scholarly journals Sodium glucose cotransporter 2 inhibitors and risk of major adverse cardiovascular events: multi-database retrospective cohort study

BMJ ◽  
2020 ◽  
pp. m3342 ◽  
Author(s):  
Kristian B Filion ◽  
Lisa M Lix ◽  
Oriana HY Yu ◽  
Sophie Dell’Aniello ◽  
Antonios Douros ◽  
...  

Abstract Objective To compare the risk of cardiovascular events between sodium glucose cotransporter 2 (SGLT2) inhibitors and dipeptidyl peptidase-4 (DPP-4) inhibitors among people with type 2 diabetes in a real world context of clinical practice. Design Multi-database retrospective cohort study using a prevalent new user design with subsequent meta-analysis. Setting Canadian Network for Observational Drug Effect Studies (CNODES), with administrative healthcare databases from seven Canadian provinces and the United Kingdom, 2013-18. Population 209 867 new users of a SGLT2 inhibitor matched to 209 867 users of a DPP-4 inhibitor on time conditional propensity score and followed for a mean of 0.9 years. Main outcome measures The primary outcome was major adverse cardiovascular events (MACE, a composite of myocardial infarction, ischaemic stroke, or cardiovascular death). Secondary outcomes were the individual components of MACE, heart failure, and all cause mortality. Cox proportional hazards models were used to estimate site specific adjusted hazards ratios and 95% confidence intervals, comparing use of SGLT2 inhibitors with use of DPP-4 inhibitors in an as treated approach. Site specific results were pooled using random effects meta-analysis. Results Compared with DPP-4 inhibitors, SGLT2 inhibitors were associated with decreased risks of MACE (incidence rate per 1000 person years: 11.4 v 16.5; hazard ratio 0.76, 95% confidence interval 0.69 to 0.84), myocardial infarction (5.1 v 6.4; 0.82, 0.70 to 0.96), cardiovascular death (3.9 v 7.7; 0.60, 0.54 to 0.67), heart failure (3.1 v 7.7; 0.43, 0.37 to 0.51), and all cause mortality (8.7 v 17.3; 0.60, 0.54 to 0.67). SGLT2 inhibitors had more modest benefits for ischaemic stroke (2.6 v 3.5; 0.85, 0.72 to 1.01). Similar benefits for MACE were observed with canagliflozin (0.79, 0.66 to 0.94), dapagliflozin (0.73, 0.63 to 0.85), and empagliflozin (0.77, 0.68 to 0.87). Conclusions In this large observational study conducted in a real world clinical practice context, the short term use of SGLT2 inhibitors was associated with a decreased risk of cardiovascular events compared with the use of DPP-4 inhibitors. Trial registration ClinicalTrials.gov NCT03939624 .

2021 ◽  
Author(s):  
Mei-Chuan Lee ◽  
Yi-Ming Hua ◽  
Chun-Ting Yang ◽  
Wei-Ting Chang ◽  
Fang-Hsiu Kuo ◽  
...  

Abstract BackgroundHeart failure (HF) has become a healthcare challenge worldwide. Recently, certain trials on sodium-glucose co-transporter-2 (SGLT2) inhibitor showed benefits for patients with HF. This study aimed to systematically review the literature and investigate the clinical efficacy of SGLT2 inhibitors in cardiovascular events among patients with and without HF. Methods We searched randomized controlled trials (RCTs) in PubMed, Cochrane databases, Embase, and ClinicalTrials.gov registry form inception to October 2020. Dichotomous variables were pooled using a random-effects model and presented with a risk ratio (RR) and 95% confidence interval (CI). Subgroup meta-analyses were carried out by high/low SGLT2/SGLT1 selectivity and individual SGLT2 inhibitor.ResultsA total of 10 RCTs comprised of 52,607 patients were eligible for the analyses. SGLT2 inhibitors reduced the risk of total cardiovascular death or hospitalization for HF (RR 0.79, [95% CI: 0.74 to 0.84]; p < 0.01, I2 = 31%). Apart from stroke, SGLT2 inhibitors contributed to a risk reduction in major adverse cardiovascular events (MACE, RR 0.93, [95% CI: 0.88 to 0.99]; p = 0.03, I2 = 0), all-cause mortality (RR 0.92, [95% CI: 0.85 to 0.99]; p = 0.03, I2 = 0), cardiovascular death (RR 0.91, [95% CI: 0.83 to 0.99]; p = 0.03, I2 = 0), hospitalization for HF (RR 0.72, [95% CI: 0.66 to 0.79]; p < 0.01, I2 = 0), and myocardial infarction (RR 0.89, [95% CI: 0.80 to 0.99]; p = 0.03, I2 = 0). For HF patients, SGLT2 inhibitors had more clinical benefits in terms of all-cause mortality and cardiovascular death, while advantages were observed in MACE and myocardial infarction for non-HF patients. Furthermore, SGLT2 inhibitors with low SGLT2/SGLT1 selectivity have better efficacy for hospitalization of HF, compared with high-selectivity inhibitors (RR 0.51 [95% CI: 0.35-0.75] versus 0.73 [95% CI: 0.66-0.81] for HF patients). ConclusionsSGLT2 inhibitors significantly mitigate hospitalization for HF. Between HF and non-HF populations, this regimen reduce mortality for HF patients and improve MACE and myocardial infarction for non-HF patients. The SGLT2 inhibitor, mixed with the effect of SGLT1 inhibitors, may lead to a lower risk of hospitalization for HF.


2018 ◽  
Vol 25 (8) ◽  
pp. 844-853 ◽  
Author(s):  
Safi U Khan ◽  
Swapna Talluri ◽  
Haris Riaz ◽  
Hammad Rahman ◽  
Fahad Nasir ◽  
...  

Background The comparative effects of statins, ezetimibe with or without statins and proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors remain unassessed. Design Bayesian network meta-analysis was conducted to compare treatment groups. Methods Thirty-nine randomized controlled trials were selected using MEDLINE, EMBASE, and CENTRAL (inception – September 2017). Results In network meta-analysis of 189,116 patients, PCSK9 inhibitors were ranked as the best treatment for prevention of major adverse cardiovascular events (Surface Under Cumulative Ranking Curve (SUCRA), 85%), myocardial infarction (SUCRA, 84%) and stroke (SUCRA, 80%). PCSK9 inhibitors reduced the risk of major adverse cardiovascular events compared with ezetimibe + statin (odds ratio (OR): 0.72; 95% credible interval (CrI), 0.55–0.95; Grading of Recommendation Assessment, Development and Evaluation (GRADE) criteria: moderate), statin (OR: 0.78; 95% CrI: 0.62–0.97; GRADE: moderate) and placebo (OR: 0.63; 95% CrI: 0.49–0.79; GRADE: high). The PCSK9 inhibitors were consistently superior to groups for major adverse cardiovascular event reduction in secondary prevention trials (SUCRA, 95%). Statins had the highest probability of having lowest rates of all-cause mortality (SUCRA, 82%) and cardiovascular mortality (SUCRA, 84%). Compared with placebo, statins reduced the risk of all-cause mortality (OR: 0.88; 95% CrI: 0.83–0.94; GRADE: moderate) and cardiovascular mortality (OR: 0.84; 95% CrI: 0.77–0.90; GRADE: high). For cardiovascular mortality, PCSK9 inhibitors were ranked as the second best treatment (SUCRA, 78%) followed by ezetimibe + statin (SUCRA, 50%). Conclusion PCSK9 inhibitors were ranked as the most effective treatment for reducing major adverse cardiovascular events, myocardial infarction and stroke, without having major safety concerns. Statins were ranked as the most effective therapy for reducing mortality.


2021 ◽  
Author(s):  
Joao Pedro Ferreira ◽  
Ana Cristina Oliveira ◽  
Francisca A. Saraiva ◽  
Francisco Vasques-Nóvoa ◽  
Adelino Leite-Moreira

Background: Patients with insulin-treated type 2 diabetes (T2D) have a high risk of major adverse cardiovascular events. Sodium-glucose cotransporter inhibitors (SGLTi) improve outcomes without hypoglycemic risk. Aims: To study the effect of SGLTi in patients with T2D with and without background insulin-treatment in outcome-driven RCTs. Methods: Random effects models. Results: A total of 54,374 patients with T2D were included in the analysis, of which 26,551 (48.8%) were treated with insulin. For 3P-MACE in patients without insulin treatment, the HR (95%CI) for the effect of SGLTi vs. placebo was 0.93 (0.81-1.05), with moderate heterogeneity (I2 =49.2%, Q statistic P =0.11). In insulin-treated patients, the HR (95%CI) was 0.88 (0.82-0.95), without evidence of heterogeneity (I2 =0.0%, Q statistic P =0.91). The pooled effect evidenced a 10% reduction of 3P-MACE with SGLTi (HR 0.90, 95%CI 0.85-0.96), without SGLTi-by-insulin interactionP=0.53. For the composite outcome of HF hospitalisation or cardiovascular death in patients without insulin treatment, the HR (95%CI) for the effect of SGLTi vs. placebo was 0.77 (0.61-0.92), with marked heterogeneity (I2 =66.8%, Q statistic P =0.02). In insulin-treated patients, the HR (95%CI) was 0.77 (0.68-0.86), without significant heterogeneity (I2 =31.7%, Q statistic P =0.25). The pooled effect evidenced a 23% reduction of HF hospitalisations or cardiovascular death with SGLTi (HR 0.77, 95%CI 0.68-0.85), without SGLTi -by-insulin interactionP=0.98. Conclusion:SGLTi reduce cardiovascular events regardless of insulin use. However, the treatment effect is more homogeneous among insulin-treated patients, supporting the use of SGLTi for the treatment of patients with T2D requiring insulin for glycemic control.


Author(s):  
Miaobo Zhai ◽  
Xin Du ◽  
Changmei Liu ◽  
Huipu Xu

BackgroundCardiovascular disease threatens the health and quality of life of individuals, particularly those with type II diabetes. Recently, some studies have reported the effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors in reducing the rates of hospitalization or urgent visits, resulting in IV therapy for heart failure in patients with type 2 diabetes mellitus (T2DM).MethodsWe did a comprehensive search in electronic databases from inception through July 2020 for randomized-controlled trials, using the keywords “sodium-glucose cotransporter-2 inhibitor”, “dapagliflozin”, “heart failure”, “cardiovascular outcomes”, “major adverse cardiovascular events”, “all-cause mortality”, and “cardiovascular death”. Random-effects summary odds ratios (OR) were constructed using M-L heterogeneity model.ResultsFive trials with 5,252 patients were ultimately included. The incidence of hospitalization for heart failure (HHF) (n=4, OR=0.74; 95% CI, 0.61 to 0.88; I2 = 0%) and all-cause mortality (ACM, n=4, OR=0.76; 95% CI, 0.66 to 0.94; I2 = 0%); was reduced by dapagliflozin, respectively, in all heart failure patients, without obvious heterogeneity. The incidence of cardiovascular death in dapagliflozin was lower than that in placebo without statistically significant (CVD, n=5, OR=0.84; 95% CI, 0.69 to 1.03; I2 = 0%). In HFrEF subgroup, dapagliflozin was associated with a reduced incidence of hospitalization for heart failure (n=4, OR=0.74; 95% CI, 0.60 to 0.91; I2 = 0%), cardiovascular death (n=4, OR=0.72; 95% CI, 0.58 to 0.91; I2 = 8%), and all-cause mortality (n=3, OR=0.70; 95% CI, 0.50 to 0.99; I2 = 43%) without significant heterogeneity. In contrast, in the HFpEF subgroup, there was no difference in the incidence of cardiovascular death (n=2, OR=1.45; 95% CI, 0.95 to 2.22; I2 = 0%) and all-cause mortality (n=2, OR=1.04; 95% CI, 0.76 to 1.43; I2 = 0%) between dapagliflozin and placebo.ConclusionIn our study, dapagliflozin performed a statistical reduction in the rate of heart failure hospitalization, cardiovascular death, and all-cause mortality in patients with HFrEF and diabetes. However, in the HFpEF subgroup, dapagliflozin did not show a significant cardiovascular protective effect.


2019 ◽  
Vol 105 (5) ◽  
pp. 1670-1681 ◽  
Author(s):  
Yue Zhou ◽  
Yajing Huang ◽  
Xiaoyun Ji ◽  
Xiang Wang ◽  
Liyan Shen ◽  
...  

Abstract Context The goal of the meta-analysis was to evaluate the effect of pioglitazone on the primary and secondary prevention of cardiovascular diseases (CVDs) and renal adverse events in patients with or at high risk of type 2 diabetes mellitus (T2DM). Design Randomized controlled trials (RCTs) comparing pioglitazone with any control were identified through PubMed, Embase, and the Cochrane Library. Cardiovascular outcomes included major adverse cardiovascular events (MACEs, defined as the composite of nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death), hospitalization for heart failure, and all-cause mortality. Renal outcomes included change in urinary albumin to creatinine ratio and 24-hour urinary protein excretion. Weighted mean difference (WMD) and risk ratio (RR) with 95% confidence intervals (CIs) were pooled. Results A total of 26 studies with 19 645 participants were enrolled. Pioglitazone reduced the risk of MACE (RR, 0.8 [95% CI, 0.7–0.9]), with benefit only seen in patients with a history of established CVDs (0.8 [0.7–0.9]) and not in those without (1.0 [0.7–1.3]). Regarding the individual components, pioglitazone reduced the risk of nonfatal myocardial infarction (0.8 [0.6–1.0]) and nonfatal stroke (0.8 [0.7–0.9]), which was confined to patients with a history of established CVDs, whereas no treatment effect was found on cardiovascular death (1.0 [0.7–1.2]) regardless of the presence of established CVDs. Pioglitazone increased the risk of hospitalization for heart failure (1.3 [1.1–1.6]) and had no treatment effect on all-cause mortality (1.0 [0.8–1.1]). Pioglitazone reduced albuminuria by 18.5% (WMD 18.5% [95% CI, 21.1-16.0]), with a similar benefit in patients with different renal function categories. Conclusions Pioglitazone should be considered in patients with or at high risk of T2DM for the prevention of cardiovascular endpoints, especially in those with a history of established CVD who might benefit the most. Robust reductions in progression of renal disease are seen regardless of baseline renal function degree.


2019 ◽  
Vol 2019 ◽  
pp. 1-8
Author(s):  
Wen-hao Luo ◽  
Yang Guo ◽  
Jie-wu Huang ◽  
Pei-dong Zhang

Objectives. To investigate the influence of statins on major adverse cardiovascular events (MACE) in patients with coronary microvascular dysfunction (CMVD). Participants. 23,494 patients who received coronary angiography (CAG) were included. Thrombolysis in Myocardial Infarction, Myocardial Perfusion Grading (TMPG), a useful angiographic method, was used to evaluate CMVD. Results. Using multivariate analysis, NYHA III/IV (HR, 1.44; 95% CI, 1.03-2.01; P=0.031), PCI history (HR, 3.69; 95% CI, 2.57-5.31; P<0.001), TG (HR, 1.15; 95% CI, 1.06-1.26; P=0.001), creatinine (HR, 1.00; 95% CI, 1.00-1.01; P<0.001), cTnT (HR, 0.98; 95% CI, 0.96-0.99; P<0.001), heart rate (HR, 0.98; 95% CI, 0.97-0.99; P=0.001), β-blocker (HR, 0.68; 95% CI, 0.51-0.91; P=0.008), aspirin (HR, 0.38; 95% CI, 0.24-0.61; P<0.001), and statins (HR, 0.33; 95% CI, 0.19-0.60; P<0.001) significantly correlated with reduced MACE in CMVD patients. In subgroups analysis, statins decreased MACE overall (HR, 0.33; 95% CI, 0.19-0.59; P<0.001) and in CMVD patients with smoking history (HR, 0.64; 95% CI, 0.43-0.93; P=0.014), diabetes (HR,0.27; 95% CI,0.12-0.61; P=0.002), hypertension (HR, 0.10; 95% CI, 0.03-0.36; P=0.001), and hypertension and diabetes (HR, 0.09; 95% CI, 0.014-0.53; P=0.008). Conclusion. Statins could reduce MACE in patients with CMVD.


2019 ◽  
Vol 18 (1) ◽  
Author(s):  
Shih-Chieh Shao ◽  
Kai-Cheng Chang ◽  
Ming-Jui Hung ◽  
Ning-I Yang ◽  
Yuk-Ying Chan ◽  
...  

Abstract Background To compare the cardiovascular event risk in type 2 diabetes patients newly receiving dapagliflozin vs. empagliflozin. Methods We conducted a retrospective cohort study by analyzing a multi-institutional electronic medical records database (Chang Gung Research Database) in Taiwan and included adult type 2 diabetes patients who were newly receiving sodium–glucose co-transporter 2 (SGLT2) inhibitors from 2016 to 2017. The primary outcome was a composite of cardiovascular death, myocardial infarction, ischemic stroke and heart failure. We followed up patients from initiation of SGLT2 inhibitors until the occurrence of cardiovascular events before December 31, 2018. We performed multivariable Cox proportional hazard modeling, adjusting for patients’ age, sex, laboratory data, co-morbidities, and concomitant medications. Results We identified 12,681 new SGLT2 inhibitor users with a mean age of 58.9 (SD 11.8) years, of whom 43.9% were female and 45.8% were new dapagliflozin users. A total of 10,442 person-years of dapagliflozin use and 12,096 person-years of empagliflozin use were included. Compared to empagliflozin users, new users of dapagliflozin were found to have similar risks for primary composite outcome (adjusted HR: 0.91; 95% CI 0.73–1.14), cardiovascular death (adjusted HR: 0.54; 95% CI 0.14–2.12), myocardial infarction (adjusted HR: 0.77, 95% CI 0.49–1.19) and ischemic stroke (adjusted HR: 1.15; 95% CI 0.80–1.65), but a lower risk of heart failure (adjusted HR: 0.68; 95% CI 0.49–0.95). Conclusion The risk of cardiovascular events was similar between dapagliflozin and empagliflozin new users, but dapagliflozin may have a better outcome in the reduction of heart failure in type 2 diabetes patients. Future prospective studies are required to confirm the findings.


2020 ◽  
Vol 31 (12) ◽  
pp. 2925-2936 ◽  
Author(s):  
Megumi Oshima ◽  
Brendon L. Neuen ◽  
JingWei Li ◽  
Vlado Perkovic ◽  
David M. Charytan ◽  
...  

BackgroundThe association between early changes in albuminuria and kidney and cardiovascular events is primarily based on trials of renin-angiotensin system blockade. It is unclear whether this association occurs with sodium-glucose cotransporter 2 inhibition.MethodsThe Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial enrolled 4401 patients with type 2 diabetes and CKD (urinary albumin-creatinine ratio [UACR] >300 mg/g). This post hoc analysis assessed canagliflozin’s effect on albuminuria and how early change in albuminuria (baseline to week 26) is associated with the primary kidney outcome (ESKD, doubling of serum creatinine, or kidney death), major adverse cardiovascular events, and hospitalization for heart failure or cardiovascular death.ResultsComplete data for early change in albuminuria and other covariates were available for 3836 (87.2%) participants in the CREDENCE trial. Compared with placebo, canagliflozin lowered UACR by 31% (95% confidence interval [95% CI], 27% to 36%) at week 26, and significantly increased the likelihood of achieving a 30% reduction in UACR (odds ratio, 2.69; 95% CI, 2.35 to 3.07). Each 30% decrease in UACR over the first 26 weeks was independently associated with a lower hazard for the primary kidney outcome (hazard ratio [HR], 0.71; 95% CI, 0.67 to 0.76; P<0.001), major adverse cardiovascular events (HR, 0.92; 95% CI, 0.88 to 0.96; P<0.001), and hospitalization for heart failure or cardiovascular death (HR, 0.86; 95% CI, 0.81 to 0.90; P<0.001). Residual albuminuria levels at week 26 remained a strong independent risk factor for kidney and cardiovascular events, overall and in each treatment arm.ConclusionsIn people with type 2 diabetes and CKD, use of canagliflozin results in early, sustained reductions in albuminuria, which were independently associated with long-term kidney and cardiovascular outcomes.


BMJ ◽  
2019 ◽  
pp. l4772 ◽  
Author(s):  
Björn Pasternak ◽  
Peter Ueda ◽  
Björn Eliasson ◽  
Ann-Marie Svensson ◽  
Stefan Franzén ◽  
...  

Abstract Objective To investigate the cardiovascular effectiveness of sodium glucose cotransporter 2 (SGLT2) inhibitors in routine clinical practice. Design Cohort study using data from nationwide registers and an active-comparator new-user design. Setting Denmark, Norway, and Sweden, from April 2013 to December 2016. Participants 20 983 new users of SGLT2 inhibitors and 20 983 new users of dipeptidyl peptidase 4 (DPP4) inhibitors, aged 35-84, matched by age, sex, history of major cardiovascular disease, and propensity score. Main outcome measures Primary outcomes were major cardiovascular events (composite of myocardial infarction, stroke, and cardiovascular death) and heart failure (hospital admission for heart failure or death due to heart failure). Secondary outcomes were the individual components of the cardiovascular composite and any cause death. In the primary analyses, patients were defined as exposed from treatment start throughout follow-up (analogous to intention to treat); additional analyses were conducted with an as-treated exposure definition. Cox regression was used to estimate hazard ratios. Results Mean age of the study cohort was 61 years, 60% were men, and 19% had a history of major cardiovascular disease. Of the total 27 416 person years of follow-up in the SGLT2 inhibitor group, 22 627 (83%) was among patients who initiated dapagliflozin, 4521 (16%) among those who initiated empagliflozin, and 268 (1%) among those who initiated canagliflozin. During follow-up, 467 SGLT2 inhibitor users (incidence rate 17.0 events per 1000 person years) and 662 DPP4 inhibitor users (18.0) had a major cardiovascular event, whereas 130 (4.7) and 265 (7.1) had a heart failure event, respectively. Hazard ratios were 0.94 (95% confidence interval 0.84 to 1.06) for major cardiovascular events and 0.66 (0.53 to 0.81) for heart failure. Hazard ratios were consistent among subgroups of patients with and without history of major cardiovascular disease and with and without history of heart failure. Hazard ratios for secondary outcomes, comparing SGLT2 inhibitors with DPP4 inhibitors, were 0.99 (0.85 to 1.17) for myocardial infarction, 0.94 (0.77 to 1.15) for stroke, 0.84 (0.65 to 1.08) for cardiovascular death, and 0.80 (0.69 to 0.92) for any cause death. In the as-treated analyses, hazard ratios were 0.84 (0.72 to 0.98) for major cardiovascular events, 0.55 (0.42 to 0.73) for heart failure, 0.93 (0.76 to 1.14) for myocardial infarction, 0.83 (0.64 to 1.07) for stroke, 0.67 (0.49 to 0.93) for cardiovascular death, and 0.75 (0.61 to 0.91) for any cause death. Conclusions In this large Scandinavian cohort, SGLT2 inhibitor use compared with DPP4 inhibitor use was associated with reduced risk of heart failure and any cause death, but not with major cardiovascular events in the primary intention-to-treat analysis. In the additional as-treated analyses, the magnitude of the association with heart failure and any cause death became larger, and a reduced risk of major cardiovascular events that was largely driven by the cardiovascular death component was observed. These data help inform patients, practitioners, and authorities regarding the cardiovascular effectiveness of SGLT2 inhibitors in routine clinical practice.


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