Hypoglycaemia and kidney events in participants with type 2 diabetes and atherosclerotic cardiovascular disease: Observations from the <scp>VERTIS CV</scp> trial

Hypoglycaemia is a common complication of some, but not all, antihyperglycaemic agents used to treat hyperglycaemia in people with type 2 diabetes (T2D).1 The risk of hypoglycaemia may be exacerbated by diabetic kidney disease; the kidneys are an important site of gluconeogenesis2 and are involved in the metabolism and clearance of insulin,3 as well as some antihyperglycaemic agents. The net clinical consequence of hypoglycaemia is poorly defined, and the association between hypoglycaemia and adverse kidney outcomes is not well described. We sought to assess associations with hypoglycaemia events and kidney outcomes. The eValuation of ERTugliflozin efficacy and Safety CardioVascular outcomes trial (VERTIS CV; NCT01986881) assessed the effects of the sodium-glucose cotransporter 2 inhibitor ertugliflozin on cardiovascular (CV) and kidney outcomes in participants with T2D and established atherosclerotic CV disease.4-6 VERTIS CV was a multicentre, double-blind, placebo-controlled, parallelgroup, event-driven, phase III, CV outcomes trial.4, 5 The trial included participants with a glycated haemoglobin level of 53–91 mmol/mol, established atherosclerotic CV disease involving the coronary, cerebrovascular and/or peripheral arterial systems, and an estimated glomerular filtration rate (eGFR) ≥30 ml/min/1.73 m2. Eligible participants were randomly assigned 1:1:1 to receive once-daily ertugliflozin 5 mg, ertugliflozin 15 mg, or placebo. In VERTIS CV, ertugliflozin was non-inferior to placebo with respect to major adverse CV events.5 Post-hoc analyses were performed to explore associations between hypoglycaemia and adverse kidney outcomes. The objectives were to conduct a hypothesis-generating study to explore the associations between hypoglycaemia and adverse kidney outcomes and the association between adverse (non-fatal) kidney outcomes, and subsequent hypoglycaemic events. Hypoglycaemic events were categorized into the following increasing severity levels: (a) symptomatic, glucose ≤3.9 mmol/mol (prespecified)5; (b) glucose <3.0 mmol/mol (post hoc); or (c) severe, requiring assistance (prespecified).5 The prespecified exploratory composite kidney outcome was defined as the time to the first occurrence of a composite of a sustained ≥40% decrease in eGFR from baseline, kidney failure (defined as the chronic need for kidney dialysis or kidney transplantation), or death because of kidney disease.6 In total, 198 participants had events for the exploratory composite kidney outcome, predominantly driven by a sustained ≥40% decrease in eGFR from baseline (Table S1).6 For these post-hoc analyses, events from both randomized treatment arms were pooled. The associations between an incident hypoglycaemic event (level 3; levels 2 or 3; and levels 1, 2 or 3) and a subsequent kidney event were examined using Cox regression with incident hypoglycaemia as a time-varying covariate factor, along with a variable for the randomized treatment and an interaction term between treatment and time-varying incident hypoglycaemia. Only the first hypoglycaemic adverse events were considered. Likewise, the association between an incident (non-fatal) kidney event and subsequent hypoglycaemic event was examined with the incident kidney event as a time-varying explanatory factor. Whether the association between incident hypoglycaemia and subsequent kidney events varied by treatment with ertugliflozin versus placebo was examined with the interaction term included in the model. Finally, a sensitivity analysis was conducted wherein baseline insulin and sulphonylurea use were included as variables in the Cox regression model. In total, 8246 participants were randomized (Table 1) and followed for a mean ± standard deviation (SD) of 3.5 ± 1.2 years, of whom, 2747 received placebo, 2752 received ertugliflozin 5 mg and 2747 received ertugliflozin 15 mg. The mean ± SD age was 64.4 ± 8.1 years, the mean ± SD duration of existing T2D was 13.0 ± 8.3 years and the mean ± SD glycated haemoglobin at baseline was 66.5 ± 10.4 mmol/mol. At baseline, insulin, metformin, or sulphonylureas were taken by 3900 (47.3%), 6292 (76.3%) and 3390 (41.1%) participants, respectively. Antihypertensive agents were taken by more than 95% of participants at baseline, with 81.1% on a renin-angiotensin-aldosterone system inhibitor. There were 2048 (24.8%), 4390 (53.2%) and 1807 (21.9%) participants with stages 1, 2 or 3 chronic kidney disease, respectively. In the overall study population, there was no association between incident hypoglycaemic events and subsequent adverse kidney outcomes, irrespective of severity of hypoglycaemia (Figure 1A; all p > .05). There were no significant hypoglycaemia-by-treatment interactions (all p > 0.05). Adverse (non-fatal) kidney events were associated with subsequent level 1, 2, or 3 hypoglycaemic events [hazard ratio (HR): 1.84, 95% confidence interval (CI): 1.16–2.91] and level 2 or 3 hypoglycaemic events (HR: 1.79, 95% CI: 1.13–2.82), but not with level 3 hypoglycaemic events alone (HR: 1.03, 95% CI: 0.33–3.20; Figure 1B). There were no significant non-fatal kidney event-by-treatment interactions (all p > .05). Results were similar with adjustments for insulin and sulphonylurea use (Tables S2 and S3). Analyses of pooled data from the VERTIS CV trial found no association between hypoglycaemia events and adverse kidney outcomes. However, a preceding adverse (non-fatal) kidney outcome was associated with a higher risk of a subsequent hypoglycaemic event. The association between an adverse kidney outcome and subsequent hypoglycaemia did not vary by treatment with ertugliflozin versus placebo (Figure 1B), therefore reaffirming the safety profile of ertugliflozin for the management of T2D. Analyses of real-world data are needed to further investigate the association between hypoglycaemia and adverse kidney outcomes and the safety of novel glucose-lowering medications. FC, SDJ, DKM, RF, CPC and DC: research idea and study design. DKM and CPC: data acquisition. AO, FC, REP, SDJ, DKM, RF, WF, CPC and DC: data analysis/interpretation. WF: statistical analysis. CPC and DC: supervision or mentorship. CPC: obtained funding. All authors contributed important intellectual content during manuscript drafting or revision and agreed to be personally accountable for the individual's own contributions and to ensure that questions pertaining to the accuracy or integrity of any portion of the work, even one in which the author was not directly involved, are appropriately investigated and resolved, including with documentation in the literature if appropriate. The authors would like to thank the participants, their families and all the investigators involved in the VERTIS CV study (registered at ClinicalTrials.gov, NCT01986881). Data from this study were previously presented at the World Congress of Nephrology 2023 in Bangkok, Thailand (30 March to 2 April 2023). Funding for this study and analysis was provided by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. (Rahway, NJ, USA), in collaboration with Pfizer Inc. (New York, NY, USA). The Sponsor was involved in the study design, collection, analysis and interpretation of data, as well as data checking of information provided in the manuscript. However, ultimate responsibility for opinions, conclusions and data interpretation lies with the authors. Medical writing and/or editorial assistance was provided by Anastasija Pesevska, PharmD and Melissa Ward, BA, both of Scion, London, UK. This assistance was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. (Rahway, NJ, USA) according to Good Publication Practice guidelines (https://www.acpjournals.org/doi/10.7326/M22-1460). AO is supported by the University of Toronto Department of Medicine Eliot Phillipson Clinician Scientist Training Program and KRESCENT Postdoctoral Fellowship. The KRESCENT program is co-sponsored by the Kidney Foundation of Canada, the Canadian Society of Nephrology and the Canadian Institute of Health Research. He is also supported by the University of Toronto Provost Postdoctoral Fellowship Program, the University of Toronto Black Research Network, the Ted Rogers Centre for Heart Research and the and the Canadian Institute for Health Research REDI Grant. AO has no conflicts of interest to declare. FC has received fees from Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Lilly, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. (Rahway, NJ, USA), Novo Nordisk and Pfizer; and research grants from the King Gustav V and Queen Victoria Foundation, the Swedish Heart & Lung Foundation and the Swedish Research Council. RP reports grants from Hanmi Pharmaceutical Co, Janssen and Poxel SA; consulting fees from Merck, Pfizer, Scohia Pharma, Inc. and Sun Pharmaceutical Industries; grants, speaker fees and consulting fees from Novo Nordisk; and grants and consulting fees from Sanofi. His services were paid for directly to AdventHealth, a non-profit organisation. SD-J has led clinical trials for AstraZeneca, Bayer, Boehringer Ingelheim and Novo Nordisk, Inc.; has received fees from AstraZeneca, Bayer, Boehringer Ingelheim, Janssen, Merck & Co., Inc. (Rahway, NJ, USA) and Sanofi; and holds equity interests in Jana Care, Inc. and Aerami Therapeutics. DM reports research support for clinical trials leadership from Boehringer Ingelheim, Merck & Co., Inc. (Rahway, NJ, USA), Pfizer, AstraZeneca, Novo Nordisk, Esperion, Lilly USA, Lexicon and CSL Behring; honoraria for consultancy from Lilly USA, Boehringer Ingelheim, Novo Nordisk, Applied Therapeutics, Altimmune, CSL Behring, Bayer, Intercept, New Amsterdam, Lexicon, Amgen. RF is an employee of Pfizer Inc., and owns shares/stock options in Pfizer Inc. WF is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. (Rahway, NJ, USA), and may own stock and/or stock options in Merck & Co., Inc. (Rahway, NJ, USA). CC reports research grants and consulting fees from Pfizer Inc., and Merck & Co., Inc. (Rahway, NJ, USA), and research grants and consulting fees from Amgen, Boehringer Ingelheim, Bristol-Myers Squibb and Janssen; research grants from Better Therapeutics, Daiichi Sankyo and Novo Nordisk; consulting fees from Aegerion/Amryt Alnylam, Amarin, Applied Therapeutics, Ascendia, Biogen, Lexicon, Sanofi, Eli Lilly and Rhoshan; and reports serving on the data and safety monitoring boards for the Veteran's Administration, Applied Therapeutics and Novo Nordisk outside the submitted work. DZIC reports institutional grant funding from Boehringer Ingelheim, Eli Lilly, Merck, Janssen, Sanofi, AstraZeneca, CSL-Behring and Novo Nordisk and consultancy fees and honorarium from AbbVie, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Bristol Myers Squibb, CSL-Behring, Gilead, Janssen, Lexicon, Maze, Merck, Mitsubishi-Tanabe, Novartis, Otsuka, Prometic, Sanofi, Youngene and Novo Nordisk. The data sharing policy, including restrictions, of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. (Rahway, NJ, USA) is available at http://engagezone.msd.com/ds_documentation.php. Requests for access to the clinical study data can be submitted through the EngageZone site or via email to Data Access mailbox. TABLE S1. Number of participants with events for the prespecified exploratory composite kidney outcome.† TABLE S2. Association between hypoglycaemic event occurrence and subsequent adverse kidney outcomes† in VERTIS CV with insulin and sulphonylurea use included as variables in the Cox regression model. TABLE S3. Association between adverse (non-fatal) kidney outcome† occurrence and subsequent hypoglycaemic events in VERTIS CV with insulin and sulphonylurea use included as variables in the Cox regression model. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. 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