Bariatric Surgery for the Metabolic Syndrome: Magic Bullet or Not?

Abstract

R ecent years have witnessed an epidemic of metabolic syndrome in developed nations. Thirty-five percent of adults in the United States have metabolic syndrome.¹ However, the problem is not restricted to Western or developed societies. Developing nations are also catching on at a furious pace. A third of the adults in Middle Eastern and South Asian countries also have the metabolic syndrome.^2,3 Metabolic syndrome confers an increased risk for both diabetes and cardiovascular diseases. In the Diabetes Prevention Program, Orchard et al. showed that both lifestyle changes and metformin therapy reduced new-onset metabolic syndrome significantly compared to usual care.⁴ Esposito et al. showed that a Mediterranean-type diet compared to a conventional diet resulted in weight loss, reduction in biomarkers of inflammation, and reduction in the diagnosis of metabolic syndrome by 43% at 2 years.⁵ Thus, therapeutic lifestyle changes resulting in weight loss are the cornerstone of therapy for the metabolic syndrome. However, adherence to a weight loss regimen is far from optimum and long-term compliance is generally poor.

Recently, various forms of bariatric surgery including Roux-en-Y gastric bypass surgery (RYGB) and biliopancreatic diversion have been shown to decrease body weight, hyperglycemia, blood pressure, cardiovascular events, and mortality.⁶ Although most studies have shown an improvement in the individual components of metabolic syndrome, only a handful of studies have evaluated the resolution of metabolic syndrome after RYGB surgery.

In a study published in this issue of the Journal, Saboya et al.⁷ evaluated the effect of RYGB surgery on metabolic syndrome and its features. They also asked the question whether preoperative body mass index (BMI) modifies the effect of RYBG on the resolution of metabolic syndrome. They retrospectively analyzed the charts of patients who had undergone RYGB surgery at their center. Sixty-eight percent of the obese subjects who had undergone RYGB at their center between 2005 and 2009 had metabolic syndrome at baseline. They selected subjects who had follow-up data available to assess for presence of metabolic syndrome for 6 months. Out of the 149 subjects thus selected, 34 subjects had a BMI between 35 and 39.9 kg/m² (group 1), 79 subjects had a BMI between 40 and 49.9 kg/m² (group 2), and 36 subjects had BMI ≥50 kg/m² (group 3). At 30 days postsurgery, more than half of the subjects in groups 1 and 2 did not have metabolic syndrome any more, whereas 75% of subjects with a pre-RYGB BMI of ≥50 kg/m² still had the metabolic syndrome. However, 6 months after RYGB, almost all subjects in groups 1 and 2 (94% and 92%, respectively) could not sustain the diagnosis of metabolic syndrome, whereas 22% of subjects in group 3 still had metabolic syndrome. Overall, only 45% of subjects had metabolic syndrome at 30 days and 10% had metabolic syndrome at 180 days. Subjects in group 3 were four times more likely than those in groups 1 and 2 to have persistent metabolic syndrome 6 months after RYGB.

Before we analyze the change in individual components of metabolic syndrome after surgery, it is important to compare the baseline prevalence of the metabolic syndrome components among the three groups. As expected, all 149 subjects had abnormal waist circumference. Approximately 80% of subjects in all groups also had abnormal triglyceride and high-density lipoprotein cholesterol (HDL-C) concentrations. Those in group 3 had significantly higher prevalence of hypertension (97%) and hyperglycemia (72%) than those in groups 1 and 2 (≈50%–70%).

So, changes in which parameters were largely responsible for the resolution of metabolic syndrome? At both 30 days and 180 days, the most impressive falls were seen in serum triglycerides, serum glucose, and blood pressure. The prevalence of high triglyceride concentrations (>150 mg/dL) was low in all three groups (22%–35%) at 30 days and 180 days (4%–9%). Probably the huge reduction in dietary intake (presumably similar in all groups) that follows RYGB surgery was responsible for the massive reduction in triglycerides. Similarly impressive reductions in triglycerides have been seen in studies on obese or diabetic subjects undergoing RYGB surgery.⁸ The prevalence of hypertension and hyperglycemia declined in all groups, but their prevalence in group 3 (55% and 33%, respectively) was still higher than the other groups (11%–24%) at day 30. The prevalence of type 2 diabetes and the reduced β-cell function in some type 2 diabetes subjects (not mentioned in this study) likely contributed to persistence of hyperglycemia. There was no change in the prevalence of abnormal waist circumference or low HDL-C concentrations in any group at 30 days. In fact, the prevalence of low HDL-C increased in group 2 (77%–87%), probably due to the marked decrease in dietary caloric and lipid intake.

The results were more impressive at 6 months. More than 90% of subjects did not have abnormal triglycerides, hyperglycemia, or hypertension 6 months post-RYGB surgery, the exception being 19% prevalence of hypertension in group 3. There was a decrease in waist circumference; however, ≈60% of subjects in groups 1 and 2 and 94% of subjects in group 3 still had abnormal waist circumference at 6 months post-RYGB. There were modest increases in HDL-C concentrations at 6 months. However, around 60% of subjects in all groups still had abnormally low HDL-C concentrations at the end of the follow-up.

The metabolic changes seen in this 6-month follow-up are more impressive than those reported in studies with longer follow-ups.⁹ In this Spanish study with a longer follow-up of 7 years, a retrospective analysis revealed that whereas the prevalence of metabolic syndrome at 1 year compared to baseline, following laparoscopic RYGB, decreased to 12.5% from 53%, it crept back to 30% at 7 years of follow-up, probably due to the weight gain.¹⁰ Thus, Saboya et al. should continue to analyze their data for a longer duration of follow-up. They have presented data on 23% of the subjects with metabolic syndrome who underwent RYGB. The rest of the subjects with metabolic syndrome did not have follow-up data at 30 days and 90 days. It is possible that subjects with lack of follow-up data had a higher complication rate and lesser resolution of metabolic syndrome components.

A major deficiency of the Saboya et al. study is the failure to report on adverse outcomes. A recent report from the Bariatric Outcomes Longitudinal Database of 23,106 patients with metabolic syndrome showed that subjects with metabolic syndrome by a nonclassical definition have a 40% higher rate of serious complications (a composite end point of death, operative complications, and postoperative morbidity) following RYGB surgery as compared to those without metabolic syndrome.⁹ We also do not know from this study if the resolution of the metabolic parameters is more in subjects with metabolic syndrome than in those without. More information on the absolute changes in serum glucose and lipid concentrations, blood pressure, and waist circumference (as well as changes in the use of medications) rather than the prevalence of abnormalities would also be informative. It is possible that these absolute changes were more impressive in those with the highest BMI (group 3), even though the resolution of the abnormalities was least in that group.

The retrospective analysis of Saboya et al. cannot decipher the cause of the changes in components of metabolic syndrome. Whereas some of the changes are undoubtedly due to decreased caloric intake and weight loss, the benefits of RYGB are also due to changes in incretins (glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide), peptide YY, and other unidentified modulators of the neuro–gastrointestinal axis. RYGB surgery increases the concentrations of glucagon-like peptide-1 concentrations that can lead to suppression of appetite, delayed gastric emptying, and enhanced insulin secretion.¹¹ In addition, it has also been shown that RYGB surgery and weight loss lead to a significant reduction in the indices of inflammation.¹² Because inflammatory mediators like tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and suppressor of cytokine signaling-3 are known to interfere with insulin signal transduction, their suppression is likely to contribute to the reversal of insulin resistance, a major component of the metabolic syndrome. The remarkable remission and possible “cure” of diabetes following bariatric surgery is exciting; however, the precise mechanisms remain elusive.¹³ To date, the molecular pathogenesis remains to be resolved for the benefits of bariatric surgery, but investigators all over the world are investigating mechanisms involving the incretin axis, other gut hormones, adipokines, hepatic metabolism (including bile acids), and their signaling.¹⁴

In conclusion, the addition of bariatric surgery is a provocative and attractive strategy for patients with metabolic syndrome because as a single intervention it can reduce the prevalence of the syndrome; however, this enthusiasm needs to be tempered by the fact that there are adverse effects related to these procedures. We are unaware of other long-term consequences of micronutrient deficiencies, and before recommending this surgery for our patients, further long-term studies and cost–benefit analyses need to be conducted, especially in patients with metabolic syndrome without overt diabetes or in patients with a BMI ≥40 or a BMI ≥35 with high risk of co-morbid conditions of obesity.¹⁵ However, it is clear that elucidating the mechanisms at the molecular level can usher in new therapeutic targets for this galloping global epidemic.

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