|Year : 2015 | Volume
| Issue : 1 | Page : 16-21
Moving goal posts: Definition of diabetes remission after bariatric surgery
Saranya Ravindra, Alexander Miras
Division of Diabetes, Endocrinology and Metabolism, 6th Floor Commonwealth Building, Hammersmith Hospital, Imperial College London, Du Cane Road, London W12 0NN, United Kingdom
|Date of Web Publication||6-Jan-2015|
65 Blenheim Road, North Harrow, Middlesex, HA2 7AQ
Source of Support: None, Conflict of Interest: None
The escalating twin pandemics of obesity and type 2 diabetes mellitus (T2DM) present a major global public health burden. Bariatric surgery is an effective treatment for obese patients with T2DM, as it not only causes weight loss, but also improves metabolic risk factors including glycemia, hypertension and dyslipidemia. Although several studies have shown impressive remission rates of T2DM following bariatric surgery, these studies have used different definitions of remission. In an attempt to solve the problem of inconsistent definitions, the American Diabetes Association and International Diabetes Federation, two large diabetes organizations, have developed standardized criteria for T2DM remission. These criteria are comprised of clinical parameters including glucose, lipid and blood pressure control and medication usage. Studies using these criteria have reported lower rates of remission than those previously reported using nonstandardized definitions. This review describes the existing literature on remission of T2DM following bariatric surgery, and emphasizes the importance of using the standardized definitions established in order to improve remission rates and thus reduce the incidence of the macrovascular and microvascular complications of T2DM.
Keywords: American Diabetes Association, bariatric, diabetes, International Diabetes Federation, remission
|How to cite this article:|
Ravindra S, Miras A. Moving goal posts: Definition of diabetes remission after bariatric surgery. J Obes Metab Res 2015;2:16-21
| The Problem of Obesity and Type 2 Diabetes Mellitus|| |
The global prevalence of type 2 diabetes mellitus (T2DM), a chronic multifactorial disease, is rising dramatically and presents a major global public health burden. , In 2013, an estimated 382 million people had T2DM, and this number is predicted to rise to 592 million by 2035 according to the International Diabetes Federation (IDF).  The rising prevalence of T2DM is associated with the current obesity epidemic driven by an obesogenic environment favoring sedentary behavior and increased consumption of calorie-dense foods. Approximately 90% of patients with T2DM are overweight or obese,  illustrating the close association between these two complex diseases.
Type 2 diabetes mellitus is a risk factor for vascular disease, including both microvascular (retinopathy, nephropathy and neuropathy) and macrovascular complications (myocardial infarction, stroke and peripheral vascular disease), leading to premature morbidity and mortality.  However, this risk may be diminished by interventions that achieve normal glycemic control. , Modest weight loss in overweight or obese patients with T2DM is associated with improvements in glycemic control and associated conditions such as hypertension and dyslipidemia. ,
| Lifestyle and Pharmacological Treatments for Obesity And Type 2 Diabetes Mellitus|| |
The initial treatment for T2DM associated with obesity is lifestyle modification, involving a healthy diet, calorie restriction and increased physical activity, in attempt to lose weight. In the Look AHEAD (action for health in diabetes) trial, intensive lifestyle intervention caused significant weight loss and improvement in glycated hemoglobin (HbA1c) levels, and was more effective than routine lifestyle advice in achieving remission of T2DM (defined as fasting plasma glucose <6.9 mmol/l, HbA1c <6.5% with no hypoglycemic medication) at 1-year. ,, However, the average weight loss in the intensive lifestyle intervention group decreased from 8.6% at 1-year to 4.7% at 4 years and the rate of patients achieving T2DM remission markedly reduced from 12% at 1-year to 7% at 4 years, indicating that weight loss and glycemic control is difficult to maintain in the long-term with lifestyle interventions.
Orlistat, a gastrointestinal lipase inhibitor, is currently the only drug licensed for the treatment of obesity. Compared to placebo, Orlistat reduced weight by ~2.8%  and HbA1c by ~0.4%  in T2DM patients; however, these effects are moderate and patients often report unpleasant gastrointestinal side effects during its use.
Glucose-lowering pharmacotherapy is the mainstay treatment of T2DM. However, until recently, the management of T2DM has been particularly challenging in obese patients, as with the exception of Metformin, most glucose-lowering agents and insulin therapy result in weight gain,  which may further impair metabolic control. Since 2006, the introduction of glucagon-like peptide-1 (GLP-1) analogues, dipeptidyl peptidase-4 inhibitors and sodium-dependent glucose transporter-2 inhibitors has dramatically altered the management of these patients, as these glucose-lowering agents are either weight neutral or cause weight loss. ,, However, there are limited data on the long-term efficacy and safety of these medications.
| Bariatric Surgery- Description Of Procedures and Effects on Weight Loss|| |
0Bariatric surgery, a form of gastrointestinal surgery designed to produce substantial weight loss, is the most effective treatment for obese patients with T2DM. ,,,, It is currently offered to those with a body mass index (BMI) of >35 kg/m 2 with comorbidities or >40 kg/m 2 without comorbidities.  Surveys by the International Federation for the Surgery of Obesity and metabolic disorders reported that the global number of bariatric procedures in 2011 was 340,768, of which the Roux-en-Y gastric bypass (RYGB), vertical sleeve gastrectomy (VSG) and adjustable gastric banding (BAND) accounted for 47%, 28% and 18% of procedures respectively. 
The RYGB, first reported in 1967, involves the division of the stomach into the upper pouch, ~15-30 ml in volume, and larger gastric "remnant". The stomach pouch is anastomosed to the mid-jejunum via a gastro-jejunal anastomosis. Bowel continuity is established by a jejuno-jejunal anastomosis between the excluded biliopancreatic limb and the alimentary limb, performed 75-150 cm distally to the gastro-jejunostomy. Thus, following RYGB, ingested food bypasses the stomach, duodenum and proximal jejunum. Gastric, pancreatic and biliary secretions still flow through the biliopancreatic limb and mix with food in the jejunum. , The BAND, described in 1993, involves the insertion of an adjustable band around the upper part of the stomach, just below the gastro-esophageal junction, to create a small pouch. The volume of fluid in the band is adjusted by injecting or withdrawing fluid through a subcutaneous port, altering the level of pressure on vagal afferents. , The VSG, a more recently established one-stage procedure, involving the surgical removal of ~70% of the stomach along its greater curvature, is also being increasingly performed due to its relative simplicity and impressive clinical outcomes. , The biliopancreatic diversion (BPD) involves a partial gastrectomy, leaving a functional 400 ml gastric pouch. The gastric pouch is anastomosed to the distal 250 cm of the small intestine, and an anastomosis between the excluded biliopancreatic limb and the alimentary limb is formed 50 cm proximally to the ileocecal valve. , The BPD-duodenal switch (BPD-DS) variant is performed as a two-stage procedure; a VSG is first performed followed by the BPD component. , Although the BPD and BPD-DS, both malabsorptive procedures, have excellent statistics for sustained weight loss and improvement of comorbidities, their use has declined during the past decade, now accounting for only 2.2% of bariatric procedures.  This is due to fat malabsorption following these procedures, causing diarrhea and nutritional complications.
Data from the Swedish Obese Subjects (SOS) study, the largest and longest nonrandomized prospective study in the field, and randomized clinical trials (RCTs) reporting the effects of bariatric surgery in obese patients with T2DM show that the RYGB and VSG cause ~25-30% and the BAND 20% total body weight loss, which is sustained in the long-term. ,,,,, These three procedures, which take ~1-1 hours to perform, carry a 1:10 risk of complications and confer a low overall early mortality rate of <0.3% at 30 days. 
| Bariatric Surgery and Type 2 Diabetes Mellitus|| |
A number of studies have illustrated the impressive effects of bariatric surgery on obesity-related comorbidities, including hypertension, dyslipidemia and T2DM. ,, The SOS study showed a greater sustained remission rate of T2DM in the 2037 obese patients that underwent bariatric surgery compared with that of well-matched control patients at 2 and 10 years follow-up.  A high-profile meta-analysis by Buchwald et al. reported that 78% of T2DM patients experienced complete resolution of T2DM following bariatric surgery.  This publication shifted the focus of clinicians from weight to glucose and gave rise to the term "metabolic" surgery. However, this meta-analysis had important limitations, as the 136 studies included were mostly retrospective, variable in their duration of follow-up and used inconsistent definitions of remission of T2DM.
Randomized controlled clinical trials
More recently, there have been 5 RCTs that provide level I evidence for the substantial effects of bariatric surgery on T2DM, shown in [Table 1]. The Diabetes Surgery Study reported that at 1-year, 49% of obese patients with T2DM who underwent RYGB achieved the composite of American Diabetes Association (ADA) treatment goals, compared to 19% of patients that received intensive lifestyle intervention.  Two RCTs investigating T2DM remission at 2 years reported substantially higher remission rates of 73%, 75% and 95% in patients that underwent BAND, RYGB and BPD respectively, compared to patients who received conventional medical therapy. , Schauer et al. showed that at 3 years, patients who underwent either RYGB or VSG achieved T2DM remission rates of 38% and 24% respectively, compared to 5% in patients that received intensive medical therapy. , These RCTs show that bariatric surgery is more effective than lifestyle modification and medical therapy in achieving glycemic control.
|Table 1. Randomized controlled clinical trials comparing bariatric surgery with medical treatment for the treatment of type 2 diabetes mellitus (T2DM)|
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| Differences Between the Surgical Procedures|| |
There is general agreement among published studies that gastrointestinal bypass procedures have a higher remission rate than non-bypass procedures including BAND and VSG.  This may be because although the RYGB, BAND and VSG all cause a long-term reduction in insulin resistance due to weight loss, the RYGB immediately improves glycemic control following bariatric surgery before there is substantial weight reduction, suggesting it also acts through weight-independent mechanisms. One proposed mechanism is that following RYGB, there is an exaggerated secretion of certain gut hormones, such as GLP-1, from the distal small bowel in response to nutrients. GLP-1 acts as an incretin, stimulating the secretion of insulin by beta cells in the pancreas, thus improving glycemic control.  There is evidence that the VSG also has incretin effects, though there is a lack of data on the metabolic effects of this procedure.
| Definition of type 2 Diabetes Mellitus Remission- The Problem and the Solutions|| |
Although all the above studies illustrate the impressive remission of T2DM after bariatric surgery, what becomes clear from the above is that the definition of T2DM "remission" after bariatric surgery is inconsistent between studies. This may account for the difference in remission rates reported, in addition to other factors including differences in preoperative BMI, duration of T2DM, medical therapy, type of bariatric procedure performed, length of follow-up postoperatively and extent of weight loss amongst others.
In an attempt to develop standardized definitions that can be used consistently in clinical studies, a consensus group from the ADA, was the first to define "complete" remission as HbA1c <6% and fasting glucose <5.6 mmol/l, and "partial" remission as HbA1c <6.5% and fasting glucose 5.6-6.9 mmol/l, both of at least 1-year duration following bariatric surgery in the absence of glucose-lowering pharmacological therapy.  Complete remission of at least 5 years' duration is defined as prolonged remission and is considered a "cure" of T2DM. In 2011, the IDF was the second large diabetes organization to introduce comprehensive criteria defining the "optimization" and "substantial improvement" of the metabolic state using not only markers of glycemia and medication usage, but also weight loss, plasma lipids and blood pressure (BP).  The ADA and IDF criteria are shown in [Table 2].
|Table 2: The American Diabetes Association (ADA) and International Diabetes Federation (IDF) criteria defining the complete and partial remission of type 2 diabetes mellitus (T2DM) and optimization and improvement of the metabolic state respectively|
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| Studies that have used the American Diabetes Association and International Diabetes Federation criteria|| |
Although bariatric surgery is associated with substantial improvements in BMI, glycemic, lipid and BP control, studies that have used the ADA criteria have reported substantially lower T2DM remission rates of 35-53% at 1-3 years following bariatric surgery, ,,,,, compared to those reported in the meta-analysis by Buchwald et al. and subsequent studies ,,,,, that used more liberal, nonstandardized definitions, shown in [Table 3]. In two retrospective studies, Ramos-Levi et al. reported 36% and 53% of patients achieved the ADA's target recommendations 1-year after bariatric surgery. , Pournaras et al. showed that at a median follow-up of 23 months after bariatric surgery, rates of complete remission were 40.6% after RYGB, 26% after VSG and 7% after BAND.  Recently, Brethauer et al. were the first to report long-term remission according to the ADA criteria, and reported complete and partial remission rates of 24% and 26% respectively in a U.S cohort 5-6 years after bariatric surgery.  Miras et al. not only used the ADA criteria, but also the IDF criteria, and reported that only 14% and 8% of patients achieved IDF optimization of the metabolic state at 1 and 2 years after bariatric surgery respectively. 
|Table 3. Studies that have assessed type 2 diabetes mellitus (T2DM) remission rates according to American Diabetes Association (ADA) criteria following bariatric surgery|
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The relatively low rates of patients achieving T2DM remission according to the ADA and IDF criteria raises questions as to the magnitude and durability of the effects of bariatric surgery.
| Explanation of the low remission rates|| |
The ADA and IDF criteria provide standardized definitions of remission of T2DM by two large, well-established organizations. The required weight loss and parameters for BP and lipid levels in the IDF criteria are consistent with the ADA treatment goals of BP < 130/80 mmHg and low-density lipoprotein cholesterol < 2.3 mmol/l.  However, certain parameters included in the criteria are very stringent. The HbA1c cut-off value of <6.0% required to achieve ADA complete remission or IDF optimization of the metabolic state is more stringent than the ADA treatment goal of HbA1c <7.0% required to be achieved by T2DM patients treated non-surgically. Additionally, the IDF criteria consist of an increased number of criterions compared to other definitions of diabetes remission. Therefore, the relatively low percentage of patients meeting the ADA and IDF criteria compared to previously used definitions of remission of diabetes may be due to the stringency of the criteria themselves.
| Limitations of the American Diabetes Association and International Diabetes Federation criteria|| |
0Although comprehensive, certain aspects of the IDF criteria are somewhat vague and leave room for interpretation. IDF optimization of the metabolic state states "no hypoglycemia", without specifically stating the acceptable number of episodes or severity of hypoglycemia. The IDF criteria also require the absence or reduction of medication from baseline, without specifying which classes of medication must be reduced. Furthermore, considering that what is important in terms of long-term prevention of macrovascular and microvascular complications is intensive control of cardio-metabolic risk factors, and not number of medications, this criterion may need to be either revised or removed from both sets of criteria.
| Conclusion|| |
It is important to use an agreed definition of the remission of T2DM to measure the success of bariatric surgery effectively. Although bariatric surgery has been shown to substantially improve cardio-metabolic risk factors, including glycemia, lower remission rates of T2DM remission according to the ADA and IDF criteria have been reported compared to previously used definitions. This may be due to the stringency of these criteria, of which certain aspects may need to be clarified and revised. In addition, there may be a need for increased use of medications postoperatively in order to increase the remission of T2DM, and more importantly reduce the incidence of the microvascular and macrovascular complications of the condition.
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[Table 1], [Table 2], [Table 3]