabetics with a BMI down to 22kg/m2!
Historical milestones of metabolic surgery evolution.
I. The American Society for Metabolic and Bariatric Surgery Position Statement
In 2016, the American Society for Metabolic and Bariatric Surgery, in response to numerous inquiries made to the Society by patients, physicians, society members, hospitals, health insurance payors, the media, and others, issued a position statement regarding the benefit of metabolic and bariatric surgery on long-term survival (23). The position statement, comparing the benefits of metabolic surgery, with those of the nonsurgical usual medical treatment in patients with BMI greater than 35 kg/m2, concluded that:
“Metabolic and bariatric surgery is associated with a reduction in all-cause mortality and increased long-term survival”.
-“Metabolic and bariatric surgery is significantly superior to current best medical management for the treatment and remission of diabetes type 2 and reduces death rates associated with the disease”.
-“Metabolic and bariatric surgery is associated with a reduction of cardiovascular risk factors and future cardiovascular events and deaths”.
-“Metabolic and bariatric surgery is associated with a reduction in the risk of certain cancers and improved cancer outcomes and mortality for women”.
II. 2nd Diabetes Surgery Summit: the new therapeutic algorithm for type 2 diabetes
In 2016, the 2nd Diabetes Surgery Summit, an international consensus conference, was convened in collaboration with 45 leading diabetes organizations, including the American Society for Metabolic and Bariatric Surgery, American Diabetes Association’s and International Diabetes Federation, to develop global guidelines to inform clinicians and policymakers about the benefits and limitations of metabolic surgery for Type 2 Diabetes (24). Representatives of the organizations stated that ‘there is sufficient clinical and mechanistic evidence to support inclusion of metabolic surgery among antidiabetes interventions for people with type 2 diabetes and obesity’. They developed a new therapeutic algorithm for type 2 diabetes, including the metabolic surgery as a treatment option, as follows:
-“Metabolic surgery should be recommended to treat type 2 diabetes: a) in obese patients with BMI greater than 40 kg/m2 regardless of the level of glycemic control or complexity of glucose-lowering regimens and b) in those with BMI of 35 to 40 kg/m2, when hyperglycemia is inadequately controlled by lifestyle and optimal medical therapy”.
-“Surgery should also be considered for patients with type 2 diabetes with BMI of 30 to 35 kg/m2, if hyperglycemia is inadequately controlled despite optimal treatment with either oral or injectable medications”.
III. The new therapeutic algorithm for type 2 diabetes in the American Diabetes Association’s guidlines
In 2018, the annually updated guidelines of the American Diabetes Association’s (ADA’s) added the treatment algorith for type 2 diabetes, regarding metabolic surgery, as it was formulated at the 2nd Diabetes Surgery Summit. Therefore, they expanded the indication for metabolic surgery in patients with inadequately controlled diabetes and a BMI as low as 30 kg/m2 (25).
V. The new therapeytic algorith for type 2 diabetes in the guidelines of the European Association for Endoscopic Surgery
In 2020, the European Association for Endoscopic Surgery modified the clinical practice guidelines on bariatric surgery in accordance with the diabetes treatment algorithm of the 2nd Diabetes Surgery Summit , including metabolic surgery as a treatment option for patients with a BMI of 30 to 35 kg/m2, with poorly control type 2 diabetes (26).
VI. The new therapeytic algorith for type 2 diabetes in the guidelines of the American Society for Metabolic and Bariatric Surgery
Finally, in 2022, the American Society for Metabolic and Bariatric Surgery followed the 2nd Diabetes Surgery Summit’s treatment algorithm for diabetes type 2, extending the role of metabolic surgery as a strong consideration treatment option for patients with inadequately controlled diabetes and BMI 30 to 35 kg/m2 (27).
Conclusion
Type 2 diabetes remains a medically incurable disease that, despite aggressive pharmacological and lifestyle change treatment, remains inadequately controlled in the majority of patients. On the other hand, according to the growing body of clinical long-term evidence, metabolic surgery is more effective than medical and/or lifestyle interventions in producing diabetes remission, glycemic control and weight loss in obese patients.
Even though metabolic surgery is a well-known and proven method of managing type 2 diabetes, we consider that diabetes care providers and patients are still inadequately informed about the indications, benefits, and potential risks of surgical treatments for diabetes type 2. As metabolic surgery is now included in the treatment algorithm for diabetes type 2, access to surgery should be adequately prioritized and offered as therapeutic approach to eligible patients.
