Elsevier

The Lancet

Volume 393, Issue 10166, 5–11 January 2019, Pages 31-39
The Lancet

Articles
SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials

https://doi.org/10.1016/S0140-6736(18)32590-XGet rights and content

Summary

Background

The magnitude of effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on specific cardiovascular and renal outcomes and whether heterogeneity is based on key baseline characteristics remains undefined.

Methods

We did a systematic review and meta-analysis of randomised, placebo-controlled, cardiovascular outcome trials of SGLT2i in patients with type 2 diabetes. We searched PubMed and Embase for trials published up to Sept 24, 2018. Data search and extraction were completed with a standardised data form and any discrepancies were resolved by consensus. Efficacy outcomes included major adverse cardiovascular events (myocardial infarction, stroke, or cardiovascular death), the composite of cardiovascular death or hospitalisation for heart failure, and progression of renal disease. Hazard ratios (HRs) with 95% CIs were pooled across trials, and efficacy outcomes were stratified by baseline presence of atherosclerotic cardiovascular disease, heart failure, and degree of renal function.

Findings

We included data from three identified trials and 34 322 patients (60·2% with established atherosclerotic cardiovascular disease), with 3342 major adverse cardiovascular events, 2028 cardiovascular deaths or hospitalisation sfor heart failure events, and 766 renal composite outcomes. SGLT2i reduced major adverse cardiovascular events by 11% (HR 0·89 [95% CI 0·83–0·96], p=0·0014), with benefit only seen in patients with atherosclerotic cardiovascular disease (0·86 [0·80–0·93]) and not in those without (1·00 [0·87–1·16], p for interaction=0·0501). SGLT2i reduced the risk of cardiovascular death or hospitalisation for heart failure by 23% (0·77 [0·71–0·84], p<0·0001), with a similar benefit in patients with and without atherosclerotic cardiovascular disease and with and without a history of heart failure. SGLT2i reduced the risk of progression of renal disease by 45% (0·55 [0·48–0·64], p<0·0001), with a similar benefit in those with and without atherosclerotic cardiovascular disease. The magnitude of benefit of SGLT2i varied with baseline renal function, with greater reductions in hospitalisations for heart failure (p for interaction=0·0073) and lesser reductions in progression of renal disease (p for interaction=0·0258) in patients with more severe kidney disease at baseline.

Interpretation

SGLT2i have moderate benefits on atherosclerotic major adverse cardiovascular events that seem confined to patients with established atherosclerotic cardiovascular disease. However, they have robust benefits on reducing hospitalisation for heart failure and progression of renal disease regardless of existing atherosclerotic cardiovascular disease or a history of heart failure.

Funding

None.

Introduction

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have now been studied in several large placebo-controlled cardiovascular outcomes trials1, 2, 3 in patients with type 2 diabetes. These trials were done to satisfy regulatory requirements, specifically to exclude an excess in risk of cardiovascular death, myocardial infarction, or stroke (ie, major adverse cardiovascular events) and to test for efficacy.4 Data to date suggest this drug class appears to moderately reduce the risk of major adverse cardiovascular events, or at least some components of them. However, the apparent greater benefit of SGLT2i on major adverse cardiovascular events in patients with established atherosclerotic cardiovascular disease than in those with multiple risk factors but without atherosclerotic cardiovascular disease complicates the interpretation of these data. This observation has resulted in European and American diabetes and cardiology society guidelines recommending SGLT2i for patients with atherosclerotic cardiovascular disease but not multiple risk factors.5, 6 However, no single trial has been adequately powered to test for such heterogeneity of cardiovascular efficacy by baseline atherosclerotic cardiovascular disease risk categories because the number of patients and events in those patients with multiple risk factors alone have been low. Results from the DECLARE-TIMI 58 trial,3 which had the highest number of patients with multiple risk factors, now allows more rigorous investigation of this issue. Additionally, these same cardiovascular outcome trials1, 2, 7, 8 have shown that SGLT2i robustly reduce the risk of hospitalisation for heart failure and progression of kidney disease. However, data from one trial9 suggested that SGLT2i might reduce the risk of cardiovascular death and hospitalisation for heart failure to a larger extent in patients with a history of heart failure than in those without. Additionally, the glucosuric effects of SGLT2i are dependent on renal function, which raises natural interest in whether the clinical benefit is also related to renal function.10, 11 In terms of safety, SGLT2i might increase the risk of amputations,2, 12 fractures,2, 13 and diabetic ketoacidosis,14, 15, 16 but these events are infrequent, making it difficult to draw meaningful conclusions from individual trials.

Research in context

Evidence before this study

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have been studied in large cardiovascular outcome trials in patients with type 2 diabetes and were shown to reduce the risk of cardiovascular events. Both patients with established atherosclerotic cardiovascular disease and those with multiple risk factors but without the disease were studied in these trials. Within individual trials, the magnitude of benefit appeared to be greater on major adverse cardiovascular events in subgroups with established atherosclerotic cardiovascular disease, although formal heterogeneity was not shown. Based on these findings, American and European guidelines recommend use of SGLT2i for patients with type 2 diabetes and atherosclerotic cardiovascular disease, independent of glucose control considerations. However, no single trial has been adequately powered to test for such heterogeneity because the number of patients and events in those patients with multiple risk factors alone have been low. We prospectively planned to meta-analyse cardiovascular outcome results from the dedicated cardiovascular outcome trials stratified by presence or absence of established atherosclerotic cardiovascular disease, once data from the DECLARE-TIMI 58 trial of dapagliflozin versus placebo became available. We searched PubMed and Embase using the Medical Subject Heading terms “diabetes mellitus, type 2”, “sodium-glucose-co transporter 2 inhibitor”, and “clinical trial” for trials published up to Sept 24, 2018, to find all randomised cardiovascular outcome trials for SGLT2i.

Added value of this study

Incorporating data from the trials EMPA-REG OUTCOME, the CANVAS Program, and DECLARE-TIMI 58, the present meta-analysis of SGLT2i cardiovascular outcome trials showed that the clinical benefit of SGLT2i in reducing the risk of myocardial infarction, stroke, or cardiovascular death was present only in patients with established atherosclerotic cardiovascular disease and not in those with multiple risk factors. Conversely, the reductions in risk of hospitalisation for heart failure or progression of renal disease were robust regardless of the presence of atherosclerotic cardiovascular disease or heart failure at baseline.

Implications of all the available evidence

These data suggest that SGLT2i should be considered in patients with type 2 diabetes regardless of presence of atherosclerotic cardiovascular disease or history of heart failure, given that SGLT2i safely reduce HbA1c and reduce the risk of hospitalisation for heart failure and progression of renal disease across a broad spectrum of patients with type 2 diabetes. Reductions in major adverse cardiovascular events can also be expected in patients with established atherosclerotic cardiovascular disease.

The goal of the present meta-analysis was to combine data from all the large-scale placebo-controlled cardiovascular outcome trials of SGLT2i to gain more reliable estimates of the efficacy and safety of specific outcomes overall and in relevant subgroups.

Section snippets

Search strategy and selection criteria

For this meta-analysis, we used the methods proposed in the Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement.17, 18, 19 This analysis was prespecified in the statistical analysis plan of the DECLARE-TIMI 58 trial.3 A data search (TAZ, MSS) of all randomised, placebo-controlled, cardiovascular outcome trials of SGLT2i published up to Sept 24, 2018, was done on PubMed and Embase. The search algorithm is presented in detail in the appendix. Data extraction was done by

Results

We identified a total of three trials1, 2, 3 and six secondary analyses7, 9, 10, 11, 24, 25 from the same trials that were eligible for inclusion (appendix). The appendix has an overview of the search and the selection process. In total, data from 34 322 patients were included. The mean age was 63·5 years and 35·1% were women (table). A total of 20 650 (60·2%) patients were known to have atherosclerotic cardiovascular disease and 13 672 (39·8%) had multiple risk factors but without known

Discussion

The present meta-analysis of SGLT2i cardiovascular outcome trials substantially expands on previous meta-analyses,26 and the totality of these data now makes several patterns clear. First, SGLT2i have their greatest and most consistent effect on reducing the relative risk of hospitalisation for heart failure (31%) and of progression of renal disease (45%). Their effect on the composite atherosclerotic outcome of myocardial infarction, stroke, or cardiovascular death (major adverse cardiac

References (40)

  • K Radholm et al.

    Canagliflozin and heart failure in type 2 diabetes mellitus: results from the CANVAS Program (Canagliflozin Cardiovascular Assessment Study)

    Circulation

    (2018)
  • BL Neuen et al.

    Cardiovascular and renal outcomes with canagliflozin according to baseline kidney function: data from the CANVAS Program

    Circulation

    (2018)
  • C Wanner et al.

    Empagliflozin and clinical outcomes in patients with type 2 diabetes mellitus, established cardiovascular disease, and chronic kidney disease

    Circulation

    (2018)
  • HY Chang et al.

    Association between sodium-glucose cotransporter 2 inhibitors and lower extremity amputation among patients with type 2 diabetes

    JAMA Intern Med

    (2018)
  • M Alba et al.

    The effects of canagliflozin, a sodium glucose co-transporter 2 inhibitor, on mineral metabolism and bone in patients with type 2 diabetes mellitus

    Curr Med Res Opin

    (2016)
  • C Bonner et al.

    Inhibition of the glucose transporter SGLT2 with dapagliflozin in pancreatic alpha cells triggers glucagon secretion

    Nat Med

    (2015)
  • SK Garg et al.

    Effects of sotagliflozin added to insulin in patients with type 1 diabetes

    N Engl J Med

    (2017)
  • 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)
  • D Moher et al.

    Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement

    Syst Rev

    (2015)
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