EFFECTS OF CANAGLIFLOZIN ON BETA-CELL FUNCTION AND INSULIN RESISTANCE IN TYPE 2 DIABETES MELLITUS: DATA FROM THE CANVAS TRIAL

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EFFECTS OF CANAGLIFLOZIN ON BETA-CELL FUNCTION AND INSULIN RESISTANCE IN TYPE 2 DIABETES MELLITUS: DATA FROM THE CANVAS TRIAL

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Co-author 1

HC Arthur Tang atang@georgeinstitute.org.au The George Institute for Global Health, University of New South Wales, Sydney, Australia School of Clinical Medicine, University of Hong Kong, Hong Kong Renal and Metabolic Hong Kong Hong Kong, China *

Co-author 2

Emily K Yeung eyeung@georgeinstitute.org.au The George Institute for Global Health, University of New South Wales, Sydney, Australia Renal and Metabolic Sydney Australia -

Co-author 3

Amanda Siriwardana asiriwardana@georgeinstitute.org.au The George Institute for Global Health, University of New South Wales, Sydney, Australia Renal and Metabolic Sydney Australia -

Co-author 4

Luke Buizen lbuizen@georgeinstitute.org The George Institute for Global Health, University of New South Wales, Sydney, Australia Biostatistics and Data Science Division Sydney Australia -

Co-author 5

Sydney C.W Tang scwtang@hku.hk School of Clinical Medicine, University of Hong Kong, Hong Kong Department of Medicine Hong Kong Hong Kong, China -

Co-author 6

Min Jun mjun@georgeinstitute.org.au The George Institute for Global Health, University of New South Wales, Sydney, Australia Renal and Metabolic Sydney Australia -

Co-author 7

Sradha Kotwal skotwal@georgeinstitute.org.au The George Institute for Global Health, University of New South Wales, Sydney, Australia Renal and Metabolic Sydney Australia -

Co-author 8

Clare Arnott carnott@georgeinstitute.org.au The George Institute for Global Health, University of New South Wales, Sydney, Australia Cardiovascular Sydney Australia -

Co-author 9

David ZI Cherney david.cherney@uhn.ca Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada Department of Medicine Toronto Canada -

Co-author 10

Bruce Neal bneal@georgeinstitute.org.au The George Institute for Global Health, University of New South Wales, Sydney, Australia George Institute Australia Sydney Australia -

Co-author 11

Vlado Perkovic vlado.perkovic@unsw.edu.au The George Institute for Global Health, University of New South Wales, Sydney, Australia George Institute Australia Sydney Australia -

Co-author 12

Hiddo JL Heerspink h.j.lambers.heerspink@umcg.nl The George Institute for Global Health, University of New South Wales, Sydney, Australia George Institute Australia Groningen Netherlands -

Co-author 13

Brendon L Neuen bneuen@georgeinstitute.org.au The George Institute for Global Health, University of New South Wales, Sydney, Australia Renal and Metabolic Sydney Australia -

Co-author 14

Co-author 15

Introduction

Sodium–glucose cotransporter 2 (SGLT2) inhibitors improve glycaemic control in those with established type 2 diabetes and reduce the incidence of new onset diabetes in those without it. The homeostatic model assessment of insulin resistance (HOMA-IR) is a validated measure of insulin resistance, while the proinsulin-to-C-peptide (PIC) ratio serves as a surrogate marker of β-cell function. We evaluated the effects of the SGLT2 inhibitor canagliflozin on insulin resistance and β-cell function, as assessed by HOMA-IR and PIC ratio, in patients with type 2 diabetes and high risk of atherosclerotic cardiovascular disease.

Methods

We performed a post-hoc analysis of the CANVAS trial, which assessed the effects of canagliflozin on cardiovascular and kidney outcomes in patients with type 2 diabetes at high risk of atherosclerotic cardiovascular disease. We used mixed-effects models for repeated measures to estimate the effects of canagliflozin on changes in log-transformed HOMA-IR and PIC ratio, expressed as geometric mean ratios, over 2 years. We further evaluated whether baseline HOMA-IR and PIC ratio modified the effects of canagliflozin on clinical outcomes, including (i) hospitalization for heart failure or cardiovascular death and (ii) chronic kidney disease progression (≥40% decline in eGFR, kidney failure, or kidney-related death), using Cox regression with treatment-by-subgroup interaction terms.

Results

Overall, 2987 (91.0%) and 1747 (53.2%) participants had available data to calculate HOMA-IR and PIC at baseline. Participants with higher baseline HOMA-IR were more likely to be younger, have higher HbA1c, higher BMI and history of heart failure. Participants with higher baseline PIC ratio were more likely to be younger, male, receiving insulin and have a higher HbA1c. Compared to placebo, canagliflozin reduced HOMA-IR over two years by 22% (95% CI -18% to -27%; P<0.001; Figure 1).

Compared to placebo, canagliflozin also reduced HOMA-IR 22% (95% CI -18% to -27%; P<0.001; Figure 1) The effects of canagliflozin on cardiovascular and kidney outcomes were consistent regardless of baseline PIC and HOMA-IR (all P-interaction >0.05; Figure 2).

Figure 1: Geometric mean changes over 2 years for PIC and HOMA-IR

Geometric mean change over 2 year for PIC and HOMA-IR

HOMA-IR: Homeostatic Model Assessment of Insulin Resistance

Figure 2a Relative effect of canagliflozin versus placebo on clinical outcomes by PIC tertile

Relative effect of canagliflozin on clinical outcome by PIC tertile

Figure 2b Relative effect of canagliflozin versus placebo on clinical outcomes by HOMA-IR tertile

Composite renal outcome: Sustained 40% decline in eGFR, end stage renal failure, death due to renal cause

Conclusion

In patients with type 2 diabetes, canagliflozin improves markers of insulin resistance and β-cell function, as measured by HOMA-IR and PIC ratio. These findings offer further mechanistic insights into the benefits of SGLT2 inhibitors, which exert cardiorenal protection independent of metabolic risk markers.

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