Impact of Enhanced External Counter-pulsation Therapy on Glycaemic Control in People With Prediabetes and Type 2 Diabetes Mellitus: A Systematic Review and Meta-analysis

Background: Enhanced external counter-pulsation (EECP) therapy is approved for refractory angina in coronary artery disease (CAD). EECP is being explored as a treatment modality in type 2 diabetes mellitus (T2DM). Methods: The Embase, Web of Science, Cochrane Library, MEDLINE (PubMed), ClinicaltTrials. gov, CNKI database, Clinical Trials Registry-india (CTRI), and Google Scholar databases were searched for randomized controlled trials (RCTs) involving patients receiving EECP therapy in the intervention arm. The primary outcome was the changes in glycated haemoglobin (HbA1c). The secondary outcomes were the changes in blood glucose parameters, inflammatory markers and any adverse events. Results: Data from 3 RCTs involving 71 people with T2DM/prediabetes was analysed to find out the impact of EECP therapy compared with placebo. As compared with placebo, patients receiving EECP had significantly lower HbA1C immediately after completion of therapy (mean difference [MD] -0.70%, 95% confidence interval (CI) -0.95. -0.45;p<0.00001), at 2–4 weeks post completion of therapy (MD -1.04%, 95%CI -1.32. -0.77; p<0.00001) and 7–12 weeks after therapy completion (MD -0.98%, 95% CI -1.22, -0.74; p<0.00001). EECP therapy was well tolerated without any increased side effects (risk ratio 2.36, 95% CI 0.11–52.41; p=0.59. Conclusion: EECP therapy is effective in blood glucose and pressure lowering over at least 7–12 weeks of therapy completion. Blood glucose and pressure should be monitored with suitable modulation of drug doses to prevent hypoglycaemia and hypotension in patients with angina undergoing EECP therapy. The PROSPERO registration number is CRD42023434533


B
ackground: Enhanced external counter-pulsation (EECP) therapy is approved for refractory angina in coronary artery disease (CAD).EECP is being explored as a treatment modality in type 2 diabetes mellitus (T2DM).Methods: The Embase, Web of Science, Cochrane Library, MEDLINE (PubMed), ClinicaltTrials.gov, CNKI database, Clinical Trials Registry-India (CTRI), and Google Scholar databases were searched for randomized controlled trials (RCTs) involving patients receiving EECP therapy in the intervention arm.The primary outcome was the changes in glycated haemoglobin (HbA1c).The secondary outcomes were the changes in blood glucose parameters, inflammatory markers and any adverse events.Results: Data from 3 RCTs involving 71 people with T2DM/prediabetes was analysed to find out the impact of EECP therapy compared with placebo.As compared with placebo, patients receiving EECP had significantly lower HbA1C immediately after completion of therapy (mean difference [MD] -0.70%, 95% confidence interval (CI) -0.95.-0.45;p<0.00001), at 2-4 weeks post completion of therapy (MD -1.04%, 95%CI -1.32.-0.77; p<0.00001) and 7-12 weeks after therapy completion (MD -0.98%, 95% CI -1.22, -0.74; p<0.00001).EECP therapy was well tolerated without any increased side effects (risk ratio 2.36, 95% CI 0.11-52.41;p=0.59.Conclusion: EECP therapy is effective in blood glucose and pressure lowering over at least 7-12 weeks of therapy completion.Blood glucose and pressure should be monitored with suitable modulation of drug doses to prevent hypoglycaemia and hypotension in patients with angina undergoing EECP therapy.The PROSPERO registration number is CRD42023434533

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Enhanced external counterpulsation (EECP) is evaluated for glycaemic control in type 2 diabetes.
• EECP is associated with a significant lowering of blood pressure.
• EECP significantly lowers the levels of high-sensitivity C-reactive protein, a measure of systemic inflammation.
Enhanced external counterpulsation (EECP) therapy is a noninvasive, nonpharmacological outpatient/daycare treatment approved by the US Food and Drug Administration therapy that has been used for treating refractory angina in people living with coronary artery disease (CAD) for more than three decades now. 1,2During EECP therapy, pneumatic compression cuffs are applied to the calf and the lower and upper thigh of each leg. 2 These cuffs are inflated sequentially through computergenerated signals while synchronized to the patient's R wave on the electrocardiogram.EECP therapy leads to retrograde blood flow in the aorta, resulting in a diastolic augmentation of blood flow and improved coronary perfusion pressure during diastole. 2Seven weeks of EECP therapy have been found to reduce angina symptoms and frequency in patients with CAD; however, the benefits of EECP therapy have been found to be more blunted in people with diabetes. 5eletal muscles are a major organ for glucose disposition and storage following meal-induced hyperglycaemia.Physiologically, glucose is uptaken and stored in skeletal muscles through three major mechanisms: insulin-mediated glucose uptake, which is impaired in people with type 2 diabetes mellitus (T2DM) due to skeletal muscle insulin resistance; 6 muscle contraction-mediated glucose uptake, which explains the beneficial impact of glycaemic control in T2DM; 7 and NO-mediated glucose uptake. 8NO-mediated glucose uptake may explain the beneficial impact of EECP therapy on glycaemia in T2DM, as EECP therapy works by enhancing NO formation, thus leading to increased NO-mediated glucose uptake in skeletal muscles.0][11] However, no systematic review and meta-analysis providing a holistic view of the role played by EECP therapy in treating T2DM has been published to date.Hence, we conducted a systematic review and meta-analysis to evaluate the safety and efficacy of EECP therapy for glycaemic control in patients with T2DM compared with control patients.

Methods
The systematic review and meta-analysis were conducted following the for the articles published untill May 2023.Methodologic details regarding literature review have been elaborated in a previous meta-analysis published by our group. 12The risk of bias assessment was done by three authors independently using the risk of bias assessment tool in the Review Manager (RevMan) version 5.4 software.The different types of bias that were assessed had been elaborated in previous metaanalyses conducted by our group: selection bias, performance bias, detection bias, attrition bias, reporting bias and other bias. 12,13Other bias included sources of funding, especially when there is a pharmaceutical/ organization involvement in the manufacture and sale of EECP devices, and conflict of interests.A random effects model was used for the metaanalysis.Forest plots were generated to assess the heterogeneity for all outcomes.Specifically, heterogeneity was analysed using the χ 2 test on N-1 degrees of freedom, an alpha of 0.05 used for statistical significance and the I 2 test. 13,14The certainty of the evidence of the major outcomes in this meta-analysis was evaluated using the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach. 15A table highlighting the grading of key outcomes was generated using the GRADE software.The details have been elaborated elsewhere. 13Publication bias was assessed for key outcomes using funnel plots (Supplementary Figure S1). 16

Results
A total of 162 articles were found from databases after the initial search (Figure 1).Eighteen duplicates were removed.After screening the titles and abstracts of the remaining 144 articles, the search was reduced to 35 studies, which were evaluated in detail for inclusion in this meta-analysis (Figure 1).Finally, three RCTs were found to fulfil all the inclusion and exclusion criteria and were analysed in our systematic review and metaanalysis. 9,10,17The three articles included in our systematic review and meta-analysis are described in detail in Table 1.
In 2 of the RCTs, the study population was patients with T2DM. 9,10In the study by Martin and Braith, 1 of 6 participants (17%) in the control group and 4 of 12 (33%) participants in the EECP therapy group had prediabetes; the remaining participants had T2DM. 17All three trials compared EECP therapy with placebo over and above the standard of care in T2DM. 9,10,17e study by Hoong et al. did not have a comparator group and hence was excluded from the analysis. 11e risk of bias in these studies is summarized in Figures 2a and b.The risk of selection, attrition and reporting bias was judged to be low in all three studies. 9,10,17There was a low risk of performance bias in one out of the three studies. 9The risk of detection bias was high in two of the three studies, 9,17 while the risk of bias was unclear in Sardina et al. 10 Other bias was judged to be at high risk in two out of the three studies. 9,10

Outcomes after therapy completion
Therapy was considered completed at around 35 sessions of EECP therapy over 7-8 weeks.Data from three studies involving a total of 71 people with T2DM or prediabetes undergoing EECP therapy were analysed to determine the impact of EECP therapy compared with the control participants.undergoing EECP therapy at trial completion.In one trial, the participants reported that they had sensitive skin, and wearing cotton pants and applying moisturiser during therapy helped to reduce their symptoms. 9tcomes at 2-4 weeks after therapy completion Data from 2 studies involving 53 people with T2DM were analysed to determine the impact of EECP therapy compared with placebo at 2-4 weeks after therapy completion. 9,10Compared with patients in the placebo or passive control group, patients receiving EECP therapy had significantly lower HbA1C (MD -1.04%, 95% CI -1.32, -0.77; p<0.00001;The key findings of the study and the side effect profile of EECP therapy are summarized in Table 2. Funnel plots were plotted to evaluate publication bias and are shown in Supplementary Figure S1.

Discussion
Standard EECP therapy consists of around 35 1-hour sessions, which typically occur once per day from Monday to Friday. 2 A maximum of two sessions per day can take place, subject to the patient's wishes and tolerance.Nearly a fifth of the patients who are not able to complete the 35-sessions program may need extended therapy. 2,18Commonly accepted contraindications for EECP therapy include arrhythmias that interfere with machine triggering, bleeding diathesis, active thrombophlebitis, severe peripheral artery disease, severe aortic valve disease, prior history of aortic surgery and severe tachycardia (>120 beats/min). 18Decompensated homeostasis needs to be stabilized before considering EECP therapy.
Our analysis noted an impressive reduction of -0.70% in HbA1c level in participants with T2DM or prediabetes following EECP therapy completion.These patients had EECP therapy for glycaemic control and had no major underlying cardiac disease.Notably, this reduction in HbA1c is not transient but last even up to 7-12 weeks after completing therapy.
HbA1c level reduced by 1.04% and 0.98% at 2-4 weeks and 7-12 weeks after completing therapy, respectively.However, the glycaemic durability of EECP therapy for glycaemic control beyond 12 weeks is not known.
Hence, longer follow-up studies investigating glycaemic durability are warranted for determining whether repeat EECP therapy follow-up sessions are needed in patients with T2DM.A similar reduction was also noted in FPG and 2-hour PPG.It is also important to note that a significant reduction in blood pressure was also noted with EECP therapy at the end of the therapy, which persisted till about 2-4 weeks after therapy and thereafter became not significant after 7-12 weeks of therapy.EECP therapy was well tolerated without any major side effects warranting treatment discontinuation.
Our analysis shows that EECP therapy is effective in reducing blood glucose and blood pressure in people with diabetes without CAD.This reduction in blood glucose was accompanied by a reduction in hs-CRP levels, which is a measure of systematic inflammation.However, interleukin-6 levels were similar in the study and the control groups.Our analysis is limited by the small number of patients evaluated.Hence, we need bigger trials with a larger number of people with T2DM with a longer duration of follow-up.The rationale for analysing both people with T2DM and prediabetes together, as was done in one of the RCTs, is that dysglycaemia is a continuum, and there is no reason for EECP therapy not to work in prediabetes if it works in T2DM. 17Furthermore, the number of patients was too small to analyse data from people with prediabetes to be analysed separately and is a limitation of this meta-analysis.
Our analysis supports the use of EECP therapy as an adjunctive therapy in people on polypharmacy for T2DM.EECP therapy may help to lower the pill burden or reduce the total daily dose of insulin requirement in these patients.However, these data need to be confirmed by bigger, multicentre clinical studies before they can be replicated in clinical practice.Furthermore, the process of EECP therapy needs to be simplified to be implemented on a large scale; as of today, this is not possible.The cost also remains a major barrier to routinely using EECP therapy, which is a required treatment for a chronic condition such as T2DM.Furthermore, patients with T2DM must go to a medical centre to undergo EECP therapy; this represents a major limitation to using EECP for glycaemic control.Finally, EECP therapy is a time-consuming procedure; consequently, it interferes with the personal and professional lives of the patients.
An important corollary that can be derived from our analysis is that people with T2DM on EECP therapy for angina due to CAD need to reduce the dose of their antidiabetes medication (oral antidiabetes medications and/or insulin) to prevent the risks of hypoglycaemia during and up until at least 12 weeks after EECP therapy completion.Similarly, these patients would also need to modulate the doses of their hypertension medications.
The current systematic review and meta-analysis have a few limitations.First, data are available only up to 12 weeks after EECP therapy completion.What happens beyond that point is not known.
The total duration of glycaemic durability of EECP therapy remains to be determined, and it represents an important area of future research in EECP therapy.Second, our analysis included data from only 3 RCTs because not enough RCTs have been published on this subject.Hence, RCTs are urgently needed to evaluate the different metabolic aspects of EECP therapy.EECP therapy has been shown to improve post-exercise recovery in elite rugby league players. 19It has also been shown to be beneficial in CAD, one of the macrovascular complications of diabetes, thus improving the quality of life in these patients. 20EECP therapy improves exercise tolerance in people with CAD. 21EECP therapy has also been shown to reduce the risk of contrast-induced nephropathy in patients with T2DM with CAD undergoing coronary angiography or percutaneous coronary intervention. 22A few small studies have suggested the beneficial impact of EECP therapy on transcranial Doppler middle cerebral artery flow velocities and National Institutes of Health Stroke Scale scores in patients with acute ischaemic stroke. 23,24e impact of EECP therapy on other macrovascular and microvascular complications of diabetes is not known and remains an important area of future research.To conclude, EECP therapy is effective in reducing blood glucose and blood pressure in people with T2DM, whose effects extend till at least 7-12 weeks of therapy completion.Hence, blood glucose and blood pressure should be routinely monitored in patients with angina undergoing EECP therapy with suitable modulation of drug doses to prevent hypoglycaemia and hypotension.q

Figure 2 :
Figure 2: (a) Risk of bias graph: the review authors' judgements about each risk of bias item presented as percentages across all included studies.(b) Risk of bias summary: the review authors' judgements about each risk of bias item for each included study

Table 1 :
Patient characteristics from the three randomized controlled trials retrieved in the systematic review

Table 2 :
Summary of findings of the key outcomes of this meta-analysis comparing external counter pulsation with placebo in type 2 diabetes mellitus The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).a. Considerable heterogeneity present as I 2 =78%.b.Considerable heterogenity present as I 2 =85%.CI = confidence interval; EECP = enhanced external counter-pulsation therapy; FPG = fasting plasma glucose; GRADE = Grades of Recommendation, Assessment, Development and Evaluation; h = hour; HbA1c = glycated haemoglobin ; IL-6 = interleukin 6; MD = mean difference; OR = odds ratio; PPG = post-prandial glucose ; PPG = post-prandial glucose ; RCT = randomized controlled trials; T2DM = type 2 diabetes mellitus.Impact of Enhanced External Counter-pulsation Therapy on Glycaemic Control in People With Prediabetes and Type 2 Diabetes Mellitus *touchREVIEWS in Endocrinology