Effect of Exercise on Risk Factors of Diabetic Foot Ulcers: A Systematic Review and Meta-Analysis : American Journal of Physical Medicine & Rehabilitation

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Original Research Articles

Effect of Exercise on Risk Factors of Diabetic Foot Ulcers

A Systematic Review and Meta-Analysis

Liao, Fuyuan PhD; An, Ruopeng PhD; Pu, Fang PhD; Burns, Stephanie PT, PhD; Shen, Sa PhD; Jan, Yih-Kuen PhD

Author Information
American Journal of Physical Medicine & Rehabilitation 98(2):p 103-116, February 2019. | DOI: 10.1097/PHM.0000000000001002

Abstract

Diabetic foot ulcers (DFUs) are one of the most common complications of diabetes mellitus.1 The annual incidence of foot ulceration in diabetic patients is reported to be higher than 2%2 and the lifetime incidence is estimated to be approximately 15%–25%.1 Diabetic foot ulcers are a major cause of hospitalization and nontraumatic lower-limb amputations in people with diabetes.3 Amputation rates in diabetic patients were 10–30 times higher than in the nondiabetic population.4,5 A cohort study of a large population of patients with DFUs from 14 centers in Europe (the EURODIALE Study) showed that 5% of the patients underwent a major amputation (above the ankle level) and 6% died during a 12-mo follow-up period.6 Because of the nonhealing wounds and high economic burden of treatment of DFUs, it has been recognized that prevention of DFUs is a priority in health care.7

The pathogenesis of DFU is multifactorial, involving a number of risk factors depending on the risk classification systems, among which peripheral neuropathy and peripheral arterial disease are most commonly documented.1,3,8,9 Other key risk factors presented in these systems include foot deformity, previous foot ulceration, and amputation of (a part of) the foot or leg.7,10,11 Peripheral neuropathy results in pathologic changes in sensory, motor, and autonomic nerves as well as their functions.12 Sensory neuropathy results in loss of protective sensation needed to detect tissue damage due to trauma and/or mechanical stresses. Motor neuropathy can lead to foot deformities shown to be associated with elevation of plantar pressures. Autonomic neuropathy contributes to excessive dryness of the skin, which can lead to skin breakdown and callus formation.12 These alterations increase the risk of trauma and subsequent ulceration.12

Peripheral arterial disease (PAD) causes impaired vasodilatory response to plantar pressures during walking and results in plantar tissue ischemia and subsequent DFUs.12 The prevalence of PAD is estimated to be 21% in the diabetics13 and at least 50%–60% in those with DFUs.14,15 Moreover, PAD is strongly related to nonhealing foot ulcers and subsequent amputation.12 The EURODIALE Study on diabetic patients with a new foot ulcer revealed a healing rate of 69% versus 84% and a major amputation rate of 8% versus 2% in patients with PAD compared with those without PAD.6 Population studies have revealed a relationship between hyperglycemia and prevalent PAD among people with diabetes.16,17 In particular, each 1% increase in glycated hemoglobin (HbA1c) was associated with an increase in the risk for PAD by 28%.18 However, the particular aspects of PAD that contribute to the development of DFUs and wound healing remain unclear.19

Various interventions have been used to prevent DFUs in clinical practice.7 Exercise training seems to be a top choice for the management of many type 2 diabetes mellitus (T2DM)-related symptoms.20 A number of studies have investigated the effectiveness of exercise on reducing risks of DFUs in people with T2DM and showed positive results on glycemic control,21–26 vascular structure and function of the lower limbs,21,22,24 and peripheral nerve function.27 However, there are still uncertainties when extrapolating these findings to clinical practice. On one hand, a number of factors such as exercise type and intensity of exercise might differ in effectiveness,28 whereas the relative effects of different types of exercise have not been well addressed. A recent meta-analysis29 showed that aerobic exercise induced a marginally greater decrease in HbA1c in patients with T2DM compared with resistance training. However, a randomized controlled trial (RCT) demonstrated that aerobic or resistance exercise alone did not reduce HbA1c, and only the combined exercise was associated with lower HbA1c levels.26 This finding was inconsistent with the result from a meta-analysis by Snowling and Hopkins,30 who reported a negligible difference in HbA1c reduction between aerobic and combined exercises. On the other hand, the impact of exercise on vascular function in the lower limbs in people with T2DM is largely unknown. A meta-analysis by Montero et al.31 showed that exercise improved flow-mediated dilation of the brachial conduit artery of patients with T2DM, suggesting an improvement in arterial endothelial function.

Currently, there is no specific evidence for the prevention of DFU.1 Nevertheless, strict glycemic control is proven to be the only intervention for halting or reducing all diabetes-related complications.1 In addition, it is well established that glycemic control is associated with reduced macrovascular and microvascular complications.32 Therefore, this review aimed to review RCTs to examine the effect of exercise on the risk factors of DFUs, including HbA1c, vascular function of the lower limbs, and diabetic peripheral neuropathy, in people with T2DM.

METHODS

This systematic review and meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PRISMA) (see Checklist, Supplemental Digital Content 1, https://links.lww.com/PHM/A659).33

Study Selection Criteria

Studies included in this review met all of the following criteria: (1) the study was a RCT in people with T2DM 18 yrs and older; (2) the exercise intervention lasted for at least 8 wks (because HbA1c reflects the average blood glucose concentration during the preceding 8–12 wks); (3) the outcomes of the trial included at least one of the following measures: HbA1c, peripheral neuropathy, and vascular structure or function or cutaneous microvascular function of the lower limbs; and (4) the study was written in English and published until January 2018. Studies were excluded from the review if they met one or more of the following criteria: (1) involving other interventions that may influence HbA1c or vascular function; (2) the dissimilarity in the basal measures between groups could falsely contribute to the pooled effect; (3) observational study or nonpeer-reviewed article such as dissertation or conference proceeding; and (4) poor research methodology of the study. In the case of multiple articles reporting findings from the same participants and same intervention, the article that reports the more outcome measures or reports the same measure at more time points was included.

Search Strategy

A key word search was performed in five electronic bibliographic databases—PubMed, Web of Science, Cochrane Library, Scopus, and CINAHL. The search algorithm included all possible combinations of the terms from the following three groups: (1) “physical activity,” “exercise,” or “training”; (2) “diabetes,” “diabetic,” or “T2DM”; and (3) “diabetic neuropath*,” “peripheral neuropath*,” “microcirculation,” “artery,” “vasculature,” or “microvasculature.” The search algorithms are documented in Appendix 1 (Supplemental Digital Content 2, https://links.lww.com/PHM/A660). The searches were limited to articles written in English and published until January 2018. Two reviewers (FL and YJ) independently conducted title and abstract screening and identified potentially relevant articles for full-text review. Interrater agreement was assessed using the Cohen's κ (κ = 0.9763). Discrepancies were resolved through discussion. Subsequently, they independently conducted full-text review and jointly decided the final pool of articles included in the review.

A reference list search (i.e., backward reference search) and cited reference search (i.e., forward reference search) were conducted based on the full-text articles meeting the study selection criteria that were identified from the key word search. Articles identified from the backward and forward reference search were further screened and evaluated using the same study selection criteria. Reference searches were repeated on all newly identified articles until no additional relevant article was found.

Data Extraction

A standardized data extraction form was used to collect the following methodological and outcome variables from each included study: author(s), publication year, sample size, participants' demographic characteristics (age, duration of T2DM, and body mass index [BMI]), exercise characteristics (type, frequency, intensity and duration [for aerobic exercise], or volume [for resistance exercise] per session), results, intervention period, and study quality score (according to the Physiotherapy Evidence-Based Database scale34).

Meta-Analysis

Meta-analysis was performed using Review Manager (Version 5.3; The Nordic Cochrane Centre, The Cochrane Collaboration). The outcomes in meta-analysis included the effect of exercise on HbA1c (both the overall effect and by exercise type, i.e., aerobic, resistance, and combined exercise) and on the ankle brachial index (ABI). According to the Cochrane Handbook for Systematic Reviews,35 either postintervention values of the outcome or changes from baseline can be used to calculate the summary statistic, i.e., the “mean difference,” which refers to the difference between the mean value in two groups. If the standard deviations (SDs) of changes from baseline are not reported and have to be imputed from baseline, analysis of post intervention values may yield more precise results.31,35 In the present review, when examining the effect of exercise on reducing HbA1c level or improving ABI, the postintervention values of the outcome were used to calculate the mean difference, because most of the included RCTs reported postintervention values rather than within-group changes. When examining the relative efficacy of three types of exercise on reducing HbA1c level, the within-group changes were used to calculate the mean difference, because in several included RCTs, HbA1c level at baseline did not show similarity.35 For studies that reported standard error (SE) of the outcome or changes in the outcome, the SD was obtained by , where n is the sample size. For studies that reported confidence interval (CI), the SD was obtained by , where lupper and llower are respectively the upper and lower limits of the CI, and c is a constant depending on the CI as well as the sample size.35 Statistical heterogeneity was assessed by the I2 index.36 The level of heterogeneity represented by the I2 index was interpreted as small (I2 ≤ 25%), moderate (25% < I2 ≤ 50%), large (50% < I2 ≤ 75%), or very large (I2 > 75%). A fixed-effect model would be estimated when a small or moderate heterogeneity was present, and a random-effect model would be estimated when a large or very large heterogeneity was present. Publication bias was assessed by the Egger's test using Stata Version 15.1 (StataCorp LP; College Station, TX).35

Study Quality Assessment

The quality of the included RCTs were evaluated using the Physiotherapy Evidence-Based Database scale,34 which consists of 10 items, including random and concealment of allocation, blinding of participant, therapist, and assessor, adequate follow-up, intention-to-treat analysis, between-group comparison, and point and variability measures. Each item was scored as either present (1 point) or absent (0 point), and a total score was obtained by adding the scores of the 10 items.

RESULTS

Study Selection

Figure 1 shows the study selection flowchart. Briefly, the initial search of PubMed, Web of Science, Cochrane library, Scopus, and CINAHL identified 1892 records. In addition, four potential articles were identified by searching the reference lists of the eligible full-text articles and relevant review articles. Of the 1896 records, 1088 records remained after removing duplicates, 47 articles remained after title/abstract screening, and 20 articles remained after full-text assessment for eligibility. Finally, 20 RCTs with a total of 1357 participants with T2DM were included in the meta-analyses.

F1
FIGURE 1:
Flowchart of study selection.

Characteristics of Selected Studies

The basic characteristics of the included studies are summarized in Table 1. Among the 20 RCTs, 18 trials reported the effect of exercise on HbA1c, one trial on ABI,52 and another trial on both HbA1c and ABI.24 The number of participants in individual trials ranged from 1844 to 262.26 All the participants were overweight or obese adults, with a mean age and BMI at baseline ranging from 4844 to 65 yrs38 and from 26.745 to 45 kg/m2,44 respectively. The baseline mean duration of T2DM in 13 (65%) trials ranged from 2.6 to 21.1 yrs and was reported to be longer than 1 yr in one trial25 and shorter than 3 mos in another trial.38 The duration of exercise intervention ranged from 837,49 to 103 wks,51 with a median of 18.5 wks.

T1
TABLE 1:
Characteristics of the included studies

Regarding the types of exercise, 18 trials involved aerobic exercise: five conducted aerobic exercise only23,37,40,47,50; four conducted combined exercise (aerobic exercise plus resistance training) only42,43,51,52; five compared resistance training with aerobic exercise41,44,45,48,49; three compared three types of exercise25,26,39; and one compared combined exercise with aerobic exercise.46 The main forms of aerobic exercise were walking, cycling, and treadmill. Among the 14 trials, 12 reported a mean frequency of 3.65 sessions per week with a length of 20–60 mins; one reported a frequency of at least four sessions per week to accumulate more than 150 mins/wk,47 and one did not report the frequency.26 The intensity, however, was reported in various forms: in six trials,25,39,42,43,49,52 at 60%–90% of maximum heart rate; in three trials,37,41,44 at 40%–85% of heart rate reserve; in six trials,23,26,46,47,50,51 at 50%–80% of peak oxygen consumption; in two trials,45,48 at 3.6–6.0 metabolic equivalents; and in another trial, at 55% to more than 70% of peak energy expenditure rate.40 There are two trials that did not provide complete information about aerobic exercise: one did not report the frequency and duration per session but provided a total duration of 150 mins per week26 and another did not report the duration per session.51

On the other hand, 14 RCTs involved resistance training (Table 1), which was generally performed using weight machines,25,44 a combination of machines and free weights,41,49,51 resistance bands,45,48 or a multistation machine.43 Seven trials26,41–45,52 adopted an exercise frequency of three sessions per week; the remaining seven trials conducted two,46,51 2–3,25 on average 2.25,49 4,39 5,48 and 14 sessions24 of exercises per week, respectively. The resistance training programs consisted of 3–15 (mostly 7–10) exercises, involving major muscle groups of upper and lower body. The exercises were generally conducted progressively, with an increasing intensity or number of repetitions. In 12 trials,25,26,39,41–45,48,49,51,52 1–4 sets (mostly 2–3 sets) of 6–20 (mostly 8–12) repetitions of each exercise were performed. In another trial,24 the number of repetitions was determined every week. The intensity was specified in all but four trials.23,24,26,44 Six trials25,39,41–43,49 used an intensity more than 30% (mostly >50%) of one repetition maximum, which generally increased with the progress of training or was adjusted if the participant could complete the prescribed repetitions. In two trials using resistance bands, the resistance gradually increased by up to 40%–50% from its minimum setting for the training period45 and was set at 40%–50% of maximal capacity,48 respectively. In another trial,51 the intensity increased from 60% to 80% of maximal voluntary contractions.

There are three trials that compared the three types of exercise.25,26,39 In one trial,39 the participants in combined exercise group performed the same exercises at the same intensity but half the volume of that in other groups. In the remaining two trials,25,26 the relationship between the volume of combined exercise and that in other groups was unclear.

Intervention Effectiveness

Effect of Exercise on HbA1c

There are 13 trials that investigated the effect of exercise on HbA1c and had a nonexercise control group, with a total of 987 participants (Table 1). Of them, eight trials reported postintervention HbA1c only23,24,37,40,45,47,51,53 and five reported both postintervention HbA1c and within-group changes.25,26,42,43,48 Thus, the differences in postintervention HbA1c between exercise and control groups were synthesized to produce a summary statistic, i.e., the mean difference. Various exercises were conducted in these trials, including aerobic, resistance, and combined exercises. Nine trials reported a significant decrease in HbA1c or significantly lower HbA1c in exercise group compared with control group after interventions.23–26,37,43,45,47,51 The pooled estimate from meta-analysis showed that postintervention HbA1c was significantly lower in exercise group than in control group, with a mean difference of −0.45% (95% CI = −0.59% to −0.31%, P < 0.00001, I2 = 4%) (Fig. 2). Subgroup analyses further revealed that aerobic, resistance, and combined exercises resulted in significantly lower HbA1c compared with controls (Fig. 2), with mean differences in postintervention HbA1c of −0.38% (95% CI = −0.57% to −0.18%, P = 0.0002, I2 = 0%), −0.58% (95% CI = −1.14% to −0.03%, P = 0.04, I2 = 71%), and −0.51% (95% CI = −0.75% to −0.26%, P < 0.0001, I2 = 0%), respectively.

F2
FIGURE 2:
Forest plot of postintervention mean differences in HbA1c between exercise and control groups. df, degrees of freedom; IV, inverse variance.

Comparisons of Three Types of Exercise

There are eight trials comparing the effect of reducing HbA1c between aerobic exercise and resistance training. Of them, two trials reported within-group changes in HbA1c only,39,41 five reported both postintervention HbA1c and within-group changes,25,26,44,48,49 and one reported postintervention HbA1c only.45 We noted that in these trials, HbA1c at baseline did not show similarity between two groups. For example, in one trial,44 baseline HbA1c levels in resistance and aerobic exercise groups were respectively 10.7 ± 2.1% (mean ± SD) and 8.9 ± 1.9%, and the postintervention values were 10.6 ± 2.4% and 8.8 ± 2.1%, respectively. Therefore, only the first seven trials that reported within-group changes in HbA1c were include in the meta-analysis. The differences in within-group changes in HbA1c were synthesized. The pooled estimate did not show a significant difference in reduction in HbA1c between two groups (P = 0.1) (Fig. 3A).

F3
FIGURE 3:
Forest plots of mean difference in reduction of HbA1c (A) between aerobic and resistance exercise groups, (B) between combined and aerobic exercise groups, and (C) between combined and resistance exercise groups. df, degrees of freedom; IV, inverse variance.

Three trials compared combined exercise with aerobic exercise or resistance training.25,26,51 Two of them provided both postintervention HbA1c and within-group changes,25,26 and another reported within-group changes in HbA1c only.39 The pooled estimates demonstrated that the within-group change in HbA1c in combined exercise group was significantly larger than that in aerobic and resistance exercise groups with mean differences of −0.25% (95% CI = −0.39% to −0.11%, P = 0.0006, I2 = 0%, fixed effect) and −0.64% (95% CI = −1.1% to −0.19%, P = 0.006, I2 = 87%, random effect), respectively (Figs. 3B, C).

Effect of Exercise Intensity on HbA1c

There are two trials examining the effect of exercise intensity on HbA1c.38,50 Of them, one reported both postintervention HbA1c and within-group changes,38 and another reported postintervention HbA1c only.50 The pooled estimate showed that high-intensity exercise significantly reduced HbA1c compared with moderate-intensity exercise, with a mean difference of −0.60 (95% CI = −0.72 to −0.48, P < 0.00001, I2 = 0%, fixed-effect) (Fig. 4).

F4
FIGURE 4:
Forest plot of postintervention mean difference in HbA1c between high-intensity exercise and moderate-intensity exercises groups. df, degrees of freedom; IV, inverse variance.

Effect of Exercise on ABI

Only two trials examined the effect of exercise on ABI24,52: one reported postintervention ABI only24 and the other reported both postintervention ABI and within-group difference.52 Meta-analysis found that exercise significantly improved ABI, with a mean difference in postintervention ABI of 0.03 (95% CI = 0.01 to 0.05, P = 0.002, I2 = 0%, fixed-effect) (Fig. 5).

F5
FIGURE 5:
Forest plot of postintervention mean difference in ABI between exercise and control groups. df, degrees of freedom; IV, inverse variance.

Effect of Exercise on Diabetic Neuropathy

The effect of exercise on diabetic neuropathy was not assessed in the review because only one RCT examined this factor.

Publication Bias

Egger's test did not identify publication bias on postintervention HbA1c between exercise and nonexercise groups (P = 0.923) and between aerobic, resistance, or combined exercise and nonexercise groups (P = 0.638, 0.49, and 0.376, respectively). No publication bias was identified in comparing reduction of HbA1c between three types of exercise (P = 0.135, 0.439, and 0.21 for aerobic vs. resistance, combined vs. aerobic, and combined vs. resistance, respectively). For the compassion of improvement of ABI between exercises, Egger's test yielded a P value of 0.05, indicating the existence of publication bias. In addition, Egger's test identified publication bias on postintervention HbA1c between high-intensity and moderate-intensity exercise groups.

Adverse Events

Among the 20 included trials, 5 clearly stated that no adverse event occurred,23,25,26,39,47 13 did not report this issue,24,37,38,40,42,43,45,46,48–52 and only 2 reported adverse events.44,53 In one trial,44 one (11.1%) of nine participants experienced syncope during performing a resistance exercise; in another trial,53 among 19 participants who conducted aerobic exercise, one (5.3%) experienced back pain, whereas among 19 participants who conducted resistance exercise, three (15.8%) experienced back pain and one (5.3%) had elbow tendonitis. In this trial, mild asymptomatic hypoglycemia was detected in nine participants (47.4%) in the aerobic exercise group and eight participants (42.1%) in the resistance exercise group after exercise sessions.

Study Quality Assessment

According to the Physiotherapy Evidence-Based Database scale,34 the quality of the included studies was moderate, with a mean ± SD score of 5 ± 1.26 of 10 points (Table 2). One trial (5%) clearly stated concealed allocation process49; 10 (50%) reported similar HbA1c at baseline among the groups23,24,26,38,41,43,47,50–52; one (5%) stated blinded subjects24; one (5%) stated blinded therapist46; six (30%) stated that the assessors were blinded to the intervention groups24,26,40,41,49,52; eight (40%) conducted intention to treat analyses.24,26,42,43,46,49,50,52 The dropout rates in 13 trials (65%)23,24,26,37–41,45–48,51 were below 15%, with a mean ± SD of 3.4% ± 3.6%, whereas dropout rates in the remaining seven trials25,42–44,49,50,52 had a mean ± SD of 22.6% ± 5.1%. All the included trials reported the results of between-group statistical comparison and provided both the mean and SD, standard error, or 95% CI for HbA1c and/or ABI.

T2
TABLE 2:
Score for the included studies according to the physiotherapy evidence-based database scale

DISCUSSION

In the present meta-analyses, data from 19 RCTs regarding the effect of exercise on HbA1c level and two RCTs on ABI were respectively synthesized. The results indicate that exercise intervention significantly reduced HbA1c level and improved ABI in people with T2DM. The results further indicate that combined exercise had greater benefit on HbA1c reduction compared with either aerobic exercise or resistance training alone.

The overall effect of exercise on glycemic control in people with T2DM has been well documented.29,30,54–56 A Cochrane review of 14 RCTs published in 2009 reported that exercise intervention reduced HbA1c by 0.6% (95% CI = 0.3% to 0.9%) compared with nonexercise.54 The degree of the reduction was greater than that of our results (0.6% vs. 0.45%). That review, however, did not further compare the effectiveness of HbA1c reduction among different types of exercise. A meta-analysis by Snowling and Hopkins30 showed that aerobic, resistance, and combined exercises respectively reduced HbA1c by 0.37%, 0.29%, and 0.43%, which were similar to our results except that our estimate yielded a greater mean decrease in HbA1c for resistance training (0.58%). Another meta-analysis by Chudyk and Petrella56 reported that aerobic, resistance, and combined exercises reduced HbA1c by 0.6%, 0.33%, and 0.67%, respectively. The magnitudes of HbA1c reduction for aerobic and combined exercises were respectively larger than that of our results (0.6% vs. 0.38% and 0.67% vs. 0.51%) and that from the study by Snowling and Hopkins30 (0.6% vs. 0.37% and 0.67% vs. 0.43%). The reasons for our estimation of a larger mean decrease in HbA1c for resistance training are as follows. In one trial,25 the mean ± SD postintervention HbA1c levels in resistant training and control groups were 7.3 ± 1.1% and 8.2 ± 1.0, respectively. This distinct difference may be due to a long training period (52 wks). In another trial,24 basal HbA1c the mean ± SD levels in resistance training and control groups were 6.189 ± 1.114% and 6.543 ± 0.757, respectively. This dissimilarity enlarged our estimation of mean decrease in HbA1c.

Our results show that aerobic exercise induced a greater reduction in HbA1c compared with resistance training, with a mean difference of −0.19% (95% CI = −0.41% to 0.04%), but the difference did not reach a significant level (P = 0.1). This observation is consistent with Yang et al.,29 who observed a mean difference of −0.18% (95% CI = −0.36% to −0.01%). This means that aerobic exercise could be more effective for reducing HbA1c compared with resistance training. In particular, our results indicate that combined exercise is the most effective intervention for reducing HbA1c compared with either aerobic or resistance exercise alone, with mean differences of −0.25% (95% CI = −0.39% to −0.11%, P = 0.0006) (Fig. 3B) and −0.64% (95% CI = −1.1% to −0.19%, P = 0.006). It should be noted that the included trials for comparing different types of exercise were not the same as those for comparing a specific type of exercise with nonexercise. As a consequence, there was an inconsistency between the result from comparing combined exercise with nonexercise and that from comparing combined exercise with resistance training.

The reason for the superior effect of combined exercise compared with aerobic or resistance exercise alone on glycemic control is unclear. Previous research has found that exercise induces improvements in microvascular vasodilation and insulin signaling and increases in capillary density in skeletal muscle, which increase glucose and insulin delivery as well as glucose uptake.20,57 Combined exercise likely engages more skeletal muscle mass compared with aerobic or resistance exercise alone. If the duration and intensity are sufficient, exercise-induced adaptations would occur in more muscle mass and associated microvasculature. Olver and Laughlin57 suggested that exercise programs should maximize whole-body skeletal muscle fiber recruitment to improve glycemic control.

Our results also show that high-intensity exercise could be more effective in reducing HbA1c compared with moderate-intensity exercise. However, the mean difference in postintervention HbA1c was slightly overestimated because of dissimilarity at baseline in one trial50: the basal HbA1c levels in high-intensity and moderate-intensity exercise groups were 7.1 ± 0.2% and 7.4 ± 0.3%, respectively.

In addition to glycemic control, our results show that exercise induced a significant increase in ABI compared with nonexercise, suggesting the role of exercise in prevention or counteraction of PAD in patients with T2DM. This result is inconsistent with that from a review by Waston et al.,58 who concluded that exercise had no effect on ABI in people with intermittent claudication. An explanation to this inconsistency is that people with intermittent claudication might have established atherosclerosis in the lower limbs, whereas exercise may be more effective for improving ABI in the earlier atherosclerotic process.52

There are several issues that need to be highlighted. First, it would be important to examine the effect of exercise on HbA1c level and ABI as well as the relative efficacy of different types of exercise change over time. This would help prescribe an optimal exercise strategy. Unfortunately, various durations of intervention were adopted in the included RCTs, ranging from 8 to 103 wks, and the available data were collected at the final time points. Therefore, we were unable to pool data at the same time point. Nevertheless, two trials26,51 demonstrated monthly HbA1c levels over the exercise durations, which however showed different trends. In one trial with an intervention period of 9 mos,26 HbA1c level in the exercise groups rapidly decreased in the first several months, then slowly increased in the following months, and finally remained stable for the rest of the period. In another trial with an intervention period of 24 mos,51 HbA1c level showed a decreasing trend during 1–18 mos. This discrepancy might be multifactorial: the type of exercise, intensity, frequency, as well as different participants may play a role. Future research investigating how the, previously mentioned factors influence the trend of HbA1c level across long periods is needed.

Although diabetic neuropathy is a key risk factor of DFUs, there are only a few studies that investigated the effect of exercise on this factor or its complications in patients with T2DM.27,59 The only RCT showed that aerobic exercise can play a role to disrupt the progression of diabetic peripheral neuropathy.27 This result, however, could not be included in the present meta-analysis. A systematic review showed that enhanced glycemic control reduced the incidence of clinical neuropathy in T2DM.60 This means that the relative effects of different types of exercise on HbA1c may apply to diabetic neuropathy. On the other hand, although there is a consensus that PAD is a major risk factor of DFUs, the key aspects of PAD that relate to the development of DFUs and wound healing remain unclear.19 In the literature, the severity of PAD has been evaluated using a variety of measures. As a consequence, the outcomes of the existing RCTs regarding the impact of exercise on vascular disorders in the lower limbs frequently differed from each other.3,19

Meta-analysis found that exercise significantly improved ABI. However, the relative effects of different types of exercise on measures of peripheral vascular disease, e.g., ABI, are unknown. In our study, one RCT adopted muscle exercises on lower limbs24 and another adopted combined exercise.52 Because both trials reported significantly higher postintervention ABI compared with control group, it is difficult to deduce what is the best form of exercise to enhance vascular function in the lower limbs.

Finally, two trials included in our review showed that interval walking was more effective in reducing HbA1c compared with energy expenditure–matched continuous walking in patients with T2DM.23,40 The results, however, could not be synthesized because in one trial HbA1c at baseline did not show similarity between two groups.40 In another study by Karstoft et al.,61 interval walking enhanced insulin sensitivity, increased peripheral glucose disposal, and improved insulin signaling in skeletal muscle in patients with T2DM but continuous walking did not. These observations suggested that for aerobic exercise such as waking and running, alternating intensity may be superior to constant intensity. However, whether this applies to resistance training remains unknown.

The present review has several limitations. First, the included RCTs had methodological limitations such as dissimilarity at baseline, inadequate blinding procedures, and improper dealing with incomplete outcome data, which may have introduced bias. Second, because peripheral vascular disease has been assessed using a variety of outcome measures, only two RCTs examining the effect of exercise on ABI were included. In future research, it may be beneficial to identify the key measures of peripheral vascular disease that relate to the development of DFUs and wound healing.

CONCLUSIONS

This review and meta-analysis shows that exercise training has a significant effect on reducing HbA1c level in people with T2DM, whereas combined exercise is more effective compared with aerobic or resistance exercise alone. Exercise also has a significant effect on improving ABI, suggesting that it can play a role in the prevention or counteraction of PAD. However, evidence regarding the association between exercise and improvements in diabetic neuropathy and risks of DFUs remains insufficient. Future research is needed to clarify the effectiveness of exercise on the development of DFUs.

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Keywords:

Diabetes Mellitus; Diabetic Foot Ulcers; Exercise; Glycated Hemoglobin; Peripheral Arterial Disease; Ankle Brachial Index

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