Effects of ON101 for Hard-to-Heal Diabetic Foot Ulcers in A Randomized Phase III Trial: A Post hoc Analysis.

OBJECTIVE: Hard-to-heal diabetic foot ulcers (DFUs) are associated with higher mortality rates and an increased medical burden for patients. ON101, a new topical cream, exhibited better healing efficacy than the control dressing in a Phase III trial. In this post-hoc analysis, we further identify whether ON101 can improve the healing of ulcers with hard-to-heal risk factors in this cohort of DFU patients. APPROACH: To compare the efficacy of ON101 with absorbent dressing among various hard-to-heal wounds in patients with DFU, a post hoc analysis of a randomized phase III trial included 276 DFU patients was performed by subgrouping those patients based on ulcer depth, location, size, duration, and patients' glycated hemoglobin (HbA1c) levels and body mass index (BMI). RESULTS: In the full analysis set, the proportion of patients achieving healing was 61.7% in the ON101 group and 37.0% in the comparator (P =0.0001). In sub-group analysis according to risk factors, ON101 demonstrated superior healing capacity on Wagner grade 2 ulcers (P < 0.0001); plantar ulcers (P = 0.0016), ulcers size ≥5 cm² (P = 0.0122), ulcers duration ≥3 months (P = 0.0043); for patients with HbA1c ≥9% (P = 0.0285); and patients with BMI ≥25 (P = 0.0005). INNOVATION: ON101, a novel therapeutic drug, can modulate the functions of macrophages and demonstrate superior healing rates to conventional absorbent dressing in patients with hard-to-heal DFUs. CONCLUSIONS: The results of this post hoc study suggest that ON101 is a better therapeutic option than conventional dressing used in treatment for DFU patients with higher HbA1c, BMI, or ulcers with complex conditions such as longer duration, deeper wounds, larger size, and plantar location.

Sodium-Glucose Cotransporter 2 Inhibitors Reduce the Risk of Hospitalization for Heart Failure and Amputation Rate Compared With Incretin-Based Therapy in Patients With Diabetic Foot Disease: A Nationwide Population-Based Study.

OBJECTIVE: Major adverse cardiovascular event (MACE) outcomes associated with sodium-glucose cotransporter 2 inhibitor (SGLT2i) and glucagon-like peptide-1 receptor agonist (GLP-1 RA) therapies remain unclear in patients with type 2 diabetes and newly diagnosed diabetic foot complications (DFCs). This study examined the impact of SGLT2i and GLP-1 RA use on the rates of MACEs and amputations in patients with type 2 diabetes and without cardiovascular disease. METHODS: Data from the Taiwan National Health Insurance Research Database (2004-2017) were analyzed, focusing on patients with type 2 diabetes without previous MACE and newly diagnosed DFCs. The primary outcome was the first MACE occurrence, and the secondary outcomes included MACE components, all-cause mortality, and lower extremity amputation (LEA) rates. RESULTS: SGLT2i users showed a significant decrease in the MACE (hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.46-0.88) and hospitalization for heart failure (HR, 0.54; 95% CI, 0.35-0.83) rates compared with dipeptidyl peptidase-4 inhibitor users. The amputation rates were also lower in SGLT2i users without LEA at the first DFC diagnosis (HR, 0.28; 95% CI, 0.10-0.75) and did not increase in those with a history of peripheral artery disease or LEA. No significant differences were observed between dipeptidyl peptidase-4 inhibitor and GLP-1 RA users in terms of the primary or secondary outcomes. CONCLUSION: In patients with type 2 diabetes initially diagnosed with DFC, SGLT2i are effective in significantly reducing the hospitalization for heart failure and MACE rates. SGLT2i lower the amputation rates, especially in patients who have not previously had a LEA, than the dipeptidyl peptidase-4 inhibitor therapy.

Microbiome of limb-threatening diabetic foot ulcers indicates the association of fastidious Stenotrophomonas and major amputation.

BACKGROUND: Proper identification of the polymicrobial microorganisms in patients with limb-threatening diabetic foot ulcers (LTDFUs) using conventional culture is insufficient. This prospective study evaluates the potential value of adjuvant molecular testing assisting in identify fastidious micro-organisms in LTDFUs compared to standard treatment alone. METHODS: Ninety patients with LTDFUs received interdisciplinary and standard antibiotic treatment in a referral diabetic foot center. A simultaneous 16S amplicon sequencing (16S AS) specimen along with conventional culture collected at admission was used to retrospectively evaluate the microbiological findings and its association with amputation outcomes. RESULTS: The microorganism count revealed by 16S AS overwhelmed that of conventional culturing (17 vs. 3 bacteria/ulcer respectively). The Stenotrophomonas spp. revealed in 29 patients were highly correlated with major (above ankle) amputation (OR: 4.76, 95% CI 1.01-22.56), while only one had been concomitantly identified by conventional culturing. Thus, there were 27 cases without proper antibiotics coverage during treatment. CONCLUSIONS: Adjuvant molecular testing assisted identification of fastidious pathogens such as Stenotrophomonas infection and might be associated with major amputation in patients with LTDFUs.

Are current wound classifications valid for predicting prognosis in people treated for limb-threatening diabetic foot ulcers?

This study aims to investigate whether the current wound classifications were valid for the treatment prognosis of subjects treated for limb-threatening diabetic foot ulcers (LTDFU). A total of 1548 patients with LTDFU and infection were studied, with wounds recorded using the Wagner, Texas, PEDIS and WIfI classifications while major lower extremity amputations (LEAs) or in-hospital mortality incidences were defined as poor outcomes. Among them, 153 (9.9%) patients received major LEAs and 38 (2.5%) patients died. After adjustments, the Wagner classification and Texas stage as well as clinical factors such as comorbidity with major adverse cardiac events (MACE), being under dialysis and having serum levels of C-reactive protein (CRP) and albumin were independent factors for prognosis. For patients without dialysis, Wagner and Texas stage stood out independently for prognosis. For patients on dialysis, only levels of CRP (odds ratio [OR] = 2.2 in Wagner, OR = 2.0 in WIfI, OR = 2.2 in Texas, OR = 2.3 in PEDIS) and albumin (OR = 0.4 in four classifications) were valid predictors. The Wagner system and Texas stage were valid for predicting prognosis in treatment for LTDFUs, suggesting a role of vascular perfusion. MACE history, levels of CRP and albumin level should assist in prediction; more significantly, only levels of CRP and albumin appeared valid for those subjects undergoing dialysis.

A comparative analysis of complementary therapies use among patients attending diabetic clinics in Taiwan: 2007 vs. 2023.

BACKGROUND: We conducted a comparative study to examine the differences in the use of complementary therapies (CT) among patients who attended diabetic clinics for follow-up treatment between 2007 and 2023 in Taiwan. METHODS: This study employed a cross-sectional survey design to recruit individuals with diabetes from two regions (northern and southern) of Taiwan. A total of 183 and 307 participants were included in the surveys of 2007 and 2023, respectively. The data were analyzed using IBM SPSS Statistics version 28.0 to compare the survey results between the two time periods. RESULTS: Among the various CTs, nutritional supplements remained the most prevalent, with a significant increase in usage from 68.3% in 2007 to 89.9% in 2023. Conversely, other therapies, such as Chinese herbal medicines, manipulative-based therapies, supernatural healings, and bioelectromagnetic-based therapies, demonstrated a significant decrease in usage between the two time periods. Furthermore, the disclosure rate of CT use to healthcare professionals remained persistently low, with only 24.6% in 2007 and a slight increase to 30.3% in 2023. CONCLUSION: The significant rise in the use of nutritional supplements in conjunction with conventional medicine, without adequate monitoring and guidance from healthcare professionals, poses a substantial risk of unregulated blood sugar control, compromised diabetes management, and potential harm to health outcomes.

Cyclodextrin-Mediated Cholesterol Depletion Induces Adiponectin Secretion in 3T3-L1 Adipocytes.

Adipocytes store a significant amount of cholesterol and triglycerides. However, whether cholesterol modulates adipocyte function remains largely unknown. We modulated the cholesterol level in adipocytes to examine its effect on the secretion of adiponectin, an important hormone specifically secreted by adipocytes. Treating differentiated 3T3-L1 adipocytes with 4 mM methyl-ß-cyclodextrin (MßCD), a molecule with a high affinity for cholesterol, rapidly depleted cholesterol in adipocytes. Interestingly, MßCD treatment increased adiponectin in the medium without affecting its intracellular level, suggesting a modulation of secretion. By contrast, cholesterol addition did not affect adiponectin secretion, suggesting that cholesterol-depletion-induced intracellular cholesterol trafficking, but not reduced cholesterol level, accounted for MßCD-induced adiponectin secretion. MßCD-induced adiponectin secretion was reduced after 10 µg/mL U18666A treatment that suppressed cholesterol transport out of late endosomes/lysosomes. Depleting Niemann-Pick type C1 (NPC1) or NPC2 proteins, which mediate endosomal/lysosomal cholesterol export, consistently reduced MßCD-induced adiponectin secretion. Furthermore, treatment with 1 µM bafilomycin A1, which neutralized acidic endosomes/lysosomes, also attenuated MßCD-induced adiponectin secretion. Finally, MßCD treatment redistributed cellular adiponectin to lower-density fractions in sucrose gradient fractionation. Our results show that MßCD-mediated cholesterol depletion elevates the secretion of adiponectin, highlighting the involvement of endosomes and lysosomes in adiponectin secretion in adipocytes.

Factors Considered Important by Healthcare Professionals for the Management of Using Complementary Therapy in Diabetes: A Text-Mining Analysis.

Text-mining algorithms can identify the most prevalent factors of risk-benefit assessment on the use of complementary and integrative health approaches that are found in healthcare professionals' written notes. The aims of this study were to discover the key factors of decision-making on patients' complementary and integrative health use by healthcare professionals and to build a consensus-derived decision algorithm on the benefit-risk assessment of complementary and integrative health use in diabetes. The retrospective study of an archival dataset used a text-mining method designed to extract and analyze unstructured textual data from healthcare professionals' responses. The techniques of classification, clustering, and extraction were performed with 1398 unstructured clinical notes made by healthcare professionals between 2019 and 2020. The most important factor for decision-making by healthcare professionals about complementary and integrative health use in patients with diabetes was the ingredients of the product. Other important factors were the patient's diabetes control, the undesirable effects from complementary and integrative health, evidence-based complementary and integrative health, medical laboratory data, and the product's affordability. This exploratory text-mining study provides insight into how healthcare professionals decide complementary and integrative health use for patients with diabetes after a risk-benefit assessment from clinical narrative notes.

Regimen comprising GLP-1 receptor agonist and basal insulin can decrease the effect of food on glycemic variability compared to a pre-mixed insulin regimen.

BACKGROUND: Increasing evidence suggests that glucagon-like peptide 1 (GLP-1) receptor agonists (RA) can stabilize glycemic variability (GV) and interfere with eating behavior. This study compared the impact of insulin, GLP-1 RA, and dietary components on GV using professional continuous glucose monitoring (CGM). METHODS: Patients with type 2 diabetes underwent CGM before and after switching from a twice-daily pre-mixed insulin treatment regimen to a GLP-1 RA (liraglutide) plus basal insulin regimen. The dietary components were recorded and analyzed by a certified dietitian. The interactions between the medical regimen, GV indices, and nutrient components were analyzed. RESULTS: Sixteen patients with type 2 diabetes were enrolled in this study. No significant differences in the diet components and total calorie intake between the two regimens were found. Under the pre-mixed insulin regimen, for increase in carbohydrate intake ratio, mean amplitude of glucose excursion (MAGE) and standard deviation (SD) increased; in contrast, under the new regimen, for increase in fat intake ratio, MAGE and SD decreased, while when the protein intake ratio increased, the coefficient of variation (CV) decreased. The impact of the food intake ratio on GV indices disappeared under the GLP-1 RA regimen. After switching to the GLP-1 RA regimen, the median MAGE, SD, and CV values decreased significantly. However, the significant difference in GV between the two regimens decreased during the daytime. CONCLUSION: A GLP-1 RA plus basal insulin regimen can stabilize GV better than a regimen of twice-daily pre-mixed insulin, especially in the daytime, and can diminish the effect of food components on GV.

Diabetic foot disease in subjects with End-stage renal Disease: A nationwide study over 14 years highlighting an emerging threat.

AIMS: To disclose prevalence, demographic, foot characteristics as well as management and lower-extremity amputations (LEAs) of subjects with end-stage renal disease (ESRD) on diabetic foot diseases (DFDs). METHODS: Data were derived from the Taiwan National Health Insurance Research Database between 2004 and 2017. DFDs were defined as ulcers, infections, or severe peripheral arterial diseases (PADs) in patients with type 2 diabetes. Clinical characteristics were analyzed between subjects with and without ESRD. RESULTS: Subjects with ESRD have increased impacts on the DFD population either from annual prevalence (2.7 % to 10.42 %, P for trend < 0.001), or proportional representation in LEAs (7.91 % to 26.37 %, P < 0.001) over 14 years. The annual trends for major-LEAs rates have decreased in both subjects with and without ESRD (13.67 % to 5.82 % and 3.48 % to 1.47 %, both P < 0.001). Notably, the concomitant increase of endovascular treatments (EVTs) (7.09 % to 29.41 %, P < 0.001) was associated with the decrease of major-LEAs (P for interaction < 0.001) in subjects with ESRD. CONCLUSIONS: As the annual prevalence of subjects with ESRD has increased 3.9-fold over years, they now account for more than 30% of annual major-LEA of the total DFD population. Interdisciplinary team approach and aggressive EVTs might reduce major-LEAs in these patients.

A Randomized Controlled Trial of R-Form Verapamil Added to Ongoing Metformin Therapy in Patients with Type 2 Diabetes.

CONTEXT: There is a medical need for effective insulin-independent antidiabetic drugs that can promote pancreatic ß-cell function and have a low risk of hypoglycemia in type 2 diabetes mellitus (T2DM) patients. R-form verapamil (R-Vera), which is able to enhance the survival of ß-cells and has higher cardiovascular safety margin compared with racemic verapamil, was developed as a novel approach for T2DM treatment. OBJECTIVE: This randomized, double-blind, placebo-controlled clinical trial was designed to evaluate the efficacy and safety of 3 dosages of R-Vera added to ongoing metformin therapy in T2DM patients who had inadequate glycemic control on metformin alone. METHODS: Participants were randomly assigned in an equal ratio to receive R-Vera 450, 300, or 150 mg per day, or matching placebo, in combination with metformin. The primary endpoint was change in hemoglobin A1c (HbA1c) after 12 weeks of treatment. RESULTS: A total of 184 eligible participants were randomized to receive either R-Vera or placebo plus metformin. At week 12, significant reductions in HbA1c were observed for R-Vera 300 mg/day (-0.36, P = 0.0373) and 450 mg/day (-0.45, P = 0.0098) compared with placebo. The reduction in HbA1c correlated with decreasing fasting plasma glucose levels and improved HOMA2-ß score. Treatment with R-Vera was well tolerated with no hypoglycemic episodes occurring during the trial. CONCLUSION: Addition of R-Vera twice daily to ongoing metformin therapy significantly improved glycemic control in T2DM patients. The favorable efficacy and safety profile of R-Vera 300 mg/day can be considered as the appropriate dose for clinical practice.

A genome-wide association study for melatonin secretion.

Melatonin exerts a wide range of effects among various tissues and organs. However, there is currently no study to investigate the genetic determinants of melatonin secretion. Here, we conducted a genome-wide association study (GWAS) for melatonin secretion using morning urine 6-hydroxymelatonin sulfate-to-creatinine ratio (UMCR). We initially enrolled 5000 participants from Taiwan Biobank in this study. After excluding individuals that did not have their urine collected in the morning, those who had history of neurological or psychiatric disorder, and those who failed to pass quality control, association of single nucleotide polymorphisms with log-transformed UMCR adjusted for age, sex and principal components of ancestry were analyzed. A second model additionally adjusted for estimated glomerular filtration rate (eGFR). A total of 2373 participants underwent the genome-wide analysis. Five candidate loci associated with log UMCR (P value ranging from 6.83 × 10-7 to 3.44 × 10-6) encompassing ZFHX3, GALNT15, GALNT13, LDLRAD3 and intergenic between SEPP1 and FLJ32255 were identified. Similar results were yielded with further adjustment for eGFR. Interestingly, the identified genes are associated with circadian behavior, neuronal differentiation, motor disorders, anxiety, and neurodegenerative diseases. We conducted the first GWAS for melatonin secretion and identified five candidate genetic loci associated with melatonin level. Replication and functional studies are needed in the future.

Corrigendum: Ankle-Brachial Index Is Independently Associated With Cardiovascular Outcomes and Foot Ulcers in Asian Patients With Type 2 Diabetes Mellitus.

[This corrects the article DOI: 10.3389/fendo.2021.752995.].

Risk factors of first and recurrent genitourinary tract infection in patients with type 2 diabetes treated with SGLT2 inhibitors: A retrospective cohort study.

AIMS: This retrospective study investigated the risk factors of sodium-glucose cotransporter 2 inhibitors (SGLT2i) -related genitourinary tract infection (GUTI). METHODS: We used longitudinal claims data from May 2016 to December 2017 from the Chang Gung Research Database. Diabetic patients who used SGLT2i were included. The baseline characteristics risk factors between patients who had GUTI and no GUTI were analyzed. RESULTS: There were 428(3.43%) patients with the first occurrence of urinary tract infection (UTI) and 5(0.04%) patients with genital tract infection (GTI). Female patients aged ≥ 65 years with HbA1c ≥ 9%, eGFR < 60 ml/min/1.73 m2, urine albumin/creatinine ratio (UACR) level ≥30 mg/g, dyslipidemia, diabetic microvascular complications and mood disorder had a higher risk of having the first occurrence of UTI. There was no significant risk factor of GTI. 117 UTI and 3 GTI patients received SGLT2i rechallenging. The recurrent UTI rate was 28.2% and no recurrent GTI was diagnosed. The risk factors included CHD, eGRF < 45 ml/min/1.73 m2, and mood disorder (OR, 95% CI: 4.39, 1.15-16.74; 4.11, 1.51-11.19; 5.93, 1.39-25.34, respectively). CONCLUSIONS: In diabetic patients who had underlying disease of eGRF < 45 ml/min/1.73 m2, CHD, and mood disorder had higher risk of recurrent UTI after rechallenging SGLT2i.

A comprehensive investigation of nutritional status and psoas muscle mass in predicting five-year survival in patients with liver transplant.

BACKGROUND/PURPOSE: Although nutrition and sarcopenia have impacts on the surgery outcome of patients who have received living donor liver transplant (LDLT), the use of the prognostic nutritional index (PNI) or psoas muscle mass index (PMI) as an indicator for five-year survival in those patients is still unclear. METHODS: A total of 138 patients receiving LDLT were followed at a medical center in Taiwan. As well as analysis of clinical factors using Cox regression, time-varying PNI and PMI values as before surgery (0) and at 3-, 6-, and 12- months after LDLT were analyzed by time-dependent Cox analysis. For those 124 patients who survived after 3 months of LDLT, the values of PNI-3m, PMI-3m and their combination were further analyzed. RESULTS: PNI and PMI were noted to be highly associated with mortality at three months post-LDLT (PNI-3m hazard ratio [HR] = 0.89, 95% confidence interval [CI]: 0.85-0.94, p < 0.001; PMI-3m HR = 0.58, 95% CI: 0.41-0.82, p = 0.002). Per the Youden index, the cut-off point of PNI-3m was 42.35, and that of PMI-3m was 1.94. Compared to the subjects with higher levels of PNI-3m and PMI-3m (N-high/M-high), the HRs for subjects with N-high/M-low, N-low/M-high, and N-low/M-low were 5.27 (p = 0.004), 4.46 (p = 0.010) and 12.97 (p < 0.001) respectively. CONCLUSION: PNI and PMI at the third month post-LDLT serve as excellent predictors for 5-year survival. For patients with lower levels of PNI-3m or PMI-3m, combination use of these indexes is suggested to provide better prognostic information.

Impact of wound microbiology on limb preservation in patients with diabetic foot infection.

AIMS/INTRODUCTION: To investigate the association between specific bacterial pathogens and treatment outcome in patients with limb-threatening diabetic foot infection (LT-DFI). MATERIALS AND METHODS: Consecutive patients treated for LT-DFI in a major diabetic foot center in Taiwan were analyzed between the years 2014 and 2017. Patients with positive wound culture results at first aid were enrolled. Clinical factors, laboratory data, and wound culture results were compared. Lower-extremity amputations and in-hospital mortality were defined as a poor outcome. RESULTS: Among the 558 patients, 272 (48.7%) patients had lower extremity amputation and 22 (3.9%) patients had in-hospital mortality. Gram-negative bacterial (GNB) infection was the independent factor following factors adjustment. When all the 31 microorganisms were analyzed, only E. coli (adjusted odds ratio [aOR], 3.01; 95% CI, 1.60-5.65), Proteus spp. (aOR, 2.99; 95% CI, 1.69-5.29), and Pseudomonas aeruginosa (aOR, 2.00; 95% CI 1.20-3.32) were associated with poor outcome. The analysis of specific GNB species in association with major- or minor- amputation have been reported. No specific pathogen was associated with cause of death in patients with mortality within 30 days. The antimicrobial-resistant strains were not associated with a poor treatment outcome. CONCLUSIONS: The presence of GNB was associated with limb amputations. This study provides insight into more timely and appropriate management of the diabetic foot infection.

Ankle-Brachial Index Is Independently Associated With Cardiovascular Outcomes and Foot Ulcers in Asian Patients With Type 2 Diabetes Mellitus.

Background and Aims: The ankle-brachial index (ABI) is an efficient tool for objectively documenting the presence of lower-extremity peripheral arterial disease (PAD). The predictive factors of cardiovascular events and diabetic foot ulcer were not clear from the ABI examination in Taiwanese patients with type 2 diabetes mellitus (DM). Methods: We enrolled 482 patients with type 2 DM who regularly visited the outpatient department of Chang Gung Memorial Hospital and received ABI as well as brachial-ankle pulse wave velocity (ba-PWV) examinations from 2010 to 2017. Age, gender, PAD symptoms, comorbidities, family history of chronic diseases, lifestyle (smoking, alcohol consumption, and exercise), height, weight, waist circumference, monofilament testing and foot ulcer status were studied. Results: There were 104 (22%) patients (mean age, 67.8 years) with the ABI <1.0. These patients with low ABI (ABI<1.0) had a significantly older age (p=0.001), higher delta PWV (p<0.001), higher rates of stroke (p=0.007), myocardial infarction (p=0.016), and foot ulcer (p=0.039). In a multivariable analysis model, the adjusted odds ratio (aOR) for myocardial infarction, stroke, and foot ulcers associated with low ABI were 1.219 (0.397-3.743, p=0.729), 1.204 (0.556-2.610, p=0.638), and 2.712 (1.199-6.133, p=0.017), respectively. The patients with low PWV (PWV<1400 cm/s) were significantly younger (p<0.001) and had a lower rate of hypertension (p<0.001), and higher percentages of stroke (p=0.027) and dialysis (p=0.041) family history. Conclusions: Low ABI was associated with cardiovascular events and diabetic foot ulcer independently in patients with type 2 DM.

Evaluation of Disease Complications Among Adults With Type 1 Diabetes and a Family History of Type 2 Diabetes in Taiwan.

Importance: Patients with type 1 diabetes (T1D) and a family history of type 2 diabetes (T2D) appear to be at a high risk of diabetes complications and other cardiovascular diseases. However, estimates of individual risks in patients in Taiwan are largely unavailable or unreliable. Objective: To evaluate the risk of diabetes complications and major adverse cardiovascular events (MACEs) in patients with T1D with a family history of T2D. Design, Setting, and Participants: A population-based cohort study used the Taiwan National Health Insurance Research Database. Participants included all individuals registered in that database on December 31, 2017, and followed up since March 1, 1995. The data were analyzed from December 6, 2018, to December 5, 2019. Exposure: Patients with T1D and a family history of T2D were evaluated. Main Outcomes and Measures: The prevalence and hazard ratios (HRs) of diabetes complications and other cardiovascular diseases in patients with T1D were analyzed. The MACEs were identified by diagnostic or procedural codes and heritability was formulated by the registry data of beneficiaries. Results: Of 27 370 965 individuals included in the database, 11 237 (mean [SD] age, 22.7 [14.4] years; 54% were female) had T1D. The crude prevalence of T1D was 0.04%, with a female to male ratio of 1.22: 1. The adjusted HRs in individuals who had a first-degree relative with T2D were 2.61 (95% CI, 1.32-5.16) for MACEs at an age at diagnosis of less than 20 years. Adjusted HRs were 1.44 (95% CI, 1.27-1.64) for diabetic neuropathy, 1.28 (95% CI, 1.12-1.47) for retinopathy, and 1.24 (95% CI, 1.06-1.47) for neuropathy at all ages of diagnosis. Conclusions and Relevance: In this study of patients in Taiwan with T1D, having relatives with T2D was associated with an increase in the individual risks of developing diabetes complications. Patients with T1D and a family history of T2D might have more complications and require close management.

Survival of Patients Following First Diagnosis of Diabetic Foot Complications: A Nationwide 15-Year Longitudinal Analysis.

Background and Aims: The long-term survival in people with type 2 diabetes following first diagnosis of diabetic foot complications (FDDFC) is unclear. The object is to evaluate the mortality rate in subjects with type 2 diabetes following FDDFC and the impacts of the major cardiovascular comorbidities. Methods: Nationwide data were analyzed for subjects with T2D and DFC between 2003 and 2017 according to ICD-9 coding. DFC was defined with the codes of ulcers, infections, or severe peripheral artery disease that required intervention (PAD) to mimic the real world diagnosis. Criteria of FDDFC were preceded by a period without any DFC for at least 5 years. Major cardiovascular comorbidities: established PAD and cardiovascular diseases (CVD: including coronary heart disease (CHD), stroke, or heart failure) before the index date as well as lower-extremity amputations (LEA) at the index episode were analyzed. Results: Among 300,115 subjects with DFC, a total of 103,396 patients had FDDFC. The mean 5-year survival rate of these subjects was 81.05%. Using subjects without associated major cardiovascular comorbidity as baseline, the adjusted hazard ratios (aHR) were1.43 (95% confidence interval 1.38-1.49) in group PAD-/CVD+, followed by 1.70 (1.59-1.80) in PAD+/CVD- and 1.98 (1.89-2.08) in PAD+/CVD+. The aHR was further increased in patients with PAD who additionally had heart failure (3.77, 3.50-4.05), stroke (2.06, 1.95-2.18), or CHD (1.89, 1.79-2.00). Subjects with PAD rather than other CVD were associated with LEA at FDDFC. Patients with major LEA (above the ankle) at FDDFC episode had lower 5-year survival rate (65.01%) followed by those with minor LEA (72.24%) and without LEA (81.61%). Conclusions: Cardiovascular comorbidity as well as LEA status at the event of FDDFCs were both associated with patient survival outcomes. Earlier identification of this large population could lead to higher survival rates.

Effect of a Novel Macrophage-Regulating Drug on Wound Healing in Patients With Diabetic Foot Ulcers: A Randomized Clinical Trial.

Importance: Delayed healing of diabetic foot ulcers (DFUs) is known to be caused by dysregulated M1/M2-type macrophages, and restoring the balance between these macrophage types plays a critical role in healing. However, drugs used to regulate M1/M2 macrophages have not yet been studied in large randomized clinical trials. Objective: To compare the topical application of ON101 cream with use of an absorbent dressing (Hydrofiber; ConvaTec Ltd) when treating DFUs. Design, Setting, and Participants: This multicenter, evaluator-blinded, phase 3 randomized clinical trial was performed in 21 clinical and medical centers across the US, China, and Taiwan from November 23, 2012, to May 11, 2020. Eligible patients with debrided DFUs of 1 to 25 cm2 present for at least 4 weeks and with Wagner grade 1 or 2 were randomized 1:1 to receive ON101 or control absorbent dressings. Interventions: Twice-daily applications of ON101 or a absorbent dressing changed once daily or 2 to 3 times a week for 16 weeks, with a 12-week follow-up. Main Outcomes and Measures: The primary outcome was the incidence of complete healing, defined as complete re-epithelialization at 2 consecutive visits during the treatment period assessed on the full-analysis set (FAS) of all participants with postrandomization data collected. Safety outcomes included assessment of the incidences of adverse events, clinical laboratory values, and vital signs. Results: In the FAS, 236 eligible patients (175 men [74.2%]; mean [SD] age, 57.0 [10.9] years; mean [SD] glycated hemoglobin level, 8.1% [1.6%]) with DFUs classified as Wagner grade 1 or 2 (mean [SD] ulcer area, 4.8 [4.4] cm2) were randomized to receive either the ON101 cream (n = 122) or the absorbent dressing (n = 114) for as long as 16 weeks. The incidence of complete healing in the FAS included 74 patients (60.7%) in the ON101 group and 40 (35.1%) in the comparator group during the 16-week treatment period (difference, 25.6 percentage points; odds ratio, 2.84; 95% CI, 1.66-4.84; P < .001). A total of 7 (5.7%) treatment-emergent adverse events occurred in the ON101 group vs 5 (4.4%) in the comparator group. No treatment-related serious adverse events occurred in the ON101 group vs 1 (0.9%) in the comparator group. Conclusions and Relevance: In this multicenter randomized clinical trial, ON101 exhibited better healing efficacy than absorbent dressing alone in the treatment of DFUs and showed consistent efficacy among all patients, including those with DFU-related risk factors (glycated hemoglobin level, ≥9%; ulcer area, >5 cm2; and DFU duration, ≥6 months). Trial Registration: ClinicalTrials.gov Identifier: NCT01898923.

Methylation status of vault RNA 2-1 promoter is a predictor of glycemic response to glucagon-like peptide-1 analog therapy in type 2 diabetes mellitus.

INTRODUCTION: Therapeutic efficiency of glucagon-like peptide-1 (GLP-1) analog is about 50%-70% in type 2 diabetes mellitus (T2DM). Discovery of potential genetic biomarkers for prediction of treatment efficiency of GLP-1 analog before therapy is still necessary. We assess whether DNA methylation was associated with glycemic response to GLP-1 analog therapy in patients with poorly controlled T2DM. RESEARCH DESIGN AND METHODS: Genomic DNA was extracted from the peripheral blood of training (n=10) and validation (n=128) groups of patients with T2DM receiving GLP-1 analogs. DNA methylome was analyzed using Infinium Human Methylation EPIC Bead Chip in the training group. The candidate genes were examined using a pyrosequencing platform in the validation group. The association between DNA methylation status and glycemic response to GLP-1 was analyzed in these patients. RESULTS: The most differential methylation region between those with a good (responsive) and poor (unresponsive) glycemic response to GLP-1 analog therapy was located on chromosome 5q31.1 (135415693 to 135416613), the promoter of VTRNA2-1 in the training group. The methylation status of the VTRNA2-1 promoter was examined in the validation group via pyrosequencing reaction, and the hypomethylation of VTRNA2-1 (<40% methylation) was significantly associated with poor glycemic response to GLP-1 treatment (OR 2.757, 95% CI 1.240 to 6.130, p=0.011). Since the VTRNA2-1 promoter region was previously reported maternal imprinting extended to the adjacent centromeric CCCTC-binding factor site that contained an A/C polymorphism (rs2346018), which was associated with methylation density of VTRNA2-1, this A/C polymorphism was also integrated to analyze association with glycemic response to GLP-1 analog therapy. In patients with the A allele of rs2346018 and hypomethylation (<40%) on the VTRNA2-1 promoter, the OR increased to 4.048 (95% CI 1.438 to 11.389, p=0.007). CONCLUSIONS: The glycemic response to GLP-1 analog treatment is associated with the methylation status of the VTRNA2-1 promoter and polymorphism of rs2346018.