Net effects of sodium-glucose co-transporter-2 inhibition in different patient groups: a meta-analysis of large placebo-controlled randomized trials

Natalie Staplin^{1

2}, Alistair J Roddick¹, Jonathan Emberson^{1

2}, Christina Reith¹, Alex Riding³, Alexa Wonnacott⁴, Apexa Kuverji⁵, Sunil Bhandari⁶, Colin Baigent¹, Richard Haynes^{1

7}, William G Herrington^{1

7

8}

Affiliations

¹ Medical Research Council Population Health Research Unit at the University of Oxford, Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health (NDPH), University of Oxford, Oxford, UK.
² Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK.
³ Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
⁴ Wales Kidney Research Unit, Cardiff University, Cardiff, UK.
⁵ John Walls Renal Unit, Leicester General Hospital, University Hospitals of Leicester, Leicester, UK.
⁶ Hull University Teaching Hospitals NHS Trust and Hull York Medical School, Hull, UK.
⁷ Oxford Kidney Unit, Churchill Hospital, Oxford, UK.
⁸ Health Data Research UK, University of Oxford, Oxford, UK.

PMID: 34765951
PMCID: PMC8571171
DOI: 10.1016/j.eclinm.2021.101163

Net effects of sodium-glucose co-transporter-2 inhibition in different patient groups: a meta-analysis of large placebo-controlled randomized trials

Natalie Staplin et al. EClinicalMedicine. 2021.

. 2021 Oct 26:41:101163.

doi: 10.1016/j.eclinm.2021.101163. eCollection 2021 Nov.

Authors

Affiliations

¹ Medical Research Council Population Health Research Unit at the University of Oxford, Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health (NDPH), University of Oxford, Oxford, UK.
² Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK.
³ Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
⁴ Wales Kidney Research Unit, Cardiff University, Cardiff, UK.
⁵ John Walls Renal Unit, Leicester General Hospital, University Hospitals of Leicester, Leicester, UK.
⁶ Hull University Teaching Hospitals NHS Trust and Hull York Medical School, Hull, UK.
⁷ Oxford Kidney Unit, Churchill Hospital, Oxford, UK.
⁸ Health Data Research UK, University of Oxford, Oxford, UK.

PMID: 34765951
PMCID: PMC8571171
DOI: 10.1016/j.eclinm.2021.101163

Abstract

Background: The net absolute effects of sodium-glucose co-transporter-2 (SGLT-2) inhibitors across different patient groups have not been quantified.

Methods: We performed a meta-analysis of published large (>500 participants/arm) placebo-controlled SGLT-2 inhibitor trials after systematically searching MEDLINE and Embase databases from inception to 28th August 2021 (PROSPERO 2021 CRD42021240468).

Findings: Four heart failure trials (n=15,684 participants), four trials in type 2 diabetes mellitus at high atherosclerotic cardiovascular risk (n=42,568), and three trials in chronic kidney disease (n=19,289) were included. Relative risks (RRs) for all cardiovascular, renal and safety outcomes were broadly similar across these three patient groups, and between people with or without diabetes. Overall, compared to placebo, allocation to SGLT-2 inhibition reduced risk of hospitalization for heart failure or cardiovascular death by 23% (RR=0.77, 95%CI 0.73-0.80; n=6658), cardiovascular death by 14% (0.86, 0.81-0.92; n=3962), major adverse cardiovascular events by 11% (0.89, 0.84-0.94; n=5703), kidney disease progression by 36% (0.64, 0.59-0.70; n=2275), acute kidney injury by 30% (0.70, 0.62-0.79; n=1013 events) and severe hypoglycaemia by 13% (0.87, 0.79-0.97; n=1484). There was no effect of SGLT-2 inhibition on risk of non-cardiovascular death (0.93, 0.86-1.01; n=2226), but a net 12% reduction in all-cause mortality remained evident (0.88, 0.84-0.93; n=6188). However, the risk of ketoacidosis was 2-times higher among those allocated SGLT-2 inhibitors compared to placebo (2.03, 1.41-2.93; n=159; absolute excess in people with diabetes ∼0.3/1000 patient years). A small increased risk of urinary tract infection was evident (1.07, 1.02-1.13; n=5384) alongside a known increased risk of mycotic genital infections. Overall, risk of lower limb amputations was increased by 16% (1.16, 1.02-1.31; n=1074), but this risk was largely driven by a single outlying trial (CANVAS).

Interpretations: The relative effects of SGLT-2 inhibition on key safety and efficacy outcomes are consistent across the different studied groups of patient. Consequently, absolute benefits and harms are determined by the absolute baseline risk of particular outcomes, with absolute benefits on mortality and on non-fatal serious cardiac/renal outcomes substantially exceeding the risks of amputation and ketoacidosis in the main patient groups studied to date.

Funding: MRC-UK & KRUK.

Keywords: CKD; Heart failure; Randomized trials; Safety; Sodium-glucose co-transporter 2 inhibitors.

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Conflict of interest statement

CTSU has a staff policy of not accepting honoraria or other payments from the pharmaceutical industry, expect for the reimbursement of costs to participate in scientific meetings. NS, JE, CR, CB, RH, and WGH report a grant paid to their institution by Boehringer Ingelheim. SB reports honoraria from Astra Zeneca and Napp. CR is on the Board of Directors for CDISC and reports funding from the British Heart Foundation. RH and WGH also report grants paid to their institution from Novartis, Roche, and Regeneron. CB, CR, and WGH report funding from MRC-UK. WGH reports personal funding from Kidney Research UK and is co-chair of the UK Kidney Association's clinical guideline for use of SGLT-2 inhibitors in adults with chronic kidney disease. All the other authors report no conflicts.

Figures

FIGURE 1: — **Figure 1**
Study selection

FIGURE 2: — **Figure 2**
Effects of SGLT-2 inhibitors on (a) HOSPITALIZATION FOR HEART FAILURE OR CARDIOVASCULAR DEATH and (b) MAJOR ADVERSE CARDIOVASCULAR EVENTS, by patient group and by trial

FIGURE 3: — **Figure 3**
Effects of SGLT-2 inhibitors on (a) CARDIOVASCULAR DEATH and (b) NON-CARDIOVASCULAR DEATH, by patient group and by trial

FIGURE 4: — **Figure 4**
Effects of SGLT-2 inhibitors on KIDNEY DISEASE PROGRESSION, by patient group and by trial

FIGURE 5: — **Figure 5**
Effects of SGLT-2 inhibitors on (a) HOSPITALIZATION FOR HF OR CARDIOVASCULAR DEATH and (b) KIDNEY DISEASE PROGRESSION, by type 2 diabetes mellitus (DM) status

FIGURE 6: — **Figure 6**
Effect of SGLT-2 inhibitors on SAFETY OUTCOMES, by patient group

See this image and copyright information in PMC

References

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Net effects of sodium-glucose co-transporter-2 inhibition in different patient groups: a meta-analysis of large placebo-controlled randomized trials

Affiliations

Net effects of sodium-glucose co-transporter-2 inhibition in different patient groups: a meta-analysis of large placebo-controlled randomized trials

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Grants and funding

LinkOut - more resources

Full Text Sources