Randomized controlled trials have demonstrated that sodium–glucose cotransporter inhibitors (SGLTi) provide glycemic benefit for people living with type 1 diabetes (PWT1D). These findings led to the initial approval of SGLTi use in PWT1D as an adjunct to insulin in some countries. However, safety concerns, especially the increased risk of diabetic ketoacidosis (DKA), have limited their use in T1D. The risk-benefit analysis limiting SGLTi use assumes that clinical efficacy of sodium–glucose cotransporter (SGLT) inhibition is limited to glycemic control and uniform across the population with type 1 diabetes (T1D). However, SGLTi consistently lower the incidence of cardiovascular events in people with type 2 diabetes (T2D) at high risk of cardiovascular disease (CVD), irrespective of glycemic benefits (1). Considering that PWT1D are disproportionately at risk for CVD, those at high cardiovascular risk may also benefit from SGLT inhibition. Unfortunately, there is a lack of data on the cardiovascular efficacy of SGLT inhibition in T1D, since adequately powered trials in this population have not been conducted. Therefore, risk prediction modeling was performed to assess the effects of SGLTi on estimated CVD risk in PWT1D. We hypothesized that SGLT inhibition in T1D would lower CVD risk estimates, with greater benefit observed in those at high CVD risk.
In the current study we used participant-level data from the Empagliflozin as Adjunctive to inSulin thErapy (EASE-2) (n = 730) and EASE-3 (n = 960) phase 3 randomized, placebo-controlled trials conducted to evaluate the safety and efficacy of empagliflozin as an adjunct to insulin in PWT1D with elevated HbA1c (2). The Steno T1 Risk Engine (SRE) and the Scottish Diabetes Research Network (SDRN) risk models were specifically developed and validated for PWT1D and therefore selected for estimation of 10-year cumulative risk of first fatal or nonfatal CVD event at baseline and 26 weeks on treatment in this cohort (3–5). With two-way repeated-measures ANCOVA we statistically compared CVD risk between the empagliflozin group (pooled group including 10- and 25-mg doses) and placebo group adjusting for multiple comparisons using Bonferroni correction. The log-transformed change in absolute and relative risk from baseline was used as the dependent variable. Subgroup analyses were based on baseline CVD risk (low <10%, moderate 10–20%, and high >20%) using the average of the SRE and SDRN models. Statistical significance was defined as P < 0.05. Analyses were performed with R (version 3.5.2).
The mean placebo-adjusted relative change in the SRE 10-year CVD risk was −9.8% (95% CI −11.6, −8.1; P < 0.01), corresponding to a placebo-adjusted absolute change from baseline of −1.5% (−1.8, −1.2; P < 0.01) (Fig. 1A) across all participants. Similarly, the placebo-adjusted relative change in the SDRN 10-year CVD risk was −9.6% (−11.7, −7.6; P < 0.01), corresponding to a placebo-adjusted absolute change from baseline of −1.7% (−2.1, −1.4; P < 0.01) (Fig. 1B) across all participants. Subgroup analyses revealed that placebo-adjusted relative change in CVD risk estimated with both models was not different across baseline CVD risk (Pinteraction ≥ 0.09). However, as the baseline CVD risk increased, so did the magnitude of its placebo-adjusted absolute reduction with therapy (Pinteraction < 0.01, both).
Subgroup CVD risk analysis by baseline cardiovascular risk following 26 weeks of empagliflozin or placebo. Placebo-adjusted relative and absolute changes in 10-year CVD risk scores were estimated using the SRE (A) and SDRN (B) risk prediction models. Risk estimates were stratified as follows: low (<10%), medium (10%–20%), and high (>20%) baseline CVD risk. Baseline and week 26 values are reported as median (interquartile range). Placebo-adjusted relative and absolute changes are reported as mean (95% CI). *P < 0.05.
Subgroup CVD risk analysis by baseline cardiovascular risk following 26 weeks of empagliflozin or placebo. Placebo-adjusted relative and absolute changes in 10-year CVD risk scores were estimated using the SRE (A) and SDRN (B) risk prediction models. Risk estimates were stratified as follows: low (<10%), medium (10%–20%), and high (>20%) baseline CVD risk. Baseline and week 26 values are reported as median (interquartile range). Placebo-adjusted relative and absolute changes are reported as mean (95% CI). *P < 0.05.
The current analysis suggests that SGLT inhibition may lead to the largest absolute reduction in predicted CVD risk in PWT1D at elevated baseline cardiovascular risk, driven by reductions in HbA1c, urine albumin–to–creatinine ratio, BMI, and blood pressure. However, the risk models do not account for changes over time and, in combination with the low baseline risk in the EASE cohort, may underestimate SGLTi-driven effects on cardiovascular risk. The SGLT2 Inhibitor Meta-Analysis Cardio-Renal Trialists Consortium (SMART-C) meta-analysis of high cardiovascular risk cohorts, predominantly with T2D, heart failure, and/or CKD (excluding T1D), demonstrated that SGLT inhibition reduced major cardiovascular events by 9% and composite of cardiovascular death or heart failure hospitalization by 23% in patients with T2D at high risk (1). The consistent class-wide cardiovascular benefit observed in patient groups at high CVD risk in the SMART-C analysis reinforces the potential for SGLTi to provide robust cardiovascular protection in T1D, particularly in those with additional risk factors, even without glycemic improvements. Although the anticipated absolute risk reductions may improve the benefit-risk ratio and support clinical implementation, it remains difficult to determine whether the observed benefits are sufficient to outweigh the 2%–3% increased risk of DKA reported for the EASE cohort (2). However, with contemporary DKA mitigation strategies in place, there is evidence to suggest that this risk in PWT1D with comorbidities like CKD or CVD may be lower than previously reported. In ongoing outcome studies like Sodium Glucose Co-Transport-2 Inhibition Diabetes and Kidney Function Loss in Type 1 Diabetes (SUGARNSALT) (clinical trial reg. no. NCT06217302, ClinicalTrials.gov), investigators are exploring the renal effectiveness of SGLTi to better evaluate the benefit-risk balance in T1D and CKD cohorts. Overall, our findings suggest that SGLTi could lead to greater reductions in CVD risk in PWT1D at high cardiovascular risk, highlighting the importance in future trials to reassess the benefit-risk ratio across different risk profiles within the population with T1D.
Article Information
Acknowledgments. This publication is based on research using data from data contributors Boehringer Ingelheim that has been made available through Vivli, Inc.
Vivli, Inc., has not contributed to or approved, and is not in any way responsible for, the contents of this publication.
Funding. L.K. is supported by the Ted Rogers Centre for Heart Research, Cardiovascular Sciences Collaborative Specialization Queen Elizabeth II/Heart & Stroke Foundation studentship in Science and Technology, and Banting & Best Diabetes Centre–Novo Nordisk studentship. M.N. is supported by a Banting & Best Diabetes Centre postdoctoral fellowship at the University of Toronto. V.S.S. is supported by the Department of Medicine Eliot Phillipson Clinician-Scientist Training Program, a Banting & Best Diabetes Centre postdoctoral fellowship at the University of Toronto, and a Canadian Institutes of Health Research (CIHR) Frederick Banting & Charles Best Canada Graduate Scholarships–Doctoral Research Award. D.Z.I.C. is the Gabor Zellerman Chair in Nephrology Research, University of Toronto, and is also supported by a CIHR–Kidney Foundation of Canada Team Grant, with additional support from Breakthrough T1D. P.S. holds the Charles A. Allard Chair in Diabetes Research and is supported by the Alberta Academic Medicine Health Services Program. I.M. is supported by investigator-initiated grants from CIHR, the Kidney Foundation of Canada, the Canadian Donation and Transplantation Research Program, the Health Canada Health Care Policy Contribution Program, and the Mount Sinai Hospital–University Health Network Academic Medical Organization Innovation Funding. V.E.R. received the Canada Research Chair (Tier 2) in Health System and Technology Evaluation as salary support. R.R.-L. has received grant support from JDRF, the National Institutes of Health, and Société Francophone du Diabète. R.R.-L. received consulting fees or speaker honoraria from CPD Network. P.S. has received grants from JDRF. A.D. received a grant from Breakthrough T1D.
Duality of Interest. V.S.S. has received conference and travel support from Merck Canada. B.A.P. has received speaker honoraria from Medtronic, Johnson & Johnson, Roche, GlaxoSmithKline Canada, Novo Nordisk, and Sanofi; has received research grant support from Medtronic and Boehringer Ingelheim; and serves as a consultant for NeuroMetrix. A.L. reports grants, nonfinancial support, and other from AstraZeneca; grants, nonfinancial support, and other from Boehringer Ingelheim International GmbH; and grants and other from Janssen during the conduct of the study. She has also received research support from Amgen, AstraZeneca, CIHR, the Heart and Stroke Foundation of Canada, Janssen, the Kidney Foundation of Canada, Merck, the Michael Smith Health Research Foundation, and Otsuka. I.M. received an unrestricted education grant from Astellas Pharma Canada and from Paladin Labs. Inc. Canada. R.R.-L. has received grant support from Diabetes Canada, AstraZeneca, Eli Lilly, Cystic Fibrosis Canada, CIHR, Fondation Francophone pour la Recherche sur le Diabète (FFRD), Janssen, Merck, Novo Nordisk, Sanofi, and Vertex Pharmaceuticals. R.R.-L. received consulting fees or speaker honoraria from Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Dexcom, Eli Lilly, HLS Therapeutics, Institut national d’excellence en santé et services sociaux (INESSS), Insulet, Janssen, Medtronic, Merck, Novo Nordisk, Pfizer, Sanofi, Dexcom, Canadian Medical & Surgical Knowledge Translation Research Group, Tandem Diabetes Care, and Vertex Pharmaceuticals. P.S. has received grants from CIHR and Brain Canada and consulting or personal fees from Abbott, Bayer, Dexcom, Eli Lilly, GlaxoSmithKline, Insulet, Novo Nordisk, Sanofi, and Vertex Pharmaceuticals. He served previously as board chair for Diabetes Canada and is a co-lead for Diabetes Action Canada’s Innovations in Type 1 Diabetes goal group. R.J.S. has received research funding from Novo Nordisk, Eli Lilly, Bayer, and Boehringer Ingelheim and consulting fees from Boehringer Ingelheim. F.P. has served as a consultant on advisory boards or as an educator for AstraZeneca, Novo Nordisk, Sanofi, Mundipharma, Merck Sharp & Dohme, Boehringer Ingelheim, Novartis, and Amgen and has received research grants to institution from Novo Nordisk, Amgen, and Astra Zeneca. A.D. received in kind support for research study from Lexicon Pharmaceuticals, Abbott, and Dexcom. D.Z.I.C. has received honoraria from Boehringer Ingelheim–Lilly, Merck, AstraZeneca, Sanofi, Mitsubishi Tanabe Pharma, AbbVie, Janssen, Bayer, Prometic Life Sciences, Bristol-Myers Squibb, Maze, Gilead, CSL Behring, Otsuka, Novartis, Youngene Therapeutics, and Novo Nordisk and has received operational funding for clinical trials from Boehringer Ingelheim–Lilly, Merck, Janssen, Sanofi, AstraZeneca, CSL Behring, and Novo Nordisk.
Author Contributions. All authors contributed to collection of data and data interpretation. P.D. and M.N. performed statistical analysis. L.K., P.D., and M.N. wrote the first draft of the manuscript. L.K., P.D., M.N., V.S.S., and D.Z.I.C. were involved in the study design. All authors provided critical revision of the manuscript for important intellectual content and approved the final version of the manuscript for submission. D.Z.I.C. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Prior Presentation. Parts of this study were presented in abstract form at the American Society of Nephrology Kidney Week, San Diego, CA, 24–27 October 2024.
Handling Editors. The journal editors responsible for overseeing the review of the manuscript were Cheryl A.M. Anderson and Jennifer B. Green.
