Physical activity has a more beneficial effect on the risk of all-cause mortality in patients with metabolic syndrome than in those without

Physical activity (PA) has a beneficial effect on reducing all-cause mortality [1, 2], and current expert guidelines recommend consistent PA of at least 150 min/week of moderate-intensity or 75 min/week of vigorous-intensity aerobic PA for adults [3]. However, roughly half of the real world population does not meet the recommended amount of PA [4]. In particular, those with cardiovascular diseases (CVDs) were reported to be more sedentary and less active than healthy individuals [5, 6], possibly because of physical unfitness, even though individuals with CVD may benefit from PA to a greater extent than healthy subjects without CVD [7]. Therefore, studies that investigate whether earlier encouragement of PA could be helpful to those at risk of CVD are needed. We previously reported that sustained PA was associated with a decreased risk of all-cause mortality in those with hypertension or diabetes mellitus, who are at a high risk of CVD, more strongly than in those without hypertension or diabetes mellitus. [8] However, whether PA is more helpful for those with metabolic syndrome (MS) than for those without MS has not yet been clarified.

MS is a cluster of cardio-metabolic risk factors including abdominal obesity, insulin resistance, hypertension, and hyperlipidemia. The estimated global prevalence of MS is approximately one-quarter of the world population, affecting more than a billion people worldwide [9]. Considering that PA is beneficial to those with cardiovascular diseases and MS is strongly linked to cardiovascular diseases [10], it is crucial to determine whether PA is also beneficial and is even more helpful to those with MS. Therefore, the aim of this study is to elucidate whether regular PA has interactions with MS on health outcomes, including the risk of all-cause mortality.

In total, 9,628,109 participants (mean age, 46.3 ± 13.7 years; 55.3% were male) were included in the analysis. Figure 1 shows the flowchart of the study enrollment. The baseline characteristics of the total population and participants according to the amount of PA are presented in Table 1. Additional file 1: Table S2 shows the baseline characteristics of the participants according to the presence of MS.

The median follow-up duration of this cohort was 8.3 years (interquartile range, 8.1- 8.6). A total of 335,970 (4.23 incidence rate per 1000 person-years) participants died during follow-up. Table 2 and Additional file 1: Figure S1 show that greater amounts of PA were associated with lower all-cause mortality regardless of the presence of MS after adjustment for age, sex, smoking status, alcohol consumption, and body mass index (aHR, 0.87; 95% CI, 0.86, 0.88 for Group 2, aHR, 0.84; 95% CI 0.83, 0.85 for Group 3, aHR 0.79, 95% CI 0.78, 0.80 for Group 4, and aHR 0.82, 95% CI 0.81, 0.84 for Group 5 compared to Group 1 in participants without MS, P for trend < 0.001; aHR, 0.86; 95% CI 0.85, 0.87 for Group 2, aHR 0.82, 95% CI 0.81, 0.83 for Group 3, aHR 0.75; 95% CI 0.74, 0.77 for Group 4, and 0.78, 95% CI 0.76, 0.80 for Group 5 in participants with MS, P for trend < 0.001). When the interaction of MS on the relationship of PA and mortality was evaluated, there was a significant multiplicative interaction (P for interaction < 0.001).

This trend was the same for incident CVD. As the amount of PA increased, incident CVD decreased regardless of the presence of MS (P for trend < 0.001 for both with and without MS groups). There was also a significant multiplicative interaction (P for interaction < 0.001) of the presence of MS on the relationship between PA and incident CVD.

A similar trend was noted in that all-cause mortality and incident CVD decreased as the amount of PA increased, and the inclination was steeper in the participants with more risk factors for MS (Fig. 2 and Additional file 1: Tables S3 and S4).

This large population-based cohort study shows that those with MS get more benefit in reduced all-cause mortality risk from PA than those without MS. PA was also associated with a decreased risk of incident CVD in individuals with MS to a greater extent than in those without MS.

It has been reported that those with MS have a higher risk of CVD outcomes and all-cause mortality compared to those without MS [16, 17]. This finding suggests that prevention and management of MS are important. The current mainstay of treatment remains lifestyle modification with PA and diet [18]. PA reforms body composition, reduces body mass index and waist circumference, and improves metabolic and cardiovascular profiles including fasting blood glucose or blood pressure in people with MS [19]. Moderate-to-vigorous PA is also associated with a reduced risk of major cardiovascular events and mortality in those with MS [16]. However, it has not yet been studied whether PA is more effective in those with MS compared to those without MS in terms of reducing all-cause mortality risk. Consistent with previous studies, this study showed that PA is associated with reduced all-cause mortality in a dose-dependent manner both in those with and without MS (Table 2). Those with MS who engaged in 1–499 MET-minutes/week had a 14% lower risk of mortality, while those who performed 500–999 MET-minutes/week had an 18% lower risk, and those who engaged in 1000–1499 MET-minutes/week had a 24% lower risk of all-cause mortality. In those without MS, the reduced risks of all-cause mortality for the three PA groups were 13%, 16% and 21%, respectively. The analysis revealed that the presence of MS has a multiplicative interaction with PA on the effects of decreased risk of all-cause mortality. To our knowledge, this is the first study demonstrating that those with MS can obtain even greater benefits in reduced all-cause mortality risk from PA than those without MS. Additionally, our study also shows that PA is more helpful to those with MS compared with those without MS for a decreased risk of CVD incidence. The majority of the observed mortality reduction in those with MS who performed sufficient PA could have resulted from a reduced CVD risk. The results of this study demonstrate that those with MS, a more common and larger group of individuals with pre-CVD status, should be encouraged to engage in PA.

The biologic mechanism for how PA has a more beneficial effect on longevity in patients with MS than in those without MS has not been clarified. Several plausible explanations are as follows. First, PA can improve the metabolic profile, including insulin sensitivity, hepatic glucose production or utilization of fatty acids, which is worse in patients with MS compared to those without MS [8]. Thus, the effect of PA might be more dramatic in individuals with MS. Second, sarcopenia is closely associated with MS and physical inactivity [20] as insulin resistance in MS is associated with hyperinsulinemia and elevated myostatin levels, both of which reduce skeletal muscle mass [21]. PA has a positive effect on muscle mass and muscle function [22, 23], and skeletal muscle is a potential antioxidant organ during inflammatory reactions such as those associated with MS. This positive effect of PA on sarcopenia might contribute to increased longevity, especially in patients with MS. Third, PA can reduce systemic inflammation and oxidative stress, which can lead to endothelial dysfunction, arterial stiffness, and vascular dysfunction; thus, PA can reduce the risk of micro- and macrovascular complications [8, 24]. As patients with MS are more vulnerable to cardiovascular disease directly because of inflammatory pathways or indirectly via increased production of reactive oxygen species, endothelial dysfunction, and vascular dysfunction [25], PA in these individuals could contribute to the improving of these phenomena, thus extending longevity.

In this study, more than half of the study participants did not reach the recommended level of PA. Intriguingly, the effect of decreasing mortality risk was also observed among those who performed PA at the level of less than recommended in this study. The mortality risk decreased most steeply in the group with the lowest level of PA (1–499 MET-minutes/week PA) (Table 2 and Additional file 1: Figure S1). This trend was similar in both with or without MS. In fact, previous studies also reported that a lesser amount of PA than what is currently recommended can still have significant health benefits [26]. A study showed that running, even with a slow speed and for a short duration, was associated with markedly reduced risks of all-cause mortality and cardiovascular disease [27]. In our study, the proportion of individuals who were completely sedentary was higher in the group with MS than in the group without MS (26.2% vs. 23.2%). These findings suggest that even a small amount of PA can lead to a significant health benefit, which can provide good motivation for the people who need PA, including those with MS.

There have not been consistent results regarding the upper limit of PA for obtaining health benefits. Whether the dose response relationship between PA levels and health benefits is curvelinear [28], U-shaped [29, 30], or reverse-J shaped [1] is still under debate. One study suggested that the optimal amount of PA is 960–2400 MET-minutes/week and that no additional benefit can be obtained above this level of PA [26]. Another study showed that strenuous runners have statistically similar mortality rates as sedentary nonrunners and reduced longevity compared to mild or moderate runners [29]. The present study showed a plateau or slight increase of the mortality in the group with ≥ 1500 MET-minutes/week compared to the other groups with lower amounts of PA, although the group with the largest amount of PA obtained more benefits than the sedentary group. There was no difference in this trend according to the presence of MS. This may suggest that extreme PA may be associated with a partial loss of health benefits. However, it should be interpreted more cautiously with additional objectively collected data such as accelerometers. Also, more detailed segmentation of higher levels of PA and additional epidemiological and interventional studies may be warranted to confirm whether the dose–response relationship between PA levels and health benefits is curvilinear, U-shaped, or inverted J-shaped.

The strengths of this study are as follows. First, this study is a large-scale population-based study with strong statistical power to show the interaction between MS and PA on longevity. Second, this is the first study focusing on the interaction of PA and MS on all-cause mortality. This study result might be helpful to emphasize and encourage PA among individuals with MS. We also admit that this study had limitations. First, the amount of PA was measured based on the self-declared 7-day recall questionnaire, which might be affected by recall bias. However, the 7-day recall survey has been widely used and is well validated in many previous studies. Second, cause-specific death was not evaluated in this study. However, judging from the similar trend in the incident CVD results, mortality from CVD seems to have had a great influence on all-cause mortality. Third, this study does not provide a specific type of exercise that is most effective in reducing negative outcomes in people with MS. Further studies should be conducted.

In conclusion, those with MS may experience even greater longevity-extending benefits from PA than those without MS. Physicians should place greater emphasis on the importance of PA, especially in those with MS, and encourage them to engage in PA.