Introduction
Ertugliflozin is a selective inhibitor of sodium–glucose cotransporter 2 (SGLT2), leading to glucosuria, with HbA
1c lowering of 8.3–9.9 mmol/mol (0.8–0.9%) and 2–3 kg of weight loss, and is approved for use as a glucose-lowering therapy in type 2 diabetes mellitus [
1]. SGLT2 inhibitors induce other physiological effects, including natriuresis, contributing to lowering of BP and beneficial effects on kidney function [
2]. Although glucosuria- and HbA
1c-lowering effects attenuate as eGFR decreases below a certain threshold [
3,
4], other effects (such as reductions in BP and weight) of SGLT2 inhibitors tend to be preserved across the range of eGFR that has been studied in humans [
5].
In addition to lowering the urinary albumin/creatinine ratio (UACR) [
6], SGLT2 inhibitors reduce the risk of the kidney composite, which includes a substantial decrease in renal filtering capacity (doubling of serum creatinine or a sustained 40% decrease in eGFR), renal replacement therapy and renal death, in cardiovascular outcome trials (CVOTs) in individuals with type 2 diabetes [
7‐
9] and in individuals with established diabetic kidney disease (DKD) and macroalbuminuria [
10]. In the eValuation of ERTugliflozin effIcacy and Safety CardioVascular outcomes (VERTIS CV) trial, the key secondary composite kidney endpoint (time to first occurrence of the composite of doubling of baseline serum creatinine, renal death, kidney dialysis/transplant) was not significantly reduced, with a HR (95% CI) of 0.81 (0.63, 1.04). The impact of ertugliflozin on kidney function with a definition used in other outcome studies [
7,
9], such as sustained 40% decline in eGFR, has not yet been reported.
In the present analyses, our aim was to explore the effects of ertugliflozin on pre-specified exploratory kidney endpoints in the overall VERTIS CV trial population and according to baseline kidney function status, and to evaluate the effect of ertugliflozin on the incidence of acute kidney failure-related adverse events.
Discussion
VERTIS CV is the fourth SGLT2 inhibitor CVOT to evaluate kidney outcomes [
7‐
9]. These outcomes have also been examined in the dedicated DKD trial, Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) [
10]. The results of the VERTIS CV trial provide further evidence supporting the beneficial effects of this drug class on cardiovascular and kidney outcomes. Based on this body of evidence, these therapies have led to major revisions of clinical practice guidelines for type 2 diabetes mellitus [
16]. Our major findings for ertugliflozin were as follows: reduced risk of the pre-specified exploratory renal composite, which included a sustained 40% decline in eGFR, chronic renal replacement therapy or renal death; significantly reduced UACR compared with placebo in participants with microalbuminuria or macroalbuminuria at baseline; preserved kidney function, especially in participants with macroalbuminuria at greatest risk of DKD progression; and a renal safety profile that was consistent with the known effects of SGLT2 inhibitors.
In previous CVOTs, SGLT2 inhibition reduced the risk of important kidney secondary endpoints. In the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients–Removing Excess Glucose (EMPA-REG OUTCOME), empagliflozin reduced the risk of the composite kidney endpoint that included doubling of serum creatinine as a measure of substantial decline in kidney function by 46%. In the Canagliflozin Cardiovascular Assessment Study (CANVAS) Program, involving a predominant atherosclerotic CVD cohort, canagliflozin reduced the risk of sustained 40% decline in eGFR, kidney replacement therapy or renal death by 40% [
7,
8]. Interestingly, even in the lowest risk cohort for atherosclerotic CVD and kidney disease progression enrolled in the Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) study, the renal composite was reduced significantly with dapagliflozin vs placebo when significant kidney function decline was defined by a sustained 40% decline in eGFR to <60 ml min
−1 [1.73 m]
−2 [
9]. In the VERTIS CV study, the secondary outcome of a kidney composite involving a doubling of creatinine did not reach statistical significance [
12]. A possible explanation for the difference is that these four studies had inconsistent definitions of the kidney composite, specifically regarding the use of doubling of serum creatinine (without a concomitant eGFR level below 45 ml min
−1 [1.73 m]
−2, as was used in EMPA-REG OUTCOME) and the requirement for sustainability of the decline. Consistent with previous CVOTs [
17,
18], ertugliflozin reduced the risk of the renal composite endpoint by 34% when sustained 40% decline in eGFR was used instead of doubling of serum creatinine. The reduction in RR for the kidney composite was observed across CKD stages, levels of UACR and KDIGO CKD risk categories. Although the definition of significant renal function decline using sustained doubling of creatinine is considered accurate as a renal endpoint, the overall risk of DKD progression in this cohort was low and hence the power to demonstrate kidney function loss of this magnitude was insufficient. By contrast, kidney function preservation using the definition of a sustained 40% decline in eGFR is likely a more precise measure, especially in cohorts at lower risk for DKD progression, and therefore more appropriate in this setting.
The effect of SGLT2 inhibitors on UACR lowering has been consistently demonstrated, occurring in individuals with type 2 diabetes with preserved and impaired kidney function [
6,
19], and tends to appear quickly after initiation of therapy, regardless of background therapy [
6,
20]. Therefore, the impact of ertugliflozin on UACR in individuals with elevated UACR at baseline was consistent with previous literature. The observations that ertugliflozin reduced albuminuria progression and increased albuminuria regression are also aligned with known effects of SGLT2 inhibitors [
6]. An expanding body of evidence supports the hypothesis that reduced intraglomerular pressure on the basis of natriuresis-activated tubuloglomerular feedback and other vasoactive pathways attenuates glomerular hypertension [
21,
22]. These haemodynamic mechanisms are perhaps best illustrated by the observations that UACR lowering occurs rapidly and is reversible shortly after cessation of therapy [
6], and by the fact that markers of reduced glomerular hypertension have been shown consistently in response to SGLT2 inhibitors [
21‐
23]. SGLT2 inhibitor trials have also served to identify patient clinical profiles linked with kidney protection with these agents, especially people with albuminuria, as demonstrated by the rapid rate of eGFR decline in patients with macroalbuminuria treated with placebo, emphasising the importance of measuring UACR according to established clinical practice guidelines [
17,
18].
SGLT2 inhibitors have characteristic effects on kidney function. In human mechanistic studies, empagliflozin reduced inulin-based GFR and renal blood flow in individuals with type 1 diabetes [
21], in conjunction with an increase in urine adenosine excretion [
24] and a rise in renal vascular resistance and afferent constriction [
25], consistent with activation of tubuloglomerular feedback [
26]. Effects on eGFR occur acutely after a single dose [
27] and then persist over time [
8]. Following the cessation of SGLT2 inhibitor therapy, eGFR rebounds rapidly back towards baseline [
8], consistent with the haemodynamic effects of these agents [
6,
28]. In the current analysis, eGFR declined acutely with ertugliflozin and was then better preserved over time compared with placebo. Consistent with results of other SGLT2 inhibitor trials, a larger effect of eGFR preservation over time (as measured by placebo-adjusted difference) was observed in the subgroup of participants who had macroalbuminuria at baseline (Fig.
3d) [
6].
Reports from the US Food and Drug Administration’s adverse event reporting system suggested higher AKI risk with SGLT2 inhibitors. In individual CVOTs, AKI risk was either neutral or reduced with SGLT2 inhibitors, and in meta-analyses involving cardiorenal outcome studies, AKI risk was reduced by approximately 25% [
7‐
10,
17,
18]. Similarly, in propensity-matched score analyses with electronic medical record data, AKI risk was lower with SGLT2 inhibitors than with other glucose-lowering therapies [
29]. Consistent with this previous literature, our analysis found no indication of an increase in AKI risk with ertugliflozin.
Our analysis does have limitations. We recognise that although observations from this analysis are generally consistent with renal-related effects in other trials with SGLT2 inhibitors, findings from this cohort with type 2 diabetes and established atherosclerotic CVD may not be generalisable to other groups of individuals. We used pre-specified exploratory endpoints and did not control for type 1 error. The protocol amendment at the end of 2015 resulted in two cohorts with different durations of follow-up. A subgroup analysis of the interaction of the secondary kidney outcome by cohort was found to be non-significant. As reported in previous event-driven trials, the number of participants decreased through the observation period, limiting the interpretability of the results for eGFR and UACR over time. Although valuable as a measure of long-term kidney risk, UACR does have inherent limitations due, in part, to variability of single UACR measures. Nevertheless, the VERTIS CV trial included a large sample size, which mitigated some of the inherent limitations around the use of single UACR measurements at each time point. Furthermore, the use of single measurements and related variability would have biased our analysis towards null. Hence, the effects of ertugliflozin may be underestimated. Early and late haemodynamic effects of the SGLT2 inhibitor class of medications may limit the interpretability of the UACR results. The assessment of acute renal failure was based on adverse event reporting by investigators; however, a blinded external independent panel adjudicated all important renal events for assessment of causality with study medication. Finally, we recognise that the endpoints were exploratory in nature; however, the use of sustained 40% decline in eGFR rather than doubling of serum creatinine is widely recognised as being clinically relevant and has been used in other kidney protection studies [
7,
9,
15,
30,
31].
In conclusion, when used in addition to standard of care medications, ertugliflozin was associated with a decrease in the risk of a sustained 40% decline in eGFR, with less albuminuria and with preservation of eGFR over time in individuals with type 2 diabetes and established atherosclerotic CVD. Observations from the VERTIS CV study suggest that the effects of ertugliflozin on the kidneys are generally consistent with the known benefits of SGLT2 inhibitors.
Acknowledgements
Funding for this research was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., (Kenilworth, NJ, USA) in collaboration with Pfizer Inc. (New York, NY, USA). The authors would like to thank the participants, their families and all investigators involved in the VERTIS CV study; the list of investigators can be found with the primary publication [
12]. Some of the results from these analyses were presented at the 56th annual meeting of the EASD. The authors would like to acknowledge J. L. and I. Gantz, both of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co Inc., (Kenilworth, NJ, USA), for their discussions with the authors and review of the manuscript and C-C. Liu of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co Inc., (Kenilworth, NJ, USA) for statistical support and review of the manuscript. Medical writing and/or editorial assistance was provided by M. Hammad and I. Norton, both of Scion (London, UK). This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., (Kenilworth, NJ, USA) and Pfizer Inc. (New York, NY, USA). Critical reviewing of an early draft was provided by S. G. Terra of Pfizer Inc.
Authors’ relationships and activities
DZIC has received consulting fees or speaking honorarium, or both, from Bristol-Myers Squibb, Novo Nordisk, Mitsubishis-Tanabe, MAZE, Janssen, Bayer, Boehringer Ingelheim, Eli Lilly, AstraZeneca, Merck & Co., Inc., Prometic and Sanofi, and has received operating funds from Janssen, Boehringer Ingelheim, Eli Lilly, Sanofi, AstraZeneca and Merck & Co., Inc. BC has received fees for the following activities: advisory boards for AstraZeneca, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. (Kenilworth, NJ, USA), Novo Nordisk, Sanofi and Servier; and speaker bureau for AstraZeneca, Eli Lilly, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. (Kenilworth, NJ, USA), Novo Nordisk, Sanofi and Takeda. FC has received fees from Abbott, AstraZeneca, Bayer, Bristol-Myers Squibb, Merck Sharp & Dohme, Novo Nordisk and Pfizer, as well as research grants from the Swedish Research Council, Swedish Heart & Lung Foundation and the King Gustav V and Queen Victoria Foundation. SD-J has led clinical trials for AstraZeneca, Novo Nordisk, Inc. and Boehringer Ingelheim, has received fees from AstraZeneca, Boehringer Ingelheim, Janssen, Merck & Co., Inc., and Sanofi, and holds equity interests in Jana care, Inc. and Aerami Therapeutics. DKM has had leadership roles in clinical trials for AstraZeneca, Boehringer Ingelheim, CSL Behring, Eisai, Esperion, GlaxoSmithKline, Janssen, Lexicon, Merck & Co., Inc., Novo Nordisk and Sanofi USA, and has received consultancy fees from AstraZeneca, Boehringer Ingelheim, Lilly USA, Merck & Co., Inc., Pfizer, Novo Nordisk, Metavant, Afimmune and Sanofi. RP has received the following fees (directed to his institution): speaker fees from Novo Nordisk; consulting fees from Merck & Co., Inc., Novo Nordisk, Pfizer, Sanofi, Scohia Pharma Inc. and Sun Pharmaceutical Industries; and grants from Lexicon Pharmaceuticals, Hanmi Pharmaceuticals Co., Novo Nordisk, Poxel SA and Sanofi. WJS has received fees for membership of the ertugliflozin advisory board of Merck & Co., Inc. (Kenilworth, NJ, USA). RF is an employee and shareholder of Pfizer Inc. MM is an employee of MSD UK and may own stock and/or stock options in Merck & Co., Inc. (Kenilworth, NJ, USA). AP is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. (Kenilworth, NJ, USA) and may own stock and/or stock options in Merck & Co., Inc. (Kenilworth, NJ, USA). CPC reports grants and personal fees from Pfizer Inc., grants, personal fees from Merck & Co., Inc., during the conduct of the study. CPC also reports grants and personal fees from Amgen, Boehringer Ingelheim, Bristol-Myers Squibb and Janssen, grants from Daiichi Sankyo and Novo Nordisk, and personal fees from Aegerion, Alnylam, Amarin, Applied Therapeutics, Ascendia, Corvidia, HLS Therapeutics, Innovent, Kowa, Sanofi, Eli Lilly, and Rhoshan, outside the submitted work.
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