Meta-Analysis of Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Cardiovascular Outcomes and All-Cause Mortality Among Patients With Type 2 Diabetes Mellitus

doi:10.1016/j.amjcard.2016.08.061

The American Journal of Cardiology

Volume 118, Issue 11, 1 December 2016, Pages 1774-1780

https://doi.org/10.1016/j.amjcard.2016.08.061 Get rights and content

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.

Section snippets

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 interventions⁷ 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,

Results

A total of 1,268 citations were retrieved through electronic search, from which 172 potentially eligible reports were identified by reviewing study titles and abstracts. Finally, 37 eligible RCTs involving 28,859 patients were included in this meta-analysis (Figure 1). These patients were randomly assigned to a SGLT2 inhibitor (canagliflozin, dapagliflozin, or empagliflozin) or control groups (placebo or other active antidiabetic treatments). Sample sizes of individual trials ranged between 180

Discussion

Our network meta-analysis of all eligible RCTs involving 30,250 patients showed that none of the 3 SGLT2 inhibitors was harmful for CV outcomes or all-cause mortality. For the primary outcomes, only empagliflozin appeared associated with a lower risk of MACE and all-cause mortality compared to placebo, whereas neither dapagliflozin nor canagliflozin was significantly associated with any harm. With respect to secondary outcomes, only empagliflozin had lower risk of heart failure or heart failure

Disclosures

The authors have no conflicts of interest to disclose.

References (30)

O. Marsenic
Glucose control by the kidney: an emerging target in diabetes
Am J Kidney Dis
(2009)
R.A. DeFronzo
The EMPA-REG study: what has it told us? A diabetologist's perspective
J Diabetes Complications
(2016)
J. Lau et al.
Cumulative meta-analysis of clinical trials builds evidence for exemplary medical care
J Clin Epidemiol
(1995)
G. Savarese et al.
Effects of dipeptidyl peptidase 4 inhibitors and sodium-glucose linked cotransporter-2 inhibitors on cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis
Int J Cardiol
(2016)
J.H. Wu et al.
Effects of sodium-glucose cotransporter-2 inhibitors on cardiovascular events, death, and major safety outcomes in adults with type 2 diabetes: a systematic review and meta-analysis
The Lancet Diabetes Endocrinol
(2016)
C. Palombo et al.
Arterial stiffness, atherosclerosis and cardiovascular risk: pathophysiologic mechanisms and emerging clinical indications
Vascul Pharmacol
(2016)
D. Vasilakou et al.
Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis
Ann Intern Med
(2013)
B. Hirshberg et al.
Impact of the U.S. Food and Drug Administration cardiovascular assessment requirements on the development of novel antidiabetes drugs
Diabetes Care
(2011)
B. Zinman et al.
Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes
N Engl J Med
(2015)
E.J. Mills et al.
How to use an article reporting a multiple treatment comparison meta-analysis
JAMA
(2012)

B. Hutton et al.

The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations

Ann Intern Med

(2015)

J.P.T. Higgins et al.

Chapter 8: assessing risk of bias in included studies

M.J. Bradburn et al.

Much ado about nothing: a comparison of the performance of meta-analytical methods with rare events

Stat Med

(2007)

F. Keus et al.

Robustness assessments are needed to reduce bias in meta-analyses that include zero-event randomized trials

Am J Gastroenterol

(2009)

I.R. White et al.

Consistency and inconsistency in network meta-analysis: model estimation using multivariate meta-regression

Res Synth Methods

(2012)

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Citation Excerpt :
Besides, the network graph showed an indirect comparative relationship between different interventions was described by using Stata software. Surface under the cumulative ranking curve (SUCRA) probability values were applied to rank the interventions, and SUCRA values of 100% and 0% were assigned to the best and worst treatments (Tang et al., 2016). Provided that the closed loop of interventions was available, a loop-specific approach was explored to examine the inconsistency of evidence (Cai et al., 2018).
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The Cochrane Library, Embase, PubMed, China National Knowledge Infrastructure (CNKI), Allied and Alternative Medieine Database (AMED), Chinese Biological Medicine Database (CBM), Wanfang Database, and Chinese Scientific Journal Database (VIP) were comprehensively searched from their inception to March 10, 2020, for randomized controlled trials (RCTs) focusing on the use of CMIs combined with WM to treat DCM-HF. The quality of the included RCTs was assessed using the Cochrane Handbook 5.1.0. Bayesian network meta-analysis were designed to access the effectiveness of different CMIs.
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The combination between CMIs and WM exerted a more positive effect in DCM-HF treatment. Xinmailong injection + WM had the best performance in treating DCM-HF, followed by Shenmai injection and Huangqi injection. However, due to the low qualities of the original studies, more high-quality studies are needed to support the findings.
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A 2-class latent class model was identified as the best fit for the responses from 147 patients. The first class (49% of sample), termed as “survival-conscious,” stated that they were willing to accept 46% (95% confidence interval [CI]: 2%-90%) UGTI risk in exchange for a reduction from 6% to 1% in all-cause mortality risk. The second class (51% of sample), termed as “UGTI/cost-conscious” were willing to accept significantly lower (6%; CI: 2%-11%, and 5%; CI: 2%-8%) UGTI risk in exchange for the same reduction in all-cause mortality and hospitalization risks, respectively.
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Diabetic macrovascular complications contribute to nonignorable causes of morbidity and mortality in patients with diabetes mellitus (DM). In this study, the trends of risk factors and macrovascular complications were examined in patients with DM in Taiwan.
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View all citing articles on Scopus

: Drs. Tang and Song were supported by the Indiana University Health–Indiana University School of Medicine Strategic Research Initiative.

: See page 1779 for disclosure information.

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ReviewMeta-Analysis of Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Cardiovascular Outcomes and All-Cause Mortality Among Patients With Type 2 Diabetes Mellitus

Section snippets

Methods

Results

Discussion

Disclosures

Am J Kidney Dis

J Diabetes Complications

J Clin Epidemiol

Int J Cardiol

The Lancet Diabetes Endocrinol

Vascul Pharmacol

Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis

Ann Intern Med

Impact of the U.S. Food and Drug Administration cardiovascular assessment requirements on the development of novel antidiabetes drugs

Diabetes Care

Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes

N Engl J Med

How to use an article reporting a multiple treatment comparison meta-analysis

JAMA

The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations

Ann Intern Med

Chapter 8: assessing risk of bias in included studies

Much ado about nothing: a comparison of the performance of meta-analytical methods with rare events

Stat Med

Robustness assessments are needed to reduce bias in meta-analyses that include zero-event randomized trials

Am J Gastroenterol

Consistency and inconsistency in network meta-analysis: model estimation using multivariate meta-regression

Res Synth Methods

Review
Meta-Analysis of Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Cardiovascular Outcomes and All-Cause Mortality Among Patients With Type 2 Diabetes Mellitus