Our population-based study demonstrates that MetS is a largely reversible phenomenon in patients with class II-III obesity and that reversibility of MetS depends more on the % of excess weight lost than on other clinical or demographic characteristics.
Although the reversibility is possibly influenced by or associated with other factors, including age, baseline serum TG, and baseline diabetes status, these factors, although significant in our univariate analysis at follow-up, were not as strongly predictive for MetS resolution as % excess weight loss. This relationship persisted even in the BMI-independent definition of MetS suggesting its importance on the other MetS components. Patients in the structured, multidisciplinary, non-surgical program demonstrated minimal weight changes associated with improvements in systolic blood pressure and lipid parameters; however, much of these improvements may have been related to more aggressive pharmacotherapy, as a significantly greater number of non-operative patients at follow-up were on statins or antihypertensive agents.
Relatively few studies have used established MetS criteria in evaluating outcomes after bariatric surgery15,16
. All have demonstrated marked improvements in the prevalence and in the number of components as outlined by the definition of MetS and confirm our results. Several studies have examined non-American populations16-19
, in whom RYGB is often not used. Of studies performed in the United States with RYGB, Madan and colleagues20
demonstrated a decrease in MetS as defined by Adult Treatment Panel (ATP) III from 78% to 2%; however, this study was relatively small, did not have a non-operative group, and follow-up was limited to one year. Another study by Mattar et al21
found a decrease from 70 to 14% in a series of 70 patients.
Although their follow-up was somewhat greater in duration, they had similar limitations to the Madan study. Mornigo's group22
examined RYGB using criteria from the ATP-III and demonstrated a decrease in MetS prevalence from 55% to 36% at six weeks, and to 11% at 52 weeks, but their study was limited to 36 patients without a control group. Our study confirms and expands these findings with the use of state-of-the-art epidemiologic methods supporting these conclusions. To the best of our knowledge, our study is the first to assess predictors of MetS resolution in patients with class II-III obesity, showing that % excess weight loss is the main contributor of whether a patient will be cured of MetS at follow-up. The use of an obesity-independent definition of MetS confirmed the importance of excess weight loss on resolution of MetS. Our study provides robust data to practicing clinicians regarding potential counseling regarding weight reduction in MetS patients.
The implications of our results are clinically important because our findings provide further understanding of the possible reversibility of MetS with weight loss. Does this reduction in MetS prevalence after bariatric surgery, and specifically after RYGB, reduce CV disease? There have been no studies using risk-prediction functions in MetS patients after bariatric surgery; however, in the past year, there have been studies projecting significant reductions in CV risk and death, including our own study that used risk modeling derived from the National Health and Nutrition Examination Surveys and applied it to this specific cohort23
. This study estimated that 4 overall deaths and 16 CV events would be prevented by bariatric surgery per 100 patients at 10-years. Only a few studies have examined specifically the decrease of actual CV events and overall mortality, and limitations due to lack of follow-up information or use of hospital controls likely underestimate the value bariatric surgery may offer 24-26
. Most recently, two studies have confirmed our previously published estimated risk reduction after bariatric surgery. One study examined 9,949 patients having undergone RYGB matched to obese controls demonstrated a 40% survival benefit27
, with cause-specific mortality due to coronary artery disease reduced by 56%. Furthermore, the Swedish Obesity Study also demonstrated a risk reduction of 29% at 10 years 28
. It is possible that mortality rates after bariatric surgery decrease in part because of the total or partial resolution of MetS.
Bariatric surgery decreases fat stores 29
and provides a better understanding of the reversibility of MetS with profound weight loss. Weight loss is known to reduce blood leptin and ghrelin levels, increase adiponectin levels, improve insulin sensitivity, and reduce fatty acid turnover, and is associated with a decrease in systemic inflammation and improved endothelial function30
. Whether there are differential effects of a duodenal bypass procedure as compared to gastric banding on the effects of incretins, insulin sensitivity, and the presence of glucose intolerance requires further investigation.
The main strength of our study lies in the use of the Rochester Epidemiology Project to ascertain all patients and outcomes referred for RYGB in Olmsted County, Minnesota. By using a population-based cohort, we minimized selection and referral bias often observed at tertiary care institutions performing this surgery. Previous studies have demonstrated reasonable extrapolation of data to other parts of the country using this population 12
. The ability to abstract a patient's entire medical record ensures that all information and outcomes relevant to this study were available. Although there have been a few studies examining the impact of bariatric surgery in patients with MetS, none have had a non-operative group whose characteristics were similar to the operative patients, and many have been performed in Europe where alternative techniques were used, including biliopancreatic bypass and gastroplasty. In addition, none of the recent studies have used the most updated MetS criteria published by the AHA/NHLBI. In studies examining MetS parameters after RYGB, the majority of studies examine outcomes up to one year, while our study provided follow-up of over three years. The use of an obesity-independent definition also provides credence to our results. We also performed a sensitivity analysis to determine the impact of missing patients on our intra-group results. Such an analysis ensures that in a worst case scenario, where these missing patients would not have metabolic improvements, the impact on our study results would be minimal, allowing adequate generalization of these results.
As with any retrospective study, recording and measurement bias are inherent issues in the study design. We had no control over when each patient had their laboratory or clinical assessment. Information regarding exercise, dietary habits, diagnosis or management of obstructive sleep apnea, leptin or insulin sensitivity, all of which are known confounders, was unavailable. These issues, however, would be present in both groups and at both points in time. The variability in the follow-up time created inherent challenges in analyzing our data. Normally, Cox-proportional hazard models should be utilized in inception cohorts where time to last follow up is variable, subjects are exposed to the predictor of interest since the beginning of the follow up and the risk is proportional to the time of follow-up and when the time when the outcome has occurred is well known. However, in our study group none of the latter three assumptions were met. Weight loss, particularly with bariatric surgery, normally occurs in a non-linear fashion within the first year 11
, with subsequent minimal weight regain following this time. On the contrary, using logistic regression appeared to be more appropriate than Cox proportional hazard models after proving that length of follow-up did not influence the association between % of excess weight loss and the resolution of MetS. We acknowledged the limitations of both approaches, and attempted to prove, by eliminating patients with less than one year of follow-up and stratifying the remaining cohort by follow-up time, that % excess weight loss was still significant in each of these analyses. Furthermore, adjusting our models by follow-up time also confirmed these results. This approach suggests that one year after baseline time, % excess weight is still the main predictor of MetS resolution.
The decision to undergo bariatric surgery cannot be allocated randomly. Finally, we made no attempt to match our non-operative group to our bariatric surgery group. In a matched analysis, ideally we would have required a greater number of non-operative patients, of which we were inherently limited. In addition, our non-operative group should not be considered as a true “control” group, but rather as a population-based cohort of patients referred for surgical intervention that did not undergo operative treatment, the results which may not be generalizable to all patients attempting weight loss with non-surgical approaches. Furthermore, very few of the non-operative patients achieved a weight loss that exceeded the mean weight loss by the operative group, implying that no significant impact on our results would be observed, even if we eliminated specific groups of patients, such as the underinsured. Our findings can only be applied to patients with class II-III obesity, who have undergone evaluation for RYGB bariatric surgery, the patient population that is most eligible for bariatric procedures10
, and hence cannot be extrapolated to non-obese patients with MetS or to patients treated with other types of bariatric procedures, including gastric banding.
Although MetS is thought to lead to the development of both type 2 diabetes mellitus and CV disease, we included patients with both of these diagnoses. One of the primary controversies in the MetS literature is the inclusion of diabetes into the ATP-definition criteria. Our study showed that the results were not altered after excluding patients with pre-existing diabetes or CV disease at baseline in our sensitivity analysis.