Principle Study: The effect of exercise training on clinical outcomes in patients with the metabolic syndrome: a systematic review and meta-analysis

Metabolic syndrome is defined as having at least three of five clinical risk factors that are shown in Figure 1: elevated fasting glucose, abdominal obesity, high blood pressure, elevated triglycerides, and reduced high-density lipoprotein (HDL). The prevalence of metabolic syndrome is increasing worldwide, and an estimated 33% of adults in the U.S. now meet the criteria for metabolic syndrome. This represents an enormous public health challenge because metabolic syndrome is associated with a 50% increased risk of developing cardiovascular disease and at least a twofold risk of developing type 2 diabetes.

Exercise has the potential to improve metabolic syndrome and reduce the risk of developing more severe diseases like heart disease and type 2 diabetes. Previous meta-analyses have shown exercise to benefit people with metabolic syndrome and patients with type 2 diabetes. However, as these analyses used studies which involved a combination of diet and exercise, the contribution of exercise per se to producing these benefits is uncertain. In addition, most studies included in these meta-analyses utilized endurance exercise interventions. At least one meta-analysis of resistance training has suggested it may benefit blood pressure but not other criteria of metabolic syndrome.

Different types of exercise and levels of exercise intensity may also have different effects on the metabolic syndrome. The above-mentioned meta-analysis in participants with type 2 diabetes suggested that there was no difference between high-intensity and low- to moderate-intensity exercise for changes in glycemic control. Another meta-analysis comparing high intensity interval training to steady state medium intensity was unable to find enough evidence to draw any conclusions around the most effective exercise intensity. Thus, how exercise type and intensity impacts factors of the metabolic syndrome remains unclear.

In the study under review, the authors set out to evaluate the health effects of exercise intensity and type in people with metabolic syndrome by conducting a meta-analysis of randomized, controlled trials.

Metabolic syndrome is an increasingly prevalent collection of risk factors for cardiovascular disease and diabetes. Exercise has been shown to improve the health of people with metabolic syndrome, but the role of exercise type and intensity remains uncertain. However, previous reviews of the evidence, which included both exercise only and exercise plus diet interventions, have not isolated the role of exercise. This study pooled the existing experimental evidence from previous trials to investigate the role of exercise alone in improving metabolic syndrome.

Who and what was studied?

This was a meta-analysis of randomized controlled trials comparing an exercise intervention to a sedentary control group in people with metabolic syndrome at baseline. Trials with a dietary component were only included if the diet was consistent across both the exercise and control group. Ultimately, the scientists included 16 studies with 23 comparisons. Of these, 19 comparisons involved only aerobic exercise and four combined aerobic and resistance training. Only four of the studies involved a diet component consistent across the control and exercise arms; the rest had strictly exercise components. The studies lasted eight to 52 weeks, with an average duration of about 16 weeks. It’s important to note that this study was preregistered, which helps minimize reporting bias.

The preregistered primary outcomes were differences between groups for changes in BMI, waist circumference, triglycerides, HDL-C, and blood pressure—the metabolic syndrome criteria. Secondary outcomes were changes in body weight, waist-to-hip ratio, fat mass, VO2peak, max heart rate, fasting blood glucose, LDL-C, HbA1c, adiponectin, IL-6, TNF-alpha, and CRP. Each of these outcomes was assessed for each of the exercise modalities separately (aerobic only and combined). A subgroup analysis was performed among the aerobic training studies to examine the role of exercise intensity.

Heterogeneity, the degree of variability between studies, was quantified using the I2 test, in which I2 values can range from 0% (homogeneous) to 100% (greater heterogeneity). Risk of bias among the included studies was assessed using funnel plots. The quality of the studies included in the meta-analysis was assessed using the TESTEX scale, a quality assessment tool specific to exercise training studies. The nine factors assessed include whether the participants were randomly allocated, groups were similar at baseline, whether exercise volume and the energy expended was reported, and activity monitoring of the control group.

This was a meta-analysis of 16 randomized controlled trials in people with metabolic syndrome investigating the effects of exercise training on the diagnostic criteria for metabolic syndrome. The analysis included studies utilizing aerobic exercise only, and studies combining aerobic and resistance exercise. Analyses were performed for each type of exercise modality separately and subgroup analyses compared interventions of differing exercise intensity.

What were the findings?

Aerobic exercise alone was shown to significantly improve BMI (-0.29), waist circumference (-1.4 cm), triglycerides (-18 mg/dL), and blood pressure (-2.5 mmHg systolic; -2.3 mmHg diastolic) when compared to the sedentary control. It also significantly reduced body weight, fat mass, fasting blood glucose, and LDL-c, and increased VO2peak. HDL-C remained unchanged when looking at all of the data, and heterogeneity was moderate to high for all primary and most secondary outcomes.

Combined aerobic and resistance exercise significantly improved waist circumference (-3.8 cm), systolic blood pressure (-3.8 mmHg), and HDL-C (+5 mg/dL). It also resulted in significant increases in VO2peak. However, it failed to significantly alter any of the other outcomes compared to the sedentary control, and heterogeneity was moderate to high for all significant outcomes. You can see a summary of how aerobic exercise alone compared to combined exercise across the different factors that make up the metabolic syndrome in Figure 2.

Subgroup analysis of the results by exercise intensity showed that VO2peak improved the most with high intensity aerobic exercise (+5.50 mL/kg/min) and combined exercise training at moderate intensity (+4.83 ml/kg/min). Reductions in systolic blood pressure were greatest with high intensity aerobic exercise (-6.4 mmHg). Changes in other outcomes were unaffected by the intensity of exercise.

Some studies had both the exercise and control groups undergo a simultaneous dietary intervention; other studies didn't. Comparing both kinds of studies suggested no difference in any outcome. Additionally, there was no influence from whether the participants had type 2 diabetes at baseline, the total weekly exercise time, or the total exercise program time. Funnel plots of the primary analyses showed mild to moderate evidence of publication bias as more than one-third of the studies fell outside the funnel plot border. This suggests that there was a good chance that one or more studies had not been published due to negative trial results. Studies averaged nine out of 15 points for study quality assessment, with the most common issues relating to assessor blinding and activity monitoring of the control group. However, the authors did not report on whether or not these biases could have impacted on their results.

Aerobic exercise significantly improved all aspects of metabolic syndrome except HDL-C, as well as several other related metabolic and body composition variables. Combined aerobic plus resistance training significantly improved waist circumference, systolic blood pressure, and HDL-C only. Exercise intensity appeared to influence cardiorespiratory fitness and blood pressure, with a greater benefit observed with more intense exercise, but other risk factors were similar between intensities.

What does the study really tell us?

This study tells us that aerobic exercise alone and combined aerobic and resistance exercise improves most parameters of metabolic syndrome. Both aerobic and combined exercise reduced waist circumference and systolic blood pressure. Aerobic exercise additionally reduced fasting plasma glucose, diastolic blood pressure, and triglycerides. Higher intensity exercise had a more favorable effects on some risk factors like blood pressure and HDL cholesterol compared to lower intensity exercise, but most changes were equivalent between intensities. Both types and intensities of exercise could reduce the risk of metabolic disease compared to sedentary control participants.

Importantly, however, some of the benefits, while statistically significant, were often small and may not be clinically meaningful. For instance, the 1.2 kg weight loss resulting from aerobic exercise, and none from combined exercise, didn’t reach the 3% to 5% weight loss considered clinically significant for health benefits. However, it should be kept in mind that the average duration of the studies was only 16 weeks; this leaves open the possibility of clinically significant weight loss if exercise is sustained over a long-term. Also, even small improvement, if sustained over the long term, could reduce the risk of developing more serious health problems such as diabetes. While the weight loss was not very impressive, some of the other changes may indeed be more impactful. For instance, combined moderate intensity aerobic and resistance exercise improved waist circumference by almost four centimeters. This result may be clinically meaningful, since a reduction in waist circumference of over two centimeters has been associated with reduced incidence of the metabolic syndrome, as shown in Figure 3. The reduction in systolic blood pressure of 2.5 - 4 mmHg for aerobic and combined exercise may also be clinically significant; this drop is large enough to result in a roughly 10% decrease in CVD risk based on trials of blood pressure lowering medication; however this exact number should be taken with a grain of salt, since medications may impact CVD risk differently than exercise does. Similarly, increases in HDL-C in response to combined exercise and high intensity aerobic exercise were large enough to be associated with reduced heart disease.

However, the clinical implications just described remain mildly speculative, as the metabolic syndrome is essentially a related cluster of risk factors for metabolic diseases; it’s not really a “disease” in itself. So, we can't know for sure how impactful exercise will be on actual diseases like CVD from these results alone. Even so, there exists a wealth of evidence that exercise prevents CVD, so it’s a pretty good assumption that the results from this study would lead to real benefits. The size of benefit is somewhat more in question, though.

Much of this evidence suggests that activity and cardiorespiratory fitness, while interlinked, independently relate to CVD risk. Thus, it is notable that VO2peak was significantly improved in both aerobic and combined exercise programs. This improvement also confirms that the participants were taking part in the exercises that were improving their cardiorespiratory fitness. The improvements in VO2peak were greater than 1 MET (3.5 ml/kg/min), which is considered to be clinically significant.

Overall, comparisons between aerobic only and combined training were not statistically significant for any outcome. However, the magnitude of improvement was notably greater in some outcomes with combined training, such as with waist circumference (-3.8 vs -1.4 cm) and VO2peak (+4.6 vs +3.0 mL/kg/min). More research investigating combined training and comparing its effectiveness directly to aerobic training only is necessary before strong conclusions about superiority (or the lack of) can be made. The fact that combined exercise did not show as large an effect in some other measures as aerobic exercise may be due to the smaller number of studies. Since only four studies utilized combined training, it is possible that a failure to detect significant differences was a result of insufficient statistical power. More research down the road would lead to higher sample sizes that may be able to reveal a difference. Also, since studies analyzing the effects of resistance training alone were completely disregarded, it is also difficult to estimate the individual contributions of the resistance and aerobic exercise components to the previously described changes.

The amount of exercise the participants took part in is an important consideration. However, in this study, neither weekly nor total exercise time significantly affected the outcomes measured. Trials involving aerobic training alone used between three to five sessions per week, for six to 52 weeks, with individual sessions lasting 30-60 minutes each. Trials involving combined exercise used between two to three sessions per week, for 12 to 52 weeks, with sessions of between 40 and 75 minutes. This suggests that this amount of exercise takes a long time to achieve benefits. Plus, since the longest trial was a year, this leaves open the question of whether improvements would continue to be seen past this mark, or whether the moderate improvements here will top out with time. Further longer-term research is needed in order to address this question.

An important limiting factor that was not included in this meta-analysis is how well the participants in these studies adhered to the exercise regimes. There is currently little agreement on how adherence should be measured in studies such as these. Adherence involves several factors beyond just attendance. For example, participants may complete the exercise sessions but not exercise at the required intensity or duration, which can be difficult to measure. Ensuring adherence using heart rate monitors results in greater improvements in health than when adherence was defined as session attendance alone. Differences and inaccuracies in measures of adherence may have resulted in larger effects in this meta-analysis.

One final limitation to mention is publication bias. The analyses of publication bias from this meta-analysis suggested that some studies with negative results may not have been published, although an exploration of how this could impact the authors’ conclusions were not presented in this paper. This lack of published negative results can make the interventions used, such as exercise, appear more effective than they are.

This meta-analysis supports the notion that both aerobic and combined aerobic and resistance exercise is useful for individuals with metabolic syndrome. The small number of trials included prevent any definite conclusions as to whether aerobic only or combined exercise is more effective and whether there is an optimal level of exercise intensity. Most importantly, however, the overall size of the some of the beneficial changes resulting from increased exercise were moderate and their clinical significance is not completely certain.

The big picture

This study attempted to evaluate the effects of exercise alone in individuals with metabolic syndrome by pooling the results of randomized controlled trials in a meta-analysis. Its results support the conclusions of previous meta-analyses that have found beneficial effects of exercise interventions for improving metabolic syndrome criteria. For example, it corroborates reviews that have reported that resistance exercise can reduce blood pressure and reduce waist circumference in people with metabolic syndrome by showing that combined aerobic and resistance training leads to larger reductions in these risk factors than aerobic-only exercise training.

While this study is interesting because it attempted to isolate the effects of exercise alone, in reality, exercise would usually be advised in combination with other healthy lifestyle changes, including diet, to improve the health of an individual’s metabolic syndrome. Overall non-sedentary activity beyond a small number of defined exercise periods each week may also be important. The amount of time spent sitting and a sedentary occupation have been associated with increased risk of metabolic syndrome. In another study, the proportion of sedentary time was strongly related to risk of metabolic syndrome, independent of exercise activity. Another potential contributor to the metabolic syndrome includes disturbed sleep and circadian rhythms, which are also emerging as a factor in the development of metabolic syndrome. In view of the plethora of different factors that influence the development of metabolic disease and their complex interactions, increasing exercise alone may not be enough to result in dramatic benefits.

There have been few studies published testing resistance training alone, although those that have have shown positive benefits. A recent meta-analysis of seven trials testing resistance training found a significant average reduction in systolic blood pressure of 4.1 mmHg. Other components of the metabolic syndrome, though, were unchanged. However, the reductions in blood pressure would have been great enough to reduce the risk of developing heart disease and stroke significantly, assuming they could be maintained.

There is a lack of large, comparative randomized trials comparing the effects of aerobic exercise to resistance exercise alone on the metabolic syndrome. One randomized controlled trial that compared both types of exercise directly reported that, while aerobic exercise was effective at improving metabolic syndrome, resistance exercise alone was not. Combined aerobic and resistance exercise was no more effective than aerobic exercise alone. However, other results from the same study show that combined aerobic and resistance exercise alone led to improvements in insulin sensitivity. Whether that is due to a special synergy of aerobic and resistance training or a mere result of the overall increase in training volume cannot be said based on this study. Overall, the results do suggest that aerobic exercise was the most effective for improving metabolic syndrome. Future studies will have to elucidate whether and to what extent greater amounts of both aerobic and resistance exercise may potentially be more effective at improving insulin resistance.

In individuals with metabolic syndrome, exercise is a promising strategy to ameliorate its long-term negative health effects. While studies investigating the effects of resistance training alone were not included in this meta-analysis, previous research suggests that resistance training can help some aspects of the metabolic syndrome. It is important to understand, though, that exercise on its own may not fully correct the metabolic problems and should be combined with other healthy lifestyle changes. An overall non-sedentary lifestyle, reduced amounts of time spent sitting, and improvements in diet and sleep quality are also likely to be important factors in improving the health of individuals with metabolic syndrome.

Frequently asked questions

How did the concept of "metabolic syndrome" come about?

The concept of the metabolic syndrome developed over the latter part of the 20th century as it became recognized as a cluster of metabolic derangements related to obesity that predisposes people to future ill health and may be linked by similar underlying mechanisms. As early as 1956, it was noted that increased abdominal obesity predisposed individuals to diabetes and heart disease. Later observations that abdominal obesity can worsen glucose metabolism and that insulin resistance can cause hypertension resulted in scientists beginning to see obesity, insulin resistance, and hypertension as the three hallmark features of a yet unnamed metabolic disorder. In 1988, Reaven proposed the name “syndrome X,” centered around insulin resistance, to describe individuals at significantly increased risk of cardiovascular disease who showed a cluster of insulin resistance, hyperinsulinemia, high triglycerides, low HDL cholesterol, and hypertension. In 1999, the WHO introduced the name “metabolic syndrome.” The etiology of metabolic syndrome is complex. Interactions between insulin, inflammation, and obesity may lie at the heart of the syndrome.

What should I know?

This meta-analysis is the first to pool the results from randomised controlled trials investigating the benefits of exercise alone in individuals with the metabolic syndrome. The results showed that both aerobic exercise and combined aerobic and resistance exercise had moderate benefits. People who exercised reduced their waist circumference, blood pressure, fasting blood glucose, triglycerides, and LDL-C while raising their HDL-C compared to sedentary control subjects. However, the overall size of the individual beneficial changes were modest, but, if sustained, were possibly large enough to lead to reduced long-term risk of disease. These individual benefits remained largely unchanged by the intensity of the exercise. The improvements in VO2peak confirmed that the participants undertaking the exercise improved their cardiorespiratory fitness. The limited number of studies available make it impossible to identify the optimal type and/or intensity of exercise, however. What appears to be certain though, is the fact that a truly “optimal” intervention will have to combine exercise with lifestyle changes in form of dietary changes, improved sleep hygiene, and a decrease in sedentary time.