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Outpatient Management of Stable Heart Failure with Reduced Ejection Fraction
Published in Andreas P. Kalogeropoulos, Hal A. Skopicki, Javed Butler, Heart Failure, 2023
Leah Reid, Jonathan Murrow, Kent Nilsson, Catherine Marti
Sodium-glucose co-transporter 2 inhibitors (SGLT2i) were initially developed as glucose-lowering agents, as these drugs block the sodium-glucose cotransporter protein 2 in the proximal convoluted tubule of the kidney, therefore increasing urinary glucose and sodium excretion. In cardiovascular safety trials, these agents led to a reduction of HF events in patients with diabetes regardless of baseline-prevalent HF.52,53 These favorable effects of SGLT2i led to the hypothesis that SGLT2i have favorable disease- modifying effects in HF. 54 The pivotal DAPA-HF trial evaluated the effect of 10 mg of dapagliflozin vs placebo in HF patients with LVEF ≤40% and NYHA II–IV HF symptoms who were on guideline-directed medical therapy.55 Patients on dapagliflozin had a 26% reduction in the composite of hospitalization or urgent visit for HF (resulting in intravenous diuretic therapy) or death from cardiovascular (CV) causes (HR 0.74, 95%CI 0.65–0.85, P<0.001).55 The effect was consistent across all the components of the primary endpoint and independent of the presence of diabetes.
Single Herb to Single Phytochemical–Based Therapy for Diabetes Mellitus
Published in Dilip Ghosh, Pulok K. Mukherjee, Natural Medicines, 2019
Bhoomika M. Patel, Hemangi Rawal, Ramesh K. Goyal
There are several antidiabetic drugs available that work by targeting different organs. Sulphonylurea and meglitinides act by increasing the secretion of insulin in the pancreas (Dornhorst 2001; Gribble and Reimann 2002). GLP-1 receptor (GLP-1R) agonists (GLP-1RA) mediate their antidiabetic action by acting on the pancreas and increasing the secretion of insulin and reducing the production of glucagon while dipeptidyl peptidase 4 (DPP-4) inhibitors (DPP-4i) increase the endogenous levels of incretin by blocking the action of DPP-4 (Verspohl 2009). Sodium–glucose cotransporter 2 (SGLT-2) inhibitors (SGLT-2i) work to reduce the renal reabsorption of glucose (Bailey 2011). Thiazolidinediones and metformin are two agents acting on the liver. Thiazolidinediones (TZDs) increase the sensitivity of insulin in the skeletal muscle, adipose tissue and liver (Yki-Jarvinen 2004). Metformin decreases the concentration of glucose by increasing the insulin sensitivity peripherally and enhancing insulin-mediated glucose uptake in skeletal muscle of type 2 diabetic subjects. It is now clear that metformin causes inhibition of gluconeogenesis, causes reduction in hepatic glucose output, and lowers fasting blood glucose concentration in the liver, in addition to its other effects on peripheral use of glucose inhibiting gluconeogenesis, reducing hepatic output of glucose and reducing the fasting glucose concentration in the liver (Delibegovic et al. 2009).
Diabetes mellitus and cardiovascular disease in the elderly
Published in Wilbert S. Aronow, Jerome L. Fleg, Michael W. Rich, Tresch and Aronow’s Cardiovascular Disease in the Elderly, 2019
Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a new class of glucose-lowering drugs. They lower glucose by inhibiting the reabsorption of glucose at the proximal renal tubule. Normally, virtually all filtered glucose is reabsorbed, leaving none excreted into the urine. Inhibition of renal glucose reabsorption by blocking the glucose transport protein SGLT2 results in urinary glucose excretion and reduction in hyperglycemia. These drugs work independently of insulin and can therefore be used with other classes of glucose-lowering medication. Randomized, controlled studies demonstrate that SGLT2 inhibitors result in mean reductions of hemoglobin A1C levels of –0.69% (95% CI, −0.75 to −0.62). In addition body weight is reduced by a mean of −2.1 kg (95% CI, −2.3 to −2.0) and systolic blood pressure by a mean of −3.9 mmHg (95% CI, −4.6 to −3.3) (145).
Clinical pharmacology of SGLT-2 inhibitors in heart failure
Published in Expert Review of Clinical Pharmacology, 2023
Maria Velliou, Effie Polyzogopoulou, Ioannis Ventoulis, John Parissis
Sodium-glucose cotransporter 2 (SGLT2) inhibitors were initially introduced as effective glucose-lowering medications in patients with type 2 diabetes mellitus (DM). However, large trials conducted during the last six years6 years revealed that SGLT2 inhibitors (SGLT2i) have a net benefit in reducing the risk of cardiovascular disease in general, with a more prominent effect on cardiovascular mortality and hospitalization for heart failure (HF) [1]. These findings prompted changes in treatment guidelines and aroused great interest on the underlying mechanisms of SGLT2 inhibition. Notably, the recently published HF guidelines (2021) by the European Society of Cardiology recommend the use of the SGLT2i empagliflozin and dapagliflozin in conjunction with optimal medical therapy for patients with HF and reduced ejection fraction (HFrEF), irrespective of DM status [2].
Efficacy and safety of finerenone for treatment of diabetic kidney disease: current knowledge and future perspective
Published in Expert Opinion on Drug Safety, 2022
Vincenzo Marzolla, Marco Infante, Andrea Armani, Manfredi Rizzo, Massimiliano Caprio
Sodium–glucose cotransporter-2 inhibitors (SGLT2is) are a relatively novel class of drug for treating T2DM that are recommended in T2DM patients with established cardiorenal disease, including T2DM patients with CKD [92]. Indeed, SGLT2is have been shown to significantly reduce cardiorenal events in patients with T2DM [93]. Sodium–glucose cotransporter-2 (SGLT2) is mainly localized in the proximal convoluted renal tubule, and mediates glucose reabsorption by the kidney. Inhibition of this cotransporter determines the excretion of glucose and sodium in the urine, reducing blood glucose levels, promoting osmotic diuresis, and favoring blood pressure reduction [94]. Finerenone exerts its renal protective effects in patients with T2DM and CKD by preserving eGFR, reducing inflammation, fibrosis, and albuminuria, while SGLT2i exert their renal protective effects through eGFR preservation, reduction of blood pressure and tubular/glomerular damage, improvement in albuminuria, and reduction of ischemic renal damage by promoting autophagy and mitochondrial biogenesis [95,96]. This point appears to be particularly important in the absence of evidence regarding whether the combination therapy, using a SGLT2i and finerenone, could lead to greater cardiorenal benefits than SGLT2i or finerenone monotherapies in patients with T2DM and CKD.
Management of chronic kidney disease in type 2 diabetes: screening, diagnosis and treatment goals, and recommendations
Published in Postgraduate Medicine, 2022
Jay H. Shubrook, Joshua J. Neumiller, Eugene Wright
The sodium-glucose cotransporter-2 (SGLT-2) typically accounts for around 90% of filtered glucose reabsorption in the proximal tubule, and its inhibitors are used in T2D to treat hyperglycemia by reducing renal glucose reabsorption and increasing urinary glucose excretion [46]. SGLT-2 inhibitors (SGLT-2is) have demonstrated beneficial effects on kidney and CV outcomes. Evidence from large-scale randomized trials support the use of SGLT2is to reduce the overall rate of kidney function decline and adverse kidney events among those with T2D [47–51]. ADA (2021) and KDIGO (2020) guidelines each recommend the use of SGLT2i treatments for people with T2D and eGFR ≥30 mL/min/1.73 m2 where the approved indication allows [13,21]. Recommendations are based on subgroup analyses from SGLT2i CV outcome trials as well as more recent data from the CREDENCE trial (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation), the first study to show efficacy of an SGLT2i agent on a background of maximally tolerated ACEi/ARB doses. CREDENCE reported a relative risk reduction of 34% with canagliflozin versus placebo in the kidney-specific composite endpoint of ESKD, doubling of serum creatinine or death from renal or CV causes in patients with T2D and CKD [48]. Consistent results were also reported in the DAPA-CKD study, which demonstrated the benefit of dapaglifozin versus placebo for improving kidney and CV outcomes in patients with diabetes and extended the findings to those without diabetes [52].