Category: Diabetes/Prediabetes/Hypoglycemia

Monitor: 29

29 - CARDIOVASCULAR AND RENAL OUTCOMES WITH CANAGLIFLOZIN IN PEOPLE WITH TYPE 2 DIABETES ACCORDING TO BASELINE USE OF METFORMIN

Saturday, Apr 27
10:30 AM – 11:00 AM

Objective : Metformin is recommended as first-line therapy for type 2 diabetes mellitus (T2DM) in almost all clinical practice guidelines. The EMPA-REG OUTCOME trial reported that the effect of empagliflozin on cardiovascular death was possibly greater in participants not on metformin compared to those on metformin. We sought to determine the effects of canagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, on cardiovascular and renal outcomes according to baseline metformin use in the CANagliflozin cardioVascular Assessment Study (CANVAS) Program.


Methods : The CANVAS Program randomized participants with T2DM at high cardiovascular risk to canagliflozin or placebo. The primary outcome was a composite of cardiovascular death, nonfatal myocardial infarction or nonfatal stroke, with a range of other pre-specified cardiovascular and renal outcomes. Hazards ratios (HR) and 95% confidence intervals (CI) were estimated with Cox regression models, with terms for interaction between metformin subgroups and treatment included to test for heterogeneity of treatment effects.


Results : Among 10,142 participants, 2,317 (22.8%) were not on metformin at baseline (mean age 65 y, HbA1c 8.3%, BP 137/77 mmHg, eGFR 67 mL/min/1.73 m2). Participants not on metformin were more likely to be older, have a longer duration of diabetes, history of micro- or macrovascular complications, and reduced kidney function (all P <0.0001). The effect of canagliflozin on the primary outcome was HR 0.76 (95% CI 0.61-0.94) in those not using metformin and HR 0.91 (95% CI 0.77-1.06) among those using metformin (P-heterogeneity = 0.14). Consistent effects in each subgroup were also observed for myocardial infarction, cardiovascular death, the renal composite outcome, and all-cause mortality (P-heterogeneity >0.30 for all).  However, the effects on fatal/nonfatal stroke (HR 0.52, 95% CI 0.35-0.78 vs. HR 1.11, 95% CI 0.84-1.48; P-heterogeneity = 0.002) and hospitalization for heart failure (HR 0.43, 95% CI 0.28-0.65 vs. HR 0.88, 95% CI 0.64-1.23; P-heterogeneity = 0.005) appeared greater in participants not receiving metformin.


Discussion : In the CANVAS Program, the observed differences in treatment effect according to baseline use of metformin broadly mirrored those from the EMPA-REG OUTCOME trial. This observation may be explained by chance, differences in participant characteristics, or may represent a true interaction. An adequately powered head-to-head trial comparing the effects of metformin versus SGLT2 inhibition would resolve this uncertainty.


Conclusion : The effect of canagliflozin on cardiovascular outcomes may vary according to concomitant use of metformin at baseline.

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Brendon L. Neuen

Research Fellow
The George Institute for Global Health, UNSW Sydney
Sydney, Australia

Research Fellow, The George Institute for Global Health, UNSW Sydney

Hiddo L. Heerspink

Professor
University of Groningen, University Medical Center Groningen
Groningen, Netherlands

Professor, University of Groningen, University Medical Center Groningen

Bruce Neal

Professor
The George Institute for Global Health, UNSW Sydney
Sydney, Australia

Professor, The George Institute for Global Health, UNSW Sydney

David R. Matthews

Professor
Oxford Centre for Diabetes, Endocrinology and Metabolism and Harris Manchester College, University of Oxford
Oxford, United Kingdom

Professor, Oxford Centre for Diabetes, Endocrinology and Metabolism and Harris Manchester College, University of Oxford

Dick de Zeeuw

Professor
University of Groningen, University Medical Center Groningen
Groningen, Netherlands

Professor, University of Groningen, University Medical Center Groningen

Kenneth W. Mahaffey

Professor
Stanford Center for Clinical Research, Department of Medicine, Stanford University School of Medicine
Stanford, California

Professor, Stanford Center for Clinical Research, Department of Medicine, Stanford University School of Medicine

Greg RONALD. Fulcher

Clinical Director, Chronic Medicine
NSLHD
Sydney, Australia

Qiang Li

Mary Lee

George Capuano

Jennifer Davidson

Vice President, Global Medical Affairs Cardiovascular and Metabolism
Janssen Research & Development, LLC
Raritan, New Jersey

Vice President, Global Medical Affairs Cardiovascular and Metabolism, Janssen Research & Development, LLC

Meg Jardine

Associate Professor
The George Institute for Global Health, UNSW Sydney
Sydney, Australia

Associate Professor, The George Institute for Global Health, UNSW Sydney

Sophia Zoungas

Professor
The George Institute for Global Health, UNSW Sydney
Sydney, Australia

Professor, The George Institute for Global Health, UNSW Sydney

Vlado Perkovic

Professor
The George Institute for Global Health, UNSW Sydney
Sydney, Australia

Vlado Perkovic is Executive Director of The George Institute, Australia, Professor of Medicine at UNSW Sydney, and a Staff Specialist in Nephrology at the Royal North Shore Hospital.