Mechanisms of Protective Effects of SGLT2 Inhibitors in Cardiovascular Disease and Renal Dysfunction

2019 ◽  
Vol 19 (20) ◽  
pp. 1818-1849 ◽  
Author(s):  
Ban Liu ◽  
Yuliang Wang ◽  
Yangyang Zhang ◽  
Biao Yan
Keyword(s):  
Diabetes Mellitus ◽  
Heart Failure ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Renal Dysfunction ◽  
Sglt2 Inhibitors ◽  
Sodium Glucose Cotransporter ◽  
Glucose Reabsorption ◽  
Renal Glucose Reabsorption

: Type 2 diabetes mellitus is one of the most common forms of the disease worldwide. Hyperglycemia and insulin resistance play key roles in type 2 diabetes mellitus. Renal glucose reabsorption is an essential feature in glycaemic control. Kidneys filter 160 g of glucose daily in healthy subjects under euglycaemic conditions. The expanding epidemic of diabetes leads to a prevalence of diabetes-related cardiovascular disorders, in particular, heart failure and renal dysfunction. Cellular glucose uptake is a fundamental process for homeostasis, growth, and metabolism. In humans, three families of glucose transporters have been identified, including the glucose facilitators GLUTs, the sodium-glucose cotransporter SGLTs, and the recently identified SWEETs. Structures of the major isoforms of all three families were studied. Sodium-glucose cotransporter (SGLT2) provides most of the capacity for renal glucose reabsorption in the early proximal tubule. A number of cardiovascular outcome trials in patients with type 2 diabetes have been studied with SGLT2 inhibitors reducing cardiovascular morbidity and mortality. : The current review article summarises these aspects and discusses possible mechanisms with SGLT2 inhibitors in protecting heart failure and renal dysfunction in diabetic patients. Through glucosuria, SGLT2 inhibitors reduce body weight and body fat, and shift substrate utilisation from carbohydrates to lipids and, possibly, ketone bodies. These pleiotropic effects of SGLT2 inhibitors are likely to have contributed to the results of the EMPA-REG OUTCOME trial in which the SGLT2 inhibitor, empagliflozin, slowed down the progression of chronic kidney disease and reduced major adverse cardiovascular events in high-risk individuals with type 2 diabetes. This review discusses the role of SGLT2 in the physiology and pathophysiology of renal glucose reabsorption and outlines the unexpected logic of inhibiting SGLT2 in the diabetic kidney.

scholarly journals The EMPEROR-Reduced trial: SGLT2 inhibitors for heart failure get more support

2020 ◽  
Vol 2020 (3) ◽  
Author(s):  
Kerolos Wagdy
Keyword(s):  
Diabetes Mellitus ◽  
Heart Failure ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Mechanism Of Action ◽  
Sglt2 Inhibitors ◽  
New Class ◽  
Glucose Reabsorption ◽  
Unique Mechanism

[no abstract - showing first paragraph]Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a relatively new class of antihyperglycemic medication that are well established for the management of type-2 diabetes mellitus (DM). They have a unique mechanism of action that targets the kidneys through inhibition of 90% of glucose reabsorption.

Targeting Renal Glucose Reabsorption for the Treatment of Type 2 Diabetes Mellitus Using the SGLT2 Inhibitor Dapagliflozin

2012 ◽  
Vol 124 (4) ◽  
pp. 62-73 ◽  
Author(s):  
Serge A. Jabbour ◽  
Jean M. Whaley ◽  
Mark Tirmenstein ◽  
Simon M. Poucher ◽  
Timothy P. Reilly ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Sglt2 Inhibitor ◽  
Glucose Reabsorption ◽  
Renal Glucose Reabsorption

scholarly journals Association between Markers of Fibrosis and Heart Failure Incidence in Patients with Type 2 Diabetes Mellitus

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Denis A. Lebedev ◽  
Elena A. Lyasnikova ◽  
Elena Yu. Vasilyeva ◽  
Nikolai P. Likhonosov ◽  
Maria Yu. Sitnikova ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Heart Failure ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Type I ◽  
Procollagen Type ◽  
Sodium Glucose Cotransporter ◽  
Increased Risk

Type 2 diabetes mellitus (T2DM) and chronic heart failure (HF) have close association, and several biomarkers have been studied to better understand this association and improve prediction of HF in T2DM. Furthermore, in recent clinical trials, sodium glucose cotransporter 2 inhibitors (SGLT2i), glucose-lowering drugs, improved HF outcomes. The objective of the present study was to evaluate association between circulating biomarkers of fibrosis and incidence of HF with preserved ejection fraction (HFpEF) in patients with T2DM receiving sodium glucose cotransporter 2 inhibitors (SGLT2i). Materials and Methods. At baseline, transthoracic echocardiography and laboratory assessment of N-terminal fragment of the brain natriuretic peptide (Nt-proBNP), soluble suppression of tumorigenesis-2 (sST2), galectin-3 (Gal-3), C-terminal propeptide of procollagen type I (PICP), N-terminal propeptide of procollagen type III (PIIINP), matrix metalloproteinase-9 (MMP-9), and tissue inhibitor of matrix proteinase-1 (TIMP-1) were done. After 3 years of follow-up, information about HF events (hospitalization for HF, established HF in outpatient department by a cardiologist) was obtained. Results. Seventy-two patients were included in the study. The mean age was 57 (49.7; 63.2) years; 44% were female. Most patients had T2DM for more than 4 years. All patients were overweight or had obesity, and 93% patients had arterial hypertension (AH). After 3 years of follow-up, HFpEF was established in 21% patients. Patients were divided into two groups according to the presence of HFpEF, and baseline characteristics were compared. Patients with HF were older and had longer diabetes and AH duration and higher Nt-proBNP, Gal-3, PIIINP, and PICP levels at baseline than patients without HF (all p < 0.05 ). Gal − 3 > 10  ng/ml ( OR = 2.25 ; 95% CI, 1.88–5.66; p = 0.01 ) and NT − pro − BNP > 80  pg/ml ( OR = 2.64 ; 95% CI, 1.56–4.44; p = 0.001 ) were associated with increased risk of HF incidence. Age > 60 years, diabetes duration > 10 years, and presence of abdominal obesity were independent predictors of HFpEF as well. Conclusions. T2DM patients treated with SLGT2i, who developed HFpEF after 3 years of follow-up, had higher PICP, PIIINP, Gal-3, and NT-proBNP serum concentrations at baseline, and Gal-3 level was an independent predictor of HFpEF.

scholarly journals Efficacy of Ertugliflozin on Heart Failure–Related Events in Patients With Type 2 Diabetes Mellitus and Established Atherosclerotic Cardiovascular Disease

Circulation ◽  
2020 ◽  
Vol 142 (23) ◽  
pp. 2205-2215 ◽  
Author(s):  
Francesco Cosentino ◽  
Christopher P. Cannon ◽  
David Z.I. Cherney ◽  
Urszula Masiukiewicz ◽  
Richard Pratley ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Heart Failure ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Risk Reduction ◽  
Rate Ratio ◽  
Controlled Trial ◽  
Atherosclerotic Cardiovascular Disease ◽  
Sodium Glucose Cotransporter

Background: In patients with type 2 diabetes mellitus, sodium-glucose cotransporter 2 inhibitors reduce the risk of hospitalization for heart failure (HHF). We assessed the effect of ertugliflozin on HHF and related outcomes. Methods: VERTIS CV (Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes Trial), a double-blind, placebo-controlled trial, randomly assigned patients with type 2 diabetes mellitus and atherosclerotic cardiovascular (CV) disease to once-daily ertugliflozin 5 mg, 15 mg, or placebo. Prespecified secondary analyses compared ertugliflozin (pooled doses) versus placebo on time to first event of HHF and composite of HHF/CV death, overall and stratified by prespecified characteristics. Cox proportional hazards modeling was used with the Fine and Gray method to account for competing mortality risk, and Andersen-Gill modeling to analyze total (first+recurrent) HHF and total HHF/CV death events. Results: A total of 8246 patients were randomly assigned to ertugliflozin (n=5499) or placebo (n=2747); n=1958 (23.7%) had a history of heart failure (HF) and n=5006 (60.7%) had pretrial ejection fraction (EF) available, including n=959 with EF ≤45%. Ertugliflozin did not significantly reduce first HHF/CV death (hazard ratio [HR], 0.88 [95% CI, 0.75–1.03]). Overall, ertugliflozin reduced risk for first HHF (HR, 0.70 [95% CI, 0.54–0.90]; P =0.006). Previous HF did not modify this effect (HF: HR, 0.63 [95% CI, 0.44–0.90]; no HF: HR, 0.79 [95% CI, 0.54–1.15]; P interaction=0.40). In patients with HF, the risk reduction for first HHF was similar for those with reduced EF ≤45% versus preserved EF >45% or unknown. However, in the overall population, the risk reduction tended to be greater for those with EF ≤45% (HR, 0.48 [95% CI, 0.30–0.76]) versus EF >45% (HR, 0.86 [95% CI, 0.58–1.29]). Effect on risk for first HHF was consistent across most subgroups, but greater benefit of ertugliflozin was observed in 3 populations: baseline estimated glomerular filtration rate <60 mL·min –1 ·1.73 m –2 , albuminuria, and diuretic use (each P interaction <0.05). Ertugliflozin reduced total events of HHF (rate ratio, 0.70 [95% CI, 0.56–0.87]) and total HHF/CV death (rate ratio, 0.83 [95% CI, 0.72–0.96]). Conclusions: In patients with type 2 diabetes mellitus, ertugliflozin reduced the risk for first and total HHF and total HHF/CV death, adding further support for the use of sodium-glucose cotransporter 2 inhibitors in primary and secondary prevention of HHF. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01986881.

scholarly journals Type 2 Diabetes Mellitus and Heart Failure: Innovative Possibilities for Management of Prognosis

Kardiologiia ◽  
2019 ◽  
Vol 59 (4) ◽  
pp. 76-87 ◽  
Author(s):  
Zh. D. Kobalava ◽  
N. V. Yeshniyazov ◽  
V. V. Medovchshikov ◽  
E. R. Khasanova
Keyword(s):  
Diabetes Mellitus ◽  
Heart Failure ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Mechanism Of Action ◽  
Systemic Disease ◽  
Central Element ◽  
Sglt2 Inhibitors ◽  
Diagnostic Methods

Type 2 diabetes mellitus (T2DM) has gone beyond the professional interests of one specialty. T2DM, cardiovascular (CV) diseases and chronic kidney disease, considered from the standpoint of a single cardio-reno-metabolic continuum, place a heavy economic burden on society. At the same time, the improvement of diagnostic methods and medical technologies led to distinct decrease in the frequency and mortality from a number of complications of T2DM, including myocardial infarction and stroke, but other states took their place. Thus, heart failure (HF) has taken the position of one of the most frequent complications with average prevalence of 24–40 % and significant predominance of HF with preserved ejection fraction (HFpEF). According to this paradigm, HFpEF is not a disease of diastolic dysfunction, but a systemic disease, the central element of which is impaired renal function. All this together has a potential value for choosing the optimal therapy. In recent years the results of specially designed studies assessing the CV-safety of antidiabetic drugs from the groups of dipeptidyl peptidase-4 (DPP4) inhibitors, glucagon-like preptide-1 (GLP-1) receptor agonists and sodium – glucose co-transporter-2 (SGLT2) inhibitors have become known. These drugs, except for SGLT2 inhibitors, by their mechanism of action affecting insulin resistance and hyperglycemia, demonstrated neutral or negative result on the frequency of hospitalizations due to HF. The EMPA-REG OUTCOME study with SGLT2, which has a special insulin-independent mechanism of action, demonstrated not only the efficacy and CV-safety of the drug in the form of a decrease in CV mortality by 38 %, but also a decrease in hospitalizations for HF by 35 %. Further studies with SGLT2 inhibitors confirmed positive effect on HF, indicating a class effect of the drugs. The recently completed study DECLARE-TIMI 58 proved the advantages of using dapagliflozin for the primary and secondary prevention of HF. This review highlights the prevalence of HF in diabetes mellitus, a new concept of the pathophysiology of HF, the main groups of sugar-lowering drugs and their effect on CV outcomes, in particular on HF. 

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