Cardiac Safety Implications of hNav1.5 Blockade and a Framework for Pre-Clinical Evaluation

The human cardiac sodium channel (hNav1.5, encoded by the SCN5A gene) is critical for action potential generation and propagation in the heart. Drug-induced sodium channel inhibition decreases the rate of cardiomyocyte depolarization and consequently conduction velocity and can have serious implications for cardiac safety. Genetic mutations in hNav1.5 have also been linked to a number of cardiac diseases. Therefore, off-target hNav1.5 inhibition may be considered a risk marker for a drug candidate. Given the potential safety implications for patients and the costs of late stage drug development, detection, and mitigation of hNav1.5 liabilities early in drug discovery and development becomes important. In this review, we describe a pre-clinical strategy to identify hNav1.5 liabilities that incorporates in vitro, in vivo, and in silico techniques and the application of this information in the integrated risk assessment at different stages of drug discovery and development

Effects of exenatide and open-label SGLT2 inhibitor treatment, given in parallel or sequentially, on mortality and cardiovascular and renal outcomes in type 2 diabetes:insights from the EXSCEL trial

Background Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) improve cardiovascular and renal outcomes in patients with type 2 diabetes through distinct mechanisms. However, evidence on clinical outcomes in patients treated with both GLP-1 RA and SGLT2i is lacking. We aim to provide insight into the effects of open-label SGLT2i use in parallel with or shortly after once-weekly GLP-1 RA exenatide (EQW) on cardiorenal outcomes. Methods In the EXSCEL cardiovascular outcomes trial EQW arm, SGLT2i drop-in occurred in 8.7% of participants. These EQW+SGLT2i users were propensity-matched to: (1) placebo-arm participants not taking SGLT2i (n = 572 per group); and to (2) EQW-arm participants not taking SGLT2i (n = 575), based on their last measured characteristics before SGLT2i initiation, and equivalent study visit in comparator groups. Time-to-first major adverse cardiovascular event (MACE) and all-cause mortality (ACM) were compared using Cox regression analyses. eGFR slopes were quantified using mixed model repeated measurement analyses. Results In adjusted analyses, the risk for MACE with combination EQW+SGLT2i use was numerically lower compared with both placebo (adjusted hazard ratio 0.68, 95% CI 0.39-1.17) and EQW alone (0.85, 0.48-1.49). Risk of ACM was nominally significantly reduced compared with placebo (0.38, 0.16-0.90) and compared with EQW (0.41, 0.17-0.95). Combination EQW+SGLT2i use also nominally significantly improved estimated eGFR slope compared with placebo (+ 1.94, 95% CI 0.94-2.94 mL/min/1.73 m(2)/year) and EQW alone (+ 2.38, 1.40-3.35 mL/min/1.73 m(2)/year). Conclusions This post hoc analysis supports the hypothesis that combinatorial EQW and SGLT2i therapy may provide benefit on cardiovascular outcomes and mortality. Trial registration Clinicaltrials.gov, Identifying number: NCT01144338, Date of registration: June 15, 2010

Prediction and validation of exenatide risk marker effects on progression of renal disease:Insights from EXSCEL

Aim To assess whether the previously developed multivariable risk prediction framework (PRE score) could predict the renal effects observed in the EXSCEL cardiovascular outcomes trial using short-term changes in cardio-renal risk markers. Materials and Methods Changes from baseline to 6 months in HbA1c, systolic blood pressure (SBP), body mass index (BMI), haemoglobin, total cholesterol, and new micro- or macroalbuminuria were evaluated. The renal outcomes were defined as a composite of a sustained 30% or 40% decline in estimated glomerular filtration rate (eGFR) or end-stage renal disease (ESRD). Relationships between risk markers and long-term renal outcomes were determined in patients with type 2 diabetes from the ALTITUDE study using multivariable Cox regression analysis, and then applied to short-term changes in risk markers observed in EXSCEL to predict the exenatide-induced impact on renal outcomes. Results Compared with placebo, mean HbA1c, BMI, SBP and total cholesterol were lower at 6 months with exenatide, as was the incidence of new microalbuminuria. The PRE score predicted a relative risk reduction for the 30% eGFR decline + ESRD endpoint of 11.3% (HR 0.89; 95% CI 0.83-0.94), compared with 12.7% (HR 0.87; 0.77-0.99) observed risk reduction. For the 40% eGFR decline + ESRD endpoint, the predicted and observed risk reductions were 11.0% (HR 0.89; 0.82-0.97) and 13.7% (HR 0.86, 0.72-1.04), respectively. Conclusions Integrating short-term risk marker changes into a multivariable risk score predicted the magnitude of renal risk reduction observed in EXSCEL

Fish assemblage stability over fifty years in the Lake Pontchartrain Estuary; comparisons among habitats using Canonical Correspondence Analysis

We assessed fish assemblage stability over the last half century in Lake Pontchartrain, an environmentally degraded oligohaline estuary in southeastern Louisiana. Because assemblage instability over time has been consistently associated with severe habitat degradation, we attempted to determine whether fish assemblages in demersal, nearshore, and pelagic habitats exhibited change that was unrelated to natural fluctuations in environmental variables (e.g., assemblage changes between wet and dry periods). Collection data from three gear types (trawl, beach seine, and gill nets) and monthly environmental data (salinity, temperature, and Secchi depth) were compared for four collecting periods: 1954 (dry period), 1978 (wet period), 1996–1998 (wet period), and 1998–2000 (dry period). Canonical correspondence analysis (CCA) revealed that although the three environmental variables were significantly associated with the distribution and abundance patterns of fish assemblages in all habitats (with the exception of Secchi depth for pelagic samples), most fish assemblage change occurred among sampling periods (i.e., along a temporal gradient unrelated to changing environmental variables). Assemblage instability was the most pronounced for fishes collected by trawls from demersal habitats. A marked lack of cyclicity in the trawl data CCA diagram indicated a shift away from a baseline demersal assemblage of 50 yr ago. Centroid positions for the five most collected species indicated that three benthic fishes, Atlantic croaker (Micropogonias undulatus), spot (Leiostomus xanthurus), and hardhead catfish (Arius felis), were more dominant inWe assessed fish assemblage stability over the last half century in Lake Pontchartrain, an environmentally degraded oligohaline estuary in southeastern Louisiana. Because assemblage instability over time has been consistently associated with severe habitat degradation, we attempted to determine whether fish assemblages in demersal, nearshore, and pelagic habitats exhibited change that was unrelated to natural fluctuations in environmental variables (e.g., assemblage changes between wet and dry periods). Collection data from three gear types (trawl, beach seine, and gill nets) and monthly environmental data (salinity, temperature, and Secchi depth) were compared for four collecting periods: 1954 (dry period), 1978 (wet period), 1996–1998 (wet period), and 1998–2000 (dry period). Canonical correspondence analysis (CCA) revealed that although the three environmental variables were significantly associated with the distribution and abundance patterns of fish assemblages in all habitats (with the exception of Secchi depth for pelagic samples), most fish assemblage change occurred among sampling periods (i.e., along a temporal gradient unrelated to changing environmental variables). Assemblage instability was the most pronounced for fishes collected by trawls from demersal habitats. A marked lack of cyclicity in the trawl data CCA diagram indicated a shift away from a baseline demersal assemblage of 50 yr ago. Centroid positions for the five most collected species indicated that three benthic fishes, Atlantic croaker (Micropogonias undulatus), spot (Leiostomus xanthurus), and hardhead catfish (Arius felis), were more dominant in past demersal assemblages (1954 and 1978). A different situation was shown for planktivorous species collected by trawls with bay anchovy (Anchoa mitchilli) becoming more dominant in recent assemblages and Gulf enhaden (Brevoortia patronus) remaining equally represented in assemblages over time. Changes in fish assemblages from nearshore (beach seine) and pelagic (gill net) habitats were more closely related to environmental fluctuations, though the CCA for beach seine data also indicated a decrease in the dominance of M. undulatus and an increase in the proportion of A. mitchilli over time. The reduced assemblage role of benthic fishes and the marked assemblage change indicated by trawl data suggest that over the last half century demersal habitats in Lake Pontchartrain have been impacted more by multiple anthropogenic stressors than nearshore or pelagic habitats. past demersal assemblages (1954 and 1978). A different situation was shown for planktivorous species collected by trawls with bay anchovy (Anchoa mitchilli) becoming more dominant in recent assemblages and Gulf menhaden (Brevoortia patronus) remaining equally represented in assemblages over time. Changes in fish assemblages from nearshore (beach seine) and pelagic (gill net) habitats were more closely related to environmental fluctuations, though the CCA for beach seine data also indicated a decrease in the dominance of M. undulatus and an increase in the proportion of A. mitchilli over time. The reduced assemblage role of benthic fishes and the marked assemblage change indicated by trawl data suggest that over the last half century demersal habitats in Lake Pontchartrain have been impacted more by multiple anthropogenic stressors than nearshore or pelagic habitats

A mechanistic modeling platform of SGLT2 inhibition: Implications for type 1 diabetes

Abstract Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by abnormally high blood glucose concentrations due to dysfunction of the insulin‐producing beta‐cells in the pancreas. Dapagliflozin, an inhibitor of renal glucose reabsorption, has the potential to improve often suboptimal glycemic control in patients with T1DM through insulin‐independent mechanisms and to partially mitigate the adverse effects associated with long‐term insulin administration. In this work, we have adapted a systems pharmacology model of type 2 diabetes mellitus to describe the T1DM condition and characterize the effect of dapagliflozin on short‐ and long‐term glycemic markers under various treatment scenarios. The developed platform serves as a quantitative tool for the in silico evaluation of the insulin‐glucose‐dapagliflozin crosstalk, optimization of the treatment regimens, and it can be further expanded to include additional therapies or other aspects of the disease

Effect of once-weekly exenatide on estimated glomerular filtration rate slope depends on baseline renal risk: A post hoc analysis of the EXSCEL trial

The effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on renal outcomes in patients with type 2 diabetes at high cardiovascular risk are modest or neutral. However, GLP-1RAs may confer clinical benefits in those at high risk of progressive renal function loss. We examined the effects of once-weekly exenatide (EQW) on estimated glomerular filtration rate (eGFR) slope and urinary albumin:creatinine ratio (UACR) as a function of baseline UACR in 3503 EXSCEL participants (23.7%) with eGFR data available and 2828 participants (19.2%) with UACR change data available. EQW improved eGFR slope assessed via mixed model repeated measures, compared with placebo, in participants with baseline UACR >100 mg/g (0.79 mL/min/1.73 m2/year [95% confidence interval {CI} 0.24–1.34]) and UACR >200 mg/g (1.32 mL/min/1.73 m2/year [95% CI 0.57–2.06]), but not at lower UACR thresholds. EQW reduced UACR, compared with placebo, assessed via analysis of covariance, consistently across subgroups with baseline UACR >30 mg/g (28.2% reduction), baseline UACR >100 mg (22.5% reduction) and baseline UACR >200 mg (34.5% reduction). This post hoc EXSCEL analysis suggests that EQW reduces UACR, with improvement in eGFR slope specifically in participants with elevated baseline UACR

Effect of once‐weekly exenatide on estimated glomerular filtration rate slope depends on baseline renal risk: A post hoc

The effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on renal outcomes in patients with type 2 diabetes at high cardiovascular risk are modest or neutral. However, GLP-1RAs may confer clinical benefits in those at high risk of progressive renal function loss. We examined the effects of once-weekly exenatide (EQW) on estimated glomerular filtration rate (eGFR) slope and urinary albumin:creatinine ratio (UACR) as a function of baseline UACR in 3503 EXSCEL participants (23.7%) with eGFR data available and 2828 participants (19.2%) with UACR change data available. EQW improved eGFR slope assessed via mixed model repeated measures, compared with placebo, in participants with baseline UACR >100 mg/g (0.79 mL/min/1.73 m2/year [95% confidence interval {CI} 0.24–1.34]) and UACR >200 mg/g (1.32 mL/min/1.73 m2/year [95% CI 0.57–2.06]), but not at lower UACR thresholds. EQW reduced UACR, compared with placebo, assessed via analysis of covariance, consistently across subgroups with baseline UACR >30 mg/g (28.2% reduction), baseline UACR >100 mg (22.5% reduction) and baseline UACR >200 mg (34.5% reduction). This post hoc EXSCEL analysis suggests that EQW reduces UACR, with improvement in eGFR slope specifically in participants with elevated baseline UACR

Reduction of Cardiovascular Risk and Improved Estimated Glomerular Filtration Rate by SGLT2 Inhibitors, Including Dapagliflozin, Is Consistent Across the Class: An Analysis of the Placebo Arm of EXSCEL

OBJECTIVE: The sodium-glucose cotransporter 2 inhibitors (SGLT2i) empagliflozin and canagliflozin reduce the incidence of major adverse cardiovascular events (MACE), all-cause mortality (ACM), and renal events in cardiovascular outcomes trials, with observational real-world evidence suggesting class effect benefits that include dapagliflozin. We examined the placebo arm of the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) to determine whether the effects of drop-in open-label dapagliflozin on MACE, ACM, and estimated glomerular filtration rate (eGFR) were consistent with the SGLT2i class as a whole. RESEARCH DESIGN AND METHODS: SGLT2i drop-in therapy occurred in 10.6% of EXSCEL participants, with 5.2% taking dapagliflozin. Propensity-matched cohorts of SGLT2i users and nonusers (n = 709 per group) were generated on the basis of their characteristics before open-label SGLT2i drop-in or at baseline for participants taking SGLT2i at enrollment and an equivalent study visit for non-SGLT2i users. Time to first adjudicated MACE and ACM was analyzed using Cox regression. eGFR slopes were compared between matched cohorts using a mixed-model repeated-measures analysis. RESULTS: In adjusted analyses, SGLT2i users (compared with nonusers) had a numerically lower risk of MACE (adjusted hazard ratio 0.79 [95% CI 0.49-1.28]), as did dapagliflozin users (0.55 [0.26-1.15]). SGLT2i users had a significantly lower ACM risk (0.51 [0.27-0.95]; dapagliflozin: 0.66 [0.25-1.72]). Compared with nonusers, eGFR slope was significantly better for SGLT2i users overall (+1.78 [95% CI 0.87-2.69] mL/min/1.73 m2 per year) and for dapagliflozin users (+2.28 [1.01-3.54] mL/min/1.73 m2 per year). CONCLUSIONS: This post hoc analysis of the placebo arm of EXSCEL supports a beneficial class effect for all SGLT2i, including dapagliflozin, for reduced ACM and less eGFR decline

Renal effects of dapagliflozin in people with and without diabetes with moderate or severe renal dysfunction: Prospective modeling of an ongoing clinical trial

Sodium glucose cotransporter 2 inhibitors (SGLT2i) reduce cardiovascular events and onset and progression of renal disease by mechanisms that remain incompletely understood but may include clearance of interstitial congestion and reduced glomerular hydrostatic pressure. The ongoing DAPASALT mechanistic clinical study will evaluate natriuretic, diuretic, plasma/extracellular volume, and blood pressure responses to dapagliflozin in people with type 2 diabetes with normal or impaired renal function (D-PRF and D-IRF, respectively) and in normoglycemic individuals with renal impairment (N-IRF). In this study, a mathematical model of renal physiology, pathophysiology, and pharmacology was used to prospectively predict changes in sodium excretion, blood and interstitial fluid volume (IFV), blood pressure, glomerular filtration rate, and albuminuria in DAPASALT. After validating the model with previous diabetic nephropathy trials, virtual patients were matched to DAPASALT inclusion/exclusion criteria, and the DAPASALT protocol was simulated. Predicted changes in glycosuria, blood pressure, glomerular filtration rate, and albuminuria were consistent with other recent studies in similar populations. Predicted albuminuria reductions were 46%in D-PRF, 34.8%in D-IRF, and 14.2%in N-IRF. The model predicts a similarly large IFV reduction between D-PRF and D-IRF and less, but still substantial, IFV reduction in N-IRF, even though glycosuria is attenuated in groups with impaired renal function. When DAPASALT results become available, comparison with these simulations will provide a basis for evaluating how well we understand the cardiorenal mechanism(s) of SGLT2i. Meanwhile, these simulations link dapagliflozin's renal mechanisms to changes in IFV and renal biomarkers, suggesting that these benefits may extend to those with impaired renal function and individuals without diabetes