The benefit or risk of sodium glucose cotransporter 2 (SGLT2) inhibitors on cardiovascular (CV) outcomes in patients with type 2 diabetes mellitus has not been established. We aimed to assess the comparative CV safety and mortality risk associated with the use of SGLT2 inhibitors. PubMed, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov were systematically searched up to January 27, 2016, to identify randomized controlled trials (RCTs) with the use of SGLT2 inhibitors of at least 24 weeks of duration. The primary outcomes included all-cause mortality and major adverse cardiovascular events. A random-effects network meta-analysis was performed to calculate the odds ratio (OR) with 95% CI. We identified 37 eligible trials involving 29,859 patients that compared 3 SGLT2 inhibitors (canagliflozin, dapagliflozin, and empagliflozin) to placebo and other active antidiabetic treatments. Of all direct and indirect comparisons, only empagliflozin compared with placebo was significantly associated with lower risk of all-cause mortality (OR 0.67, 95% CI 0.56 to 0.81) and major adverse cardiovascular events (OR 0.81, 95% CI 0.70 to 0.93). However, the significant effect of empagliflozin was largely driven by one large randomized trial (EMPA-REG OUTCOME trial). Neither dapagliflozin nor canagliflozin was significantly associated with any harm. In conclusion, current RCT evidence suggests that 3 common SGLT2 inhibitors are not associated with increased risk of all-cause mortality and CV outcomes when used to treat patients with type 2 diabetes mellitus. Although empagliflozin may have a protective effect, further confirmative data from rigorous RCTs are needed.
Sodium glucose cotransporter 2 (SGLT2) inhibitors are a novel class of glucose-lowering agents for treating type 2 diabetes mellitus (T2DM), which act insulin independent to selectively inhibit renal glucose reabsorption, thereby increasing urinary glucose excretion. SGLT2 inhibitors have the potential to improve cardiovascular (CV) risk profiles (e.g., lower blood pressure and weight loss). In 2008, the US Food and Drug Administration required a careful CV safety assessment for all novel glucose-lowering agents. Recently, one large rigorously conducted clinical trial (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients, EMPA-REG OUTCOME) found that patients with T2DM at high risk for CV events achieved a CV benefit from empagliflozin as compared with placebo. However, despite such intriguing results, it remains uncertain whether the CV benefits are attributable specifically to empagliflozin alone or represent a class effect. In contrast to conventional pairwise meta-analysis comparing only 2 interventions (A vs B), a network meta-analysis is a useful method for comparing multiple interventions (A vs B vs C vs …), as it analyzed simultaneously both direct comparisons of interventions within randomized controlled trials (RCTs) and indirect comparisons across trials referred to a common comparator (e.g., placebo). We therefore conducted a network meta-analysis of all available RCTs to comprehensively assess the comparative effects of SGLT2 inhibitors on CV safety and mortality and clarify whether potential effects on CV outcomes are a specific drug effect or a class effect.
Methods
This review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions and was registered with international prospective register of systematic reviews (PROSPERO) (number, CRD42015026853).
An electronic search was performed in PubMed, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) through January 27, 2016, to identify eligible RCTs with a combination of relevant search terms ( Supplementary Table 1 ). No limitations of language and year of publication were applied. Additional data from the reference lists of relevant reviews and ClinicalTrials.gov were further searched to ensure identification of published and unpublished trials.
Eligible trials met the following criteria: (1) RCTs with follow-up duration at least 24 weeks; (2) adults (≥18 years of age) with T2DM; (3) SGLT2 inhibitors with any licensed dose used as monotherapy or in combination with other antidiabetic drugs compared with placebo, another SGLT2 inhibitor, or other active antidiabetic treatments; and (4) at least one of our selected CV outcomes was reported in the published study or the results were presented on ClinicalTrials.gov . Our primary outcomes included all-cause mortality and major adverse cardiovascular events (MACE), including death from CV causes, nonfatal myocardial infarction, or nonfatal stroke. The secondary outcomes included heart failure or heart failure requiring hospitalization, unstable angina or unstable angina requiring hospitalization, atrial fibrillation, and transient ischemic attack. The CV events were reported by investigators as an adverse event (or serious adverse event) identified in the database using prespecified lists from the Medical Dictionary for Regulatory Activities.
Two reviewers independently selected the studies and extracted relevant information about trial characteristics and outcomes. If multiple reports from the same trial were retrieved, only the most complete and/or longest follow-up data were used. If CV events were not reported in the manuscript, data from the “Serious Adverse Events” section on the ClinicalTrials.gov were extracted. In addition, if specific CV events were not reported on ClinicalTrials.gov , the incidence of the events was assumed to be 0. If 2 different groups of randomization of nonoverlapping patient groups (e.g., A vs B and C vs D) were included in the same report, each group was considered separately. If 3 arms (e.g., A vs B vs A + B) were evaluated in the RCTs, data from only 2 arms (A vs B) were included. When placebo was switched to an active comparator in the extended period of trials, only the period with placebo was documented. In addition, 2 reviewers independently critically assessed all included RCTs according to the modified Cochrane risk of bias tool. If any data were unclear or missing, the investigators of the original RCTs were contacted for further information. Any disagreements were resolved by consensus or by discussion with a third reviewer.
Pairwise and network meta-analyses were conducted to calculate odds ratios (ORs) with 95% CIs for the primary and secondary outcomes.
For pairwise meta-analyses, a Peto OR was calculated for the effect sizes from direct comparisons because of very low event rate. An I 2 statistic was used to evaluate the presence of heterogeneity within meta-analyses, with I 2 of <25%, ≥25% and <75%, and ≥75% indicating a low, moderate, and high level of evidence of statistical heterogeneity, respectively.
For indirect and mixed comparisons, a network meta-analysis with a random-effects model was performed to compare different SGLT2 inhibitors. For zero-event RCT, a 0.5 zero-cell correction was applied before meta-analysis. The network meta-analysis was performed with Stata version 14 using the “mvmeta” command and programmed STATA routines. To rank the SGLT2 inhibitors for a specified outcome, we estimated the relative ranking probability of each treatment using surface under the cumulative ranking curve (SUCRA) and mean ranks. For all-cause mortality and CV outcomes, higher SUCRA score and lower mean rank indicate a safer intervention. In addition, a clustered ranking plot of the network was performed to group the treatments based on the SUCRA probabilities for MACE and any-cause mortality. The heterogeneity variance (tau) was used to estimate the extent of between-study heterogeneity.
To check for the presence of inconsistency, a loop inconsistency–specific approach was introduced to evaluate the difference between direct and indirect estimates for a specific comparison. To check the assumption of consistency in the entire network, a design-by-treatment interaction model using the chi-square test was used. Otherwise, to investigate the robustness of the findings, we assessed the effect of differing trial and participant characteristics on the primary outcomes in sensitivity analyses by restricting to trials with follow-up at least 52 weeks, white patients, SGLT2 inhibitors combination therapy, and trials without prespecified CV events as primary outcomes. In addition, when primary outcomes with any SGLT2 inhibitor detected a significant difference, a cumulative meta-analysis was conducted to assess the robustness of evidence over time. Finally, a comparison-adjusted funnel plot was used to assess small study effects within a network of interventions.
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