Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors and Cardiovascular Disease: A Systematic Review.
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ABSTRACT: Funding
AstraZeneca Pharma India Ltd.
SUBMITTER: Kalra S
PROVIDER: S-EPMC5125111 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND:The association between sodium-glucose cotransporter 2 inhibitors (SGLT2i's) and lower extremity amputation is unclear. PURPOSE:To systematically review randomized control trials (RCTs) and observational studies quantifying risk of lower extremity amputations associated with SGLT2i use. DATA SOURCES AND STUDY SELECTION:We searched PubMed, EMBASE, Scopus, and the Cochrane Central Register of Controlled Trials from January 2011 to February 2020 for RCTs and observational studies including lower extremity amputation outcomes for individuals with type 2 diabetes mellitus treated with SGLT2i's vs. alternative treatments or placebo. DATA EXTRACTION AND SYNTHESIS:Two reviewers independently extracted data. MAIN OUTCOMES AND MEASURES:Our primary outcome was risk of lower limb amputation. Secondary outcomes included peripheral arterial disease, peripheral vascular disease, venous ulcerations, and diabetic foot infections. We also evaluated the risk of bias. We conducted random and fixed effects relative risk meta-analysis of RCTs. RESULTS:After screening 2,006 studies, 12 RCTs and 18 observational studies were included, of which 7 RCTs and 18 observational studies had at least one event. The random effects meta-analysis of 7 RCTs suggested the absence of a statistically significant association between SGLT2i exposure with evidence of substantial statistical heterogeneity (n = 424/23,716 vs n = 267/18,737 in controls; RR 1.28, CI's 0.93-1.76; I2 = 62.0%; p = 0.12) whereas fixed effects analysis showed an increased risk with statistical heterogeneity (RR 1.27, 1.09-1.48; I2 = 62%; p = 0.003). Subgroup analysis of canagliflozin vs placebo showed a statistically significantly increased risk in a fixed effects meta-analysis (n = 2 RCTs, RR 1.59, 1.26-2.01; I2 = 88%; p = 0.0001) whereas the meta-analysis of dapagliflozin or empagliflozin (n = 2 RCTs each) and a single RCT for ertugliflozin did not show a significantly increased risk. The findings from observational studies were too heterogeneous to be pooled in a meta-analysis and draw meaningful conclusions. Both randomized and observational studies were of generally good methodological quality. CONCLUSIONS:Overall, there was no consistent evidence of SGLT2i exposure and increased risk of amputation. The increased risk of amputation seen in the large, long-term Canagliflozin Cardiovascular Assessment Study (CANVAS) trial for canagliflozin, and select observational studies, merits continued exploration.
| S-EPMC7274434 | biostudies-literature
Project description:As the first cardiovascular (CV) outcome trial of a glucose-lowering agent to demonstrate a reduction in the risk of CV events in patients with type 2 diabetes mellitus (T2DM), the EMPAgliflozin Removal of Excess Glucose: Cardiovascular OUTCOME Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME®) trial, which investigated the sodium glucose cotransporter 2 (SGLT2) inhibitor empagliflozin, has generated great interest among health care professionals. CV outcomes data for another SGLT2 inhibitor, canagliflozin, have been published recently in the CANagliflozin CardioVascular Assessment Study (CANVAS) Program, as have CV data from the retrospective real-world study Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors (CVD-REAL), which compared SGLT2 inhibitors with other classes of glucose-lowering drugs. This review discusses the results of these three studies and, with a focus on EMPA-REG OUTCOME, examines the possible mechanisms by which SGLT2 inhibitors may reduce CV risk in patients with T2DM.
| S-EPMC5905845 | biostudies-literature
Project description:Recent studies have shown that sodium/glucose cotransporter 2 (SGLT2) inhibitors might exert favourable changes on cardiac parameters as observed on cardiovascular imaging. We conducted a systematic review and meta-analysis to determine the effects of SGLT2 inhibitors on cardiac imaging parameters. Four electronic databases (PubMed, Embase, Cochrane, Scopus) were searched for studies in which the effects of SGLT2 inhibitors on cardiac imaging parameters were examined. Studies in which a population was administered SGLT2 inhibitors and analysed by echocardiography and/or cardiac magnetic resonance (CMR) imaging were included. Random-effects pair-wise meta-analysis models were utilized to summarize the studies. A total of 11 randomized controlled trials was included with a combined cohort of 910 patients. Comparing patients receiving SGLT2 inhibitors with subjects receiving placebo, the mean change in CMR-measured left ventricular mass (LVM) was -3.87 g (95% confidence interval [CI], -7.77 to 0.04), that in left ventricular end-systolic volume (LVESV) was -5.96 mL (95% CI, -10.52 to -1.41) for combined LVESV outcomes, that in left atrial volume index (LAVi) was -1.78 mL/m² (95% CI, -3.01 to -0.55) for combined LAVi outcomes, and that in echocardiography-measured E/e' was -0.73 (95% CI, -1.43 to -0.03). Between-group differences were not observed in LVM and LVESV after indexation. The only between-group difference that persisted was for LAVi. Treatment with SGLT2 inhibitors resulted in reduction in LAVi and E/e' on imaging, indicating they might have an effect on outcomes associated with LV diastolic function.
| S-EPMC9314220 | biostudies-literature
Project description:Background Recent studies have increasingly shown that sodium-glucose cotransporter 2 (SGLT2) inhibitors may have beneficial cardiovascular and metabolic effects in patients without diabetes mellitus. Hence, we conducted a systematic review and meta-analysis to determine the effect of SGLT2 inhibitors on cardiovascular and metabolic outcomes in patients without diabetes mellitus. Methods and Results Four electronic databases (PubMed, Embase, Cochrane, and SCOPUS) were searched on August 30, 2020 for articles published from January 1, 2000 to August 30, 2020, for studies that examined the effect of SGLT2 inhibitors on cardiovascular and metabolic outcomes in patients without diabetes mellitus. A random-effects pairwise meta-analysis model was used to summarize the studies. A total of 8 randomized-controlled trials were included with a combined cohort of 5233 patients. In patients without diabetes mellitus, those with heart failure treated with SGLT2 inhibitors had a 20% relative risk reduction in cardiovascular deaths and heart failure hospitalizations, compared with those who were not treated (risk ratio, 0.78; P<0.001). We additionally found that treatment with SGLT2 inhibitors improved multiple metabolic indices. Patients on SGLT2 inhibitors had a reduction in body weight of -1.21 kg (P<0.001), body mass index of -0.47 kg/m2 (P<0.001), systolic blood pressure of -1.90 mm Hg (P=0.04), and fasting plasma glucose of -0.38 mmol/L (P=0.05), compared with those without. There were no between-group differences in NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels, waist circumference, diastolic blood pressure, glycated hemoglobin, low-density lipoprotein cholesterol levels, and estimated glomerular filtration rates. Across our combined cohort of 5233 patients, hypoglycemia was reported in 22 patients. Conclusions SGLT2 inhibitors improve cardiovascular outcomes in patients without diabetes mellitus with heart failure. In patients without diabetes mellitus, SGLT2 inhibitors showed positive metabolic outcomes in weight and blood pressure control.
| S-EPMC8174267 | biostudies-literature
Project description:BackgroundAn increasing number of studies have shown that sodium glucose cotransporter 2 (SGLT2) inhibitors, initially used as antidiabetic agents, have cardiovascular (CV) benefits. However, few bibliometric analyses have examined this field systematically. Our study aimed to visualize the publications to determine the trends and hotspots in CV research on SGLT2 inhibitors.MethodsPublications on SGLT2 inhibitors in cardiovascular research were retrieved from the Web of Science Core Collection. Microsoft Excel 2019, VOSviewer, and CiteSpace V were used to analyze and plot the references.ResultsOn July 3, 2020, 1509 records of CV research on SGLT2 inhibitors published from 2013 to 2020 were retrieved. Nearly half were authored by American scholars, and most were published in Diabetes Obesity Metabolism, Cardiovascular Diabetology, and Diabetes Therapy. The USA was the leading driving force, with a strong academic reputation in this area. Inzucchi SE published the most related articles, while Neal B was cited the most frequently. All the top 10 co-cited references were in the leading co-cited journal, The New England Journal of Medicine. "Atherosclerotic cardiovascular event" was the leading research hotspot. The keywords "cardiac metabolism," "heart failure hospitalization," and "heart failure with preserved ejection fraction" appeared most recently as research frontiers.ConclusionMost studies focused on clinical trial outcomes, such as cardiovascular death and heart failure (HF) hospitalization. The mechanisms of SGLT2 inhibitors, especially those related to cardiac metabolism, may soon become hotspots and should be closely monitored.
| S-EPMC7522576 | biostudies-literature
Project description:ObjectiveSodium-glucose cotransporter-2 inhibitors (SGLT2Is) reduce cardio-metabolic and renal outcomes in patients with type 2 diabetes (T2D) but their efficacy and safety in older or frail individuals remains unclear.MethodsWe searched PubMed, Scopus, Web of Science, Cochrane CENTRA and Google Scholar and selected randomised controlled trials and observational studies comparing SGLT2Is versus placebo/other glucose-lowering agent for people with frailty or older individuals (>65 years) with T2D and heart failure (HF). Extracted data on the change in HbA1c % and safety outcomes were pooled in a random-effects meta-analysis model.ResultsWe included data from 20 studies (22 reports; N = 77,083 patients). SGLT2Is did not significantly reduce HbA1c level (mean difference -0.13, 95%CI: -0.41 to 0.14). SGLT2Is were associated with a significant reduction in the risk of all-cause mortality (risk ratio (RR) 0.81, 95%CI: -0.69 to 0.95), cardiac death (RR 0.80, 95%CI: -0.94 to 0.69) and hospitalisation for heart failure (HHF) (RR 0.69, 95%CI: 0.59-0.81). However, SGLT2Is did not demonstrate significant effect in reducing in the risk of macrovascular events (acute coronary syndrome or cerebral vascular occlusion), renal progression/composite renal endpoint, acute kidney injury, worsening HF, atrial fibrillation or diabetic ketoacidosis.ConclusionsIn older or frail patients with T2D and HF, SGLT2Is are consistently linked with a decrease in total mortality and the overall burden of cardiovascular (CV) events, including HHF events and cardiac death, but not protective for macrovascular death or renal events. Adverse events were more difficult to quantify but the risk of diabetic ketoacidosis or acute kidney injury was not significantly increase.
| S-EPMC10825241 | biostudies-literature
Project description:BackgroundCardiac arrhythmias are associated with poorer outcomes in patients with heart failure (HF), diabetes mellitus (DM), and chronic kidney disease (CKD). Previous studies have shown inconsistent conclusions regarding the association between sodium-glucose cotransporter 2 inhibitors (SGLT2i) and the risk of developing arrhythmias. This study aims to investigate the association of SGLT2i treatment with arrhythmia outcomes in clinical trials of patients with HF, DM, or CKD.MethodsMEDLINE, EMBASE, and ClinicalTrials.gov were searched from inception up to 27 August 2020. Randomized controlled trials that randomized patients with DM, CKD, or HF to SGLT2i or placebo were included. The outcomes of interest include atrial fibrillation (AF), embolic stroke, atrial flutter (AFL), AF/AFL, ventricular tachycardia (VT), and cardiac arrest. Relative risks (RRs) and 95% confidence intervals (CI) were pooled using a random-effects model.ResultsOut of 4,532 citations, 22 trials with altogether 52,115 patients were included (mean age 63.2 years; 33,747 [64.8%] of participants were men). SGLT2i were associated with a lower risk of AF (RR 0.82, 95% CI 0.70-0.96), embolic stroke (RR 0.32, 95% CI 0.12-0.85), AF/AFL (RR 0.82, 95% CI 0.71-0.95), and VT (RR 0.73, 95% CI 0.53-0.99), while the risk reductions in AFL (RR 0.83, 95% CI 0.58-1.17) and cardiac arrest (RR 0.83, 95% CI 0.61-1.14) did not reach statistical significance. The associations appeared to be consistent across different baseline conditions (DM vs CKD vs HF; atherosclerotic cardiovascular disease [ASCVD] vs no ASCVD) and the SGLT2i used.ConclusionsSGLT2i reduced the risk of cardiac arrhythmias. Our study provides further evidence for recommending the use of SGLT2i in patients with DM, CKD, and HF. Further research is needed to fully elucidate the mechanism by which SGLT2i protect against arrhythmias.
| S-EPMC8106208 | biostudies-literature
Project description:Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease affecting more than 1% of the population over 65 years old. The etiology of the disease is unknown and there are only symptomatic managements available with no known disease-modifying treatment. Aging, genes, and environmental factors contribute to PD development and key players involved in the pathophysiology of the disease include oxidative stress, mitochondrial dysfunction, autophagic-lysosomal imbalance, and neuroinflammation. Recent epidemiology studies have shown that type-2 diabetes (T2DM) not only increased the risk for PD, but also is associated with PD clinical severity. A higher rate of insulin resistance has been reported in PD patients and is suggested to be a pathologic driver in this disease. Oral diabetic drugs including sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and dipeptidyl peptidase-4 (DPP-4) inhibitors have been shown to provide neuroprotective effects in both PD patients and experimental models; additionally, antidiabetic drugs have been demonstrated to lower incidence rates of PD in DM patients. Among these, the most recently developed drugs, SGLT2 inhibitors may provide neuroprotective effects through improving mitochondrial function and antioxidative effects. In this article, we will discuss the involvement of mitochondrial-related oxidative stress in the development of PD and potential benefits provided by antidiabetic agents especially focusing on sglt2 inhibitors.
| S-EPMC8750793 | biostudies-literature
Project description:Purpose of the reviewSodium-glucose cotransporter-2 inhibitors (SGLT2is) are recommended for eligible patients with type 2 diabetes for the secondary prevention of adverse cardiovascular and kidney disease outcomes. Patients with type 2 diabetes and albuminuric chronic kidney disease, a history of atherosclerotic cardiovascular disease, and/or heart failure with reduced ejection fraction should be assessed for the use of these therapies.Sources of informationThe sources include published clinical trials with SGLT2is, with a focus on cardiovascular safety studies and kidney protection trials.MethodsInformation was gathered via a review of relevant literature and clinical practice guidelines, incorporated with real-life clinical experience.Key findingsClinicians prescribing these agents must be familiar with the benefits of SGLT2is on cardiovascular and renal endpoints, and with adverse effects of SGLT2is, including mycotic genital infections and diabetic ketoacidosis. Primary care physicians and specialists should know how to adjust antihypertensive, antiglycemic, and diuretic agents. With the results of completed cardiovascular outcome trials and the Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy trial, nephrologists specifically have a unique opportunity to impact the safe, effective, and equitable implementation of SGLT2is into clinical practice.LimitationsFurther work is needed in specific patient subgroups, including patients with chronic kidney disease stages IV and V, patients with kidney disease but lower levels of albuminuria, and in patients without diabetes.
| S-EPMC7315675 | biostudies-literature
Project description:BackgroundSodium-glucose cotransporter 2 inhibitors (SGLT2i) are a group of antidiabetic medications with a favourable cardiovascular, renal and overall safety profile. Given the limited treatment options available for neurological disorders, it is important to determine whether the pleiotropic effects of SGLT2i can be utilised in their prevention and management.MethodsAll articles published before 20 March 2021 were systematically searched in MEDLINE, EMBASE, Scopus, Web of Science, APA PsycINFO and ClinicalTrials.gov. Overall, 1395 titles were screened, ultimately resulting in 160 articles being included in the qualitative analysis. Screening and data extraction were conducted by two independent authors and studies were excluded if they were not an original research study.FindingsOf the 160 studies, 134 addressed stroke, 19 cognitive impairment, 4 epilepsy and 4 movement disorders, encompassing a range from systematic reviews and randomised controlled trials to bioinformatic and animal studies. Most animal studies demonstrated significant improvements in behavioural and neurological deficits, which were reflected in beneficial changes in neurovascular units, synaptogenesis, neurotransmitter levels and target receptors' docking energies. The evidence from the minority clinical literature was conflicting and many studies did not reach statistical significance.InterpretationSGLT2i may exert neurological benefits through three mechanisms: reduction in cardiovascular risk factors, augmentation of ketogenesis and anti-inflammatory pathways. Most clinical studies were observational, meaning that a causal relationship could not be established, while randomised controlled trials were heterogeneous and powered to detect cardiovascular or renal outcomes. We suggest that a longitudinal study should be conducted and specifically powered to detect neurological outcomes.
| S-EPMC9006360 | biostudies-literature