Does the Role of Metabolic Surgery in Class I Obesity Differ by Race?

| May 15, 2014

by CPT Margaret E. Clark, MD, and LTC (P) Robert B. Lim, MD, FACS

Dr. Robert B. Lim, MD, and Margaret E. Clark, MD, are from the Tripler Army Medical Center, Honolulu, Hawaii.

Abstract
It has been consistently shown that metabolic surgery improves and controls diabetes and metabolic syndrome in patients with body mass indices above than 35kg/m2. However, the majority of patients with type 2 diabetes mellitus have a body mass index less than 35kg/m2. Patients with longer standing type 2 diabetes mellitus are more resistant to remission, which suggests that newly diagnosed patients should be considered for metabolic surgery. Moreover, the level where body mass index is associated with type 2 diabetes mellitus differs among different ethnicities. Asian patients are at greater risk for metabolic syndrome and type 2 diabetes mellitus at a lower body mass index than Caucasians. Given this large cohort of patients and the continued advances in metabolic surgery, there is increased consideration to performing surgery on patients with type 2 diabetes mellitus and a body mass index above 30kg/m2, or even 27.5kg/m2 in Asian populations. Here, we review the current literature regarding the use of metabolic surgery to obtain type 2 diabetes mellitus remission in class I obesity, the differences between different races and their metabolic risks, and the mechanisms in which metabolic surgery allows for the remission, and potential cure, for diabetes melliutus.

Introduction
It has been consistently shown that metabolic surgery improves and controls diabetes and metabolic syndrome in patients with body mass indices more than 35kg/m2. The National Institutes of Health (NIH) guidelines from 1991 recommended that weight loss surgery should be considered in those individuals with a body mass index (BMI) above 40kg/m2 or 35kg/m2 with a high-risk comorbidity such as severe type 2 diabetes mellitus (T2DM), life-threatening cardiopulmonary problems, or obesity-induced physical problems that interfere with lifestyle.[1] This may be forcing or encouraging patients to gain weight simply so they can qualify for surgery; or we, as physicians, are simply not offering these patients the opportunity to have T2DM remission, improved cardiovascular risk status, and overall improved health based on guidelines that are over 20 years old. Furthermore, these guidelines have not been revised despite continued advances that show weight loss surgery has profound metabolic effects even at lower BMIs and the fact that surgery appears to be potentially curative for individuals with class I obesity (BMI 30–35kg/m2) and T2DM.

Metabolic Surgery and Diabetes
In a meta-analysis and review of the literature in 2006, 78 percent of patients with T2DM experienced complete resolution, and 87 percent either improved or had resolution of their disease after bariatric surgery.[2] The biliopancreatic diversion/duodenal switch (BPD/DS) had the best T2DM remission rate, 95 percent, followed by Roux-en-Y gastric bypass (RYGB), 80 percent. The laparoscopic adjustable gastric banding (LAGB) showed resolution in 57 percent of patients.[2]

The Swedish Obese Subject (SOS) study, among many others, demonstrated improved recovery rates from hypertension, T2DM, hypo-high-density lipoprotein (HDL), and hypertriglyceridemia in surgically treated patients. They found that the incidence of T2DM was reduced 30-fold in those who underwent metabolic surgery.[3]

Bariatric surgery has continued to show better results when compared head-to-head against the best medical therapy. In a prospective study that included 34 percent of subjects with a BMI below 35kg/m2, Schauer et al[4] showed statistically significant remission rates for T2DM in the surgery versus medical group at 1 Year. The remission rate for the surgery group was 42 percent versus 12 percent for in the medical treatment group.4 When looking at the cardiovascular effects of intensive lifestyle modifications in patients with obesity and T2DM, the Look AHEAD (Action for Health in Diabetes) research group stopped their trial at 9.6 years due to futility analysis showing that intense medical interventions did not reduce the rate of cardiovascular events.[5] Given the continued published data demonstrating that surgery leads to an overall improvement of the metabolic status of the patient, the presence of T2DM or metabolic syndrome, rather than a patient’s BMI, may be a better indicator for the consideration of surgery.

Mechanisms of T2DM Improvement
There are multiple mechanisms in which metabolic surgery is thought to improve, or even cure, T2DM. Metabolic changes are observed shortly after surgery that suggests that the mechanism of action is not due only to weight loss.[6] It is thought that the mechanism in the early phase postoperatively is relief of insulin resistance, and later the combination of this relief along with the augmentation of insulin secretion.[7] Bypassing of the foregut is thought to play an important role in T2DM reversal. By excluding the proximal small intestine, there is less secretion of anti-incretin hormones, which leads to improvement of blood glucose control. The more rapid delivery of nutrients into the distal small bowel causes an increase in hormones such as glucagon-like peptide-1 (GLP-1).[6,8] The increase in GLP-1 levels stimulates the normal glucose-induced insulin secretion, suppressing glucagon and improving glucose metabolism. In order for this increase in GLP-1 to play a role in reversing diabetes, the patient needs to have sufficient residual beta cells.9 Patients with long-standing diabetes may be less likely to have resolution of their disease due to the disease’s effect on beta cells.

Hormone removal, specifically the decrease in grehlin levels, assists with weight loss and diabetes management post-metabolic surgery. Ghrelin is produced in the fundus of the stomach and upper intestine. After sleeve gastrectomy (SG) and RYGB, ghrelin levels are reduced and peptide YY levels are increased. Reduction of ghrelin levels and increased peptide YY levels are thought to be associated with greater appetite suppression and weight loss.10 Leptin may also play a role, as plasma leptin concentrations usually reflect the amount of fat present in the body. Lower leptin levels have been reported in patients after weight loss, and have also been shown to be reduced even early after RYGB, prior to seeing a decrease in the patient’s weight.[8]

Weight loss alone also plays a role in the resolution of T2DM, since it has been shown that weight loss achieved by lifestyle changes can be effective in preventing and treating T2DM. Some have expressed concern that operating on a lower BMI population would cause excess weight loss; however, this has not been shown to occur. Even in procedures that typically produce the greatest reduction in weight, such as the BPD, there is not a risk of excessive or undue weight loss due to a maximum energy absorption capacity, which corresponds to a stabilization of weight.[11] There appears to be a homeostatic mechanism that prevents excess weight loss. The NIH Consensus Development Conference Panel on gastrointestinal surgery for severe obesity1 examined 18 studies and found that 477 patients with BMIs below 35kg/m2 experienced reasonable weight loss and did not report serious excessive weight loss or malnutrition after undergoing bariatric surgery.[1]

The remission rate of T2DM does, however, vary according to the surgical procedure. Malabsorptive techniques have been shown to obtain improved T2DM remission rates over restrictive techniques. Though the LAGB has shown less resolution of T2DM, this may still be a valid option in a lower BMI cohort of patients given its lower mortality/morbidity rate. Since the LAGB is a restrictive procedure, the improvement in T2DM is likely not only due to weight loss, but also the decreased calorie intake. Strict calorie restriction can bring normalization of plasma glucose and insulin levels before seeing the decrease in weight.[7] The stress of any metabolic surgery can also lead to an improvement in T2DM by inducing the secretion of catecholamine and inhibiting insulin secretion.[7]

Table 1

The Role of Surgery in Class I Obesity
Given the multiple mechanisms in which metabolic surgery leads to a reversal in T2DM, and that patients with a lower BMI have not been shown to have excessive weight loss or malnutrition, we believe that weight loss surgery should be considered for patients with T2DM and metabolic syndrome, and not only for those patients with BMIs above 35kg/m2. In 2013 the American Society for Metabolic and Bariatric Surgery (ASMBS) released a position statement recommending that patients with class I obesity who do not achieve substantial weight loss and improvement in their comorbidities with nonsurgical methods should be offered bariatric surgery as an available option for the management of their disease.[13] Randomized, control trials have shown gastric banding, sleeve gastrectomy, and gastric bypass to be a well-tolerated and effective treatment for patients with BMIs between 30 and 35kg/m2. Metabolic surgery appears to be as beneficial in patients with BMIs below 35kg/m2 as it is for patients with BMIs above 35kg/m2, especially in regards to T2DM control and remission. In a recent review, 16 studies examining patients with lower BMIs who underwent metabolic surgery showed an average T2DM remission rate of 85.3 percent.[14] In the NIH review of 18 studies totaling 477 patients with BMIs below 35kg/m2, the complete T2DM remission rate was 64.7 percent, but a total of 86.8 percent of patients were off medications.[12] Subsequently the International Diabetes Federation (IDF) has also recommended that surgery be considered an alternative treatment option in patients with a BMIs between 30 and 35kg/m2 when optimal medical management, especially in the presence of major cardiovascular disease risk factors, cannot adequately control T2DM.[15] There continues to be growing evidence that proves that surgery should be considered a treatment option for patients with BMIs between 30 and 35kg/m2 and T2DM or metabolic syndrome.

Obesity Differences in Race
The recommendation for metabolic surgery for patients with a BMIs above 30kg/m2 may not be adequate for every race. According to the World Health Organization (WHO), the number of people with diabetes worldwide is projected to increase and reach 366 million by 2030 with T2DM in India, China, and some other Southeastern Asian countries at the forefront of the T2DM epidemic.[16] It has been estimated that the Asia Pacific region will have more than half of the world’s diabetic population by 2025.[16] Despite Americans having the highest rates of obesity, they have the lowest levels of diabetes,17 and Caucasians have been found to have a lower T2DM risk than all other ethnic groups.18 Despite these differences, the same guidelines for bariatric surgery have been followed independent of ethnicity. The Asian population tends to develop diabetes and cardiovascular disease with a lesser degree of obesity than in other areas of the world. In some Asian countries, 27.5kg/m2 has become a cut-off point for Class I obesity. The World Health Organization (WHO) determined that the cut-off point for high risk of T2DM and cardiovascular disease varied from 26 to 31kg/m2.[19] Unfortunately, it is difficult to determine a universal BMI scale. While the Asian populations have lowered cut-off values by three units, which seemed appropriate for Hong Kong Chinese, Indonesians, and Singaporeans, this BMI cut-off value would be too much of a drop for northern Chinese and Japanese. The WHO uses 27.5kg/m2 as a trigger point for public health action, indicating a BMI over 27.5kg/m2 as high risk and 23 to 27.5kg/m2 as increased risk for metabolic disease. Given that there is not a constant correlation between BMI and T2DM risk, the use of BMI may not be the best indicator for metabolic surgery. For instance, in a hospital in Taiwan, only 1.8 percent of 2,555 patients with T2DM have a BMI above 35kg/m2, and still only 25 percent have a BMI above 27kg/m2.17 The risk of metabolic syndrome in the Asian population starts at what is considered a normal BMI in Caucasians (22–23kg/m2).[20] If a patient develops metabolic syndrome and T2DM at a BMI between 22 and 23kg/2 and has to wait until he or she has a BMI of even 27kg/m2 for surgery, their T2DM may be too long standing to have the best chance of recovery. A recent study showed that non-Hispanic black and Hispanic patients were less likely than non-Hispanic white patients to experience metabolic syndrome resolution.[21] These patients may already have had permanently impaired metabolic processes and long-standing disease, further emphasizing that metabolic surgery may be most effective for patients earlier in their disease course, especially in certain races/ethnicities.

Metabolic Surgery in an Asian Population
The Asian population has been studied extensively given their known risks at lower BMIs, and metabolic surgery has been shown to be effective when specifically looking at this population. Shah et al[22] reviewed RYGB outcomes in 15 Asian Indian patients with T2DM and BMIs between 22 and 34kg/m2. They found that these patients had a 100-percent remission rate at nine months.[22] All patients were euglycemic and off all anti-diabetic medications by three months. At nine months, hypertension was corrected in 6 of 9 patients and dyslidemia corrected in 14 of 14 patients. Despite their average BMI starting at 28.9, these patients benefited from metabolic surgery.

In a study out of Taiwan, Lee et al[17] studied 44 patients with BMIs below 35kg/m2. They found a return to normoglycemia in 89.5 percent of patients at 12 months. Even with the Asia-Pacific Bariatric Society modifying the indication for bariatric surgery to include patients with a BMI above 32kg/m2 and T2DM,23 most patients in this population with T2DM still do not meet criteria for metabolic surgery.

The Asian population has a different body composition and insulin sensitivity than Caucasians.[22] Increased visceral adiposity leads to an increased rate of T2DM and metabolic syndrome. Asians generally have a higher percentage of body fat than Caucasians of the same age, sex, and BMI; and the proportion of Asians with risk factors for T2DM and cardiovascular disease is significant even below the cut-off point for overweight (BMI>25kg/m2).[19] In Asians, BMI is not a significant predictor of diabetes, hypertension, and/or comorbidity, as opposed to Caucasians and African-Americans where BMI and waist circumference are positively related to all three.24 In a longitudinal study of incident diabetes in a multiethnic American population, Asians overall had lower BMIs but a steeper increase in T2DM risk as their BMI and visceral adiposity increased when compared to other ethnicities.[18] Asians have shown the greatest risk per increase in BMI, followed by Caucasians and Hispanics, then African Americans; though for a given level of obesity, the risk of diabetes was lower in Caucasians than all other ethnic groups.[18]

Long-Term Effects of Surgery
If metabolic surgery continues to be offered at earlier ages and lower BMIs, there needs to be more long-term data on the remission rates and outcomes of surgery. There are limited data on the short- versus long-term effects of metabolic surgery on the amelioration of diabetes; however, most of the data that have been presented in the literature have been positive. In the SOS study,25 it was found that after 10 years, the risk of developing T2DM was over three times lower in patients who had undergone bypass surgery, and all types of bariatric surgery were associated with a reduced incidence of T2DM.[25] This study found that bariatric surgery reduced the long-term incidence of T2DM by 78 percent in patients with obesity. In the patients that started with an impaired fasting glucose, bariatric surgery reduced their risk of T2DM by 87 percent. The SOS study also found that baseline BMI did not influence the preventive effect of surgery on T2DM, implying that BMI alone is not useful in the selection of candidates for surgery and that data on impaired fasting glucose levels may be helpful in selection.

In a study of 53 patients with BMIs between 30 and 35kg/m2, 73.1 percent of patients had complete remission of T2DM, 84.6 percent achieved euglycemia, and most importantly, 96.2 percent had improvement in their metabolic status even at the end of five years.[26] In those patients with mild obesity, hypertension and dyslipidemia also improved and yielded a 50 to 84-percent reduction in predicted 10-year cardiovascular disease risks of fatal and nonfatal coronary heart disease and stroke.[27] For up to six years following RYGB in this cohort of patients, T2DM remission remained in 88 percent of patients with gylcemic improvement in another 11 percent.[27]

Long-Standing T2DM
In order to obtain the best T2DM remission rates after metabolic surgery it should not be considered a “last resort,” as it has been shown that patients who have had T2DM for longer than five years have less chance of reversal.[26,28] The natural evolution of T2DM is progression toward persistent insulin resistance in association with decreased insulin secretion.[9] Patients, who undergo metabolic surgery and remain diabetic afterwards, have shown to have a longer duration of the disease, which suggests they lack sufficient residual beta cells to recover normal glucose regulation.[28]

In a study of 71 patients with diabetes who underwent RYGB,29 having a preoperative duration of T2DM greater than 10 years was shown to significantly reduce the chance of remission. As preoperative duration increased, there was a trend toward reduced remission rates from 75 to 33 percent.[29] Schauer et al[28] found that those patients who had the disease for less than five years were most likely to achieve complete remission after RYGB.[28] Given that a mechanism for remission is the improvement of beta cell function, patients need to have sufficient residual cells in order to show this improvement. With long-standing T2DM there is a progression toward complete destruction of beta cells. Thsi is why we believe that metabolic surgery should be considered early before irreparable pancreatic damage occurs, and not viewed as a last resort in the management of T2DM.

Conclusion
Metabolic surgery is effective for T2DM and metabolic syndrome, and is beneficial at lower BMIs, especially in certain ethnicities. Patients with longer standing T2DM are more resistant to cure after metabolic surgery, which suggests that even patients with mild obesity who are newly diagnosed with T2DM should be considered for metabolic surgery. In the United States, immigrants will obtain the obesity rates of US born adults by about 15 years,[30] but by this time their T2DM may be so long standing that surgery may not be as beneficial. More research needs to be done to fully appreciate the impact of metabolic surgery on the lower BMI patients as it pertains to race. All healthcare providers should be aware of the use of surgery in patients with class I obesity and be cognizant that this recommendation may be at an even lower BMI for certain ethnicities.

References
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DISCLAIMER: The views expressed in this article are those of the authors and do not reflect the official policy of the Department of the Army, Department of Defense, or the United States Government.

FUNDING: No funding was provided.

DISCLOSURES: The authors report no conflicts of interest relevant to the content of this article.

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