Comparative effect of physical exercise versus statins on improving arterial stiffness in patients with high cardiometabolic risk: A network meta-analysis

Iván Cavero-Redondo; Jonathan J Deeks; Celia Alvarez-Bueno; Kate Jolly; Alicia Saz-Lara; Malcolm Price; Carlos Pascual-Morena; Vicente Martínez-Vizcaíno

doi:10.1371/journal.pmed.1003543

. 2021 Feb 16;18(2):e1003543. doi: 10.1371/journal.pmed.1003543

Comparative effect of physical exercise versus statins on improving arterial stiffness in patients with high cardiometabolic risk: A network meta-analysis

Iván Cavero-Redondo ¹, Jonathan J Deeks ², Celia Alvarez-Bueno ^1,^*, Kate Jolly ², Alicia Saz-Lara ¹, Malcolm Price ², Carlos Pascual-Morena ¹, Vicente Martínez-Vizcaíno ^1,³

Editor: Kazem Rahimi⁴

PMCID: PMC7924736 PMID: 33591983

Abstract

Background

The comparative analysis of the effect of several doses of statins against different intensities of physical exercise on arterial stiffness (a measure of cardiovascular risk) could shed light for clinicians on which method is most effective in preventing cardiovascular disease (CVD) and be used to inform shared decision-making between doctors and patients. This study was aimed at analyzing the effect, in high cardiometabolic risk patients, of different statins doses and exercise intensities on arterial stiffness (a measure of cardiovascular risk) by integrating all available direct and indirect evidence in network meta-analyses.

Methods and findings

We systematically searched MEDLINE, Embase, SPORTDiscus, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Web of Science databases from their inception to February 28, 2020; for unpublished trials, we also searched ClinicalTrials.gov. We searched for studies concerning the effect of statins or physical exercise on arterial stiffness, measured by pulse wave velocity (PWV). For methodological quality assessment, Cochrane Collaboration’s tool for assessing risk of bias (RoB2) was used. A network geometry graph was used to assess the strength of the evidence. Comparative evaluation of the interventions effect was performed by conducting a standard pairwise meta-analysis and a network meta-analysis (NMA) for direct and indirect comparisons between interventions and control/nonintervention. A total of 22 studies were included in the analyses (18 randomized controlled trials (RCTs) and 4 nonrandomized experimental studies), including 1,307 patients with high cardiometabolic risk from Asia (3 studies), Oceania (2 studies), Europe (10 studies), North America (5 studies), and South America (2 studies). The overall risk of bias assessed with RoB2 was high in all included studies. For standard pairwise meta-analysis and NMA, high-intensity exercise versus control (mean difference (MD) −0.56; 95% CI: −1.01, −0.11; p = 0.015 and −0.62; 95% CI: −1.20, −0.04; p = 0.038, respectively) and moderate statin dose versus control (MD −0.80, 95% CI: −1.59, −0.01; p = 0.048 and −0.73, 95% CI: −1.30, −0.15; p = 0.014, respectively) showed significant MDs. When nonrandomized experimental studies were excluded, the effect on high-intensity exercise versus control and moderate statin dose versus was slightly modified. The main limitation of this study was that the magnitude of the effect of the exercise interventions could be underestimated due to regression toward the mean bias because the baseline cardiometabolic risk profile of patients in the physical exercise intervention trials was healthier than those in the statins ones; consequently, more modest improvements in physical exercise interventions compared to statins interventions can be expected. Additionally, we might consider as limitations the small study sizes, the heterogeneous patient groups, the focus on a proxy endpoint (PWV), and the high risk of bias.

Conclusions

In this NMA, we found that although many patients could benefit from statins for reducing CVD risk, our results support that, considering the beneficial effects of high-intensity exercise on arterial stiffness, it would be worthwhile to refocus our attention on this type of exercise as an effective tool for the prevention of CVD.

Systematic review registration

PROSPERO CRD42019123120.

In this network meta-analysis, Iván Cavero-Redondo and colleagues synthesise findings on statins vs. exercise for alleviating arterial stiffness.

Author summary

Why was this study done?

Arterial stiffness is associated with the early stages of vascular aging, being an independent predictor for the onset of acute or chronic cardiovascular disease (CVD).
Although statins and physical exercise have demonstrated a beneficial role on vascular health, physical exercise has been clearly undervalued in clinical settings.
There is a lack of clinical trials comparing the effect of statins versus physical exercise on most CVD risk outcomes such as arterial stiffness.

What did the researchers do and find?

Using network meta-analysis (NMA), we were able to integrate all available randomized evidence on the effect of statin doses and physical exercise intensities on arterial stiffness in a single analysis for preserving randomization benefits.
Both moderate statin dose and high-intensity exercise are effective approaches for reducing arterial stiffness.

What do these findings mean?

Although many appropriately selected patients could benefit from statins for reducing CVD risk, our result support that, considering the beneficial effects of high-intensity exercise on arterial stiffness, it would be worthwhile to refocus our attention on this type of exercise as an effective tool for the prevention of CVD.
However, the choice of interventions should be based on the needs and preferences of individual patients.

Introduction

Arterial stiffness is associated with the early stages of vascular aging [1], being an independent predictor for the onset of acute or chronic cardiovascular disease (CVD) [2]. Inflammation and oxidative stress have been proposed as the underlying mechanisms responsible for the stiffening of vessels’ walls, since they induce rapid changes in the endothelium and longer changes in the structural configuration of the arterial wall, through elastin fragmentation, collagen deposition, and smooth muscle cell proliferation [3]. Preventing these deteriorations in vascular structure and function at preclinical stages by using appropriate disease risk stratification strategies leads to health benefits for individuals [4,5]. The accepted gold standard for noninvasive measurement of arterial stiffness is pulse wave velocity (PWV), which has proven to be an independent predictor of cardiovascular events [2,6]. Although PWV is a useful surrogate marker of arterial stiffness with reclassification value over traditional cardiovascular risk estimating scores [2,7,8] and considered as indicative of target organ damage [5], the long-term effects of lowering arterial stiffness (measured by PWV) remain to be demonstrated [5].

In recent years, statins have been the most prescribed drugs worldwide for primary prevention of CVD [9] because of their lipid-lowering effects [10], which could improve the vascular system contributing to reduce arterial stiffness [11,12]. In parallel, physical exercise has demonstrated to be an effective approach for improving arterial stiffness [13]. Although both have demonstrated a beneficial role on vascular health [14], physical exercise has been clearly undervalued in clinical settings. There are many factors why statins are the first line of clinicians’ prescription, instead of physical exercise, for primary and secondary prevention of CVD: the ease of prescription, the duration of primary care consultations, and that clinicians have traditionally undervalued the exercise and are rarely trained to prescribe it properly [15,16]. The comparative analysis of the effect of several doses of statins and different intensities of physical exercise on arterial stiffness could shed light for clinicians on the effectiveness of both methods in preventing CVD and be used to inform shared decision-making between doctors and patients.

There is a worldwide concern as to whether the undeniable cardioprotective benefits of the statins have masked the importance of the exercise in the prevention of CVD [17,18]. Moreover, an alleged dilemma about whether to prescribe statins or exercise, because statins would reduce the effect of exercise on fitness, has emerged in recent years [14]. The results provided by the National Runners’ and Walkers’ Health Study [19] do not suggest that statins reduce the amount of exercise. Likewise, a therapy strategy based on the combination of statins and exercise have proven to be more effective than statin monotherapy not only for improved aerobic capacity, but also in terms of insulin sensitivity and inflammation [20].

However, there is a lack of clinical trials comparing the effect of statins and physical exercise on most CVD risk outcomes such as arterial stiffness, and standard meta-analyses are unable to resolve which treatment is more effective. The network meta-analysis (NMA) approach allows a comprehensive and consistent analysis of all randomized controlled trials (RCTs) comparing, head to head or with placebo, the usually prescribed statins doses and different physical exercise intensities while fully respecting randomization. Thus, this study was aimed at analyzing the effect, in high cardiometabolic risk patients, of different statins doses and exercise intensities on arterial stiffness by integrating all available direct and indirect evidence in NMA.

Methods

This systematic review and NMA is reported according to the Preferred Reporting Items for Systematic Review incorporating Network Meta-Analysis (PRISMA-NMA) [21] (S1 Table) and the Cochrane Collaboration Handbook [22]. The study protocol was registered in PROSPERO (registration number: CRD42019123120) and has been published elsewhere [23]. Since in this study the researchers did not collect primary data for the systematic review and NMA, ethical approval was not required.

Search strategy

Two reviewers (IC-R and CA-B) independently systematically searched MEDLINE, Embase, SPORTDiscus, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Web of Science databases from their inception to February 28, 2020; for unpublished trials, we also searched ClinicalTrials.gov. The search strategy combined relevant terms related to (a) cardiometabolic risk; (b) clinical trials; (c) statins or exercise; and (d) arterial stiffness. Finally, the reference lists of the included articles in this review as well as those included in previous systematic reviews and meta-analyses were reviewed for additional relevant studies (S2 Table).

Eligibility

Studies concerning the effect of statins or physical exercise on arterial stiffness were included. Inclusion criteria were as follows: (1) Type of studies: RCTs or nonrandomized experimental studies and controlled pre–post studies, without language restrictions; (2) Type of participants: studies performed in cardiometabolic disease risk patients as considered by the American Diabetes Association (ADA) [24]. Studies were selected regardless of the age of the participants included. When more than 1 study provided data referring to the same sample, we chose the one presenting the most detailed results or providing the largest sample size; (3) Type of interventions: Studies reporting any type of intervention consisting mainly of statin treatment or physical exercise (endurance, interval training, or combined exercise [either of the previous 2 with resistance]) understood as repeated bouts of physical exercise over time involving more than 1 session/week with a duration of at least 3 weeks were eligible for inclusion. Also, studies comparing different type of statins or comparing different types of physical exercise interventions; (4) Type of outcome assessment: arterial stiffness measured by carotid–femoral PWV (cfPWV). Exclusion criteria were (1) single-arm pre–post studies; (2) studies combining statins or physical exercise with other health interventions, such as nutritional interventions, were excluded when data concerning the effect of statins or physical exercise interventions on arterial stiffness could not be extracted separately; (3) studies where the type and dose of statins or the intensity of physical exercise could not be estimated; and (4) finally, studies reporting arterial stiffness using other additional PWV measurements sites, such as brachial–ankle PWV or cardiac–ankle PWV (S1 Text).

Data extraction

After the study selection, 2 reviewers extracted the following information for each study (Tables 1 and 2): (1) year of publication; (2) country; (3) type of study design; (4) sample characteristics (sample size, mean age, and type of population); (5) outcome characteristics (measuring device, baseline cfPWV, and their standard deviation (SD) values as well as arterial stiffness status according with cfPWV reference values) [25]; and (6) intervention characteristics (length, type, and intensity of intervention). According to Cochrane Handbook recommendations, when data on cfPWV SD of change from baseline are lacking, our estimates were calculated on the basis of standard errors, 95% confidence intervals, p-values, or t statistics to calculate SD. Finally, when outcomes were scaled inversely, the mean in each group was multiplied by −1.

Table 1. Characteristics of included studies analyzing the effect of statins on PWV.

Study (year)	Country	Study design	Sample size (n)	Population characteristics		Intervention characteristics			Outcome
Study (year)	Country	Study design	Sample size (n)	Age [years (mean ± SD)	Type of population	Length (weeks)	Type and dose of statin	Level	Measuring device	Basal PWV [m/s (mean ± SD)]	Arterial stiffness status
Davenport et al. (2015)	Ireland	Non-RCT	IG1:25 IG2:26	IG1:66.0 ± 9.5 IG2: 65.5 ± 10.5	T2DM	12 and 48	IG1: Atorvastatin 10 mg IG2: Atorvastatin 80 mg	IG1: Moderate IG2: High	Vicorder	IG1:10.5 ± 1.1 IG2:10.3 ± 1.5	Normal
Fasset et al. (2009)	Australia	RCT	IG:16 CG:18	IG:62.3 ± 16.3 CG:64.8 ± 15.0	CKD	48	Atorvastatin 10 mg	Moderate	SphygmoCor	IG:8.5 ± 2.2 CG:8.0 ± 1.3	Normal
Grigoropoulou et al. (2019)	Greece	Non-RCT	IG:46 CG:33	IG:60.0 ± 8.0 CG:59.9 ± 9.0	T2DM Dyslipidemia	48	Atorvastatin 10 mg	Moderate	SphygmoCor	IG:11.3 ± 2.7 CG:10.7 ± 2.4	Normal
Kanaki et al. (2013)	Greece	RCT	IG:25 CG:25	IG:59.7 ± 8.9 CG:58.8 ± 10.8	HTA Hypercholesterolemia	26	Atorvastatin 10 mg	Moderate	SphygmoCor	IG:11.0 ± 1.8 CG:10.5 ± 2.1	Elevated
Mitsiou et al. (2018)	Greece	RCT	IG:20 IG2:20	IG1:52.8 ± 8.2 IG2:53.6 ± 8.8	HTA	24	IG1: Rosuvastatin 5 mg IG2: Rosuvastatin 20–40 mg	IG1: Moderate IG2: High	Mobil-O-Graph	IG1:8.4 ± 1.2 IG2:8.2 ± 1.4	Normal
Orr et al. (2009)	USA	RCT	IG:16 CG:10	IG:53.0 ± 3.0 CG:53.0 ± 2.0	Overweight/obese	12	Atorvastatin 80 mg	High	SPT-301	IG:11.0 ± 0.4 CG:12.4 ± 0.9	Elevated
Pirro et al. (2006)	Italy	RCT	IG:35 CG:36	IG:56.0 ± 17.0 CG:58.0 ± 14.0	Hypercholesterolemia	4	Rosuvastatin 10 mg	Moderate	SphygmoCor	IG:9.5 ± 1.9 CG:9.2 ± 2.1	Normal
Raison et al. (2002)	France	RCT	IG:12 CG:11	IG:56.8 ± 10.9 CG:56.1 ± 9.5	HTA Hypercholesterolemia	12	Atorvastatin 10 mg	Moderate	Complior	IG:12.5 ± 2.7 CG:11.6 ± 1.9	Elevated
Wang et al. (2011)	China	RCT	IG:46 CG:50	IG:64.2 ± 7.8 CG:65.7 ± 8.2	HTA	NR	Atorvastatin 20 mg	Moderate	NR	IG:14.4 ± 2.7 CG:14.3 ± 3.1	Elevated
Qi et al. (2008)	China	RCT	IG:45 CG:42	IG:58.4 ± 5.9 CG:56.4 ± 5.3	HTA	12	Atorvastatin 20 mg	Moderate	Complior	IG:13.1 ± 3.2 CG:12.8 ± 3.1	Elevated
Zhang et al. (2003)	China	RCT	IG:15 CG:15	IG:63.7 ± 8.8 CG:66.0 ± 9.6	HTA	12	Fluvastatin 40 mg	Low	Complior	IG:12.8 ± 2.5 CG:13.0 ± 3.2	Normal

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CG, control group; CKD, chronic kidney disease; HTA, hypertension; IG, intervention group; m/s, meters per second; NR, not reported; PWV, pulse wave velocity; RCT, randomized controlled trial; SD, standard deviation; T2DM, type 2 diabetes mellitus.

Table 2. Characteristics of included studies analyzing the effect of physical exercise on PWV.

Study (year)	Country	Study design	Sample size (n)	Population characteristics		Outcome			Intervention characteristics
Study (year)	Country	Study design	Sample size (n)	Age [years (mean ± SD)	Type of population	Length (weeks)	Type of physical exercise	Intensity	Measuring device	Basal PWV [m/s (mean ± SD)]	Arterial stiffness status
Chrysohoou et al. (2015)	Greece	RCT	IG:50 CG:50	IG:63.0 ± 9.0 CG:56.0 ± 11.0	Chronic heart failure	12	Interval training	High	NR	IG:9.5 ± 2.5 CG:8.8 ± 1.3	Normal
Dobrosielski et al. (2012)	USA	RCT	IG:70 CG:70	IG:57.0 ± 6.0 CG:56.0 ± 6.0	T2DM	24	Combined exercise	Moderate	NR	IG:9.2 ± 2.5 CG:9.1 ± 1.7	Normal
Donley et al. (2014)	USA	Non-RCT	IG: 11 CG: 11	IG:46.0 ± 13.3 CG:44.0 ± 10.0	Metabolic syndrome	8	Endurance training	High	SphygmoCor	IG:7.9 ± 2.0 CG:7.5 ± 1.5	Normal
Guimaraes et al. (2010)	Brazil	RCT	IG1:26 IG2:26 CG:13	IG1:50.0 ± 8.0 IG2:45.0 ± 9.0 CG:47.0 ± 0.6	HTA	16	IG1: Combined exercise IG2: Combined exercise	IG1: High IG2: High	Complior	IG1:10.2 ± 1.7 IG2:9.4 ± 0.9 CG:10.2 ± 1.8	Elevated
Koh et al. (2010)	Australia	RCT	IG1:13 IG2:14 CG:15	IG1:52.3 ± 10.9 IG2:52.1 ± 13.6 CG:51.3 ± 14.4	CKD	24	IG1: Endurance training IG2: Endurance training	IG1: Moderate IG2: Moderate	SPT-301	IG1:9.1 ± 2.8 IG2:9.7 ± 3.2 CG:8.7 ± 2.5	Normal
Loimaala et al. (2009)	Finland	RCT	IG:25 CG:25	IG:53.6 ± 6.2 CG:54.0 ± 5.0	Type 2 diabetes	24	Combined exercise	High	CircMon B 202	IG:14.1 ± 2.5 CG:14.1 ± 2.5	Elevated
Madden et al. (2013)	Canada	RCT	IG:25 CG:27	IG:68.5 ± 0.9 CG:70.0 ± 0.8	T2DM HTA Hyperlipidemia	24	Endurance training	High	Complior	IG:13.4 ± 0.7 CG:12.0 ± 0.6	Normal
Mora-Rodriguez et al. (2017)	Spain	RCT	IG:25 CG:25	53.5 ± 8.9	Metabolic syndrome Hypertension	24	Interval training	High	SphygmoCor	IG:8.5 ± 2.1 CG: 8.5 ± 2.2	Normal
Nualnim et al. (2012)	USA	Non-RCT	IG:24 CG:19	IG:58.0 ± 9.8 CG:61.0 ± 8.6	Pre-HTA HTA	12	Endurance training	Moderate	VP-2000	IG:9.1 ± 1.0 CG:9.4 ± 0.7	Normal
e Silva et al. (2019)	Brazil	RCT	IG:15 CG:15	IG:50.0 ± 17.2 CG:58.0 ± 15.0	CKD	16	Endurance training	Moderate	SphygmoCor	IG:8.5 ± 2.9 CG:10.3 ± 3.8	Normal
Slivovskaja et al. (2018)	Lithuania	RCT	IG:84 CG:42	IG:53.9 ± 6.4 CG:52.0 ± 7.7	Metabolic syndrome	8	Endurance training	High	SphygmoCor	IG:8.5 ± 1.4 CG:8.0 ± 1.1	Normal

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Categorization of the interventions’ available evidence

Statin interventions were classified by type and dose as high, moderate, and low following the Statin Dosing and ACC/AHA Classification of Intensity [26]. Furthermore, physical exercise interventions, considered as a subset of structured and repetitive physical activity, were classified by intensity as high, moderate, or light following the American College of Sports Medicine guidelines for prescribing exercise [27]. This classification of statin doses and exercise intensity was performed by 2 researchers (IC-R and CA-B) independently.

Risk of bias assessment

Two researchers (IC-R and CA-B) independently conducted a methodological quality assessment of the included RCTs by applying the Cochrane Collaboration’s tool for assessing risk of bias (RoB2) [28]. according to the Cochrane Collaboration Handbook recommendations [22]. Risk of bias was evaluated according to 6 domains: selection bias, performance bias, detection bias, attrition bias, reporting bias, and other bias. Overall, bias was categorized as “low risk of bias” if the paper had been classified as “low risk” in all domains, “some concerns” if there was at least 1 domain with rating of “some concern,” and “high risk of bias” if there was at least 1 domain with a “high risk,” or several domains with some concerns in such a way that the validity of the results could be affected. As in studies that include physical exercise interventions, patient allocation to treatment could not be blinded, thus patient blinding domain was deemed as a high risk of bias, and we did not include this domain in the overall risk of bias assessment. Any disagreements were solved by discussion and a third reviewer (VM-V).

Grading the quality of evidence

The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) tool was used to evaluate the quality of the evidence and make recommendations [29]. Each outcome obtained a high, moderate, low, or very low evidence value, depending on the design of the studies, risk of bias, inconsistency, indirect evidence, imprecision, and publication bias.

Data synthesis and statistical analysis

The included clinical trials were summarized qualitatively in an ad hoc table describing the types of direct and indirect comparisons. As noted above, we conducted our NMA accordingly with PRISMA-NMA statement distinguishing the following steps:

A network geometry graph was used to display the evidence in the network. In this graph, the size of the nodes was proportional to the number of participants in trials who received the intervention specified in the node, the thickness of continuous line connecting nodes proportional to number of participants in trials directly comparing the 2 treatments [30].
Consistence assessment, by checking whether the treatment effects estimated from direct comparisons were consistent with those estimated by indirect comparisons procedures. For this aim, we used the Wald test; moreover, we assessed local inconsistency using the side-splitting method.
Comparative evaluation of the interventions effect, by conducting a standard pairwise meta-analysis for comparisons between interventions and control/nonintervention. For this, we used the random effects DerSimonian–Laird method [31], and the statistical heterogeneity was examined by calculating the I² statistic, separately for each statin doses and for each exercise intensity, which ranges from 0% to 100%. According to the values of I², the heterogeneity will be considered as not important (0% to 40%), moderate (30% to 60%), substantial (50% to 90%), or considerable (75% to 100%) [22]. Additionally, the corresponding p-values were also be considered. Finally, to determine the size and clinical relevance of heterogeneity, the τ² statistic was calculated. A τ² estimate of 0.04 may be interpreted as a low, 0.14 as a moderate, and 0.40 as a substantial degree of clinical relevance of heterogeneity [32]. These results were displayed by creating both forest plots and a league table.
Transitivity assessment, to check that the synthesis of direct comparisons of 2 treatments have been conducted in studies that were similar in the most important clinical and methodological characteristics; thus, it supposed to assume that the populations included in these studies were similar in the baseline distribution of the effect modifier. For this aim, we checked that all the participants in the studies included in the NMA have the same baseline characteristics (on average) that might modify the treatment effect [33].
Relative rankings of treatments. Once we had comparatively estimated the effectiveness of the different treatment strategies, the next step was to rank the treatments in order to identify superiority. The probability that each intervention, statin, or physical exercise were the most effective was presented graphically using rankograms [34]. Additionally, the surface under the cumulative ranking (SUCRA) was estimated for each intervention. SUCRA involves the assignment of a numerical value between 0 and 1 to simplify the classification of each intervention in the rankogram. The best intervention would obtain a value for SUCRA close to 1, and the worst intervention would be a value close to 0 [30].
Sensitivity analysis and small-study effect. Sensitivity analyses were conducted to assess the robustness of the summary estimates and to detect whether any particular study represented a large proportion of the heterogeneity. Additionally, a sensitivity analysis was performed excluding nonrandomized experimental studies and controlled pre–post studies. For examining the presence of bias due to small-study effect, a network funnel plot was used to visually scrutinize the criterion of symmetry [35]. All the analyses were conducted in Stata 15.0 (Stata, College Station, Texas, USA).

Results

A total of 22 studies [36–57] (18 RCTs and 4 nonrandomized experimental studies) were included in the analyses (Fig 1). Moreover, 11 studies analyzed the effect of statins and 11 the effect of physical exercises on cfPWv (Tables 1 and 2). Two of the physical exercise studies have 3 arms (2 interventions and 1 control). The statin therapy includes atorvastatin, rosuvastatin, and fluvastatin. In most studies, the intervention group received a moderate dose of statin (9 studies). Low statin dose was evaluated only in 1 study. High-intensity exercise was evaluated in 7 studies (8 intervention samples), and moderate-intensity exercise was evaluated in 4 studies (5 intervention samples) (Fig 2).

Fig 2 — Size of node is proportional to number of trial participants, and thickness of continuous line connecting nodes is proportional to number of participants randomized in trials directly comparing the 2 treatments. Dash lines display indirect comparisons.

Transitivity assessment

Statin and physical exercise studies included a similar total number of patients (587 and 720, respectively). Participants in physical exercise interventions groups had lower baseline cardiometabolic risk profile than statins intervention group: systolic blood pressure (SBP) 133.0 mmHg versus 140.8 mmHg (p = 0.023), total cholesterol 5.0 mmol/L versus 6.0 mmol/L (p = 0.001), and low-density lipoprotein cholesterol (LDLc) 3.1 mmol/L versus 4.2 mmol/L (p = 0.001) (S3 Table).

Risk of bias

The overall risk of bias was high in all included studies. Regarding each domain, the risk of bias for deviations from intended interventions domain was high in all studies; the risk of bias for statins and exercise was high for, respectively, 100% and 90.9% of studies for deviations from intended interventions. However, the risk of bias for statins and exercise was low for, respectively, 90.9% and 72.7% of studies for measurement of the outcome domain, and 90.9% and 90.9% for missing outcome data domain (S1 and S2 Figs).

When the quality of evidence of each pairwise comparison was evaluated using the GRADE system, 50.0% of the pairwise comparisons were categorized as high, 33.3% as moderate, and 16.7% as very low (S4 Table).

Arterial stiffness

In Table 3, considering both the direct pairwise pooled estimates (upper diagonal) and the NMA estimates (lower diagonal), the highest mean differences (MDs) in cfPWv were for high statin dose versus control (−1.17; 95% CI: −3.50, 1.16; p = 0.326 and −0.86; 95% CI: −1.82, 0.10; p = 0.080, respectively). Furthermore, high-intensity exercise versus control (−0.56; 95% CI: −1.01, −0.11; p = 0.015 and −0.62; 95% CI: −1.20, −0.04; p = 0.038, respectively) and moderate statin dose versus control (−0.80, 95% CI: −1.59, −0.01; p = 0.048 and −0.73, 95% CI: −1.30, −0.15; p = 0.014, respectively) had confidence intervals which excluded the no effect value.

Table 3. Pooled MDs on arterial stiffness.

Placebo	−1.17 (−3.50, 1.16)	−0.80 (−1.59, −0.01)	−0.50 (−3.20, 2.20)	−0.27 (−1.00, 0.46)	−0.56 (−1.01, −0.11)
−0.86 (−1.82, 0.10)	High statin dose	0.11 (−0.59, 0.80)	na	na	na
−0.73 (−1.30, −0.15)	0.13 (−0.67, 0.94)	Moderate statin dose	na	na	na
−0.50 (−3.29, 2.29)	0.38 (−2.59, 3.31)	0.23 (−2.62, 3.07)	Low statin dose	na	na
−0.28 (−1.16, 0.60)	0.58 (−0.72, 1.88)	0.45 (0.60, −1.46)	0.22 (−2.70, 3.14)	Moderate-intensity exercise	na
−0.62 (−1.20, −0.04)	0.24 (−0.85, 1.34)	0.11 (−0.67, 0.89)	−0.12 (−2.96, 2.73)	−0.34 (−1.39, 0.71)	High-intensity exercise

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Upper right triangle gives the pooled MDs from pairwise comparisons (column intervention relative to row), and lower left triangle gives the pooled MDs from the NMA (row intervention relative to column).

MD, mean difference; na, not available; NMA, network meta-analysis.

Treatment ranking

The high statin dose showed the higher SUCRA (74%) (Fig 3, S5 Table, S3 Fig). Moderate statin dose and high-intensity exercise showed the second and third higher SUCRA (67% and 60%), showing high-intensity exercise as the best mean and median rank (lower mean and median values mean better rank).

Sensitivity analysis, heterogeneity, and small-study effect

The pooled MD was not significantly modified when the individual study data were removed, one at a time, from any pairwise comparison analysis. When nonrandomized experimental studies and controlled pre–post studies were excluded from the pairwise comparison analysis, the effect on moderate statin dose versus control (−0.52; 95% CI: −0.97, −0.08) and high-intensity exercise versus control (−0.55; 95% CI: −1.01, −0.08) was slightly modified. Furthermore, moderate statin dose showed substantial heterogeneity (I² = 61.2, τ² = 0.650). The other direct comparison showed no heterogeneity (I² = 0.0, τ² = 0.000) (S6 Table). Finally, there was evidence of small-study effect in funnel plot asymmetry and Egger test for high-intensity exercise versus control (p = 0.035), but not for all other comparisons: moderate statin dose versus control (p = 0.294), moderate statin dose versus high statin dose (p = 0.686), and moderate-intensity exercise versus control (p = 0.557) (S4 Fig).

Discussion

Statins as pharmacological treatment and physical exercise as lifestyle recommendation are the most used strategies for the treatment of patients with high cardiometabolic risk. Clearly, as for any treatment, doing more harm than good with this class of treatments should be avoided (primum non nocere). Taking this into account, we presented arterial stiffness as an outcome of vascular health in which an effective treatment could be associated with a decrease in risk of CVD. In this NMA of the effect of 3 statin doses and 2 intensities of physical exercise on arterial stiffness, moderate statin dose and high-intensity exercise seemed to be more effective. The effect on arterial stiffness, as measured by cfPWv, of statins and physical exercise varied considerably depending on the doses and intensities, respectively.

Our findings on the available scientific evidence allow prescribers and their patients an understanding of the clinical circumstances where statins might provide substantial improvements in arterial stiffness, and the intensity of exercise required that could yield potentially similar gains. Our analysis covered 1,307 cardiometabolic disease/risk patients (587 for statins and 720 for physical exercise), but only a limited number of studies examined the effect of high and low statin doses as well as for light-intensity exercise. Even so, with the studies included, a dose response trend can be assumed both for statins and exercise. This is evident from the SUCRA findings that showed that the high statin dose may be the best treatment, but the limited number of studies may not find a statistically significant effect, but it should be highlighted that when choosing the safest treatment, increasing the dose of statins has been associated with pain and muscle damage, liver injury, or increased risk of type 2 diabetes [58,59]. Conversely, exercise has demonstrated positive benefits for most prevalent noncommunicable diseases [60].

The findings of our NMA suggest that moderate statin dose and high-intensity exercise interventions are often potentially effective in terms of improvements on arterial stiffness. High-intensity exercise interventions should therefore be considered as a viable alternative to, or alongside, moderate statin dose therapy. Indeed, an increasing number of experts recommend prescribing an “exercise pill” as a preventive strategy to reduce CVD [61,62]. However, as opposed to the findings of this NMA, international guidelines have reduced the threshold for statin treatment after intensive lifestyle modifications and considerably extended both the scope and dosage of statin treatment [63].

We used a comprehensive search strategy and searched pertinent sources to retrieve potentially eligible RCTs. It therefore seems unlikely that we missed any relevant trial. Using NMA, we were able to integrate all available randomized evidence on the effect of statin doses and physical exercise intensities on arterial stiffness in a single analysis for preserving randomization benefits. The integration of direct and indirect comparisons results in a gain of statistical power for formal comparisons of statins doses and physical exercise intensities with placebo [12,13].

The results of this NMA may be affected by some limitations that should be acknowledged. First, the high overall risk of bias in all included studies, mainly due to all trials lacked information regarding deviations from intended interventions domain from the RoB2; however, based on the others quality domains of the RoB2, the methodological quality of included trials was generally satisfactory. Second, the inclusion of nonrandomized experimental studies and controlled pre–post studies, although the exclusion of the nonrandomized experimental studies in the sensitivity analysis was only reflected in small modifications of the effect in both moderate statin dose versus control and high-intensity exercise versus control. Third, the limited number of samples included in the evaluation of some interventions (high statin dose versus control n = 1 and low statin dose versus control n = 1), which influenced the GRADE evaluation. Fourth, the transitivity assessment showed a lower risk cardiometabolic profile at baseline in the patients in physical exercise interventions trials than those in statins interventions; consequently, more modest improvements in physical exercise interventions compared to statins interventions can be expected. Fifth, a high heterogeneity in the characteristics of population included in the studies such as clinical (including patients with hypertension, obesity, diabetes mellitus, chronic kidney disease, or heart failure) or cardiometametabolic risk profile; certainly, this heterogeneity in cardiovascular risk status affects the statistical procedures of the study, and their estimates must be cautiously examined, although it also makes our findings generalizable to real clinical practice. Sixth, an additional source of heterogeneity is that the devices used for measuring cfPWv differ largely, since while some used a tonometric method, other were oscillometric devices, but the robustness of our estimates was not modified after removing studies including oscillometric devices in the sensitivy analyses. Seventh, there was evidence of small-study effect on the funnel plot asymmetry (S4 Fig) and Egger test, for high-intensity exercise versus control comparison, produced mainly by the scarcity of studies and their small sample sizes. Furthermore, the funnel plot asymmetry showed that the studies appear to be highly clustered round common estimates for each type of intervention; this phenomenon can be explained by the similarity of sample sizes, but in addition to the reliability of the direction and the power of the effect for each type of intervention. Eighth, it should be acknowledged that because in this NMA, comparisons between physical exercise and statins are indirect, the same biases may occur as in nonrandom comparisons, and the results should be carefully interpreted. Finally, our results are based on the analysis of the effect of statins and exercise on reducing PWV, and although consistent evidence support that PWV is a good predictor of CVD, it is indeed a surrogate measure of the appropriate main outcomes for these interventions, which are CVD events, CVD mortality, and all-cause mortality, with all the clinical and epidemiological implications that this fact entails.

Conclusions

In summary, our study confirms that both statins and physical exercise are effective approaches for reducing arterial stiffness. Our results, based on data from experimental studies, represent the best available evidence of the effect on arterial stiffness of these 2 different therapeutic and preventive strategies. Although many appropriately selected patients could benefit from the effects of statins on arterial stiffness, our results support that, considering the beneficial effects of high-intensity exercise on arterial stiffness, the choice of this intervention should be based on the needs and preferences of each patient.

Disclaimer

The views expressed in this article are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care.

Supporting information

S1 Table. PRISMA NMA Checklist of Items to Include When Reporting A Systematic Review Involving a Network Meta-analysis.

(DOCX)

Click here for additional data file.^{(23.5KB, docx)}

S2 Table. Search strategy for the MEDLINE database.

(DOCX)

Click here for additional data file.^{(14.5KB, docx)}

S3 Table. Pooled baseline characteristics from statins and physical exercise interventions.

(DOCX)

Click here for additional data file.^{(28.1KB, docx)}

S4 Table. Quality grading of evidence.

(DOCX)

Click here for additional data file.^{(15.5KB, docx)}

S5 Table. Effectiveness ranking of stain doses and physical exercise intensities interventions.

(DOCX)

Click here for additional data file.^{(13.3KB, docx)}

S6 Table. Heterogeneity statistics for each pairwise comparison.

(DOCX)

Click here for additional data file.^{(13KB, docx)}

S1 Fig. Risk of bias for statin interventions.

(DOCX)

Click here for additional data file.^{(3.3MB, docx)}

S2 Fig. Risk of bias for physical exercise interventions.

(DOCX)

Click here for additional data file.^{(2.6MB, docx)}

S3 Fig. Rankogram for each intervention.

(DOCX)

Click here for additional data file.^{(70KB, docx)}

S4 Fig. Funnel plot for comparison-specific pooled mean differences.

(DOCX)

Click here for additional data file.^{(94.2KB, docx)}

S1 Text. References of excluded studies (with reasons) from network meta-analysis.

(DOCX)

Click here for additional data file.^{(19.8KB, docx)}

Abbreviations

ADA: American Diabetes Association
cfPWV: carotid–femoral PWV
CVD: cardiovascular disease
GRADE: Grading of Recommendations, Assessment, Development, and Evaluation
LDLc: low-density lipoprotein cholesterol
MD: mean difference
NMA: network meta-analysis
PRISMA-NMA: Preferred Reporting Items for Systematic Review incorporating Network Meta-Analysis
PWV: pulse wave velocity
RCT: randomized controlled trial
SBP: systolic blood pressure
SD: standard deviation
SUCRA: surface under the cumulative ranking

Data Availability

All relevant data are within the manuscript and its Supporting Information files.

Funding Statement

This study was funded by the Consejería de Educación, Cultura y Deportes – Junta de Comunidades de Castilla-La Mancha and European Regional Development Fund (SBPLY/17/ 180501/000533 to IC-R, CA-B and VM-V). KJ is part funded by the National Institute for Health Research (NIHR) Applied Research Collaboration West Midlands. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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PLoS Med. doi: 10.1371/journal.pmed.1003543.r001

Decision Letter 0

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6 Jul 2020

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PLoS Med. doi: 10.1371/journal.pmed.1003543.r002

Decision Letter 1

Emma Veitch

28 Sep 2020

Dear Dr. Alvarez-Bueno,

Thank you very much for submitting your manuscript "Comparative effect of physical exercise versus statins on improving arterial stiffness in patients with high cardiometabolic risk: a network meta-analysis" (PMEDICINE-D-20-03097R1) for consideration at PLOS Medicine.

Your paper was evaluated by a senior editor and discussed among all the editors here. It was also evaluated by three independent reviewers, including a statistical reviewer. The reviews are appended at the bottom of this email and any accompanying reviewer attachments can be seen via the link below:

[LINK]

In light of these reviews, I am afraid that we will not be able to accept the manuscript for publication in the journal in its current form, but we would like to consider a revised version that addresses the reviewers' and editors' comments. Obviously we cannot make any decision about publication until we have seen the revised manuscript and your response, and we plan to seek re-review by one or more of the reviewers.

In revising the manuscript for further consideration, your revisions should address the specific points made by each reviewer and the editors. Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments, the changes you have made in the manuscript, and include either an excerpt of the revised text or the location (eg: page and line number) where each change can be found. Please submit a clean version of the paper as the main article file; a version with changes marked should be uploaded as a marked up manuscript.

In addition, we request that you upload any figures associated with your paper as individual TIF or EPS files with 300dpi resolution at resubmission; please read our figure guidelines for more information on our requirements: http://journals.plos.org/plosmedicine/s/figures. While revising your submission, please upload your figure files to the PACE digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at PLOSMedicine@plos.org.

We expect to receive your revised manuscript by Oct 19 2020 11:59PM. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

***Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.***

We ask every co-author listed on the manuscript to fill in a contributing author statement, making sure to declare all competing interests. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. If new competing interests are declared later in the revision process, this may also hold up the submission. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT. You can see our competing interests policy here: http://journals.plos.org/plosmedicine/s/competing-interests.

Please use the following link to submit the revised manuscript:

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To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see http://journals.plos.org/plosmedicine/s/submission-guidelines#loc-methods.

Please ensure that the paper adheres to the PLOS Data Availability Policy (see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it.

We look forward to receiving your revised manuscript.

Sincerely,

Emma Veitch, PhD

PLOS Medicine

On behalf of Adya Misra, PhD, Senior Editor,

PLOS Medicine

plosmedicine.org

-----------------------------------------------------------

Requests from the editors:

*In the Abstract (ideally Methods and Findings section), please include a brief note summarising any key limitation(s) of the study's methodology.

*The main Limitations section of the paper seems to omit mention of a key point, that is the focus specifically in this network meta on a surrogate outcome measure - some discussion of this could be added.

*The authors have used the PRISMA guideline (specifically the one focussed on network meta-analyses) to help with reporting, and this is valuable, but a "flowchart" of study eligibility/inclusion seems to have been omitted - please see the generic PRISMA statement (https://www.equator-network.org/reporting-guidelines/prisma/) for a template Word figure for the flowchart and that could be filled out and included as a figure with the revised paper.

-----------------------------------------------------------

Comments from the reviewers:

Reviewer #1: See attachment

Michael Dewey

-----------------------------------------------------------

Reviewer #2:

The Authors of this paper carried out a network meta-analysis on the effect of different statins doses and exercise intensities on arterial stiffness (expressed as carotid-femoral pulse wave velocity), in high cardio-metabolic risk patients. Nineteen studies were included in the analyses, including 1151 patients.

The main results showed in addition to a benefit from statins for reducing cardiovascular risk, also a beneficial effects of high-intensity exercise on arterial stiffness.

This is an interesting paper, however there are some concerns.

1. The results may be affected by some limitations: a) the high overall risk of bias in all included studies; b) the inclusion of non-randomized controlled trials; c) the limited number of samples included in the evaluation of some interventions (high-statin dose vs control n=1, low-statin dose vs control n=1), that also affected the GRADE evaluation; d) the statistical difference in baseline cardio-metabolic risk profile between physical exercise and statin intervention group; e) a high heterogeneity in the characteristics of the studies (e.g. cardio-metabolic risk profile of the populations, arterial stiffness assessment).

2. The visual inspection of the funnel plot pointed out a slight asymmetrical distribution. Moreover, the result of Egger's test was not reported in the text.

3. Please consider another reference for the effect of statins on arterial stiffness, expressed only as carotid-femoral pulse wave velocity (Clin Exp Hypertens. 2018;40(7):601-608. doi: 10.1080/10641963.2017.1411498), because Upala et al (ref 11) combined the results of different expression of arterial stiffness.

4. Please check typo-errors at page 4,9, and Figure 2

5. Please re-check the references (e.g. reference 12, it should be Upala et al)

6. The different number of samples/studies included reported in the abstract and manuscript may generate confusion

-----------------------------------------------------------

Reviewer #3:

Although many patients could benefit from statins to reduce CVD risk, our results

support that, considering the beneficial effects of high-intensity exercise on arterial

stiffness, it would be worthwhile to refocus our attention on this type of exercise as an

effective tool for prevention of CVD.

A well written paper with practical implications.

Any issues with the original submission were resolved in the revision in a satisfactory way.

-----------------------------------------------------------

Any attachments provided with reviews can be seen via the following link:

[LINK]

Attachment

Submitted filename: caveroredondo.pdf

Click here for additional data file.^{(53KB, pdf)}

PLoS Med. 2021 Feb 16;18(2):e1003543. doi: 10.1371/journal.pmed.1003543.r003

Author response to Decision Letter 1

14 Oct 2020

Attachment

Submitted filename: Response to reviewers.docx

Click here for additional data file.^{(32.3KB, docx)}

PLoS Med. doi: 10.1371/journal.pmed.1003543.r004

Decision Letter 2

Artur Arikainen

15 Jan 2021

Dear Dr. Alvarez-Bueno,

Thank you very much for re-submitting your manuscript "Comparative effect of physical exercise versus statins on improving arterial stiffness in patients with high cardiometabolic risk: a network meta-analysis" (PMEDICINE-D-20-03097R2) for review by PLOS Medicine.

I have discussed the paper with my colleagues and the academic editor and it was also seen again by two reviewers. I am pleased to say that provided the remaining editorial and production issues are dealt with we are planning to accept the paper for publication in the journal.

The remaining issues that need to be addressed are listed at the end of this email. Any accompanying reviewer attachments can be seen via the link below. Please take these into account before resubmitting your manuscript:

[LINK]

In revising the manuscript for further consideration here, please ensure you address the specific points made by each reviewer and the editors. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments and the changes you have made in the manuscript. Please submit a clean version of the paper as the main article file. A version with changes marked must also be uploaded as a marked up manuscript file.

Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. If you haven't already, we ask that you provide a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract.

We expect to receive your revised manuscript within 1 week. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

We ask every co-author listed on the manuscript to fill in a contributing author statement. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT.

Please note, when your manuscript is accepted, an uncorrected proof of your manuscript will be published online ahead of the final version, unless you've already opted out via the online submission form. If, for any reason, you do not want an earlier version of your manuscript published online or are unsure if you have already indicated as such, please let the journal staff know immediately at plosmedicine@plos.org.

If you have any questions in the meantime, please contact me or the journal staff on plosmedicine@plos.org.

We look forward to receiving the revised manuscript by Jan 22 2021 11:59PM.

Sincerely,

Artur Arikainen,

Associate Editor

PLOS Medicine

plosmedicine.org

------------------------------------------------------------

Requests from Editors:

1. Financial Disclosure: Please add “The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.”; or explain otherwise.

2. Data Availability Statement (DAS): If the data are owned by a third party but freely available upon request, please note this and state the owner of the data set and contact information for data requests (web or email address). Note that a study author cannot be the contact person for the data. If the data are not freely available, please describe briefly the ethical, legal, or contractual restriction that prevents you from sharing it. Please also include an appropriate contact (web or email address) for inquiries (again, this cannot be a study author).

3. Please include line numbers in the margin throughout.

4. Abstract:

a. Please include search dates, and databases searched.

b. Please include a summary of included study types (RCTs, non-randomized cohorts, etc.), and a summary of study location by global region/country.

c. Please include the name of the quality/bias assessment method, and a summary of included study quality.

d. Please include p values alongside 95% CIs/CrIs for comparisons.

e. Please mention the results of the sensitivity analysis (removal of non-randomized studies).

f. Please clarify where in the main Results/Tables the following data values can be verified (we were unable to locate all of these): “For standard pairwise meta-analysis and a network meta-analysis, high-intensity exercise versus control (mean difference (MD) -0.82; 95%CI: -1.48, -0.15; and -0.80; 95%CrI: -1.55, -0.06, respectively) and moderate-statin dose versus control (MD -0.80, 95%CrI: -1.59, -0.01; and -0.74, 95%CrI: -1.33, -0.15, respectively) showed significant mean differences.”

g. At the end of the ‘Methods and findings’ subsection, please more clearly state: “Limitations of this study were…”; and mention other major issues, such as small study sizes, heterogeneous patient groups, focus on a proxy endpoint, and high risk of bias.

h. Conclusions: Please begin with: “In this network meta-analysis, we found that…”

5. Author Summary: Under "What do these findings mean", please mention that choices of interventions will need to be based on the needs and preferences of individual patients (i.e., not everyone can do high-intensity exercise, and statins have their drawbacks too).

6. Please use the "Vancouver" style for reference formatting, and see our website for other reference guidelines https://journals.plos.org/plosmedicine/s/submission-guidelines#loc-references. Citations should be in square brackets, before punctuation, and not superscript, eg. “…[1,2].”

7. Methods:

a. Please include the exact search date (including day).

b. Please mention that separate ethical approval was not required for your study.

8. Results: Please include p values alongside 95% CIs/CrIs for all comparisons.

9. Please remove the Contributors, Funding, and Disclosures sections on p. 16-17 – these details are taken from the online submission from.

10. Please provide access details (eg. volume/issue/pages, DOI or URL) for references 9, 22, 26.

11. Please upload each item of Supporting Information as a separate file.

12. When completing the PRISMA checklist, please use section and paragraph numbers, rather than page numbers.

---

Comments from Reviewers:

Reviewer #1: The authors have addressed all my points

Michael Dewey

Reviewer #2: The paper was improved. No further comments.

Any attachments provided with reviews can be seen via the following link:

[LINK]

PLoS Med. 2021 Feb 16;18(2):e1003543. doi: 10.1371/journal.pmed.1003543.r005

Author response to Decision Letter 2

18 Jan 2021

Attachment

Submitted filename: Response to Reviewers .docx

Click here for additional data file.^{(20KB, docx)}

PLoS Med. doi: 10.1371/journal.pmed.1003543.r006

Decision Letter 3

Artur Arikainen

19 Jan 2021

Dear Dr. Alvarez-Bueno,

I am pleased to say that provided the remaining minor editorial and production issues are dealt with we are planning to accept the paper for publication in the journal.

[LINK]

We expect to receive your revised manuscript within 1 week. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

If you have any questions in the meantime, please contact me or the journal staff on plosmedicine@plos.org.

We look forward to receiving the revised manuscript by Jan 26 2021 11:59PM.

Sincerely,

Artur Arikainen,

Associate Editor

PLOS Medicine

plosmedicine.org

------------------------------------------------------------

Requests from Editors:

1. Abstract:

a. Line 47: Please give numbers of studies included from each region.

b. Line 55: Delete duplicate “The main”

2. Some final additional comments from the Academic Editor for consideration (apologies that these were not included in our previous email):

a. Methods/interpretation: The authors should acknowledge and discuss that network meta-analysis (in particular when comparisons are indirect) is by many considered as prone to the same issues that non-randomised comparisons are subject to. So, all indirect comparisons between PA and statins are potentially biased and should be carefully interpreted.

b. Intro/discussion: I recommend that the authors tone down the PA vs statin debate and recommendations. It is not really one or the other but the emphasis should be on both (and this paper arguing that we should put more emphasis on PA - but not at the cost of drug treatment).

c. Discussion: Following from the point above, one key limitation of the work is that focuses on one surrogate outcome but then draws far-reaching conclusions on clinical and public health decision making. This is stretching things too far and should be emphasised.

3. Line 369: Typo in “meta-analysis”.

4. Lines 414-420: Please remove the Data Availability and financial Disclosures sections – these details are taken from the online submission form.

5. Reference 63: Please remove italic formatting here.

6. When completing the PRISMA checklist, please use section and paragraph numbers, rather than page or line numbers – page and line numbers will change in the final published document.

---

Comments from Reviewers:

n/a

Any attachments provided with reviews can be seen via the following link:

[LINK]

PLoS Med. 2021 Feb 16;18(2):e1003543. doi: 10.1371/journal.pmed.1003543.r007

Author response to Decision Letter 3

20 Jan 2021

Attachment

Submitted filename: Response to Reviewers.docx

Click here for additional data file.^{(17.9KB, docx)}

PLoS Med. doi: 10.1371/journal.pmed.1003543.r008

Decision Letter 4

Artur Arikainen

22 Jan 2021

Dear Dr Alvarez-Bueno,

On behalf of my colleagues and the Academic Editor, Kazem Rahimi, I am pleased to inform you that we have agreed to publish your manuscript "Comparative effect of physical exercise versus statins on improving arterial stiffness in patients with high cardiometabolic risk: a network meta-analysis" (PMEDICINE-D-20-03097R4) in PLOS Medicine.

Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. Please be aware that it may take several days for you to receive this email; during this time no action is required by you. Once you have received these formatting requests, please note that your manuscript will not be scheduled for publication until you have made the required changes.

In the meantime, please log into Editorial Manager at http://www.editorialmanager.com/pmedicine/, click the "Update My Information" link at the top of the page, and update your user information to ensure an efficient production process.

PRESS

We frequently collaborate with press offices. If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximise its impact. If the press office is planning to promote your findings, we would be grateful if they could coordinate with medicinepress@plos.org. If you have not yet opted out of the early version process, we ask that you notify us immediately of any press plans so that we may do so on your behalf.

We also ask that you take this opportunity to read our Embargo Policy regarding the discussion, promotion and media coverage of work that is yet to be published by PLOS. As your manuscript is not yet published, it is bound by the conditions of our Embargo Policy. Please be aware that this policy is in place both to ensure that any press coverage of your article is fully substantiated and to provide a direct link between such coverage and the published work. For full details of our Embargo Policy, please visit http://www.plos.org/about/media-inquiries/embargo-policy/.

Thank you again for submitting to PLOS Medicine. We look forward to publishing your paper.

Sincerely,

Artur A. Arikainen

Associate Editor

PLOS Medicine

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Table. PRISMA NMA Checklist of Items to Include When Reporting A Systematic Review Involving a Network Meta-analysis.

(DOCX)

Click here for additional data file.^{(23.5KB, docx)}

S2 Table. Search strategy for the MEDLINE database.

(DOCX)

Click here for additional data file.^{(14.5KB, docx)}

S3 Table. Pooled baseline characteristics from statins and physical exercise interventions.

(DOCX)

Click here for additional data file.^{(28.1KB, docx)}

S4 Table. Quality grading of evidence.

(DOCX)

Click here for additional data file.^{(15.5KB, docx)}

S5 Table. Effectiveness ranking of stain doses and physical exercise intensities interventions.

(DOCX)

Click here for additional data file.^{(13.3KB, docx)}

S6 Table. Heterogeneity statistics for each pairwise comparison.

(DOCX)

Click here for additional data file.^{(13KB, docx)}

S1 Fig. Risk of bias for statin interventions.

(DOCX)

Click here for additional data file.^{(3.3MB, docx)}

S2 Fig. Risk of bias for physical exercise interventions.

(DOCX)

Click here for additional data file.^{(2.6MB, docx)}

S3 Fig. Rankogram for each intervention.

(DOCX)

Click here for additional data file.^{(70KB, docx)}

S4 Fig. Funnel plot for comparison-specific pooled mean differences.

(DOCX)

Click here for additional data file.^{(94.2KB, docx)}

S1 Text. References of excluded studies (with reasons) from network meta-analysis.

(DOCX)

Click here for additional data file.^{(19.8KB, docx)}

Attachment

Submitted filename: caveroredondo.pdf

Click here for additional data file.^{(53KB, pdf)}

Attachment

Submitted filename: Response to reviewers.docx

Click here for additional data file.^{(32.3KB, docx)}

Attachment

Submitted filename: Response to Reviewers .docx

Click here for additional data file.^{(20KB, docx)}

Attachment

Submitted filename: Response to Reviewers.docx

Click here for additional data file.^{(17.9KB, docx)}

Data Availability Statement

All relevant data are within the manuscript and its Supporting Information files.

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PERMALINK

Comparative effect of physical exercise versus statins on improving arterial stiffness in patients with high cardiometabolic risk: A network meta-analysis

Iván Cavero-Redondo

Jonathan J Deeks

Celia Alvarez-Bueno

Kate Jolly

Alicia Saz-Lara

Malcolm Price

Carlos Pascual-Morena

Vicente Martínez-Vizcaíno

Roles

Abstract

Background

Methods and findings

Conclusions

Systematic review registration

Author summary

Why was this study done?

What did the researchers do and find?

What do these findings mean?

Introduction

Methods

Search strategy

Eligibility

Data extraction

Table 1. Characteristics of included studies analyzing the effect of statins on PWV.

Table 2. Characteristics of included studies analyzing the effect of physical exercise on PWV.

Categorization of the interventions’ available evidence

Risk of bias assessment

Grading the quality of evidence

Data synthesis and statistical analysis

Results

Fig 1. PRISMA flowchart.

Fig 2. Network of available comparisons between statins doses and physical exercise intensities interventions in arterial stiffness.

Transitivity assessment

Risk of bias

Arterial stiffness

Table 3. Pooled MDs on arterial stiffness.

Treatment ranking

Fig 3. SUCRA.

Sensitivity analysis, heterogeneity, and small-study effect

Discussion

Conclusions

Disclaimer

Supporting information

Abbreviations

Data Availability

Funding Statement

References

Decision Letter 0

Helen Howard

Roles

Decision Letter 1

Emma Veitch

Roles

Author response to Decision Letter 1

Decision Letter 2

Artur Arikainen

Roles

Author response to Decision Letter 2

Decision Letter 3

Artur Arikainen

Roles

Author response to Decision Letter 3

Decision Letter 4

Artur Arikainen

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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