PROGNOSTIC IMPLICATIONS OF DIABETIC KETOACIDOSIS ON LONG-TERM MORTALITY AND DIABETES-RELATED COMPLICATIONS.

BACKGROUND: Diabetic ketoacidosis (DKA) occurring after diabetes diagnosis is often associated with risk factors for other diabetes-related complications. We aimed to determine the prognostic implications of DKA on all-cause mortality and complications in type 1 diabetes (T1D). METHODS: Previously collected data from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study was obtained through the NIDDK central repository. Using Cox proportional-hazards models with time-dependent covariates, we examined age- and sex-, HbA1c-, and fully-adjusted associations of DKA with all-cause mortality, cardiovascular disease, microvascular, and acute complications over 34 years. FINDINGS: Of 1441 participants, 297 had 488 DKA events. Prior DKA was associated with a higher risk of age- and sex-adjusted all-cause mortality (hazard ratio (HR) 8.28, 95% confidence interval (CI) 3.74-18.32, p<0.001), major adverse cardiovascular events (MACE) (HR 2.05, 95%CI 1.34-3.13, p<0.001), and all advanced microvascular and acute complications compared to no prior DKA. Most associations except retinopathy were significant even after adjustment for covariates. In our fully-adjusted analysis, prior DKA was associated with a significantly higher risk of subsequent all-cause mortality (HR 9.13, 95%CI 3.87-21.50; p<0.001), MACE (HR 1.66, 95%CI 1.07-2.59; p=0.03), advanced kidney disease (HR 2.10, 95%CI 1.00-4.22; p=0.049), advanced neuropathy (HR 1.49, 95%CI 1.05 to 2.13; p=0.03), severe hypoglycemia (HR 1.53, 95%CI 1.28-1.81; p<0.001) and recurrent DKA (HR 3.24, 95%CI 2.41-4.36, p<0.001) compared to person-time without DKA. INTEPRETATION: DKA is a prognostic marker for diabetes complications, including excess all-cause mortality. Intensified clinical interventions such as cardiovascular prevention strategies may be warranted following the diagnosis of DKA.

Effect of hyperglycemia and empagliflozin on markers of cardiorenal injury and inflammation in patients with type 1 diabetes.

AIMS: To investigate the effect of hyperglycemia and empagliflozin on cardiorenal injury and inflammation in patients with uncomplicated type 1 diabetes (T1D). METHODS: Serum cardiac (sST2, Gal-3, cTnT), kidney injury (KIM-1, NGAL), inflammatory (sTNFR1, sTNFR2), and hemodynamic (NT-proBNP, EPO) markers were assessed post-hoc in two separate T1D cohorts. The glycemic clamp trial (NCT02344602) evaluated 49 adults with T1D and 27 controls under euglycemic and acute hyperglycemic conditions. The crossover BETWEEN trial (NCT02632747) investigated empagliflozin 25 mg plus ramipril for 4 weeks compared to placebo-ramipril for 4 weeks in 30 adults with T1D. RESULTS: In the glycemic clamp study, hyperglycemia acutely increased levels of NT-proBNP (p = 0.0003) and sTNFR2 (p = 0.003). BETWEEN participants treated with empagliflozin exhibited a paradoxical subacute rise in NT-proBNP (p = 0.0147) compared to placebo, independent of hematocrit. Individuals with higher baseline levels of sST2 and sTNFR1 had greater empagliflozin-associated reductions in systolic blood pressure and greater activation of renin-angiotensin-aldosterone system (RAAS) mediators, whereas those with higher baseline levels of KIM-1 and sTNFR1 had greater glomerular filtration rate (GFR) dip. CONCLUSION: The protective mechanisms of SGLT2 inhibition on blood pressure, RAAS activation, and renal hemodynamics are apparent in the subset of people with uncomplicated T1D with adverse cardiorenal and inflammatory markers.

The utility of remote cognitive screening tools in identifying cognitive impairment in older surgical patients: An observational cohort study.

STUDY OBJECTIVES: To determine the prevalence of suspected cognitive impairment using the Centers for Disease Control and Prevention (CDC) cognitive question, Ascertain Dementia Eight-item Questionnaire (AD8), Modified Telephone Interview for Cognitive Status (TICS-M), and Telephone Montreal Cognitive Assessment (T-MoCA), the agreement between each tool beyond chance, and the risk factors associated with a positive screen. DESIGN: Multicenter prospective study. SETTING: Remote preoperative assessments. PATIENTS: 307 non-cardiac surgical patients aged ≥65 years. MEASUREMENTS: Prevalence, Cohen's kappa (κ). MAIN RESULTS: The T-MoCA detected the highest prevalence of suspected cognitive impairment (28%), followed by the AD8 (17%), CDC cognitive question (9%), and TICS-M (6%). The four screening tools showed poor agreement beyond chance with one another, with the CDC cognitive question and AD8 approaching the threshold for weak agreement (κ = 0.39). Depression was associated with screening positive on the CDC cognitive question (OR: 2.81; 95% CI: 1.04, 7.68). Obstructive sleep apnea (OSA) (OR: 3.10; 95% CI: 1.26, 7.71) and functional disability (OR: 3.74; 95% CI: 1.34, 11.11) were associated with a positive AD8 screen. Older age (OR: 1.56; 95% CI: 1.01, 2.41), male sex (OR: 3.08; 95% CI: 1.09, 9.40), and higher pain level (OR: 1.21; 95% CI: 1.01, 1.47) were associated with a positive TICS-M screen. Similarly, older age (OR: 1.33; 95% CI: 1.03, 1.73), male sex (OR: 2.02; 95% CI: 1.09, 3.83), and higher pain level (OR: 1.15; 95% CI: 1.02, 1.30) were associated with a positive T-MoCA screen. CONCLUSIONS: The CDC cognitive question, AD8, TICS-M, and T-MoCA were easily implemented during preoperative assessment among older surgical patients. OSA, functional disability, and depression were associated with complaints on the CDC cognitive question and AD8. Older age, male sex, and higher pain level were associated with screening positive on the TICS-M and T-MoCA. Early remote cognitive screening may enhance risk stratification of vulnerable patients.

Declining Levels of Neutralizing Antibodies to SARS-CoV-2 Omicron Variants Are Enhanced by Hybrid Immunity and Original/Omicron Bivalent Vaccination.

We determined neutralizing antibody levels to the ancestral Wuhan SARS-CoV-2 strain and three Omicron variants, namely BA.5, XBB.1.5, and EG.5, in a heavily vaccinated cohort of 178 adults 15-19 months after the initial vaccine series and prospectively after 4 months. Although all participants had detectable neutralizing antibodies to Wuhan, the proportion with detectable neutralizing antibodies to the Omicron variants was decreased, and the levels were lower. Individuals with hybrid immunity at the baseline visit and those receiving the Original/Omicron bivalent vaccine between the two sampling times demonstrated increased neutralizing antibodies to all strains. Both a higher baseline neutralizing antibody titer to Omicron BA.5 and hybrid immunity were associated with protection against a breakthrough SARS-CoV-2 infection during a 4-month period of follow up during the Omicron BA.5 wave. Neither were associated with protection from a breakthrough infection at 10 months follow up. Receipt of an Original/Omicron BA.4/5 vaccine was associated with protection from a breakthrough infection at both 4 and 10 months follow up. This work demonstrates neutralizing antibody escape with the emerging Omicron variants and supports the use of additional vaccine doses with components that match circulating SARS-CoV-2 variants. A threshold value for neutralizing antibodies for protection against reinfection cannot be determined.

Fasted C-Peptide Distribution and Associated Clinical Factors in Adults With Longstanding Type 1 Diabetes: Analysis of the Canadian Study of Longevity in Type 1 Diabetes.

OBJECTIVE: Although insulin production is reportedly retained in many people with longstanding type 1 diabetes (T1D), the magnitude and relevance of connecting peptide (C-peptide) production are uncertain. In this study, we aimed to define fasted C-peptide distributions and associated clinical factors. METHODS: In a cross-sectional analysis of the Canadian Study of Longevity, fasted serum and urinary C-peptide was measured in 74 patients with longstanding T1D (duration ≥50 years) and 75 age- and sex-matched controls. Extensive phenotyping for complications was performed and patient-reported variables were included. C-peptide distributions were analyzed, and multivariable logistic regression was used to assess the variable association in participants with T1D. RESULTS: The 74 participants with T1D had a mean age of 66±8 years, a disease duration of 54 (interquartile range 52 to 58) years, and a glycated hemoglobin (A1C) of 7.4%±0.8% (56.8±9.15 mmol/mol). The 75 controls had a mean age of 65±8 years and an A1C of 5.7%±0.4% (38.4±4.05 mmol/mol). Participants with T1D had lower fasted serum C-peptide than controls (0.013±0.022 vs 1.595±1.099 nmol/L, p<0.001). Of the participants with T1D, C-peptide was detectable in 30 of 73 (41%) serum samples, 32 of 74 (43%) urine samples, and 48 of 74 (65%) for either serum or urine. The variables independently associated with detectable serum or urinary C-peptide were lower total daily insulin requirement (odds ratio 2.351 [for 1 lower unit/kg], p=0.013) and lower hypoglycemia worry score (odds ratio 1.059 [for 1 point lower on the worry subscore of the Hypoglycemia Fear Survey], p=0.030). CONCLUSIONS: Although detectable C-peptide in longstanding diabetes was common, the magnitude of concentration was extremely low when compared with age- and sex-matched controls. Despite minimal detectability, its presence is validated by lower insulin requirements and strongly associated with lower hypoglycemia worry.

Interactive Effects of Empagliflozin and Hyperglycemia on Urinary Amino Acids in Individuals With Type 1 Diabetes.

Optimizing energy use in the kidney is critical for normal kidney function. Here, we investigate the effect of hyperglycemia and sodium-glucose cotransporter 2 (SGLT2) inhibition on urinary amino acid excretion in individuals with type 1 diabetes (T1D). The open-label ATIRMA trial assessed the impact of 8 weeks of 25 mg empagliflozin orally once per day in 40 normotensive normoalbuminuric young adults with T1D. A consecutive 2-day assessment of clamped euglycemia and hyperglycemia was evaluated at baseline and posttreatment visits. Principal component analysis was performed on urinary amino acids grouped into representative metabolic pathways using MetaboAnalyst. At baseline, acute hyperglycemia was associated with changes in 25 of the 33 urinary amino acids or their metabolites. The most significant amino acid metabolites affected by acute hyperglycemia were 3-hydroxykynurenine, serotonin, glycyl-histidine, and nicotinic acid. The changes in amino acid metabolites were reflected by the induction of four biosynthetic pathways: aminoacyl-tRNA; valine, leucine, and isoleucine; arginine; and phenylalanine, tyrosine, and tryptophan. In acute hyperglycemia, empagliflozin significantly attenuated the increases in aminoacyl-tRNA biosynthesis and valine, leucine, and isoleucine biosynthesis. Our findings using amino acid metabolomics indicate that hyperglycemia stimulates biosynthetic pathways in T1D. SGLT2 inhibition may attenuate the increase in biosynthetic pathways to optimize kidney energy metabolism.

Modeling multiple correlated end-organ disease trajectories: A tutorial for multistate and joint models with applications in diabetes complications.

State-of-the-art biostatistics methods allow for the simultaneous modeling of several correlated non-fatal disease processes over time, but there is no clear guidance on the optimal analysis in most settings. An example occurs in diabetes, where it is not known with certainty how microvascular complications of the eyes, kidneys, and nerves co-develop over time. In this article, we propose and contrast two general model frameworks for studying complications (sequential state and parallel trajectory frameworks) and review multivariate methods for their analysis, focusing on multistate and joint modeling. We illustrate these methods in a tutorial format using the long-term follow-up from the Diabetes Control and Complications Trial and Epidemiology of Diabetes Interventions and Complications study public data repository. A formal comparison of prediction error and discrimination is included. Multistate models are particularly advantageous for determining the order and timing of complications, but require discretization of the longitudinal outcomes and possibly a very complex state space process. Intermittent observation of the states must be accounted for, and discretization is a probable disadvantage in this setting. In contrast, joint models can account for variations of continuous biomarkers over time and are particularly designed for modeling complex association structures between the complications and for performing dynamic predictions of an outcome of interest to inform clinical decisions (eg, a late-stage complication). We found that both models have helpful features that can better-inform our understanding of the complex trajectories that complications may take and can therefore help with decision making for patients presenting with diabetes complications.

Point-of-Care Capillary Blood Ketone Measurements and the Prediction of Future Ketoacidosis Risk in Type 1 Diabetes.

OBJECTIVE: Rather than during illness while diabetic ketoacidosis (DKA) is developing, we aimed to determine if levels of routine point-of-care capillary blood ketones could predict future DKA. RESEARCH DESIGN AND METHODS: We examined previously collected data from placebo-assigned participants in an adjunct-to-insulin medication trial program that included measurement of fasted capillary blood ketone levels twice per week in a 2-month baseline period. The outcome was 6- to 12-month trial-adjudicated DKA. RESULTS: DKA events occurred in 12 of 484 participants at a median of 105 (interquartile range 43, 199) days. Maximum ketone levels were higher in patient cases compared with in control patients (0.8 [0.6, 1.2] vs. 0.3 [0.2, 0.7] mmol/L; P = 0.002), with a nonparametric area under the receiver operating characteristic curve of 0.77 (95% CI 0.66-0.88). Ketone levels ≥0.8 mmol/L had a sensitivity of 64%, a specificity of 78%, and positive and negative likelihood ratios of 2.9 and 0.5, respectively. CONCLUSIONS: This proof of concept that routine capillary ketone surveillance can identify individuals at high risk of future DKA implies a role for future technologies including continuous ketone monitoring.

Systematic Comparison of Muscle Ultrasound Thickness in Polyneuropathies and Other Neuromuscular Diseases.

BACKGROUND: We have aimed to assess whether muscle thickness ultrasound (US) shows differences between patients with chronic inflammatory demyelinating polyneuropathy (CIDP), chronic axonal polyneuropathy (CAP), and other neuromuscular (NM) diseases compared to controls and to each other. METHODS: We performed a cross-sectional study from September 2021 to June 2022. All subjects underwent quantitative sonographic evaluation of muscle thickness in eight relaxed muscles and four contracted muscles. Differences were assessed using multivariable linear regression, correcting for age and body mass index (BMI). RESULTS: The study cohort consisted of 65 healthy controls, and 95 patients: 31 with CIDP, 34 with CAP, and 30 with other NM diseases. Both relaxed and contracted muscle thickness in all patient groups were lower than in the healthy controls, after controlling for age and body mass index (BMI). Regression confirmed that the differences persisted between patient groups and healthy controls. Differences between patient groups were not apparent. CONCLUSION: The current study shows that muscle ultrasound thickness is not specific in NM disorders, but shows a global reduction in thickness compared with healthy controls after corrections for age and BMI.

Decentralized study of COVID Vaccine Antibody Response (STOPCoV): Results of a participant satisfaction survey.

The Covid-19 pandemic required many clinical trials to adopt a decentralized framework to continue research activities during lock down restrictions. The STOPCoV study was designed to assess the safety and efficacy of Covid-19 vaccines in those aged 70 and above compared to those aged 30-50 years of age. In this sub-study we aimed to determine participant satisfaction for the decentralized processes, accessing the study website and collecting and submitting study specimens. The satisfaction survey was based on a Likert scale developed by a team of three investigators. Overall, there were 42 questions for respondents to answer. The invitation to participate with a link to the survey was emailed to 1253 active participants near the mid-way point of the main STOPCoV trial (April 2022). The results were collated and answers were compared between the two age cohorts. Overall, 70% (83% older, 54% younger cohort, no difference by sex) responded to the survey. The overall feedback was positive with over 90% of respondents answering that the website was easy to use. Despite the age gap, both the older cohort and younger cohort reported ease of performing study activities through a personal electronic device. Only 30% of the participants had previously participated in a clinical trial, however over 90% agreed that they would be willing to participate in future clinical research. Some difficulties were noted in refreshing the browser whenever updates to the website were made. The feedback attained will be used to improve current processes and procedures of the STOPCoV trial as well as share learning experiences to inform future fully decentralized research studies.

Associations Among Biomarkers of Inflammation, Tubular Injury and Lipid Metabolism With Gestational Diabetes Mellitus Status, Microalbuminuria and Retinopathy in the Microalbuminuria and Retinopathy in Gestational Diabetes Study.

OBJECTIVES: Pregnancy may be complicated by gestational diabetes mellitus (GDM) and/or microvascular complications like albuminuria, retinopathy and pre-eclampsia. In this study we aimed to identify whether mechanistic pathways associated with microvascular complications are active in pregnant women with GDM or microvascular disease. METHODS: Urinary albumin excretion and biomarkers of inflammation, lipoprotein metabolism and tubular injury were quantified in 355 pregnant women with and without GDM. Participants underwent fundus photography graded for retinopathy. Adjusted associations between individual biomarkers and each outcome variable of interest, including GDM status, albuminuria and retinopathy, were performed using logistic regression. RESULTS: After adjusting for age, systolic blood pressure, body mass index and ethnicity, significant associations between GDM status and apolipoprotein A1, interleukin (IL)-6, IL-8, soluble tumour necrosis factor receptor-I and -II (sTNFR-I and -II), vascular endothelial growth factor and von Willebrand factor were observed. Increased high-sensitivity C-reactive protein (hsCRP) and sTNFR-II were associated with higher levels of albuminuria. hsCRP and previous GDM were associated with retinopathy. CONCLUSION: Mechanistic pathways associated with microvascular complications appear to be active in pregnant women with GDM or microvascular disease.

Predictors of Breakthrough SARS-CoV-2 Infection after Vaccination.

The initial two-dose vaccine series and subsequent booster vaccine doses have been effective in modulating SARS-CoV-2 disease severity and death but do not completely prevent infection. The correlates of infection despite vaccination continue to be under investigation. In this prospective decentralized study (n = 1286) comparing antibody responses in an older- (≥70 years) to a younger-aged cohort (aged 30-50 years), we explored the correlates of breakthrough infection in 983 eligible subjects. Participants self-reported data on initial vaccine series, subsequent booster doses and COVID-19 infections in an online portal and provided self-collected dried blood spots for antibody testing by ELISA. Multivariable survival analysis explored the correlates of breakthrough infection. An association between higher antibody levels and protection from breakthrough infection observed during the Delta and Omicron BA.1/2 waves of infection no longer existed during the Omicron BA.4/5 wave. The older-aged cohort was less likely to have a breakthrough infection at all time-points. Receipt of an original/Omicron vaccine and the presence of hybrid immunity were associated with protection of infection during the later Omicron BA.4/5 and XBB waves. We were unable to determine a threshold antibody to define protection from infection or to guide vaccine booster schedules.

Renal hemodynamic dysfunction and neuropathy in longstanding type 1 diabetes: Results from the Canadian study of longevity in type 1 diabetes.

AIMS: To determine the relationship between renal hemodynamic function and neuropathy in adults with ≥50-years of type 1 diabetes (T1D) compared to nondiabetic controls. METHODS: Glomerular filtration rate (GFR, inulin), effective renal plasma flow (ERPF, p-aminohippurate), modified Toronto Clinical Neuropathy Score (mTCNS), corneal confocal microscopy, nerve conduction, and heart rate variability (autonomic function) were measured; afferent (RA) and efferent (RE) arteriolar resistances were estimated using the Gomez equations in 74 participants with T1D and in 75 controls. Diabetic kidney disease (DKD) non-resistors were defined by eGFRMDRD < 60 ml/min/1.73 m2 or 24-h urine albumin excretion >30 mg/day. Linear regression was applied to examine the relationships between renal function (dependent variable) and neuropathy measures (independent variable), adjusted for age, sex, HbA1c, systolic blood pressure, low density lipoprotein cholesterol, and 24-h urine albumin to creatinine ratio. RESULTS: Higher mTCNS associated with lower renal blood flow (ß ± SE:-9.29 ± 4.20, p = 0.03) and greater RE (ß ± SE:32.97 ± 15.43, p = 0.04) in participants with T1D, but not in controls. DKD non-resistors had a higher mTCNS and worse measures of corneal nerve morphology compared to those without DKD. Renal hemodynamic parameters did not associate with autonomic nerve function. CONCLUSIONS: Although neurological dysfunction in the presence of diabetes may contribute to impaired renal blood flow resulting in ischemic injury in patients with T1D, early autonomic dysfunction does not appear to be associated with kidney function changes.

Supporting the Heterogeneous and Evolving Treatment Preferences of Patients With Heart Failure Through Collaborative Home-Based Palliative Care.

Background We characterized the treatment preferences, care setting, and end-of-life outcomes among patients with advanced heart failure supported by a collaborative home-based model of palliative care. Methods and results This decedent cohort study included 250 patients with advanced heart failure who received collaborative home-based palliative care for a median duration of 1.9 months of follow-up in Ontario, Canada, from April 2013 to July 2019. Patients were categorized into 1 of 4 groups according to their initial treatment preferences. Outcomes included location of death (out of hospital versus in hospital), changes in treatment preferences, and health service use. Among patients who initially prioritized quantity of life, 21 of 43 (48.8%) changed their treatment preferences during follow-up (mean 0.28 changes per month). The majority of these patients changed their preferences to avoid hospitalization and focus on comfort at home (19 of 24 changes, 79%). A total of 207 of 250 (82.8%) patients experienced an out-of-hospital death. Patients who initially prioritized quantity of life had decreased odds of out-of-hospital death (versus in-hospital death; adjusted odds ratio, 0.259 [95% CI, 0.097-0.693]) and more frequent hospitalizations (mean 0.45 hospitalizations per person-month) compared with patients who initially prioritized quality of life at home. Conclusions Our results yield a more detailed understanding of the interaction of advanced care planning and patient preferences. Shared decision making for personalized treatment is dynamic and can be enacted earlier than at the very end of life.

Empagliflozin add-on therapy to closed-loop insulin delivery in type 1 diabetes: a 2 × 2 factorial randomized crossover trial.

There is a need to optimize closed-loop automated insulin delivery in type 1 diabetes. We assessed the glycemic efficacy and safety of empagliflozin 25 mg d-1 as add-on therapy to insulin delivery with a closed-loop system. We performed a 2 × 2 factorial randomized, placebo-controlled, crossover two-center trial in adults, assessing 4 weeks of closed-loop delivery versus sensor-augmented pump (SAP) therapy and empagliflozin versus placebo. The primary outcome was time spent in the glucose target range (3.9-10.0 mmol l-1). Primary comparisons were empagliflozin versus placebo in each of closed-loop or SAP therapy; the remaining comparisons were conditional on its significance. Twenty-four of 27 randomized participants were included in the final analysis. Compared to placebo, empagliflozin improved time in target range with closed-loop therapy by 7.2% and in SAP therapy by 11.4%. Closed-loop therapy plus empagliflozin improved time in target range compared to SAP therapy plus empagliflozin by 6.1% but by 17.5% for the combination of closed-loop therapy and empagliflozin compared to SAP therapy plus placebo. While no diabetic ketoacidosis or severe hypoglycemia occurred during any intervention, uncomplicated ketosis events were more common on empagliflozin. Empagliflozin 25 mg d-1 added to automated insulin delivery improves glycemic control but increases ketone concentration and ketosis compared to placebo.

Orthostatic blood pressure changes and diabetes duration.

To determine the prevalence and the associated clinical characteristics of orthostatic hypotension and orthostatic hypertension in patients with diabetic sensorimotor polyneuropathy (DSP). METHODS: A single-center retrospective cross-sectional study was conducted on 200 DSP patients who had 3-minute orthostatic measures as part of the standard clinic evaluation. We measured the heart rate (HR) and blood pressure (BP) supine and again after 3 min of standing. RESULTS: The prevalence of orthostatic hypotension was 19.5% and that of orthostatic hypertension was 23%. Subjects with orthostatic hypotension had significantly longer diabetes duration than subjects who were normotensive and those with orthostatic hypertension. Quantitatively, BP changes from supine to standing correlated with diabetes duration (R = 0.306; P = 0.0582) and age (R = 0.434; P = 0.006) in subjects with orthostatic hypotension. CONCLUSIONS: Orthostatic hypertension and orthostatic hypotension are frequent in patients with DSP. Orthostatic hypertension is associated with shorter diabetes duration than orthostatic hypotension.

Markers of Kidney Injury, Inflammation, and Fibrosis Associated With Ertugliflozin in Patients With CKD and Diabetes.

INTRODUCTION: Sodium-glucose cotransporter-2 (SGLT2) inhibitors improve cardiovascular and kidney outcomes through mechanisms that are incompletely understood. In this exploratory post-hoc analysis of the VERTIS RENAL trial, we report the association between the SGLT2 inhibitor, ertugliflozin, and markers of kidney injury, inflammation, and fibrosis in participants with type 2 diabetes (T2D) and stage 3 chronic kidney disease (CKD). METHODS: Participants were randomized to ertugliflozin (5 or 15 mg/d) or placebo, and plasma samples for biomarker analysis were collected at baseline, 26 weeks, and 52 weeks. RESULTS: Ertugliflozin-treated participants had lower plasma levels of kidney injury molecule-1 (KIM-1) at 26 weeks (P = 0.044) and 52 weeks (P = 0.007) and higher eotaxin-1 at 52 weeks (P = 0.007) postrandomization compared with placebo. The change in KIM-1 was not associated with the baseline urine albumin to creatinine ratio (UACR) or the estimated glomerular filtration rate (eGFR, P interaction > 0.05). Additionally, the change in KIM-1 was positively correlated with the change in UACR in participants treated with ertugliflozin (P = 0.0071). No other significant associations between ertugliflozin and changes in the markers of tubular injury, inflammation, fibrosis, oxidative stress, and endothelial dysfunction were observed. CONCLUSION: In conclusion, in participants with T2D and stage 3 CKD, ertugliflozin was associated with a sustained lowering of the tubular injury marker KIM-1 regardless of baseline kidney function.

Clinical profile and impact of comorbidities in patients with very-late-onset myasthenia gravis.

INTRODUCTION/AIMS: The purpose of this study was to evaluate the clinical profile of myasthenia gravis (MG) in older patients and determine the impact of medical comorbidities on their MG status and outcome. METHODS: This was a retrospective chart review of patients with a symptom onset of MG at or after 65 years of age. Correlations were made between demographics, clinical characteristics, the Myasthenia Gravis Foundation of America (MGFA) severity scale scores, and Myasthenia Gravis Impairment Index (MGII) scores with two outcome measures: MGFA Post-Intervention Status (MGFA-PIS) and Simple Single Question (SSQ). RESULTS: The study population included 109 patients, with 90 of them having more than one follow-up visit. Their mean age was 75.3 ± 6.9 years and sex distribution was even. Of these patients, 67.7% had generalized MG. Nine-one percent of patients had one comorbidity. None of the demographic factors or comorbidities showed an association with MGFA-PIS, SSQ, or MGII after correction for multiple comparisons. Seventy-one percent of the patients improved with treatment, 12.4% remained unchanged, and 16.6% showed worsening at their last follow-up visit. DISCUSSION: Our study shows that patients with very-late-onset MG had a good prognosis and treatment response. None of the comorbidities had an impact on the severity of myasthenic symptoms or on outcome in these patients.

Corneal Confocal Microscopy Predicts the Development of Diabetic Neuropathy: A Longitudinal Diagnostic Multinational Consortium Study.

OBJECTIVE: Corneal nerve fiber length (CNFL) has been shown in research studies to identify diabetic peripheral neuropathy (DPN). In this longitudinal diagnostic study, we assessed the ability of CNFL to predict the development of DPN. RESEARCH DESIGN AND METHODS: From a multinational cohort of 998 participants with type 1 and type 2 diabetes, we studied the subset of 261 participants who were free of DPN at baseline and completed at least 4 years of follow-up for incident DPN. The predictive validity of CNFL for the development of DPN was determined using time-dependent receiver operating characteristic (ROC) curves. RESULTS: A total of 203 participants had type 1 and 58 had type 2 diabetes. Mean follow-up time was 5.8 years (interquartile range 4.2-7.0). New-onset DPN occurred in 60 participants (23%; 4.29 events per 100 person-years). Participants who developed DPN were older and had a higher prevalence of type 2 diabetes, higher BMI, and longer duration of diabetes. The baseline electrophysiology and corneal confocal microscopy parameters were in the normal range but were all significantly lower in participants who developed DPN. The time-dependent area under the ROC curve for CNFL ranged between 0.61 and 0.69 for years 1-5 and was 0.80 at year 6. The optimal diagnostic threshold for a baseline CNFL of 14.1 mm/mm2 was associated with 67% sensitivity, 71% specificity, and a hazard ratio of 2.95 (95% CI 1.70-5.11; P < 0.001) for new-onset DPN. CONCLUSIONS: CNFL showed good predictive validity for identifying patients at higher risk of developing DPN ∼6 years in the future.

Changes in plasma and urine metabolites associated with empagliflozin in patients with type 1 diabetes.

AIM: To examine the impact of the sodium-glucose co-transporter-2 inhibitor, empagliflozin, on plasma and urine metabolites in participants with type 1 diabetes. MATERIAL AND METHODS: Participants (n = 40, 50% male, mean age 24.3 years) with type 1 diabetes and without overt evidence of diabetic kidney disease had baseline assessments performed under clamped euglycaemia and hyperglycaemia, on two consecutive days. Participants then proceeded to an 8-week, open-label treatment period with empagliflozin 25 mg/day, followed by repeat assessments under clamped euglycaemia and hyperglycaemia. Plasma and urine metabolites were first grouped into metabolic pathways using MetaboAnalyst software. Principal component analysis was performed to create a representative value for each sufficiently represented metabolic group (false discovery rate ≤ 0.1) for further analysis. RESULTS: Of the plasma metabolite groups, tricarboxylic acid (TCA) cycle (P < .0001), biosynthesis of unsaturated fatty acids (P = .0045), butanoate (P < .0001), propanoate (P = .0053), and alanine, aspartate and glutamate (P < .0050) metabolites were increased after empagliflozin treatment under clamped euglycaemia. Of the urine metabolite groups, only butanoate metabolites (P = .0005) were significantly increased. Empagliflozin treatment also attenuated the increase in a number of urine metabolites observed with acute hyperglycaemia. CONCLUSIONS: Empagliflozin was associated with increased lipid and TCA cycle metabolites in participants with type 1 diabetes, suggesting a shift in metabolic substrate use and improved mitochondrial function. These effects result in more efficient energy production and may contribute to end-organ protection by alleviating local hypoxia and oxidative stress.