Effects of SGLT2 inhibitors on stroke and its subtypes in patients with type 2 diabetes: a systematic review and meta-analysis.
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SUBMITTER: Tsai WH
PROVIDER: S-EPMC8319393 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Previous trial evidence suggested potential risk of serious urinary tract infections (UTIs) and genital infections in type 2 diabetes patients using sodium glucose co-transporter-2 inhibitors (SGLT2) inhibitors. We conducted a systematic review and meta-analysis to assess the effects of SGLT2 inhibitors on UTIs and genital infections in patients with type 2 diabetes. In total, 77 RCTs involving 50,820 participants were eligible. The meta-analyses of randomized controlled trials (RCTs) showed no significant difference in UTIs between SGLT2 inhibitors versus control (2,526/29,086 vs. 1,278/14,940; risk ratio (RR) 1.05, 95% confidence interval (CI) 0.98 to 1.12; moderate quality evidence), but suggested increased risk of genital infections with SGLT2 inhibitors (1,521/24,017 vs. 216/12,552; RR 3.30, 95% CI 2.74 to 3.99; moderate quality evidence). Subgroup analyses by length of follow up (interaction p?=?0.005), type of control (interaction p?=?0.04) and individual SGLT2 inhibitors (interaction p?=?0.03) also showed statistically significant differences in genital infections. The upcoming major trials may provide important additional insights on UTIs, and more efforts are needed to address comparative effects of each individual SGLT2 inhibitors on the infections.
| S-EPMC5460243 | biostudies-literature
Project description:BACKGROUND:Type 2 diabetes is closely related to an increased risk of atrial fibrillation (AF) and atrial flutter (AFL). Whether sodium-glucose cotransporter 2 (SGLT2) inhibitors can attenuate AF/AFL progression remains unclear. METHODS:We searched electronic databases (PubMed, Embase and ClinicalTrials.gov) from their inception to January 2020 for trials evaluating the AF outcomes of SGLT2 inhibitors in patients with type 2 diabetes. The data search and extraction were conducted with a standardized data form and any conflicts were resolved by consensus. Relative risks (RRs) with 95% confidence intervals (CIs) were used for binary variables, and the weighed mean differences (WMDs) with the standard deviation (SDs) were applied for continuous variables. RESULTS:We included data from 16 identified trials consisting of 38,335 patients with type 2 diabetes. Incorporated data demonstrated that compared to placebo, SGLT2 inhibitors significantly reduced AF/AFL (RR: 0.76; 95% CI 0.65-0.90; p?=?0.001) and all-cause mortality (RR: 0.91; 95% CI 0.83-0.99; p?=?0.03). AF/AFL reductions were not modified by age, body weight, glycated haemoglobin (HbA1c), or systolic blood pressure (SBP) at baseline (all p-interactions?>?0.3). SGLT2 inhibitors also significantly reduced heart failure events (RR: 0.73; 95% CI 0.64-0.84; p?<?0.00001), HbA1c (WMD: -?0.62%; 95% CI -?0.89 to -?0.34; p?<?0.00001), body weight (WMD: -?2.12 kg; 95% CI -?2.91 to -?1.34; p?<?0.00001), SBP (WMD: -?3.34 mmHg; 95% CI -?4.12 to -?2.56; p?<?0.00001), and diastolic blood pressure (DBP) (WMD: -?1.11 mmHg; 95% CI -?1.62 to -?0.60; p?<?0.0001). Of note, cerebrovascular events and myocardial infarction did not increase in patients taking SGLT2 inhibitors. CONCLUSION:SGLT2 inhibitors may confer a specific AF/AFL-reduction benefit in the susceptible type 2 diabetes population, regardless of age, body weight, HbA1c, and systolic blood pressure at baseline. Such an AF/AFL-reduction benefit may be partly attributed to pharmacological effects on reductions in HbA1c, body weight, blood pressure, and the occurrence of heart failure.
| S-EPMC7448518 | biostudies-literature
Project description:To assess the efficacy and safety of the SGLT-2 inhibitors as adjunct therapy to insulin in T1DM, clinical trials indexed in PubMed, Cochrane Library, EMbase from inception through April 5, 2016. A meta-analysis was conducted on trials of SGLT-2 inhibitors in patients with T1DM on insulin therapy using RevMan 5.3 software. Of the 371 articles identified, ten met eligibility criteria. Seven clinical trials including four randomized controlled trials and 581 patients were included. Compared with the control group, SGLT-2 inhibitors group had significantly reduced fasting plasma glucose by 0.69 mmol/L [1.32; 0.07], glycosylated hemoglobin A1C by 0.37% [0.54; 0.20], body weight by 2.54 kg [3.48; 1.60] and total daily insulin dose by 6.22 IU [8.04; 4.40]. The total incidence of adverse events (AEs), hypoglycemia, and genital and urinary infections were also similar to placebo, while an increased incidence of diabetic ketoacidosis (DKA) (n = 16) was seen in SGLT-2 inhibitors group. The present study demonstrates that SGLT-2 inhibitors are effective as adjunct therapy to insulin in T1DM, heralding improved glycemic control, reduced body weight and total daily insulin dose without an increase in total AEs, hypoglycemia, or genital and urinary infections. However, the risk of DKA should be carefully monitored in future clinical trials.
| S-EPMC5343472 | biostudies-literature
Project description:BackgroundDespite the number of medications for type 2 diabetes, many people with the condition do not achieve good glycaemic control. Some existing glucose-lowering agents have adverse effects such as weight gain or hypoglycaemia. Type 2 diabetes tends to be a progressive disease, and most patients require treatment with combinations of glucose-lowering agents. The sodium glucose co-transporter 2 (SGLT2) receptor inhibitors are a new class of glucose-lowering agents.ObjectiveTo assess the clinical effectiveness and safety of the SGLT2 receptor inhibitors in dual or triple therapy in type 2 diabetes.Data sourcesMEDLINE, Embase, Cochrane Library (all sections); Science Citation Index; trial registries; conference abstracts; drug regulatory authorities; bibliographies of retrieved papers.Inclusion criteriaRandomised controlled trials of SGLT2 receptor inhibitors compared with placebo or active comparator in type 2 diabetes in dual or combination therapy.MethodsSystematic review. Quality assessment used the Cochrane risk of bias score.ResultsSeven trials, published in full, assessed dapagliflozin and one assessed canagliflozin. Trial quality appeared good. Dapagliflozin 10 mg reduced HbA1c by -0.54% (weighted mean differences (WMD), 95% CI -0.67 to -0.40) compared to placebo, but there was no difference compared to glipizide. Canagliflozin reduced HbA1c slightly more than sitagliptin (up to -0.21% vs sitagliptin). Both dapagliflozin and canagliflozin led to weight loss (dapagliflozin WMD -1.81 kg (95% CI -2.04 to -1.57), canagliflozin up to -2.3 kg compared to placebo).LimitationsLong-term trial extensions suggested that effects were maintained over time. Data on canagliflozin are currently available from only one paper. Costs of the drugs are not known so cost-effectiveness cannot be assessed. More data on safety are needed, with the Food and Drug Administration having concerns about breast and bladder cancers.ConclusionsDapagliflozin appears effective in reducing HbA1c and weight in type 2 diabetes, although more safety data are needed.
| S-EPMC3488745 | biostudies-literature
Project description:BACKGROUND:Optimal glycemic control is required to restrain the increase of cardiovascular events in patients with type 2 diabetes. The effects of sodium-glucose cotransporter-2 (SGLT-2) inhibitors on cardiovascular events and mortality in those patients are not well established. This meta-analysis was conducted to assess the effects of SGLT2 inhibitors on cardiovascular events and mortality in patients with type 2 diabetes. METHODS:We conducted a systematic literature search of Medline, Embase and Cochrane Library and included randomized controlled trials (RCTs) of 3 different SGLT2 inhibitors (canagliflozin, dapagliflozin and empagliflozin) that evaluated the effects on cardiovascular outcomes and mortality in the final meta-analysis. The intervention arm was defined either as SGLT2 inhibitor monotherapy or as SGLT2 inhibitor add-on to other non-SGLT2 inhibitor antidiabetic agents (ADAs). RESULTS:Forty-two trials with a total of 61,076 patients with type 2 diabetes were included in the meta-analysis. Compared with the control, SGLT2 inhibitor treatment was associated with a reduction in the incidence of major adverse cardiovascular events (MACEs) (OR?=?0.86, 95% CI 0.80-0.93, P?<?.0001), myocardial infarction (OR?=?0.86, 95% CI 0.79-0.94, P?=?.001), cardiovascular mortality (OR?=?0.74, 95% CI 0.67-0.81, P?<?.0001) and all cause mortality (OR?=?0.85, 95% CI 0.79-0.92, P?<?.0001). However, the risk of ischemic stroke was not reduced after SGLT2 inhibitor treatment in patients with type 2 diabetes (OR?=?0.95, 95% CI 0.85-1.07, P?=?.42). CONCLUSION:These data suggest a decreased risk of harm with SGLT2 inhibitor as a class with respect to cardiovascular events and mortality.
| S-EPMC6919451 | biostudies-literature
Project description:ObjectiveClinical trials suggest that SGLT2 inhibitors reduce the risk of cardiovascular mortality in patients with type 2 diabetes, however the mechanism is unclear. Our objective was to test the hypothesis that blood pressure reduction is one potential mechanism underlying the observed improvements in cardiovascular outcomes with SGLT2 inhibitors.MethodsWe searched MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials (inception-June 2019) for randomized controlled trials that reported the effect of SGLT2 inhibitors compared with placebo on cardiovascular outcomes in adults with type 2 diabetes. Two reviewers independently extracted data and assessed study quality. Random effects meta-analyses, stratified meta-analyses and meta-regressions were conducted to evaluate the association between blood pressure reduction in SGLT2 inhibitor treated patients and cardiovascular outcomes.ResultsOf 11,232 articles identified, 40 articles (n = 54,279 participants) were included. The relative risk of cardiovascular mortality was reduced by 18% with the use of SGLT2 inhibitors compared with placebo (RR 0.82; 95%CI 0.74, 0.91, I2 = 0.0%). Meta-regression analysis revealed no detectable difference in cardiovascular mortality (RR 0.93; 95%CI 0.88, 1.13, p = 0.483), 3-point major adverse cardiovascular events (p = 0.839) or congestive heart failure hospitalizations (p = 0.844) with change in mean systolic blood pressure.ConclusionsCardiovascular events are reduced in participants with type 2 diabetes treated with SGLT2 inhibitors compared with placebo. There was no significant relationship between the risk of developing adverse cardiovascular events and blood pressure reduction with SGLT2 inhibitors. There is insufficient evidence to suggest that blood pressure reduction is a significant contributor to the cardiovascular benefits observed.
| S-EPMC7892922 | biostudies-literature
Project description:BackgroundA precision medicine approach in type 2 diabetes requires the identification of clinical and biological features that are reproducibly associated with differences in clinical outcomes with specific anti-hyperglycaemic therapies. Robust evidence of such treatment effect heterogeneity could support more individualized clinical decisions on optimal type 2 diabetes therapy.MethodsWe performed a pre-registered systematic review of meta-analysis studies, randomized control trials, and observational studies evaluating clinical and biological features associated with heterogenous treatment effects for SGLT2-inhibitor and GLP1-receptor agonist therapies, considering glycaemic, cardiovascular, and renal outcomes. After screening 5,686 studies, we included 101 studies of SGLT2-inhibitors and 75 studies of GLP1-receptor agonists in the final systematic review.ResultsHere we show that the majority of included papers have methodological limitations precluding robust assessment of treatment effect heterogeneity. For SGLT2-inhibitors, multiple observational studies suggest lower renal function as a predictor of lesser glycaemic response, while markers of reduced insulin secretion predict lesser glycaemic response with GLP1-receptor agonists. For both therapies, multiple post-hoc analyses of randomized control trials (including trial meta-analysis) identify minimal clinically relevant treatment effect heterogeneity for cardiovascular and renal outcomes.ConclusionsCurrent evidence on treatment effect heterogeneity for SGLT2-inhibitor and GLP1-receptor agonist therapies is limited, likely reflecting the methodological limitations of published studies. Robust and appropriately powered studies are required to understand type 2 diabetes treatment effect heterogeneity and evaluate the potential for precision medicine to inform future clinical care.
| S-EPMC10551026 | biostudies-literature
Project description:SGLT2 inhibitors are plausible second-line drugs that provide powerful additional A1c-lowering effects while inducing weight loss without hypoglycemia.
| S-EPMC6375399 | biostudies-literature
Project description:BackgroundGuidelines differ with regard to indications for initial combination pharmacotherapy for type 2 diabetes.AimsTo compare the efficacy and safety of (i) sodium-glucose cotransporter 2 (SGLT2) inhibitor combination therapy in treatment-naïve type 2 diabetes adults; (ii) initial high and low dose SGLT2 inhibitor combination therapy.MethodsPubMed, Embase and Cochrane Library were searched for randomised controlled trials (RCTs) of initial SGLT2 combination therapy. Mean difference (MD) for changes from baseline (HbA1c, weight, blood pressure) after 24?26 weeks of treatment and relative risks (RR, safety) were calculated using a random-effects model. Risk of bias and quality of evidence was assessed.ResultsIn 4 RCTs (n = 3749) there was moderate quality evidence that SGLT2 inhibitor/metformin combination therapy resulted in a greater reduction in HbA1c (MD (95% CI); -0.55% (-0.67, -0.43)) and weight (-2.00 kg (-2.34, -1.66)) compared with metformin monotherapy, and a greater reduction in HbA1c (-0.59% (-0.72, -0.46)) and weight (-0.57 kg (-0.89, -0.25)) compared with SGLT2 inhibitor monotherapy. The high dose SGLT2 inhibitor/metformin combination resulted in a similar HbA1c but greater weight reduction; -0.47 kg (-0.88, -0.06) than the low dose combination therapy. The RR of genital infection with combination therapy was 2.22 (95% CI 1.33, 3.72) and 0.69 (95% CI 0.50, 0.96) compared with metformin and SGLT2 inhibitor monotherapy, respectively. The RR of diarrhoea was 2.23 (95% CI 1.46, 3.40) with combination therapy compared with SGLT2 inhibitor monotherapy.ConclusionsInitial SGLT2 inhibitor/metformin combination therapy has glycaemic and weight benefits compared with either agent alone and appears relatively safe. High dose SGLT2 inhibitor/metformin combination therapy appears to have modest weight, but no glycaemic benefits compared with the low dose combination therapy.
| S-EPMC6352265 | 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