Diabetic Foot Infections: an Update in Diagnosis and Management.

Foot infections are a common problem in patients with diabetes and a risk factor for limb amputation. They occur as a result of skin ulceration, which facilitates penetration of pathogens to deeper tissues. The diagnosis of infection is clinical. Aerobic gram-positive cocci are the most common pathogens. Ulcers which are chronic, preceded by administration of antibiotics and hospitalization or complicated by severe infection are polymicrobial. Antibiotic therapy is initially empiric based on the severity of the infection. Definitive therapy is modified according to the results of the microbiological culture and the response to empiric treatment. The optimal duration of antibiotic therapy ranges from 1-2 weeks for mild infections to 2-4 weeks and even longer for severe infections and osteomyelitis. Surgical consultation should be sought for infections complicated with abscesses, necrotizing fasciitis or osteomyelitis. With appropriate care, infection resolves in about 80-90% of non-limb threatening and in about 60% of severe infections.

Glycemic and lipid profile of patients with COVID-19: Impact on morbidity and mortality.

INTRODUCTION: Recent studies have shown that patients with COVID-19, who have underlying diabetes mellitus, develop a severe clinical course and have increased mortality. Similarly, dyslipidemia is a common complication in patients with COVID-19, indicating that there may be a pathophysiological interaction between lipid metabolism and SARS-CoV-2. The main manifestation is hypocholesterolemia, which is associated with severe illness and unfavorable outcome. AIM: The aim of the present study was to assess the impact of glucose and lipid levels on the progression and outcome of patients with COVID-19 infection. MATERIAL AND METHODS: The study sample consisted of 301 patients who became ill with SARS-CoV-2 and hospitalized during the calendar year 2021. Data were collected from the patients themselves and from their clinical and laboratory follow-up. RESULTS: A total of 301 patients were included in the study, 56.8 % were male and 82.4 % of patients were not vaccinated for SARS-CoV-2 at baseline. The mean age was 66.7 years and the body mass index was 28.8. More specifically 27.6 % had diabetes mellitus and 34.2 % reported known dyslipidemia. The comparison of the course of the disease with the laboratory data of patients, on the day of admission, found that death was more frequently observed in the elderly [83.0 ± 11.0 (p < 0.001)], in patients with abnormal glucose values [159.8 ± 51.4 (p = 0.039)], abnormal creatinine values (p < 0.001), low glomerular filtration rate (p < 0.001), lower total cholesterol values (p = 0.044), higher triglycerides values [124 ± 64,8 (p = 0,003)], abnormal CRP values (p < 0.001), cTnT (p = 0.001), D-dimers (p < 0.001), and SatO2 (p < 0.001). CONCLUSION: The present study showed that death was more frequently observed in subjects with hyperglycemia and hypocholesterolemia, and other pathological findings. It is therefore evident that these patients should be a priority in the development of studies and guidelines.

COVID-19 Outcomes and Diabetes Mellitus: A Comprehensive Multicenter Prospective Cohort Study.

The link between type 2 diabetes (T2D) and the severe outcomes of COVID-19 has raised concerns about the optimal management of patients with T2D. This study aimed to investigate the clinical characteristics and outcomes of T2D patients hospitalized with COVID-19 and explore the potential associations between chronic T2D treatments and adverse outcomes. This was a multicenter prospective cohort study of T2D patients hospitalized with COVID-19 in Greece during the third wave of the pandemic (February-June 2021). Among the 354 T2D patients included in this study, 63 (18.6%) died during hospitalization, and 16.4% required ICU admission. The use of DPP4 inhibitors for the chronic management of T2D was associated with an increased risk of in-hospital death (adjusted odds ratio (adj. OR) 2.639, 95% confidence interval (CI) 1.148-6.068, p = 0.022), ICU admission (adj. OR = 2.524, 95% CI: 1.217-5.232, p = 0.013), and progression to ARDS (adj. OR = 2.507, 95% CI: 1.278-4.916, p = 0.007). Furthermore, the use of DPP4 inhibitors was significantly associated with an increased risk of thromboembolic events (adjusted OR of 2.249, 95% CI: 1.073-4.713, p = 0.032) during hospitalization. These findings highlight the importance of considering the potential impact of chronic T2D treatment regiments on COVID-19 and the need for further studies to elucidate the underlying mechanisms.

Development and validation of SCOPE score: A clinical score to predict COVID-19 pneumonia progression to severe respiratory failure.

Most patients infected with SARS-CoV-2 (COVID-19) experience mild, non-specific symptoms, but many develop severe symptoms associated with an excessive inflammatory response. Elevated plasma concentrations of soluble urokinase plasminogen activator receptor (suPAR) provide early warning of progression to severe respiratory failure (SRF) or death, but access to suPAR testing may be limited. The Severe COvid Prediction Estimate (SCOPE) score, derived from circulating concentrations of C-reactive protein, D- dimers, interleukin-6, and ferritin among patients not receiving non-invasive or invasive mechanical ventilation during the SAVE-MORE study, offers predictive accuracy for progression to SRF or death within 14 days comparable to that of a suPAR concentration of ≥6 ng/mL (area under receiver operator characteristic curve 0.81 for both). The SCOPE score is validated in two similar independent cohorts. A SCOPE score of 6 or more is an alternative to suPAR for predicting progression to SRF or death within 14 days of hospital admission for pneumonia, and it can be used to guide treatment decisions.

Factors associated with sclerostin levels - A calcification inhibitor - In individuals with type 2 diabetes mellitus; Is autonomic neuropathy the missing link?

BACKGROUND: Sclerostin inhibits bone formation and its expression is upregulated in the vasculature during the arterial calcification process as a counterregulatory mechanism preventing further calcification. Lower extremity arterial calcification (LEAC) is common in neuropathic patients with type 2 diabetes (T2DM). Herein, we investigated for associations between plasma sclerostin levels and diabetic neuropathy as well as LEAC in subjects with T2DM. METHODS: A total of 74 individuals with and 76 without T2DMwere recruited. Plasma sclerostin levels were measured by ELISA. Diagnosis of cardiac autonomic neuropathy (CAN) was based on the battery of the four autonomic tests, while of somatosensory peripheral neuropathy (DPN) on neuropathy symptom score and neuropathy disability score. LEAC was assessed with conventional ankle and foot x-rays. RESULTS: Plasma sclerostin levels were higher in participants with LEAC vs. those without LEAC in both diabetes and non-diabetes cohorts (p = 0.035 and p = 0.003, respectively). In the diabetes cohort, patients with CAN, but not with DPN, had higher sclerostin levels when compared with those without CAN (p < 0.001). Multivariate analysis in the diabetes cohort demonstrated that sclerostin levels were associated positively with CAN and LEAC, while in the non-diabetes cohort there was a trend for a positive association with male gender and presence of LEAC. CONCLUSION: Plasma sclerostin levels are increased in individuals with LEAC irrespectively of diabetes status. In addition, plasma sclerostin concentrations are associated independently with LEAC and CAN in people with T2DM.

Association of Circulating Osteopontin Levels With Lower Extremity Arterial Disease in Subjects With Type 2 Diabetes Mellitus: A Cross-Sectional Observational Study.

Osteopontin (OPN) is involved in the atherosclerotic and inflammatory process. In this article, we examined the relationship between circulating OPN levels with lower extremity arterial disease (LEAD) in individuals with type 2 diabetes mellitus (T2DM). Seventy individuals with T2DM and 66 individuals without T2DM were recruited. Diagnosis of LEAD was based on the absence of triphasic waveform on the pedal arteries. Plasma OPN levels were determined by Luminex Multiplex immunoassay. LEAD was present in 34 (48.6%) patients with T2DM. In the diabetes cohort, individuals with LEAD had higher plasma OPN concentrations than those without LEAD (geometric mean [95% confidence intervals]; 43.4 [37.5-50.4] vs 26.1 [22.9-29.8] ng/mL, respectively, P < .001). Multivariable analysis showed that presence of LEAD independently associated with higher OPN levels in subjects with T2DM, with marginal statistical significance (P = .049). In both cohorts, plasma OPN concentrations were negatively associated with ankle-brachial index values (P < .05). In the total sample, there was a gradual increase of OPN levels across subgroups with triphasic, biphasic, and monophasic/blunted waveforms (P < .001). In conclusion, plasma OPN levels are associated with the presence and severity of LEAD in subjects with T2DM. Further studies are needed to investigate the role of OPN in the pathogenesis and progression of LEAD.

Prevalence of diabetes mellitus as well as cardiac and other main comorbidities in a representative sample of the adult Greek population in comparison with the general population.

BACKGROUND: Diabetes mellitus (DM) is the most common metabolic disorder that increases the risk of cardiovascular disease by two to four times compared with the general population. There are limited data on the prevalence of heart diseases in subjects with DM in Greece. In this study, we examined the prevalence of self-reported DM as well as cardiac and other main comorbidities in a representative sample of the adult Greek population. METHODS: The target study population included 30,843 participants stratified by gender, age, and district, and this was a representative sample of the adult Greek population in 2010. A structured questionnaire was built to report the prevalence of self-reported DM and the main comorbidities in participants with and without DM. Collection of data was performed through telephone interviews. RESULTS: The prevalence of self-reported DM was 6.6%. The prevalence of the main comorbidities in participants with DM vs. those without DM was as follows: heart diseases 24.0% vs. 8.9%, p<0.001; lung diseases 11.3% vs. 5.3%, p<0.001; kidney diseases 3.4% vs. 1.2%, p=0.001; liver diseases 1.4% vs. 0.7%, p=0.001; benign blood diseases 1.6% vs. 0.9%, p=0.005; and solid organ and/or blood malignancies 2.9% vs. 1.5%, p<0.001. CONCLUSIONS: The prevalence of self-reported DM in a representative sample of the adult Greek population in 2010 was 6.6%. The prevalence of heart diseases in subjects with DM was 2.7-fold higher than the prevalence in those without DM. Diseases of the lung, kidney, liver, and blood as well as malignancies were significantly more common among participants with DM.

Effect of 12-month intervention with low-dose atorvastatin on pulse wave velocity in subjects with type 2 diabetes and dyslipidaemia.

Cardiovascular disease is the leading cause of morbidity and mortality in subjects with type 2 diabetes mellitus. Increased aortic stiffness, assessed with the carotid-femoral pulse wave velocity, is an independent risk factor for cardiovascular disease. Statins reduce effectively cardiovascular disease and mortality in high-risk patients. The aim of this prospective non-randomized, observational study was to examine the impact of treatment with either 10 mg atorvastatin plus diet or diet alone on carotid-femoral pulse wave velocity in subjects with type 2 diabetes mellitus and dyslipidaemia. A total of 79 subjects with type 2 diabetes mellitus and dyslipidaemia were included; 46 subjects were treated with atorvastatin 10 mg daily plus diet and 33 were managed by diet alone for 12 months. Carotid-femoral pulse wave velocity and carotid-radial pulse wave velocity were measured using applanation tonometry. In the atorvastatin-treated group, carotid-femoral pulse wave velocity reduced significantly during the study and there was a trend for reduction in the carotid-radial pulse wave velocity. Total cholesterol, low-density lipoprotein cholesterol, triglycerides and C-reactive protein were reduced only in the atorvastatin-treated participants. No significant changes were found in body mass index, blood pressure, heart rate, diabetes control and high-density lipoprotein cholesterol in either study group. Treatment with low-dose atorvastatin for 12 months improves carotid-femoral pulse wave velocity in subjects with type 2 diabetes mellitus and dyslipidaemia.

The association of diabetic microvascular and macrovascular disease with cutaneous circulation in patients with type 2 diabetes mellitus.

AIMS: To study the impact of diabetic neuropathy, both peripheral sensorimotor (DPN) and cardiac autonomic neuropathy (CAN), on transcutaneous oxygen tension (TcPO2) in patients with type 2 diabetes mellitus (T2DM). METHODS: A total of 163 participants were recruited; 100 with T2DM and 63 healthy individuals. Peripheral arterial disease (PAD) was defined as ankle-brachial index (ABI) values ≤0.90. Diagnosis of DPN was based on neuropathy symptom score and neuropathy disability score (NDS), while diagnosis of CAN on the battery of the cardiovascular autonomic function tests. TcPO2 was measured using a TCM30 system. RESULTS: Patients with T2DM had lower TcPO2 levels when compared with healthy individuals. Among the diabetic cohort, those who had either PAD, DPN or CAN had significantly lower TcPO2 values than participants without these complications. Multivariate linear regression analysis, after controlling for diabetes duration, diastolic blood pressure, HbA1c, albumin to creatinine ratio and CAN score, demonstrated that TcPO2 levels were significantly and independently associated with current smoking (p = 0.013), ABI (p = 0.003), and NDS (p = 0.013). CONCLUSION: Presence of DPN is independently associated with impaired cutaneous perfusion. Low TcPO2 in subjects with DPN may contribute to delay in healing of diabetic foot ulcers, irrespectively of PAD.

Update on Cardiovascular Effects of Older and Newer Anti-diabetic Medications.

It is known that Cardiovascular (CV) disease is the leading cause of morbidity and mortality in individuals with type 2 diabetes. Over the last years, one of the most discussed topics is the CV safety of anti-diabetic medications. Regarding CV safety of older antidiabetic agents the data are less clear and conclusions about their CV safety are mostly based on randomized controlled trials designed to assess their glucose lowering efficacy. In this review, we summarize the current knowledge about the CV safety of older and newer antidiabetic medications. According to the published literature metformin is the first line agent for the treatment of type 2 diabetes and seems to have cardio-protective effects. The choice of the second line agent when metformin monotherapy fails to achieve HbA1c targets is less clear. In the light of the findings of the EMPA-REG OUTCOME trial and the recently published LEADER and SUSTAIN 6 trials, empagliflozin, liraglutide and semaglutide seem reasonable options as second line agents for patients with CV disease. Sulfonylureas on the other hand, with the exception of gliclazide, should be avoided in those patients, although CV safety trials are still lacking. In individuals without CV disease any of the other classes of anti-diabetic medication can be selected on a patient-centered approach. Saxagliptin, alogliptin, sitagliptin and lixisenatide have been evaluated in CV safety trials and have neutral effects on CV outcomes, while pioglitazone may have some CV benefits. Saxagliptin and alogliptin, however, should be avoided in patients with heart failure, while pioglitazone is contraindicated in this population.

The association between pulse wave velocity and peripheral neuropathy in patients with type 2 diabetes mellitus.

AIMS: Diabetic peripheral neuropathy (DPN) is the most common diabetic complication, affecting up to half of the patients with type 2 diabetes mellitus (T2DM). Increased aortic stiffness, measured with the carotid-femoral pulse wave velocity (PWV), has been associated with incidence of cardiovascular disease independently of traditional risk factors. Previous data showed associations between risk factors for macroangiopathy and DPN in diabetes. However, the association between PWV and DPN is not well known. In this study we examined the association between PWV and presence as well as severity of DPN in subjects with T2DM. MATERIAL AND METHODS: A total of 381 patients with T2DM were recruited. Participants were classified as having DPN and not having DPN. PWV was measured at the carotid-femoral segment with a non-invasive method using applanation tonometry. DPN was assessed by determination of the Neuropathy Symptom Score (NSS) and the Neuropathy Disability Score (NDS). RESULTS: A hundred and seven participants (28.1%) had DPN. Patients with DPN were significantly more often male and older, had longer diabetes duration, higher height, larger waist circumference, higher systolic arterial blood pressure (SBP) and higher PWV (all P<0.05). Furthermore, participants with DPN were treated more often with statins and had lower low density lipoprotein cholesterol; in addition, they were treated more often with antiplatelets, b-blockers and insulin than those without DPN. Univariative logistic regression analysis demonstrated that presence of DPN was significantly associated with age, male gender, longer diabetes duration, height, waist circumference, SBP, PWV, dyslipidemia, HbA1c, retinopathy, nephropathy and peripheral arterial disease. Multivariate logistic regression analysis, after adjustment for age, gender, waist circumference, SBP, nephropathy and use of b-blockers, demonstrated that the odds [OR (95% confidence intervals)] of peripheral neuropathy were associated significantly and independently only with diabetes duration [1.044 (1.009-1.081), P=0.013], height [1.075 (1.041-1.110), P<0.001], HbA1c [1.468 (1.164-1.851), P<0.001], PWV [1.174 (1.054-1.309), P=0.004], dyslipidemia [1.941 (1.015-3.713), P=0.045], retinopathy [4.426 (2.217-8.837), P<0.001] and peripheral arterial disease [4.658 (2.264-9.584), P<0.001]. In addition, multivariate linear regression analysis, after controlling for age, gender, diabetes duration, SBP, HbA1c and nephropathy, demonstrated that an increased NDS was significantly and independently associated with height [standardized regression coefficient (beta=0.229, P<0.001)], PWV (beta=0.197, P<0.001), retinopathy (beta=0.268, P<0.001) and peripheral arterial disease (beta=0.374, P<0.001). CONCLUSION: Increased PWV is associated strongly and independently not only with the presence but also with the severity of DPN in patients with T2DM, irrespective of known risk factors.

Association of plasma fetuin-a levels with peripheral arterial disease and lower extremity arterial calcification in subjects with type 2 diabetes mellitus.

AIMS: Fetuin-A is a hepatic glycoprotein that is involved in insulin resistance and atherosclerosis. Herein we examined the association of plasma fetuin-A levels with peripheral arterial disease (PAD) in patients with type 2 diabetes mellitus (T2DM). MATERIAL AND METHODS: A total of 71 patients with T2DM and 57 non-diabetic individuals were recruited. Diagnosis of PAD was based on the absence of triphasic waveform at pedal arteries, while ankle-brachial index (ABI) was calculated. Radiographs of both feet and ankles were taken for the assessment of lower extremity arterial calcification (LEAC). Plasma fetuin-A levels were measured using ELISA. RESULTS: Patients with T2DM had higher fetuin-A levels than non-diabetic participants. Participants with diabetes and PAD had lower fetuin-A levels than non-PAD diabetic patients. In subjects with T2DM fetuin-A levels were associated with ABI. Multivariate analysis demonstrated that in patients with T2DM the odds of PAD increased with long diabetes duration, smoking, presence of arterial hypertension and dyslipidemia, as well as with lower fetuin-A levels. A trend towards higher fetuin-A levels in subjects with less severe LEAC was found. CONCLUSION: Plasma fetuin-A levels are lower in patients with T2DM and PAD and are associated with PAD, irrespective of traditional cardiovascular risk factors. Moreover, fetuin-A may be involved in arterial calcification.

Effect of atorvastatin on baroreflex sensitivity in subjects with type 2 diabetes and dyslipidaemia.

In this prospective study, we examined the effect of atorvastatin treatment on baroreflex sensitivity (BRS) in subjects with type 2 diabetes. A total of 79 patients with type 2 diabetes with dyslipidaemia were recruited. A total of 46 subjects were enrolled to atorvastatin 10 mg daily and low-fat diet and 33 patients to low-fat diet only. BRS was assessed non-invasively using the sequence method at baseline, 3, 6 and 12 months. Treatment with atorvastatin increased BRS after 12 months (from 6.46 ± 2.79 ms/mmHg to 8.05 ± 4.28 ms/mmHg, p = 0.03), while no effect was seen with low-fat diet. Further sub-analysis according to obesity status showed that BRS increased significantly only in the non-obese group (p = 0.036). A low dose of atorvastatin increased BRS in non-obese subjects with type 2 diabetes and dyslipidaemia after 1-year treatment. This finding emphasizes the beneficial effect of atorvastatin on cardiovascular system, beyond the lipid-lowering effects.

Incretin-based therapies for type 2 diabetes mellitus: effects on insulin resistance.

Insulin resistance has been associated with the development of type 2 diabetes, obesity, hypertension, dyslipidemia, atherosclerosis, and thus with increased cardiovascular morbidity and mortality. Insulin resistance precedes the onset of type 2 diabetes by many years. Targeting the pathophysiologic defects that characterize the onset of diabetes is more likely to achieve a durable glucose control and to delay disease progression. Incretins are gut-derived peptides that stimulate in a glucose-dependent mechanism insulin secretion and action. Glucose-like peptide 1 (GLP-1) analogues and dipeptidyl peptidase-4 (DPP-4) inhibitors both decrease fasting and postprandial glucose levels. In addition, GLP-1 analogues promote weight loss and exert a favorable effect on several cardiovascular risk factors. Data from human and experimental studies implicate that GLP-1 analogues and to a less extend DPP-4 inhibitors enhance insulin sensitivity. This review summarizes the current knowledge regarding the impact of GLP-1 analogues and DPP-4 inhibitors on insulin resistance.

The effect of hyperhomocysteinemia on aortic distensibility in healthy individuals.

OBJECTIVE: Elevated plasma homocysteine (HCY) levels have been associated with increased risk for cardiovascular disease. Aortic distensibility and aortic pulse wave velocity (PWV) are indices of aortic elasticity. The potential effect of acute hyperhomocysteinemia (HHCY) on the elastic properties of the aorta in healthy individuals is not known. The aim of the present study was to determine the effect of acute methionine-induced HHCY on aortic distensibility and PWV in healthy individualsand the effect of acute HHCY on myocardial performance of the left ventricle (Tei index). METHODS: Thirty healthy volunteers were included in this crossover study. An oral methionine (100 mg/kg) or water load was given in random order on separate days at weekly intervals. Aortic distensibility and Tei index were determined non-invasively by ultrasonography at baseline and 3 h after methionine or water consumption, while PWV was measured by applanation tonometry at baseline and every 1 h for the same time interval. RESULTS: Oral methionine induced an increase in total plasma HCY concentrations (P < 0.001), whereas HCY concentrations did not change after water consumption. Aortic distensibility decreased 3 h after methionine load (P < 0.001) and Tei index increased (P < 0.001), suggesting worsening compared with baseline values. Water consumption had no effect on aortic distensibility or Tei index values. PWV values did not change after either methionine or water consumption. CONCLUSIONS: Acute methionine-induced HHCY reduces aortic distensibility and worsens myocardial performance in healthy individuals. Further research is warranted to examine in the long term the direct effects of HHCY on cardiovascular function and the indirect effects on structural remodeling.