Interventions in the management of infection in the foot in diabetes: a systematic review.

The optimal approaches to managing diabetic foot infections remain a challenge for clinicians. Despite an exponential rise in publications investigating different treatment strategies, the various agents studied generally produce comparable results, and high-quality data are scarce. In this systematic review, we searched the medical literature using the PubMed and Embase databases for published studies on the treatment of diabetic foot infections as of June 2018. This systematic review is an update of previous reviews, the first of which was undertaken in 2010 and the most recent in 2014, by the infection committee of the International Working Group of the Diabetic Foot. We defined the context of literature by formulating clinical questions of interest, then developing structured clinical questions (PICOs) to address these. We only included data from controlled studies of an intervention to prevent or cure a diabetic foot infection. Two independent reviewers selected articles for inclusion and then assessed their relevant outcomes and the methodological quality. Our literature search identified a total of 15 327 articles, of which we selected 48 for full-text review; we added five more studies discovered by means other than the systematic literature search. Among these selected articles were 11 high-quality studies published in the last 4 years and two Cochrane systematic reviews. Overall, the outcomes in patients treated with the different antibiotic regimens for both skin and soft tissue infection and osteomyelitis of the diabetic foot were broadly equivalent across studies, except that treatment with tigecycline was inferior to ertapenem (±vancomycin). Similar outcomes were also reported in studies comparing primarily surgical and predominantly antibiotic treatment strategies in selected patients with diabetic foot osteomyelitis. There is insufficient high-quality evidence to assess the effect of various adjunctive therapies, such as negative pressure wound therapy, topical ointments or hyperbaric oxygen, on infection related outcomes of the diabetic foot. In general, the quality of more recent trial designs are better in past years, but there is still a great need for further well-designed trials to produce higher quality evidence to underpin our recommendations.

Diagnosis of infection in the foot in diabetes: a systematic review.

BACKGROUND: Securing an early accurate diagnosis of diabetic foot infections and assessment of their severity are of paramount importance since these infections can cause great morbidity and potentially mortality and present formidable challenges in surgical and antimicrobial treatment. METHODS: In June 2018, we searched the literature using PuEbMed and EMBASE for published studies on the diagnosis of diabetic foot infection. On the basis of predetermined criteria, we reviewed prospective controlled, as well as noncontrolled, studies in any language, seeking translations for those not in English. We then developed evidence statements on the basis of the included papers. RESULTS: From the 4242 records screened, we selected 35 papers that met our inclusion criteria. The quality of all but one of the evidence statements was low because of the weak methodology of nearly all of the studies. The available data suggest that diagnosing diabetic foot infections on the basis of clinical signs and symptoms and classified according to the International Working Group of the Diabetic Foot scheme correlates with the patient's likelihood of ulcer healing, of lower extremity amputation, and risk of death. Elevated levels of selected serum inflammatory markers are supportive, but not diagnostic, of soft tissue or bone infection. In patients with suspected diabetic foot osteomyelitis, both a positive probe-to-bone test and an elevated erythrocyte sedimentation rate are strongly associated with its presence. Culturing tissue samples of soft tissues or bone, when care is taken to avoid contamination, provides more accurate microbiological information than culturing superficial (swab) samples. Plain X-ray remains the first-line imaging examination when there is suspicion of diabetic foot osteomyelitis, but advanced imaging methods help in cases when either the diagnosis or the localization of infection is uncertain. CONCLUSION: The results of this first reported systematic review on the diagnosis of diabetic foot infections provide some guidance for clinicians, but there is a need for more prospective controlled studies of high quality.

Guidelines on the diagnosis and treatment of foot infection in persons with diabetes (IWGDF 2019 update).

The International Working Group on the Diabetic Foot (IWGDF) has published evidence-based guidelines on the prevention and management of diabetic foot disease since 1999. This guideline is on the diagnosis and treatment of foot infection in persons with diabetes and updates the 2015 IWGDF infection guideline. On the basis of patient, intervention, comparison, outcomes (PICOs) developed by the infection committee, in conjunction with internal and external reviewers and consultants, and on systematic reviews the committee conducted on the diagnosis of infection (new) and treatment of infection (updated from 2015), we offer 27 recommendations. These cover various aspects of diagnosing soft tissue and bone infection, including the classification scheme for diagnosing infection and its severity. Of note, we have updated this scheme for the first time since we developed it 15 years ago. We also review the microbiology of diabetic foot infections, including how to collect samples and to process them to identify causative pathogens. Finally, we discuss the approach to treating diabetic foot infections, including selecting appropriate empiric and definitive antimicrobial therapy for soft tissue and for bone infections, when and how to approach surgical treatment, and which adjunctive treatments we think are or are not useful for the infectious aspects of diabetic foot problems. For this version of the guideline, we also updated four tables and one figure from the 2016 guideline. We think that following the principles of diagnosing and treating diabetic foot infections outlined in this guideline can help clinicians to provide better care for these patients.

Importance of the Average Glucose Level and Estimated Glycated Hemoglobin in a Diabetic Patient with Hereditary Hemolytic Anemia and Liver Cirrhosis.

Glycated hemoglobin (HbA1c) is a widely used marker of glycemic control but can be affected by hemolytic anemia. Glycated albumin (GA) is also affected in patients with liver cirrhosis. We herein report the assessment of glycemic control in a 41-year-old man with dehydrated hereditary stomatocytosis and a PIEZO1 gene mutation complicated by diabetes mellitus and liver cirrhosis due to hemochromatosis. The estimated HbA1c calculated from the average glucose level obtained by continuous glucose monitoring or by self-monitoring of blood glucose was useful for evaluating the glycemic control in this patient, as HbA1c and GA were unreliable due to the coexisting conditions.

Serum free thyroxine levels are associated with the efficacy of weight reduction therapy in obese female patients.

Thyroid function is strongly associated with obesity. The aim of this study is to investigate whether serum free thyroxine (FT4) and/or thyrotropin (TSH) levels are associated with the efficacy of weight reduction therapy in obese patients. We enrolled a total of 283 obese patients and cross-sectionally investigated the association of serum FT4 and/or TSH levels with metabolic features. Furthermore, in 97 obese patients who received 6-month weight reduction therapy, we assessed the relationship of serum FT4 and/or TSH levels to the efficacy of weight reduction therapy. Neither baseline serum FT4 nor TSH levels showed any correlations with body weight (BW) and body mass index (BMI) in these obese patients. However, in 57 obese female patients who underwent weight reduction therapy for six months, serum FT4 levels prior to the therapy was negatively correlated with the degrees of reduction of BW (r = -0.354, p = 0.007) and BMI (r = -0.373, p = 0.004). The correlation between baseline serum FT4 levels with the efficacy of weight reduction therapy was not observed in obese male or postmenopausal female patients. This study demonstrates that baseline serum FT4 levels are associated with weight reduction in obese female premenopausal patients. Therefore, baseline FT4 levels can be used as a clinical, noninvasive, hormonal predictor of weight reduction efficacy in obese patients.

The utility of dual bioelectrical impedance analysis in detecting intra-abdominal fat area in obese patients during weight reduction therapy in comparison with waist circumference and abdominal CT.

An increase in intra-abdominal fat area (IAFA) is an essential component of metabolic syndrome (MetS). Waist circumference (WC) is not a precise measure of IAFA, and computed tomography (CT) is unsuitable for frequent monitoring. Here, we examined utility of a dual bioelectrical impedance analysis (Dual BIA) for measuring IAFA in obese patients during weight reduction. Fat distribution was measured by Dual BIA and CT in 100 obese outpatients. All fat areas including total, IAFA, and subcutaneous fat by Dual BIA were more closely correlated with those by CT than WC. Estimated IAFA by Dual BIA was significantly correlated with number of MetS components as well as CT, but WC was not. Furthermore, in 61 obese patients who received 6-month weight reduction therapy, estimated IAFA by Dual BIA showed an earlier and greater decrease as well as that by CT than WC and BMI. In addition, decrease in estimated IAFA by Dual BIA through weight reduction had a higher correlation with decrease in IAFA by CT, than WC. This study is the first to demonstrate that the change in estimated IAFA by Dual BIA was highly correlated with that in IAFA by CT during weight reduction therapy. Our findings also indicate that estimated IAFA by Dual BIA is, potentially, a better indicator of severity of MetS, cardiovascular risk factors, and effectiveness of weight reduction than WC, and equal to IAFA by CT. Estimated IAFA by Dual BIA may be useful for monitoring the effectiveness of weight reduction therapy in obese patients.

An increase in the EPA/AA ratio is associated with improved arterial stiffness in obese patients with dyslipidemia.

AIM: Previous epidemiological studies demonstrated that the ratio of n-6 to n-3 polyunsaturated fatty acids is associated with cardiovascular diseases. We herein investigated whether the beneficial effect of highly purified eicosapentaenoic acid(EPA) on arterial stiffness is associated with changes in the ratio of polyunsaturated fatty acids, such as EPA, docosahexaenoic acid(DHA) and dihomo-γ-linolenic acid(DGLA), relative to arachidonic acid(AA), in obese Japanese patients with dyslipidemia. METHODS: The EPA/AA, DHA/AA and DGLA/AA ratios were compared between obese patients with(n=94) and without (n=31) dyslipidemia. Among the former group, 88 patients received either highly purified EPA treatment(1.8g daily, n=45) or treatment without EPA(control, n=43). RESULTS: At baseline, the ratios of DHA/AA and DGLA/AA were significantly(P＜0.05) higher in obese patients with dyslipidemia than in those without, while the EPA/AA ratio was similar between patients with and without dyslipidemia. EPA significantly reduced the hemoglobin A1c, total cholesterol, triglycerides, CRP, cardio-ankle vascular index(CAVI)(an index of arterial stiffness) and the DGLA/AA ratio relative to the control at three months after the treatment. On the other hand, EPA significantly increased the adiponectin level and EPA/AA ratio(P＜0.05). A multivariate regression analysis revealed that only age, an increase in the EPA/AA ratio and a decrease in the CRP level were significant determinants of a reduction of the CAVI by EPA. CONCLUSION: These findings suggest that EPA improves the arterial stiffness in association with an increase in the EPA/AA ratio and a decrease in inflammation in obese patients with dyslipidemia.

Effects of weight reduction therapy on obstructive sleep apnea syndrome and arterial stiffness in patients with obesity and metabolic syndrome.

AIM: Obesity and metabolic syndrome (MetS) and obstructive sleep apnea (OSA), which are often accompanied by obesity, are each independently associated with cardiovascular disease (CVD). However, the influence of OSA on arterial stiffness in obese patients remains unclear. We herein examined the relationships between the severity of OSA and CVD risk factors, including the severity of MetS and arterial stiffness, in obese patients. In addition, we evaluated the effects of weight reduction therapy on OSA and arterial stiffness. METHODS: Among the 60 overweight or obese Japanese outpatients enrolled, 46 (76.7%) met the MetS criteria. RESULTS: The apnea-hypopnea index (AHI) and cardio-ankle vascular index (CAVI), a new index of arterial stiffness, were significantly higher in the MetS patients than in the non-MetS patients, whereas there were no significant differences in body mass index, blood pressure or the low-density lipoprotein cholesterol level. A multivariate regression analysis revealed that waist circumference, the C-reactive protein level and CAVI were independently correlated with AHI. In addition, age, SBP, IRI and AHI were independently correlated with CAVI. Furthermore, weight reduction therapy, including diet and exercise, over a three-month period significantly decreased the AHI and CAVI values in parallel with a reduction in BMI. CONCLUSIONS: This study demonstrated that the severity of OSA is significantly correlated with the severity of MetS and arterial stiffness in obese patients. Short-term weight reduction therapy improves not only metabolic dysfunction, but also the severity of OSA and arterial stiffness, as measured according to the CAVI. Such changes may help to prevent atherosclerosis in obese patients.

A dipeptidyl peptidase-4 inhibitor, sitagliptin, exerts anti-inflammatory effects in type 2 diabetic patients.

AIMS/HYPOTHESIS: Glucagon-like peptide-1 (GLP-1) exerts beneficial effects on the cardiovascular system. Here, we examined the effect of sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, on systemic inflammation and pro-inflammatory (M1)/anti-inflammatory (M2)-like phenotypes of peripheral blood monocytes in diabetic patients. METHODS: Forty-eight type 2 diabetic patients were divided into the following two groups: sitagliptin-treatment (50mg daily for 3months) (n=24) and untreated control (n=24) groups. Measurements were undertaken to assess changes in glucose-lipid metabolism, serum levels of inflammatory cytokines such as serum amyloid A-LDL (SAA-LDL), C-reactive protein (CRP), interleukin-6 (IL-6), IL-10 and tumor necrosis factor-α (TNF-α). Furthermore, the effects of sitagliptin treatment on M1/M2-like phenotypes in peripheral blood monocytes were examined. RESULTS: Treatment with sitagliptin significantly decreased fasting plasma glucose, hemoglobin A1c (HbA1c), serum levels of inflammatory markers, such as SAA-LDL, CRP, and TNF-α. In contrast, sitagliptin increased serum IL-10, an anti-inflammatory cytokine, as well as plasma GLP-1. In addition, sitagliptin increased monocyte IL-10 expression and decreased monocyte TNF-α expression. Multivariate regression analysis revealed that the sitagliptin treatment was the only factor independently associated with an increase in monocyte IL-10 (ß=0.499; R(2)=0.293, P<0.05). However, other factors including the improvement of glucose metabolism were not associated with the increase. CONCLUSIONS/INTERPRETATION: This study is the first to show that a DPP-4 inhibitor, sitagliptin, reduces inflammatory cytokines and improves the unfavorable M1/M2-like phenotypes of peripheral blood monocytes in Japanese type 2 diabetic patients.

Highly purified eicosapentaenoic acid increases interleukin-10 levels of peripheral blood monocytes in obese patients with dyslipidemia.

OBJECTIVE: It has recently been highlighted that proinflammatory (M1) macrophages predominate over anti-inflammatory (M2) macrophages in obesity, thereby contributing to obesity-induced adipose inflammation and insulin resistance. A recent clinical trial revealed that highly purified eicosapentaenoic acid (EPA) reduces the incidence of major coronary events. In this study, we examined the effect of EPA on M1/M2-like phenotypes of peripheral blood monocytes in obese dyslipidemic patients. RESEARCH DESIGN AND METHODS: Peripheral blood monocytes were prepared from 26 obese patients without and 90 obese patients with dyslipidemia. Of the latter 90 obese patients with dyslipidemia, 82 patients were treated with or without EPA treatment (1.8 g daily) for 3 months. RESULTS: Monocytes in obese patients with dyslipidemia showed a significantly lower expression of interleukin-10 (IL-10), an M2 marker, than those without dyslipidemia. EPA significantly increased serum IL-10 and EPA levels, the EPA/arachidonic acid (AA) ratio, and monocyte IL-10 expression and decreased the pulse wave velocity (PWV), an index of arterial stiffness, compared with the control group. After EPA treatment, the serum EPA/AA ratio was significantly correlated with monocyte IL-10 expression. Only increases in monocyte IL-10 expression and serum adiponectin were independent determinants of a decreased PWV by EPA. Furthermore, EPA significantly increased the expression and secretion of IL-10 in human monocytic THP-1 cells through a peroxisome proliferator-activated receptor (PPAR)γ-dependent pathway. CONCLUSIONS: This study is the first to show that EPA increases the monocyte IL-10 expression in parallel with decrease of arterial stiffness, which may contribute to the antiatherogenic effect of EPA in obese dyslipidemic patients.

Salivary cortisol levels are associated with outcomes of weight reduction therapy in obese Japanese patients.

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis can increase the risk of cardiovascular disease (CVD). However, the detailed relationships of HPA axis activity with weight reduction and CVD risk factors in obese patients have not been examined. This study was designed to elucidate the associations of salivary cortisol levels with weight reduction and CVD risk factors in obese patients. As a marker of HPA axis activity, we measured the morning salivary cortisol levels of 83 obese Japanese outpatients. We also examined metabolic parameters, inflammatory markers, and indicators of arterial stiffness, that is, the pulse wave velocity and cardio-ankle vascular index. All 83 obese patients underwent 3-month weight reduction therapy with lifestyle modification. At the baseline, multivariate regression analysis revealed that only logarithmic transformation of C-reactive protein (ß = 0.258, P < .05) and cardio-ankle vascular index (ß = 0.233, P < .05) were independent determinants of the salivary cortisol levels. However, other metabolic parameters were not significantly associated with the salivary cortisol levels. In addition, lower salivary cortisol levels and higher body weight at the baseline were the only independent determinants of successful weight loss through the weight reduction therapy (P < .01). The present study demonstrates that the baseline morning salivary cortisol levels are significantly associated with the levels of an inflammatory marker, arterial stiffness, and successful weight reduction in obese patients. Therefore, salivary cortisol could be a useful marker for assessing and managing body weight and CVD risk factors in obese patients.

Urinary cystatin C as a potential risk marker for cardiovascular disease and chronic kidney disease in patients with obesity and metabolic syndrome.

BACKGROUND AND OBJECTIVES: Obesity and metabolic syndrome (MS) increase the risk of cardiovascular disease (CVD), chronic kidney disease (CKD), and all-cause mortality. Serum cystatin C (S-CysC), a marker of GFR, has been shown to be associated with CVD and CKD. This study was designed to elucidate the association of urinary CysC (U-CysC), a marker of renal tubular dysfunction, with CVD and CKD risk factors in patients with obesity and MS. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The U-CysC-creatinine ratio (UCCR) was examined in 343 Japanese obese outpatients enrolled in the multi-centered Japan Obesity and Metabolic Syndrome Study. RESULTS: UCCR was positively correlated with urine albumin-creatinine ratio (UACR) and S-CysC and negatively correlated with estimated GFR (eGFR). Among obese patients, UCCR was significantly higher in MS patients than in non-MS patients. UCCR had significant correlations with the number of components of MS and arterial stiffness, all of which are CVD predictors, similarly to UACR (P<0.05). Interestingly, diet- and exercise-induced weight reduction for 3 months significantly decreased only UCCR among all of the renal markers examined (P<0.01), in parallel with the decrease in BMI, HbA1c, and arterial stiffness, suggesting the beneficial effect of weight reduction on renal tubular dysfunction. CONCLUSIONS: This study demonstrates that UCCR is significantly associated with renal dysfunction, the severity of MS, arterial stiffness, and weight change in obese patients. The data of this study suggest that U-CysC could serve as a CVD and CKD risk factor in patients with obesity and MS.

Antiatherogenic effect of pioglitazone in type 2 diabetic patients irrespective of the responsiveness to its antidiabetic effect.

OBJECTIVE: Thiazolidinediones (TZDs), a class of insulin-sensitizing agents used clinically to treat type 2 diabetes, are also antiatherogenic. This study was designed to elucidate the relationship between the antiatherogenic and antidiabetic effects of pioglitazone, a TZD, in type 2 diabetic patients. RESEARCH DESIGN AND METHODS: A total of 136 Japanese type 2 diabetic patients were included and divided into two groups: the pioglitazone-treated group (30 mg daily for 3 months) (n = 70) and the untreated control group (n = 66). The changes in glycolipid metabolism as well as plasma high-sensitivity C-reactive protein (CRP), leptin, adiponectin, and pulse wave velocity (PWV) were monitored to analyze the relationship between the antiatherogenic and antidiabetic effects of pioglitazone. RESULTS: The pioglitazone treatment significantly reduced hyperglycemia, hyperinsulinemia, and HbA(1c) levels and increased plasma adiponectin concentrations relative to the control group (P < 0.01). It also significantly decreased CRP and PWV (P < 0.01). The antiatherogenic effect was observed in both the nonresponders showing <1% of reduction in HbA(1c) (n = 30) and responders showing >1% of reduction (n = 40). ANCOVA revealed that treatment with pioglitazone was associated with a low CRP and PWV, independent of the changes in parameters related to glucose metabolism. CONCLUSIONS: This study represents the first demonstration of the antiatherogenic effect of pioglitazone in both nonresponders and responders with respect to its antidiabetic effect and suggests that pioglitazone can exert its antiatherogenic effect independently of its antidiabetic effect.