Dataset Information

SGLT-2 inhibitors and cardiorenal outcomes in patients with or without type 2 diabetes: a meta-analysis of 11 CVOTs.

ABSTRACT:

Background

It has been suggested that sodium-glucose cotransporter 2 (SGLT-2) inhibitors reduce the cardiorenal risk in patients with type 2 diabetes (T2D). The purpose of this study is to provide an update of all large cardiovascular outcome trials (CVOTs) with SGLT-2 inhibitors to assess their cardiorenal efficacy in patients with and without T2D.

Methods

An electronic search up to 30 September 2021 was conducted in PubMed, EMBASE, the Cochrane Database of Systematic Reviews, and ClinicalTrials.gov. to determine eligible trials. We included CVOTs comparing any SGLT-2 inhibitor with placebo, reporting desired cardiovascular or renal outcomes and with a follow-up duration of at least 6 months.

Results

Eleven CVOTs, with data from five SGLT-2 inhibitors (empagliflozin, canagliflozin, dapagliflozin, ertugliflozin and sotagliflozin) and 77,541 participants, were included. In the overall analysis, the risk of the composite CV mortality or hospitalization for heart failure (HF) was reduced by 23% (HR = 0.77, 95% CI 0.73-0.82, P < 0.001) compared with placebo, with not significant heterogeneity (I² = 26%, P = 0.20), and irrespective of the presence of T2D (P for interaction = 0.81) and age (> 65 vs ≤ 65 years, P for interaction = 0.78). The risk of CV mortality, total mortality and hospitalization for HF was significantly reduced by 16%, 13%, and 32%, respectively; similarly, the risk of the composite renal outcome was reduced by 35% (HR = 0.65, 95% CI 0.56-0.75), with moderate heterogeneity (I² = 32%). In the analysis of 6 CVOTs reporting the data, the risk of major cardiovascular events (MACE) was reduced by 12%, with low heterogeneity (I² = 21.2%, P = 0.19) and irrespective of the presence of established CV disease at baseline (P for interaction = 0.46).

Conclusions

Therapy with SGLT-2 inhibitors in patients with cardiometabolic and renal diseases results in a sustained to moderate reduction of the composite CV death or hospitalization for HF, robust reduction of HF and renal outcomes, moderate reduction of CV mortality, total mortality and MACE.

SUBMITTER: Giugliano D

PROVIDER: S-EPMC8680308 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:IntroductionFor people with type 2 diabetes (T2DM) inadequately controlled with oral antidiabetic drugs (OADs), evidence from both randomized controlled trials (RCTs) and real-world studies has demonstrated that treatment intensification with liraglutide offers effective glycemic control, weight reduction, and a lower risk of hypoglycemia compared to treatment intensification with insulin or additional OADs. Sodium glucose cotransporter 2 (SGLT-2) inhibitors are a new class of OADs that have also been shown to be effective in T2DM patients inadequately controlled with OADs. Currently there are no head-to-head RCTs comparing these to liraglutide.MethodsWe aimed to evaluate the relative efficacy, using network meta-analysis (NMA), of treatment intensification with liraglutide and SGLT-2 inhibitors people with T2DM who have been treated with metformin (alone or in combination with SU, DPP-4, and TZD). We performed a systematic literature review to identify relevant RCTs comparing liraglutide (1.2 and 1.8 mg), canagliflozin (100 and 300 mg), empagliflozin (10 and 25 mg), or dapagliflozin (5 and 10 mg) to placebo. To strengthen the indirect evidence base, we also included non-placebo RCTs where sitagliptin (100 mg) was the active comparator. Bayesian NMA was performed on the following outcomes to assess the relative efficacy and safety of interventions: reduction (change) in HbA1c, weight, and fasting plasma glucose (FPG) as well as proportion reaching target HbA1c (<7%), and risk of hypoglycemia. Doses for each intervention were considered separately.ResultsA total of 16 RCTs were identified. All trials were similar with respect to important baseline characteristics and study design. Both doses of liraglutide were generally statistically significantly superior to the SGLT-2s with respect to change from baseline in HbA1c and FPG as well as odds of reaching target HbA1c <7%. For weight, canagliflozin 300 mg was superior to liraglutide 1.2 mg, and SGLT-2s were generally associated with larger change from baseline in weight. For risk of major or minor hypoglycemia, no differences were found between treatments.ConclusionsCompared to SGLT-2 inhibitors, liraglutide offers improvement in HbA1c and FPG. Reductions in weight are likely comparable between liraglutide and SGLT-2s. Liraglutide did not differ from SGLT-2s in terms of risk of hypoglycemia. Given the lack of head-to-head evidence, this analysis provides valuable insight into the comparative outcomes of liraglutide versus SGLT-2 inhibitors.

Project description:Background and aimsGlucose lowering agents that reduce the risk of major adverse cardiovascular events (MACE) would be considered a major advance. The reduction of cardiovascular risk by sodium-glucose cotransporter 2 inhibitors (SGLT-2i) has been confirmed by some large-scale randomized controlled studies (RCTs) and systematic reviews of RCTs, but exact indicators of cardiovascular risk remained controversial. Whether consistent results can be obtained in clinical practice is unclear. Therefore, in this meta-analysis, we analyzed the real-world effect of SGLT-2i on cardiovascular outcome in patients with type 2 diabetes mellitus (T2DM).MethodsWe did a real-world systematic review and meta-analysis of cardiovascular outcome of SGLT-2i in patients with T2DM. We searched PubMed and Embase for trials published up to October 23, 2019. Data search and extraction were completed with a standardized data form and any discrepancies were resolved by consensus. The primary outcome was MACE and all-cause mortality (ACM). Secondary outcomes were hospitalization for heart failure (HHF), atrial fibrillation (AF), myocardial infarction (MI), stroke, cardiovascular mortality (CVM), unstable angina (UA), heart failure (HF). Odds ratio (OR) with 95% CIs were pooled across trials, and cardiovascular outcomes were stratified by baseline incidence of cardiovascular disease (CVD), usage rate of cardiovascular benefit drug, follow-up period and region.ResultsFourteen trials enrolling 3,157,259 patients were included. SGLT-2i reduced MACE (OR, 0.71; 95% CI 0.67,0.75, P<0.001) and ACM (OR, 0.53; 95% CI 0.49,0.57, P<0.001) compared to other glucose lowering drugs (oGLD). Compared with oGLD, SGLT-2i had significantly lowered the risk of HHF (OR, 0.56; 95% CI 0.46,0.68, P<0.001), MI (OR, 0.77; 95% CI 0.73,0.81, P<0.001), stroke (OR, 0.75; 95% CI 0.72,0.78, P<0.001), CVM (OR, 0.58; 95% CI 0.49,0.69, P<0.001) and HF (OR, 0.56; 95% CI 0.48,0.67, P<0.001), but there was no benefit from UA or AF. SGLT-2i significantly reduced the risk of severe hypoglycemia (OR, 0.78; 95% CI 0.69,0.90, P<0.001) and lower limb amputation (OR, 0.83; 95% CI 0.71,0.98, P<0.001), but it may increase the risk of diabetic ketoacidosis. Subgroup analysis showed SGLT-2i reduced the risk of MACE, ACM, HHF, MI, stroke, CVM and HF with a similar benefit regardless of the incidence of CVD was (20-30)% or < 15%, (15-30)% or <15% have been treated with GLP-1 receptor agonists (GLP-1RA), >80% or <70% have been treated with statins or both GLP-1RA and statins. SGLT-2i reduced the risk of ACM in low-risk population (P<0.001). No inconsistencies were found when stratification was performed at 1 or (3-4) years of follow-up except for BKA followed up for 1 year. SGLT-2i showed similar cardiovascular benefits in the Nordic countries, Asia and the United States.ConclusionsThe predominant impact of SGLT-2i is on cardiovascular outcome driven predominantly by reduction in MACE, ACM, HHF, MI, stroke, CVM, HF, but not UA or AF. SGLT-2i has robust benefits on reducing MACE, ACM, HHF, MI, stroke, CVM and HF regardless of a history of usage rate of GLP-1RA and/or statins and /or metformin. SGLT-2i does not increase the risk of severe hypoglycemia and lower limb amputation.

Project description:Aims: This study aimed to investigate the association between the use of sodium-glucose transporter 2 inhibitors (SGLT-2i) and the risk of diabetic ketoacidosis (DKA), lower limb amputation (LLA), urinary tract infections (UTI), genital tract infections (GTI), bone fracture, and hypoglycemia in cohort studies. Methods: A systematic search was conducted in the PubMed and Embase databases to identify cohort studies comparing the safety of SGLT-2i versus other glucose-lowering drugs (oGLD) in patients with type 2 diabetes mellitus (T2DM). The quality of the studies was assessed using the Newcastle-Ottawa Scale. Primary endpoints were DKA and LLA, while secondary endpoints included UTI, GTI, bone fracture, and hypoglycemia. Hazard ratios (HR) with 95% confidence intervals (CI) were calculated. Results: A total of 9,911,454 patients from 40 cohort studies were included in the analysis. SGLT-2i use was associated with a higher risk of DKA (HR: 1.21, 95% CI: 1.07-1.38, p = 0.003) and GTI (HR: 2.72, 95% CI: 2.48-2.98, p < 0.01). However, it was not associated with an increased risk of LLA (HR: 1.06, 95% CI: 0.92-1.23, p = 0.42), UTI (HR: 0.99, 95% CI: 0.89-1.10, p = 0.83), or bone fracture (HR: 0.99, 95% CI: 0.94-1.04, p = 0.66). Furthermore, SGLT-2i was associated with a reduced risk of hypoglycemia. Furthermore, compared to dipeptidyl peptidase 4 inhibitors, SGLT-2i as a class and individually was associated with an increased risk of DKA. Canagliflozin specifically increased the risk of LLA (HR: 1.19, 95% CI: 1.04-1.36, p = 0.01). The subgroup analysis suggested that SGLT-2i increased the risk of LLA among patients with a history of cardiovascular disease. Conclusion: SGLT-2i versus oGLD was associated with a similar occurrence of LLA, UTI, and bone fracture. However, SGLT-2i was associated with a higher risk of DKA and GTI than oGLD. These findings provide valuable information on the safety profile of SGLT-2i in patients with T2DM and can help inform clinical decision-making.

Project description:BackgroundRandomized controlled trials showed that sodium/glucose cotransporter-2 inhibitors (SGLT2i) protect the heart and kidney in an array of populations with type 2 diabetes (T2D) and increased cardiorenal risk. However, the extent of these benefits also in lower kidney-risk T2D populations needs further investigation.MethodsMembers of Maccabi Healthcare Systems listed in their T2D registry who initiated new glucose lowering agents (GLA), were divided into SGLT2i initiators and other GLAs (oGLAs). Groups were propensity score-matched by baseline demographic and medical characteristics. Two composite cardiovascular outcomes were defined: all-cause mortality (ACM) or hospitalization for heart failure (hHF); and ACM, myocardial infraction (MI) or stroke. The cardiorenal outcome was: ACM, new end-stage kidney disease (ESKD) or ≥ 40% reduction from baseline estimated glomerular filtration rate (eGFR). Renal-specific outcome was new ESKD or ≥ 40% eGFR reduction. Single components of cardiovascular and kidney outcomes were also assessed. Three subgroup definitions of low baseline kidney-risk were used: eGFR > 90 ml/min/1.73 m2; urinary albumin below detectable levels; and low risk according to Kidney Disease: Improving Global Outcomes (KDIGO) classification. Analyses were performed utilizing an unadjusted model, and a model adjusted to baseline eGFR and urinary albumin-to-creatinine ratio.ResultsBetween April 1, 2015 and June 30, 2018; 68,187 patients initiated new GLAs - 11,321 SGLT2i initiators and 42,077 oGLAs initiators were eligible. Propensity score-matching yielded two comparable cohorts; each included 9219 participants. Median follow-up was 1.7 years. Compared to oGLAs, SGLT2i initiators had lower incidence of ACM or hHF [HR95%CI = 0.62(0.51-0.75)]; ACM, MI or stroke [0.67(0.57-0.80)]; the cardiorenal outcome [0.65(0.56-0.76)]; and the renal-specific outcome [0.70(0.57-0.85)]. SGLT2i initiators also had lower risk for ACM, hHF and ≥ 30%, ≥ 40%, ≥ 50%, ≥ 57% eGFR reduction. No difference between groups was observed for MI or stroke. In the low baseline kidney-risk subgroups, SGLT2i initiation was generally associated with lower risk of the cardiovascular and cardiorenal outcomes, driven mainly by lower ACM incidence.ConclusionsOur findings in the general population of patients with T2D demonstrates lower risk of cardiorenal outcomes associated with initiation of SGLT2i compared with oGLAs, including specifically in patients with low baseline kidney-risk.

Project description:ObjectiveType 2 diabetes mellitus(T2DM) is closely related to sarcopenic obesity(SO). Body composition measurement including body weight, body mass index, waist circumference, percentage body fat, fat mass, muscle mass, visceral adipose tissue and subcutaneus adipose tissue, plays a key role in evaluating T2DM and SO. The weight reduction effect of sodium-glucose cotransporter 2(SGLT-2) inhibitors has been demonstrated. However, there are warnings that SGLT-2 inhibitors should be used with caution because they may increase the risk of sarcopenia. The effect of SGLT-2 inhibitors on body composition in T2DM is inconclusive. In this work, a meta-analysis of randomized controlled trials was conducted to evaluate the effect of SGLT-2 inhibitors on body composition in T2DM.MethodsPubMed, the Cochrane Library, EMbase and Web of Science databases were searched by computer. All statistical analyses were carried out with Review Manager version 5. 3. Results were compared by weight mean difference(WMD), with 95% confidence intervals(CI) for continuous outcomes. A random effects model was applied regardless of heterogeneity. The I2 statistic was applied to evaluate the heterogeneity of studies. Publication bias was assessed using Funnel plots.Results18 studies with 1430 participants were eligible for the meta-analysis. SGLT-2 inhibitors significantly reduced body weight(WMD:-2. 73kg, 95%CI: -3. 32 to -2. 13, p<0. 00001), body mass index(WMD:-1. 13kg/m2, 95%CI: -1. 77 to -0. 50, p = 0. 0005), waist circumference(WMD:-2. 20cm, 95%CI: -3. 81 to -0. 58, p = 0. 008), visceral fat area(MD:-14. 79cm2, 95%CI: -24. 65 to -4. 93, p = 0. 003), subcutaneous fat area(WMD:-23. 27cm2, 95% CI:-46. 44 to -0. 11, P = 0. 05), fat mass(WMD:-1. 16kg, 95%CI: -2. 01 to -0. 31, p = 0. 008), percentage body fat(WMD:-1. 50%, 95%CI:-2. 12 to -0. 87, P<0. 00001), lean mass(WMD:-0. 76kg, 95%CI:-1. 53 to 0. 01, P = 0. 05) and skeletal muscle mass(WMD:-1. 01kg, 95%CI:-1. 91 to -0. 11, P = 0. 03).ConclusionSGLT-2 inhibitors improve body composition in T2DM including body weight, body mass index, waist circumference, visceral fat area, subcutaneous fat area, percentage body fat and fat mass reduction, but cause adverse effects of reducing muscle mass. Therefore, until more evidence is obtained to support that SGLT-2 inhibitors increase the risk of sarcopenia, not only the benefit on body composition, but also the adverse effect of the reduction in muscle mass by SGLT-2 inhibitors in T2DM should be considered.

Project description:BackgroundSodium-glucose cotransporter-2 (SGLT2) inhibitors (SGLT2i) showed benefits in type 1 diabetes mellitus (T1DM), but the risk of diabetic ketoacidosis (DKA) limits their use. Ability to predict DKA risk and therapeutic responses would enable appropriate patient selection for SGLT2i. We conducted a meta-analysis and meta-regression of randomized controlled trials (RCTs) evaluating SGLT2i in T1DM to assess moderators of the relative risk (RR) of DKA, of glycemic (HbA1c, fasting plasma glucose, continuous glucose monitoring parameters, insulin dose, and insulin sensitivity indices) and non-glycemic (body mass index (BMI), systolic BP, renal function, albuminuria, and diabetic eye disorders) efficacy, and of other safety outcomes (including hypoglycemia, infections, major adverse cardiovascular events, and death).Methods and findingsWe searched MEDLINE, Cochrane Library, EMBASE, ClinicalTrials.gov, Cochrane CENTRAL Register of Controlled Trials, and other electronic sources through August 30, 2020, for RCTs comparing SGLT2i with active comparators or placebo in adult patients with T1DM. Reviewers extracted data for relevant outcomes, performed random effects meta-analyses, subgroup analyses, and multivariable meta-regression. The strength of evidence was summarized with the GRADE approach. Among 9,914 records identified, 18 placebo-controlled RCTs (7,396 participants, 50% males, mean age 42 y (range 23 to 55 y), 5 different SGLT2i evaluated), were included. Main outcome measures were effect sizes and moderators of glycemic and non-glycemic efficacy and of safety outcomes. In a multivariable meta-regression model, baseline BMI (β = 0.439 [95% CI: 0.211, 0.666], p < 0.001) and estimated glucose disposal rate (eGDR) (β = -0.766 [-1.276, -0.256], p = 0.001) were associated with the RR of DKA (RR: 2.81; 95% CI:1.97, 4.01; p < 0.001, R2 = 61%). A model including also treatment-related parameters (insulin dose change-to-baseline insulin sensitivity ratio and volume depletion) explained 86% of variance across studies in the risk of DKA (R2 = 86%). The association of DKA with a BMI >27 kg/m2 and with an eGDR <8.3 mg/kg/min was confirmed also in subgroup analyses. Among efficacy outcomes, the novel findings were a reduction in albuminuria (WMD: -9.91, 95% CI: -16.26, -3.55 mg/g, p = 0.002), and in RR of diabetic eye disorders (RR: 0.27[0.11, 0.67], p = 0.005) associated with SGLT2i. A SGLT2i dose-response gradient was consistently observed for main efficacy outcomes, but not for adverse events (AEs). Overall, predictors of DKA and of other AEs differed substantially from those of glycemic and non-glycemic efficacy. A limitation of our analysis was the relatively short (≤52 weeks) duration of included RCTs. The potential relevance for clinical practice needs also to be confirmed by real-world prospective studies.ConclusionsIn T1DM, the risk of DKA and main therapeutic responses to SGLT2i are modified by baseline BMI and insulin resistance, by total insulin dose reduction-to-baseline insulin sensitivity ratio, and by volume depletion, which may enable the targeted use of these drugs in patients with the greatest benefit and the lowest risk of DKA.

Project description:BackgroundEmerging evidence suggests that sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are associated with decreased risk of cardiovascular and renal events in type 2 diabetes mellitus (DM) patients. However, no study to date has compared the effect of SGLT-2 inhibitors with that of GLP-1 RAs in type 2 DM patients with chronic kidney disease (CKD). We herein investigated the benefits of SGLT-2 inhibitors and GLP-1 RAs in CKD patients.MethodsWe performed a systematic literature search through November 2020. We selected randomized control trials that compared the risk of major adverse cardiovascular events (MACE) and a composite of renal outcomes. We performed a network meta-analysis to compare SGLT-2 inhibitors with GLP-1 RAs indirectly. Risk ratios (RRs) with corresponding 95% confidence intervals (CI) were synthesized.ResultsThirteen studies were selected with a total of 32,949 patients. SGLT-2 inhibitors led to a risk reduction in MACE and renal events (RR [95% CI]; 0.85 [0.75-0.96] and 0.68 [0.59-0.78], respectively). However, GLP-1 RAs did not reduce the risk of cardiovascular or renal adverse events (RR 0.91 [0.80-1.04] and 0.86 [0.72-1.03], respectively). Compared to GLP-1 RAs, SGLT-2 inhibitors did not demonstrate a significant difference in MACE (RR 0.94 [0.78-1.12]), while SGLT-2 inhibitors were associated with a lower risk of renal events compared to GLP-1 RAs (RR 0.79 [0.63-0.99]). A sensitivity analysis revealed that GLP-1 analogues significantly decreased MACE when compared to placebo treatment (RR 0.81 [0.69-0.95]), while exendin-4 analogues did not (RR 1.03 [0.88-1.20]).ConclusionsIn patients with type 2 DM and CKD, SGLT-2 inhibitors were associated with a decreased risk of cardiovascular and renal events, but GLP-1 RAs were not. SGLT-2 inhibitors significantly decreased the risk of renal events compared to GLP-1 RAs. Among GLP-1 RAs, GLP-1 analogues showed a positive impact on cardiovascular and renal outcomes, while exendin-4 analogues did not.