Characterizing diabetic cardiomyopathy: baseline results from the ARISE-HF trial.

BACKGROUND: Diabetic cardiomyopathy (DbCM) is a form of Stage B heart failure (HF) at high risk for progression to overt disease. Using baseline characteristics of study participants from the Aldose Reductase Inhibition for Stabilization of Exercise Capacity in Heart Failure (ARISE-HF) Trial we sought to characterize clinical characteristics of individuals with findings consistent with DbCM. METHODS: Among study participants meeting inclusion criteria, clinical characteristics, laboratory testing, imaging, Kansas City Cardiomyopathy Questionnaire (KCCQ), Physical Activity Scale of the Elderly (PASE) and cardiopulmonary exercise testing (CPET) results were tabulated. Cluster phenogroups were identified. RESULTS: Among 691 study participants (mean age 67.4 years; 50% were female), mean duration of type 2 diabetes mellitus (T2DM) was 14.5 years. The median (Q1, Q3) N-terminal pro-B type natriuretic peptide and high sensitivity cardiac troponin T were 71 (35, 135) ng/L and 9 [6, 12] ng/L. The most common echocardiographic abnormalities were reduced global longitudinal strain in 25.3% and impaired diastolic relaxation in 17.7%. Despite rather well-preserved KCCQ scores the average PASE score was markedly impaired at 155 accompanied by an average maximal oxygen consumption of 15.7 mL/Kg/minute on CPET. In K-means clustering, 4 phenogroups were identified including a higher-risk group with more advanced age, greater elevation of cardiac biomarkers, and more prevalent evidence for diastolic dysfunction and left ventricular hypertrophy. CONCLUSIONS: Baseline data from the ARISE-HF Trial provide clinical characterization of individuals with T2DM and features of stage B HF, and may help clarify the diagnosis of DbCM. TRIAL REGISTRATION: ARISE-HF, NCT04083339.

Rationale and design of the Aldose Reductase Inhibition for Stabilization of Exercise Capacity in Heart Failure Trial (ARISE-HF) in patients with high-risk diabetic cardiomyopathy.

BACKGROUND: Diabetic cardiomyopathy (DbCM) is a specific form of heart muscle disease that may result in substantial morbidity and mortality in individuals with type 2 diabetes mellitus (T2DM). Hyperactivation of the polyol pathway is one of the primary mechanisms in the pathogenesis of diabetic complications, including development of DbCM. There is an unmet need for therapies targeting the underlying metabolic abnormalities that drive this form of Stage B heart failure (HF). METHODS: Aldose reductase (AR) catalyzes the first and rate-limiting step in the polyol pathway, and AR inhibition has been shown to reduce diabetic complications, including DbCM in animal models and in patients with DbCM. Previous AR inhibitors (ARIs) were limited by poor specificity resulting in unacceptable tolerability and safety profile. AT-001 is a novel investigational highly specific ARI with higher binding affinity and greater selectivity than previously studied ARIs. ARISE-HF (NCT04083339) is an ongoing Phase 3 randomized, placebo-controlled, double blind, global clinical study to investigate the efficacy of AT-001 (1000 mg twice daily [BID] and 1500 mg BID) in 675 T2DM patients with DbCM at high risk of progression to overt HF. ARISE-HF assesses the ability of AT-001 to improve or prevent decline in exercise capacity as measured by functional capacity (changes in peak oxygen uptake [peak VO2]) over 15 (and possibly 27) months of treatment. Additional endpoints include percentage of patients progressing to overt HF, health status metrics, echocardiographic measurements, and changes in cardiacbiomarkers. RESULTS: The ARISE-HF Trial is fully enrolled. CONCLUSIONS: This report describes the rationale and study design of ARISE-HF.

Aldose reductase inhibition alleviates diabetic cardiomyopathy and is associated with a decrease in myocardial fatty acid oxidation.

BACKGROUND: Cardiovascular diseases, including diabetic cardiomyopathy, are major causes of death in people with type 2 diabetes. Aldose reductase activity is enhanced in hyperglycemic conditions, leading to altered cardiac energy metabolism and deterioration of cardiac function with adverse remodeling. Because disturbances in cardiac energy metabolism can promote cardiac inefficiency, we hypothesized that aldose reductase inhibition may mitigate diabetic cardiomyopathy via normalization of cardiac energy metabolism. METHODS: Male C57BL/6J mice (8-week-old) were subjected to experimental type 2 diabetes/diabetic cardiomyopathy (high-fat diet [60% kcal from lard] for 10 weeks with a single intraperitoneal injection of streptozotocin (75 mg/kg) at 4 weeks), following which animals were randomized to treatment with either vehicle or AT-001, a next-generation aldose reductase inhibitor (40 mg/kg/day) for 3 weeks. At study completion, hearts were perfused in the isolated working mode to assess energy metabolism. RESULTS: Aldose reductase inhibition by AT-001 treatment improved diastolic function and cardiac efficiency in mice subjected to experimental type 2 diabetes. This attenuation of diabetic cardiomyopathy was associated with decreased myocardial fatty acid oxidation rates (1.15 ± 0.19 vs 0.5 ± 0.1 µmol min-1 g dry wt-1 in the presence of insulin) but no change in glucose oxidation rates compared to the control group. In addition, cardiac fibrosis and hypertrophy were also mitigated via AT-001 treatment in mice with diabetic cardiomyopathy. CONCLUSIONS: Inhibiting aldose reductase activity ameliorates diastolic dysfunction in mice with experimental type 2 diabetes, which may be due to the decline in myocardial fatty acid oxidation, indicating that treatment with AT-001 may be a novel approach to alleviate diabetic cardiomyopathy in patients with diabetes.

The Diabetes Unmet Need with Basal Insulin Evaluation (DUNE) study in type 2 diabetes: Achieving HbA1c targets with basal insulin in a real-world setting.

AIMS: To describe in a real-world setting the achievement of physician-selected individualized HbA1c targets in individuals with type 2 diabetes, newly or recently initiated with basal insulin, and the association of hypoglycaemia with target achievement. MATERIALS AND METHODS: A 12-week, prospective, single-arm, observational study of adults with type 2 diabetes, either newly initiated with any basal insulin or start on basal insulin within the preceding 12 months. At enrollment, eligible participants from 28 countries were treated with or without oral antihyperglycaemic drugs and/or GLP-1 receptor agonists. RESULTS: Individualized targets for almost all of the 3139 evaluable participants (99.7%) had been set by their physicians, with 57% of participants having HbA1c targets between 7.0% and <7.5% (53 and <58 mmol/mol). By week 12, 28% and 27% of newly and previously initiated participants, respectively, achieved individualized HbA1c targets with modest average increases in daily insulin dose of 9 and 5 U (0.10 and 0.06 U/kg), respectively, from baseline (14 and 23 U [0.17 and 0.29 U/kg], respectively). Overall, 16% of participants experienced at least one episode of hypoglycaemia. Both the incidence and frequency of hypoglycaemia, but not the severity, were positively associated with a higher likelihood of achieving individualized HbA1c targets (P < 0.05). CONCLUSIONS: In this prospective real-world study, most participants using basal insulin did not achieve the individualized HbA1c targets set by their physicians. Participants who experienced symptomatic hypoglycaemia were more likely to achieve HbA1c targets than those who did not.

Propensity-score-matched comparative analyses of simultaneously administered fixed-ratio insulin glargine 100 U and lixisenatide (iGlarLixi) vs sequential administration of insulin glargine and lixisenatide in uncontrolled type 2 diabetes.

AIM: To conduct two exploratory analyses to compare indirectly the efficacy and safety of simultaneous administration of insulin glargine 100 U (iGlar) and the glucagon-like peptide-1 receptor agonist (GLP-1RA) lixisenatide (Lixi) as a single-pen, titratable, fixed-ratio combination (iGlarLixi [LixiLan trials]) vs sequential administration of iGlar + Lixi (GetGoal Duo trials) in people with type 2 diabetes (T2D). MATERIALS AND METHODS: Propensity-score matching based on baseline covariates was used to compare simultaneous iGlarLixi vs sequential combination of iGlar + Lixi with the addition of Lixi in patients who did not reach the glycated haemoglobin (HbA1c) goal of <53 mmol/mol (<7%) after short-term use of iGlar alone (LixiLan-O vs GetGoal Duo-1 comparison) and vs sequential addition of Lixi in uncontrolled patients after long-term use of iGlar alone (LixiLan-L vs GetGoal Duo-2 comparison). RESULTS: In both analyses, compared with sequential iGlar + Lixi, iGlarLixi led to significantly greater HbA1c reductions with associated weight loss and significantly more patients reaching target HbA1c <53 mmol/mol despite lower insulin doses. Symptomatic hypoglycaemia rates were similar, despite greater HbA1c reductions with iGlarLixi. Lower rates of gastrointestinal adverse events were observed with iGlarLixi, probably as a result of the more gradual titration of Lixi with iGlarLixi. CONCLUSIONS: Indirect propensity-score-matched exploratory comparisons suggest that early treatment with a simultaneous, titratable, fixed-ratio combination of basal insulin and a GLP-1RA (iGlarLixi) may be more effective and possess better gastrointestinal tolerability than a sequential approach of adding a GLP-1RA in patients with uncontrolled T2D initiating or intensifying basal insulin therapy.

Differential effects of glucagon-like peptide-1 receptor agonists on heart rate.

While glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are known to increase heart rate (HR), it is insufficiently recognized that the extent varies greatly between the various agonists and is affected by the assessment methods employed. Here we review published data from 24-h time-averaged HR monitoring in healthy individuals and subjects with type 2 diabetes mellitus (T2DM) treated with either short-acting GLP-1 RAs, lixisenatide or exenatide, or long-acting GLP-1 RAs, exenatide LAR, liraglutide, albiglutide, or dulaglutide (N = 1112; active-treatment arms). HR effects observed in two independent head-to-head trials of lixisenatide and liraglutide (N = 202; active-treatment arms) are also reviewed. Short-acting GLP-1 RAs, exenatide and lixisenatide, are associated with a transient (1-12 h) mean placebo- and baseline-adjusted 24-h HR increase of 1-3 beats per minute (bpm). Conversely, long-acting GLP-1 RAs are associated with more pronounced increases in mean 24-h HR; the highest seen with liraglutide and albiglutide at 6-10 bpm compared with dulaglutide and exenatide LAR at 3-4 bpm. For both liraglutide and dulaglutide, HR increases were recorded during both the day and at night. In two head-to-head comparisons, a small, transient mean increase in HR from baseline was observed with lixisenatide; liraglutide induced a substantially greater increase that remained significantly elevated over 24 h. The underlying mechanism for increased HR remains to be elucidated; however, it could be related to a direct effect at the sinus node and/or stimulation of the sympathetic nervous system, with this effect related to the duration of action of the respective GLP-1 RAs. In conclusion, this review indicates that the effects on HR differ within the class of GLP-1 RAs: short-acting GLP-1 RAs are associated with a modest and transient HR increase before returning to baseline levels, while some long-acting GLP-1 RAs are associated with a more pronounced and sustained increase during the day and night. Findings from recently completed trials indicate that a GLP-1 RA-induced increase in HR, regardless of magnitude, does not present an increased cardiovascular risk for subjects with T2DM, although a pronounced increase in HR may be associated with adverse clinical outcomes in those with advanced heart failure.

Patient-led versus physician-led titration of insulin glargine in patients with uncontrolled type 2 diabetes: a randomized multinational ATLAS study.

OBJECTIVE: Self-adjustment of insulin dose is commonly practiced in Western patients with type 2 diabetes but is usually not performed in Asian patients. This multinational, 24-week, randomized study compared patient-led with physician-led titration of once-daily insulin glargine in Asian patients with uncontrolled type 2 diabetes who were on 2 oral glucose-lowering agents. METHODS: Patient-led (n = 275) or physician-led (n = 277) subjects followed the same dose-titration algorithm guided by self-monitored fasting blood glucose (FBG; target, 110 mg/dL [6.1 mmol/L]). The primary endpoint was change in mean glycated hemoglobin (HbA1c) at week 24 in the patient-led versus physician-led titration groups. RESULTS: Patient-led titration resulted in a significantly higher drop in HbA1c value at 24 weeks when compared with physician-led titration (-1.40% vs. -1.25%; mean difference, -0.15; 95% confidence interval, -0.29 to 0.00; P = .043). Mean decrease in FBG was greatest in the patient-led group (-2.85 mmol/L vs. -2.48 mmol/L; P = .001). The improvements in HbA1c and FBG were consistent across countries, with similar improvements in treatment satisfaction in both groups. Mean daily insulin dose was higher in the patient-led group (28.9 units vs. 22.2 units; P<.001). Target HbA1c of <7.0% without severe hypoglycemia was achieved in 40.0% and 32.9% in the patient-led and physician-led groups, respectively (P = .086). Severe hypoglycemia was not different in the 2 groups (0.7%), with an increase in nocturnal and symptomatic hypoglycemia in the patient-led arm. CONCLUSION: Patient-led insulin glargine titration achieved near-target blood glucose levels in Asian patients with uncontrolled type 2 diabetes who were on 2 oral glucose-lowering drugs, demonstrating that Asian patients can self-uptitrate insulin dose effectively when guided.

Safety, Pharmacokinetics, and Pharmacodynamics of the New Aldose Reductase Inhibitor Govorestat (AT-007) After a Single and Multiple Doses in Participants in a Phase 1/2 Study.

In classic galactosemia (CG) patients, aldose reductase (AR) converts galactose to galactitol. In a phase 1/2, placebo-controlled study (NCT04117711), safety, pharmacokinetics (PK), and pharmacodynamics (PD) of govorestat were evaluated after single and multiple ascending doses (0.5-40 mg/kg) in healthy adults (n = 81) and CG patients (n = 14). Levels of govorestat in plasma and cerebrospinal fluid (CSF) and blood levels of galactitol, galactose, and galactose-1-phosphate (Gal-1p) were measured for population PK and PK/PD analyses. Govorestat was well tolerated. Adverse event frequency was comparable between placebo and govorestat. Govorestat PK displayed a 2-compartment model with sequential zero- and first-order absorption, and no effect of demographic factors. Multiple-dose PK of govorestat was linear in the 0.5-40 mg/kg range, and CSF levels increased dose dependently. Elimination half-life was ∼10 h. PK/PD modeling supported once-daily dosing. Change from baseline in galactitol was -15% ± 9% with placebo and -19% ± 10%, -46% ± 4%, and -51% ± 5% with govorestat 5, 20, and 40 mg/kg, respectively, thus was similar for 20 and 40 mg/kg. Govorestat did not affect galactose or Gal-1p levels. In conclusion, govorestat displayed a favorable safety, PK, and PD profile in humans, and reduced galactitol levels in the same magnitude (∼50%) as in a rat model of CG that demonstrated an efficacy benefit on neurological, behavioral, and ocular outcomes.

Racial Differences in Diabetic Cardiomyopathy: The ARISE-HF Trial.

BACKGROUND: Diabetic cardiomyopathy (DbCM) increases risk of overt heart failure in individuals with diabetes mellitus. Racial and ethnic differences in DbCM remain unexplored. OBJECTIVES: The authors sought to identify racial and ethnic differences among individuals with type 2 diabetes mellitus, structural heart disease, and impaired exercise capacity. METHODS: The ARISE-HF (Aldolase Reductase Inhibitor for Stabilization of Exercise Capacity in Heart Failure) trial is assessing the efficacy of an aldose reductase inhibitor for exercise capacity preservation in 691 persons with DbCM. Baseline characteristics, echocardiographic parameters, and functional capacity were analyzed and stratified by race and ethnicity. RESULTS: The mean age of the study participants was 67.4 years; 50% were women. Black and Hispanic patients had lower use of diabetes mellitus treatments. Black patients had poorer baseline ventricular function and more impaired global longitudinal strain. Overall, health status was preserved, based on Kansas City Cardiomyopathy Questionnaire scores, but reduced exercise capacity was present as evidenced by reduced Physical Activity Scale for the Elderly (PASE) scores. When stratified by race and ethnicity and compared with the entire cohort, Black patients had poorer health status, more reduced physical activity, and a greater impairment in exercise capacity during cardiopulmonary exercise testing, whereas Hispanic patients also displayed compromised cardiopulmonary exercise testing functional capacity. White patients demonstrated higher physical activity and functional capacity. CONCLUSIONS: Racial and ethnic differences exist in baseline characteristics of persons affected by DbCM, with Black and Hispanic study participants demonstrating higher risk features. These insights inform the need to address differences in the population with DbCM. (Safety and Efficacy of AT-001 in Patients With Diabetic Cardiomyopathy [ARISE-HF]; NCT04083339).

Randomized Trial of a Selective Aldose Reductase Inhibitor in Patients With Diabetic Cardiomyopathy.

BACKGROUND: Progression to symptomatic heart failure is a complication of type 2 diabetes; heart failure onset in this setting is commonly preceded by deterioration in exercise capacity. OBJECTIVES: This study sought to determine whether AT-001, a highly selective aldose reductase inhibitor, can stabilize exercise capacity among individuals with diabetic cardiomyopathy (DbCM) and reduced peak oxygen uptake (Vo2). METHODS: A total of 691 individuals with DbCM meeting inclusion and exclusion criteria were randomized to receive placebo or ascending doses of AT-001 twice daily. Stratification at inclusion included region of enrollment, cardiopulmonary exercise test results, and use of sodium-glucose cotransporter 2 inhibitors or glucagon-like peptide-1 receptor agonists. The primary endpoint was proportional change in peak Vo2 from baseline to 15 months. Subgroup analyses included measures of disease severity and stratification variables. RESULTS: The mean age was 67.5 ± 7.2 years, and 50.4% of participants were women. By 15 months, peak Vo2 fell in the placebo-treated patients by -0.31 mL/kg/min (P = 0.005 compared to baseline), whereas in those receiving high-dose AT-001, peak Vo2 fell by -0.01 mL/kg/min (P = 0.21); the difference in peak Vo2 between placebo and high-dose AT-001 was 0.30 (P = 0.19). In prespecified subgroup analyses among those not receiving sodium-glucose cotransporter 2 inhibitors or glucagon-like peptide-1 receptor agonists at baseline, the difference between peak Vo2 in placebo vs high-dose AT-001 at 15 months was 0.62 mL/kg/min (P = 0.04; interaction P = 0.10). CONCLUSIONS: Among individuals with DbCM and impaired exercise capacity, treatment with AT-001 for 15 months did not result in significantly better exercise capacity compared with placebo. (Safety and Efficacy of AT-001 in Patients With Diabetic Cardiomyopathy [ARISE-HF]; NCT04083339).

Understanding the patient experience of Classic Galactosemia in pediatric and adult patients: increased disease burden, challenges with daily living, and how they evolve over time.

BACKGROUND: Classic Galactosemia (CG) is a rare, autosomal recessive condition. Newborn screening and a timely galactose-restricted diet can resolve acute symptoms and decrease fatalities, but significant chronic, progressive morbidities remain and significantly impact daily life. The objective of this study was to better understand the burden of disease in children and adults with CGs and describe how morbidities evolve over time. METHODS: A total of 49 individuals with CG from the United States (US) were included in the qualitative surveys (13 adults [9 self-reported] and 36 pediatric patients). Fifteen follow-up interviews were conducted with 5 adults and 10 caregivers, discussing 17 individuals with CG overall (2 caregivers each discussed 2 children). RESULTS: Qualitative survey and interview data demonstrated the substantial burden of CG. Difficulties in a wide range of functions were experienced, which included: speech articulation; language and communication; cognition, memory and learning; emotions; and social interactions. Most difficulties appeared in childhood and persisted or worsened with age. Most adults did not live independently. Others lived semi-independently and experienced many daily challenges and required support. Caregivers also described the burden of caring for someone with CG and spoke about the impact this has on their day-to-day life, work, and relationships. CONCLUSIONS: These findings demonstrate the pronounced and persistent burden of disease encountered by individuals with CG, and that the condition has a significant impact on the quality of life of caregivers.

Sorbitol reduction via govorestat ameliorates synaptic dysfunction and neurodegeneration in sorbitol dehydrogenase deficiency.

Sorbitol dehydrogenase (SORD) deficiency has been identified as the most frequent autosomal recessive form of hereditary neuropathy. Loss of SORD causes high sorbitol levels in tissues due to the inability to convert sorbitol to fructose in the 2-step polyol pathway, leading to degenerative neuropathy. The underlying mechanisms of sorbitol-induced degeneration have not been fully elucidated, and no current FDA-approved therapeutic options are available to reduce sorbitol levels in the nervous system. Here, in a Drosophila model of SORD deficiency, we showed synaptic degeneration in the brain, neurotransmission defect, locomotor impairment, and structural abnormalities in the neuromuscular junctions. In addition, we found reduced ATP production in the brain and ROS accumulation in the CNS and muscle, indicating mitochondrial dysfunction. Applied Therapeutics has developed a CNS-penetrant next-generation aldose reductase inhibitor (ARI), AT-007 (govorestat), which inhibits the conversion of glucose to sorbitol. AT-007 significantly reduced sorbitol levels in patient-derived fibroblasts, induced pluripotent stem cell-derived (iPSC-derived) motor neurons, and Drosophila brains. AT-007 feeding in Sord-deficient Drosophila mitigated synaptic degeneration and significantly improved synaptic transduction, locomotor activity, and mitochondrial function. Moreover, AT-007 treatment significantly reduced ROS accumulation in Drosophila CNS, muscle, and patient-derived fibroblasts. These findings uncover the molecular and cellular pathophysiology of SORD neuropathy and provide a potential treatment strategy for patients with SORD deficiency.

Qualitative interviews with adults with Classic Galactosemia and their caregivers: disease burden and challenges with daily living.

BACKGROUND: Classic Galactosemia is a rare, autosomal recessive disease in which galactose is not metabolized properly due to severe deficiency/absence of the galactose-1-phosphate uridylyltransferase (GALT) enzyme, converting to an aberrant and toxic metabolite, galactitol. Newborn screening and timely galactose-restricted diet can resolve acute symptoms and decrease fatalities. However, despite this, significant chronic, progressive morbidities remain which have a real impact upon daily life. To better understand the burden of disease, 20 in-depth qualitative interviews were undertaken with adult patients (n = 12), and their caregivers (n = 8), enrolled in the ACTION-Galactosemia trial, part of a clinical program designed to investigate the safety and efficacy of AT-007 (govorestat) in reducing toxic galactitol and long-term clinical outcomes in Classic Galactosemia. RESULTS: Interviews revealed the substantial burden of Classic Galactosemia on patients and families. Most adults were not able to live independently, and all required support with day-to-day activities. Short- and long-term memory difficulties and tremors were identified as the most frequently experienced and challenging symptoms. Other difficulties such as fine motor skills and slow/slurred speech contribute to the significant impact on daily activities, affecting ability to communicate and interact with others. Symptoms were first noticed in early childhood and worsened with age. Classic Galactosemia impacted all areas of daily functioning and quality of life, leading to social isolation, anxiety, anger/frustration and depression. This demonstrates the significant burden of disease and challenges associated with Classic Galactosemia. CONCLUSIONS: The impact on both patients and caregivers underscores the severity of the unmet medical need and the importance of pharmacological intervention to halt or prevent disease progression. Any treatment that could reduce symptoms or slow functional decline would ease the burden of this condition on patients and caregivers.

A pilot open-label study of aldose reductase inhibition with AT-001 (caficrestat) in patients hospitalized for COVID-19 infection: Results from a registry-based matched-control analysis.

BACKGROUND AND AIMS: Cardiometabolic disease may confer increased risk of adverse outcomes in COVID-19 patients by activation of the aldose reductase pathway. We hypothesized that aldose reductase inhibition with AT-001 might reduce viral inflammation and risk of adverse outcomes in diabetic patients with COVID-19. METHODS: We conducted an open-label prospective phase 2 clinical trial to assess safety, tolerability and efficacy of AT-001 in patients hospitalized with COVID-19 infection, history of diabetes mellitus and chronic heart disease. Eligible participants were prospectively enrolled and treated with AT-001 1500 mg BID for up to 14 days. Safety, tolerability, survival and length of hospital stay (LOS) were collected from the electronic medical record and compared with data from two matched control groups (MC1 and MC2) selected from a deidentified registry of COVID-19 patients at the same institution. RESULTS: AT-001 was safe and well tolerated in the 10 participants who received the study drug. In-hospital mortality observed in the AT-001 group was 20% vs. 31% in MC1 and 27% in MC2. Mean LOS observed in the AT-001 group was 5 days vs. 10 days in MC1 and 25 days in MC2. CONCLUSIONS: In hospitalized patients with COVID-19 and co-morbid diabetes mellitus and heart disease, treatment with AT-001 was safe and well tolerated. Exposure to AT-001 was associated with a trend of reduced mortality and shortened LOS. While the observed trend did not reach statistical significance, the present study provides the rationale for investigating potential benefit of AT-001 in COVID 19 affected patients in future studies.

Low Blood Glucose Index and Hypoglycaemia Risk: Insulin Glargine 300 U/mL Versus Insulin Glargine 100 U/mL in Type 2 Diabetes.

INTRODUCTION: We examined differences in hypoglycaemia risk between insulin glargine 300 U/mL (Gla-300) and insulin glargine 100 U/mL (Gla-100) in individuals with type 2 diabetes (T2DM) using the low blood glucose index (LBGI). METHODS: Daily profiles of self-monitored plasma glucose (SMPG) from the EDITION 2, EDITION 3 and SENIOR treat-to-target trials of Gla-300 versus Gla-100 were used to compute the LBGI, which is an established metric of hypoglycaemia risk. The analysis also examined documented (blood glucose readings < 3.0 mmol/L [54 mg/dL]) symptomatic hypoglycaemia (DSH). RESULTS: Overall LBGI in EDITION 2 and SENIOR and night-time LBGI in all three trials were significantly (p < 0.05) lower with Gla-300 versus Gla-100. The largest differences between Gla-300 and Gla-100 were observed during the night. In all three trials, individual LBGI results correlated with the observed number of DSH episodes per participant (EDITION 2 [r = 0.35, p < 0.001]; EDITION 3 [r = 0.26, p < 0.001]; SENIOR [r = 0.30, p < 0.001]). Participants at moderate risk of experiencing hypoglycaemia (defined as LBGI > 1.1) reported 4- to 8-fold more frequent DSH events than those at minimal risk (LBGI ≤ 1.1) (p ≤ 0.009). CONCLUSIONS: The LBGI identified individuals with T2DM at risk for hypoglycaemia using SMPG data and correlated with the number of DSH events. Using the LBGI metric, a lower risk of hypoglycaemia with Gla-300 than Gla-100 was observed in all three trials. The finding that differences in LBGI are greater at night is consistent with previously published differences in the pharmacokinetic profiles of Gla-300 and Gla-100, which provides the physiological foundation for the presented results.

Hepatocyte growth factor protects rat RINm5F cell line against free fatty acid-induced apoptosis by counteracting oxidative stress.

Type 2 diabetes is characterized by peripheral insulin resistance, pancreatic beta-cells dysfunction, and decreased beta-cell mass with increased rate of apoptosis. Chronic exposure to high levels of free fatty acids (FFAs) has detrimental effects on beta-cell function and survival. FFAs have adverse effects on mitochondrial function, with a consequent increase in the production of reactive oxygen species. Hepatocyte growth factor (HGF) plays a critical role in promoting beta-cell survival. In the present study, we investigated whether HGF was capable of protecting beta-cells from death induced by prolonged exposure to FFAs. RINm5F cell line was cultured in the presence of FFAs (oleate:palmitate 2:1) for 72 h in order to induce apoptosis. Simultaneous administration of HGF and FFAs significantly suppressed the impaired insulin secretion and FFA-induced apoptosis. Specifically, HGF exerted its protective effect by counteracting: (i) the overproduction of either hydrogen peroxide and superoxide anion, (ii) the reduction of intracellular gamma-glutamylcysteinylglycine level, and (iii) the depolarization of mitochondrial membrane, induced by prolonged FFAs exposure. These effects appear to be mediated by bcl-2 and phosphatidylinositol 3 kinase (PI3K)/Akt pathways. Indeed, HGF increased mRNA and protein expression of bcl-2 downregulated by FFAs-treatment; moreover, pre-treatment with the specific PI3-kinase inhibitor LY294002, significantly abolished the protective effect of HGF. In conclusion, in rat insulin-producing RINm5F cells, HGF exerts its prosurvival effect by counteracting the increased intracellular oxidative stress and, consequently, by inhibiting apoptosis induced by chronic exposure to FFAs.

Lixisenatide Therapy in Older Patients With Type 2 Diabetes Inadequately Controlled on Their Current Antidiabetic Treatment: The GetGoal-O Randomized Trial.

OBJECTIVE: To evaluate the efficacy and safety of lixisenatide versus placebo on glycemic control in older patients with type 2 diabetes uncontrolled on their current antidiabetic treatment. RESEARCH DESIGN AND METHODS: In this phase III, double-blind, randomized, placebo-controlled, two-arm, parallel-group, multicenter trial, patients aged ≥70 years were randomized to receive once-daily lixisenatide 20 µg or placebo before breakfast concomitantly with their existing antidiabetic therapy (including insulin) for 24 weeks. Patients at risk for malnutrition or with moderate to severe cognitive impairment were excluded. The primary end point was absolute change in HbA1c from baseline to week 24. Secondary end points included change from baseline to week 24 in 2-h postprandial plasma glucose (PPG) and body weight. RESULTS: A total of 350 patients were randomized. HbA1c decreased substantially with lixisenatide (-0.57% [6.2 mmol/mol]) compared with placebo (+0.06% [0.7 mmol/mol]) from baseline to week 24 (P < 0.0001). Mean reduction in 2-h PPG was significantly greater with lixisenatide (-5.12 mmol/L) than with placebo (-0.07 mmol/L; P < 0.0001). A greater decrease in body weight was observed with lixisenatide (-1.47 kg) versus placebo (-0.16 kg; P < 0.0001). The safety profile of lixisenatide in this older population, including rates of nausea and vomiting, was consistent with that observed in other lixisenatide studies. Hypoglycemia was reported in 17.6% of patients with lixisenatide versus 10.3% with placebo. CONCLUSIONS: In nonfrail older patients uncontrolled on their current antidiabetic treatment, lixisenatide was superior to placebo in HbA1c reduction and in targeting postprandial hyperglycemia, with no unexpected safety findings.

Adenovirus-mediated XIAP gene transfer reverses the negative effects of immunosuppressive drugs on insulin secretion and cell viability of isolated human islets.

Immunosuppressive drugs are routinely used to provide tolerance after whole pancreas and islet cell transplantations. While they are essential in inhibiting graft rejection, little is known about their effect on islet function and beta-cell viability. In this study, we report that tacrolimus, sirolimus, and mycophenolic acid, when added to cultures of freshly isolated human islets, induce a downregulation of the synthesis and secretion of insulin. These functional changes are associated with decreased islet cell viability. All three agents induce a decrease of intracellular levels of Bcl-2 and Bcl-xL, with an increased level of Smac, indicating that they are capable of promoting a downregulation of anti-apoptotic factors and an accumulation of pro-apoptotic mediators. Transduction of islet cells with the anti-apoptotic gene XIAP prevents the negative effects of these drugs on the function and viability of islets. XIAP-infected cells show a higher expression of phospho-CREB (cAMP-responsive element binding protein) and a reduced level of Smac, resulting in a significant reduction of apoptotic cells and a preservation of the glucose-dependent secretion of insulin. In conclusion, the present study demonstrates that genetically modified human islets expressing XIAP are resistant to the negative effects of immunosuppressive drugs on insulin secretion and cell viability.