Prevention of peripheral distal polyneuropathy in patients with diabetes: a systematic review

  Citation: Carvajal-Moreno, L.; Coheña-Jiménez, M.; García-Ventura, I.; Pabón-Carrasco, M.; Pérez-Belloso, A.J. Prevention of Peripheral Distal Polyneuropathy in Patients with Diabetes: A Systematic Review. J. Clin. Med. 2022,11, 1723. https:// doi.org/10.3390/jcm11061723 Academic Editor: Manuel Aguilar-Diosdado Received: 10 February 2022 Accepted: 18 March 2022 Published: 21 March 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Journal of Clinical Medicine Systematic Review Prevention of Peripheral Distal Polyneuropathy in Patients with Diabetes: A Systematic Review Lidia Carvajal-Moreno 1, Manuel Coheña-Jiménez 1,* , Irene García-Ventura 1, Manuel Pabón-Carrasco 2 and Ana Juana Pérez-Belloso 1 1Department of Podiatry, University of Seville, 41009 Seville, Spain; lidiacarvajalmor[email protected] (L.C.-M.); [email protected] (I.G.-V.); aper[email protected] (A.J.P.-B.) 2Spanish Red Cross Nursing School, University of Seville, Avda. de la Cruz Roja, nº 1 Dpdo., 41009 Seville, Spain; [email protected] *Correspondence: [email protected]; Tel.: +34-954-48-60-48 Abstract: Background: Diabetic peripheral neuropathy (DPN) is the most frequent chronic complication and is that which generates the highest disability and mortality in diabetes mellitus (DM). As it is currently the only microvascular complication of DM without a specific treatment, prevention is essential. The aim of this study was to determine the most effective preventive strategy to avoid or delay the appearance and/or development of DPN in patients with DM. Methods: A systematic search was carried out in the main health science databases (PubMed, Scopus, CINAHL, PEDro and The Cochrane Library) from 1 January 2010 to 31 August 2020. The study selection was conducted by two independent reviewers and data extraction was performed by the author. The eligibility criteria included randomized clinical trials (RCTs) and cohort studies from RCTs. Results: Eleven studies were selected that included 23,595 participants with DM. The interventions evaluated were intensive or standard glycemic control, the use of drugs to achieve glycemic control, and the promotion of a healthy lifestyle and exercise. Intensive glucose control achieved a significant reduction in the development of DPN in TIDM patients, and lifestyle modifications and exercise achieved it moderately in TIIDM patients. Conclusions: The main preventive strategy for DPN is intensive glycemic control with a target HbA1c < 6% in patients with TIDM and standard control of 7.0–7.9 in patients with TIIDM, incorporating lifestyle modifications. Keywords: diabetes mellitus; diabetic complications; diabetic neuropathy; prevention and control; evidence; systematic review 1. Introduction Diabetic neuropathy (DN) is the most frequent chronic complication in diabetes mellitus (DM) [ 1 – 4 ], and is considered the most important predictor of mortality in patients with type II diabetes (TIIDM), being currently the only microvascular complication of DM without specific treatment [ 5 ]. Diabetic peripheral neuropathy (DPN) is the most common cause of diabetic foot complications, with chronic sensorimotor symptoms and signs [ 1 ]. There are several forms of DPN. The most common type is distal symmetric polyneuropathy, which causes neuropathic pain symptoms. Atypical forms of DPN include mononeuritis multiplex, radiculopathies, and treatment-induced neuropathies. Other diabetic neuropathies include autonomic neuropathies that affect the cardiovascular, gastrointestinal, and urogenital systems [ 5 , 6 ]. Due to the lack of treatments targeting the underlying nerve damage, prevention is the key component in this complication of DM, and for this reason it is essential to emphasize special attention paid to the feet, as these patients are at risk of injury due to a lack of sensation [6–8]. In this sense, diabetic foot is considered one of the conditions that generates more disability, economic costs in health systems and mortality [ 9 ]. It may be considered as a J. Clin. Med. 2022,11, 1723. https://doi.org/10.3390/jcm11061723 https://www.mdpi.com/journal/jcm J. Clin. Med. 2022,11, 1723 2 of 27 supercomplication of several complications. Thus, patients with DM have a high rate of lower limb amputation, which increases when DN is present, and consequently the risk of foot ulceration is three times higher in patients with DN [ 10 – 13 ]. This complication in the lower extremities can be life-threatening in patients with foot ulceration, and can lead to subsequent infection. In this sense, since most amputations are preceded by foot ulceration, infection must be avoided. More extensive research is necessary for determining more precisely the need for amputation. It is important to avoid non-painful foot injuries by wearing well-fitting footwear and by performing regular inspections [ 4 , 6 ]. Health education is essential. DPN is the most common form of DN; its presentation is slow and progressive, usually distal and symmetrical. There is a progressive loss of sensitivity as well as motor weakness of the affected muscles, and dysfunction of the peripheral nerves of the autonomic nervous system, acting mainly on the lower limbs. Patients often report a sensation of “numb” feet, have altered distal vibratory sensation as well as altered joint position and sensations of tactile pressure and abnormal reflexes [ 12 ]. Normally, none of these alterations are painful, although it is reported that up to 25% of these patients may experience symptoms of neuropathic pain. It is described as numbness, paresthesias, hyperesthesias, allodynia, loss of sensation, muscle weakness, or loss of temperature sensation, risk of the complications of diabetic ulceration and non-traumatic amputation [ 3 ]. Amputation decisions are determined by patient comorbidities, performance, imaging studies, and clinical examination results [ 7 , 8 ]. In this sense, more extensive research is necessary to determine more precisely the need for amputation. The most important risk factor for the development of this complication, apart from the duration of the disease, is hyperglycemia [ 14 ]. Intensive control is associated with a reduction in the prevalence of DN and painful symptomatology, especially in patients with type I DM (TIDM). In the case of patients with type II DM (TIIDM), good glycemic control is recommended in addition to the control of cardiovascular risk factors and lifestyle modifications [15–19]. Some studies reported that screening for symptoms and signs is very important, as it allows for early diagnosis in the early stages of DN [ 20 ]. It is estimated that about half of patients with DM are undiagnosed [ 21 ], and it is also established that the group of patients with glucose intolerance and prediabetes may also develop neuropathies, mainly DPN, as this is the most common form of presentation [ 11 ]. In addition, it is stated that up to 50% of patients with DPN may be asymptomatic [ 8 ]. DPN affects at least 20% of patients with TIDM, 20 years after disease onset, and 10–15% of newly diagnosed patients with TIIDM, increasing to 50% 10 years after diagnosis [ 20 ]. Of these patients, 10–15% may develop painful DPN, and symptomatic treatment may be necessary. Painful symptoms, as well as other types of complications derived from DPN, can have a significant impact on the quality of life of these patients. In addition, patients with DM with pain have three times the expenditure on medication, so in this sense, prevention is essential [ 14 ], considering that the expenditure on medication is expensive to health systems [1,9]. On the other hand, early diagnosis, prevention and treatment of symptoms help to reduce sequelae, costs and improve the quality of life of patients with DN. Despite a large body of evidence, current medication prescribing patterns are inconsistent. Previous studies reported first-line drugs for the treatment of neuropathic pain in painful DPN, including the α -2-delta subunit voltage-gated calcium channel blockers gabapentin and pregabalin, the selective serotonin and norepinephrine reuptake inhibitors (SNRIs) duloxetine, and the tricyclic antidepressant (TCA) amitriptyline. The most studied drug, and with the most beneficial results, is pregabalin [ 15 , 22 ]. Thus, the American Diabetes Association (ADA) recommends starting symptomatic treatment of neuropathic pain in DM with pregabalin or duloxetine, although gabapentin can also be used, but the patient’s socioeconomic status, comorbidities, and possible drug interactions must be taken into account [ 7 ]. Opioid and atypical opioid analgesics are associated with a high risk of addiction and safety concerns and numerous serious adverse effects such as abuse or mortality. To date, prevention of DN has focused primarily on glycemic control [ 19 , 22 ]. Although studies have been published J. Clin. Med. 2022,11, 1723 3 of 27 that point out other types of preventive strategies to avoid the onset, development and evolution of this complication of DM, these lack great scientific evidence due to the poor quality of the studies, and on numerous occasions provide confusing results [ 7 ]. In this sense, this research attempts to shed light on the existing preventive alternatives for DN, not only highlighting the role of glycemic control as a preventive factor, but also revealing other options. In view of these considerations, the aim of the present review was to determine which was the most effective preventive strategy to avoid or delay the appearance and/or development of DPN in patients with DM. 2. Materials and Methods 2.1. Protocol and Registration This systematic review was carried out according to the general guidelines and recommendations made by the Preferred Reporting Items for Systematic Reviews and Meta- Analyses (PRISMA) and was registered in the PROSPERO database (CRD:42020206120). 2.2. Eligibility Criteria The study population consisted of patients with DPN. Documents published up to 30 September 2021 were included. We excluded documents that did not meet the eligibility criteria and those dealing with the diagnosis of DPN, studies on gestational diabetes and on the treatment of painful DPN, and investigations related to any neuropathy other than DPN. Documents that were not published in English, Spanish, French or Portuguese were excluded. Cohort studies and RCTs carried out from 1 January 2010 to 31 August 2020, following the PICO strategy. 1. Participants: Patients with DM, aged ≥18 years. 2. Interventions: Any strategy that entailed prevention or delay of DPN onset. 3. Comparisons: Placebo substances, any other alternative or natural progression of the disease in the control group. 4. Outcomes or results: The effectiveness of the intervention in terms of the prevention of DPN at the end of the studies in patients who did not present this condition at the beginning, or the improvement of this condition if they presented it at the beginning of the study, should be evaluated. Other outcomes may include quality of life measurements, adverse events, related costs, changes in neuropathic pain symptoms, presence of foot ulcerations and/or amputations, and events that prevented continuation of clinical trials. 2.3. Sources and Search The databases used were Scopus, Cochrane, PubMed, PEDro, EMBASE, SciELO and CINAHL. PubMed was used as a free access tool for the search in Medline and Premedline. The search and the free search were done via Mesh terms. The following search terms were used, together with the operators “OR” and “AND”. According to each database, the following search strategy was used. The key words used for the search were “diabetic neuropathies”, “prevention”, “control”, “wound”, “randomized controlled trial”, “diabetic nephropathy”, “case control studies”, “quality of life”, “cerebrovascular accident”, “cardiovascular disease”, “diabetic nephropathies”, “peripheral occlusive artery disease”, “autonomic neuropathy”, “coronary artery disease”, “depression”, “neuropathic pain”, “healthcare cost”, and “diabetic retinopathy”. The search strategy used can be consulted in Appendix A. J. Clin. Med. 2022,11, 1723 4 of 27 2.4. Study Selection Two blinded reviewers (XXX) (XXX) participated in each stage of the study selection. First, they screened by titles and abstracts of the references identified through the search strategy. The authors assessed whether the studies collected through the literature search met the eligibility criteria, excluding those that were irrelevant and/or whose level of methodological quality was questionable. Full reports of all potentially relevant documents were then assessed for eligibility based on the eligibility criteria of this review. Disagreements were resolved by discussion between the two evaluators, or if consensus was not possible, further opinion was sought (XXX) (XXXX). 2.5. Data Extraction and Synthesis of Results For the data extraction process, review authors used a standardized template containing information related to the eligibility criteria of the publications and the exclusion reasons for the selection of articles, and full title, country, and year of publication. After carrying out the first evaluation of the reports, the results obtained were discussed between the investigators, as well as the inclusion or exclusion of incompatible papers and, if necessary, the intervention of a third independent investigator. Finally, a form was designed for the extraction of data from the articles ultimately selected. This task was carried out by a single researcher. The data extracted were synthesized in an evidence table (including study design and setting, population characteristics, risk of bias assessment). 2.6. Risk of Bias Assessment The assessment of the risk of bias in the studies was carried out using the Review Manager tool (RevMan) of the Cochrane Collaboration, version 5.3.77. This software evaluates the risk of bias of individual studies as well as among the studies included in the review by generating graphs, tables and percentages from the following domains. The risks of bias criteria are classified as: “low risk”, “high risk” or “unclear risk”, assessing the risks of selection, conduct, detection, attrition, reporting and other possible biases. This task was carried out by the review author and is currently the main tool used for the assessment of risk of bias in studies and for the evaluation of methodological quality [ 23 ]. Thus, studies without a high risk of bias in any category were considered to be of high quality (1++), and those with a high risk or two unclear risks were considered to be of medium quality (1+). The rest were considered low quality (1−). In addition, the STROBE [ 24 ] and CASPe [ 25 ] checklists were used to assess the quality of cohort studies and RCTs, respectively. These two methodological quality assessment scales are expressed as a numerical score based on the number of items completed. A statistical assessment was performed by two independent assessors using the IBM SPSS Statistics 22 80 software. The data were analyzed using the intraclass correlation coefficient (ICC), the purpose of which is to assess the agreement between two or more continuous measurements carried out repeatedly in a sample. The ICC takes values between 0 and 1. A significance level of less than 0.04 would indicate poor reliability, and values above 0.75 would indicate excellent reproducibility; intermediate values are considered adequate. 3. Results The flow diagram summarizes the study selection processes, and each stage for the studies included in this review (see for details the PRISMA flow diagram in Figure 1) [ 26 ]. In total, 11 documents were included in our systematic review. Table 1shows the studies excluded and the reasons after the application of the quality appraisal filter. J. Clin. Med. 2022,11, 1723 5 of 27 J. Clin. Med. 2022, 11, x FOR PEER REVIEW 5 of 26 Figure 1. PRISMA flow diagram adapted with permission from the PRISMA group, 2020. Table 1. Potential studies excluded. Reason for Exclusion Authors RCTs that specifically address treatment rather than prevention of DPN Farvid et al., 2011 [27] Song et al., 2011 [28] Rizzo et al., 2012 [29] Lavery et al., 2012 [30] Mueller et al., 2013 [31] Ulbrecht et al., 2014 [32] Dixit et al., 2016 [33] Ziegler et al., 2016 [34] Sharoni et al., 2018 [35] Venkataraman et al., 2019 [36] López-Moral et al., 2019 [37] Stubbs et al., 2019 [38] Ahmad et al., 2019 [39] Shu et al., 2019 [40] Sari et al., 2020 [41] Cohort studies not from RCTs Müller-Stich et al., 2013 [42] Hur et al., 2013 [43] Cho et al., 2014 [44] Ishibashi et al., 2018 [45] O’Brien et al., 2018 [46] Yang et al., 2020 [47] Cárdenas et al., 2019 [48] Cohort studies that do not specifically address the prevention of DPN, but from RCTs Aroda et al., 2016 [49] Gaede et al., 2016 [50] Abraham et al., 2018 [51] Braffett et al., 2020 [52] Figure 1. PRISMA flow diagram adapted with permission from the PRISMA group, 2020. Table 1. Potential studies excluded. Reason for Exclusion Authors RCTs that specifically address treatment rather than prevention of DPN Farvid et al., 2011 [27] Song et al., 2011 [28] Rizzo et al., 2012 [29] Lavery et al., 2012 [30] Mueller et al., 2013 [31] Ulbrecht et al., 2014 [32] Dixit et al., 2016 [33] Ziegler et al., 2016 [34] Sharoni et al., 2018 [35] Venkataraman et al., 2019 [36] López-Moral et al., 2019 [37] Stubbs et al., 2019 [38] Ahmad et al., 2019 [39] Shu et al., 2019 [40] Sari et al., 2020 [41] Cohort studies not from RCTs Müller-Stich et al., 2013 [42] Hur et al., 2013 [43] Cho et al., 2014 [44] Ishibashi et al., 2018 [45] O’Brien et al., 2018 [46] Yang et al., 2020 [47] Cárdenas et al., 2019 [48] Cohort studies that do not specifically address the prevention of DPN, but from RCTs Aroda et al., 2016 [49] Gaede et al., 2016 [50] Abraham et al., 2018 [51] Braffett et al., 2020 [52] J. Clin. Med. 2022,11, 1723 6 of 27 3.1. Risk of Biases among the Studies Included Figures 2and 3show the risk of biases of the study included in this systematic review. J. Clin. Med. 2022, 11, x FOR PEER REVIEW 6 of 26 3.1. Risk of Biases among the Studies Included Figures 2 and 3 show the risk of biases of the study included in this systematic review. Figure 2. Risk of biases of included studies, overall analysis. Figure 3. Risk of biases of the included studies [15,53–62], individual analysis. Green: low risk, yellow: unclear risk, red: high risk. Allocation concealment and random sequence generation was evident in 100% of the studies. Blinding of participants and staff was present in less than 25%, and blinding of assessors was present in less than 50% of the included articles. Due to the nature of some included studies, such as cohort studies, 25% of the included studies were considered to be at high risk of other biases. The levels of evidence evaluated according to the quality of the selected articles received a score of 1++ in 9.2% (n = 1) [53] qualifying it as high quality, 27.3% of the studies Figure 2. Risk of biases of included studies, overall analysis. J. Clin. Med. 2022, 11, x FOR PEER REVIEW 6 of 26 3.1. Risk of Biases among the Studies Included Figures 2 and 3 show the risk of biases of the study included in this systematic review. Figure 2. Risk of biases of included studies, overall analysis. Figure 3. Risk of biases of the included studies [15,53–62], individual analysis. Green: low risk, yellow: unclear risk, red: high risk. Allocation concealment and random sequence generation was evident in 100% of the studies. Blinding of participants and staff was present in less than 25%, and blinding of assessors was present in less than 50% of the included articles. Due to the nature of some included studies, such as cohort studies, 25% of the included studies were considered to be at high risk of other biases. The levels of evidence evaluated according to the quality of the selected articles received a score of 1++ in 9.2% (n = 1) [53] qualifying it as high quality, 27.3% of the studies Figure 3. Risk of biases of the included studies [ 15 , 53 – 62 ], individual analysis. Green: low risk, yellow: unclear risk, red: high risk. J. Clin. Med. 2022,11, 1723 7 of 27 Allocation concealment and random sequence generation was evident in 100% of the studies. Blinding of participants and staff was present in less than 25%, and blinding of assessors was present in less than 50% of the included articles. Due to the nature of some included studies, such as cohort studies, 25% of the included studies were considered to be at high risk of other biases. The levels of evidence evaluated according to the quality of the selected articles received a score of 1++ in 9.2% (n= 1) [ 53 ] qualifying it as high quality, 27.3% of the studies received a score of 1+ or medium quality (n= 3) [ 54 – 56 ], and the rest of the articles were scored as low quality, 1−, representing 63.5% (n= 7) [15,57–62]. 3.2. Statistical Analysis of the Quality of the Included Studies Detailed assessment ICC is summarized in Table 2. Table 3summarizes the scores of the quality scales of the studies included in this review. The limitations of the review are summarized in Table 4. Table 2. Intraclass correlation coefficient. Evaluation of agreement between continuous measurements. Intraclass Correlation a 95% Confidence Interval F Test with True Value 0 Lower Bound Lower Bound Value df1 df2 Sig. Single Measures 0.997 b0.995 0.995 687.400 10 10 0.000 Average Measures 0.999 c0.995 1.000 687.400 10 10 0.000 Two-way mixed effects model where people’s effects are random and measures’ effects are fixed. a Type C intraclass correlation coefficients using a consistency definition—the between measure variance is excluded from the denominator variance. b The estimator is the same, whether the interaction effect is present or not. c This estimate is computed assuming the interaction effect is ab-sent, because it is not estimable otherwise. Table 3. Scores of the investigators on the quality scales of the included studies. Authors Scale Review 1 Review 2 Ismail-Beigi et al., 2010 CASpe 10/11 10/11 Charles et al., 2011 CASpe 6/11 6/11 Gong et al., 2011 STROBE 16/22 16/22 Pop-Busui et al., 2013 STROBE 17/22 17/22 Dixit et al., 2014 CASpe 11/11 11/11 Martin et al., 2014 STROBE 16/22 16/22 Diabetes Prevention Program Research Group et al., 2015 STROBE 17/22 17/22 Look AHEAD Research Group et al., 2017 CASpe 9/11 9/11 Gholami et al., 2018 CASpe 9/11 9/11 Brock et al., 2019 CASpe 11/11 11/11 Gholami et al., 2020 CASpe 9/11 9/11 3.3. Limitations of Included Studies Table 4shows some of the studies with their limitations. Some of the reasons for its limitation were the sample size, number of dropouts or that not all patients were evaluated with all the measures, among other reasons. J. Clin. Med. 2022,11, 1723 8 of 27 Table 4. Limitations of the review. Authors Limitations Ismail-Beigi et al., 2010 Early termination of the RCT due to increased mortality among participants. Charles et al., 2011 Not all patients were evaluated with all measurements. Patients in the CASE IV subgroup were younger than the rest, so microvascular complications may have been lower in this group. Gong et al., 2011 No results were obtained for 25% of the participants who died. Low incidence of nephropathy and neuropathy due to short duration of diabetes in participants. Pop-Busui et al., 2013 Study not designed to detect an effect of the groups on DPN. A lower incidence of neuropathy was found in the IS group; however, the authors were unable to identify whether the benefit was specific to biguanides or thiazolidinediones. Small fiber neuropathy was not evaluated, as only the Michigan Neuropathy Screening Instrument (MNSI), which evaluates large fibers, was used. Subjectivity of the MNSI. Dixit et al., 2014 The effect of aerobic exercise to halt or interrupt the natural course of DPN was not studied. The study had a large number of dropouts. Martin et al., 2014 Intentional exclusion at the start of Diabetes Control and Complications Trial (DDCT) of participants with severe neuropathy. Patients in the conventional insulin therapy (CON) group were switched to intensive insulin therapy (INT) group because of the benefits of intensive glycemic control in patients with TIDM. Diabetes Prevention Program Research Group et al., 2015 The combination of three different microvascular outcomes in the aggregate microvascular outcome. Look AHEAD Research Group et al., 2017 Relationship of biguanide use with vitamin B12 depletion and the development of DPN. Levels of this vitamin were not recorded. Diagnosis of DPN by questionnaire, MNSI physical examination and Semmes-Weinstein (SW) monofilament. Gholami et al., 2018 Small sample size, large number of dropouts, and only male participation. Brock et al., 2019 Severe irreversible neuropathy, more male representation. Gholami et al., 2020 Small sample size. 3.4. Synthesis of Results 3.4.1. Studies Included Of the 11 included studies, seven were parallel-group RCTs [ 59 , 61 ], of which one was placebo-controlled [ 53 ]. The remaining four studies were cohort studies from RCTs, [ 58 , 60 ], of which one was placebo-controlled. The total follow-up period of the studies ranged from 8 weeks to 20 years. Table 5summarizes the characteristics of the included studies. J. Clin. Med. 2022,11, 1723 9 of 27 Table 5. Main characteristics of the studies included. Authors Design Participants (N)Groups Diabetes Type Average Age (Years) Duration of the Study Interventions Measured Results Brock et al. (2019) RCT, double-blind, placebocontrolled 39 IG (Liraglutide) N= 19 CG (placebo) N= 20 TIDM 50.4 32 weeks Liraglutide Placebo Changes in nerve potentials, proinflammatory cytokines, autonomic function and peripheral neurophysiological tests. MNSI Charles et al. (2011) RCT with parallel groups 1161 Routine Care (RC) N= 459 Intensive multifactorial treatment (IT) N= 702 TIIDM 59.9 6 years IT: Education, medication and promotion of healthy lifestyle. CR: Danish recommendations for diabetes care. AAI Vibration detection threshold (tuning fork) Light touch (SW) Diabetes Prevention Program Research Group et al. (2015) Cohort study of a parallel-group placebocontrolled RCT 2776 Placebo N= 935 Metformin N= 926 Lifestyle N= 915 TIIDM 51 15 years Metformin Placebo Lifestyle Diagnosis of diabetes HbA1c Albuminuria (Nephropathy) Fundus evaluation (Retinopathy) SW light touch (Neuropathy) Dixit et al. (2014) RCT of parallel groups 87 CG N= 47 (10 lost) EG N= 40 (11 lost) TIIDM CG: 59.45 EG: 54.40 8 weeks EG: Moderate aerobic exercise, foot care education, healthy diet CG: Standard medical care, education Motor and sensory nerve conduction studies in peroneal and sural nerves MDNS J. Clin. Med. 2022,11, 1723 16 of 27 conduction. Gu et al. [ 85 ] in 2019 observed a positive influence of aerobic exercise on nerve function. In the case of DM associated with obesity, patients with DM who have to undergo bariatric surgery show an improvement in neuropathic symptoms [86]. 4.5. Limitations of the Study The review presents several limitations. Firstly, many of the studies analyzed present heterogeneity in outcome measures, while others studies report small sample size and short duration of follow-up. The authors have found that there is little evidence, and many knowledge gaps persist in the use of preventive alternatives; this should be considered. Furthermore, the risk of detection in eight included studies. In addition, in terms of the neuropathy evaluation technique and according to the literature consulted, there is variability, which is why it should be considered as another limitation. 5. Conclusions According to the present review, DPN cannot be cured, so preventive measures are essential, with glycemic control being the main strategy. The preventive interventions studied included intensive or standard glycemic control, the use of drugs for glycemic control, lifestyle modifications and the practice of physical exercise. In the case of patients with TIDM, a clear benefit of intensive glycemic control with an HbA1c < 6% in the prevention of microvascular complications. In patients with TIIDM, standard glycemic control with an HbA1c between 7.0 and 7.9% is recommended and lifestyle modifications based on the practice of physical exercise, dietary control and control of cardiovascular risk factors are emphasized. Intensive glycemic control with insulin-sensitizing drugs is recommended in patients with TIDM, as well as lifestyle modifications in patients with TIIDM. The practice of moderate aerobic physical exercise is emerging as an important preventive factor in the development of neuropathy. More consistent studies are needed and with unification in the evaluation techniques that allow for consolidating some aspects of the knowledge of DPN. Therefore, the main principles of treatment for peripheral neuropathy are glycemic control, foot care, and pain management. Author Contributions: All authors have made substantial contributions to this systematic review. Conceptualization, M.C.-J., L.C.-M., I.G.-V., M.P.-C. and A.J.P.-B.; methodology, L.C.-M., A.J.P.-B., M.C.-J., I.G.-V. and M.P.-C.; software, L.C.-M., M.P.-C. and I.G.-V.; validation, L.C.-M., M.P.-C., A.J.P.- B., M.C.-J. and I.G.-V.; formal analysis, A.J.P.-B., L.C.-M. and I.G.-V.; investigation, L.C.-M., I.G.-V., M.P.-C. and M.C.-J.; resources, L.C.-M., A.J.P.-B. and M.P.-C.; data curation, L.C.-M. and M.P.-C.; writing—original draft preparation, M.P.-C., I.G.-V. and L.C.-M.; writing—review and editing, A.J.P.- B., M.P.-C., I.G.-V., M.C.-J. and L.C.-M.; visualization, A.J.P.-B., M.P.-C., I.G.-V., M.C.-J. and L.C.-M.; supervision, A.J.P.-B., M.P.-C., M.C.-J. and L.C.-M.; project administration, L.C.-M. and A.J.P.-B. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Data Availability Statement: Details of the literature search are reported in Appendices Aand B. Extracted data and details of the risk of bias assessments are available from the authors upon request. Conflicts of Interest: The authors declare no conflict of interest. Appendix A. Search Strategy Appendix A.1. PubMed Appendix A.1.1. Clinical Trials Free search: (diabet* neuropath*) AND (“prevention” OR “control”) NOT (“ulcer” OR “wound” OR “cardiovascular” OR “pain” OR “nephropath*” OR “retinopath*” OR J. Clin. Med. 2022,11, 1723 17 of 27 “protocol”)—Filters “Clinical trial”, “10 years” and “human” were applied: 74 results were obtained. Search by descriptors: “Diabetic Neuropathies/prevention and control” [Mesh]. Clinical trial”, “10 years” and “human” filters were applied: 48 results were obtained. Unified search: “Diabetic Neuropathies/prevention and control” [Mesh] OR [(diabet* neuropath*) AND (“prevention” OR “control”) NOT (“ulcer” OR “wound” OR “cardiovascular” OR “pain” OR “nephropath*” OR “retinopath*” OR “protocol”)]. The filters “Clinical trial”, “10 years” and “human” were applied: In this PubMed search, we obtained a total of 122 results, and with the unified search we obtained 84, eliminating 38 duplicate records. Appendix A.1.2. Cohort Studies Free search: (diabet* neuropath*) AND (“prevention” OR “control”) NOT (“ulcer” OR “wound” OR “cardiovascular” OR “pain” OR “netinopathy*” OR “retinopathy*” OR “systematic review” OR “meta-analysis”) AND (“cohort stud*” OR “cohort analysis”). The filters “10 years” and “human” were applied: 40 results were obtained. Search by descriptors: “Diabetic Neuropathies/prevention and control” [Mesh] AND (“cohort stud*” OR “cohort analysis”). The filters “10 years” and “human” were applied: 20 results were obtained. Unified search: (diabet* neuropath*) AND (“prevention” OR “control”) NOT (“ulcer” OR “wound” OR “cardiovascular” OR “pain” OR “netinopathy*” OR “retinopathy*” OR “systematic review” OR “meta-analysis”) OR [“Diabetic Neuropathies/prevention and control” [Mesh]] AND (“cohort stud*” OR “cohort analysis”). The filters “10 years” and “human” are applied: in this search, we obtained a total of 60 results, and with the unified search 56 were obtained, so four duplicate records were eliminated. Appendix A.2. Scopus Free search: (“diabet* neuropath*”) AND (“prevention” OR control). This is limited to the last 5 years, from 2015 to 2020, with “article”, in the “keywords” section. We limited the search to “randomized controlled trial”, “Cohort Studies” and “human”. The terms “diabetic nephropathy”, “case control studies”, “qualitfy of life”, “incidence”, “cerebrovascular accident”, “cardiovascular risk”, “cardiovascular disease”, “diabetic nephropathies”, “peripheral occlusive artery disease”, “child”, “autonomic neuropathy”, “case report”, “diagnostic imaging”, “coronary artery disease”, “depression”, “practical guideline”, “neuropathic pain”, “healthcare cost”, “pilot study” and “diabetic retinopathy” were excluded. Search strategy: KEY((“diabet* neuropath*”) AND (“prevention” OR control)) AND DOCTYPE (ar) AND PUBYEAR > 2014 AND (LIMIT-TO (EXACTKEYWORD,”Human”) OR LIMIT-TO (EXACTKEYWORD,”Cohort Studies”) OR LIMIT-TO (EXACTKEYWORD,” Randomized Control Trial”)) AND (EXCLUDE (EXACTKEYWORD,”Case Control Study”) OR EXCLUDE (EXACTKEYWORD,”Diabetic Nephropathy”) OR EXCLUDE (EXACTKEYWORD,”Case-Control Studies”) OR EXCLUDE (EXACTKEYWORD,”Cardiovascular Disease”) OR EXCLUDE (EXACTKEYWORD,”Quality Of Life”) OR EXCLUDE (EXACTKEYWORD,”Incidence”) OR EXCLUDE (EXACTKEYWORD,”Cerebrovascular Accident”) OR EXCLUDE (EXACTKEYWORD,”Diabetic Nephropathies”) OR EXCLUDE (EXACTKEYWORD,”Peripheral Occlusive Artery Disease”) OR EXCLUDE (EXACTKEYWORD,”Child”) OR EXCLUDE (EXACTKEYWORD,”Autonomic Neuropathy”) OR EXCLUDE (EXACTKEYWORD,”Cardiovascular Risk”) OR EXCLUDE (EXACTKEYWORD,”Case Report”) OR EXCLUDE (EXACTKEYWORD,”Diagnostic Imaging”) OR EXCLUDE (EXACTKEYWORD,”Coronary Artery Disease”) OR EXCLUDE (EXACTKEYWORD,”Depression”) OR EXCLUDE (EXACTKEYWORD,”Practice Guideline”) OR EXCLUDE (EXACTKEYWORD,”Neuropathic Pain”) OR EXCLUDE (EXACTKEYWORD,”Health Care Cost”)). J. Clin. Med. 2022,11, 1723 18 of 27 In this database, the unified search could be performed directly, since filters were added. A total of 233 results were obtained. Appendix A.3. The Cochrane Library Search strategy in “advanced search”: “diabetic neuropathy” AND (“prevention” OR “control”) NOT (“ulcer*” OR “wound*” OR “cardiovascular” OR “pain*” OR “nephropath*” OR “retinopath*” OR “treatment*” OR “protocol”). The filters from 2010 to present and “trials” are added: 154 results were obtained. Cohort studies could not be found in this search engine, since it only indexes RCTs and systematic reviews. In this database, we manually selected the duplicates that appeared, since it collects records from other databases, and, consequently, there were eight duplicates. Appendix A.4. CINAHL Appendix A.4.1. Clinical Trials Search strategy: (“diabet* neuropath*”) AND (“prevention” OR “control”). Filters applied: “Search all my search terms” “apply related words” “apply equivalent subjects”, limit publication date from 2010 to 2020, publication type “clinical trial”, “excludes pre-CINAHL”, and gender “all”: 26 results were obtained. Appendix A.4.2. Cohort Studies Strategy: (“diabet* neuropath*”) AND (“prevention” OR “control”)) AND (“cohort study” OR “cohort analysis”). Filters applied: limit publication date from 2010 to 2020, “Search all my search terms” “apply related words” “apply equivalent subjects”, “exclude pre-CINAHL”, and gender “all”: 13 results were obtained. Subsequently, all the references resulting from the search in all the databases were added to the bibliographic manager to eliminate possible duplicates between them, obtaining 13 more duplicates, which were eliminated. Finally, a total of 203 duplicates were eliminated. Appendix B. Individual Characteristics of the Studies Included in the Review •Study 1: Brock et al., 2019 [53] Methods: Double-blind, parallel-group, placebo-controlled RCT. Participants: Adults with TIDM and confirmed symmetrical polyneuropathy. Thirtynine participants were randomized to receive liraglutide (N= 19) or placebo (N= 20). Interventions: To test whether long-term treatment with liraglutide (an injectable drug used for the treatment of diabetes and obesity, acting in the same way as incretins), induces a decrease in inflammation, thus improving neuronal function, and consequently diabetic neuropathy. The duration was 6 weeks with a dose of 1.2 mg/day, continuing until 26 weeks, for a total of 32 weeks. Results: The primary endpoint was change in latency of early brain evoked potentials. Secondary endpoints were changes in proinflammatory cytokines, cortical evoked potentials, autonomic function and peripheral neurophysiological tests. Compared to placebo, liraglutide reduced interleukin-6 (p= 0.025) with similar reductions in other proinflammatory cytokines. However, neuronal function was not altered at the central, autonomic or peripheral levels. Treatment was associated with 3.38 kg (p< 0.001) of weight loss and a decrease in urine albumin/creatinine ratio (p= 0.02). Conclusions: The study concluded that treatment with liraglutide reduced interleukin- 6 in adults with TIDM but did not improve established DPN. Lowering the systemic level of proinflammatory cytokines could lead to the prevention or treatment of the neuroinflammatory component in the early stages of diabetic neuropathy. •Study 2: Charles et al., 2011 [62] J. Clin. Med. 2022,11, 1723 19 of 27 Methods: Parallel-group RCT examining the effects of early detection and intensive multifactorial treatment (IT) of patients with TIIDM in primary care on the prevalence of DPN and PAD over 6 years. Participants: The study sample of 1161 participants was divided into two groups, the routine care group, RC (N= 459) and the intensive multifactorial treatment group, IT (N= 702). Interventions: The interventions employed were different for the groups, consisting in the IT group of physician and patient education, medication use and promotion of healthy lifestyle, control of hyperglycemia, blood pressure and cholesterol, according to the regimen used in the Steno-2 Study [ 70 ], and in the CR group, patients received the standard pattern of diabetes care according to the Danish national recommendations. Results: No statistically significant effect of IT on the prevalence of DPN and PAD was found compared to CR. The prevalence of an AAI ≤ 0.9 was 9.1% (95% CI 6.0–12.2) in the CR group and 7.3% (5.0–9.6) in the IT group. In participants evaluated for vibration detection threshold and light touch sensation the prevalence of at least one abnormal test was 34.8% (26.7–43.0) in the CR group and 30.1% (24.1–36.1) in the IT group. Conclusion: It was determined that in a population with patients with type 2 diabetes screen-detected, screening followed by IT was not found to lead to a statistically significant difference in the prevalence of DPN and PAD 6 years after diagnosis. Additional information: also called “ADDITION-Denmark”study. •Study 3: Diabetes Prevention Program Research Group et al., 2015 [57] Methods: Study of the 3-year Diabetes Prevention Program (DPP) [ 87 ] RCT surviving cohort. Participants: All participants were offered lifestyle training at the end of DPP. Overall, 2776 (88%) of the surviving DPP cohort were followed in the DPP Outcomes Study (DPPOS 2002–2013) and were analyzed by intention-to-treat. Interventions: The 1996–2001 DPPOS was an RCT comparing an intensive lifestyle intervention or masked metformin with placebo in a cohort selected to be at high risk of developing diabetes. During DPPOS, the lifestyle group received a semiannual booster and the metformin group received unmasked metformin. This research aimed to determine the long-term extent of the beneficial effects of the lifestyle intervention or metformin on diabetes prevention originally demonstrated in the DPP and whether diabetes-associated microvascular complications would be reduced. Results: During 15 years of follow-up, lifestyle intervention and metformin reduced diabetes incidence rates by 27% (p< 0.0001) and 18% (p= 0.001), respectively, compared to the placebo group. At year 15, the cumulative incidence of DM was 55%, 56% and 62%, respectively. The end-of-study prevalence of the aggregate microvascular outcome, composed of nephropathy, neuropathy and retinopathy, was not significantly different between treatment groups (11–13%) compared to the overall cohort. However, in women (n= 1887), the lifestyle intervention was associated with a lower prevalence (8.7%) than in the placebo (11%) and metformin (11.2%) groups, with a 21% (p= 0.03) and 22% ( p= 0.02 ) reduction in the lifestyle group compared to placebo and metformin, respectively. Compared to participants who progressed to DM, those who did not do so had a 28% lower prevalence of microvascular complications (p< 0.0001). Conclusion: This study claims that lifestyle intervention or metformin significantly reduced the development of DM over 15 years in predisposed cohorts, although there were no overall differences in aggregate microvascular outcome between treatment groups. However, those who did not progress to DM had a lower prevalence of microvascular complications than those who did. •Study 4: Dixit et al., 2014 [54] Methods: Parallel group RCT. The authors proposed evaluating the effect of moderateintensity aerobic exercise (40–60% of heart rate reserve) on DPN. Participants: Patients with TIIDM and clinical neuropathy, defined with a minimum score of 7 on the Michigan J. Clin. Med. 2022,11, 1723 20 of 27 Diabetic Neuropathy Scale (MDNS). An experimental group (N= 47) and a control group (N= 40) were included. Interventions: The experimental group (N= 47) received guidelines for moderateintensity aerobic exercise, accompanied by standard medical care, foot care education and individual dietary recommendations. The control group (N= 40) received only standard medical care, foot care education and dietary recommendations. Results: The groups suffered losses of 10 and 11 participants, respectively. Measurements were performed at baseline and at 8 weeks, including nerve conduction studies in the peroneal motor and sural sensory nerve, as well as the MDNS score. For the peroneal nerve, regarding nerve conduction velocity there was a significant difference in the two groups at 8 weeks (p= 0.03). This difference was also observed at 8 weeks in the sural sensory nerve, (p= 0.00). Significant differences were observed in the mean MDNS scores in the two groups at 8 weeks (p< 0.05). Conclusion: It was established that moderate-intensity aerobic exercise may play a valuable role in interrupting the normal progression of MDNS in patients with TIIDM. •Study 5: Gholami et al., 2018 [61] Methods: Parallel group RCT. The study set out to examine the effects of aerobic training on nerve conduction velocity and action potential amplitude in lower limbs. Participants: Men patients with TIIDM and DPN, 24 volunteers randomized into two groups: exercise group (N= 12) and control group (N= 12). Interventions: Aerobic training consisted of 20–45 min walking or running at 50–70% of the heart rate reserve in three sessions per week for 12 weeks. Before and 48 h after the experimental period, nerve conduction studies were performed and blood samples were taken to analyze HbA1c, and fasting and 2 h postprandial glucose concentration. Results: Sural nerve sensory conduction velocity (SNV) in the exercise group was significantly increased (from 35.2 ± 4.3 m/s to 37.3 ± 6.2 m/s) compared to the control group (p= 0.007). Changes in motor NCV in peroneal and tibial nerves and action potential amplitude (APAN) in all nerves studied were not significant between groups (p> 0.05). In addition, HbA1c decreased to a greater extent in the exercise group compared to the control (p= 0.014). Conclusion: It was determined that aerobic exercise training may have the potential to hinder DPN progression by improving NCV. Given the scarce evidence in this domain, related to exercise, the mechanisms should be studied in the future. •Study 6: Gholami et al., 2020 [59] Methods: Parallel-group RCT. In relation to the previous study, in this case, the investigators evaluated the effect of physical training on superficial femoral artery (SFA) measurements and neuropathic symptoms in patients with DPN to observe the relationship of DPN with PAD. Participants: Thirty-one volunteers with established DPN randomly assigned to the experimental (N= 16) and control (N= 15) groups. Interventions: The experimental group performed cycling exercise (50–70% of heart rate reserve, 30–45 min, three sessions/week) for 12 weeks. Before and 48 h after the experimental period a 5-min flow-mediated dilation (FMD) response, changes in intima media thickness and basal diameter in SFA using color Doppler ultrasound and neuropathic score in MDNS were assessed as primary outcomes, and fasting glucose level, HbA1c and neuropathic score as secondary outcomes. Results: The FMD percentage increased significantly in the experimental group (from 3.2 ± 1.1% to 5.7 ± 1.2%) compared to the control condition (p= 0.0001). However, there were no significant alterations in the basement membrane diameter and intima media thickness (p< 0.05). Significant improvements in fasting glucose, HbA1c and Michigan diabetic neuropathy score (MDNS) after exercise intervention (all p< 0.05) were also observed. Linear regression analysis indicated that the change in MDNS was significantly associated with change in HbA1c (p= 0.001) and FMD (p= 0.001). J. Clin. Med. 2022,11, 1723 21 of 27 Conclusion: This finding may be clinically of great importance, as metabolic and vascular factors have been indicated to be involved in the development of DPN. •Study 7: Gong et al., 2011 [58] Methods: Cohort study of participants in a parallel-group RCT. A 20-year follow-up study of the original participants was conducted to compare the incidence of microvascular complications in the combined intervention group versus the control group. Participants: The original RCT involving 577 adults with impaired glucose tolerance (IGT) who were randomly assigned to a control group or the lifestyle intervention group (divided into three subgroups: diet, exercise, and diet plus exercise). Follow-up information was obtained on 542 (94%) of the original 577 participants. Interventions: The aim of the diet intervention was to increase vegetable intake and reduce alcohol and sugar consumption of the participants and, in those who were overweight or obese, to reduce total calorie intake in order to lose weight. In the case of the exercise intervention, this consisted of increasing leisure time physical activity. The interventions were carried out over 6 years. Results: The cumulative incidence of severe retinopathy was 9.2% in the combined intervention group and 16.2% in the control group (p= 0.03). After clinical and age adjusting, the incidence of severe retinopathy was 47% lower in the intervention group than in the control group (p= 0.048). No significant differences were found in the incidence of severe nephropathy (p= 0.96) or in the prevalence of neuropathy (p= 0.89) among survivors after 20 years. Conclusion: Lifestyle intervention over 6 years in persons with IGT was associated with a 47% reduction in the incidence of severe vision-threatening retinopathy over a 20-year interval, mainly due to the lower incidence of diabetes in the intervention group. However, no similar benefits were observed for nephropathy or neuropathy. Additional information: also called “China Da Qing Diabetes Prevention Outcome Study”. •Study 8: Ismail-Beigi et al., 2010 [55] Methods: A parallel-group RCT, called the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study [ 72 ], aimed to determine whether lowering blood glucose levels reduced the rate of microvascular complications in patients with TIIDM. Participants: Patients with DM and with high HbA1c concentrations (>7.5%) and cardiovascular disease (or two or more cardiovascular risk factors) were randomized by central randomization to the intensive (target HbA1c of <6.0%) or standard (7.0–7.9%) glycemic control group. 10,251 patients were randomized, (N= 5128) to the intensive glycemic control group and (N= 5123) to the standard group. Interventions: Intensive glycemic control compared with standard glycemic therapy. In this analysis, the predefined composite outcomes were: dialysis or renal transplantation, high serum creatinine (>291.7 µ mol/L) or retinal photocoagulation or vitrectomy (first composite outcome), or peripheral neuropathy plus the first composite outcome (second composite outcome). Thirteen secondary measures of renal, ocular, and peripheral nerve function were also assessed. Investigators and participants were aware of the treatment group assignment. An analysis was performed for all patients who were evaluated for the microvascular outcome on the basis of the treatment assignment, regardless of treatments received or adherence to therapies. Results: Intensive therapy was discontinued before the end of the study due to higher mortality in that group, and patients transitioned to standard therapy. At transition, the first composite outcome was recorded in 443 of 5107 patients in the intensive group versus 444 of 5108 in the standard group (HR 1.00, 95% CI 0.88–1.14; p= 1.00), and the second composite outcome was observed in 1591 of 5107 versus 1659 of 5108 (0.96, 0.89–1.02; p= 0.19 ). The results were similar at the end of the study, first composite outcome 556 of 5119 vs. 586 of 5115 (HR 0.95, 95% CI 0.85–1.07, p= 0.42); and the second 1956 of 5119 vs. 2046 of 5115, respectively (0.95, 95% CI 0.89–1.01, p= 0.12)). Intensive therapy did J. Clin. Med. 2022,11, 1723 22 of 27 not reduce the risk of microvascular outcomes, but delayed the onset of albuminuria. Six secondary end-of-study measures favored intensive therapy (p< 0.05). Conclusion: The research concludes that the microvascular benefits of intensive therapy must be weighed against increased total and cardiovascular disease-related mortality, weight gain, and high risk of severe hypoglycemia, so as ACCORD proved, intensive glycemic control therapy does not provide significant benefits in patients with TIIDM. •Study 9: Look AHEAD Research Group et al., 2017 [56] Methods: The study Look AHEAD (Action for Health in Diabetes) [ 88 ] was a parallelgroup RCT. It examined whether the intensive lifestyle intervention weight loss decreased cardiovascular morbidity and mortality in overweight or obese adults with TIIDM. Due to the nature of the study, patients and center investigators were not blinded. In addition, the coordinating center staff members responsible for data management and statistical analysis were also not blinded. Participants: Beginning in 2001, a total of 5145 overweight and obese individuals with TIIDM were randomized to intensive intervention (ILI) (N= 2570) or diabetes support and education (DSE) control group (N= 2575) using a web-based management system at the study coordinating center at Wake Forest School of Medicine (Winsto-Salem, NC, USA). Randomization was stratified by clinical center and was not disclosed to clinical staff responsible for obtaining data on study outcomes. Interventions: Intensive intervention (ILI) or diabetes support and education (DSE) control group. Interventions ended in September 2012, 9–11 years after randomization, but both groups continued to be followed for primary and secondary outcomes. Neuropathy assessments included MNSI completed at baseline in all participants, 5145 (ILI N= 2570; DSE N= 2575) and repeated annually thereafter, as well as SW monofilament testing performed in 3775 participants (ILI N= 1905, DSE N= 1870) at 1 and 2.3 years after intervention discontinuation. Results: At baseline, the MNSI questionnaire scores were 1.9 ± 0.04 and 1.8 ± 0.04 in the ILI and DSE groups, respectively (difference not statistically significant). After 1 year, when weight loss was maximal in the ILI group (8.6 ± 6.9%) compared with DSE ( 0.7 ±4.8% ), the respective MNSI scores were 1.7 ± 0.04 and 2.0 ± 0.04 (p ≤ 0.001). Subsequently, scores increased gradually in both groups, but remained significantly lower in the ILI group during the first 3 years and at the end of follow-up. In both groups, there was a significant association between the MNSI scores and changes in body weight, HbA1c and plasma lipids. There was no significant difference between groups in participants with MNSI physical examination scores ≥ 2.5, considered indicative of DN. Light tactile sensation measured separately in the right and left great toes did not differ between ILI and DSE, but when the data were combined for both toes, a light touch was better preserved in the ILI group. Conclusion: It was determined that the ILI group had a significant decrease in DPN based on questionnaire diagnosis, which was associated with the magnitude of weight loss. In both the ILI and DSE groups, changes in MNSI score were also associated with changes in HbA1c and lipids. There were no significant effects of ILI on DPN physical examination measures performed 1–2.3 years after completion of the active intervention, except for light touch sensation, which was significantly better in the ILI group when measures were combined for both toes. •Study 10: Martin et al., 2014 [15] Methods: Surviving cohort study from the RCT Diabetes Control and Complications Trial and its follow-up study Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) [ 87 , 88 ]. The authors described the development and progression of neuropathy and related findings among patients with TIDM at 14 years after intervention. Participants: Patients with TIDM. There were a total of 1441 (100%) DCCT participants, of whom 1375 (95.4%) agreed to participate in EDIC, of whom 1274 (92.7%) were active J. Clin. Med. 2022,11, 1723 23 of 27 in year 13 in EDIC, of whom 1226 (96.2%) were evaluated for CAN and 1186 (93.1%) for DPN [89]. Interventions: Intensive glycemic control vs. standard control. The primary outcome of DPN was assessed by clinical symptoms, signs and results of nerve conduction studies during DCCT and repeated in EDIC in year 13/14. CAN was assessed by the R-R response to stimulated breathing, Valsalva ratio and blood pressure response during years 13/14 and 16/17. In addition, symptoms reflecting neuropathic pain and autonomic function (including hypoglycemia awareness) were collected annually in EDIC using standardized questionnaires; peripheral neuropathy was also assessed annually using the MDNS. Genitourinary function assessments were collected in EDIC year 10. Results: Intensive therapy during DCCT significantly reduced the risk of DPN and CAN at the end of DCCT (64% and 45%, respectively, p< 0.01). The prevalence and incidence of DPN and CAN remained significantly lower in the intensive therapy DCCT group compared to the conventional therapy DCCT group until year 13/14 of EDIC [90]. Conclusion: It was established that the persistent effects of prior intensive therapy on neuropathy measures over 14 years of EDIC largely mirror those observed for other complications of DM. DCCT/EDIC provides important information on the influence of glycemic control and the clinical course of DN and, most importantly, on how to prevent neuropathy in patients with TIDM. •Study 11: Pop-Busui et al., 2013 [60] Methods: Cohort study from the parallel-group RCT Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) [ 91 ] published in 2009. This trial demonstrated similar long-term clinical effectiveness of insulin-sensitizing (IS) versus insulin-providing (IP) treatments for patients with TIIDM on cardiovascular outcomes in a cohort with documented coronary artery disease. Participants: A total of 2159 participants with TIIDM with documented coronary artery disease. IS (N= 1080), IP (N= 1079). Interventions: Randomized glycemic control strategy of insulin-sensitizing (IS) versus insulin-providing (IP) treatments for TIIDM on the prevalence and incidence of DPN. DPN (defined as Michigan Neuropathy Screening Questionnaire (MNSI) > 2 clinical examination score) was assessed at baseline and annually for 4 years. Prevalence and incidence of DPN were compared by intention-to-treat models using generalized estimating equations logistic models for prevalence and Kaplan–Meier estimates and Cox regression models for incidence rates. Results: The results were obtained for 2159 participants in the BARI 2D study (70% male) with baseline values and at least one follow-up MNSI score (mean age 62 ± 9 years, mean HbA1c 7.7 ± 1.6%, duration of diabetes 10 ± 9 years). There was no difference in the prevalence of DPN between the IS and IP groups during the 4 years of follow-up. 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