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Do background ischemic heart disease and baseline left ventricular ejection fraction affect cardiovascular efficacy of SGLT-2 inhibitors in heart failure with reduced ejection fraction?
Patoulias, D, Papadopoulos, C, Kassimis, G, Doumas, M
Journal of cardiovascular medicine (Hagerstown, Md.). 2022;(1):e30-e32
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Meta-Analysis Assessing the Impact of Major Co-Morbidities, Gender, and Race on Cardiovascular Efficacy of Sodium-Glucose Co-Transporter-2 Inhibitors Among Patients With Heart Failure With Preserved or Reduced Ejection Fraction.
Patoulias, D, Papadopoulos, C, Imprialos, K, Stavropoulos, K, Doumas, M
The American journal of cardiology. 2022;:201-205
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Association of Sodium-Glucose Cotransporter 2 Inhibitors With Cardiovascular Outcomes in Patients With Type 2 Diabetes and Other Risk Factors for Cardiovascular Disease: A Meta-analysis.
Bhattarai, M, Salih, M, Regmi, M, Al-Akchar, M, Deshpande, R, Niaz, Z, Kulkarni, A, Siddique, M, Hegde, S
JAMA network open. 2022;(1):e2142078
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Abstract
IMPORTANCE The cardiovascular outcome in selected populations when sodium-glucose cotransporter 2 inhibitors (SGLT2-Is) are emerging as standard therapy is not clearly understood. It is important to learn the magnitude of cardiovascular benefit using SGLT2-Is across the select subgroups that include both sexes and multiple age and racial and ethnic groups. OBJECTIVES To evaluate the association between use of SGLT2-Is and cardiovascular benefits in a prespecified group in a larger sample size using data obtained from randomized clinical trials. DATA SOURCES Search of electronic databases PubMed, Google Scholar, Web of Science, and Cochrane from inception to January 10, 2021, with additional studies identified through conference papers and meeting presentations, ClinicalTrials.gov, and reference lists of published studies. STUDY SELECTION Placebo-controlled randomized clinical trials in which participants had atherosclerotic cardiovascular disease (ASCVD) or risk factors for ASCVD, diabetes, or heart failure and which reported the primary outcome were included in this study. Multicenter observational and nonobservational studies and those with different outcomes of interest were excluded. DATA EXTRACTION AND SYNTHESIS Medical Subject Heading search terms included SGLT2-I and multiple cardiovascular outcomes in different combinations. The study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. The analysis of all outcomes was performed using a Mantel-Haenszel equation and the random-effects model. MAIN OUTCOMES AND MEASURES Six efficacy outcomes of SGLT2-I use (cardiovascular death and hospitalization for heart failure [HHF] as the primary outcome and major adverse cardiovascular event, HHF, cardiovascular death, acute myocardial infarction, and all-cause mortality as secondary outcomes), were evaluated. Subgroup analysis was performed for the primary outcome of cardiovascular death or HHF. Odds ratios (ORs) and 95% CIs were used to compare 2 interventions. RESULTS Ten studies with 71 553 participants were included, among whom 39 053 received SGLT2-Is; among studies that reported these data, 28 809 were men and 15 655 were women (mean age, 65.2 [range, 61.9-70.0] years). Race and ethnicity were defined in the original trials and were categorized as Asian, Black, or other (6900 participants) and White (26 646 participants) for the purposes of this analysis (the category "other" was not specified consistently). In terms of age, 16 793 were younger than 65 years and 17 087 were 65 years or older. At a mean follow-up 2.3 (range, 0.8-4.2) years, the SGLT2-I group favored reduction in primary outcome (3165 of 39 053 [8.10%] vs 3756 of 32 500 [11.56%]; OR, 0.67 [95% CI, 0.55-0.80]; P < .001). No difference was noted in the rate of acute myocardial infarction compared with the placebo group (1256 of 26 931 [4.66%] vs 958 of 20 373 [4.70%]; OR, 0.95 [95% CI, 0.87-1.03]; P = .22). Subgroup analysis favored SGLT2-I use for the primary outcome in both sexes, age groups, and racial and ethnic groups. CONCLUSIONS AND RELEVANCE This meta-analysis supports that SGLT2-Is have emerged as an effective class of drugs for improving cardiovascular morbidity and mortality in selected patients. Sodium-glucose cotransporter 2 inhibitors were not associated with reduced risk of acute myocardial infarction. Future long-term prospective studies are warranted to understand the long-term cardiovascular benefits.
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Meta-Analysis Addressing the Effect of Sodium-Glucose Cotransporter 2 Inhibitors on Flow-Mediated Dilation in Patients With Type 2 Diabetes Mellitus.
Patoulias, D, Papadopoulos, C, Kassimis, G, Vassilikos, V, Karagiannis, A, Doumas, M
The American journal of cardiology. 2022;:133-135
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Effects of SGLT2 inhibitors on cardiovascular outcomes in patients with stage 3/4 CKD: A meta-analysis.
Li, N, Zhou, G, Zheng, Y, Lv, D, Zhu, X, Wei, P, Zheng, M, Liu, S, Zhou, E, Sun, W, et al
PloS one. 2022;(1):e0261986
Abstract
INTRODUCTION After 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. METHOD To 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. RESULTS In 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. CONCLUSIONS For 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.
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Sodium-Glucose Co-Transporter-2 Inhibitors in Non-Diabetic Adults With Overweight or Obesity: A Systematic Review and Meta-Analysis.
Zheng, H, Liu, M, Li, S, Shi, Q, Zhang, S, Zhou, Y, Su, N
Frontiers in endocrinology. 2021;:706914
Abstract
BACKGROUND Sodium-glucose-cotransporter-2 (SGLT2) inhibitors have proven to be effective in improving glycemic control and lowering body weight in patients with type 2 diabetes mellitus. However, the efficacy and safety on weight loss in adults with overweight or obesity but not diabetes remain unclear. In this article, we aimed to identify the efficacy and safety of SGLT2 inhibitors in adults with overweight or obesity but not diabetes in randomized controlled studies (RCTs). METHODS We searched for RCTs concerning SGLT2 inhibitors in adults with overweight or obesity but not diabetes in Medline (Ovid SP), Embase (Ovid SP), Cochrane Central Register of Controlled Trials (Ovid SP), and ClinicalTrials.gov up to February 2021. The primary outcomes were changes in body weight and body mass index (BMI). Trial sequential analysis (TSA) was used to test the reliability of the primary outcomes. We analyzed the data using Review Manager 5.3 and pooled data to calculate the mean differences (MDs) or the relative risk (RR). We assessed the evidence quality of evidence of outcomes according to GRADE. RESULTS Six randomized controlled trials involving 872 individuals were included in the meta-analysis. Compared to the placebo group, the SGLT2 inhibitors group had statistically significant reductions in absolute changes in body weight (MD: -1.42 kg, 95% CI: -1.70 to -1.14; P<0.00001) and BMI (MD: -0.47 kg/m2, 95% CI: -0.63 to -0.31; P<0.00001) in SGLT2 inhibitors group, as indicated by TSA. However, no significant benefits were observed in the SGLT2 inhibitors group in terms of waist circumference (MD: -1.34 cm, 95%CI: -2.75 to 0.07; Z=1.86, P=0.06) compared with the placebo group. The GRADE profiles indicated very low-quality evidence for body weight change and low-quality evidence for BMI change. SGLT2 inhibitors were generally safe and well tolerated. CONCLUSION SGLT2 inhibitors could be used in selected adults with overweight and obesity but not diabetes if they are at low risk of genital infection and urinary infection. Further studies are warranted to confirm the efficacy and safety of SGLT2 inhibitors in adults with overweight or obesity but not diabetes for long-term weight management. SYSTEMATIC REVIEW REGISTRATION [https://www.crd.york.ac.uk/prospero/#loginpage], identifier [PROSPERO, CRD42021252931].
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Effects of sodium-glucose cotransporter 1 and 2 inhibitors on cardiovascular and kidney outcomes in type 2 diabetes: A meta-analysis update.
Salah, HM, Al'Aref, SJ, Khan, MS, Al-Hawwas, M, Vallurupalli, S, Mehta, JL, Mounsey, JP, Greene, SJ, McGuire, DK, Lopes, RD, et al
American heart journal. 2021;:86-91
Abstract
In this report, we aim to provide an updated meta-analysis of the sodium-glucose cotransporter 2 (SGLT2) inhibitors trial data with the new trial data on sotagliflozin, a first-in-class dual SGLT1 and SGLT2 inhibitor. We searched Medline, Cochrane library, and Embase databases for randomized clinical trials comparing cardiovascular and kidney outcomes between SGLT2 and dual SGLT1/2 inhibitors and placebo. Nine randomized clinical trials with a total of 60,914 patients with type 2 diabetes were included. In patients with type 2 diabetes, the use of SGLT2 and dual SGLT1/2 inhibitors improves the cardiovascular and kidney outcome.
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Efficacy and safety of a sodium-glucose co-transporter-2 inhibitor versus placebo as an add-on therapy for people with type 2 diabetes inadequately treated with metformin and a dipeptidyl peptidase-4 inhibitor: a systematic review and meta-analysis of randomised controlled trials.
De Buitléir, C, O' Connor, E, Satti, MM, Shaw, J, Liew, A
Diabetic medicine : a journal of the British Diabetic Association. 2021;(2):e14409
Abstract
AIMS: To conduct a systematic review and meta-analysis to assess the efficacy, safety and tolerability of sodium-glucose co-transporter-2 inhibitors vs placebo as add-on therapy after metformin and dipeptidyl peptidase-4 inhibitor dual therapy in type 2 diabetes. METHODS This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PROSPERO registration number: CRD42018099398). A search was conducted via PubMed, www.clinicaltrials.gov and Cochrane Central Register of Controlled Trials of relevant randomised controlled trials up until 14 August 2020 that compared sodium-glucose co-transporter-2 inhibitors vs placebo as add-on therapy after metformin and dipeptidyl peptidase-4 inhibitor therapy. A random-effects model was used. RESULTS Six randomised controlled trials (1661 participants) met the inclusion criteria. Compared with placebo, sodium-glucose co-transporter-2 inhibitor treatment, as add-on to metformin and dipeptidyl peptidase-4 inhibitor therapy, was associated with a significant reduction in HbA1c level [mean difference -8 mmol/mol, 95% CI -10, -6 (-0.7%, 95% CI -0.9, -0.6); P < 0.00001], in fasting plasma glucose level [mean difference -1.70 mmol/l, 95% CI -1.91, -1.49; P < 0.00001], in weight (mean difference -1.76 kg, 95% CI -2.04, -1.48; P < 0.00001) and in blood pressure (systolic blood pressure: mean difference -3.6 mmHg, 95% CI -4.8, -2.4; P < 0.00001; diastolic blood pressure: mean difference -1.5 mmHg; 95% CI -2.4, -0.6; P = 0.002). Genital mycotic infections (odds ratio 7.37, 95% CI 3.06, 17.76; P < 0.00001) were more common with sodium-glucose co-transporter-2 inhibitors, but there was no significant statistical difference in urinary tract infections (odds ratio 1.16, 95% CI 0.63, 2.13; P = 0.64), in hypoglycaemia (odds ratio 1.36, 95% CI 0.61, 3.04; P = 0.45), or in discontinuation rates due to adverse events (odds ratio 1.52, 95% CI 0.78, 2.97; P = 0.22) between the two groups. CONCLUSIONS In comparison with placebo, add-on therapy with a sodium-glucose co-transporter-2 inhibitor is significantly more efficacious in lowering HbA1c , fasting plasma glucose and weight in people with type 2 diabetes following inadequate glycaemic control with metformin and a dipeptidyl peptidase-4 inhibitor. The rate of discontinuation due to adverse events was similar despite higher risk of genital mycotic infections.
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Effect of sodium-glucose cotransporter 2 inhibitors on cardiovascular and kidney outcomes-Systematic review and meta-analysis of randomized placebo-controlled trials.
Salah, HM, Al'Aref, SJ, Khan, MS, Al-Hawwas, M, Vallurupalli, S, Mehta, JL, Mounsey, JP, Greene, SJ, McGuire, DK, Lopes, RD, et al
American heart journal. 2021;:10-22
Abstract
UNLABELLED Sodium-glucose cotransporter 2 inhibitor (SGLT2i) use is associated with improved cardiovascular and kidney outcomes. However, the magnitude and potential heterogeneity of effect across patients with varying types of cardiometabolic and kidney disease is unclear. To examine the effect of SGLT2i on cardiovascular and kidney outcomes among patients with type 2 diabetes mellitus (T2DM), and independent of T2DM status, among patients with heart failure (HF), and chronic kidney disease. METHOD Medline, Embase, Cochrane library and scientific conferences were searched from inception till September 24, 2020 for randomized controlled trials comparing cardiovascular and kidney outcomes between SGLT2i and placebo. Random effects hazard ratios (HR) with 95% confidence intervals (CIs) were calculated. RESULTS Eight trials with a combined 59,747 patients were included. In the overall population, SGLT2i reduced the risk of all-cause mortality (HR 0.84; 95% CI [0.78-0.91]), cardiovascular mortality (HR 0.84; 95% CI [0.76-0.93]) hospitalization for HF (HR 0.69; 95% CI [0.64-0.74]), myocardial infarction (HR 0.91; 95% CI [0.84-0.99]), and composite kidney outcome (HR 0.62; 95% CI [0.56-0.70]). There was no significant effect on the risk of stroke (HR 0.98; 95% CI [0.86-1.11]). Results were consistent across subgroups stratified by diabetes and HF status. SGLT2i use was not associated with a greater risk of hypoglycemia (OR 0.92; 95% CI [0.84-1.01]) or amputation (OR 1.25; 95% CI [0.97-1.62]). There were 64 diabetic ketoacidosis events with SGLT2i use and 18 with placebo (OR 2.86; 95% CI [1.39-5.86]). CONCLUSIONS In patients with cardiometabolic and kidney disease, SGLT2i improved cardiovascular and kidney outcomes, regardless of T2DM, HF, and/or CKD status. The magnitude of risk reduction was largest for hospitalization for HF and progression of kidney disease, more modest for mortality and MI and absent for stroke.
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Meta-analysis of Dedicated Renal Outcome Trials Assessing the Cardio-renal Efficacy of Sodium-Glucose Co-transporter-2 Inhibitors in Patients With Chronic Kidney Disease and Albuminuria.
Patoulias, D, Papadopoulos, C, Stavropoulos, K, Imprialos, K, Doumas, M
The American journal of cardiology. 2021;:116-118