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Impact of Exercise Training on Cardiac Function Among Patients With Type 2 Diabetes: A SYSTEMATIC REVIEW AND META-ANALYSIS

Anand, Vidhu, MD; Garg, Sushil, MD; Garg, Jalaj, MD; Bano, Shah, MD; Pritzker, Marc, MD

Journal of Cardiopulmonary Rehabilitation and Prevention: November 2018 - Volume 38 - Issue 6 - p 358–365
doi: 10.1097/HCR.0000000000000353
Scientific Review

Purpose: Type 2 diabetes (T2D) is associated with subclinical abnormalities in left ventricular function and an increased downstream risk for heart failure. Exercise training has been associated with significant improvement in cardiorespiratory fitness among these patients. However, its impact on cardiac function is not well established.

Methods: We conducted a meta-analysis including all randomized and nonrandomized trials that evaluated effects of exercise training on cardiac function among patients with T2D. Primary outcomes were measures of left ventricular systolic (global longitudinal strain) and diastolic (early diastolic velocity [é]) function. The effects of exercise training on peak oxygen uptake; other markers of diastolic dysfunction: mitral peak early-to-late diastolic filling velocity (E/A), mitral inflow to annular ratio (E/é), and deceleration time (DT); and systolic velocity were also assessed.

Results: Our study included 441 patients enrolled in 6 trials. Exercise training significantly improved early diastolic velocity (standardized mean difference [SMD], 0.58; 95% CI, 0.09-1.07), global longitudinal strain (SMD, 0.62; 95% CI, 0.04-1.21), and peak oxygen uptake (SMD, 1.43; 95% CI, 0.51-2.35) as compared with control group. However, no significant changes were observed in other markers of diastolic function (E/A, E/é and DT) and systolic velocity.

Conclusion: Exercise training in patients with T2D is associated with a significant improvement in some echocardiographic indicators of systolic and diastolic function and cardiorespiratory fitness. These findings suggest that exercise training may improve subclinical systolic and diastolic dysfunction in patients at risk for clinical heart failure.

We examined the effect of exercise training on cardiac function in patients with type 2 diabetes (T2D) by conducting a meta-analysis. Results indicated significant improvement in some echocardiographic indicators of systolic and diastolic function and cardiorespiratory fitness with exercise. Exercise training may reduce the risk of heart failure in patients with T2D.

Department of Medicine, Division of Cardiology, University of Minnesota School of Medicine, Minneapolis (Drs Anand, Garg, and Pritzker); Division of Cardiology, Lehigh Valley Health Network, Allentown, Pennsylvania (Dr Garg); and Department of Medicine, University of Texas Southwestern, Dallas (Dr Bano).

Correspondence: Vidhu Anand, MD, Department of Cardiovascular Medicine, Mayo Clinic-Rochester, 200 First St SW, Rochester, MN 55905 (

The authors declare no conflicts of interest.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (

Diabetes mellitus is associated with increased incidence of heart failure,1 even in the absence of hypertension and coronary artery disease. Development of clinical heart failure in these individuals involves progression through several intermediate cardiac phenotypes including abnormal left ventricular remodeling and subclinical systolic and diastolic dysfunction.2 , 3 Subclinical diastolic dysfunction is one of the earliest manifestations of the effects of diabetes on cardiac function seen in up to 75% patients.4 , 5

Numerous studies have shown that higher level of cardiorespiratory fitness is associated with favorable cardiac structural and functional changes and lower risk of incident heart failure.6–8 Exercise training is a well-established, widely available, and low-cost intervention that has been shown to improve cardiorespiratory fitness levels in patients at risk for heart failure as well as those with established heart failure.9 , 10 Several studies have evaluated the impact of exercise training in individuals with diabetes who are at risk for future heart failure development.10 , 11 While, these studies have demonstrated improvement in cardiorespiratory fitness with training, the impact of exercise on diastolic performance has not been well defined.

A crucial step in evaluation of interventions such as exercise training as a potential strategy for prevention is to understand their impact on the intermediate cardiac phenotypes such as asymptomatic systolic and diastolic dysfunction, particularly in high-risk patients. Accordingly, we performed a meta-analysis to evaluate the effects of exercise training on cardiac function in patients with type 2 diabetes (T2D).

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We conducted a comprehensive search of the following databases: MEDLINE, PubMed, EMBASE, and Cochrane library using the MeSH terms and key words included exercise training, cardiac rehabilitation, pulmonary rehabilitation, cardiopulmonary rehabilitation, exercise, walking, and diabetes. In addition, we also searched the reference lists of review articles to identify relevant studies. We conducted search from 1965 to February 2014 and updated in December 2017. We did not apply language restrictions. The protocol of our systematic review and meta-analysis was pre-specified but not published or registered.

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We searched for all types of articles (randomized and nonrandomized study designs) that enrolled adult patients (age ≥18 y) with T2D and diastolic dysfunction who underwent exercise training versus control/no intervention. We excluded patients with metabolic syndrome, cardiovascular disease, and overt heart failure. Our initial search identified 23 315 studies after removing duplicates. To retain sensitivity and not to miss any important studies, we used a broad search strategy. Two authors carried out the process of study selection independently. We excluded 23 293 studies by review of title and abstract. The full text was obtained for 22 studies, out of which 16 studies were excluded after assessing them against the selection criteria. Other authors were consulted in case of disagreements or discrepancies. A flowchart of the study selection process was developed as suggested by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement (see Supplemental Digital Content 1, available at: Six studies were included in the final analysis. The primary outcome variables of the study were the earliest markers of diastolic (mitral annulus early diastolic velocity [é in cm/sec]) and systolic (myocardial strain expressed as %) functions. Secondary variables included others markers of diastolic function: E/A (mitral peak early [E] to late diastolic [A] filling velocity); E/é (mitral inflow to annular ratio); DT (deceleration time in msec); systolic velocity reported in cm/sec; and peak

O2 (peak oxygen uptake expressed in mL/kg/min). Studies failing to report at least 1 of the primary outcomes were excluded from analysis.

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Two authors independently extracted data. If more than 1 publication of the same study existed, we grouped the reports together and used the publication with the most complete data in the analyses. The data extraction was carried out using a pre-defined data extraction form, including general characteristics of the trials, risk of bias, and characteristics of intervention and control.

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Two authors independently assessed the risk of bias in included studies using the Cochrane Collaboration's tool for assessing risk of bias.12 Disagreements were resolved by discussion with other authors. We assessed the included studies for selection bias (sequence generation and allocation sequence concealment), performance bias (blinding of participants), detection bias (blinding of outcome assessors), attrition bias (incomplete outcome data), reporting bias (selective outcome reporting), and other biases (ie, baseline imbalance). Those findings of the final assessment for all included studies are summarized in Supplemental Digital Content 2, available at:

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All the analyses were performed using Stata (StataCorp) version 12.1 software. The meta-analysis has been reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.13 A fixed-effects model was used to conduct the meta-analysis of the outcomes. Heterogeneity was assessed using the I 2 test and the random-effects model was used for significant heterogeneity (I 2 > 50%). Data were analyzed using the standardized mean difference (SMD) with 95% CI for all the outcomes. To assess the effect of demographic factors, age, and body mass index (BMI) on primary outcomes of é and global longitudinal strain, a random-effects meta-regression model was used.

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Six studies14–19 (n = 441 individuals) were included in the analyses. Mean age of the participants was 56 ± 10 y and 74.5% were males. Four of the included studies were randomized controlled trials, and 2 studies18 , 19 were nonrandomized controlled studies that were initially planned as randomized but, because of enrollment difficulties, were later changed to a nonrandomized controlled design. The mean duration of exercise training in the included studies was 12 mo. Baseline demographic and clinical characteristics of the study participants from the included studies are summarized in Table 1. All the included studies included participants with T2D without overt cardiovascular disease. The inclusion and exclusion criteria, exercise protocol, control group, duration of follow-up, and the outcomes measured in the included studies are summarized in Table 2. All the study participants had an echocardiographic assessment at baseline and follow-up.

Table 1

Table 1

Table 2

Table 2

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Overall, the quality of included studies was moderate to low (see Supplemental Digital Content 2, available at: The random sequence generation was defined in 4 included trials.14–17 Allocation sequence was concealed in only 2 of the 4 randomized studies15 , 17 and was unclear in 2 studies.14 , 16 The risk of bias for allocation concealment was high in the nonrandomized studies. The participants were unblinded for the intervention in all the included studies due to the nature of the intervention (exercise); however, this is unlikely to introduce a bias. The outcomes assessors were blinded in 4 studies, reflecting a low risk of detection bias. The blinding of outcome assessors is unclear in 2 studies.14 , 18 Two studies had a high dropout rate and, therefore, had high risk of attrition bias.14 , 19 All included studies reported all the clinically relevant outcomes, except for 1,17 which did not report peak oxygen uptake, thereby reflecting a high risk of reporting bias. We also found significant other biases in all included studies: small sample size14–16; lack of true control group14; self-reporting of physical activity15; differences in baseline characteristics between the 2 groups16; and change in study design from randomized to nonrandomized controlled.18 , 19

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Effect of exercise on é

Alterations in é being the earliest and most sensitive marker of diastolic dysfunction was our primary outcome. Five included studies14 , 15 , 17–19 reported this outcome at baseline and after exercise training and our meta-analysis showed a significant improvement in é with exercise (SMD = 0.58; 95% CI, 0.09-1.07) compared with the control group (Figure 1A). The analysis was performed using random-effects model because of significant heterogeneity between the studies (I 2 = 77.4%). Metaregression analysis showed a nonsignificant effect of BMI (kg/m2) and age on the pooled SMD (BMI metaregression coefficient = −0.36; P = .24, and age: metaregression coefficient = −0.14; P = .10).

Figure 1

Figure 1

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Effect of exercise on global longitudinal strain

Six included studies14–19 reported this outcome by either tissue Doppler imaging14–18 or 2-D Speckle-tracking echo19 and meta-analysis demonstrated a significant improvement from baseline to follow-up with exercise training compared with the control group (SMD = 0.62; 95% CI, 0.04-1.21). This analysis was also performed using random-effects model due to significant heterogeneity between the studies (I 2 = 86.2%) (Figure 1B). Metaregression analysis showed a significant effect of age but nonsignificant effect of BMI on the pooled SMD (age metaregression coefficient, −0.32; P = .0012, and BMI metaregression coefficient, −0.43; P = .31).

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Secondary outcomes

There were nonsignificant differences noted between exercise and control groups when other parameters of diastolic dysfunction E/A, E/é and DT were analyzed from baseline to follow-up. Four of the 6 studies reported both E/A and E/é outcomes.14 , 17–19 Meta-analysis using random-effects model did not show a significant difference between exercise and control groups (SMD = 0.59; 95% CI, −0.40 to 1.58, and SMD = −0.34; 95% CI, −0.99 to 0.31, respectively) (Figures 2A and 2B). Pooling across the available studies17–19 was done using fixed-effects analysis for DT and found no significant difference between the groups (SMD = 0.14; 95% CI, −0.16 to 0.44; I 2 = 39%) (Figure 2C).

Figure 2

Figure 2

Our meta-analysis showed a significant improvement in peak

O2 between exercise and control groups (SMD = 1.43; 95% CI, 0.51-2.35) from baseline to follow-up in patients with T2D (Figure 3A). The analysis was performed using random-effects model, since there was significant heterogeneity between the studies, I 2 = 93.8%.

Figure 3

Figure 3

All 6 studies14–19 reported the effect of exercise on systolic velocity and pooling data from the studies using random-effects meta-analysis showed nonsignificant changes in systolic function (SMD = −0.66; 95% CI, −1.51 to 0.19; I 2 = 93.2%) (Figure 3B). The weighted mean differences with standard errors for all outcomes are presented in Table 3. No adverse effects of exercise training were reported in any of the included studies.

Table 3

Table 3

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In this meta-analysis, we observed several clinically relevant findings. First, exercise training was associated with improvement in cardiorespiratory fitness among individuals with diabetes, which is consistent with a previous study.20 Second, exercise training was associated with improvement in the earliest, preload independent measure of diastolic dysfunction (é) in patients with T2D.21 The improvement in é was noted even in patients with longer duration of diabetes.19 Third, exercise training was also associated with improvement in measures of systolic function as measured by global longitudinal strain. Finally and interestingly, the effect of exercise training on various measures of diastolic function was different, with improvements in é but no significant change in measures of E/A, E/é, or deceleration time.

We observed robust improvement in fitness, as noted by improvement in peak

O2, with exercise training in obese patients and patients with diabetes. This highlights the importance of exercise training in these individuals for improving fitness and potentially altering long-term cardiovascular risk.

Previous studies evaluating the impact of exercise training on diastolic function have demonstrated mixed results. A randomized controlled trial looking at the effects of exercise training in patients with diastolic heart failure showed significantly improved peak

O2 and markers of cardiac diastolic function including E/é, é, and left atrial volume index.22 This benefit of atrial reverse remodeling and improved left ventricular diastolic function also translated into improved quality of life in diastolic heart failure patients.22 Another study involving patients with systolic and diastolic dysfunction showed improvement in peak

O2 with exercise training but no improvement in echocardiographic diastolic parameters.23 Also, a randomized controlled trial in older patients with heart failure and preserved ejection fraction showed increased peak

O2 with exercise training; however, it did not assess changes in the diastolic function using novel tissue Doppler techniques.24

Our results are similar to the studies conducted in obese patients and patients with metabolic syndrome with subclinical diastolic dysfunction which showed favorable effects of exercise intervention on é,25 , 26 but no improvement in other markers of diastolic dysfunction. It is important to note that improvement in some of the markers of diastolic dysfunction was also observed with good glycemic control in 1 study27; however, the results were not reproducible in other studies,28 , 29 suggesting that glycemic control without exercise training is insufficient in producing improvement in diastolic function.

Strain and strain-rate imaging is a new echocardiographic method for comprehensive assessment of early myocardial dysfunction30; therefore, we assessed it as our coprimary outcome and observed improvements in systolic function measured as longitudinal strain. This is consistent with studies that have shown significantly higher left ventricular longitudinal strain and strain rates in athletes than in controls.31 , 32

The mechanisms underlying the improvement in cardiac function are unclear. Some of the proposed mechanisms include decreased afterload; improved cardiac sympathovagal balance18; cardiac remodeling as seen in an athletic heart33 , 34; enhanced endothelial function; alterations in cardiac lipid deposition; receptor for advanced glycation end products; and improved myofilament calcium sensitivity.16 , 20 However, these could not be assessed in the current meta-analysis because of lack of reporting of these outcomes in the included trials.

The limitations of this study include the number of included studies and inclusion of nonrandomized trials that were initially planned as randomized, reflecting the paucity of and challenges to conduct randomized controlled trials addressing this question. The high allocation bias seen in some of the included studies reflects the difficulties in allocation of participants in the control arm. Also, there is a high dropout rate and subjectivity in assessment during the maintenance phase of the intervention. There was also suspected detection bias in 2 included studies that did not specify whether the cardiologists reading the echocardiograms were blinded. In addition, the small sample size of some included trials and high dropout rate in a few included studies resulted in wide CIs for effect estimates. This emphasizes the significance of this systematic review and meta-analysis, which pooled all the available data.

It is important to note that there was, overall, a short duration follow-up in the included studies (mean = 12 mo), thereby probably leading to lack of significant changes in other parameters of diastolic dysfunction which may be affected by longer-term remodeling with consistent exercise. Longer duration trials are also needed to assess sustainability of effects and clinical outcomes such as development of heart failure and mortality. Other potential bias in this meta-analysis is the inclusion of only published studies.

Current studies do not allow us to draw conclusions regarding the evolution and maintenance of improvements in a broader panel of indices of diastolic function. Overall, our findings suggest that exercise training in patients with T2D in the pre-clinical stage, without overt coronary artery disease or congestive heart failure, improves early diastolic dysfunction, myocardial strain, and peak

O2 and thus may be used as a therapeutic intervention in this population. Long-term studies are needed to assess the benefits on other markers of diastolic dysfunction, quality of life, and overall mortality. This review of the limited data available suggests that sustained exercise training in patients with risk factors for key, early underpinnings of heart failure with preserved ejection fraction may enhance cardiac function and, hopefully, this would translate into sustained improvements in quality of life and delay the progression to symptomatic heart failure with preserved ejection fraction. Future studies with adequate sample sizes, longer follow-up duration, and relevant clinic end points are needed to establish the effects of exercise in this important patient population.

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cardiorespiratory fitness; diastolic dysfunction; exercise training; type 2 diabetes

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