The potential role and rationale for treatment of heart failure with sodium–glucose co‐transporter 2 inhibitors

Heart failure (HF) and type 2 diabetes mellitus (T2DM) are both growing public health concerns contributing to major medical and economic burdens to society. T2DM increases the risk of HF, frequently occurs concomitantly with HF, and worsens the prognosis of HF. Several anti‐hyperglycaemic medications have been associated with a concern for worse HF outcomes. More recently, the results of the EMPA‐REG OUTCOME trial showed that the sodium–glucose co‐transporter 2 (SGLT2) inhibitor empagliflozin was associated with a pronounced and precocious 38% reduction in cardiovascular mortality in subjects with T2DM and established cardiovascular disease [Correction added on 8 September 2017, after first online publication: “32%” in the previous sentence was corrected to “38%”]. These benefits were more related to a reduction in incident HF events rather than to ischaemic vascular endpoints. Several mechanisms have been put forward to explain these benefits, which also raise the possibility of using these drugs as therapies not only in the prevention of HF, but also for the treatment of patients with established HF regardless of the presence or absence of diabetes. Several large trials are currently exploring this postulate.     

Training tomorrow's doctors in diabetes: self-reported confidence levels,practice and perceived training needs of post-graduate trainee doctors in the UK. A multi-centre survey

Objective  

To assess the confidence, practices and perceived training needs in diabetes care of post-graduate trainee doctors in the UK.     

FDA guidance on antihyperglyacemic therapies for type 2 diabetes: One decade later

In 2008, the US Food and Drug Administration (FDA) issued a guidance to industry statement concerning evaluation of the cardiovascular (CV) safety of new antihyperglycaemic therapies for type 2 diabetes. Fifteen CV outcome trials assessing three novel classes of antihyperglycaemic therapies, DPP-4 inhibitors, GLP-1 receptor agonists and SGLT-2 inhibitors, were completed by the end of 2018 and several others are ongoing. In addition, one comparative insulin trial also has been completed. None of these trials reported an increase in risk for major adverse CV events (MACE), and six agents have demonstrated CV benefits. This experience has led to the first FDA-approved indications for antihyperglycaemic medications to reduce the risk of CV death (empagliflozin) and to reduce the risk of MACE (liraglutide, canagliflozin), both indications specific to patients with established atherosclerotic cardiovascular disease (ASCVD). Because of the aggregate results from dedicated CV outcomes trials conducted in response to the FDA guidance statement, the contemporary paradigm for treatment of patients with type 2 diabetes has evolved substantially. However, the guidance has substantially increased the cost of developing new medications to address this important disease that afflicts hundreds of millions of adults worldwide, with reduction in quality of life as well as in life expectancy. The cost burden of drug development of medications proven effective that may directly impact cost to patients and to their insurers might be alleviated by modifications to the present guidance statement. These include areas of trial design, aspects of trial operation, expansion of composite outcomes to include broader component CV outcomes and continued evolution of analytic methodology. The guidance statement will benefit from consideration of a number of modifications to support continued innovation and, of course, the safety of marketed medications for type 2 diabetes. However, the requirement to assess each new antihyperglycaemic medication in at least one large-scale standard randomized clinical outcomes trial should remain, so that clinicians can be reassured about the favourable efficacy/safety profiles of the medications they prescribe.     

Association between uric acid levels and cardio-renal outcomes and death in patients with type 2 diabetes: A subanalysis of EMPA-REG OUTCOME

In the EMPA-REG OUTCOME trial, we explored the association between pre-randomization uric acid level tertile (<309.30 μmol/L; 309.30 to <387.21 μmol/L; ≥387.21 μmol/L) and cardiovascular (CV) death, hospitalization for heart failure (HHF), HHF or CV death, all-cause mortality, three-point major adverse CV events (MACE), and incident or worsening nephropathy. Patients with type 2 diabetes and CV disease received empagliflozin or placebo. The median baseline plasma uric acid level was 344.98 μmol/L, and patients’ baseline characteristics were mainly balanced across tertiles. Baseline uric acid levels were associated with cardio-renal outcomes: in the placebo group, for the highest versus lowest tertile, the multivariable hazard ratios for three-point MACE, HHF or CV death, and incident or worsening nephropathy were 1.22 (95% confidence interval [CI] 0.89–1.67; P = 0.2088), 1.51 (95% CI 1.02–2.23; P = 0.0396) and 1.77 (95% CI 1.33–2.34; P < 0.0001), respectively. When tested as a continuous variable, baseline uric acid was associated with all outcomes in the placebo group. Empagliflozin improved all cardio-renal outcomes across tertiles, with all interaction P values >0.05. Further investigation of these relationships is required.     

Studies on biofilm formation and virulence factors associated with uropathogenic Escherichia coli isolated from patient with acute pyelonephritis

The current study aims to the detection of pathogenic potential and virulence factor identification of uropathogenic Escherichia coli BRL-17 isolated from patients urine. The organism was isolated from the patient with chronic pyelonephritis. The identification of organism was done by analyzing gram staining, biochemical, 16S rDNA analysis, Raman microscopy and SEM analysis. The pathogenic potential was identified by multiplex PCR analysis of virulence factor genes like sfa, hly D, pap C. The biofilm forming ability was tested by congo red agar assay and tissue culture plate assay. The result of gram staining and biochemical analysis shows the characteristics of E-coli. The 16S rDNA analysis of the clinically isolated uropathogen showed 100% similarity with uropathogenic Escherichia coli strain. Raman microscopy and SEM confirms the organism as E-coli. The Multiplex PCR study identifies virulence genes like sfa, hly D, pap C in isolated E-coli. The presence of P fimbriae coded pap C gene, S fimbriae coded sfa gene and hemolysin-D coded hly D gene discloses its potential to cause urinary tract infection. Biofilm assay result enhances the organism’s role as strong biofilm former. This biofilm forming ability of Escherichia coli strain BRL-17 made the organism to escape from host immune system and helps to colonize in bladder and kidney. This also helps to enhance the resistance to antibiotics. Our study confirms the organism as multidrug resistant, highly virulent, strong biofilm forming E-coli. The strain may be used for the development of animal models of pyelonephritis for the purpose of drug discovery.     

Empagliflozin reduces cardiovascular events,mortality and renal events in participants with type 2 diabetes after coronary artery bypass graft surgery: subanalysis of the EMPA-REG OUTCOME® randomised trial

Aims/hypothesis

After coronary artery bypass graft (CABG) surgery in individuals with type 2 diabetes, there remains a considerable residual cardiovascular risk. In the EMPA-REG OUTCOME® trial in participants with type 2 diabetes and established cardiovascular disease, empagliflozin reduced the risk of cardiovascular death by 38%, all-cause mortality by 32%, hospitalisation for heart failure by 35% and incident or worsening nephropathy by 39% vs placebo when given in addition to standard of care. The aim of this post hoc analysis of the EMPA-REG OUTCOME® trial was to determine the effects of the sodium glucose cotransporter 2 inhibitor empagliflozin on cardiovascular events and mortality in participants with type 2 diabetes and a self-reported history of CABG surgery.

Methods

The EMPA-REG OUTCOME® trial was a randomised, double-blind, placebo-controlled trial. Participants with type 2 diabetes and established cardiovascular disease were randomised 1:1:1 to receive placebo, empagliflozin 10 mg or empagliflozin 25 mg, once daily, in addition to standard of care. In subgroups by self-reported history of CABG (yes/no) at baseline, we assessed: cardiovascular death; all-cause mortality; hospitalisation for heart failure; and incident or worsening nephropathy (progression to macroalbuminuria, doubling of serum creatinine, initiation of renal replacement therapy or death due to renal disease). Differences in risk between empagliflozin and placebo were assessed using a Cox proportional hazards model.

Results

At baseline, 25% (1175/4687) of participants who received empagliflozin and 24% (563/2333) of participants who received placebo had a history of CABG surgery. In participants with a history of CABG surgery, HRs (95% CI) with empagliflozin vs placebo were 0.52 (0.32, 0.84) for cardiovascular mortality, 0.57 (0.39, 0.83) for all-cause mortality, 0.50 (0.32, 0.77) for hospitalisation for heart failure and 0.65 (0.50, 0.84) for incident or worsening nephropathy. Results were consistent between participants with and without a history of CABG surgery (p?>?0.05 for treatment by subgroup interactions).

Conclusions/interpretation

In participants with type 2 diabetes and a self-reported history of CABG surgery, treatment with empagliflozin was associated with profound reductions in cardiovascular and all-cause mortality, hospitalisation for heart failure, and incident or worsening nephropathy. These data have important implications for the secondary prevention of cardiovascular events after CABG in individuals with type 2 diabetes.

Trial registration:

ClinicalTrials.gov NCT01131676