Charcot Foot: An Update on Diagnosis, Treatment, and Areas of Uncertainty.

BACKGROUND AND AIMS: Charcot neuroosteoarthropathy (CN) is considered a rare complication of diabetic neuropathy. Due to its insidious mode of presentation, CN may be difficult to diagnose timely and a high index of suspicion is required from both, the diabetic patient (especially those with neuropathy) and their physicians for the early diagnosis and treatment to prevent major complications. METHODS: We planned a narrative review and searched MEDLINE database to identify evidence regarding CN incidence, treatment options, and recent guidelines. As practitioners do not commonly treat CN, a characteristic clinical case is also presented. RESULTS: The available evidence for diagnosis and treatment remains of low quality. On the one hand, there is an urgent need for action to increase awareness of the disease in both practitioners and people with diabetes. On the other hand, prospective nationwide registries of patients with diabetic neuropathy will help clarify the prognostic factors that may predispose to this complication, and more randomized clinical trials are needed to identify whether medical treatment may improve CN outcomes. For the time being, offloading of the foot to stop the perpetuation of trauma, and inflammation, and importantly to arrest the progression to a deformed nonfunctional foot is the cornerstone of medical therapy of CN. Multidisciplinary assessment between diabetologists and radiologists is fundamental for prompt diagnosis. CONCLUSIONS: To avoid potentially deleterious delays in diagnosis and treatment, every physician should bear in mind that every patient with diabetic neuropathy presenting with a warm swollen foot should be treated as having CN until proven otherwise.

Rifampicin in the Treatment of Refractory Diabetic Foot Ulcer and Diabetic Foot Osteomyelitis-an Observational Study.

INTRODUCTION: Refractory diabetic foot ulcer (rDFU) and osteomyelitis (diabetic foot osteomyelitis [DFO]) are a major problem in people with diabetes. Often resulting from multidrug-resistant polymicrobial infection, these may result in amputation or nonhealing ulcers. In this nonrandomized open-label study, we looked at the outcome of treatment with rifampicin in patients with nonhealing diabetic foot ulcers. MATERIAL AND METHODS: Patients with DFUs (n = 67, n = 55 with DFO) unresponsive to conventional antimicrobial therapy for >3 months (rDFU) were taken as the study group. All patients received rifampicin for a minimum of 3 months (maximum 6 months if DUFs did not heal after 3 months) in addition to standard antibiotics and compared with similar kind of DFUs (n = 68, n = 55 DFO) who formed the control group, treated with conventional antimicrobial therapy. Patients were followed up for 12 months. Healing of DFU at 6 months and amputation were primary endpoints of the study. RESULTS: In total, 43 patients (64.2%) in the rifampicin group healed at 3 months and another 4 patients healed when rifampicin was continued for 6 months (n = 47, 70.1%). In the control group, 11 patients healed at 3 months (16.2%) and 25 patients healed at 6 months (36.8%). In total, 14 patients (20.9%) in the study group and 29 patients (42.6%) in the control group had to undergo minor amputation. Comparison between the rate of healing at 3 and 6 months and minor amputation between the study group and control group showed statistically significant results (P ≤ .00001, <.00001, and .008, respectively). In total, 6 and 8 patients despite healing of the primary ulcer had a subsequent recurrence of ulcer in the rifampicin and control group, respectively. CONCLUSION: Rifampicin used in conjunction with other standard poly-microbial therapy in refractory complex diabetic foot ulcer unresponsive to standard antimicrobial therapy, can significantly improve wound healing as well as decrease the need for amputation in addition to standard of care.

Hypoglycaemia following the 2-hour 75g OGTT in pregnancy - Investigating maternal and foetal outcomes.

AIMS: To investigate differences in maternal and foetal outcomes in pregnancy, where patients developed hypoglycaemia following the 2-hour 75g oral glucose tolerance test (OGTT). METHOD: A retrospective cohort study of 200 pregnancies attending the Antenatal Clinic at Tameside General Hospital between 2018 and 2022. Outcomes were compared between 4 groups: normal OGTT [G1; (n = 39, 20%), diagnosis of gestational diabetes mellitus (GDM) based on OGTT [G2; BG ≥ 5.6 mmol/L or 2-h OGTT ≥7.8 (n = 41, 21%)], hypoglycaemia [G3; 2 h OGTT 3.0-3.9 mmol/L (n = 93, 47%)], or clinically significant hypoglycaemia [G4; 2 h OGTT <3.0 mmol/L (n = 27, 14%)]. Maternal BMI, foetal birth weight (FBW), neonatal complications, neo-natal intensive care unit (NICU) stay and conversion to GDM were assessed. RESULTS: Maternal BMI was lower in G3 and G4 (27.3 kg/m2 and 28.1 kg/m2 respectively) compared to G1 (30.4 kg/m2) (p = 0.02). NICU stay was more frequent in G3 (12%, n = 11) and G4 (8%, n = 2) compared to G1 (5%, n = 2). Foetal complications occurred in 27% of G3 (n = 25) and 33% of G4 (n = 9) compared to 23% in G1 (n = 9) and 17% in G2 (n = 7). FBW was similar in G1 when compared to G3 and G4 (p = 0.34). Of the 120 patients in G3 and G4, 25 patients self-monitored blood glucose for two weeks; 28% (n = 7) subsequently developed GDM. CONCLUSION: Higher rates of NICU stay and foetal complications were seen in both hypoglycaemic groups. In patients with hypoglycaemia following OGTT there is evidence to support self-monitoring blood glucose as 28% were later diagnosed with GDM.

The Association of Vitamin D Receptor Polymorphisms with COVID-19 Severity.

BACKGROUND: Association studies of vitamin D receptor (VDR) polymorphisms with COVID-19 severity have produced inconsistent results in different populations. Herein we examined VDR gene polymorphisms in a Caucasian Greek cohort of COVID-19 patients. METHODS: This was a case-control study in a tertiary university hospital in Greece including 137 COVID-19 patients with varying disease severities and 72 healthy individuals. In total 209 individuals were genotyped for the FokI (rs10735810), ApaI (rs7975232), TaqI (rs731236) and BsmI (rs1544410) single-nucleotide polymorphisms (SNP) of the VDR gene by polymerase chain reaction and restriction fragment length polymorphism analysis (PCR-RFLPs). Statistical analyses were performed to determine the association between genotype and disease severity, adjusting for various confounding factors. RESULTS: Genotype distribution of the studied VDR SNPs in the control group was in Hardy-Weinberg equilibrium. The TaqI variant was differentially distributed between controls and COVID-19 patients according to the additive model (p = 0.009), and the CC genotype was significantly associated with an increased risk for severe COVID-19 according to the recessive model [OR: 2.52, 95%CI:1.2-5.29, p = 0.01]. Multivariate analysis demonstrated a robust association of COVID-19 severity and TaqI polymorphism in the recessive model even after adjusting for multiple confounders, including age, sex and CRP levels [Adj.OR:3.23, 95%CI:1.17-8.86, p = 0.023]. The distribution of FokI, ApaI and BsmI genotypes was similar between COVID-19 patients and controls. CONCLUSIONS: The CC genotype of TaqI polymorphism is significantly associated with an increased risk for severe COVID-19 independently of age, sex or degree of inflammation.

Advancing type 2 diabetes therapy with iGlarLixi in older people: Pooled analysis of four randomized controlled trials.

AIM: To assess the efficacy and safety of iGlarLixi in older people (≥65 years) with type 2 diabetes (T2D) advancing or switching from oral agents, a glucagon-like peptide-1 receptor agonist (GLP-1RA), or basal insulin. MATERIALS AND METHODS: The data of participants aged <65 years and ≥65 years from four LixiLan trials (LixiLan-O, LixiLan-G, LixiLan-L, SoliMix) were evaluated over 26 or 30 weeks. RESULTS: Participants aged <65/≥65 years (n = 1039/n = 497) had a mean baseline body mass index of 31.4 and 30.7 kg/m2 and glycated haemoglobin (HbA1c) concentration of 66 mmol/mol (8.2%) and 65 mmol/mol (8.1%), respectively. Least squares mean HbA1c change from baseline to end of treatment (EOT) was -14.32 mmol/mol (-1.31%) (95% confidence interval [CI] -14.97, -13.77 [-1.37%, -1.26%]) for those aged <65 years and -13.66 mmol/mol (-1.25%) (95% CI -14.54, -12.79 [-1.33%, -1.17%]) for those aged ≥65 years. At EOT, achievement of HbA1c targets was similar between the group aged <65 years and the group aged ≥65 years: <53 mmol/mol (<7%) (59.0% and 56.5%, respectively), <59 mmol/mol (<7.5%) (75.5% and 73.0%, respectively) and <64 mmol/mol (<8%) (83.8% and 84.1%, respectively). The incidence and event rate of American Diabetes Association Level 1 hypoglycaemia during the studies were also comparable between the two groups: 26.7% and 28.2% and 1.7 and 2.1 events per patient-year for the group aged <65 years and the group aged ≥65 years, respectively. A clinically relevant reduction in HbA1c (>1% from baseline for HbA1c ≥64 mmol/mol [≥8%] or ≥0.5% from baseline for HbA1c <64 mmol/mol [<8%]) without hypoglycaemia was attained by 50.0% and 47.6% of participants aged <65 years and ≥65 years, respectively. Adverse events were similar between the two age groups. CONCLUSIONS: iGlarLixi is a simple, well-tolerated, once-daily alternative for treatment advancement in older people with T2D that provides significant improvements in glycaemic control without increasing hypoglycaemia risk, thus reducing the treatment burden.

A paradigm shift for cardiovascular outcome evaluation in diabetes: Major adverse cardiovascular events (MACE) to major adverse vascular events (MAVE).

BACKGROUND AND AIMS: Drugs for diabetes are required to demonstrate cardiovascular safety through CV outcome trials (CVOT). The pre-defined end-points for cardiovascular outcome studies may not be sufficient to capture all clinically relevant atherosclerotic cardio vascular disease (ASCVD) events particularly peripheral arterial disease (PAD). METHODS: We planned a scoping review and searched database to identify CVOT conducted in population with diabetes measuring lower limb events due to PAD as the primary outcome measure. We also searched CVOT for reported differential cardiovascular outcomes in population with PAD. RESULTS: We identified that CV outcomes are measured as 3 point major adverse cardiovascular outcomes (3P-MACE) that includes nonfatal MI and nonfatal stroke or 4P-MACE that included additional unstable angina which is further expanded to 5P-MACE by the inclusion of hospitalization for heart failure (HHF). These CV end points are captured as surrogate for CV mortality based on the biological plausibility of relation between the surrogate and final outcome from pathophysiological studies. We found the prevalence of PAD is no lesser than other CV events in people with diabetes. Moreover, PAD contributes to the significant morbidity associated with diabetes as a surrogate for mortality. However, none of the CVOT with anti-diabetic drugs include PAD events as primary outcome measure despite the inclusion of 6-25 % participants with PAD in major CVOT. PAD outcomes are objectively measurable with tibial arterial waveforms and clinical end-point as lower extremity amputation. PAD outcomes do improve with treatment including intensive glycemic control and novel oral anticoagulants. We suggest the inclusion of PAD to MACE as a pre-specified outcome for a comprehensive capture of major adverse vascular event in future studies for people with diabetes. CONCLUSIONS: MACE should be expanded to include PAD event as major adverse vascular event in cardiovascular outcome studies since PAD is clinically relevant and objectively measurable in diabetes.

Cell Therapy of Severe Ischemia in People with Diabetic Foot Ulcers-Do We Have Enough Evidence?

This current opinion article critically evaluates the efficacy of autologous cell therapy (ACT) for chronic limb-threatening ischemia (CLTI), especially in people with diabetes who are not candidates for standard revascularization. This treatment approach has been used in 'no-option' CLTI in the last two decades and more than 1700 patients have received ACT worldwide. Here we analyze the level of published evidence of ACT as well as our experience with this treatment method. Many studies have shown that ACT is safe and an effective method for patients with the most severe lower limb ischemia. However, some trials did not show any benefit of ACT, and there is some heterogeneity in the types of injected cells, route of administration and assessed endpoints. Nevertheless, we believe that ACT plays an important role in a comprehensive treatment of patients with diabetic foot and severe ischemia.

Pedal acrometastasis secondary to urothelial carcinoma masquerading as Charcot arthropathy in a patient with diabetes.

A woman in her 80s with known diabetes mellitus and bladder cancer presented to her general practitioner (GP) with pain and swelling in her left foot following trauma. Initial radiographs were reported as normal, prompting a diagnosis of a simple sprain and conservative management. Three months later, the patient was referred to the orthopaedic team due to progressively increasing pain and swelling. Repeat X-rays revealed lytic lesions in both the talus and navicular bones; MRI confirmed the presence of a lytic and proliferative defect in the mid-foot, which was reported as acute Charcot arthropathy with superimposed infection. This was also considered the most likely diagnosis when imaging was reviewed in two separate multidisciplinary team) meetings. However, biopsy demonstrated that the cause of the presentation was in fact acrometastasis from urothelial carcinoma, an infrequently described entity.

Diabetes foot complications and standardized mortality rate in type 2 diabetes.

AIM: To quantify the impact of foot complications on mortality outcomes in people with type 2 diabetes (T2D), and how routinely measured factors might modulate that risk. MATERIALS AND METHODS: Data for individuals with T2D for 2010-2020, from the Salford Integrated Care Record (Salford, UK), were extracted for laboratory and clinical data, and deaths. Annual expected deaths were taken from Office of National Statistics mortality data. An index of multiple deprivation (IMD) adjusted the standardized mortality ratio (SMR_IMD). Life years lost per death (LYLD) was estimated from the difference between expected and actual deaths. RESULTS: A total of 11 806 T2D patients were included, with 5583 new diagnoses and 3921 deaths during 2010-2020. The number of expected deaths was 2135; after IMD adjustment, there were 2595 expected deaths. Therefore, excess deaths numbered 1326 (SMR_IMD 1.51). No foot complications were evident in n = 9857. This group had an SMR_IMD of 1.13 and 2.74 LYLD. In total, 2979 patients had any foot complication recorded. In this group, the SMD_IMR was 2.29; of these, 2555 (75%) had only one foot complication. Patients with a foot complication showed little difference in percentage HbA1c more than 58 mmol/mol. In multivariate analysis, for those with a foot complication and an albumin-to-creatinine ratio of more than 3 mg/mmol, the odds ratio (OR) for death was 1.93, and for an estimated glomerular filtration rate of less than 60 mL/min/1.73m2 , the OR for death was 1.92. CONCLUSIONS: Patients with T2D but without a foot complication have an SMR_IMD that is only slightly higher than that of the general population. Those diagnosed with a foot complication have a mortality risk that is double that of those without T2D.

Endothelial Dysfunction in Diabetes Mellitus: New Insights.

Endothelial dysfunction (ED) is an important marker of future atherosclerosis and cardiovascular disease, especially in people with diabetes. This article summarizes the evidence on endothelial dysfunction in people with diabetes and adds different perspectives that can affect the presence and severity of ED and its consequences. We highlight that data on ED in type 1 diabetes are lacking and discuss the relationship between ED and arterial stiffness. Several interesting studies have been published showing that ED modulates microRNA, microvesicles, lipid levels, and the endoplasmatic reticulum. A better understanding of ED could provide important insights into the microvascular complications of diabetes, their treatment, and even their prevention.

Euvolaemic hyponatraemia as a rare first presentation of chronic hypopituitarism.

A man in his late 40s with no significant medical history presented with 2 weeks of lethargy, nausea and dizziness, alongside worsening headaches. Initial assessment revealed severe hyponatraemia and secondary hypothyroidism; urgent MRI pituitary was requested with a clinical suspicion of pituitary apoplexy. This demonstrated a likely cystic pituitary adenoma, with further testing revealing pituitary gland suppression, leading to a diagnosis of chronic secondary hypopituitarism. Initiating hormone replacement allowed substantial reported improvements in this patient's quality of life.A review of the patient's work-up revealed areas in which best practice was not followed. Cortisol measurements and paired urinary and serum osmolalities were initially not sent, nor results appropriately chased. A subsequent literature review identified that conformation with national and local guidelines on hyponatraemia management is poor. This patient's case, when combined with the literature review, provides evidence to support methods to increase educational awareness of an appropriate work-up of hyponatraemia among clinicians.

Parathyroid carcinoma presenting as severe hypercalcaemia responding to steroids.

A man in his 50s was referred with profound, symptomatic hypercalcaemia. He was diagnosed with primary hyperparathyroidism, confirmed on 99mTc-sestamibi scan. He was treated for the hypercalcaemia and referred to ear, nose and throat (ENT) surgeons for parathyroidectomy, which was delayed due to the COVID-19 pandemic. In the ensuing 18 months, he had five hospital admissions with severe hypercalcaemia requiring intravenous fluids and bisphosphonate infusions. During the last admission, hypercalcaemia was resistant to maximal medical management. Emergency parathyroidectomy was planned, but delayed due to intervening COVID-19 infection. Due to persistent severe hypercalcaemia (serum calcium: 4.23 mmol/L), he was commenced on intravenous steroids, following which serum calcium normalised. Subsequently, he underwent emergency parathyroidectomy, which normalised his serum parathyroid and calcium levels. On histopathological examination, a diagnosis of parathyroid carcinoma was made. On follow-up, patient remained well and normocalcaemic. In patients with primary hyperparathyroidism unresponsive to standard therapy, but responsive to steroids, underlying parathyroid malignancy should be considered.

Inflammatory Arthritis Associated with COVID-19 Vaccination.

COVID-19 vaccines have been shown to be highly efficacious in preventing symptomatic COVID-19 infections throughout the pandemic. There have been emerging cases of inflammatory arthritis occurring in close relation to COVID-19 vaccination. We illustrate a case of new-onset inflammatory arthritis 10 days after receiving their second Vaxzevria COVID-19 vaccine. The patient responded dramatically to prednisolone treatment but subsequently required hydroxychloroquine due to persistent inflammatory joint symptoms. Inflammatory arthritis is an increasingly recognized rare adverse effect of COVID-19 vaccination and clinicians should actively consider this in patients with new or flares of inflammatory joint disease.

Spinal disinhibition: evidence for a hyperpathia phenotype in painful diabetic neuropathy.

The dominant sensory phenotype in patients with diabetic polyneuropathy and neuropathic pain is a loss of function. This raises questions as to which mechanisms underlie pain generation in the face of potentially reduced afferent input. One potential mechanism is spinal disinhibition, whereby a loss of spinal inhibition leads to increased ascending nociceptive drive due to amplification of, or a failure to suppress, incoming signals from the periphery. We aimed to explore whether a putative biomarker of spinal disinhibition, impaired rate-dependent depression of the Hoffmann reflex, is associated with a mechanistically appropriate and distinct pain phenotype in patients with painful diabetic neuropathy. In this cross-sectional study, 93 patients with diabetic neuropathy underwent testing of Hoffmann reflex rate-dependent depression and detailed clinical and sensory phenotyping, including quantitative sensory testing. Compared to neuropathic patients without pain, patients with painful diabetic neuropathy had impaired Hoffmann reflex rate-dependent depression at 1, 2 and 3 Hz (P ≤ 0.001). Patients with painful diabetic neuropathy exhibited an overall loss of function profile on quantitative sensory testing. However, within the painful diabetic neuropathy group, cluster analysis showed evidence of greater spinal disinhibition associated with greater mechanical pain sensitivity, relative heat hyperalgesia and higher ratings of spontaneous burning pain. These findings support spinal disinhibition as an important centrally mediated pain amplification mechanism in painful diabetic neuropathy. Furthermore, our analysis indicates an association between spinal disinhibition and a distinct phenotype, arguably akin to hyperpathia, with combined loss and relative gain of function leading to increasing nociceptive drive.

The Performance and Interrater Agreement of Vibration Perception for the Diagnosis of Loss of Protective Sensation in People With Diabetes Mellitus.

This study examined the performance of VibraTip for the diagnosis of loss of protective sensation (LOPS) and the interrater agreement of different neurological modalities performed by 3 health care professionals, a consultant diabetologist, a diabetes specialist nurse, and a podiatrist. Diagnosis of LOPS was based on 10-g Semmes Weinstein monofilament testing performed by a consultant diabetologist (reference method), while examination with a 128-Hz tuning form was also performed. The performance of VibraTip for the diagnosis of LOPS was examined using the receiver operating characteristic curves analysis. Interrater agreement was determined by weighted kappa (κ) statistics. Diagnosis of LOPS (%) was 37.5%. Receiver operating characteristic curve analysis showed that VibraTip examination versus 10-g monofilament, both performed by a consultant, could diagnose LOPS (P < .001). Sensitivity, specificity, positive predictive value, and negative predictive value of VibraTip versus 10-g monofilament, both performed by a consultant (value, 95% confidence interval), was 0.705 (0.591-0.803), 0.836 (0.758-0.897), 0.733 (0.642-0.808), and 0.816 (0.757-0.863), respectively. The interrater agreement among the health care professionals for 10-g monofilament, VibraTip, and 128-Hz tuning fork in neurological assessment was good with κ > 0.61. VibraTip can be used as a screening tool for the detection of LOPS. There was good overall agreement in the results of neurological examination using 10-g monofilament, 128-Hz tuning fork, and VibraTip among health care professionals.

Re-Epithelialization of Neuropathic Diabetic Foot Wounds with the Use of Cryopreserved Allografts of Human Epidermal Keratinocyte Cultures (Epifast).

The application of tissue-engineering technology to wound healing has become an option for the treatment of diabetic foot ulcers (DFU). A comparative, prospective study was conducted to assess the efficacy of a cryopreserved allograft of human epidermal keratinocytes (Epifast) to enhance wound healing in granulating DFU. Eighty patients were assigned to receive Epifast (n = 40) or Standard Care (SC) treatment (n = 40). The Epifast group displayed a shorter duration of the epithelialization phase (3.5 ± 4 vs. 6.4 ± 3.6 weeks, p < 0.05) and upon the entire wound healing process than the SC group (10 ± 5.7 vs. 14.5 ± 8.9 weeks, p < 0.05), reaching wound closure at 16 and 30 weeks, respectively. The Kaplan−Meier analysis revealed that Epifast group patients were 50% more likely than the SC to heal wounds faster (Cox-hazards ratio of 0.5, 95% CI = 0.3−0.8, p < 0.0001; Likelihood Ratio of 7.8. p < 0.05). Patients in the control group displayed a slower healing as the Saint Elian (SEWSS) severity grade increased (group differences of 0.6, 3.8, and 4.3 weeks for grades I, II, and III, respectively). DFW treated with Epifast displayed a shorter time to complete re-epithelialization than wounds treated with standard care.

Prevalence and risk factors of diabetic foot disease among the people with type 2 diabetes using real-world practice data from Catalonia during 2018.

Background: Our study aimed to assess the prevalence of diabetic foot disease (DFD) and its associated risk factors among subjects attending primary care centers in Catalonia (Spain). Methods: We undertook a cross-sectional analysis of data from the primary health care (SIDIAP) database. The presence of comorbidities and concomitant medication were analyzed for subjects with or without DFD. DFD prevalence was estimated from 1st January 2018 to 31st December 2018. Results: During the 12-month observational period, out of 394,266 people with type 2 diabetes, we identified 3,277 (0.83%) active episodes of DFD in the database. The majority of these episodes were foot ulcers (82%). The mean age of patients with DFD was 70.3 (± 12.5) years and 55% were male. In the multivariable descriptive models, male gender, diabetes duration, hypertension, macrovascular, microvascular complications, and insulin and antiplatelet agents were strongly associated with DFD. A previous history of DFD was the stronger risk factor for DFD occurrence in subjects with T2DM (OR: 13.19, 95%CI: 11.81; 14.72). Conclusions: In this real-world primary care practice database, we found a lower prevalence of DFD compared to similar previous studies. Risk factors such as male sex, duration of diabetes, diabetes complications and previous history of DFD were associated with the presence of DFD.

The Importance of PTH for Heart Failure. Comment on Thiele et al. The Role of Vitamin D3 as an Independent Predicting Marker for One-Year Mortality in Patients with Acute Heart Failure. J. Clin. Med. 2022, 11, 2733.

The communication by Thiele et al. reported that there were no significant differences in serum 25-hydroxyvitamin D (25(OH)D) for the 22 of 118 acute heart failure (HF) patients, 71% with de novo HF and 29% with chronic HF, who died within 12 months after admission to the intermediate care unit of a maximum care hospital in Germany compared to those who survived [...].

Comparison of the impact of autologous cell therapy and conservative standard treatment on tissue oxygen supply and course of the diabetic foot in patients with chronic limb-threatening ischemia: A randomized controlled trial.

Background: Autologous cell therapy (ACT) is a new treatment method for patients with diabetes and no-option chronic limb-threatening ischemia (NO-CLTI). We aimed to assess the impact of ACT on NO-CLTI in comparison with standard treatment (ST) in a randomized controlled trial. Methods: Diabetic patients with NO-CLTI were randomized to receive either ACT (n=21) or ST (n=19). After 12 weeks, those in the ST group, who did not improve were treated with ACT. The effect of ACT on ischemia and wound healing was assessed by changes in transcutaneous oxygen pressure (TcPO2) and the number of healed patients at 12 weeks. Pain was evaluated by Visual Analogue Scale (VAS). Amputation rates and amputation-free survival (AFS) were assessed in both groups. Results: During the first 12 weeks, TcPO2 increased in the ACT group from 20.8 ± 9.6 to 41.9 ± 18.3 mm Hg (p=0.005) whereas there was no change in the ST group (from 21.2 ± 11.4 to 23.9 ± 13.5 mm Hg). Difference in TcPO2 in the ACT group compared to ST group was 21.1 mm Hg (p=0.034) after 12 weeks. In the period from week 12 to week 24, when ST group received ACT, the TcPO2 in this group increased from 20.1 ± 13.9 to 41.9 ± 14.8 (p=0.005) while it did not change significantly in the ACT in this period. At 24 weeks, there was no significant difference in mean TcPO2 between the two groups. Wound healing was greater at 12 weeks in the ACT group compared to the ST group (5/16 vs. 0/13, p=0.048). Pain measured using VAS was reduced in the ACT group after 12 weeks compared to the baseline, and the difference in scores was again significant (p<0.001), but not in the ST group. There was no difference in rates of major amputation and AFS between ACT and ST groups at 12 weeks. Conclusions: This study has showed that ACT treatment in patients with no-option CLTI and diabetic foot significantly improved limb ischemia and wound healing after 12 weeks compared to conservative standard therapy. Larger randomized controlled trials are needed to study the benefits of ACT in patients with NO-CLTI and diabetic foot disease. Trial registration: The trial was registered in the National Board of Health (EudraCT 2016-001397-15).

Comparison of amitriptyline supplemented with pregabalin, pregabalin supplemented with amitriptyline, and duloxetine supplemented with pregabalin for the treatment of diabetic peripheral neuropathic pain (OPTION-DM): a multicentre, double-blind, randomised crossover trial.

BACKGROUND: Diabetic peripheral neuropathic pain (DPNP) is common and often distressing. Most guidelines recommend amitriptyline, duloxetine, pregabalin, or gabapentin as initial analgesic treatment for DPNP, but there is little comparative evidence on which one is best or whether they should be combined. We aimed to assess the efficacy and tolerability of different combinations of first-line drugs for treatment of DPNP. METHODS: OPTION-DM was a multicentre, randomised, double-blind, crossover trial in patients with DPNP with mean daily pain numerical rating scale (NRS) of 4 or higher (scale is 0-10) from 13 UK centres. Participants were randomly assigned (1:1:1:1:1:1), with a predetermined randomisation schedule stratified by site using permuted blocks of size six or 12, to receive one of six ordered sequences of the three treatment pathways: amitriptyline supplemented with pregabalin (A-P), pregabalin supplemented with amitriptyline (P-A), and duloxetine supplemented with pregabalin (D-P), each pathway lasting 16 weeks. Monotherapy was given for 6 weeks and was supplemented with the combination medication if there was suboptimal pain relief (NRS >3), reflecting current clinical practice. Both treatments were titrated towards maximum tolerated dose (75 mg per day for amitriptyline, 120 mg per day for duloxetine, and 600 mg per day for pregabalin). The primary outcome was the difference in 7-day average daily pain during the final week of each pathway. This trial is registered with ISRCTN, ISRCTN17545443. FINDINGS: Between Nov 14, 2017, and July 29, 2019, 252 patients were screened, 140 patients were randomly assigned, and 130 started a treatment pathway (with 84 completing at least two pathways) and were analysed for the primary outcome. The 7-day average NRS scores at week 16 decreased from a mean 6·6 (SD 1·5) at baseline to 3·3 (1·8) at week 16 in all three pathways. The mean difference was -0·1 (98·3% CI -0·5 to 0·3) for D-P versus A-P, -0·1 (-0·5 to 0·3) for P-A versus A-P, and 0·0 (-0·4 to 0·4) for P-A versus D-P, and thus not significant. Mean NRS reduction in patients on combination therapy was greater than in those who remained on monotherapy (1·0 [SD 1·3] vs 0·2 [1·5]). Adverse events were predictable for the monotherapies: we observed a significant increase in dizziness in the P-A pathway, nausea in the D-P pathway, and dry mouth in the A-P pathway. INTERPRETATION: To our knowledge, this was the largest and longest ever, head-to-head, crossover neuropathic pain trial. We showed that all three treatment pathways and monotherapies had similar analgesic efficacy. Combination treatment was well tolerated and led to improved pain relief in patients with suboptimal pain control with a monotherapy. FUNDING: National Institute for Health Research (NIHR) Health Technology Assessment programme.