scholarly journals Effects of SGLT2 Inhibitors beyond Glycemic Control—Focus on Myocardial SGLT1

2021 ◽  
Vol 22 (18) ◽  
pp. 9852
Author(s):  
Alex Ali Sayour ◽  
Mihály Ruppert ◽  
Attila Oláh ◽  
Kálmán Benke ◽  
Bálint András Barta ◽  
...  

Selective sodium–glucose cotransporter 2 (SGLT2) inhibitors reduced the risk of hospitalization for heart failure in patients with or without type 2 diabetes (T2DM) in large-scale clinical trials. The exact mechanism of action is currently unclear. The dual SGLT1/2 inhibitor sotagliflozin not only reduced hospitalization for HF in patients with T2DM, but also lowered the risk of myocardial infarction and stroke, suggesting a possible additional benefit related to SGLT1 inhibition. In fact, several preclinical studies suggest that SGLT1 plays an important role in cardiac pathophysiological processes. In this review, our aim is to establish the clinical significance of myocardial SGLT1 inhibition through reviewing basic research studies in the context of SGLT2 inhibitor trials.

2020 ◽  
Vol 55 (2) ◽  
pp. 252-260
Author(s):  
Judy W. M. Cheng ◽  
Vincent Colucci ◽  
James S. Kalus ◽  
Sarah A. Spinler

Sodium-glucose cotransporter (SGLT2) inhibitors have demonstrated cardiovascular (CV) benefits in large-scale clinical trials of people who have type 2 diabetes and either established CV disease or multiple CV risk factors. These studies also indicated early signals in benefiting heart failure (HF) patients and those with chronic kidney diseases. This article reviews recent and future clinical studies that focus on evaluation of the use of SGLT2 inhibitors in HF management and renal protection.


2021 ◽  
Vol 26 (2S) ◽  
pp. 4534
Author(s):  
N. B. Perepech ◽  
I. E. Mikhailova

The review is devoted to the clinical efficacy of sodium-glucose cotransporter type 2 (SGLT2) inhibitors. Information on the mechanisms of drug action is given, as well as rationale for their use in the management of patients with diabetes and heart failure (HF) is provided. The results of large-scale randomized clinical trials evaluating the efficacy of SGLT2 inhibitors are discussed. We showed the beneficial effect of SGLT-2 inhibitors on the risk of cardiovascular events in patients with type 2 diabetes. In addition, an evidence of the ability of dapagliflozin and empagliflozin to improve the prognosis of patients with HF with reduced ejection fraction without diabetes are presented. The evidence and mechanisms of the nephroprotective action of SGLT2 inhibitors in patients with diabetes and HF are considered.


2019 ◽  
Vol 19 (20) ◽  
pp. 1818-1849 ◽  
Author(s):  
Ban Liu ◽  
Yuliang Wang ◽  
Yangyang Zhang ◽  
Biao Yan

: 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.


2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Akinobu Nakamura ◽  
Hideaki Miyoshi ◽  
Hiraku Kameda ◽  
Kumiko Yamashita ◽  
Yoshio Kurihara

Abstract Background We compared the effects of sodium–glucose cotransporter 2 (SGLT2) inhibitors on renal function in participants with type 2 diabetes and chronic kidney disease (CKD) classified by degree of albuminuria. Methods A retrospective review of the clinical records of Japanese participants with type 2 diabetes (age > 20 years; SGLT2 inhibitor treatment > 2 years; estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2) was conducted. Based on the urinary albumin-to-creatinine ratio (UACR) or urinary protein-to-creatinine ratio (UPCR) at the start of SGLT2 inhibitor administration, participants were categorized into three groups: normoalbuminuria (A1; UACR < 30 mg/g Cr or UPCR < 0.15 g/g Cr), microalbuminuria (A2; UACR 30 to < 300 mg/g Cr or UPCR 0.15 to < 0.50 g/g Cr), and macroalbuminuria (A3; UACR ≥ 300 mg/g Cr or UPCR ≥ 0.50 g/g Cr). The study outcome was a comparison of the rates of change in renal function evaluated by eGFR at 2 years after starting SGLT2 inhibitor among the three groups. Results A total of 87 participants (40 females, 47 males) were categorized into three groups: A1 (n = 46), A2 (n = 25), and A3 (n = 16). eGFR was similarly decreased at 2 years before starting SGLT2 inhibitor in all three groups. However, the decline in eGFR was ameliorated at 2 years after starting SGLT2 inhibitor, and eGFR was rather increased in the A1 and A2 groups. Interestingly, the rate of change in eGFR at 2 years after starting SGLT2 inhibitor in the A1 group was significantly higher than that in the A3 group. Conclusions These results demonstrate that more favorable effects of SGLT2 inhibitors on renal function were observed in participants with type 2 diabetes and CKD with normoalbuminuria compared with those with macroalbuminuria. Trial registration UMIN-CTR: UMIN000035263. Registered 15 December 2018


2019 ◽  
Vol 18 (1) ◽  
Author(s):  
Shih-Chieh Shao ◽  
Kai-Cheng Chang ◽  
Ming-Jui Hung ◽  
Ning-I Yang ◽  
Yuk-Ying Chan ◽  
...  

Abstract Background To compare the cardiovascular event risk in type 2 diabetes patients newly receiving dapagliflozin vs. empagliflozin. Methods We conducted a retrospective cohort study by analyzing a multi-institutional electronic medical records database (Chang Gung Research Database) in Taiwan and included adult type 2 diabetes patients who were newly receiving sodium–glucose co-transporter 2 (SGLT2) inhibitors from 2016 to 2017. The primary outcome was a composite of cardiovascular death, myocardial infarction, ischemic stroke and heart failure. We followed up patients from initiation of SGLT2 inhibitors until the occurrence of cardiovascular events before December 31, 2018. We performed multivariable Cox proportional hazard modeling, adjusting for patients’ age, sex, laboratory data, co-morbidities, and concomitant medications. Results We identified 12,681 new SGLT2 inhibitor users with a mean age of 58.9 (SD 11.8) years, of whom 43.9% were female and 45.8% were new dapagliflozin users. A total of 10,442 person-years of dapagliflozin use and 12,096 person-years of empagliflozin use were included. Compared to empagliflozin users, new users of dapagliflozin were found to have similar risks for primary composite outcome (adjusted HR: 0.91; 95% CI 0.73–1.14), cardiovascular death (adjusted HR: 0.54; 95% CI 0.14–2.12), myocardial infarction (adjusted HR: 0.77, 95% CI 0.49–1.19) and ischemic stroke (adjusted HR: 1.15; 95% CI 0.80–1.65), but a lower risk of heart failure (adjusted HR: 0.68; 95% CI 0.49–0.95). Conclusion The risk of cardiovascular events was similar between dapagliflozin and empagliflozin new users, but dapagliflozin may have a better outcome in the reduction of heart failure in type 2 diabetes patients. Future prospective studies are required to confirm the findings.


2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
H Tanaka ◽  
F Soga ◽  
K Tatsumi ◽  
Y Mochizuki ◽  
H Sano ◽  
...  

Abstract Background Type 2 diabetes mellitus (T2DM) has come to be considered an independent predictor of mortality, and also a contributor to the development of heart failure (HF) with reduced ejection fraction (HFrEF) and with preserved ejection fraction (HFpEF). Left ventricular (LV) longitudinal myocardial dysfunction as assessed in terms of lower global longitudinal strain (GLS), has been identified even in T2DM patients with preserved LV ejection fraction (LVEF), and should be considered the first marker of a preclinical form of DM-related cardiac dysfunction, leading to HFpEF. Sodium glucose cotransporter type 2 (SGLT2) inhibitors represent a new class of anti-hyperglycemic agents for T2DM, but the effect of SGLT2 inhibitors on LV longitudinal myocardial function in T2DM patients with HF remains uncertain. To examine this effect, as well as the association of LV longitudinal myocardial function with LV diastolic function after administration of SGLT2 inhibitor in T2DM patients with stable HF, we analyzed data from our previous prospective multicenter study, in which we investigated the effect of SGLT2 inhibitor on LV diastolic functional parameters of T2DM patients with stable HF at five institutions in Japan. Methods Our previous trial was a prospective multicenter study of 58 T2DM patients with stable HF at five institutions in Japan. Patients who had been taking at least one antidiabetic drugs other than SGLT2 inhibitors started the administration of 5 mg/day of dapagliflozin. Echocardiography was performed at baseline and 6 months after administration of dapagliflozin. LV diastolic function was defined as the ratio of mitral inflow E to mitral e' annular velocities (E/e'). LV longitudinal myocardial function was assessed as GLS based on the current guidelines. Results E/e' significantly decreased from 9.3 to 8.5 cm/s 6 months after administration of dapagliflozin (p=0.020) as previously described, while GLS showed significant improvement from 15.5±3.5% to 16.9±4.1% (p&lt;0.01) 6 months after administration of dapagliflozin. Furthermore, improvement of GLS in HFpEF patients was more significant from 17.0±1.9% to 18.7±2.0% (p&lt;0.001), compared to that in HFrEF patients from 11.3±3.8% to 11.8±4.6% (p=0.13). It was noteworthy that multiple regression analysis showed that the change in GLS after administration of dapagliflozin was the only independent determinant parameter for the change in E/e' after administration of dapagliflozin. Conclusion Dapagliflozin was found to be associated with improvement of LV longitudinal myocardial function, which led to further improvement of LV diastolic function of T2DM patients with stable HF. GLS-guided management may thus lead to improved management of T2DM patients with stable HF. Representative case Funding Acknowledgement Type of funding source: None


2020 ◽  
pp. 32-41
Author(s):  
V. V. Salukho ◽  
T. A. Ilyinskay

Type 2 diabetes mellitus (T2DM) is closely associated with the risk of developing cardiovascular complications. A new approach to treatment of T2DM, based on the inhibition of the sodium-glucose cotransporter type 2 (SGLT2) ensures reliable insulin-independent glycemic control with quick overcome of glucotoxicity, reduction of insulin resistance, and positive effects on body mass, blood pressure and other rates. Besides, pronounces clinical efficacy of SGLT2 inhibitor is marked by its use safety and minimized frequency of adverse events. Along with this, the results of carried-out, randomized clinical studies of cardiovascular safety of different SGLT2 inhibitors showed, that apart from bearing on the risk factors, the inhibition of sodium-glucose cotransporter type 2 leads to cardioand renoprotective effects. In addition, their influence on cardiovascular and renal outcomes is the stronger the more different the pre-existing status of cardiovascular diseases of the patient is, the condition of his renal function and the severity of albuminuria. This article summarizes the main results of carried-out randomized clinical studies of SGLT2 inhibitors, which demonstrate their cardiovascular advantages and compile encouraging results of multicentered studies VERTIS, examining different aspects of the use of the ertugliflazine SGLT2 inhibitor in patients with type 2 diabetes. There is data provided demonstrating a powerful glucoselowering, body-mass lowering and hypotensive impacts of ertugliflazine comparable to the same performance of the best representatives of the class. This article describes an evidence base of the use of the drug in monotherapy and its ability to be combined with other oral hypoglycemic agentsand highlightes a high level of safety of the use of ertugliflazine correspondinding to minimized frequency of adverse outcomes of SGLT2 inhibition and so the potential of SGLT2 inhibitors as a new promising class for the treatment of patients with type 2 diabetes and established cardiovascular disease is revealed.


BMJ ◽  
2019 ◽  
pp. l4772 ◽  
Author(s):  
Björn Pasternak ◽  
Peter Ueda ◽  
Björn Eliasson ◽  
Ann-Marie Svensson ◽  
Stefan Franzén ◽  
...  

Abstract Objective To investigate the cardiovascular effectiveness of sodium glucose cotransporter 2 (SGLT2) inhibitors in routine clinical practice. Design Cohort study using data from nationwide registers and an active-comparator new-user design. Setting Denmark, Norway, and Sweden, from April 2013 to December 2016. Participants 20 983 new users of SGLT2 inhibitors and 20 983 new users of dipeptidyl peptidase 4 (DPP4) inhibitors, aged 35-84, matched by age, sex, history of major cardiovascular disease, and propensity score. Main outcome measures Primary outcomes were major cardiovascular events (composite of myocardial infarction, stroke, and cardiovascular death) and heart failure (hospital admission for heart failure or death due to heart failure). Secondary outcomes were the individual components of the cardiovascular composite and any cause death. In the primary analyses, patients were defined as exposed from treatment start throughout follow-up (analogous to intention to treat); additional analyses were conducted with an as-treated exposure definition. Cox regression was used to estimate hazard ratios. Results Mean age of the study cohort was 61 years, 60% were men, and 19% had a history of major cardiovascular disease. Of the total 27 416 person years of follow-up in the SGLT2 inhibitor group, 22 627 (83%) was among patients who initiated dapagliflozin, 4521 (16%) among those who initiated empagliflozin, and 268 (1%) among those who initiated canagliflozin. During follow-up, 467 SGLT2 inhibitor users (incidence rate 17.0 events per 1000 person years) and 662 DPP4 inhibitor users (18.0) had a major cardiovascular event, whereas 130 (4.7) and 265 (7.1) had a heart failure event, respectively. Hazard ratios were 0.94 (95% confidence interval 0.84 to 1.06) for major cardiovascular events and 0.66 (0.53 to 0.81) for heart failure. Hazard ratios were consistent among subgroups of patients with and without history of major cardiovascular disease and with and without history of heart failure. Hazard ratios for secondary outcomes, comparing SGLT2 inhibitors with DPP4 inhibitors, were 0.99 (0.85 to 1.17) for myocardial infarction, 0.94 (0.77 to 1.15) for stroke, 0.84 (0.65 to 1.08) for cardiovascular death, and 0.80 (0.69 to 0.92) for any cause death. In the as-treated analyses, hazard ratios were 0.84 (0.72 to 0.98) for major cardiovascular events, 0.55 (0.42 to 0.73) for heart failure, 0.93 (0.76 to 1.14) for myocardial infarction, 0.83 (0.64 to 1.07) for stroke, 0.67 (0.49 to 0.93) for cardiovascular death, and 0.75 (0.61 to 0.91) for any cause death. Conclusions In this large Scandinavian cohort, SGLT2 inhibitor use compared with DPP4 inhibitor use was associated with reduced risk of heart failure and any cause death, but not with major cardiovascular events in the primary intention-to-treat analysis. In the additional as-treated analyses, the magnitude of the association with heart failure and any cause death became larger, and a reduced risk of major cardiovascular events that was largely driven by the cardiovascular death component was observed. These data help inform patients, practitioners, and authorities regarding the cardiovascular effectiveness of SGLT2 inhibitors in routine clinical practice.


2020 ◽  
Vol 26 ◽  
Author(s):  
Dimos Karangelis ◽  
C. David Mazer ◽  
Dimitrios Stakos ◽  
Aphrodite Tzifa ◽  
Spiros Loggos ◽  
...  

Background: Type 2 diabetes mellitus (DM) is associated with a considerable risk of cardiovascular and renal disease, including heart failure. Sodium–glucose cotransporter 2 (SGLT2) inhibitors have demonstrated unprecedented cardiorenal protective effects in large scale clinical trials of patients with or without diabetes and either established cardiovascular disease (CV) or multiple CV risk factors. Objective: Herein we aim to focus on the role of SGLT2 inhibitors regarding the improvement in heart failure outcomes and the proposed mechanisms of action by which these drugs confer their beneficial effect. Methods: PubMed, Embase and Google Scholar databases were searched to identify eligible articles which are comprehensively summarized and discussed. Results: The most commonly discussed mechanisms of action are diuresis and natriuresis, reduction in preload, afterload, and ventricular mass, as well as stimulation of erythropoietin production and improved myocardial energetics. SGLT2 inhibitors improve outcomes in patients with established heart failure (HF) and reduce the risk of death and HF admissions in patients with established chronic HF with reduced ejection fraction (HFrEF), either with or without diabetes. Conclusion: Potential key mechanisms that may explain the notable cardioprotective benefits of SGLT2 inhibitors have been outlined. These agents have recently received class Ia recommendation in specific groups of people with DM to lower the risk of hospitalization for HF and risk of death, while these benefits may also extend to people without diabetes. It remains to be seen whether they will also emerge as treatment approaches in the acute phase of CV episodes.


Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Yu Hoshika ◽  
Yoshiaki Kubota ◽  
Kosuke Mozawa ◽  
Shuhei Tara ◽  
Yukichi Tokita ◽  
...  

Background: Plasma volume status (PVS), a parameter of the discrepancy between actual plasma volume (PV) and ideal PV, has been evaluated recently as a prognostic marker of patients with heart failure. This subgroup analysis of the EMBODY trial was designed to determine whether the sodium-glucose cotransporter 2 (SGLT2) inhibitor affect the improvement of heart failure and PVS in patients after acute myocardial infarction (AMI) with congestive heart failure (CHF). Methods: The EMBODY trial was a prospective, multicenter, randomized, double-blind, placebo-controlled trial to identify the effect of the SGLT2 inhibitor on cardiac sympathetic hyperactivity in patients with AMI and type 2 diabetes mellitus (T2DM) in Japan. A total of one hundred and five patients were randomized (1:1) to receive once-daily 10 mg empagliflozin or placebo 2 weeks after the onset of AMI. In this subanalysis, we investigated the time-course of PVS on baseline, weeks 4, 12 and 24. Results: Overall, 96 patients were included in the subgroup analysis set (64.3±10.9 years, male 80.2%, and 46 in the empagliflozin group and 50 in the placebo group). The empagliflozin group showed significant decreases in body weight, systolic blood pressure, and PVS compared with the placebo group at 24 weeks (-2.2 vs. +0.1 kg, P=0.0007; -6.6 vs. +3.5 mmHg, P=0.003; and -5.1 vs. -0.3%, P=0.0006; respectively). Decreased of PVS, defined as change of PVS < -4.5 % was associated with received empagliflozin (odds ratio, 2.61; 95% confidence interval, 1.11 - 6.15; P=0.028). On the other hand, NT-Pro BNP levels significantly decreased in the empagliflozin group and placebo group (1028.7 to 370.3 pg/ml, P=0.0001 and 1270.6 to 673.7 pg/ml, P=0.006, respectively). Conclusion: Empagliflozin reduced not only body weight but also PVS. These results suggested that early SGLT2 inhibitor administration in patients with AMI, CHF and T2DM could be effective to reduce body weight and PVS.


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