Sodium Glucose Cotransporter 2 (SGLT2) Inhibitors and CKD: Are You a #Flozinator?

Abstract

Sodium/glucose cotransporter 2 (SGLT2) inhibitors have rapidly emerged as a novel therapy to reduce the rate of progression of chronic kidney disease (CKD). With humble beginnings in the 19th century for treating malaria, this class of drugs initially developed for the treatment of diabetes has now revolutionized the management of heart failure and CKD. SGLT2 inhibitors trigger glucosuria, thus modestly improving glycemic control. In addition, they have pleiotropic effects, such as reducing intraglomerular pressure and improving tubuloglomerular feedback, which lead to their beneficial effects on CKD progression. Recent data from randomized controlled trials have demonstrated the efficacy of this class of drugs in CKD. We briefly review the evidence from major trials on SGLT2 inhibitors in CKD, discuss the mechanisms of action and provide an overview of the safe and successful prescription of these medications. Sodium/glucose cotransporter 2 (SGLT2) inhibitors have rapidly emerged as a novel therapy to reduce the rate of progression of chronic kidney disease (CKD). With humble beginnings in the 19th century for treating malaria, this class of drugs initially developed for the treatment of diabetes has now revolutionized the management of heart failure and CKD. SGLT2 inhibitors trigger glucosuria, thus modestly improving glycemic control. In addition, they have pleiotropic effects, such as reducing intraglomerular pressure and improving tubuloglomerular feedback, which lead to their beneficial effects on CKD progression. Recent data from randomized controlled trials have demonstrated the efficacy of this class of drugs in CKD. We briefly review the evidence from major trials on SGLT2 inhibitors in CKD, discuss the mechanisms of action and provide an overview of the safe and successful prescription of these medications. The chemical phlorizin was first isolated from the bark of apple trees in the 19th century by French scientists and was used in treating malaria. It was later found to inhibit glucose reabsorption in the kidney.1Ehrenkranz J.R.L. Lewis N.G. Kahn C.R. Roth J. Phlorizin: a review.Diabetes Metab Res Rev. 2005; 21: 31-38Crossref PubMed Scopus (762) Google Scholar Several decades later, sodium/glucose cotransporter 2 (SGLT2) inhibitors were developed using this chemical. The SGLT2 protein is located in the proximal tubules of the kidneys, contributing to nearly 90% of glucose reabsorption via the cotransport of glucose and sodium.2Panchapakesan U. Pegg K. Gross S. et al.Effects of SGLT2 inhibition in human kidney proximal tubular cells--renoprotection in diabetic nephropathy?.PLOS ONE. 2013; 8e54442Crossref PubMed Scopus (231) Google Scholar SGLT2 inhibitors suppress this glucose reabsorption, resulting in glucosuria. Although these medications were originally developed to improve glycemic control, the evidence from randomized clinical trials has shone a light on their efficacy in kidney and heart protection among even individuals without diabetes. SGLT2 inhibitors have come a long way in a short period of time. Although they have a modest impact on glycemic control, this group of drugs has revolutionized the management of chronic kidney disease (CKD) and heart failure, irrespective of the underlying diabetes status. The initial cardiovascular (CV) outcome trials not only showed the efficacy of SGLT2i agents in reducing CV mortality and hospitalization for heart failure in patients with type 2 diabetes mellitus (T2DM), but secondary outcomes from these early trials also revealed up to 40% reduction in the risk of progression of kidney disease.3Zinman B. Wanner C. Lachin J.M. et al.Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.N Engl J Med. 2015; 373: 2117-2128Crossref PubMed Scopus (7870) Google Scholar, 4Neal B. Perkovic V. Mahaffey K.W. et al.Canagliflozin and cardiovascular and renal events in type 2 diabetes.N Engl J Med. 2017; 377: 644-657Crossref PubMed Scopus (2493) Google Scholar, 5Wiviott S.D. Raz I. Bonaca M.P. et al.Dapagliflozin and cardiovascular outcomes in type 2 diabetes.N Engl J Med. 2019; 380: 347-357Crossref PubMed Scopus (3512) Google Scholar, 6Wanner C. Inzucchi S.E. Lachin J.M. et al.Empagliflozin and progression of kidney disease in type 2 diabetes.N Engl J Med. 2016; 375: 323-334Crossref PubMed Scopus (2248) Google Scholar Notably, the cohort of patients in these initial studies mostly had preserved kidney function without significant albuminuria. Figure 1 demonstrates the key SGLT2i trials over the last few years. Subsequently, randomized controlled trials (RCTs) were specifically designed to evaluate primary kidney endpoints, focusing on patients with various degrees of baseline kidney impairment and higher albuminuria (Table 1).Table 1Landmark Trials of SGLT2 Inhibitors in CKDCREDENCEDAPA-CKDEMPA-KIDNEYInterventionCanagliflozin 100 mg daily vs placeboDapagliflozin 10 mg daily vs placeboEmpagliflozinPopulation4,401 patients with T2DM and CKDOn RAAS blockadeExcluded suspected non-diabetic CKD4,304 patients with and without T2DMOn RAAS blockadeExcluded PCKD, T1DM, lupus/AAV, recent immunosuppression6,609 with and without T2DMOn RAAS blockadeExcluded PCKDeGFR (mL/min/1.73 m2)30 to <9025-7520 to <45 or,45 to <90 with albuminuriaAlbuminuria (mg/g)>300-5,000200-5,000Any level of albuminuria if eGFR 20 to <45 mL/min/1.73 m2At least 200 if eGFR 45 to <90 mL/min/1.73 m2% without diabetes032%54%% with glomerular disease016%25%Mean (SD) eGFR, mL/min/1.73 m256 (18)43 (12)37 (14)Median (IQR) UACR, mg/g927 (463-1,833)949 (477-1,885)329 (49-1,069)Median (IQR) follow-up, y2.62 (0.02-4.53)2.4 (2.0-2.7)2.0 (1.5-2.4)Primary outcomesComposite of ESKD, doubling of SCr from baseline, or death from renal or CV causesComposite of any of a decline of at least 50% in eGFR, onset of ESKD, or death from renal or CV causesFirst occurrence of kidney disease progression or death from CV causesSecondary outcomesComposite of CV death or heart failure hospitalization; composite of ESKD, doubling of SCr, or death; CV death; death from any causeComposite kidney outcome (sustained decline in eGFR of 50%, ESKD, or death from renal cause); composite CV outcomes (hospitalization for heart failure or CV death); death from any causeComposite of hospitalization for heart failure, death from CV causes, all-cause hospitalization, and death from any causePrimary outcomes (HR, 95%CI)0.70 (0.59-0.82)0.61 (0.51-0.72)0.72 (0.64-0.82)Key secondary outcomes (HR, 95%CI) Death from any cause0.83 (0.68-1.02)0.69 (0.53-0.88)0.87 (0.70-1.08) Hospitalization for heart failure or death from CV cause0.69 (0.57-0.83)0.71 (0.55-0.92)0.84 (0.67-1.07) Composite of decline in eGFR, ESKD, or death from renal cause0.66 (0.53-0.81))0.56 (0.45-0.68)—AAV, antineutrophil cytoplasmic antibody-associated vasculitis; CI, confidence interval; CKD, chronic kidney disease; CV, cardiovascular; eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease; HR, hazard ratio; IQR, interquartile range; PCKD, polycystic kidney disease; RAAS, renin-angiotensin-aldosterone system; SGLT2, sodium/glucose cotransporter 2; SCr, serum creatinine; SD, standard deviation; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus; UACR, urinary albumin-creatinine ratio. Open table in a new tab AAV, antineutrophil cytoplasmic antibody-associated vasculitis; CI, confidence interval; CKD, chronic kidney disease; CV, cardiovascular; eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease; HR, hazard ratio; IQR, interquartile range; PCKD, polycystic kidney disease; RAAS, renin-angiotensin-aldosterone system; SGLT2, sodium/glucose cotransporter 2; SCr, serum creatinine; SD, standard deviation; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus; UACR, urinary albumin-creatinine ratio. CREDENCE (Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy) was the first double-blind, placebo-controlled RCT that investigated the efficacy of an SGLT2i agent for primary composite kidney outcomes in 4,401 participants with T2DM and CKD with estimated glomerular filtration rate (eGFR) 30 to <90 mL/min/1.73 m2 and severe albuminuria (urine albumin-creatinine ratio [UACR] >300 to 5,000 mg/g [33-565 mg/mmol]).7Perkovic V. Jardine M.J. Neal B. et al.Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.N Engl J Med. 2019; 380: 2295-2306Crossref PubMed Scopus (3170) Google Scholar The trial was stopped early because of an interim analysis showing clear efficacy for the primary outcome (median follow-up 2.62 years; interquartile range, 0.02-4.53). The results of this trial showed a significant benefit of canagliflozin in patients with T2DM and CKD. Canagliflozin led to a 30% reduction in the composite risk for kidney failure (sustained eGFR <15 mL/min/1.73 m2 or treatment with dialysis or transplantation), doubling of serum creatinine level, or death from kidney or CV causes (hazard ratio [HR], 0.70; 95% CI, 0.59-0.82). The canagliflozin group also had a lower risk of CV death, myocardial infarction, or stroke (HR, 0.61; 95% CI, 0.47-0.80). Rates of adverse events, particularly of fractures and amputations, were similar across the 2 groups, with the treatment group having a slightly higher risk of developing diabetic ketoacidosis (DKA) (2.2 vs 0.2 per 1,000-patient years). The DAPA-CKD (Dapagliflozin in Patients With Chronic Kidney Disease) trial investigated primary composite kidney outcomes in 4,304 participants with CKD (eGFR of 25 to <75 mL/min/1.73 m2) and albuminuria (UACR 200-5,000 mg/g [22-565 mg/mmol]), on maximal tolerated renin-angiotensin-aldosterone system (RAAS) inhibitors, with or without T2DM.8Heerspink H.J.L. Stefánsson B.V. Correa-Rotter R. et al.Dapagliflozin in patients with chronic kidney disease.N Engl J Med. 2020; 383: 1436-1446Crossref PubMed Scopus (1866) Google Scholar The primary composite outcome was the first occurrence of any of the following: a decline of at least 50% in eGFR, the onset of end-stage kidney disease (ESKD), an eGFR of <15 mL/min/1.73 m2, or death from renal or CV causes. The mean eGFR was 43.1 ± 12.3 mL/min/1.73 m2, and nearly 15% had an eGFR of <30 mL/min/1.73 m2. This trial was stopped early (median follow-up 2.4 years; interquartile range, 2-2.7) because of the overwhelming efficacy of dapagliflozin, which slowed the rate of decline in eGFR, reduced progression to ESKD, and mortality from kidney or CV causes, regardless of diabetic status. The primary composite outcome occurred in 9.2% of patients on dapagliflozin versus 14.5% on placebo (HR, 0.61; 95% CI, 0.51-0.72). The number needed to treat to prevent one primary event was 19. Organ-protective benefits were observed across all stages of CKD (including 624 patients with advanced stage 4 CKD) and all levels of albuminuria. The incidence of all secondary outcomes, in particular mortality, were lower in the treatment group. The incidence of adverse events was similar across the groups with no notable predisposition toward amputation or DKA in the treatment arm. Notably, this study excluded patients with type 1 diabetes, polycystic kidney disease, CKD from lupus nephritis, or antineutrophil cytoplasmic antibody-associated vasculitis, and those on immunosuppressants 6 months before enrollment. Most recently, EMPA-KIDNEY (Empagliflozin in Patients with Chronic Kidney Disease), a large randomized, double-blind, placebo-controlled trial, evaluated the effects of empagliflozin on the progression of CKD in patients with or without T2DM with even lower eGFR of 20-45 mL/min/1.73 m2 regardless of albuminuria or eGFR 45-90 mL/min/1.73 m2 with UACR ≥200 mg/g (22 mg/mmol) on a single RAAS blockade agent if tolerated.9EMPA-KIDNEY Collaborative GroupDesign, recruitment, and baseline characteristics of the EMPA-KIDNEY trial.Nephrol Dial Transplant. 2022; 37: 1317-1329Crossref PubMed Scopus (40) Google Scholar,10The EMPA-KIDNEY Collaborative Group Herrington W.G. Staplin N. et al.Empagliflozin in patients with chronic kidney disease.N Engl J Med. 2023; 388: 117-127Crossref PubMed Scopus (239) Google Scholar The primary outcome was the first occurrence of progression of kidney disease (defined as any of ESKD [initiation of dialysis or receipt of a kidney transplant], a sustained decrease in eGFR to <10 mL/min/1.73 m2, a sustained decrease in eGFR of at least 40% from baseline, or death from renal causes) or death from CV causes. This study examined a cohort likely underrepresented in previous studies (lower eGFR and lower UACR). The investigators enrolled 6,609 patients with CKD (mean eGFR of 37.3 ± 14.5 mL/min/1.73 m2); over 50% did not have a history of diabetes, 25% had a history of glomerulonephritis, and 34% had an eGFR of <30 mL/min/1.73 m2. Once again, the study was stopped early by the independent safety monitoring committee because of overwhelmingly positive results. The median follow-up was 2 years (interquartile range, 1.5-2.4). The primary outcome occurred in 13.1% of the empagliflozin group compared with 16.9% in the placebo group (HR, 0.72; 95% CI, 0.64-0.82). The benefits of empagliflozin were similar among patients with or without diabetes and irrespective of eGFR. No differences were noted in the primary outcome in the subgroup with UACR <30 or ≥30 to ≤300 mg/g. However, between-group differences in the mean rate of eGFR decline remained preserved among key subgroups including in those with UACR ≤300 mg/g. Although the progression of kidney disease (HR, 0.71; 95% CI, 0.62-0.81) and hospitalization for any cause (HR, 0.86; 95% CI, 0.78-0.95) were lower in the treatment arm, no significant differences were noted with respect to hospitalization for heart failure, death from CV causes, or death from any cause (secondary outcomes). Though rates of serious adverse events were similar between the 2 groups, there were more episodes of DKA vs and amputation vs in the treatment EMPA-KIDNEY Collaborative Group Herrington W.G. Staplin N. et al.Empagliflozin in patients with chronic kidney disease.N Engl J Med. 2023; 388: 117-127Crossref PubMed Scopus (239) Google Scholar The results of EMPA-KIDNEY an review and of trials eGFR from mL/min/1.73 m2, with with SGLT2i agents reduced the risk of kidney disease progression by irrespective of diabetes and underlying kidney they also reduced the risk of kidney by and the risk of CV death or hospitalization for heart failure by SGLT2i agents did not reduce the risk of of Renal of diabetes on the effects of glucose inhibitors on kidney of large placebo-controlled 2022; PubMed Scopus Google Scholar DAPA-CKD and EMPA-KIDNEY enrolled patients with primary glomerular analysis of the DAPA-CKD trial patients with of were randomized to dapagliflozin and to The mean eGFR was mL/min/1.73 m2, and the mean UACR was mg/g with a median follow-up of years. rates of eGFR decline with dapagliflozin and placebo were and mL/min/1.73 reduced UACR by compared with the Stefánsson B.V. et analysis of the DAPA-CKD trial demonstrates the effects of dapagliflozin on major adverse kidney events in patients with PubMed Scopus Google Scholar EMPA-KIDNEY trial patients with review and demonstrated a beneficial of SGLT2 inhibitors on kidney disease progression in primary glomerular disease the effects of DAPA-CKD and EMPA-KIDNEY were events in the treatment group vs events in the placebo risk ratio CI, particularly in underlying events in the treatment group vs in the placebo 95% CI, of Renal of diabetes on the effects of glucose inhibitors on kidney of large placebo-controlled 2022; PubMed Scopus Google Scholar Although the in the management of efficacy data and have a significant adverse data now that agents a safe and to RAAS inhibition in the management of glomerular disease, particularly studies have the benefits of SGLT2i agents in the clinical The study was a cohort study of over participants with T2DM with mean eGFR mL/min/1.73 m2. In this compared with of SGLT2 inhibitors was with a rate of decline in and progression to H.J.L. et outcomes with of SGLT2 inhibitors in clinical a cohort Diabetes 2020; PubMed Scopus Google Scholar 4 SGLT2i agents dapagliflozin, and has in various clinical trials and The results of these clinical trials have significant in protection and outcomes irrespective of the SGLT2i agent The the in chemical and the the of class of the similar for SGLT2 compared with sodium/glucose cotransporter protein and a large of C. N. the effects of SGLT2 inhibitors a or there differences between PubMed Scopus Google Scholar The results of the major CV outcome trials showed similar irrespective of the SGLT2i agent the of a SGLT2i agent in of the with primary kidney outcomes in dapagliflozin in and empagliflozin in they all showed overwhelming efficacy of these agents in protection to early of In addition, the in these were similar the of individuals without diabetes in DAPA-CKD and EMPA-KIDNEY V. Jardine M.J. Neal B. et al.Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.N Engl J Med. 2019; 380: 2295-2306Crossref PubMed Scopus (3170) Google H.J.L. Stefánsson B.V. Correa-Rotter R. et al.Dapagliflozin in patients with chronic kidney disease.N Engl J Med. 2020; 383: 1436-1446Crossref PubMed Scopus (1866) Google Scholar,10The EMPA-KIDNEY Collaborative Group Herrington W.G. Staplin N. et al.Empagliflozin in patients with chronic kidney disease.N Engl J Med. 2023; 388: 117-127Crossref PubMed Scopus (239) Google Scholar of the 4 SGLT2i agents that they reduced all-cause mortality, CV mortality, because of heart failure, of kidney and kidney as a class among a of the the safety was with the benefits of SGLT2i the No the in of or C. The cardiovascular outcomes, heart failure and kidney disease trials that the to glucose cotransporter 2 inhibitors is 2020; PubMed Scopus Google Scholar Several have to the of SGLT2 and effects of SGLT2 inhibitors, which have a on contributing to the outcomes of these for the of these agents the of tubuloglomerular In diabetes, SGLT2 and resulting in and glucose reabsorption and reduced of to The in the to and intraglomerular SGLT2 inhibitors to to of the and reduced intraglomerular pressure and glomerular C. et and chronic effects of SGLT2 blockade on glomerular and tubular function in the early diabetic J PubMed Scopus Google Scholar the significant evidence for the efficacy of SGLT2 inhibitors in individuals with and without diabetes, the benefits of these agents their and tubuloglomerular mechanisms have reducing and of the proximal tubular and that in et inhibition for CKD and cardiovascular disease in type 2 of a by the Kidney J Kidney PubMed Scopus Google Scholar recent study showed that the of empagliflozin to treatment in patients with diabetes in a significant decrease in proximal tubular and reabsorption, with evidence of lower urinary of a reduction in proximal tubular This therapy also reduced a of which to K. N. et and effects of SGLT2 and 2022; PubMed Scopus Google Scholar is needed to the of in the on the results of randomized clinical trials and the SGLT2i agents with a risk of serious adverse C. The cardiovascular outcomes, heart failure and kidney disease trials that the to glucose cotransporter 2 inhibitors is 2020; PubMed Scopus Google Scholar Notably, SGLT2 inhibitors in an in eGFR the first few the of This decline in eGFR is to because of the intraglomerular to these underlying of with of eGFR over time. In the analysis of the trial, an initial eGFR decline of was in of the empagliflozin cohort as compared with in the placebo group ratio 95% CI, In independent with a higher risk of this initial eGFR and a higher risk at the efficacy of empagliflozin on protection was across and the initial eGFR decline did not have an impact on the beneficial effects of SGLT2i et and of the initial estimated glomerular filtration rate inhibition with empagliflozin in the PubMed Scopus Google Scholar analysis of the (Dapagliflozin in Patients with and trial showed an ratio of CI, for a in eGFR with dapagliflozin compared with lower eGFR at baseline, higher and T2DM were independent risk for this decline in eGFR. This decline in eGFR was not with more adverse events or a eGFR C. H.J.L. et decline in estimated glomerular filtration rate of dapagliflozin in patients with heart failure and reduced from 2022; PubMed Scopus Google Scholar across clinical trials of these Jardine M.J. R. et from CREDENCE trial an in estimated glomerular filtration rate treatment with canagliflozin with for clinical PubMed Scopus Google Scholar In this is not of kidney decline in eGFR up to 30% the initial these medications not a to from trials and studies showed that SGLT2 inhibitors in with lower kidney of Renal of diabetes on the effects of glucose inhibitors on kidney of large placebo-controlled 2022; PubMed Scopus Google J.M. SGLT2 inhibitors and the risk of kidney in with type 2 J Kidney 2022; PubMed Scopus Google Scholar, J. kidney and adverse renal events in patients review and Med. 2019; PubMed Scopus Google Scholar, of SGLT2 inhibitors in chronic of large randomized trials of SGLT2 Scholar In a recent analysis of the DAPA-CKD trial, compared with patients with decline in eGFR, patients decline in eGFR 2 dapagliflozin had a rate of eGFR decline in the N. et and of an in eGFR in to the SGLT2 dapagliflozin in patients with 2022; PubMed Scopus Google Scholar No significant adverse events were with this decline in eGFR. This study patients and to the a in eGFR. and before an The of and medications in patients to and the of these agents in a or for has the higher risk of Notably, no significant events were noted in the large that patients without diabetes. SGLT2i agents only lower glucose levels by the reabsorption of which is reduced as levels the risk of is in the of such as and in is to reduce the of these agents before an SGLT2i to reduce the risk of to the is with an initial reduction of by and management on of SGLT2 to the including drugs and PubMed Scopus Google Scholar a recent did not a risk of severe in a large group of participants on compared with placebo 95% CI, of Renal of diabetes on the effects of glucose inhibitors on kidney of large placebo-controlled 2022; PubMed Scopus Google Scholar DKA is among the adverse effects with SGLT2 inhibitors in patients with diabetes 95% CI, of Renal of diabetes on the effects of glucose inhibitors on kidney of large placebo-controlled 2022; PubMed Scopus Google Scholar This results in such as and with and serum glucose level on DKA is to from the of levels because of the of the to a in the of and to K. diabetic ketoacidosis by SGLT2 and contributing Diabetes 2016; PubMed Scopus Google Scholar that the risk of DKA of and a such as or Patients on this and with a to reduce the risk of The risk among patients without diabetes is with only 1 event noted in a large years of of Renal of diabetes on the effects of glucose inhibitors on kidney of large placebo-controlled 2022; PubMed Scopus Google Scholar more in T2DM and SGLT2i 95% CI, of Renal of diabetes on the effects of glucose inhibitors on kidney of large placebo-controlled 2022; PubMed Scopus Google Scholar is focusing on daily and monitoring for early of In a or an of therapy is to treat the of therapy not a of from and a from the and data from large and results of studies have not a significant risk of severe urinary in patients using SGLT2 inhibitors compared with H.J.L. Stefánsson B.V. Correa-Rotter R. et al.Dapagliflozin in patients with chronic kidney disease.N Engl J Med. 2020; 383: 1436-1446Crossref PubMed Scopus (1866) Google in patients with chronic heart a review and Res Scopus Google N. inhibitors and risk for in with type 2 PubMed Scopus Google Scholar of severe urinary have in patients with V. J. with dapagliflozin in the of urinary 2017; Google Scholar is needed these drugs in patients with a history of In the (Canagliflozin and and Renal in Type 2 trial, patients with diabetes to canagliflozin had a doubling in risk of mostly at the level of the or compared with placebo vs events per 1,000-patient years; HR, 95% CI, this was not noted in clinical B. Perkovic V. Mahaffey K.W. et al.Canagliflozin and cardiovascular and renal events in type 2 diabetes.N Engl J Med. 2017; 377: 644-657Crossref PubMed Scopus (2493) Google of Renal of diabetes on the effects of glucose inhibitors on kidney of large placebo-controlled 2022; PubMed Scopus Google Scholar Although the and for canagliflozin in the risk is in the of is in patients with diabetes on SGLT2i Patients on the of SGLT2 inhibitors, and glucose and and an Patients a clear and to their SGLT2i if or for any Figure 2 a to successful and of these S. SGLT2 inhibitors in diabetic kidney J PubMed Scopus Google Scholar SGLT2 inhibitors have to benefit CV and kidney disease regardless of diabetes status. drugs have a adverse and the of kidney and urinary have now demonstrated to lower initially by using of and and of or agents to the adverse effects of these medications. The results of trials to the impact of SGLT2i agents on glomerular lower eGFR, CKD, dialysis and and

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