Short-term glucose variability as a determinant of the healing rate of diabetic foot ulcer: A retrospective study.

BACKGROUND: The aim of this study was to describe the clinical characteristics of people with diabetic foot ulcer (DFU) according to glucose variability (GV) and to investigate the relationship between GV and DFU outcome in a population with type 2 diabetes (T2D) and DFU. METHODS: This is a retrospective study of 300 individuals aged 64.3 years (181 males) treated for DFU in a tertiary-care center with a regular follow-up for 6 months. Laboratory measurements and clinical assessments were collected at baseline. According to the coefficient of variation (CV) cut-off (≥36%), people were divided into two groups (low and high GV). RESULTS: Compared with low GV group (n = 245), high GV group (n = 55) had significant longer duration of diabetes [low vs high GV, mean ± Standard Deviation (SD), 17.8 ± 11.8 vs 22.4 ± 10.8, P = 0.012], higher levels of glycated haemoglobin [median (IQR), 7.4 (6.6, 8.8) vs 8.2 (7.0, 9.6), P = 0.010] and urinary albumin excretion [25.2 (11.9, 77.0) vs 48.0 (23.2, 106.0), P = 0.031]. Moreover, 10 days self-monitoring of blood glucose-derived glycemic metrics were significantly different between groups. No differences among clinical features were found. The multiple logistic regression analysis identified CV and SD as negative predictors of healing. CONCLUSIONS: In a population of people with T2D and DFU treated in a tertiary-care center, individuals with high GV had a 3-fold higher risk of healing failure, as compared with those with low GV. CV and SD were related to poor healing within 6 months follow-up.

Liraglutide for Lower Limb Perfusion in People With Type 2 Diabetes and Peripheral Artery Disease: The STARDUST Randomized Clinical Trial.

Importance: Peripheral artery disease (PAD) in diabetes may lead to diabetic foot ulcer and lower-extremities amputation. Glucagon-like peptide 1 receptor agonists have proven cardiovascular benefits in trials of people with type 2 diabetes at high cardiovascular risk. Objective: To examine the effect of liraglutide on peripheral perfusion measured as peripheral transcutaneous oxygen pressure (TcPo2) in individuals with type 2 diabetes and PAD. Design, Setting, and Participants: This open-label randomized clinical trial was conducted between February 1, 2021, and June 30, 2022, with a final follow-up on December 30, 2022, at University of Campania "Luigi Vanvitelli," Naples, Italy. Fifty-five individuals with type 2 diabetes, PAD, and TcPo2 between 30 and 49 mm Hg were included. Interventions: Patients were randomized to receive 1.8 mg of subcutaneous liraglutide or conventional treatment of cardiovascular risk factors (control group) for 6 months. Main Outcomes and Measures: Coprimary outcomes were the change from baseline of peripheral perfusion between groups and the comparison of the proportion of individuals who reached 10% increase of TcPo2 from baseline in each group. Results: Fifty-five participants (mean [SD] age, 67.5 [8.5] years; 43 [78%] male) were randomized (27 to the liraglutide group and 28 to the control group) and analyzed. Participants had a median (IQR) hemoglobin A1c level of 6.9% (6.5%-7.8%) and a mean (SD) TcPo2 of 40.3 (5.7) mm Hg. Transcutaneous Po2 increased over time in both groups, with significant differences favoring the liraglutide group after 6 months (estimated treatment difference, 11.2 mm Hg; 95% CI, 8.0-14.5 mm Hg; P < .001). The 10% increase of TcPo2 occurred in 24 participants (89%) in the liraglutide group and 13 (46%) in the control group (relative risk, 1.91; 95% CI, 1.26-2.90; P < .001). Compared with the control group, individuals in the liraglutide group had a significant reduction of C-reactive protein (-0.4 mg/dL; 95% CI, -0.7 to -0.07 mg/dL; P = .02), urinary albumin to creatinine ratio (-119.4 mg/g; 95% CI, -195.0 to -43.8 mg/g; P = .003), and improvement of 6-minute walking distance (25.1 m; 95% CI, 21.8-28.3 m; P < .001). Conclusions and Relevance: In this randomized clinical trial of people with type 2 diabetes and PAD, liraglutide increased peripheral perfusion detected by TcPo2 measurement during 6 months of treatment. These results support the use of liraglutide to prevent the clinical progression of PAD in individuals with type 2 diabetes. Trial Registration: ClinicalTrials.gov Identifier: NCT04881110.

BEYOND 2 years: durability of metabolic benefits by simplification of complex insulin regimens in type 2 diabetes.

PURPOSE: To assess the magnitude and durability of the metabolic benefits by simplification of complex insulin treatments in patients with type 2 diabetes inadequately controlled by a full basal-bolus insulin regimen. Herein we report the results of the scheduled 2-year extension of the BEYOND trial. METHODS: Originally, 305 participants with inadequate glycemic control (HbA1c > 7.5%) were randomly assigned to intensification of basal-bolus insulin regimen (n = 101), to a fixed-ratio combination (basal insulin + GLP-1RA, n = 102), or to an association of basal insulin plus an SGLT-2 inhibitor (gliflo-combo, n = 102). The primary efficacy outcome was change from baseline in HbA1c at 24 months assessed by an intention-to-treat analysis. A per-protocol analysis was also performed. RESULTS: Fifty-five percent of patients completed the study in the two comparison arms. Compared with patients randomized to basal-bolus, patients of the other groups experienced non statistically different reductions in HbA1c level according to either an intention-to-treat analysis (-0.8 ± 1.1%, -0.7 ± 1.1%, and -1.3 ± 1.1%, mean ± SD, fixed-ratio, gliflo-combo and basal bolus, respectively) or per-protocol analysis (-1.2 ± 1.0%, -1.2 ± 1.1%, and -1.3 ± 1.0%, respectively). The final HbA1c level (per protocol) was 7.2 ± 0.8%, 7.3 ± 0.9%, and 7.5 ± 0.9%, respectively (P = NS). Treatment satisfaction (DTSQ) increased in both exchange groups, whereas the proportion of patients with hypoglycemia was lower. CONCLUSION: Simplification of complex insulin regimen may be a durable option in at least one-half of patients with type 2 diabetes. CLINICAL TRIAL REGISTRATION: Clinical trial registration no. NCT04196231, clinicaltrials.gov.

Biochemical predictors of diabetic foot osteomyelitis: A potential diagnostic role for parathormone.

AIMS: The aims of this study were to evaluate parathormone (PTH) levels in people with diabetic foot ulcers (DFU) and investigate the relationship between PTH levels and osteomyelitis (OM) in this population. MATERIALS AND METHODS: Eighty-eight patients were admitted for DFU in a tertiary-care centre from October 2021 to May 2022. OM was diagnosed by clinical, laboratory, and radiological evaluations. Laboratory measurements and clinical parameters were collected from medical records. Participants in the study were divided into two groups according to the diagnosis of OM (patients with OM, group 1 [n = 54] and patients without OM, group 2 [n = 34]). RESULTS: Compared with group 2, patients in group 1 were younger and had a longer duration of diabetes. Erythrocyte sedimentation rate and fibrinogen were significantly higher in group 1 compared with group 2. PTH levels were significantly lower (group 1 vs. group 2, median [interquartile range] 16.2 (11.6, 31.0) vs. 23.7 (17.0, 38.1), p = 0.008) and alkaline phosphatase was significantly higher (97.0 (79.0, 112.0) vs. 88.0 (63.0, 107.0), p = 0.031) in group 1. In multiple linear regression analysis, the only independent predictors of PTH concentrations were alkaline phosphatase levels (ß-coefficient 0.441, p < 0.001) and the presence of OM (ß-coefficient -0.290, p = 0.038). CONCLUSIONS: In a population of patients with diabetes and OM admitted to a tertiary university centre, PTH levels were lower as compared with diabetic individuals without OM. The OM and alkaline phosphatase levels were independent predictors of PTH levels in this selected population.

When amputation is not the end of the challenge: A successful therapy for osteomyelitis and soft tissue infection in a patient with type 1 diabetes.

Infection is a common complication in patients with diabetic foot ulcer, leading to lower extremities amputation and healing failure. In this article, we report the case of a 39-year-old man with diabetes who developed a severe soft tissue infection and osteomyelitis after experiencing a major amputation for wet gangrene of both the foot and the ankle.

Antibiotic resistance in diabetic foot infection: how it changed with COVID-19 pandemic in a tertiary care center.

AIM: To investigate the rate of antibiotic resistance and its main risk factors in a population of patients with diabetic foot infection (DFI) during the COVID-19 pandemic, in comparison with the population of 2019. METHODS: Two hundred and twenty-five patients with DFI were admitted in a tertiary care center from January 2019 to December 2020. Antibiotic resistance was evaluated by microbiological examination of soft tissues' or bone's biopsy. RESULTS: Compared with 2019 group (n = 105), 2020 group (n = 120) had a significantly higher prevalence of antibiotic resistance [2019 vs 2020, 36% vs 63%, P <0.001] and more often was admitted with recent or current antibiotic therapy (18% vs 52%, P <0.001), which was frequently self-administered (5% vs 30%, P = 0.032). The risk of antibiotic resistance was also higher in 2020 group [OR 95% CI, 2.90 (1.68 to 4.99)]. Prior hospitalization, antibiotic self-administration and antibiotic prescription by general practitioners resulted as independent predictors of antibiotic resistance. CONCLUSIONS: In a population of people with DFI admitted in a tertiary care center during the COVID-19 pandemic the prevalence of antibiotic resistance was higher than 2019. Previous hospitalization, antibiotic self-administration /prescription by general practitioners were related to higher risk of antibiotic resistant infections.

Feasibility of Simplification From a Basal-Bolus Insulin Regimen to a Fixed-Ratio Formulation of Basal Insulin Plus a GLP-1RA or to Basal Insulin Plus an SGLT2 Inhibitor: BEYOND, a Randomized, Pragmatic Trial.

OBJECTIVE: BEYOND trial evaluated the feasibility of either basal insulin plus glucagon-like peptide 1 receptor agonist (GLP-1RA) or basal insulin plus sodium-glucose cotransporter 2 inhibitor (SGLT2i) to replace a full basal-bolus insulin (BBI) regimen in participants with type 2 diabetes and inadequate glycemic control. RESEARCH DESIGN AND METHODS: Participants were randomized (1:1:1) to: 1) intensification of the BBI regimen (n = 101), 2) fixed ratio of basal insulin plus GLP-1RA (fixed-combo group; n = 102), and 3) combination of basal insulin plus SGLT2i (gliflo-combo group; n = 102). The primary efficacy outcome was change from baseline in HbA1c at 6 months. RESULTS: Baseline characteristics were similar among the three groups (mean HbA1c was 8.6% [70 mmol/mol]). At 6 months, patients experienced similar reduction in HbA1c level (-0.6 ± 0.8, -0.6 ± 0.8, and -0.7 ± 0.9%, mean ± SD, respectively; noninferiority P < 0.001 vs. BBI), and the proportion of patients with HbA1c ≤7.5% was also similar (34%, 28%, and 27%, respectively; P = 0.489). Total insulin dose increased in the BBI group (62 units/day) and decreased both in the fixed-combo and gliflo-combo groups (27 units/day and 21 units/day, respectively; P < 0.01). The proportion of patients with hypoglycemia was 17.8%, 7.8%, and 5.9%, respectively (P = 0.015). There were 12 dropouts in the fixed-combo group, 9 in the gliflo-combo group, and none in the BBI group. CONCLUSIONS: BEYOND provides evidence that it is possible and safe to switch from a BBI regimen to either a once-daily fixed-combo injection or once-daily gliflozin added to basal insulin, with similar glucose control, fewer insulin doses, fewer injections daily, and less hypoglycemia.

Glycemic control in people with type 1 diabetes using a hybrid closed loop system and followed by telemedicine during the COVID-19 pandemic in Italy.

AIMS: This study aims at evaluating the metrics of glycemic control in people with type 1 diabetes using the hybrid closed loop (HCL) system during the COVID-19 lockdown. METHODS: This is a retrospective study of thirty adults with type 1 diabetes using HCL and followed with telemedicine at an Italian University Hospital. Data on metrics of glucose control were collected at different times: two weeks before the lockdown (Time 0), first two weeks of lockdown (Time 1), last two weeks of lockdown (Time 2) and first two weeks after the lockdown (Time 3). The primary endpoint was the change in glucose management indicator (GMI) across the different time points. RESULTS: GMI did not worsen over time (Time 1 vs Time 3, 7% vs 6.9%, P < 0.05), whereas a reduction of mean glucose (P = 0.004) and indices of glucose variability was observed. Time in range (TIR) significantly increased (68.5% vs 73.5%, P = 0.012), and time above range (TAR) level 2 (251-400 mg/dL) significantly decreased (P = 0.002). The improvement of TIR and glucose variability was mainly observed in participants < 35 years. CONCLUSIONS: Adults with type 1 diabetes using HCL showed a significant improvement of most of the metrics of glucose control during the COVID-19 lockdown.

Long-term diabetic complications as predictors of foot ulcers healing failure: A retrospective study in a tertiary-care center.

AIM: The aim of this study was to investigate the factors involved in healing failure in a population of patients with diabetic foot ulcers (DFU) after one year of follow-up. METHODS: One hundred and forty-four patients were treated for DFU in a tertiary-care center and had a regular follow-up for one year. Laboratory measurements and clinical assessments, including long-term diabetes complications and risk factors for DFU, were collected at baseline and patients were divided in two groups according to the outcome [Healed group (H, n = 91), and Not Healed group (NH, n = 53)]. RESULTS: Compared with H group, NH group had significant higher levels of urinary albumin excretion [H vs NH, median (IQR), 23.5 (10.1, 41.1) vs 26.4 (20.8, 141.1), P = 0.032] and significantly increased prevalence of diabetic kidney disease (DKD) (22% vs 40%, P = 0.038) and Charcot Arthropathy (3% vs 16%, P = 0.025). No differences among the other long-term complications of diabetes, risk factors for DFU or clinical features were found. The multiple logistic regression analysis identified DKD and Charcot Arthropathy as negative predictors of healing. CONCLUSIONS: In a population of people with type 2 diabetes with DFU treated in a tertiary-care center, DKD and Charcot Arthropathy were related to poor healing within one year-follow-up.

Metabolic effectiveness of gliflozins and gliptins in the routine clinical practice of patients with type 2 diabetes: preliminary results from GIOIA, a prospective multicentre study.

AIMS: GIOIA is an ongoing prospective multicentre study aiming to assess the vascular and metabolic effects of SGLT-2 inhibitors (gliflozins) and DPP-4 inhibitors (gliptins) in the routine clinical practice of patients with type 2 diabetes (T2D). Herein we describe the preliminary effectiveness data at 6 months. METHODS: SGLT-2i and DPP-4i-naïve adult patients with T2D (N = 301 and 260, respectively), with glycated haemoglobin A1c (A1C) >7%, an estimated glomerular filtration rate (eGFR) ≥60 ml/min/1.73 m2, on background therapy with metformin, insulin or both, are being followed to evaluate markers of vascular (carotid intima-media thickness), myocardial (myocardial diastolic function) and renal (urinary albumin/creatinine ratio) damage during treatment with SGLT-2i or DPP-4i for a period of 24 months. RESULT: At baseline, patients initiated on SGLT-2i are younger (about 6 years) and more heavy (about 7.5 kg), have higher A1C level (0.5% more), a longer diabetes duration and more CV events (20% more) than patients initiated on DPP-4i. At 6 months, patients on SGLT-2i (N = 298) and DPP-4i (N = 258) exhibit significant ameliorations in A1C (-1.% and -0.7%, respectively), which were greater (-1.2% and -0.81%) in those on a background metformin treatment only. The composite endpoint (A1C ≤ 7.0% + weight loss ≥ 3 kg) was achieved by 24% and 16% of patients receiving SGLT-2i or DPP-4i, respectively. No unexpected adverse events were reported. CONCLUSIONS: Both SGLT-2i and DPP-4i provide substantial improvements in metabolic parameters in the usual clinical practice of T2D, especially when used as second-line treatment.

Gender-differences in glycemic control and diabetes related factors in young adults with type 1 diabetes: results from the METRO study.

PURPOSE: To describe gender differences concerning glycemic control, cardiovascular risk factors, diabetic complications, concomitant pathologies, and circulating endothelial progenitor cells (EPCs), in a population of young adults with type 1 diabetes. METHODS: We collected data from 300 consecutively patients (168 males and 132 females), aged 18-30 years, among those admitted at Diabetes Unit of University of Campania "Luigi Vanvitelli" (Naples, Italy) from March 2012 to January 2017. Circulating levels of seven EPCs phenotypes were determined by flow cytometry. RESULTS: As compared to men, women with type 1 diabetes had a significantly higher HbA1c levels (%, 8.4 ± 1.3 vs. 8.1 ± 1.3, P = 0.020), body mass index (Kg/m2, 24.8 ± 4.2 vs. 23.9 ± 3.9, P = 0.034), HDL-cholesterol (mg/dL, 61.7 ± 13.7 vs. 54.7 ± 13.9, P < 0.001), and a lower count of both CD133+KDR+ and CD34+KDR+CD133+ EPCs (P = 0.022, P < 0.001, respectively). A higher proportion of women had overweight/obesity, and thyroiditis; smoking and sexual dysfunctions were more prevalent in men than in women. CONCLUSIONS: Young adults with type 1 diabetes present gender differences with regard to glycemic control, prevalence of some cardiovascular risk factors, sexual dysfunctions and circulating levels of EPCs, most often to the detriment of women.

The Effects of Subcutaneous Insulin Infusion Versus Multiple Insulin Injections on Glucose Variability in Young Adults with Type 1 Diabetes: The 2-Year Follow-Up of the Observational METRO Study.

BACKGROUND: Type 1 diabetic patients have high instability of daily glucose levels. The aim of this study was to evaluate the long-term effects of continuous subcutaneous insulin infusion (CSII) therapy, compared with multiple daily injections of insulin (MDI), on glucose variability, in young type 1 diabetic patients transitioned to the adult diabetes care. METHODS: Patients aged 18-30 years and considered eligible for insulin pump therapy were included in the study. Ninety-eight patients who started CSII therapy and 125 who remained in MDI completed a 2-year follow-up. Glucose variability was assessed with continuous glucose monitoring using blood glucose standard deviation (BGSD), mean amplitude of glycemic excursion (MAGE), continuous overall net glycemic action (CONGA-2 h), low blood glucose index, high blood glucose index, and average daily risk range. RESULTS: MAGE and BGSD decreased in both groups, with adjusted differences at 2 years of -0.74 mM (95% confidence interval [CI] -1.22 to -0.26, P = 0.003) and -0.3 (CI -0.52 to -0.1, P = 0.005) favoring the pump-therapy group. No significant differences between groups in the other variability indexes were observed. HbA1c decreased in both groups without significant difference (0.05%, -0.26, 0.35, P = 0.77); fasting glucose, insulin dose, and overall hypoglycemia (daily, nocturnal, and severe) decreased more in patients with CSII, compared with those with MDI. CONCLUSIONS: Among young adults with type 1 diabetes transitioning from the pediatric care, the use of CSII is associated with lower glucose variability, fasting glycemia, and overall hypoglycemic events than MDI during a 2-year period of follow-up.

Effect of a Mediterranean diet on endothelial progenitor cells and carotid intima-media thickness in type 2 diabetes: Follow-up of a randomized trial.

Background We assessed the long-term effects of a Mediterranean diet on circulating levels of endothelial progenitor cells (EPCs) and the carotid intima-media thickness (CIMT) in patients with type 2 diabetes. Design This was a parallel, two-arm, single-centre trial. Methods Two hundred and fifteen men and women with newly diagnosed type 2 diabetes were randomized to a Mediterranean diet ( n = 108) or a low-fat diet ( n = 107). The primary outcome measures were changes in the EPC count and the CIMT of the common carotid artery after the treatment period defined as the end of trial (EOT). Results At the EOT, both the CD34+KDR+ and CD34+KDR+CD133+ counts had increased with the Mediterranean diet compared with the low-fat diet ( p < 0.05 for both). At the EOT evaluation, there was a significant ( p = 0.024) difference of -0.025 mm in the CIMT favouring the Mediterranean diet. Compared with the low-fat diet, the rate of regression in the CIMT was higher in the Mediterranean diet group (51 vs. 26%), whereas the rate of progression was lower (25 vs. 50%) ( p = 0.032 for both). Changes in the CIMT were inversely correlated with the changes in EPC levels (CD34+KDR+, r = -0.24, p = 0.020; CD34+KDR+CD133+, r = -0.28, p = 0.014). At the EOT, changes in levels of HbA1c, HOMA, total cholesterol, high-density lipoprotein cholesterol and systolic blood pressure were significantly greater with the Mediterranean diet than with the low-fat diet. Conclusion Compared with a low-fat diet, a long-term trial with Mediterranean diet was associated with an increase in circulating EPCs levels and prevention of the progression of subclinical atherosclerosis in patients with newly diagnosed type 2 diabetes.

Effects of a Mediterranean-style diet on the need for antihyperglycemic drug therapy in patients with newly diagnosed type 2 diabetes: a randomized trial.

BACKGROUND: Low-carbohydrate and low-fat calorie-restricted diets are recommended for weight loss in overweight and obese people with type 2 diabetes. OBJECTIVE: To compare the effects of a low-carbohydrate Mediterranean-style or a low-fat diet on the need for antihyperglycemic drug therapy in patients with newly diagnosed type 2 diabetes. DESIGN: Single-center, randomized trial. Randomization was computer-generated and unstratified. Allocation was concealed in sealed study folders held in a central, secure location until participants gave informed consent. Participants and investigators were aware of treatment assignment, and assessors of the primary outcome were blinded. SETTING: Teaching hospital in Naples, Italy. PATIENTS: 215 overweight people with newly diagnosed type 2 diabetes who were never treated with antihyperglycemic drugs and had hemoglobin A(1c) (HbA(1c)) levels less than 11%. INTERVENTION: Mediterranean-style diet (<50% of daily calories from carbohydrates) (n = 108) or a low-fat diet (<30% of daily calories from fat) (n = 107). MEASUREMENTS: Start of antihyperglycemic drug therapy, defined by protocol as indicated for follow-up HbA(1c) level greater than 7% (primary outcome), and changes in weight, glycemic control, and coronary risk factors (secondary outcomes). RESULTS: After 4 years, 44% of patients in the Mediterranean-style diet group and 70% in the low-fat diet group required treatment (absolute difference, -26.0 percentage points [95% CI, -31.1 to -20.1 percentage points]; hazard ratio, 0.63 [CI, 0.51 to 0.86]; hazard ratio adjusted for weight change, 0.70 [CI, 0.59 to 0.90]; P < 0.001). Participants assigned to the Mediterranean-style diet lost more weight and experienced greater improvements in some glycemic control and coronary risk measures than did those assigned to the low-fat diet. LIMITATIONS: Investigators responsible for initiating drug therapy were not blinded to treatment assignment. Dietary intake was self-reported. CONCLUSION: Compared with a low-fat diet, a low-carbohydrate, Mediterranean-style diet led to more favorable changes in glycemic control and coronary risk factors and delayed the need for antihyperglycemic drug therapy in overweight patients with newly diagnosed type 2 diabetes. PRIMARY FUNDING SOURCE: Second University of Naples.