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The nephrological perspective on SGLT-2 inhibitors in type 1 diabetes.
Gillard, P, Schnell, O, Groop, PH
Diabetes research and clinical practice. 2020;:108462
Abstract
Prevalence of type 1 diabetes mellitus (T1DM) is globally continuously increasing. T1DM is accompanied by a high risk of developing cardiovascular and renal comorbidities and is one of the leading causes of end-stage renal disease (ESRD). However, current therapeutic approaches for chronic and/or diabetic kidney disease (CKD/DKD) existed for a long time, and offer room for improvement, particularly in T1DM. In 2019, the European Medicines Agency (EMA) approved a first sodium/glucose co-transporter 2 inhibitor (SGLT-2i) and a first dual SGLT-1/-2i to improve glycaemic control, as an adjunctive treatment to insulin in persons with T1DM and a body mass index ≥27 kg/m2. Of note, SGLT-1/2is and SGLT-2is are not approved by the Food and Drug Administration (FDA) as an adjunct treatment in T1DM, nor approved for the treatment of CKD or DKD by EMA and FDA. SGLT is have shown to mediate different renoprotective effects in type 2 diabetes mellitus in corresponding cardiovascular and renal outcome trials. First efficacy trials offer insights into potential positive effects on renal function and kidney disease of SGLTis in T1DM. This review summarizes and discusses latest available data on SGLT inhibition and provides an update on the nephrological perspective on SGLTis, specifically in T1DM.
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Effect of sodium-glucose co-transporter 2 inhibitors on lipid profile: A systematic review and meta-analysis of 48 randomized controlled trials.
Sánchez-García, A, Simental-Mendía, M, Millán-Alanís, JM, Simental-Mendía, LE
Pharmacological research. 2020;:105068
Abstract
Previous studies have suggested additional beneficial effects of sodium-glucose co-transporter-2 (SGLT2) inhibitors including the lipid-lowering effect; however, results on lipid profile are controversial. Thus, this meta-analysis aimed to determine the effect of SGLT2 inhibitors treatment on lipid levels in patients with type 2 diabetes. Randomized controlled trials assessing the impact of SGLT2 inhibitors on lipid parameters were searched in PubMed-MEDLINE, SCOPUS, Web of Science, and Google Scholar databases. Meta-analysis was conducted using a random-effects model and generic inverse variance method. Meta-analysis of 48 randomized controlled trials revealed that SGLT2 inhibitors therapy had a significant increase on total cholesterol (WMD: 0.09 mmol/L, 95 % CI: 0.05, 0.13, I2 = 79 %, p < 0.0001), LDL-cholesterol (WMD: 0.10 mmol/L, 95 % CI: 0.07, 0.12, I2 = 94 %, p < 0.00001), HDL-cholesterol (WMD: 0.06 mmol/L, 95 % CI: 0.05, 0.08, I2 = 99 %, p < 0.00001), and non-HDL-cholesterol (WMD: 0.09 mmol/L, 95 % CI: 0.06, 0.12, I2 = 96 %, p < 0.00001). Additionally, SGLT2 inhibitors administration showed a significant decrease in triglyceride levels (WMD: -0.10 mmol/L, 95 % CI: -0.13, -0.07, I2 = 96 %, p < 0.00001). Finally, no significant alteration was found on LDL/HDL ratio after SGLT2 inhibitors treatment (WMD: -0.01 mmol/L, 95 % CI: -0.05, 0.03, I2 = 99 %, p = 0.65). In conclusion, SGLT2 inhibitors significantly increase total cholesterol, LDL-cholesterol, non-HDL-cholesterol, and HDL-cholesterol, and decrease triglyceride levels.
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Acute pancreatitis risk in type 2 diabetes patients treated with canagliflozin versus other antihyperglycemic agents: an observational claims database study.
Yuan, Z, DeFalco, F, Wang, L, Hester, L, Weaver, J, Swerdel, JN, Freedman, A, Ryan, P, Schuemie, M, Qiu, R, et al
Current medical research and opinion. 2020;(7):1117-1124
Abstract
Objective: Observational evidence suggests that patients with type 2 diabetes mellitus (T2DM) are at increased risk for acute pancreatitis (AP) versus those without T2DM. A small number of AP events were reported in clinical trials of the sodium glucose co-transporter 2 inhibitor canagliflozin, though no imbalances were observed between treatment groups. This observational study evaluated risk of AP among new users of canagliflozin compared with new users of six classes of other antihyperglycemic agents (AHAs).Methods: Three US claims databases were analyzed based on a prespecified protocol approved by the European Medicines Agency. Propensity score adjustment controlled for imbalances in baseline covariates. Cox regression models estimated the hazard ratio of AP with canagliflozin compared with other AHAs using on-treatment (primary) and intent-to-treat approaches. Sensitivity analyses assessed robustness of findings.Results: Across the three databases, there were between 12,023-80,986 new users of canagliflozin; the unadjusted incidence rates of AP (per 1000 person-years) were between 1.5-2.2 for canagliflozin and 1.1-6.6 for other AHAs. The risk of AP was generally similar for new users of canagliflozin compared with new users of glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, sulfonylureas, thiazolidinediones, insulin, and other AHAs, with no consistent between-treatment differences observed across databases. Intent-to-treat and sensitivity analysis findings were qualitatively consistent with on-treatment findings.Conclusions: In this large observational study, incidence rates of AP in patients with T2DM treated with canagliflozin or other AHAs were generally similar, with no evidence suggesting that canagliflozin is associated with increased risk of AP compared with other AHAs.
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Prognosis of patients eligible for dapagliflozin in acute heart failure.
Carballo, S, Stirnemann, J, Garin, N, Darbellay Farhoumand, P, Serratrice, J, Carballo, D
European journal of clinical investigation. 2020;(6):e13245
Abstract
BACKGROUND Dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, was shown in the DAPA-HF study to reduce the risk of worsening heart failure or death in symptomatic patients with left ejection fraction <40%, irrespective of diabetes. The aim of this study was to evaluate eligibility status for dapagliflozin in non-selected patients hospitalized for acute decompensated heart failure (ADHF), as well as prognostic implications of this status. MATERIALS AND METHODS Analysis of 815 patients recruited in a prospective cohort of acute heart failure at the University Hospitals of Geneva, consisting of consecutive patients admitted with ADHF. Eligibility for dapagliflozin was determined using criteria described DAPA-HF. RESULTS Of 815 patients, 220 (27%) were eligible for dapagliflozin treatment. In survival analysis, patients who were eligible for dapagliflozin had better clinical outcomes with respect to all-cause mortality and rehospitalization as compared to those who were not eligible. In multivariate analysis, the hazard ratio for all-cause mortality or readmission in patients eligible for dapagliflozin was 0.82 (95% CI 0.68-0.999, P = .049) as compared to the non-eligible. CONCLUSIONS Using DAPA-HF criteria, only 27% of non-selected patients admitted for ADHF are theoretically eligible for dapagliflozin. This eligibility for dapagliflozin is associated with better outcomes. Further evaluation of the benefits of dapagliflozin in selected HF patients may be of interest. This may have implications for selection criteria in future randomized effectiveness studies.
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Effects of glucagon-like peptide 1 receptor agonists and sodium glucose cotransporter 2 inhibitors on major adverse cardiovascular events in type 2 diabetes by race, ethnicity, and region: A meta-analysis.
Qiu, M, Ding, L, Wei, X, Wei, W, Zhou, H
Medicine. 2020;(49):e23489
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Abstract
BACKGROUND The effects of sodium-glucose cotransporter-2 inhibitors (SGLT2is) and glucagon-like peptide 1 receptor agonists on major adverse cardiovascular events (MACE) in type 2 diabetic subgroups defined by race, ethnicity, and region are unestablished. METHODS We searched PubMed and Embase for related randomized controlled trials. We conducted random-effects meta-analysis, stratified by drug class, on MACE in various subgroups defined by 3 factors of interest (ie, race, ethnicity, and region) to estimate pooled hazard ratio (HR) and 95% confidence interval. Random-effects meta-regression was conducted to evaluate the differences between 2 drug classes. RESULTS We included 11 randomized controlled trials for pooled analysis. Compared with placebo, SGLT2is and GLP-1 RAs significantly reduced the risk of MACE (HR ranged from 0.76 to 0.93) in most diabetic subgroups defined by 3 factors of interest. The 2 drug classes did not significantly reduced this risk in the Black race group (HR 0.92, 95% confidence interval 0.70-1.20). The effect of the 2 drug classes on MACE was not significantly different in all diabetic subgroups of interest (P-value for subgroup differences ranged from .101 to .971). CONCLUSIONS SGLT2is and glucagon-like peptide 1 receptor agonists can significantly reduce the risk of MACE in most type 2 diabetic subgroups defined by race, ethnicity, and region, whereas they fail to do it in Black individuals.
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Insulin resistance and heart failure during treatment with sodium glucose cotransporter 2 inhibitors: proposed role of ketone utilization.
Hattori, Y
Heart failure reviews. 2020;(3):403-408
Abstract
Sodium glucose cotransporter 2 (SGLT2) inhibitors reduce the rate of hospitalization for heart failure in individuals with type 2 diabetes, but the underlying mechanisms remain elusive. Modestly elevated circulating β-hydroxybutyrate (βOHB) during treatment with SGLT2 inhibitors causes different beneficial effects on organs and cells, depending on succinyl-CoA:3-ketoacid CoA transferase (SCOT) levels. In the heart, in which SCOT is highly expressed/up-regulated, βOHB may be an alternative energy source apart from fat and glucose oxidation. The type 2 diabetic failing heart may be energy inefficient. In skeletal muscle, in which SCOT is not highly expressed/down-regulated, βOHB may cause antioxidant effects, resulting in amelioration of insulin resistance, which could lead to improvement in cardiac insulin resistance with metabolic, endocrine, and cytokine alterations. Although various mechanisms have been suggested, we postulate that the potential impact of SGLT2 inhibitors on heart failure lies in fuel energetics and amelioration of insulin resistance with ketone utilization depending upon SCOT levels.
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Sodium-Glucose Co-Transporter 2 Inhibitors for Non-Alcoholic Fatty Liver Disease in Asian Patients With Type 2 Diabetes: A Meta-Analysis.
Wong, C, Yaow, CYL, Ng, CH, Chin, YH, Low, YF, Lim, AYL, Muthiah, MD, Khoo, CM
Frontiers in endocrinology. 2020;:609135
Abstract
OBJECTIVE Non-alcoholic fatty liver disease (NAFLD) is a very common disorder among patients with type 2 diabetes and may share causal relationship. Type 2 diabetes is a risk factor for progression and potential poor outcomes in NAFLD patients. This meta-analysis aimed to analyze the current evidence of sodium-glucose co-transporter-2 inhibitors (SGLT2i), a glucose-lowering drug to improve NAFLD in patients with Type 2 Diabetes. METHODS Medline, Embase and Cochrane Central Register of Controlled Trials were searched for articles examining efficacy of SGLT2i on treatments of NAFLD in type 2 diabetes in July 2020, and articles were sieved. Continuous data were extracted in the form of mean and standard deviation and were pooled with standardized mean difference (SMD). RESULTS 10 articles involving 555 patients from seven randomized controlled trials (RCTs) and three cohort studies, were included in this meta-analysis. Our analysis revealed significant improvements in hepatic fat content (after treatment: -0.789 (-1.404 to -0.175), p = 0.012; compared with control: -0.923 (-1.562 to -0.285), p = 0.005), AST (After Treatment: -0.539 (-0.720 to -0.357), p < 0.001; compared with control: -0.421 (-0.680 to -0.161), p = 0.001), ALT (after treatment: -0.633 (-0.892 to -0.373), p < 0.001; compared with Control: -0.468 (-0.685 to -0.251), p < 0.001), body composition (BMI: after treatment: -0.225 (-0.456 to 0.005), p = 0.055; compared with Control: -1.092 (-2.032 to -0.153), p = 0.023), glycemic control (HbA1c: After Treatment: -0.701 (-1.098 to -0.303), p = 0.001; compared with control: -0.210 (-0.603 to 0.183), p = 0.295), lipid parameters (Triglycerides: after treatment: -0.230 (-0.409 to -0.052), p = 0.011; compared with control: -0.336 (-0.597 to -0.076), p = 0.011), inflammatory markers (serum ferritin: after treatment: -0.409 (-0.694 to -0.124), p = 0.005; compared with control: -0.814 (-1.688 to 0.059), p = 0.068) after SGLT2i treatment, and when compared against controls. There was a trend in the improvement in fibrosis markers after SGLT2i treatment. CONCLUSIONS SGLT2i is an effective treatment to improve NAFLD among patients with type 2 diabetes. Further studies are needed to understand the direct and indirect effects of SGLT2i on NAFLD and if SGLT2i could prevent the progression of NAFLD or NASH. SGLT2i could potentially be considered for patients with type 2 diabetes and NAFLD, if there are no contraindications.
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Effects of dapagliflozin on the serum levels of fibroblast growth factor 21 and myokines and muscle mass in Japanese patients with type 2 diabetes: A randomized, controlled trial.
Yamakage, H, Tanaka, M, Inoue, T, Odori, S, Kusakabe, T, Satoh-Asahara, N
Journal of diabetes investigation. 2020;(3):653-661
Abstract
AIMS/INTRODUCTION Our aims were to examine the add-on effects of a sodium-glucose cotransporter 2 inhibitor, dapagliflozin, compared with existing antidiabetes treatments, on anthropometric/metabolic parameters, the levels of an endocrine regulator, fibroblast growth factor 21 (FGF21); a skeletal muscle mass (SMM) negative regulator, myostatin; and a metabolic regulator, irisin, in patients with type 2 diabetes. MATERIALS AND METHODS A total of 54 patients with type 2 diabetes were randomly divided into dapagliflozin and control groups. The dapagliflozin group received dapagliflozin 5 mg/day in addition to conventional therapy for 24 weeks. The primary outcome was the change in the level of serum FGF21 from baseline. The secondary outcomes included changes from baseline in anthropometric/metabolic parameters and serum levels of myostatin and irisin. RESULTS Bodyweight decreased in the dapagliflozin group compared with the control group (P < 0.001), but the changes in SMM were not significant between the groups (P = 0.611), thereby elevating the ratio of SMM-to-bodyweight in the dapagliflozin group (P = 0.028). Myostatin levels were significantly decreased (P = 0.010), and irisin levels showed a nearly significant reduction (P = 0.052) in the dapagliflozin group compared with the control group, whereas FGF21 levels did not change significantly from baseline to the end of the intervention in both the dapagliflozin (P = 0.673) and the control (P = 0.823) groups. CONCLUSIONS Dapagliflozin add-on therapy in patients with type 2 diabetes reduced myostatin levels significantly and maintained SMM, without significant changes in FGF21 levels.
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Effect of Empagliflozin on Hemodynamics in Patients With Heart Failure and Reduced Ejection Fraction.
Omar, M, Jensen, J, Frederiksen, PH, Kistorp, C, Videbæk, L, Poulsen, MK, Möller, S, Ali, M, Gustafsson, F, Køber, L, et al
Journal of the American College of Cardiology. 2020;(23):2740-2751
Abstract
BACKGROUND Inhibition of the sodium-glucose cotransporter-2 (SGLT2i) improves outcomes in patients with heart failure (HF) and reduced ejection fraction (HFrEF), but the mechanism by which they improve outcomes remains unclear. OBJECTIVES This study aimed to investigate the effects of sodium-glucose cotransporter-2 inhibitor empagliflozin on central hemodynamics in patients with HF and HFrEF. METHODS This investigator-initiated, double-blinded, placebo-controlled, randomized trial enrolled 70 patients with HFrEF from March 6, 2018, to September 10, 2019. Patients were assigned to empagliflozin of 10 mg or matching placebo once daily on guideline-driven HF therapy for 12 weeks. The primary outcome was ratio of pulmonary capillary wedge pressure (PCWP) to cardiac index (CI) at peak exercise after 12 weeks. Patients underwent right-heart catheterization at rest and during exercise at baseline and 12-week follow-up. RESULTS Patients with HFrEF, mean age of 57 years, mean left-ventricular ejection fraction, 26%, and 12 (17%) with type 2 diabetes mellitus were randomized. There was no significant treatment effect on peak PCWP/CI (-0.13 mm Hg/l/min/m2; 95% confidence interval: -1.60 to 1.34 mm Hg/l/min/m2; p = 0.86). Considering hemodynamics over the full range of exercise loads, PCWP was significantly reduced (-2.40 mm Hg; 95% confidence interval: -3.96 to -0.84 mm Hg; p = 0.003), but not CI (-0.09 l/min/m2; 95% confidence interval: -0.14 to 0.32 l/min/m2; p = 0.448) by empagliflozin. This was consistent among patients with and without type 2 diabetes. CONCLUSIONS Among patients with stable HFrEF, empagliflozin for 12 weeks reduced PCWP compared with placebo. There was no significant improvement in neither CI nor PCWP/CI at rest or exercise.
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Sodium-glucose co-transporter-2 inhibitor cardiovascular outcome trials and generalizability to English primary care.
Hinton, W, Feher, M, Munro, N, Joy, M, de Lusignan, S
Diabetic medicine : a journal of the British Diabetic Association. 2020;(9):1499-1508
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Abstract
AIM: To identify people in English primary care with equivalent cardiovascular risk to participants in the sodium-glucose co-transporter-2 inhibitor (SGLT-2i) cardiovascular outcome trials (CVOTs). A secondary objective was to report the usage of SGLT-2is. METHODS Cross-sectional analysis of people registered with participating practices in the Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) network on the 31 December 2016. We derived: (1) proportions of the primary care population eligible for inclusion in each SGLT-2i CVOT (CANVAS, DECLARE, EMPA-REG and VERTIS); (2) characteristics of the eligible population compared with trial participants (demographics, disease duration and vascular risk); and (3) differences within the eligible population prescribed SGLT-2is. RESULTS The proportions of people with type 2 diabetes (N = 84 394) meeting the inclusion criteria for each CVOT were: DECLARE 27% [95% confidence interval (CI) 26.5-27.1]; CANVAS 17% (16.6-17.1); VERTIS 7% (7.1-7.4); and EMPA-REG 7% (6.5-6.8). Primary care populations fulfilling inclusion criteria were 5-8 years older than trial cohorts, and <10% with inclusion criteria of each trial were prescribed an SGLT-2i; a greater proportion were men, and of white ethnicity. CONCLUSIONS There was variation in proportions of the primary care type 2 diabetes population fulfilling inclusion criteria of SGLT-2i CVOTs. The more stringent the inclusion criteria, the lower the proportion identified in a primary care setting. Prescription rates for SGLT-2is were low in this national database, and there were demographic disparities in prescribing.