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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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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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Effects of Sodium/Glucose Cotransporter 2 (SGLT2) Inhibitors on Cardiovascular and Metabolic Outcomes in Patients Without Diabetes Mellitus: A Systematic Review and Meta-Analysis of Randomized-Controlled Trials.
Teo, YH, Teo, YN, Syn, NL, Kow, CS, Yoong, CSY, Tan, BYQ, Yeo, TC, Lee, CH, Lin, W, Sia, CH
Journal of the American Heart Association. 2021;(5):e019463
Abstract
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.
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Systematic review and meta-analysis for prevention of cardiovascular complications using GLP-1 receptor agonists and SGLT-2 inhibitors in obese diabetic patients.
Uneda, K, Kawai, Y, Yamada, T, Kinguchi, S, Azushima, K, Kanaoka, T, Toya, Y, Wakui, H, Tamura, K
Scientific reports. 2021;(1):10166
Abstract
Patients with type 2 diabetes mellitus (T2DM) and obesity are at high risk of developing cardiovascular disease (CVD). Both glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter (SGLT-2) inhibitors have been shown to prevent CVD in T2DM patients. Additionally, the two drugs reduce body mass. However, it is unknown which drug is more effective at reducing the risk of CVD in such patients. We searched Medline, EMBASE, and Cochrane Library records to February 20, 2021 and performed a network meta-analysis to compare the efficacy with which the drugs reduced the risk of major adverse cardiovascular events (MACE). We included 102,728 patients in 12 studies containing data of obesity subgroup analyses. In T2DM patients with obesity, GLP-1 RAs significantly reduced the risk of MACE versus placebo (relative risk, RR [95% confidence interval, CI]: 0.88 [0.81-0.96]), whereas SGLT-2 inhibitors showed a tendency (RR [95% CI]: 0.91 [0.83-1.00]). In an indirect comparison, GLP-1 RAs were not associated with a significant difference in MACE compared with SGLT-2 inhibitors (RR [95% CI]: 0.97 [0.85-1.09]). Thus, GLP-1 RAs are effective at preventing MACE than placebo in T2DM patients with obesity, although further studies are warranted to conclude their superiority to SGLT-2 inhibitors.
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Sodium-glucose cotransporter inhibitors as add-on therapy in addition to insulin for type 1 diabetes mellitus: A meta-analysis of randomized controlled trials.
Zou, H, Liu, L, Guo, J, Wang, H, Liu, S, Xing, Y, Deng, C, Xiao, Y, Zhou, Z
Journal of diabetes investigation. 2021;(4):546-556
Abstract
AIMS/INTRODUCTION Several clinical trials reported the effects of sodium-glucose cotransporter (SGLT) inhibitors in type 1 diabetes patients. This meta-analysis aimed to assess the efficacy and safety of SGLT inhibitors in type 1 diabetes patients. MATERIALS AND METHODS Relevant studies were identified in the PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure and Wan Fang databases through 1 April 2020. Differences were expressed as the 95% confidence interval (CI) or weighted mean difference (WMD) for continuous outcomes, and risk ratio (RR) for discontinuous outcomes. RESULTS A total of 13 RCTs with 7,962 cases were included. SGLT inhibitors reduced the fasting plasma glucose level (WMD -1.320 mmol/L, 95% CI -1.609 to -1.031, P < 0.001), glycated hemoglobin level (WMD -0.386%, 95% CI -0.431 to -0.342, P < 0.001) and daily total insulin dose (WMD -5.403, 95% CI -7.218 to -3.859, P < 0.001). However, higher risks of diabetic ketoacidosis (RR 5.042, 95% CI 3.160-8.046, P < 0.001), urinary tract infections (RR 1.259, 95% CI 1.034-1.533,P = 0.022) and genital infections (RR 2.995, 95% CI 1.953-4.594, P < 0.001) were associated with SGLT inhibitors, but SGLT inhibitors did not increase the hypoglycemia risk (RR 0.980, 95% CI 0.840-1.144,P = 0.799). In subgroup analysis, with a significant reduction of fasting plasma glucose, glycated hemoglobin and daily insulin doses, SGLT1/2 inhibitor did not increase genitourinary tract infections compared with a placebo. CONCLUSIONS SGLT2 and SGLT1/2 inhibitors can improve glycemic control in patients with type 1 diabetes.
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Cardiovascular safety and efficacy of metformin-SGLT2i versus metformin-sulfonylureas in type 2 diabetes: systematic review and meta-analysis of randomized controlled trials.
Gebrie, D, Getnet, D, Manyazewal, T
Scientific reports. 2021;(1):137
Abstract
Diabetes is a serious threat to global health and among the top 10 causes of death, with nearly half a billion people living with it worldwide. Treating patients with diabetes tend to become more challenging due to the progressive nature of the disease. The role and benefits of combination therapies for the management of type 2 diabetes are well-documented, while the comparative safety and efficacy among the different combination options have not been elucidated. We aimed to systematically synthesize the evidence on the comparative cardiovascular safety and efficacy of combination therapy with metformin-sodium-glucose cotransporter-2 inhibitors versus metformin-sulfonylureas in patients with type 2 diabetes. We searched MEDLINE-PubMed, Embase, Cochrane Library, and ClinicalTrials.gov up to 15 August 2019 without restriction in the year of publication. We included randomized controlled trials of patients with type 2 diabetes who were on metformin-sodium-glucose cotransporter-2 inhibitors or metformin-sulphonylureas combination therapy at least for a year. The primary endpoints were all-cause mortality and serious adverse events, and the secondary endpoints were cardiovascular mortality, non-fatal myocardial infarction, non-fatal stroke, hypoglycemia, and changes in glycated hemoglobin A1c (HbA1c), body weight, fasting plasma glucose, blood pressure, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol. We used a random-effects meta-analysis model to estimate mean differences for continuous outcomes and risk ratio for dichotomous outcomes. We followed PICOS description model for defining eligibility and the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) 2015 guidelines for reporting results. Of 3,190 citations, we included nine trials involving 10,974 participants. The pooled analysis showed no significant difference in all-cause mortality (risk ration [RR] = 0.93, 95% CI [0.52, 1.67]), serious adverse events (RR = 0.96, 95% CI [0.79, 1.17]) and adverse events (RR = 1.00, 95% CI [0.99, 1.02]) between the two, but in hypoglycemia (RR = 0.13, 95% CI [0.10, 0.17], P < 0.001). Participants taking metformin-sodium glucose cotransporter-2 inhibitors showed a significantly greater reduction in HbA1c (mean difference [MD] = - 0.10%, 95% CI [- 0.17, - 0.03], body weight (MD = - 4.57 kg, 95% CI [- 4.74, - 4.39], systolic blood pressure (MD = - 4.77 mmHg, 95% CI [- 5.39, - 4.16]), diastolic blood pressure (MD = - 2.07 mmHg, 95% CI [- 2.74, - 1.40], and fasting plasma glucose (MD = - 0.55 mmol/L, 95% CI [- 0.69, - 0.41]), p < 0.001. Combination therapy of metformin and sodium-glucose cotransporter-2 inhibitors is a safe and efficacious alternative to combination therapy of metformin and sulphonylureas for patients with type 2 diabetes who are at risk of cardiovascular comorbidity. However, there remains a need for additional long-term randomized controlled trials as available studies are very limited and heterogeneous.
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Protective Effects of Sodium-Glucose Transporter 2 Inhibitors on Atrial Fibrillation and Atrial Flutter: A Systematic Review and Meta- Analysis of Randomized Placebo-Controlled Trials.
Li, D, Liu, Y, Hidru, TH, Yang, X, Wang, Y, Chen, C, Li, KHC, Tang, Y, Wei, Y, Tse, G, et al
Frontiers in endocrinology. 2021;:619586
Abstract
BACKGROUND Hyperglycemia is associated with an increased risk of developing atrial fibrillation (AF) and atrial flutter (AFL). Sodium-glucose transporter 2 inhibitors (SGLT2i) have been reported to prevent AF/AFL in some studies, but not others. Therefore, a meta-analysis was performed to investigate whether SGLT2i use is associated with lower risks of AF/AFL. METHODS PubMed, Scopus, Web of Science, Cochrane library databases were searched for randomized placebo-controlled trials comparing SGLT2i and placebo. RESULTS A total of 33 trials involving 66,685 patients were included. The serious adverse events (SAEs) of AF/AFL occurrence were significantly lower in the SGLT2i group than the placebo group (0.96% vs. 1.19%; RR 0.83; 95% CI 0.71-0.96; P = 0.01; I2 25.5%). Similarly, the SAEs of AF occurrence was significantly lower in the SGLT2i group (0.82% vs. 1.06%; RR 0.81; 95% CI 0.69-0.95; P = 0.01; I2 10.2%). The subgroup analysis showed that the reduction in AF/AFL was significant only for dapagliflozin (1.02% vs. 1.49%; RR 0.73; 95% CI 0.59-0.89; P = 0.002; I2 0%), but not for canagliflozin (1.00% vs 1.08%; RR 0.83; 95% CI 0.62-1.12; P = 0.23; I2 0%), empagliflozin (0.88% vs 0.70%; RR 1.20; 95% CI 0.76-1.90; P = 0.43; I2 0%), ertugliflozin (1.01% vs 0.96%; RR 1.08; 95% CI 0.66-1.75; P = 0.76; I2 0%), and sotagliflozin (0.16% vs 0.10%; RR 1.09; 95% CI 0.13-8.86; P = 0.93; I2 0%). CONCLUSIONS SGLT2i use is associated with a 19.33% lower SAEs of AF/AFL compared with the placebo. Dapagliflozin users had the lowest SAEs of AF/AFL incidence. Further studies are needed to determine whether canagliflozin, empagliflozin, ertugliflozin, and sotagliflozin similarly exert protective effects against AF/AFL development.
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The efficacy of dapagliflozin for type 1 diabetes: a meta-analysis of randomized controlled studies.
Ma, J, Zhao, Y, Fan, H, Liu, J
African health sciences. 2021;(1):1-7
Abstract
INTRODUCTION The efficacy of dapagliflozin for type 1 diabetes remains controversial. We conduct a systematic review and meta-analysis to explore the treatment efficacy of dapagliflozin versus placebo in patients with type 1 diabetes. METHODS We have searched PubMed, EMbase, Web of science, EBSCO and Cochrane library databases through May 2019 for randomized controlled trials (RCTs) assessing the effect of dapagliflozin versus placebo for type 1 diabetes. This meta-analysis is performed using the random-effect model. RESULTS Six RCTs are included in the meta-analysis. Overall, compared with control group for type 1 diabetes, dapagliflozin treatment shows favorable impact on glycated hemoglobin HbA1c (standard mean difference SMD=-3.93; 95% confidence interval CI =-4.44 to -3.48; P<0.00001), HbA1c reduction of ≥0.5% (risk ratio RR=1.98; 95% CI=1.65 to 2.39; P<0.00001), and fasting plasma glucose FPG (SMD=-0.93; 95% CI=-1.77 to -0.10; P=0.03). There is no statistical difference of hypoglycemia (RR=1.09; 95% CI=0.66 to 1.79; P=0.75) or adverse events (RR=1.07; 95% CI=0.96 to 1.20; P=0.20) between two groups, but the incidence of ketone-related events is higher than those in control group (RR=0.28; 95% CI=3.96 to 11.52; P=0.01). CONCLUSIONS Dapagliflozin treatment benefits to reduce HbA1c and FPG for type 1 diabetes.
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Patients With Type 2 Diabetes Mellitus and Heart Failure Benefit More From Sodium-Glucose Cotransporter 2 Inhibitor: A Systematic Review and Meta-Analysis.
Chen, C, Peng, H, Li, M, Lu, X, Huang, M, Zeng, Y, Dong, G
Frontiers in endocrinology. 2021;:664533
Abstract
BACKGROUND Patients with type 2 diabetes mellitus (T2DM) and heart failure (HF) are at higher risk of mortality and hospitalization for heart failure (HHF). A recent study showed that sodium-glucose cotransporter 2 (SGLT-2) inhibitors may be a promising choice. METHODS We searched the PubMed, Embase, and Cochrane databases of clinical trials for randomized controlled trials investigating the long-term effects of SGLT-2 inhibitors in patients with T2DM and HF compared with placebo. The primary outcome was cardiovascular death or HHF, and the secondary outcomes included cardiovascular death (CV death), HHF, and all-cause mortality. We also conducted an exploratory analysis and tried to identify the population, which will benefit more from the treatment. RESULTS After the study selection, a total of 5 trials, including 4 subgroup analyses, met the eligibility criteria. The results suggested that the use of SGLT-2 inhibitors was associated with a reduction in the incidence of CV death or HHF (HR, 0.69[95%CI, 0.63-0.77], P<0.00001), CV death (HR, 0.80[95%CI, 0.69-0.92], P = 0.001), HHF (HR, 0.67[95%CI, 0.60-0.76], P < 0.00001), and all-cause mortality (HR, 0.74[95%CI, 0.64-0.86], P < 0.0001). Moreover, patients with T2DM and HF may benefit more from the treatment than those with T2DM/HF. CONCLUSION The long-term use of SGLT-2 inhibitors can help reduce the risk of mortality and HHF in patients with T2DM and HF. SYSTEMATIC REVIEW REGISTRATION PROSPERO [https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021233156], identifier [CRD42021233156].
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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].