Effects of vildagliptin on wound healing and markers of inflammation in patients with type 2 diabetic foot ulcer: a prospective, randomized, double-blind, placebo-controlled, single-center study.

INTRODUCTION: Diabetic foot ulcers (DFU) are one of the leading long-term complications experienced by patients with diabetes. Dipeptidyl Peptidase 4 inhibitors (DPP4is) are a class of antihyperglycemic medications prescribed to patients with diabetes to manage glycaemic control. DPP4is may also have a beneficial effect on DFU healing. This study aimed to determine vildagliptin's effect on inflammatory markers and wound healing. TRIAL DESIGN: Prospective, randomized, double-blind, placebo-controlled, single-center study. METHODS: Equal number of participants were randomized into the treatment and placebo groups. The treatment was for 12 weeks, during which the participants had regular visits to the podiatrist, who monitored their DFU sizes using 3D camera, and blood samples were taken at baseline, six weeks, and 12 weeks during the study for measurement of inflammatory markers. In addition, demographic characteristics, co-morbidities, DFU risk factors, and DFU wound parameters were recorded. RESULTS: 50 participants were recruited for the study, with 25 assigned to placebo and 25 to treatment group. Vildagliptin treatment resulted in a statistically significant reduction of HBA1c (p < 0.02) and hematocrit (p < 0.04), total cholesterol (p < 0.02), LDL cholesterol (p < 0.04), and total/HDL cholesterol ratio (P < 0.03) compared to the placebo group. Also, vildagliptin had a protective effect on DFU wound healing, evidenced by the odds ratio (OR) favoring the intervention of 11.2 (95% CI 1.1-113.5; p < 0.04) and the average treatment effect on the treated (ATET) for vildagliptin treatment group showed increased healing by 35% (95%CI; 10-60, p = 0.01) compared to placebo with the model adjusted for microvascular complications, smoking, amputation, dyslipidemia, peripheral vascular disease (PVD) and duration of diabetes. CONCLUSIONS: Vildagliptin treatment was effective in healing DFU in addition to controlling the diabetes. Our findings support the use of DPP4is as a preferred option for treating ulcers in patients with diabetes. Further studies on a larger population are warranted to confirm our findings and understand how DPP4is could affect inflammation and DFU healing.

Influence of Ethnicity on Outcomes of Diabetes Inpatient Hypoglycemia: an Australian Perspective.

AIMS: To evaluate outcomes of diabetic inpatient hypoglycemia among Aboriginal and Torres Strait Islander (ATSI) compared with Australian Caucasian patients. METHODS: A retrospective audit of diabetic patients aged > 18 years admitted at a regional hospital general ward between April 1, 2015, and March 31, 2016, was analyzed. The database contains clinical information at the time of admission and initial discharge and readmission within 4 weeks thereafter. RESULTS: A total of 1618 (of 6027) patients were admitted with diabetes representing 23.7% of the total ward admissions, of which 484 (29.9%) had inpatient hypoglycemia. Of the 91 patients with available data analyzed, ATSI origin with inpatient hypoglycemia was associated with longer length of stay (LOS) (hazard ratio [HR], 2.1, 95% confidence interval [CI], 1.2-3.5), whereas severe hypoglycemia (≤ 2.2 mmol/L) in both ATSI and non-ATSI was significantly associated with longer LOS (HR, 2.3; 95% CI, 1.2-4.2). No significant differences in LOS were found for gender, age, and Carlson comorbidity index (CCI). The adjusted model for likelihood of readmission, gender, indigenous status, and CCI were not significant risk factors for readmission to the hospital. Readmitted patients were older (50-59 years vs < 50 years, P = 0.001; 60-69 years vs < 50 years, P = 0.032; 70+ years vs < 50 years, P = 0.031). CONCLUSION: We reported high rate of inpatient hypoglycemia in our study population. Indigenous Australian diabetic patients with inpatient hypoglycemia had significantly longer LOS compared with non-Indigenous Caucasian counterparts. Further prospective studies on a larger population are needed to confirm our findings.

Gait in People With Nonhealing Diabetes-Related Plantar Ulcers.

BACKGROUND: Abnormalities in gait have been associated with high plantar pressures and diabetes-related plantar foot ulcers. Whether these are a transient response to the ulcer or are representative of long-term lower limb biomechanical abnormalities is currently unknown. OBJECTIVE: The aim of this study was to examine whether 12 gait parameters identified as being associated with nonhealing diabetes-related plantar foot ulcers at baseline remained associated during a 6-month follow-up period. DESIGN: This was a longitudinal observational case-control study. METHODS: Gait assessments were performed at entry and twice during follow-up over a 6-month period in 12 participants with nonhealing diabetes-related plantar foot ulcers (case participants) and 62 people with diabetes and no history of foot ulcers (control participants) using a standardized protocol. Linear mixed-effects random-intercept models were used to identify gait parameters that consistently differed between case participants and control participants at all assessments after adjustment for age, sex, body mass index, presence of peripheral neuropathy, and follow-up time. Standardized mean differences (SMD) were used to measure effect sizes. RESULTS: Five of the 12 gait parameters were significantly different between case participants and control participants at all 3 time points. Case participants had a more abducted foot progression angle (SMD = 0.37), a higher pelvic obliquity at toe-off (SMD = -0.46), a greater minimum pelvic obliquity (SMD = -0.52), a lower walking speed (SMD = -0.46), and a smaller step length (SMD = -0.46) than control participants. LIMITATIONS: The limitations included a small sample size, the observational nature of the study, and the inability to evaluate the impact of gait on wound healing. CONCLUSIONS: This study identified abnormal gait parameters consistently associated with nonhealing diabetes-related plantar foot ulcers. Further research is needed to test the clinical importance of these gait characteristics.

Within- and Between-Body-Site Agreement of Skin Autofluorescence Measurements in People With and Without Diabetes-Related Foot Disease.

BACKGROUND: Skin autofluorescence has been used to assess longer term glycemic control and risk of complications. There is however no agreed site at which autofluorescence should be measured. This study evaluated the within- and between-site agreement in measurement of skin autofluorescence using a noninvasive advanced glycation end product (AGE) reader. METHODS: Overall, 132 participants were included: 16 with diabetes-related foot ulcers (DFU), 63 with diabetes but without foot ulcers (DMC), 53 without diabetes or foot ulcers (HC). Skin autofluorescence was measured using the AGE Reader (DiagnOptics technologies BV, the Netherlands). Three consecutive skin autofluorescence measurements were each performed at six different body sites: the volar surfaces of both forearms (arms), dorsal surfaces of both calves (legs), and plantar surfaces of both feet (feet). Within- and between-site agreements were analyzed with concordance correlation coefficients (CCC) and 95% confidence intervals (95% CI), absolute mean differences (±standard deviation), and Bland-Altman limits of agreement. RESULTS: The agreement between repeat assessments at the same site was almost perfect (CCC [95% CI] ranging from 0.94 [0.91-0.96] for assessments in the right foot to 0.99 [0.99-0.99] for assessments in the left arm). The limits of agreement were narrow within ±0.5 arbitrary units for all sites. The between-site agreement in measurements was poor (CCC < 0.65) with large maximum absolute mean differences (±SD) in arbitrary units (DFU = 3.40 [±2.04]; DMC = 3.15 [±2.45]; HC = 2.72 [±1.83]) and wide limits of agreement. CONCLUSIONS: Skin autofluorescence measurements can be repeated at the same site with adequate repeatability but measurements at different sites in the same patient have marked differences. The reason for this variation across sites and whether this has any role in diabetes-related complications needs further investigation.

Plantar pressures are elevated in people with longstanding diabetes-related foot ulcers during follow-up.

OBJECTIVE: High plantar pressures are implicated in the development of diabetes-related foot ulcers. Whether plantar pressures remain high in patients with chronic diabetes-related foot ulcers over time is uncertain. The primary aim of this study was to compare plantar pressures at baseline and three and six months later in participants with chronic diabetes-related foot ulcers (cases) to participants without foot ulcers (controls). METHODS: Standardised protocols were used to measure mean peak plantar pressure and pressure-time integral at 10 plantar foot sites (the hallux, toes, metatarsals 1 to 5, mid-foot, medial heel and lateral heel) during barefoot walking. Measurements were performed at three study visits: baseline, three and six months. Linear mixed effects random-intercept models were utilised to assess whether plantar pressures differed between cases and controls after adjusting for age, sex, body mass index, neuropathy status and follow-up time. Standardised mean differences (Cohen's d) were used to measure effect size. RESULTS: Twenty-one cases and 69 controls started the study and 16 cases and 63 controls completed the study. Cases had a higher mean peak plantar pressure at several foot sites including the toes (p = 0.005, Cohen's d = 0.36) and mid-foot (p = 0.01, d = 0.36) and a higher pressure-time integral at the hallux (p<0.001, d = 0.42), metatarsal 1 (p = 0.02, d = 0.33) and mid-foot (p = 0.04, d = 0.64) compared to controls throughout follow-up. A reduction in pressure-time integral at multiple plantar sites over time was detected in all participants (p<0.05, respectively). CONCLUSIONS: Plantar pressures assessed during gait are higher in diabetes patients with chronic foot ulcers than controls at several plantar sites throughout prolonged follow-up. Long term offloading is needed in diabetes patients with diabetes-related foot ulcers to facilitate ulcer healing.

Plantar pressures are higher in cases with diabetic foot ulcers compared to controls despite a longer stance phase duration.

BACKGROUND: Current international guidelines advocate achieving at least a 30 % reduction in maximum plantar pressure to reduce the risk of foot ulcers in people with diabetes. However, whether plantar pressures differ in cases with foot ulcers to controls without ulcers is not clear. The aim of this study was to assess if plantar pressures were higher in patients with active plantar diabetic foot ulcers (cases) compared to patients with diabetes without a foot ulcer history (diabetes controls) and people without diabetes or a foot ulcer history (healthy controls). METHODS: Twenty-one cases with diabetic foot ulcers, 69 diabetes controls and 56 healthy controls were recruited for this case-control study. Plantar pressures at ten sites on both feet and stance phase duration were measured using a pre-established protocol. Primary outcomes were mean peak plantar pressure, pressure-time integral and stance phase duration. Non-parametric analyses were used with Holm's correction to correct for multiple testing. Binary logistic regression models were used to adjust outcomes for age, sex and body mass index. Median differences with 95 % confidence intervals and Cohen's d values (standardised mean difference) were reported for all significant outcomes. RESULTS: The majority of ulcers were located on the plantar surface of the hallux and toes. When adjusted for age, sex and body mass index, the mean peak plantar pressure and pressure-time integral of toes and the mid-foot were significantly higher in cases compared to diabetes and healthy controls (p < 0.05). The stance phase duration was also significantly higher in cases compared to both control groups (p < 0.05). The main limitations of the study were the small number of cases studied and the inability to adjust analyses for multiple factors. CONCLUSIONS: This study shows that plantar pressures are higher in cases with active diabetic foot ulcers despite having a longer stance phase duration which would be expected to lower plantar pressure. Whether plantar pressure changes can predict ulcer healing should be the focus of future research. These results highlight the importance of offloading feet during active ulceration in addition to before ulceration.

Gait parameters of people with diabetes-related neuropathic plantar foot ulcers.

BACKGROUND: Foot ulceration associated with diabetic peripheral neuropathy is a global concern. Biomechanical investigation allows the identification of gait abnormalities that may adversely affect ulcer healing. The objective of this case-control study was to compare the gait parameters of cases with diabetes-related foot ulcers to controls. METHODS: Three-dimensional movement analyses were performed on 21 people with diabetes-related neuropathic plantar foot ulcers (cases), 69 people with diabetes without a foot ulcer history (diabetes controls) and 56 healthy controls. Outcome data were reported as mean differences, 95% confidence intervals and Cohen's d effect sizes. Binary logistic regressions were used to adjust for age, sex and body mass index. FINDINGS: People with foot ulcers had a smaller plantar flexion (Cohen's d=-0.6 vs. diabetes controls and d=-0.8 vs. healthy controls), knee flexion (d=-0.6 vs. diabetes controls and d=-1.0 vs. healthy controls) and pelvic obliquity (d=-0.9 vs. diabetes controls and d=-0.7 vs. healthy controls) (all P<0.05). They also had a significantly greater range of anterior-posterior ground reaction force (d=1.0 vs. diabetes controls and d=1.7 vs. healthy controls) and total vertical ground reaction force (d=0.9 vs. diabetes controls and d=1.1 vs. healthy controls) and significantly slower walking speed and smaller step length compared to controls (all P<0.05). INTERPRETATION: People with plantar foot ulcers have considerably different gait parameters to controls. Whether the observed gait parameters contributed to the ulcer development or are a response to the ulcer is currently unclear and needs further investigation.

Non-traumatic lower limb amputation in patients with end-stage renal failure on dialysis: an Australian perspective.

BACKGROUND: End-stage renal failure (ESRF) and dialysis have been identified as a risk factor for lower limb amputations (LLAs). High rate of ESRF amongst the Australian population has been reported, however till date no study has been published identifying magnitude and risk factors of LLA in subjects on renal dialysis. OBJECTIVE: The study aims to document trends in the prevalence and identify risk factors of non-traumatic LLA in Australian patients on dialysis. METHODS: A retrospective review of all patients (218) who attended the regional dialysis center between 1st January 2009 and 31st December 2013 was conducted. Demographic, clinical and biochemical data were analyzed. RESULTS: We identified a high prevalence of 13.3% of LLAs amongst Australian patients with ESRF on dialysis at our center. The associated risk factors were the presence of diabetes (OR 1.67 [1.49-1.88] p < 0.001), history of foot ulceration (OR 81 [18.20-360.48] p < 0.001), peripheral arterial disease (OR 31.29 [9.02-108.56] p < 0.001), peripheral neuropathy (OR 31.29 [9.02-108.56] p < 0.001), foot deformity (OR 23.62 [5.82-95.93] p < 0.001), retinopathy (OR 6.08 [2.64-14.02] p < 0.001), dyslipidemia (OR 4.6 [1.05-20.05] p= 0.049) and indigenous background (OR 3.39 [1.38-8.33] p= 0.01). 75% of the amputees had aboriginal heritage. We also identified higher HbA1c and CRP levels as well as low serum albumin, hemoglobin and vitamin D levels to have a strong association with LLAs (p < 0.05). CONCLUSION: There is high prevalence of LLAs amongst Australian indigenous patients with diabetes on dialysis in North Queensland. Other strongly associated risk factors include history of foot ulceration, foot deformity and peripheral neuropathy as well as high HbA1c levels and low serum albumin levels.

The reproducibility of acquiring three dimensional gait and plantar pressure data using established protocols in participants with and without type 2 diabetes and foot ulcers.

BACKGROUND: Several prospective studies have suggested that gait and plantar pressure abnormalities secondary to diabetic peripheral neuropathy contributes to foot ulceration. There are many different methods by which gait and plantar pressures are assessed and currently there is no agreed standardised approach. This study aimed to describe the methods and reproducibility of three-dimensional gait and plantar pressure assessments in a small subset of participants using pre-existing protocols. METHODS: Fourteen participants were conveniently sampled prior to a planned longitudinal study; four patients with diabetes and plantar foot ulcers, five patients with diabetes but no foot ulcers and five healthy controls. The repeatability of measuring key biomechanical data was assessed including the identification of 16 key anatomical landmarks, the measurement of seven leg dimensions, the processing of 22 three-dimensional gait parameters and the analysis of four different plantar pressures measures at 20 foot regions. RESULTS: The mean inter-observer differences were within the pre-defined acceptable level (<7 mm) for 100 % (16 of 16) of key anatomical landmarks measured for gait analysis. The intra-observer assessment concordance correlation coefficients were > 0.9 for 100 % (7 of 7) of leg dimensions. The coefficients of variations (CVs) were within the pre-defined acceptable level (<10 %) for 100 % (22 of 22) of gait parameters. The CVs were within the pre-defined acceptable level (<30 %) for 95 % (19 of 20) of the contact area measures, 85 % (17 of 20) of mean plantar pressures, 70 % (14 of 20) of pressure time integrals and 55 % (11 of 20) of maximum sensor plantar pressure measures. CONCLUSION: Overall, the findings of this study suggest that important gait and plantar pressure measurements can be reliably acquired. Nearly all measures contributing to three-dimensional gait parameter assessments were within predefined acceptable limits. Most plantar pressure measurements were also within predefined acceptable limits; however, reproducibility was not as good for assessment of the maximum sensor pressure. To our knowledge, this is the first study to investigate the reproducibility of several biomechanical methods in a heterogeneous cohort.

Intensive versus conventional glycaemic control for treating diabetic foot ulcers.

BACKGROUND: The estimated likelihood of lower limb amputation is 10 to 30 times higher amongst people with diabetes compared to those without diabetes. Of all non-traumatic amputations in people with diabetes, 85% are preceded by a foot ulcer. Foot ulceration associated with diabetes (diabetic foot ulcers) is caused by the interplay of several factors, most notably diabetic peripheral neuropathy (DPN), peripheral arterial disease (PAD) and changes in foot structure. These factors have been linked to chronic hyperglycaemia (high levels of glucose in the blood) and the altered metabolic state of diabetes. Control of hyperglycaemia may be important in the healing of ulcers. OBJECTIVES: To assess the effects of intensive glycaemic control compared to conventional control on the outcome of foot ulcers in people with type 1 and type 2 diabetes. SEARCH METHODS: In December 2015 we searched: The Cochrane Wounds Specialised Register; The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library); Ovid MEDLINE; Ovid MEDLINE (In-Process & Other Non-Indexed Citations); Ovid EMBASE; EBSCO CINAHL; Elsevier SCOPUS; ISI Web of Knowledge Web of Science; BioMed Central and LILACS. We also searched clinical trial databases, pharmaceutical trial databases and current international and national clinical guidelines on diabetes foot management for relevant published, non-published, ongoing and terminated clinical trials. There were no restrictions based on language or date of publication or study setting. SELECTION CRITERIA: Published, unpublished and ongoing randomised controlled trials (RCTs) were considered for inclusion where they investigated the effects of intensive glycaemic control on the outcome of active foot ulcers in people with diabetes. Non randomised and quasi-randomised trials were excluded. In order to be included the trial had to have: 1) attempted to maintain or control blood glucose levels and measured changes in markers of glycaemic control (HbA1c or fasting, random, mean, home capillary or urine glucose), and 2) documented the effect of these interventions on active foot ulcer outcomes. Glycaemic interventions included subcutaneous insulin administration, continuous insulin infusion, oral anti-diabetes agents, lifestyle interventions or a combination of these interventions. The definition of the interventional (intensive) group was that it should have a lower glycaemic target than the comparison (conventional) group. DATA COLLECTION AND ANALYSIS: All review authors independently evaluated the papers identified by the search strategy against the inclusion criteria. Two review authors then independently reviewed all potential full-text articles and trials registry results for inclusion. MAIN RESULTS: We only identified one trial that met the inclusion criteria but this trial did not have any results so we could not perform the planned subgroup and sensitivity analyses in the absence of data. Two ongoing trials were identified which may provide data for analyses in a later version of this review. The completion date of these trials is currently unknown. AUTHORS' CONCLUSIONS: The current review failed to find any completed randomised clinical trials with results. Therefore we are unable to conclude whether intensive glycaemic control when compared to conventional glycaemic control has a positive or detrimental effect on the treatment of foot ulcers in people with diabetes. Previous evidence has however highlighted a reduction in risk of limb amputation (from various causes) in people with type 2 diabetes with intensive glycaemic control. Whether this applies to people with foot ulcers in particular is unknown. The exact role that intensive glycaemic control has in treating foot ulcers in multidisciplinary care (alongside other interventions targeted at treating foot ulcers) requires further investigation.

Extreme hypertriglyceridemia managed with insulin.

Extreme hypertriglyceridemia can lead to acute pancreatitis and rapid lowering of serum triglycerides (TG) is necessary for preventing such life-threatening complications. However, there is no established consensus on the acute management of extreme hypertriglyceridemia. We retrospectively reviewed 10 cases of extreme hypertriglyceridemia with mean serum TG on presentation of 101.5 ± 23.4 mmol/L (8982 ± 2070 mg/dL) managed with insulin. Serum TG decreased by 87 ± 4% in 24 hours in those patients managed with intravenous insulin and fasting and 40 ± 8.4% in those managed with intravenous insulin alone (P = .0003). The clinical course was uncomplicated in all except 1 patient who subsequently developed a pancreatic pseudocyst. Thus, combination of intravenous insulin with fasting appears to be an effective, simple, and safe treatment strategy in immediate management of extreme hypertriglyceridemia.

A sporadic case of pseudohypoparathyroidism type 1 and idiopathic primary adrenal insufficiency associated with a novel mutation in the GNAS1 gene.

OBJECTIVE: We report an atypical association of primary adrenal insufficiency and pseudohypoparathyroidism (PHP) and a novel GNAS1 gene mutation in a Caucasian female who initially presented with adrenal crisis. METHODS: A case report and literature review. RESULTS: A 37-year-old female presented with shock at 11 years of age, and investigations revealed primary adrenal insufficiency and pseudohypoparathyroidism (PHP). She had typical features of Albright hereditary osteodystrophy (AHO) and evidence of thyroid-stimulating hormone (TSH), growth-hormone-releasing hormone (GHRH), and gonadotrophin resistance fitting with the diagnosis of PHP type 1a/1c. She did not have a family history of any autoimmune disease or PHP. Her mother was phenotypically normal. Genomic DNA sequencing of those GNAS exons and adjacent intronic regions that encode the stimulatory guanine nucleotide-binding protein Gsα revealed a novel heterozygous mutation in exon 11, c.857-858delCT. CONCLUSION: The association of primary adrenal insufficiency and PHP has not been reported in literature and may prove an area for further research. The novel mutation in this case adds to the spectrum of mutations associated with these disorders.

Use of a standardised diabetic ketoacidosis management protocol improved clinical outcomes.

We analysed the clinical outcomes of using a standardised protocol in the management of diabetic ketoacidosis. Of 71 admissions, the protocol group (n=35) had significantly shorter length of hospitalisation, shorter time to normalise bicarbonate, fewer incidence of hypokalaemia and hypoglycaemia compared with the control group (n=36).

Calciphylaxis in a morbidly obese woman with rheumatoid arthritis presenting with severe weight loss and vitamin D deficiency.

OBJECTIVE: To present an unusual case of calciphylaxis in an obese patient with inactive rheumatoid arthritis and normal renal function. METHODS: We describe a 46-year-old morbidly obese Caucasian woman who had previously weighed 200 kg and presented with painful leg ulcers following a rapid weight loss of 102 kg in 1 year. RESULTS: The subject was admitted with a 6-week history of painful leg ulcers that progressed to her thighs. Vasculitis and active rheumatoid arthritis were excluded clinically and biochemically. A skin biopsy confirmed calciphylaxis in the context of normal renal function. Serum 25-hydroxyvitamin D was low at 14 ng/mL (reference range, 20 to 200 ng/mL), with an elevated serum parathyroid hormone level of 241 pg/mL (reference range, 10 to 65 pg/mL), but normal serum calcium and phosphorus levels. The skin lesions persisted despite local wound care, daily hyperbaric oxygen, and parenteral sodium thiosulfate therapies. After normalizing the serum vitamin D level through oral supplementation, she responded well to pamidronate infusion with complete healing of the ulcers and regained 13% of her premorbid weight. CONCLUSION: This is the first case of calciphylaxis preceded by weight loss of greater than 100 kg in a patient with hypovitaminosis D who responded to pamidronate therapy.

Severe hypoglycaemia associated with ingesting counterfeit medication.

Cross-border importation of traditional and prescription medications is common, and many of these drugs are not approved by the Australian Therapeutic Goods Administration. Furthermore, counterfeit versions of prescription medications are also available (eg, weight-loss medications, anabolic steroids, and medications to enhance sexual performance). We describe a 54-year-old man with the first Australian case of severe hypoglycaemia induced by imported, laboratory-confirmed counterfeit Cialis. This serves to remind medical practitioners that counterfeit medication may be the cause of severe hypoglycaemia (or other unexplained illness).