Effect of SGLT2 inhibitors on stroke and atrial fibrillation in diabetic kidney disease: Results from the CREDENCE trial and meta-analysis

BACKGROUND AND PURPOSE: Chronic kidney disease with reduced estimated glomerular filtration rate or elevated albuminuria increases risk for ischemic and hemorrhagic stroke. This study assessed the effects of sodium glucose cotransporter 2 inhibitors (SGLT2i) on stroke and atrial fibrillation/flutter (AF/AFL) from CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) and a meta-Analysis of large cardiovascular outcome trials (CVOTs) of SGLT2i in type 2 diabetes mellitus. METHODS: CREDENCE randomized 4401 participants with type 2 diabetes mellitus and chronic kidney disease to canagliflozin or placebo. Post hoc, we estimated effects on fatal or nonfatal stroke, stroke subtypes, and intermediate markers of stroke risk including AF/AFL. Stroke and AF/AFL data from 3 other completed large CVOTs and CREDENCE were pooled using random-effects meta-Analysis. RESULTS: In CREDENCE, 142 participants experienced a stroke during follow-up (10.9/1000 patient-years with canagliflozin, 14.2/1000 patient-years with placebo; hazard ratio [HR], 0.77 [95% CI, 0.55-1.08]). Effects by stroke subtypes were: ischemic (HR, 0.88 [95% CI, 0.61-1.28]; n=111), hemorrhagic (HR, 0.50 [95% CI, 0.19-1.32]; n=18), and undetermined (HR, 0.54 [95% CI, 0.20-1.46]; n=17). There was no clear effect on AF/AFL (HR, 0.76 [95% CI, 0.53-1.10]; n=115). The overall effects in the 4 CVOTs combined were: Total stroke (HRpooled, 0.96 [95% CI, 0.82-1.12]), ischemic stroke (HRpooled, 1.01 [95% CI, 0.89-1.14]), hemorrhagic stroke (HRpooled, 0.50 [95% CI, 0.30-0.83]), undetermined stroke (HRpooled, 0.86 [95% CI, 0.49-1.51]), and AF/AFL (HRpooled, 0.81 [95% CI, 0.71-0.93]). There was evidence that SGLT2i effects on total stroke varied by baseline estimated glomerular filtration rate (P=0.01), with protection in the lowest estimated glomerular filtration rate (45 mL/min/1.73 m2]) subgroup (HRpooled, 0.50 [95% CI, 0.31-0.79]). CONCLUSIONS: Although we found no clear effect of SGLT2i on total stroke in CREDENCE or across trials combined, there was some evidence of benefit in preventing hemorrhagic stroke and AF/AFL, as well as total stroke for those with lowest estimated glomerular filtration rate. Future research should focus on confirming these data and exploring potential mechanisms

Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to 300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m 2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to &lt;90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], &gt;300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of &lt;15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P&lt;0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P&lt;0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Nonlinear event-based state estimation using sequential Monte Carlo approach

\u3cp\u3eState estimation of nonlinear stochastic system in the setting of event-based (EB) measurements is quite challenging, because the measurements are not available at each sampling period, but are available only when a certain pre-specified event occurs. Recently, a nonlinear EB state estimator using Sequential Monte-Carlo approach is proposed in [21], where the authors obtained a EB state estimator for a given threshold. In this work, the results of [21] are extended as follows. Firstly, an empirical relation between the EB threshold and the average communication rate is obtained. Then, the performance of the estimator is evaluated by comparing the approximate error covariance matrix with the posterior Cramér-Rao bound. In addition, the computational complexity is addressed using the equivalent flop measure. Finally, the effectiveness of the proposed approach is demonstrated using two simulation examples.\u3c/p\u3

DC motor position control using discrete-time fixed-order H∞ controllers

This paper describes the design and experimental implementation of a discrete-time fixed-order H8 controller for a DC motor position control. Based on grey box modeling, a model of the DC motor is identified. An extension of HIFOO toolbox to discrete-time controller design developed recently is used to synthesize the controller. The performance of the designed controller in comparison with various control strategies is demonstrated. The paper aims at demonstrating simple modeling and control synthesis techniques with the help of available software tools to design low-complexity controllers in terms of design and implementation. Consequently, cheap hardware can be utilized for several applications

Bayesian Frequency Domain Identification of LTI Systems with OBFs kernels

\u3cp\u3eRegularised Frequency Response Function (FRF) estimation based on Gaussian process regression formulated directly in the frequency-domain has been introduced recently The underlying approach largely depends on the utilised kernel function, which encodes the relevant prior knowledge on the system under consideration. In this paper, we show how to construct a rich class of kernel functions, directly in the frequency-domain, based on Orthonormal Basis Functions (OBFs), which is capable of representing a wide range of dynamical properties, e.g., stability, resonance frequencies, damping, etc, in terms of the poles of the employed basis functions that are treated as hyperparameters to efficiently shape the model class, i.e., the prior in the corresponding Bayesian setting. This class of kernel functions also implicitly guarantees the stability of the estimated FRF. The generating poles of the OBFs are tuned along with other hyperparameters, e.g., noise variance, by maximising the marginal likelihood. Multiple case studies are considered to show the potential of the considered kernels.\u3c/p\u3

Sparse RKHS estimation via globally convex optimization and its application in LPV-IO identification

\u3cp\u3eFunction estimation using the Reproducing Kernel Hilbert Space (RKHS) framework is a powerful tool for identification of a general class of nonlinear dynamical systems without requiring much a priori information on model orders and nonlinearities involved. However, the high degrees-of-freedom (DOFs) of RKHS estimators has its price, as in case of large scale function estimation problems, they often require a serious amount of data samples to explore the search space adequately for providing high-performance model estimates. In cases where nonlinear dynamic relations can be expressed as a sum of functions, the literature proposes solutions to this issue by enforcing sparsity for adequate restriction of the DOFs of the estimator, resulting in parsimonious model estimates. Unfortunately, all existing solutions are based on greedy approaches, leading to optimization schemes which cannot guarantee convergence to the global optimum. In this paper, we propose an ℓ\u3csub\u3e1\u3c/sub\u3e-regularized non-parametric RKHS estimator which is the solution of a quadratic optimization problem. Effectiveness of the scheme is demonstrated on the non-parametric identification problem of LPV-IO models where the method solves simultaneously (i) the model order selection problem (in terms of number of input–output lags and input delay in the model structure) and (ii) determining the unknown functional dependency of the model coefficients on the scheduling variable directly from data. The paper also provides an extensive simulation study to illustrate effectiveness of the proposed scheme.\u3c/p\u3