metabolic syndrome and cardiovasc events

A nationwide population-based Korean study found that changes in metabolic syndrome status were associated with altered risk for cardiovascular events (see metabolic synd rx dec cv risk aim2019 in dropbox, or doi:10.7326/M19-0563)

Details:
-- 27,161,051 people involved in national health screenings from 2009 to 2014 were evaluated in 2009, 2011, and 2013 for changes in metabolic syndrome (MetS) and cardiovascular outcomes. 9,553,042 people had appropriate data to qualify, in the following groups:
    -- MetS-free group: 6,940,663 people without MetS on the three screenings
    -- MetS-chronic group: 1,486,485 people with MetS on all three screenings
    -- MetS-developed group: 587,088 people without MetS on the initial screen but with MetS on the second and final screen
    -- MetS-recovery group: 538,806 people with MetS on initial screen but without MetS on the second and final screen
-- MetS was defined as at least three of: increased waist circumference (> 90 cm for Asian men and > 80 cm for Asian women), elevated triglyceride level (> 150 mg/dL, though by error they say 50), low HDL (<40 mg/dL for men and <50 mg/dL for women), elevated blood pressure (systolic> 130 mmHg, and/or diastolic> 80 mmHg), elevated fasting glucose (> 100 mg/dL)
-- there were some significant differences in the baseline characteristics of these groups of patients: the MetS-chronic group had the oldest population (median age 58 versus 45 in the MetS-free); the MetS-free and MetS-recovery groups had the highest proportion who exercised; heavy or moderate alcohol consumption was more common in younger participants in all groups; the MetS-developed group included a higher percent of older people and people with high BMIs or Charlson Comorbidity Index scores; and the MetS-chronic group more often had five MetS components at the health examination than the other MetS groups
 -- primary outcome: occurrence of MACE (major adverse cardiovascular events), defined as an acute myocardial infarction, revascularization, and acute ischemic stroke
-- median follow-up 3.5 years after the final screen

Results:
-- incidence rate of MACE:
    -- MetS-free: 1.92 per 1000 person-years
    -- MetS-recovery: 4.55 per 1000 person-years
    -- MetS-developed: 6.05 per 1000 person-years
    -- MetS-chronic: 8.52 per 1000 person-years
    -- per their graphs, the cumulative incidence of MACE was linear and continued to increase over six years, with the greatest slope in the MetS-chronic, next in the MetS-developed, then next in MetS-recovery, and the lowest slope in the Met-S free group
-- for those whose MetS status changed, the single MetS component of hypertension was associated with the largest difference in MACE risk:
    --for those developing MetS, blood pressure was 3x more likely to be the major component leading to MACE differences over triglycerides and HDL, and 5x more than impaired glucose tolerance (IGT) and waist circumference
    --for those recovering from MetS, blood pressure was slightly more likely than IGT, but was 6x more likely than waist circumference or triglycerides; and HDL had no relationship with MACE events
--comparing those with MetS-recovery vs MetS-free, there was a 19% increase in MACE, adjusted incidence rate ratio aIRR 1.19 (1.16-1.22), p<0.001 [ie, a history of MetS in those who later recovered seemed to confer an increased MACE risk over those consistently without MetS]; and there was no difference between those who developed MetS vs those with chronic MetS, aIRR 1.00 (0.98-1.02)
--comparing those with MetS-recovery vs MetS-chronic, there was a 15% decrease in the former group, aIRR 0.85 (0.83-0.87), p<0.001; and comparing those who developed MetS vs those who remained MetS-free, there was a 36% increase MACE with aIRR 1.36 (1.33-1.39), p<0.001 [ie, developing MetS led to more MACE, and recovering from MetS led to less]


Commentary:
-- the metabolic syndrome (MetS) has long been associated with major adverse cardiovascular events, the leading cause of death in adults worldwide
-- MetS is expected to continue to increase in the future as obesity increases worldwide:
    -- an analysis of the 2016 National Health and Nutrition Examination Survey found that the prevalence of prediabetes was 18% in adolescents and 24% in young adults, moreso in males and those with obesity (though, of note, prediabetes was still present in 16% of those with normal weight, though 26% in obese adolescents and 37% in obese young adults). Also, those with prediabetes had significantly higher non-HDL cholesterol levels, systolic BP, central obesity and lower insulin sensitivity: ie, metabolic syndrome (see dm prevalence kids jamaped2019 in dropbox or doi:10.1001/jamapediatrics.2019.4498 )
     --one important take-home message in the NHANES study is that even in adolescents/young adults, prediabetes and metabolic syndrome overall seem to be remarkably prevalent (this study does not provide granular data on combinations of cardiometabolic parameters which would better define metabolic syndrome accurately, but the overall groups who were prediabetic had increased likelihood of the other components of the metabolic syndrome)
    -- studies have confirmed that glucose intolerance itself, without full-fledged diabetes, is associated with increased cardiovasc effects: see http://gmodestmedblogs.blogspot.com/2016/12/prediabetes-and-cardiovascular-risk.html
    --and, many with prediabetes had normal weight (ie, we should probably still be checking A1c’s in normal weight adolescents and young adults, since 1 in 7 are still likely to have prediabetes); and we should encourage appropriate lifestyle changes (esp diet, exercise) and follow them more closely given the longterm risks of prediabetes and metabolic syndrome

-- the above Korean study found a gradient of MACE, correlating with the intensity of MetS, with those recovering from MetS having a lower rate than those developing it [not sure exactly how to interpret this: did those developing MetS have a higher rate of MACE because they had MetS for a longer time? Perhaps they  had it for close to 6 years in this study (developing it one month after the initial negative screen), then continued for the 3.5 subsequent years; but those recovering just had it for 2 years between the first and second screen??? we really need a longterm observational study with many datapoints to understand if it is the quantitative load of MetS (ie number of years with the number of MetS components) that really mattered]
-- it is not clear that those recovering from MetS might have been through medical intervention versus lifestyle change, or what the role of these were
-- I am also not sure why blood pressure was the component most associated with altering the risk of MACE. Perhaps, in this short study, it was the one that changes most rapidly leading to MACE changes. and, my guess, more clinicians are focused on addressing hypertension more quickly than high lipids. and waist circumference does take a longer time to change (since there is no magic pill)
--limitations of the study: a single largely homogenous population, so ??generalizability (though was a huge study, with pretty consistent findings); retrospective analysis so cannot attribute causality; short followup so no info about changes in MetS over the long-term or the quantitative effect of MetS over time in MACE


So, the study reinforces on a large scale a few things:
-- the various components of the metabolic syndrome confer a large increase in adverse cardiovascular outcomes, and these adverse outcomes are (unsurprisingly) moderated by a regression in the metabolic syndrome
-- the magnitude of this increase is quite impressive: there was more than a fourfold increased risk of major adverse cardiovascular outcomes when comparing those with MetS versus those without MetS
-- and this study suggests that there may be a residual risk of increased MACE in those who had MetS in the past, since those who recovered from MetS had more cardiovasc events than those who did not have MetS (though this should be tested further in subsequent longer-term studies). this suggests that we clinicians should inquire about past history of MetS components (eg changes in waist circumference, knowledge about prediabetes) as a potential risk factor for subsequent clinical cardiovasc events.

bottom line: metabolic syndrome is really common, getting more common with global increases in obesity, has profound longterm impact on major cardiovascular outcomes, and really needs to be addressed aggressively. And, as with all really important lifestyle changes, this involves a concerted public health initiative that is not only well-funded and organized, but also includes real fundamental social changes to reinforce a healthy lifestyle (improved focus and access for exercise, healthy diet, weight loss programs, etc). And, as clinicians, more resources to help us implement healthy lifestyle programs for patients: eg motivational interviewing, perhaps group visits, cooking classes (since it seems that many people do not cook healthy foods at home), group exercise programs, and (perhaps most important given the large number of kids who have prediabetes) focused interventions on kids and families to prevent metabolic syndrome in the first place... 

geoff​

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geoff