Meta-analysis of the effects of four factors on the efficacy of SGLT2 inhibitors in patients with HFrEF.
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ABSTRACT:
SUBMITTER: Qiu M
PROVIDER: S-EPMC8006700 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:There are no relevant meta-analyses that have assessed the safety of the sodium-glucose transporter 2 (SGLT2) inhibitors in different chronic diseases. We aimed at evaluating the safety of four SGLT2 inhibitors in three chronic diseases by meta-analysis of the large randomized trials of SGLT2 inhibitors. We performed random-effects meta-analysis and carried out subgroup analysis according to type of underlying diseases and type of SGLT2 inhibitors. SGLT2 inhibitors versus placebo significantly reduced the risk of acute kidney injury (RR 0.75, 95% CI 0.66-0.85), and showed the reduced trend in the risk of severe hypoglycemia (RR 0.86, 95% CI 0.71-1.03). SGLT2 inhibitors significantly increased the risks of diabetic ketoacidosis (RR 2.57), genital infection (RR 3.75), and volume depletion (RR 1.14); and showed the increased trends in the risks of fracture (RR 1.07), amputation (RR 1.21), and urinary tract infection (RR 1.07). These effects exhibited by SGLT2 inhibitors were consistent across three chronic diseases (i.e. type 2 diabetes, chronic heart failure, and chronic kidney disease) and four SGLT2 inhibitors (i.e. dapagliflozin, empagliflozin, ertugliflozin, and canagliflozin) (all Psubgroup > 0.05). These findings will guide that specific adverse events are monitored when SGLT2 inhibitors are used in clinical practice.
| S-EPMC8481734 | biostudies-literature
Project description:The burden of diabetic kidney disease (DKD) has increased worldwide in the last two decades. Besides the growth of diabetic population, the main contributors to this phenomenon are the absence of novel nephroprotective drugs and the limited efficacy of those currently available, that is, the inhibitors of renin-angiotensin system. Nephroprotection in DKD therefore remains a major unmet need. Three recent trials testing effectiveness of sodium-glucose cotransporter 2 inhibitors (SGLT2-i) have produced great expectations on this therapy by consistently evidencing positive effects on hyperglycemia control, and more importantly, on the cardiovascular outcome of type 2 diabetes mellitus. Notably, these trials also disclosed nephroprotective effects when renal outcomes (glomerular filtration rate and albuminuria) were analyzed as secondary endpoints. On the other hand, the use of SGLT2-i can be potentially associated with some adverse effects. However, the balance between positive and negative effects is in favor of the former. The recent results of Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation Study and of other trials specifically testing these drugs in the population with chronic kidney disease, either diabetic or non-diabetic, do contribute to further improving our knowledge of these antihyperglycemic drugs. Here, we review the current state of the art of SGLT2-i by addressing all aspects of therapy, from the pathophysiological basis to clinical effectiveness.
| S-EPMC6630922 | biostudies-literature
Project description:Introduction: The effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors on renal outcomes in patients with chronic kidney disease (CKD) were initially demonstrated in recent trials. However, the magnitude of renal benefits for CKD patients with different baseline features and underlying diseases remains unclear. Method: We systematically searched the Embase, PubMed, Web of Science, and Cochrane library databases from inception to April 15, 2021 to identify eligible trials. The primary outcome was a composite of worsening kidney function, end-stage kidney disease (ESKD), or renal death. Efficacy and safety outcomes were stratified by baseline features, such as type 2 diabetes, heart failure, atherosclerotic cardiovascular disease, proteinuria, and renal function. Results: A total of nine studies were included. These studies included 25,749 patients with estimated glomerular filtration rate (eGFR)<60 mL/min/1.73 m2 and 12,863 patients with urine albumin-to-creatinine ratio (UACR) >300 mg/g. SGLT2 inhibitors reduced the risk of the primary renal outcome by 30% in patients with eGFR<60 mL/min/1.73 m2 (HR 0.70, [95% CI 0.58-0.83], I2 = 0.00%) and by 43% in patients with UACR > 300 mg/g (HR 0.57, [95% CI 0.48-0.67], I2 = 16.59%). A similar benefit was observed in CKD patients with type 2 diabetes. SGLT2 inhibitors had no clear effects on renal outcomes in patients with eGFR<60 mL/min/1.73 m2 combined with atherosclerotic cardiovascular disease (HR 0.74, [95% CI 0.51-1.06], I2 = 0.00%). However, they reduced the risk of major renal outcomes by 46% (HR 0.54, [95% CI 0.38-0.76], I2 = 0.00%) in patients with atherosclerotic cardiovascular disease and macroalbuminuria (defined as UACR > 300 mg/g). SGLT2 inhibitors did not significantly reduce the risk of major renal outcomes in CKD patients with heart failure (eGFR<60 mL/min/1.73 m2: HR 0.81, [95% CI 0.47-1.38], I2 = 0.00%; UACR > 300 mg/g: HR 0.66, [95% CI 0.41-1.07], I2 = 0.00%). SGLT2 inhibitors showed consistent renal benefits across different levels of eGFR (P interaction = 0.48). Conclusion: SGLT2 inhibitors significantly reduced the risk of the primary outcome in CKD patients. However, for patients with different features and underlying diseases, there exists differences in the renal protective effect.
| S-EPMC8591237 | biostudies-literature
Project description:AimsWe sought to conduct a meta-analysis regarding the safety and efficacy of sodium-glucose co-transporter 2 (SGLT2) inhibitors in patients with heart failure (HF).Methods and resultsMEDLINE, Scopus, Cochrane CENTRAL, and ClinicalTrials.gov were searched from their inception to November 2020 for placebo-controlled randomized controlled trials of SGLT2 inhibitors. Randomized controlled trials were selected if they reported at least one of the prespecified outcomes in patients with HF. Hazard ratios (HRs) or risk ratios and their corresponding 95% confidence intervals were pooled using a random-effects model. A total of seven trials including 16 820 HF patients (N = 8884 in the SGLT2 inhibitor arms; N = 7936 in the placebo arms) were included. In the overall HF cohort, SGLT2 inhibitors compared with placebo significantly reduced the risk of the composite endpoint of first HF hospitalization or cardiovascular death [HR: 0.77 (0.72-0.83); P < 0.001; I2 = 0%], time to first HF hospitalization [HR: 0.71 (0.64-0.78); P < 0.001; I2 = 0], cardiovascular mortality [HR: 0.87 (0.79-0.96); P = 0.005; I2 = 0%], and all-cause mortality [HR: 0.89 (0.82-0.96); P = 0.004; I2 = 0%]. Results remained consistent across HF-specific trials and according to diabetes mellitus status. A trend towards benefit was observed in patients with HF with preserved ejection fraction for the composite of HF hospitalization and cardiovascular death [HR: 0.80 (0.63-1.00); P = 0.05; I2 = 29%]. No increased risk of hypovolaemia, hyperkalaemia, and hypotension was seen with SGLT2 inhibitors compared with placebo.ConclusionsSGLT2 inhibitors significantly improve cardiovascular outcomes including cardiovascular and all-cause mortality in patients with HF without an increased risk of serious adverse events. A trend towards benefit was observed in patients with HF with preserved ejection fraction.
| S-EPMC7755023 | biostudies-literature
Project description:IntroductionAfter 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.MethodTo 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.ResultsIn 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.ConclusionsFor 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.
| S-EPMC8754287 | biostudies-literature
Project description:To jointly assess the safety and effectiveness of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on cardiorenal outcomes and all-cause mortality in type 2 diabetes mellitus (T2DM) with or at high risk of cardiovascular disease (CVD). We performed a systematic review and network meta-analysis, systematically searching the MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and Web of Science databases up to September 2020. Primary outcomes were composite major adverse cardiovascular events (MACEs), hospitalization for heart failure, all-cause mortality and a composite renal outcome. We performed a random effects network meta-analysis estimating the pooled hazard ratio (HR), risk ratio and number needed to treat (NNT). Six trials evaluating empagliflozin, canagliflozin, dapagliflozin and ertugliflozin met the inclusion/exclusion criteria, which comprised 46,969 patients, mostly with established CVD. Pooled estimates (95% CI) of benefits of SGLT2i in terms of HR and NNT were as follows: for all-cause mortality, 0.85 (0.75, 0.97) and 58 (28, 368); for MACE, 0.91 (0.85, 0.97) and 81 (44, 271); for hospitalization for heart failure, 0.70 (0.62, 0.78) and 32 (20, 55); and for composite renal outcome, 0.61 (0.50, 0.74) and 20 (11, 44). Pooled estimates for serious adverse events were 0.92 (95% CI 0.89, 0.95). In patients with T2DM at cardiovascular risk, ertugliflozin is a less potent drug than empagliflozin, canagliflozin or dapagliflozin to prevent cardiorenal events and all-cause mortality. In addition, our data endorse that empagliflozin is the best treatment option among SGLT2i for this type of patient, but the evidence is not consistent enough.
| S-EPMC8233997 | biostudies-literature
Project description:Background: Sodium-glucose co-transporter 2 (SGLT2) inhibitors are an emerging class of glucose-lowering drugs that have become increasingly relevant for the treatment and prevention of heart failure (HF). Therefore, we aimed to investigate various SGLT2 inhibitors in patients with established HF at baseline and focused on the different types of HF. Methods: An extensive search of PubMed and Web of Science until January 2021 was done. Two reviewers, independently and in duplicate, applied the selection criteria. This meta-analysis was conducted according to the PRISMA guidelines. Data were pooled using a random-effects model. Randomized controlled trials (RCTs) of SGLT2 inhibitors vs. a comparator in patients with HF reporting clinical outcomes were included. The primary efficacy outcome was the composite of hospitalization for HF (HHF) or cardiovascular (CV) mortality. All-cause mortality, CV mortality, and HHF were considered as secondary endpoints. Subgroup analyses involving the status of diabetes, type of HF, administered type of SGLT2 inhibitor, sex, age, body mass index (BMI), estimated glomerular filtration rate (eGFR), cause of HF, and concomitant medication were performed. Results: Seventeen RCTs, comprising a total of 20,749 participants, were included (n = 10,848 treated with SGLT2 inhibitors and n = 9,901 treated with a comparator). Treatment with SGLT2 inhibitors in a HF population was associated with a 27% relative risk reduction (RRR) of HHF or CV mortality [risk ratio (RR) = 0.73, 95% CI = 0.68-0.78], 32% RRR of HHF (RR = 0.68, 95% CI = 0.62-074), 18% RRR of CV mortality (RR = 0.82, 95% CI = 0.73-0.91), and 17% RRR of all-cause mortality (RR = 0.83, 95% CI = 0.75-0.91). The effect of SGLT2 inhibitors on the primary endpoint was consistent among the different gliflozines. The effect of SGLT2 inhibitors on the primary endpoint was independent of underlying diabetes mellitus, age, sex, BMI, renal function, and HF type. Conclusions: SGLT2 inhibitors are associated with improved CV outcomes in patients with HF.
| S-EPMC8316592 | biostudies-literature
Project description:AimsThe aim of the present study was to quantitate the hypoglycaemic effects of dipeptidyl peptidase-4 inhibitors (DPP-4i), glucagon-like peptide-1 receptor agonists (GLP-1r) and sodium glucose cotransporter 2 inhibitors (SGLT2i) as add-on treatments to metformin monotherapy in patients with type 2 diabetes mellitus (T2DM) using a model-based meta-analysis (MBMA).MethodsA systematic literature search of public databases was conducted to develop models that describe the time courses of the fasting plasma glucose (FPG)- and haemoglobin A1c (HbA1c)-lowering effects of three antidiabetic classes using NONMEM 7.3.0.ResultsSeventy-six publications were eligible for this study, and 873 FPG and 1086 HbA1c values were collected. We developed a physiological indirect response model that described the time courses of FPG and HbA1c and simulated reductions in these values 90 days after the initiation of add-on treatments. FPG and HbA1c reductions with once weekly exenatide, liraglutide and dulaglutide were greater than those with other drugs. Mean changes from baseline FPG and HbA1c with these drugs were as follows: exenatide (-22.5 and -16.6%), liraglutide (-22.1 and -16.3%), and dulaglutide (-19.3 and -14.3%). The hypoglycaemic effects of DPP-4i and SGLT2i were similar.ConclusionsOnce weekly exenatide, liraglutide and dulaglutide provided better hypoglycaemic effects among the antidiabetic drugs analysed. Long-acting GLP-1r appears to be more useful for T2DM patients inadequately controlled with metformin monotherapy.
| S-EPMC6339993 | biostudies-literature
Project description:To explore the effect and magnitude of effect of sodium-glucose cotransporter-2 (SGLT2) inhibitors on haematocrit and haemoglobin and the related cardiorenal benefits in patients with type 2 diabetes mellitus (T2DM), PubMed, Web of Science, CENTRAL and EMBASE were searched to identify eligible trials. Weighted mean differences (WMDs) with 95% confidence intervals (CIs) were calculated using a random-effects model. Seventy-eight studies were included in the meta-analysis. SGLT2 inhibitors significantly increased haematocrit and haemoglobin levels compared with control (total WMD 2.27% [95% CI 2.08, 2.47] and 6.20 g/L [95% CI 5.68, 6.73], respectively). Except for dapagliflozin (p = 0.000), no notable dose-dependent relationship was revealed for other SGLT2 inhibitors. The effect could be sustained or even slightly increased with long-term therapy (coef. =0.009, 95% CI [0.005, 0.013], p = 0.000). In subgroup analyses, haematocrit elevation increased with higher body mass index (BMI). A greater haematocrit elevation could be observed in white patients or when compared with active controls. In conclusion, SGLT2 inhibitors increased haematocrit and haemoglobin levels in T2DM patients. Changes in haematocrit and haemoglobin seem to be surrogate markers of improvement in renal metabolic stress, and important mediators involved in cardiorenal protection.
| S-EPMC8814934 | biostudies-literature
Project description:BackgroundHeart failure (HF) prognosis without therapy is poor, however introduction of a range of drugs has improved it. We aimed to perform a systematic review on the effects and safety of sodium-glucose transporter 2 inhibitors (SGLT2i) in HF patients.MethodsWe carried out a systematic review of randomized controlled trials (RCTs) on SGLT2i compared to placebo for HF patients. We searched in PubMed, Scopus, Web of Science and EMBASE, with no language restriction, from inception to 31 August 2020. We included nine RCTs comprising three arms (empagliflozin, dapagliflozin and placebo). Effects sizes for continuous variables were expressed as mean differences (MDs) and 95% confidence intervals (CIs). Effects sizes for dichotomous variables were expresses as risk ratio (RR) and 95% CIs. We used random-effect models with the inverse variance method. We performed subgroup meta-analyses by intervention drug and follow-up period.ResultsSGLT2i significantly reduced all-cause mortality (RR: 0.88, 95%CI 0.79-0.98, I2 = 0%), cardiovascular mortality (RR: 0.87, 95%CI 0.77-0.99, I2 = 0%), HF hospitalization (RR: 0.73, 95%CI 0.66-0.81, I2 = 0%) and emergency room visits due to HF (RR: 0.40, 95%CI 0.21-0.76, I2 = 0%), as well as composite outcomes including the previous ones. Besides, it significantly improved the score of the Kansas City Cardiomyopathy Questionnaire (KCCQ, MD: 1.70, 95%CI 1.67-1.73, I2 = 54%). SGLT2i reduced any serious adverse events, blood pressure and weight. However, it increased hematocrit and creatinine. The meta-analysis of RCTs of > 12 weeks of follow-up showed that SGTL2i significantly reduced NT-proBNP.ConclusionsSGLT2i showed to improve critical outcomes in HF patients, and it is apparently safe.
| S-EPMC7734238 | biostudies-literature