Portal de Periódicos da CAPES

A Big Win for Diabetic Kidney Disease: CREDENCE

2019; Cell Press; Volume: 29; Issue: 5 Linguagem: Inglês

10.1016/j.cmet.2019.04.011

1932-7420

David Z.I. Cherney, Ayodele Odutayo, Subodh Verma,

Diabetes Management and Research

Diabetic kidney disease (DKD), a major cause of morbidity, mortality, and economic hardship globally, is on the rise. The results of the recently reported CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) trial have ushered in hope and optimism for the treatment of DKD. Diabetic kidney disease (DKD), a major cause of morbidity, mortality, and economic hardship globally, is on the rise. The results of the recently reported CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) trial have ushered in hope and optimism for the treatment of DKD. Sodium glucose co-transporter 2 (SGLT2) inhibitors are glucose-lowering agents used for the treatment of type 2 diabetes (T2D). By blocking SGLT2 at the renal proximal tubule, these agents induce glucosuria, which in turn reduces hyperglycemia and body weight. SGLT2 inhibitors promote natriuresis, which has been associated with blood pressure lowering via contraction of plasma volume (Heerspink et al., 2016Heerspink H.J. Perkins B.A. Fitchett D.H. Husain M. Cherney D.Z. Sodium glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus: cardiovascular and kidney effects, potential mechanisms, and clinical applications.Circulation. 2016; 134: 752-772Crossref PubMed Scopus (733) Google Scholar). Natriuresis also contributes to reductions in intraglomerular hypertension, hyperfiltration, and albuminuria through activation of tubuloglomerular feedback (Verma and McMurray, 2018Verma S. McMurray J.J.V. SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review.Diabetologia. 2018; 61: 2108-2117Crossref PubMed Scopus (486) Google Scholar, Verma et al., 2017Verma S. McMurray J.J.V. Cherney D.Z.I. The metabolodiuretic promise of sodium-dependent glucose cotransporter 2 inhibition: the search for the sweet spot in heart failure.JAMA Cardiol. 2017; 2: 939-940Crossref PubMed Scopus (124) Google Scholar) (Figure 1). Beyond these physiological effects (Lopaschuk and Verma, 2016Lopaschuk G.D. Verma S. Empagliflozin's fuel hypothesis: not so soon.Cell Metab. 2016; 24: 200-202Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar), SGLT2 inhibitors have been shown in cardiovascular outcome trials (CVOTs) to reduce cardiovascular events. Over the last 5 years, three seminal CVOTs examining empagliflozin (EMPA-REG OUTCOME) (Zinman et al., 2015Zinman B. Wanner C. Lachin J.M. Fitchett D. Bluhmki E. Hantel S. Mattheus M. Devins T. Johansen O.E. Woerle H.J. et al.EMPA-REG OUTCOME InvestigatorsEmpagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.N. Engl. J. Med. 2015; 373: 2117-2128Crossref PubMed Scopus (7148) Google Scholar), canagliflozin (the CANVAS Program) (Neal et al., 2017Neal B. Perkovic V. Mahaffey K.W. de Zeeuw D. Fulcher G. Erondu N. Shaw W. Law G. Desai M. Matthews D.R. CANVAS Program Collaborative GroupCanagliflozin and cardiovascular and renal events in type 2 diabetes.N. Engl. J. Med. 2017; 377: 644-657Crossref PubMed Scopus (2168) Google Scholar), and dapagliflozin (DECLARE TIMI-58) (Wiviott et al., 2019Wiviott S.D. Raz I. Bonaca M.P. Mosenzon O. Kato E.T. Cahn A. Silverman M.G. Zelniker T.A. Kuder J.F. Murphy S.A. et al.DECLARE–TIMI 58 InvestigatorsDapagliflozin and cardiovascular outcomes in type 2 diabetes.N. Engl. J. Med. 2019; 380: 347-357Crossref PubMed Scopus (3017) Google Scholar) have reported. In a pooled analysis of these trials, SGLT2 inhibition conferred a 14% reduction in the incidence of major adverse cardiovascular events and a 24% reduction in the incidence of hospitalization for heart failure (HHF) compared to placebo in adults with atherosclerotic cardiovascular disease at baseline (Verma et al., 2019Verma S. Jüni P. Mazer C.D. Pump, pipes, and filter: do SGLT2 inhibitors cover it all?.Lancet. 2019; 393: 3-5Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar, Zelniker et al., 2019Zelniker T.A. Wiviott S.D. Raz I. Im K. Goodrich E.L. Bonaca M.P. Mosenzon O. Kato E.T. Cahn A. Furtado R.H.M. et al.SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials.Lancet. 2019; 393: 31-39Abstract Full Text Full Text PDF PubMed Scopus (1550) Google Scholar). Importantly, the incidence of HHF was reduced in all three CVOTs, despite differences in baseline cardiovascular and renal risk. Moreover, SGLT2 inhibition reduced mortality risk in the EMPA-REG OUTCOME trial composed exclusively of a patient cohort with established atherosclerotic disease at baseline. While the mechanisms responsible for these benefits remain unknown, existing trial data suggest that the cardioprotective effects of SGLT2 inhibitors are largely independent of glycemic control and other traditional cardiovascular risk factors such as blood pressure lowering. Instead, the benefits may be due to plasma volume contraction and improved myocardial oxygenation, as discussed elsewhere (Heerspink et al., 2016Heerspink H.J. Perkins B.A. Fitchett D.H. Husain M. Cherney D.Z. Sodium glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus: cardiovascular and kidney effects, potential mechanisms, and clinical applications.Circulation. 2016; 134: 752-772Crossref PubMed Scopus (733) Google Scholar, Verma and McMurray, 2018Verma S. McMurray J.J.V. SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review.Diabetologia. 2018; 61: 2108-2117Crossref PubMed Scopus (486) Google Scholar, Verma et al., 2018Verma S. Rawat S. Ho K.L. Wagg C.S. Zhang L. Teoh H. Dyck J.E. Uddin G.M. Oudit G.Y. Mayoux E. et al.Empagliflozin increases cardiac energy production in diabetes: novel translational insights into the heart failure benefits of SGLT2 inhibitors.JACC Basic Transl Sci. 2018; 3: 575-587Crossref PubMed Scopus (213) Google Scholar). From a cardiovascular perspective, the reduction in HHF in the three published CVOTs was consistent and robust given that the magnitude of the effect was >25% across the three studies (Figure 1). Equally compelling, however, was the observation that SGLT2 inhibition reduced the risk of diabetic kidney disease (DKD), which is the most common cause of chronic kidney disease leading to end-stage kidney disease (ESKD) (GBD 2015 Disease and Injury Incidence and Prevalence Collaborators, 2016GBD 2015 Disease and Injury Incidence and Prevalence CollaboratorsGlobal, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015.Lancet. 2016; 388: 1545-1602Abstract Full Text Full Text PDF PubMed Scopus (4513) Google Scholar). In the three CVOTs, where approximately 80% of the patients were taking an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) at baseline, SGLT2 inhibition substantially reduced albuminuria in patients across the spectrum of micro- and macroalbuminuria, and more modestly reduced urine albumin-to-creatinine ratio (UACR) by the end of the trial period in patients with normoalbuminuria at baseline. Beyond these surrogate endpoints, SGLT2 inhibition also reduced clinically important renal composite endpoints. For example, in a secondary analysis of the EMPA-REG OUTCOME, the renal composite of doubling of creatinine, renal replacement therapy, or renal death was reduced by 46%; similar effects were reported in the CANVAS Program, the DECLARE-TIMI 58 trial, and in pooled analysis of these CVOTs (Zelniker et al., 2019Zelniker T.A. Wiviott S.D. Raz I. Im K. Goodrich E.L. Bonaca M.P. Mosenzon O. Kato E.T. Cahn A. Furtado R.H.M. et al.SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials.Lancet. 2019; 393: 31-39Abstract Full Text Full Text PDF PubMed Scopus (1550) Google Scholar). Notably, in the meta-analysis by Zelniker and colleagues, the effect size of this renal benefit was preserved, and perhaps even accentuated, in participants with earlier stage CKD at baseline compared to those who were at a more advanced stage of the disease. Despite the consistent and moderate treatment effects observed in the CVOTs, the secondary renal outcome benefits have largely been considered hypothesis-generating, since the CVOTs were not powered for these outcomes and since <30% patients had existing CKD at baseline. The major change in practice emerging from these CVOTs has been changes in approved indications for SGLT2 inhibitors. In some jurisdictions, empagliflozin and canagliflozin are now approved for reducing cardiovascular risk as an adjunct to metformin, including use down to a lower estimated glomerular filtration rate (eGFR) limit of 30 mL/min/1.73 m2 to align with renal inclusion/exclusion criteria in their associated CVOTs. Notably, several authorities have recently lowered the eGFR threshold for dapagliflozin to 45 mL/min/1.73 m2. More definitive clinical evidence for the use of SGLT2 inhibitors has only emerged 4 years after the publication of the first CVOT in 2015. The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial was conducted to determine the safety and efficacy of the SGLT2 inhibitor canagliflozin as a renal protective therapy in macroalbuminuric patients with T2D and DKD. As described in the design and baseline paper, this multi-center parallel group study randomized 4,401 adults with DKD to 100 mg canagliflozin daily or placebo (Jardine et al., 2017Jardine M.J. Mahaffey K.W. Neal B. Agarwal R. Bakris G.L. Brenner B.M. Bull S. Cannon C.P. Charytan D.M. de Zeeuw D. et al.CREDENCE study investigatorsThe Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) study rationale, design, and baseline characteristics.Am. J. Nephrol. 2017; 46: 462-472Crossref PubMed Scopus (162) Google Scholar). The primary endpoint, which was the composite of ESKD, doubling of serum creatinine, or renal or cardiovascular death, was accompanied by a variety of secondary outcomes (Jardine et al., 2017Jardine M.J. Mahaffey K.W. Neal B. Agarwal R. Bakris G.L. Brenner B.M. Bull S. Cannon C.P. Charytan D.M. de Zeeuw D. et al.CREDENCE study investigatorsThe Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) study rationale, design, and baseline characteristics.Am. J. Nephrol. 2017; 46: 462-472Crossref PubMed Scopus (162) Google Scholar). Compared to other ongoing SGLT2 inhibitor renal protection trials, CREDENCE is relatively unique in that it was restricted to participants with DKD, defined as an eGFR of ≥30 to 300 to ≤5,000 mg/g). Participants were also required to be taking the maximum tolerated dose of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. The Dapa-CKD trial with dapagliflozin (ClinicalTrials.gov Identifier: NCT03036150) has enrolled patients with macroalbuminuria (eGFR ≥ 25 to <75 mL/min/1.73 m2), with a planned subgroup of patients with non-diabetic CKD. EMPA-KIDNEY (ClinicalTrials.gov Identifier: NCT03594110) with empagliflozin will include patients with eGFR values down to 20 mL/min/1.73 m2. In the ≥20 to <45 mL/min/1.73 m2 range, participants can be normo-, micro- or macroalbuminuric. In the overall landscape, therefore, CREDENCE provides the most focused evidence around protection against DKD and renal protection with SGLT2 inhibition to date. Importantly, the CREDENCE cohort was at a much higher risk of renal disease progression compared to the patients in the previously reported SGLT2 inhibitor CVOTs. The mean eGFR was 56 mL/min/1.73 m2, compared to ∼75 mL/min/1.73 m2 in EMPA-REG OUTCOME and the CANVAS Program, and ∼85 mL/min/1.73 m2 in DECLARE-TIMI 58. Moreover, the median UACR was 927 mg/g in CREDENCE, whereas less than one-third of the patients in the published CVOTs had micro- or macroalbuminuria at baseline. Finally, baseline blood pressure was higher in CREDENCE (systolic blood pressure 140 mmHg, compared to ∼135 mmHg in the previous CVOTs), further increasing the risk of accruing renal and cardiovascular events. In the fall of 2018, the CREDENCE trial was stopped early due to efficacy after a planned interim analysis; the full results were recently published (Perkovic et al., 2019Perkovic V. Jardine M.J. Neal B. Bompoint S. Heerspink H.J.L. Charytan D.M. Edwards R. Agarwal R. Bakris G. Bull S. et al.CREDENCE Trial InvestigatorsCanagliflozin and renal outcomes in type 2 diabetes and nephropathy.N. Engl. J. Med. 2019; https://doi.org/10.1056/NEJMoa1811744Crossref PubMed Scopus (2619) Google Scholar). In the overall cohort, the primary endpoint in the canagliflozin group was reduced by 30% (HR 0.70, 95% CI 0.59-0.82, p = 0.00001), an effect mediated by significant reductions in doubling of creatinine (−40%) and ESKD (−32%)—including a 26% reduction in the risk of renal replacement therapy. No heterogeneity was observed across CKD status or baseline albuminuria level, or across relevant baseline clinical characteristics. Renal death and cardiovascular death were numerically (but not statistically) reduced. The risk of HHF was, perhaps as expected based on previous CVOT results, reduced by 39%. In the canagliflozin treatment group, albuminuria was reduced by 31%, eGFR decline attenuated by 2.7 mL/min/year, blood pressure lowered by a mean of 3.30/0.95 mmHg, and body weight by 0.80 kg. The impact of canagliflozin on important adverse events was also of critical importance for the future clinical application of the CREDENCE trial results in the setting of DKD. In contrast to the CANVAS Program, there was no signal for lower limb amputation and no increased risk of fracture. While a full discussion around the underlying reasons for differences in the safety profile of canagliflozin in the CANVAS Program versus CREDENCE trials is outside the scope of this discussion, it is reasonable to conclude that in patients with DKD, the safety profile of canagliflozin is reassuring. In fact, pre-clinical studies have suggested that canagliflozin is associated with an improvement in leg perfusion after acute limb ischemia (Sherman et al., 2018Sherman S.E. Bell G.I. Teoh H. Al-Omran M. Connelly K.A. Bhatt D.L. Hess D.A. Verma S. Canagliflozin improves the recovery of blood flow in an experimental model of severe limb ischemia.JACC Basic Transl Sci. 2018; 3: 327-329Crossref PubMed Scopus (22) Google Scholar). Ongoing vigilance around limb ischemia and mitigating fracture risk is nevertheless warranted as part of routine clinical care in all patients with diabetes, regardless of the type of background glucose-lowering therapy. In the current clinical trial landscape, CREDENCE is therefore the fourth trial to demonstrate improvements in hard renal and cardiovascular endpoints in patients with T2D. The CREDENCE trial is, of course, set apart from previous work based on the unique DKD-specific study cohort, and its design and implementation around primary renal endpoints. Accordingly, it seems inevitable that major diabetes and nephrology guidelines will evolve in the near future to closely align with results of the CREDENCE trial. In the 1990s and early 2000s, medical subspecialists and general practitioners modified their clinical practices around the results of ACE inhibitor and ARB trials once it became clear that these therapies were not only anti-hypertensive agents, but also disease-modifying treatments for atherosclerosis, heart failure, and kidney disease, independent of blood pressure lowering. In a similar way, physicians will now have to learn how to shift the rationale for the use of SGLT2 inhibitors away from use solely as glucose-lowering agents, to instead consider them as disease-modifying treatments for DKD, and as a strategy to reduce cardiovascular risk in appropriate clinical situations. This includes the safe, evidence-based use of these drugs, in DKD patients, for the time being, with eGFR ≥ 30 mL/min/1.73 m2 and macroalbuminuria when selected for use in renal protection. While CREDENCE has answered several critical clinical questions and addressed a current gap in the management of DKD, other issues will only be investigated in future work. First, the results of CREDENCE make it all the more urgent to determine whether SGLT2 inhibitors can reduce renal and cardiovascular risk in patients with type 1 diabetes, independent of glucose lowering. The EMPA-KIDNEY trial will include patients with type 1 diabetes, thereby providing information about cardiorenal protection in the setting of type 1 diabetes, although it is anticipated that only a small number of individuals with T1D will be enrolled. Similarly, use of SGLT2 inhibitors in non-diabetic CKD is being studied in smaller mechanistic studies and in large outcome trials such as EMPA-KIDNEY and Dapa-CKD, in an effort to take advantage of proposed glucose-independent mechanism of action of these agents. In the near term, the renal, cardiovascular, endocrine, and general practice communities will need to focus on knowledge translation and dissemination of the CREDENCE results to physicians and allied health professionals through continuing medical education and changes in practice guideline, including how to use the agents safely through appropriate patient education. The CREDENCE trial results are clearly a big win for patients with DKD. D.Z.I.C. is supported by a Department of Medicine, University of Toronto Merit Award and receives support from the Canadian Institutes of Health Research, Diabetes Canada, the Heart and Stroke Richard Lewar Centre of Excellence, and the Heart and Stroke Foundation of Canada. S.V. holds a Tier 1 Canada Research Chair in Cardiovascular Surgery. D.Z.I.C. has received consulting fees or speaking honorarium or both from Janssen, Boehringer Ingelheim-Eli Lilly, AstraZeneca, Merck, and Sanofi, and has received operating funds from Janssen, Boehringer Ingelheim-Eli Lilly, AstraZeneca, and Merck. S.V. reports receiving research grants and/or speaking honoraria from Amgen, AstraZeneca, Bayer Healthcare, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Janssen, Merck, Novartis, Novo Nordisk, and Sanofi. He is also the President of the Canadian Medical and Surgical Knowledge Translation Research Group, a federally incorporated not-for-profit physician organization.