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Meta-Analysis
. 2018 Jan 20;7(2):e007165.
doi: 10.1161/JAHA.117.007165.

Cardiovascular Safety, Long-Term Noncardiovascular Safety, and Efficacy of Sodium-Glucose Cotransporter 2 Inhibitors in Patients With Type 2 Diabetes Mellitus: A Systemic Review and Meta-Analysis With Trial Sequential Analysis

Xin-Lin Zhang  1 , Qing-Qing Zhu  2 , Yu-Han Chen  1 , Xue-Ling Li  1 , Fu Chen  1 , Jian-An Huang  3 , Biao Xu  4
Affiliations
Meta-Analysis

Cardiovascular Safety, Long-Term Noncardiovascular Safety, and Efficacy of Sodium-Glucose Cotransporter 2 Inhibitors in Patients With Type 2 Diabetes Mellitus: A Systemic Review and Meta-Analysis With Trial Sequential Analysis

Xin-Lin Zhang et al. J Am Heart Assoc. .

Abstract

Background: The cardiovascular and long-term noncardiovascular safety and efficacy of SGLT2 (sodium-glucose cotransporter 2) inhibitors have not been well documented.

Methods and results: For cardiovascular outcomes, we performed a meta-analysis with trial sequential analysis of randomized controlled trials and adjusted observational studies, each with a minimum of 26 weeks and 2000 patient-years of follow-up. For long-term noncardiovascular safety and efficacy outcome analyses, we included only randomized controlled trials with at least 2 years and 1000 patient-years of follow-up. Five studies with 351 476 patients were included in cardiovascular outcomes analysis. Meta-analyses showed that SGLT2 inhibitors significantly reduced the risks of major adverse cardiac events (hazard ratio [HR]: 0.80; 95% confidence interval [CI], 0.69-0.92; P=0.002), all-cause mortality (HR: 0.67; 95% CI, 0.54-0.84; P<0.001), cardiovascular mortality (HR: 0.77; 95% CI, 0.60-0.98; P=0.03), nonfatal myocardial infarction (HR: 0.86; 95% CI, 0.76-0.98; P=0.02), hospitalization for heart failure (HR: 0.62; 95% CI, 0.55-0.69; P<0.001), and progression of albuminuria (HR: 0.68; 95% CI, 0.58-0.81; P<0.001). No significant difference in nonfatal stroke was found. Analyses limited to randomized controlled trials showed similar findings. Trial sequential analysis provided firm evidence of a 20% reduction in major adverse cardiac events, all-cause mortality, and hospitalization for heart failure with SGLT2 inhibitors, but evidence remains inconclusive for cardiovascular mortality. Nine randomized controlled trials contributed to long-term noncardiovascular and efficacy analyses. SGLT2 inhibitors reduced incidence of hypoglycemia and acute kidney injury but increased the risks of urinary tract and genital infections.

Conclusions: SGLT2 inhibitors showed remarkable cardiovascular- and renal-protective effects and good long-term noncardiovascular safety with sustained efficacy.

Keywords: SGLT2 (sodium–glucose cotransporter 2) inhibitor; cardiovascular disease; meta‐analysis; observational study; randomized controlled trial; trial sequential analysis.

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Figures

Figure 1
Figure 1
Effects of SGLT2 inhibitors on MACE. CI indicates confidence interval; CANVAS, Canagliflozin Cardiovascular Assessment Study trial; EASEL, the evidence for cardiovascular outcomes with sodium glucose co‐transporter 2 inhibitors in the real world study; EMPA‐REG OUTCOME, BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients; HR, hazard ratio; MACE, major adverse cardiovascular event; SGLT2, sodium–glucose cotransporter 2.
Figure 2
Figure 2
A, Trial sequential analysis for MACE in patients receiving SGLT2 inhibitors vs control. B, Funnel plots showing the trajectory of the overall point estimates and the evolution of their corresponding precision as each study enters the meta‐analysis. CI indicates confidence interval; CANVAS, Canagliflozin Cardiovascular Assessment Study trial; EASEL, the evidence for cardiovascular outcomes with sodium glucose co‐transporter 2 inhibitors in the real world study; EMPA‐REG OUTCOME, BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients; HR, hazard ratio; MACE, major adverse cardiovascular event; SGLT2, sodium–glucose cotransporter 2.
Figure 3
Figure 3
Effects of SGLT2 inhibitors on all‐cause death (top) and cardiovascular death (bottom). CI indicates confidence interval; CANVAS, Canagliflozin Cardiovascular Assessment Study trial; CVD‐REAL, the Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT‐2 Inhibitors study; EASEL, the evidence for cardiovascular outcomes with sodium glucose co‐transporter 2 inhibitors in the real world study; EMPA‐REG OUTCOME, BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients; HR, hazard ratio; SGLT2, sodium–glucose cotransporter 2.
Figure 4
Figure 4
A, Trial sequential analysis for all‐cause death in patients receiving SGLT2 inhibitors vs control. B, Funnel plots showing the trajectory of the overall point estimates and the evolution of their corresponding precision as each study enters the meta‐analysis. CI indicates confidence interval; CANVAS, Canagliflozin Cardiovascular Assessment Study trial; CVD‐REAL, the Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT‐2 Inhibitors study; EASEL, the evidence for cardiovascular outcomes with sodium glucose co‐transporter 2 inhibitors in the real world study; EMPA‐REG OUTCOME, BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients; HR, hazard ratio; SGLT2, sodium–glucose cotransporter 2.
Figure 5
Figure 5
Effects of SGLT2 inhibitors on nonfatal MI (top) and nonfatal stroke (bottom). CI indicates confidence interval; CANVAS, Canagliflozin Cardiovascular Assessment Study trial; EASEL, the evidence for cardiovascular outcomes with sodium glucose co‐transporter 2 inhibitors in the real world study; EMPA‐REG OUTCOME, BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients; HR, hazard ratio; MI, myocardial infarction; SGLT2, sodium–glucose cotransporter 2.
Figure 6
Figure 6
Effects of SGLT2 inhibitors on hospitalization for HF (top) and the composite of hospitalization for HF and cardiovascular death (bottom). CI indicates confidence interval; CANVAS, Canagliflozin Cardiovascular Assessment Study trial; CVD‐REAL, the Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT‐2 Inhibitors study; EASEL, the evidence for cardiovascular outcomes with sodium glucose co‐transporter 2 inhibitors in the real world study; EMPA‐REG OUTCOME, BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients; HF, heart failure; HR, hazard ratio; SGLT2, sodium–glucose cotransporter 2.
Figure 7
Figure 7
Effects of SGLT2 inhibitors on progression of albuminuria. CI indicates confidence interval; CANVAS, Canagliflozin Cardiovascular Assessment Study trial; EMPA‐REG OUTCOME, BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients; HR, hazard ratio; SGLT2, sodium–glucose cotransporter 2.
Figure 8
Figure 8
Meta‐analyses of effects of SGLT2 inhibitors vs control on HbA1c levels. CI indicates confidence interval; CANVAS, Canagliflozin Cardiovascular Assessment Study trial; EMPA‐REG OUTCOME, BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients; SGLT2, sodium–glucose cotransporter 2; WMD, weighted mean difference.
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