scholarly journals Clinical and Economic Rationale for the Early use of SGLT2 Inhibitors in Patients with Type 2 Diabetes

2020 ◽  
Vol 21 (1S) ◽  
Author(s):  
Edoardo Mannucci ◽  
Pier Paolo Mangia ◽  
Lorenzo Pradelli
Keyword(s):  
Heart Failure ◽  
Type 2 Diabetes ◽  
Hospital Admissions ◽  
Microvascular Complications ◽  
Sglt2 Inhibitors ◽  
Risk Category ◽  
Duration Of Treatment ◽  
The Cost

Type 2 diabetes (T2D) is a chronic disease associated with a high epidemiological and economic burden. It is associated with a high risk of developing both macrovascular and microvascular complications and cardiovascular diseases represent the main cause of mortality and morbidity in T2D patients. The economic impact of diabetes is primarily due to the cost and duration of treatment and secondary complications of diabetes and associated costs. Sodium-glucose co-transporter-2 (SGLT2) inhibitors are an effective therapy for providing a long-term improvement of glucose control, thus contributing to the long-term prevention of diabetic (particularly microvascular) complications. Furthermore, SGLT-2 inhibitors seem to lead to significant reductions in hospital admissions due to heart failure and progression of renal disease, regardless of baseline atherosclerotic risk category or history of heart failure. Evidence from randomized controlled trials, observational and pharmacoeconomic studies suggest that SGLT2 inhibitors should be considered not only in patients with established cardiovascular disease and incipient nephropathy but also in earlier stages of T2D in order to prevent the first onset of cardiovascular and renal complications and contain the cost of illness.

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 Comparative risk evaluation for cardiovascular events associated with dapagliflozin vs. empagliflozin in real-world type 2 diabetes patients: a multi-institutional cohort study

2019 ◽  
Vol 18 (1) ◽  
Author(s):  
Shih-Chieh Shao ◽  
Kai-Cheng Chang ◽  
Ming-Jui Hung ◽  
Ning-I Yang ◽  
Yuk-Ying Chan ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Type 2 Diabetes ◽  
Cohort Study ◽  
Ischemic Stroke ◽  
Cardiovascular Events ◽  
Cardiovascular Death ◽  
Sglt2 Inhibitors ◽  
Diabetes Patients

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.

scholarly journals Endothelial Dysfunction: A Contributor to Adverse Cardiovascular Remodeling and Heart Failure Development in Type 2 Diabetes beyond Accelerated Atherogenesis

2020 ◽  
Vol 9 (7) ◽  
pp. 2090 ◽  
Author(s):  
Aleksandra Gamrat ◽  
Michał A. Surdacki ◽  
Bernadeta Chyrchel ◽  
Andrzej Surdacki
Keyword(s):  
Heart Failure ◽  
Type 2 Diabetes ◽  
Endothelial Dysfunction ◽  
Microvascular Complications ◽  
Cardiovascular Remodeling ◽  
Lv Dysfunction ◽  
Lv Remodeling ◽  
No Bioavailability ◽  
Lv Diastolic Dysfunction

Endothelial dysfunction, associated with depressed nitric oxide (NO) bioavailability, is a well-recognized contributor to both accelerated atherogenesis and microvascular complications in type 2 diabetes (DM). However, growing evidence points to the comorbidities-driven endothelial dysfunction within coronary microvessels as a key player responsible for left ventricular (LV) diastolic dysfunction, restrictive LV remodeling and heart failure with preserved ejection fraction (HFpEF), the most common form of heart failure in DM. In this review we have described: (1) multiple cellular pathways which may link depressed NO bioavailability to LV diastolic dysfunction and hypertrophy; (2) hemodynamic consequences and prognostic effects of restrictive LV remodeling and combined diastolic and mild systolic LV dysfunction on cardiovascular outcomes in DM and HFpEF, with a focus on the clinical relevance of endothelial dysfunction; (3) novel therapeutic strategies to improve endothelial function in DM. In summary, beyond associations with accelerated atherogenesis and microvascular complications, endothelial dysfunction supplements the multiple interwoven pathways affecting cardiomyocytes, endothelial cells and the extracellular matrix with consequent LV dysfunction in DM patients. The association amongst impaired endothelial function, reduced coronary flow reserve, combined LV diastolic and discrete systolic dysfunction, and low LV stroke volume and preload reserve—all of which are adverse outcome predictors—is a dangerous constellation of inter-related abnormalities, underlying the development of heart failure. Nevertheless, the relevance of endothelial effects of novel drugs in terms of their ability to attenuate cardiovascular remodeling and delay heart failure onset in DM patients remains to be investigated.

scholarly journals Study of the Functional State of the Proximal Renal Tubules in Patients with Asymptomatic Chronic Heart Failure in Dyslipidemia and its Correction with Simvastatin Treatment

2020 ◽  
Vol 16 (6) ◽  
pp. 925-930
Author(s):  
V. Yu. Kopylov
Keyword(s):  
Diabetes Mellitus ◽  
Heart Failure ◽  
Type 2 Diabetes ◽  
Chronic Heart Failure ◽  
Functional State ◽  
Renal Tubules ◽  
Healthy Individuals ◽  
Organ Specific

Aim. To study indicators of epithelial dysfunction in the proximal renal tubules by determining the activity of organ-specific enzymes neutral α-glucosidase (NAG) and L-alanine aminopeptidase (LAAP), in patients with the initial stage of chronic heart failure in dyslipidemia, and the possibility of reducing with simvastatin.Material and methods. The study involved 90 subjects, who were divided into control and main groups. The control group consisted of 30 practically healthy individuals, the main group was divided into 2 subgroups: patients with stage I chronic heart failure (CHF) without type 2 diabetes mellitus (DM2) and patients with CHF with DM2. Patients of each of the main subgroups received simvastatin 20-40 mg/day in addition to treatment of the main pathology. The main group included patients with a total serum cholesterol level of more than 6.0 mmol/l, a BMI level of more than 30 kg/m2, and who had not previously taken statins. The exclusion criterion was a violation of the filtration capacity of the kidneys and the presence of gross dysfunction of organs and systems of the body. The functional state of the proximal renal tubules was assessed by the concentration of NAG and LAAP in dialized urine.Results. Initially, the level of activity of renal enzymes in representatives of both major subgroups is higher than the group of practically healthy individuals. Taking simvastatin in the CHF without DM2 subgroup does not cause an increase in enzyme activity throughout the entire observation period, either at a daily dosage of 20 mg (NAG - 12.36±2.65 ncat/1 14.1±5.23 ncat/1 and after 3 and 6 months, LAAP - 9.4±1.62 and 11.2±2.99 ncat/1 after 3 and 6 months), or at a dosage of 40 mg/day (NAG - 30.47±3.85 and 26.2±6.75 ncat/1 after 3 and 6 months; LAAP -17.3±3.56 and 19.58±3.83 ncat/1 after 3 and 6 months). Taking simvastatin 20 mg/day in patients with CHF with DM 2 causes an increase in the NAG activity: 26.68±6.03 and 34.57±9.73 ncat/1 after 3 and 6 months). Taking simvastatin 40 mg/day increase both enzyme activity: NAG -34.3±8.7 and 46.94±9.02 ncat/1 after 3 and 6 months, LAAP - 17.08±5.81 and 22.41±4.89 ncat/1 after 3 and 6 months).Conclusion. The appointment of simvastatin in patients with dyslipidemia on the background of obesity is permissible in order to normalize lipid metabolism. Safe for the functional state of the proximal renal tubules, long-term administration of simvastatin, within the limits of medium-therapeutic dosages, is possible for patients without type 2 diabetes. Long-term use of simvastatin in patients with dyslipidemia on the background of type 2 diabetes mellitus has a negative effect on the epithelium of the proximal renal tubules, in the form of an increase in the activity of renal organ-specific enzymes, which indicates an increased dystrophy of the epithelium.

scholarly journals Effects of SGLT2 inhibitors on cardiovascular outcomes in patients with stage 3/4 CKD: A meta-analysis

PLoS ONE ◽  
2022 ◽  
Vol 17 (1) ◽  
pp. e0261986
Author(s):  
Ning Li ◽  
Guowei Zhou ◽  
Yawei Zheng ◽  
Dan Lv ◽  
Xiangjun Zhu ◽  
...  
Keyword(s):  
Heart Failure ◽  
Type 2 Diabetes ◽  
Cardiovascular Disease ◽  
Ejection Fraction ◽  
Cardiovascular Outcomes ◽  
Sglt2 Inhibitors ◽  
Atherosclerotic Cardiovascular Disease ◽  
Reduced Ejection Fraction ◽  
Stage 4

Introduction After stage 3 CKD, the risk of adverse cardiovascular events increased significantly. Therefore, we performed a meta-analysis to investigate the cardiovascular protective effect of SGLT2 inhibitors in patients with stage 3/4 CKD with different baseline kidney function or underlying diseases. Method To identify eligible trials, we systematically searched the Embase, PubMed, Web of Science, and Cochrane library databases from inception to April 15, 2021. The primary cardiovascular outcome was defined as a combination of cardiovascular mortality and hospitalization due to heart failure. Baseline kidney functions (stage 3a CKD: eGFR45-59mL/min per 1.73m2, stage 3b CKD: eGFR30-44mL/min per 1.73m2, stage 4 CKD: eGFR<30mL/min per 1.73m2) and underlying diseases (Type 2 diabetes, heart failure (Preserved ejection fraction or reduced ejection fraction), atherosclerotic cardiovascular disease) were used to stratify efficacy and safety outcomes. The results were subjected to a sensitivity analysis to ensure that they were reliable. Results In the present study, a total of eleven trials were included that involved a total of 27,823 patients with stage 3/4 CKD. The treatment and control groups contained 14,451 and 13,372 patients, respectively. In individuals with stage 3/4 CKD, SGLT2 inhibitors reduced the risk of primary cardiovascular outcomes by 26% (HR 0.74, [95% CI 0.69–0.80], I2 = 0.00%), by 30% in patients with stage 3a CKD (HR 0.70, [95% CI 0.59–0.84], I2 = 18.70%), by 23% in patients with stage 3b CKD (HR 0.77, [95% CI 0.66–0.90], I2 = 2.12%), and by 29% in patients with stage 4 CKD (HR 0.71, [95% CI 0.53–0.96], I2 = 0.00%). The risk of primary outcomes was reduced by 29% (HR 0.71, [95% CI 0.63–0.80], I2 = 0.00%) in patients with type 2 diabetes, by 28% (HR 0.72, [95% CI 0.56–0.93], I2 = 37.23%) in patients with heart failure with preserved ejection fraction, by 21% (HR 0.79, [95% CI 0.70–0.89], I2 = 0.00%) in patients with heart failure with reduced ejection fraction, and by 25% (HR 0.75, [95% CI 0.64–0.88], I2 = 0.00%) in patients with atherosclerotic cardiovascular disease. Conclusions For stage 3/4 CKD, SGLT2 inhibitors significantly decreased the risk of primary cardiovascular outcomes, and these benefits were consistent throughout the spectrum of different kidney functions, even in stage 4 CKD. There was no evidence of increased adverse outcomes across different baseline clinical complications, such as type 2 diabetes, heart failure, or atherosclerotic cardiovascular disease.

Serum Magnesium Is Inversely Associated With Heart Failure, Atrial Fibrillation, and Microvascular Complications in Type 2 Diabetes

Diabetes Care ◽  
2021 ◽  
pp. dc210236
Author(s):  
Lynette J. Oost ◽  
Amber A.W.A. van der Heijden ◽  
Emma A. Vermeulen ◽  
Caro Bos ◽  
Petra J.M. Elders ◽  
...  
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Type 2 Diabetes ◽  
Microvascular Complications ◽  
Serum Magnesium
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