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SGLT2 Inhibition for CKD and Cardiovascular Disease in Type 2 Diabetes: Report of a Scientific Workshop Sponsored by the National Kidney Foundation

Published:October 26, 2020DOI:https://doi.org/10.1053/j.ajkd.2020.08.003
      Diabetes is the most frequent cause of chronic kidney disease (CKD), leading to nearly half of all cases of kidney failure requiring replacement therapy. The principal cause of death among patients with diabetes and CKD is cardiovascular disease (CVD). Sodium/glucose cotransporter 2 (SGLT2) inhibitors were developed to lower blood glucose levels by inhibiting glucose reabsorption in the proximal tubule. In clinical trials designed to demonstrate the CVD safety of SGLT2 inhibitors in type 2 diabetes mellitus (T2DM), consistent reductions in risks for secondary kidney disease end points (albuminuria and a composite of serum creatinine doubling or 40% estimated glomerular filtration rate decline, kidney failure, or death), along with reductions in CVD events, were observed. In patients with CKD, the kidney and CVD benefits of canagliflozin were established by the CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) trial in patients with T2DM, urinary albumin-creatinine ratio > 300 mg/g, and estimated glomerular filtration rate of 30 to <90 mL/min/1.73 m2. To clarify and support the role of SGLT2 inhibitors for treatment of T2DM and CKD, the National Kidney Foundation convened a scientific workshop with an international panel of more than 80 experts. They discussed the current state of knowledge and unanswered questions to propose therapeutic approaches and delineate future research. SGLT2 inhibitors improve glomerular hemodynamic function and are thought to ameliorate other local and systemic mechanisms involved in the pathogenesis of CKD and CVD. SGLT2 inhibitors should be used when possible by people with T2DM to reduce risks for CKD and CVD in alignment with the clinical trial entry criteria. Important risks of SGLT2 inhibitors include euglycemic ketoacidosis, genital mycotic infections, and volume depletion. Careful consideration should be given to the balance of benefits and harms of SGLT2 inhibitors and risk mitigation strategies. Effective implementation strategies are needed to achieve widespread use of these life-saving medications.

      Index Words

      Introduction

      Diabetes and chronic kidney disease (CKD) commonly co-exist and are associated with high risk for morbidity and mortality. In the United States, 34.2 million adults (10.5% of the population) are estimated to have diabetes, with only 26.9 million aware of the diagnosis.
      Centers for Disease Control and Prevention
      National Diabetes Statistics Report, 2020.
      Type 2 diabetes mellitus (T2DM) accounts for 90% to 95% of cases of diagnosed diabetes.
      Centers for Disease Control and Prevention
      National Diabetes Statistics Report, 2020.
      Worldwide, 463 million had diabetes in 2019, with a predicted growth in prevalence to nearly 700 million by 2045.
      International Diabetes Foundation
      IDF Diabetes Atlas.
      Diabetic kidney disease (DKD), CKD in diabetes, occurs in ~30% of people with type 1 diabetes mellitus (T1DM) and in ~40% of those with T2DM.
      National Kidney Foundation
      KDOQI clinical practice guideline for diabetes and CKD: 2012 update.
      Diabetes is the leading cause of CKD globally, accounting for nearly half of all cases of kidney failure requiring replacement therapy. However, patients with T2DM and CKD are more likely to die than progress to kidney failure.
      International Diabetes Foundation
      IDF Diabetes Atlas.
      ,
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      • Dwyer J.P.
      • et al.
      Relative incidence of ESRD versus cardiovascular mortality in proteinuric type 2 diabetes and nephropathy: results from the DIAMETRIC (Diabetes Mellitus Treatment for Renal Insufficiency Consortium) database.
      As such, the population with diabetes requiring kidney replacement therapy (KRT) is a survivor cohort of ~10% of those who originally had CKD.
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      • Tuttle K.R.
      Diabetic kidney disease: challenges, progress, and possibilities.
      The most common causes of death in patients with T2DM and CKD are atherosclerotic cardiovascular disease (ASCVD) and heart failure (HF).
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      • et al.
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      Glycemic control is the cornerstone of optimal diabetes care. For those with CKD, hypertension control and use of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) are also foundations of optimal care. Many glucose-lowering medications are now available. Until recently, no class of glucose-lowering agent was considered as preferred treatment. Rather, the recommendation was to achieve a glycemic target determined by hemoglobin A1c (HbA1c) level. People with diabetes and CKD have had limited choice of glucose-lowering agents due to safety issues, adverse effects, or lack of evidence in people with low glomerular filtration rates (GFR).
      Sodium/glucose cotransporter 2 (SGLT2) inhibitors lower blood glucose levels by preventing glucose and sodium reabsorption in the proximal tubule.
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      Update on developments with SGLT2 inhibitors in the management of type 2 diabetes.
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      • Chang Y.Y.
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      • et al.
      The kidney as a new target for antidiabetic drugs: SGLT2 inhibitors.
      The US Food and Drug Administration (FDA) has approved 4 SGLT2 inhibitors for the treatment of hyperglycemia in T2DM: canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin. The first reported cardiovascular disease (CVD) outcome trial (CVOT) to demonstrate safety of an SGLT2 inhibitor, the EMPA-REG OUTCOME trial, was also the first to show clear benefit of a particular glucose-lowering agent for protection against major adverse cardiovascular events (MACE) in people with T2DM and ASCVD. Empagliflozin also reduced the risk for secondary kidney disease end points (albuminuria progression, serum creatinine doubling, kidney failure, and death).
      • Wanner C.
      • Inzucchi S.E.
      • Lachin J.M.
      • et al.
      Empagliflozin and progression of kidney disease in type 2 diabetes.
      These results have subsequently been demonstrated across the class of SGLT2 inhibitors with canagliflozin
      • Neal B.
      • Perkovic V.
      • Mahaffey K.W.
      • et al.
      Canagliflozin and cardiovascular and renal events in type 2 diabetes.
      and dapagliflozin
      • Wiviott S.D.
      • Raz I.
      • Bonaca M.P.
      • et al.
      Dapagliflozin and cardiovascular outcomes in type 2 diabetes.
      in their respective CVOTs. These collective findings were subsequently proven by the CREDENCE trial, the first to show superiority of an SGLT2 inhibitor added to the standard of care for CKD in T2DM for a primary outcome of kidney disease end points.
      • Perkovic V.
      • Jardine M.J.
      • Neal B.
      • et al.
      Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.
      To address the groundbreaking science for the emerging role of SGLT2 inhibition for the treatment of patients with T2DM and CKD, the National Kidney Foundation (NKF) held a scientific workshop in June 2019 with an international panel of more than 80 experts in nephrology, endocrinology, cardiology, primary care, pharmacology, regulatory affairs, public health, and physiology. These experts deliberated on the current state of knowledge, methods to improve clinical care, and research that is needed to advance the field. The objective of this report is to publicly disseminate the conference proceedings and recommendations with an ultimate goal of providing knowledge that will improve CKD and CVD outcomes for people with T2DM.

      Mechanisms of Kidney Protection by SGLT2 Inhibitors

      The kidney benefits of SGLT2 inhibitors appear to be largely independent of glycemic control based on a growing series of observations. Their glucose-lowering effects are modest, especially in people with baseline estimated GFR (eGFR) < 45 mL/min/1.73 m2. Nevertheless, kidney protection is consistent and substantial in this population.
      • Perkovic V.
      • Jardine M.J.
      • Neal B.
      • et al.
      Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.
      SGLT2 inhibitors also have kidney benefits in people with well-controlled glycemia (HbA1c < 7%) in whom further glucose lowering was minimal.
      • Cannon C.P.
      • Perkovic V.
      • Agarwal R.
      • et al.
      Evaluating the effects of canagliflozin on cardiovascular and renal events in patients with type 2 diabetes mellitus and chronic kidney disease according to baseline HbA1c, including those with HbA1c <7%: results from the CREDENCE Trial.
      In the DAPA-HF trial, which included people with or without diabetes, the effects on HF and kidney disease end points were consistent regardless of diabetes status.

      Solomon SD, Jhund P, Kosiborod M, et al. The Dapagliflozin in heart failure with reduced ejection fraction trial (DAPA-HF): outcomes in patients with CKD and effects on renal function. Oral presentation at: American Society of Nephrology-Kidney Week; November 8, 2019; Washington DC.

      Finally, kidney protection of this type and magnitude has not been observed with other glucose-lowering agents.

       Tubuloglomerular Feedback and Glomerular Hemodynamics

      In addition to improvement in CKD and CVD risk factors, many other mechanisms have been postulated.
      • Heerspink H.J.L.
      • Kosiborod M.
      • Inzucchi S.E.
      • Cherney D.Z.I.
      Renoprotective effects of sodium-glucose cotransporter-2 inhibitors.
      The concept of restoring tubuloglomerular feedback is frequently used to explain the salutary kidney effects of SGLT2 inhibitors (Fig 1
      • Alicic R.Z.
      • Johnson E.J.
      • Tuttle K.R.
      SGLT2 inhibition for the prevention and treatment of diabetic kidney disease: a review.
      ). Restoration of tubuloglomerular feedback occurs as a consequence of increased sodium chloride delivery to the macula densa.
      • Heerspink 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.
      ,
      • Vallon V.
      • Thomson S.C.
      Targeting renal glucose reabsorption to treat hyperglycaemia: the pleiotropic effects of SGLT2 inhibition.
      When sodium chloride enters the macula densa, vasoactive substances such as adenosine are locally formed and released. In a paracrine manner, adenosine constricts the afferent arteriole through the adenosine 1 receptor, thereby decreasing glomerular perfusion and hyperfiltration, a central mechanism for progressive glomerular injury.
      • Tonneijck L.
      • Muskiet M.H.
      • Smits M.M.
      • et al.
      Glomerular hyperfiltration in diabetes: mechanisms, clinical significance, and treatment.
      ,
      • Vallon V.
      • Thomson S.C.
      The tubular hypothesis of nephron filtration and diabetic kidney disease.
      Consistent with this concept, SGLT2 inhibition by empagliflozin was observed to reduce kidney blood flow and increase vascular resistance in hyperglycemic patients with T1DM through afferent arteriolar vasoconstriction.
      • Cherney D.Z.
      • Perkins B.A.
      • Soleymanlou N.
      • et al.
      Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus.
      Another recent study in patients with T2DM reported that SGLT2 inhibition reduced GFR through efferent arteriolar dilation.
      • van Bommel E.J.M.
      • Muskiet M.H.A.
      • van Baar M.J.B.
      • et al.
      The renal hemodynamic effects of the SGLT2 inhibitor dapagliflozin are caused by post-glomerular vasodilatation rather than pre-glomerular vasoconstriction in metformin-treated patients with type 2 diabetes in the randomized, double-blind RED trial.
      Notably, preclinical data suggest that tubuloglomerular feedback may also occur by locally produced adenosine binding receptors that activate vasodilation in the efferent arteriole.
      • Ren Y.
      • Garvin J.L.
      • Carretero O.A.
      Efferent arteriole tubuloglomerular feedback in the renal nephron.
      Thus, although the acute reduction in GFR is consistent in patients with T1DM and T2DM, the underlying glomerular hemodynamic effectors may differ.
      Figure thumbnail gr1
      Figure 1Sodium/glucose cotransporter 2 (SGLT-2) inhibition and glomerular hemodynamics in diabetes. Abbreviations: ADP, adenosine diphosphate; ATP, adenosine triphosphate; P, phosphate. Reproduced from Alicic et al
      • Alicic R.Z.
      • Johnson E.J.
      • Tuttle K.R.
      SGLT2 inhibition for the prevention and treatment of diabetic kidney disease: a review.
      with permission of the copyright holder; original graphic © 2018 by the National Kidney Foundation.

       Tubular Workload and Hypoxia

      Reabsorption of electrolytes and organic solutes in the proximal tubule is energy and adenosine triphosphate (ATP) dependent. The proximal tubule accounts for the largest amount of oxygen consumption in the kidney.
      • Korner A.
      • Eklof A.C.
      • Celsi G.
      • Aperia A.
      Increased renal metabolism in diabetes. Mechanism and functional implications.
      In patients with diabetes, proximal tubular glucose reabsorption through SGLT2 is increased due to an increase in luminal glucose driven by hyperglycemia and glomerular hyperfiltration.
      • Wang C.
      • Zhou Y.
      • Kong Z.
      • et al.
      The renoprotective effects of sodium-glucose cotransporter 2 inhibitors versus placebo in patients with type 2 diabetes with or without prevalent kidney disease: a systematic review and meta-analysis.
      The resulting increased glucose and sodium reabsorption increases oxygen demand, which in turn renders the proximal tubule relatively hypoxic.
      • Layton A.T.
      • Vallon V.
      SGLT2 inhibition in a kidney with reduced nephron number: modeling and analysis of solute transport and metabolism.
      Tubular hypoxia may be a major mechanism of kidney disease progression in diabetes.
      • Fine L.G.
      • Norman J.T.
      Chronic hypoxia as a mechanism of progression of chronic kidney diseases: from hypothesis to novel therapeutics.
      By reducing sodium and glucose reabsorption, SGLT2 inhibitors reduce tubular workload and mitigate hypoxia in the proximal tubule. However, the shift of glucose and sodium reabsorption downstream to the S3 segment of the proximal tubule and medullary thick ascending limb of the loop of Henle increases oxygen demand, making these tubular segments vulnerable to ischemia. Lower medullary oxygen tension stimulates hypoxia-inducible factors, including erythropoietin, to increase red blood cell production and improve oxygen-carrying capacity.
      • Layton A.T.
      • Vallon V.
      SGLT2 inhibition in a kidney with reduced nephron number: modeling and analysis of solute transport and metabolism.
      Hypoxia in the kidney cortex can be quantified using blood oxygen level–dependent magnetic resonance imaging (BOLD-MRI).
      • Yin W.J.
      • Liu F.
      • Li X.M.
      • et al.
      Noninvasive evaluation of renal oxygenation in diabetic nephropathy by BOLD-MRI.
      Different BOLD-MRI techniques lead to varying results and current technology is not sufficiently sensitive to identify tubular segments. Thus, insight into where SGLT2 inhibitors alleviate hypoxia will require advances in techniques for more precise imaging.

       Glucose Metabolic Fluxes and Mitochondrial Dysfunction

      Glucose metabolic flux increases in the kidney cortex in early experimental and human diabetes, as indicated by higher urinary levels of tricarboxylic acid cycle and glycolytic metabolites.
      • Li M.
      • Wang X.
      • Aa J.
      • et al.
      GC/TOFMS analysis of metabolites in serum and urine reveals metabolic perturbation of TCA cycle in db/db mice involved in diabetic nephropathy.
      ,
      • Sas K.M.
      • Kayampilly P.
      • Byun J.
      • et al.
      Tissue-specific metabolic reprogramming drives nutrient flux in diabetic complications.
      This process occurs by increased proximal tubular glucose uptake. Moreover, higher urinary levels of tricarboxylic acid cycle metabolites predict kidney disease progression, and higher glucose metabolic flux promotes proximal tubular mitochondrial dysfunction.
      • Sas K.M.
      • Kayampilly P.
      • Byun J.
      • et al.
      Tissue-specific metabolic reprogramming drives nutrient flux in diabetic complications.
      Glucose metabolic flux decreases over time in progressive DKD with worsening mitochondrial dysfunction.
      • Sharma K.
      • Karl B.
      • Mathew A.V.
      • et al.
      Metabolomics reveals signature of mitochondrial dysfunction in diabetic kidney disease.
      Mitochondrial dysfunction may further aggravate ATP deficiency and hypoxia, which could conceivably be alleviated by SGLT2 inhibition.

       Diuresis and Natriuresis

      SGLT2 inhibitors promote diuresis due to glucosuria and natriuresis.
      • Lambers Heerspink H.J.
      • de Zeeuw D.
      • Wie L.
      • Leslie B.
      • List J.
      Dapagliflozin a glucose-regulating drug with diuretic properties in subjects with type 2 diabetes.
      Diuresis is an important mechanism for reducing blood pressure and risk for HF events.
      • Wanner C.
      • Inzucchi S.E.
      • Lachin J.M.
      • et al.
      Empagliflozin and progression of kidney disease in type 2 diabetes.
      • Neal B.
      • Perkovic V.
      • Mahaffey K.W.
      • et al.
      Canagliflozin and cardiovascular and renal events in type 2 diabetes.
      • Wiviott S.D.
      • Raz I.
      • Bonaca M.P.
      • et al.
      Dapagliflozin and cardiovascular outcomes in type 2 diabetes.
      • Perkovic V.
      • Jardine M.J.
      • Neal B.
      • et al.
      Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.
      • Cannon C.P.
      • Perkovic V.
      • Agarwal R.
      • et al.
      Evaluating the effects of canagliflozin on cardiovascular and renal events in patients with type 2 diabetes mellitus and chronic kidney disease according to baseline HbA1c, including those with HbA1c <7%: results from the CREDENCE Trial.

      Solomon SD, Jhund P, Kosiborod M, et al. The Dapagliflozin in heart failure with reduced ejection fraction trial (DAPA-HF): outcomes in patients with CKD and effects on renal function. Oral presentation at: American Society of Nephrology-Kidney Week; November 8, 2019; Washington DC.

      ,
      • Zinman B.
      • Wanner C.
      • Lachin J.M.
      • et al.
      Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
      Lack of a compensatory increase in heart rate suggests commensurate blunting of sympathetic nervous system activity, which may also contribute to salutary effects of SGLT2 inhibitors compared with other diuretics.
      • Sano M.
      • Goto S.
      Possible mechanism of hematocrit elevation by sodium glucose cotransporter 2 inhibitors and associated beneficial renal and cardiovascular effects.
      ,
      • Scheen A.J.
      Effect of SGLT2 inhibitors on the sympathetic nervous system and blood pressure.
      In addition, a study that coupled plasma and urinary water and electrolyte data with mathematical modeling to compare effects of dapagliflozin and bumetanide on volumes of blood and interstitial fluid suggested that SGLT2 inhibitors have a preferential effect to mobilize fluid from the interstitial compartment rather than the intravascular space.
      • Hallow K.M.
      • Helmlinger G.
      • Greasley P.J.
      • McMurray J.J.V.
      • Boulton D.W.
      Why do SGLT2 inhibitors reduce heart failure hospitalization? A differential volume regulation hypothesis.
      Reduction in interstitial fluid in the kidney and reduced proximal tubular energy requirements may alleviate cortical and outer medullary hypoxia.

       Inflammation and Fibrosis

      SGLT2 inhibitors reduce levels of nuclear factor-κB (NFκB), interleukin 6 (IL-6), monocyte chemoattractant protein 1 (MCP-1), and other factors implicated in inflammation and tissue fibrosis in experimental models of diabetes.
      • Han J.H.
      • Oh T.J.
      • Lee G.
      • et al.
      The beneficial effects of empagliflozin, an SGLT2 inhibitor, on atherosclerosis in ApoE (-/-) mice fed a western diet.
      ,
      • Vallon V.
      • Gerasimova M.
      • Rose M.A.
      • et al.
      SGLT2 inhibitor empagliflozin reduces renal growth and albuminuria in proportion to hyperglycemia and prevents glomerular hyperfiltration in diabetic Akita mice.
      Similar effects on urinary IL-6 and MCP-1, as well as serum tumor necrosis factor receptor 1 (TNFR1) and IL-6, were observed in clinical trials of SGLT2 inhibitors in patients with T2DM.
      • Dekkers C.C.J.
      • Petrykiv S.
      • Laverman G.D.
      • Cherney D.Z.
      • Gansevoort R.T.
      • Heerspink H.J.L.
      Effects of the SGLT-2 inhibitor dapagliflozin on glomerular and tubular injury markers.
      ,
      • Heerspink H.J.L.
      • Perco P.
      • Mulder S.
      • et al.
      Canagliflozin reduces inflammation and fibrosis biomarkers: a potential mechanism of action for beneficial effects of SGLT2 inhibitors in diabetic kidney disease.
      Although the mechanism for reduced inflammation with SGLT2 inhibition is unknown, study participants receiving canagliflozin had lower plasma levels of inflammatory and fibrotic mediators compared with those receiving glimepiride despite similar levels of glycemia, suggesting a glucose-independent effect.
      • Heerspink H.J.L.
      • Perco P.
      • Mulder S.
      • et al.
      Canagliflozin reduces inflammation and fibrosis biomarkers: a potential mechanism of action for beneficial effects of SGLT2 inhibitors in diabetic kidney disease.
      Hyperuricemia may induce kidney inflammation and has been reported to be a risk factor for incident DKD in T2DM.
      • Zoppini G.
      • Targher G.
      • Chonchol M.
      • et al.
      Serum uric acid levels and incident chronic kidney disease in patients with type 2 diabetes and preserved kidney function.
      A meta-analysis suggested that SGLT2 inhibitors reduce serum uric acid levels in patients with T2DM.
      • Zhao Y.
      • Xu L.
      • Tian D.
      • et al.
      Effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on serum uric acid level: a meta-analysis of randomized controlled trials.

       Future Research

      SGLT2 inhibitors have numerous effects on local and systemic factors involved in DKD onset and progression. The mechanistic hierarchy and pleiotropy of these agents are unknown. More comprehensive understanding of the kidney-protective pathways is crucial to facilitate research that will elucidate SGLT2 inhibitor actions and optimize their use (Table 1).
      Table 1Proposed Research for Kidney-Protective Mechanisms of SGLT-2 Inhibitors
      StudyRationale/Objective
      Glomerular Hemodynamics
      Evaluate glomerular hemodynamics in younger patients with T2DM, patients with T1DM, and patients with obesity but not diabetes.Provide insight on effects of SGLT2 inhibitors in different populations with varying glomerular hemodynamic status and glucose metabolism.
      Tubular Workload and Hypoxia
      Elucidate effects of SGLT2 inhibition on urine metabolomics and kidney oxygenation using advanced imaging techniques such as PET.Knowledge about metabolism and hypoxia in the pathogenesis of DKD and effects of SGLT2 inhibition are needed.
      Diuretic Effects
      Investigate effects of SGLT2 inhibition on SNS in patients with and without DKD.Mechanisms for reduction in SNS activity of SGLT2 inhibitors are unknown. Studying patients with nondiabetic CKD could help understand these effects.
      Anti-inflammatory and Antifibrotic Effects
      Determine anti-inflammatory and antifibrotic effects of SGLT2 inhibitors in patients with and without DKD. Consider kidney biopsies to determine effects at the tissue level.Mechanisms for anti-inflammatory and antifibrotic effects of SGLT2 inhibitors are unknown. Studying patients with nondiabetic CKD could help understand these effects.
      Abbreviations: CKD, chronic kidney disease; DKD, diabetic kidney disease; PET, positron emission tomography; SGLT2, sodium/glucose cotransporter 2; SNS, sympathetic nervous system; T2(1)DM, type 2 (1) diabetes mellitus.

      Cardiovascular Protection by SGLT2 Inhibitors

      Three SGLT2 inhibitors (empagliflozin, canagliflozin, and dapagliflozin) were studied across 6 large-scale completed CVD and CKD clinical trials,
      • Neal B.
      • Perkovic V.
      • Mahaffey K.W.
      • et al.
      Canagliflozin and cardiovascular and renal events in type 2 diabetes.
      • Wiviott S.D.
      • Raz I.
      • Bonaca M.P.
      • et al.
      Dapagliflozin and cardiovascular outcomes in type 2 diabetes.
      • Perkovic V.
      • Jardine M.J.
      • Neal B.
      • et al.
      Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.
      • Cannon C.P.
      • Perkovic V.
      • Agarwal R.
      • et al.
      Evaluating the effects of canagliflozin on cardiovascular and renal events in patients with type 2 diabetes mellitus and chronic kidney disease according to baseline HbA1c, including those with HbA1c <7%: results from the CREDENCE Trial.

      Solomon SD, Jhund P, Kosiborod M, et al. The Dapagliflozin in heart failure with reduced ejection fraction trial (DAPA-HF): outcomes in patients with CKD and effects on renal function. Oral presentation at: American Society of Nephrology-Kidney Week; November 8, 2019; Washington DC.

      ,
      • Zinman B.
      • Wanner C.
      • Lachin J.M.
      • et al.
      Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
      with assessment of ertugliflozin
      • Cannon C.P.
      • McGuire D.K.
      • Pratley R.
      • et al.
      Design and baseline characteristics of the eValuation of ERTugliflozin effIcacy and Safety CardioVascular outcomes trial (VERTIS-CV).
      in a subsequent clinical trial.

       Atherosclerotic CVD

      The CVOTs designed to test safety and a CKD trial (CREDENCE) were comparable in key aspects: participants with T2DM, placebo controls, SGLT2 inhibitor dose not based on glycemia, all participants treated by standard of care, and similarly defined and adjudicated outcomes. There were differences in risk profiles of participants in the CVOTs, ranging from 100% to 40% with prevalent ASCVD at baseline, the balance having 1 or more ASCVD risk factors. Although the findings across these trials on the composite outcome of MACE (3-point MACE; CVD death, myocardial infarction, and stroke) were consistent,
      • Zelniker T.A.
      • Wiviott S.D.
      • Raz I.
      • 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.
      differences in study design may explain varying effect estimates of SGLT2 inhibition on ASCVD events.
      The EMPA-REG OUTCOME trial randomly assigned 7,020 patients with established ASCVD including coronary, peripheral vascular, or cerebral artery disease.
      • Zinman B.
      • Inzucchi S.E.
      • Lachin J.M.
      • et al.
      Rationale, design, and baseline characteristics of a randomized, placebo-controlled cardiovascular outcome trial of empagliflozin (EMPA-REG OUTCOME).
      After a median follow-up of 3.1 years, patients treated with empagliflozin had a 14% lower relative risk for cardiovascular death, myocardial infarction, or stroke (hazard ratio [HR], 0.86; 95% CI, 0.74-0.99).
      • Zinman B.
      • Wanner C.
      • Lachin J.M.
      • et al.
      Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
      The benefit of empagliflozin on the primary CVD composite outcome was largely driven by a significant reduction in CVD death rates (3.7% vs 5.9%; HR, 0.62 [95% CI, 0.49-0.77]).
      The CANVAS trials program evaluated the CVD safety and efficacy of canagliflozin.
      • Neal B.
      • Perkovic V.
      • Mahaffey K.W.
      • et al.
      Canagliflozin and cardiovascular and renal events in type 2 diabetes.
      This program integrated data from 2 separate trials that included a total of 10,142 participants in combination. Most patients included in these trials had established ASCVD at baseline, whereas ~35% met eligibility criteria based on the presence of ASCVD risk factors with T2DM. In the CANVAS program, canagliflozin reduced the risk for the primary outcome of MACE (HR, 0.86; 95% CI, 0.75-0.97). Although formal interaction testing did not identify statistically significant differences in the effect of canagliflozin in patients with or without established ASCVD, HRs in participants with and without ASCVD were 0.82 (95% CI, 0.72-0.95) and 0.98 (95% CI, 0.74-1.30), respectively.
      • Mahaffey K.W.
      • Neal B.
      • Perkovic V.
      • et al.
      Canagliflozin for primary and secondary prevention of cardiovascular events: results from the CANVAS Program (Canagliflozin Cardiovascular Assessment Study).
      The DECLARE–TIMI 58 trial randomly assigned 17,160 patients with T2DM to treatment with either dapagliflozin or placebo. This trial had dual primary outcomes: (1) MACE and (2) composite of CVD death or HF hospitalization. Unlike the EMPA-REG OUTCOME trial and CANVAS program, most participants in the DECLARE-TIMI 58 trial did not have established ASCVD (59%; n = 10,186). The overall effect of dapagliflozin on MACE was not statistically significantly different versus placebo (HR, 0.93; 95% CI, 0.84-1.03).
      • Wiviott S.D.
      • Raz I.
      • Bonaca M.P.
      • et al.
      Dapagliflozin and cardiovascular outcomes in type 2 diabetes.
      The point estimate of efficacy was numerically lower in participants with ASCVD (HR, 0.90; 95% CI, 0.79-1.02) than in those without ASCVD (HR, 1.01; 95% CI, 0.86-1.20), but results in neither subgroup achieved statistical significance nor was the interaction significant.
      The CREDENCE trial, although primarily designed to assess efficacy on kidney outcomes, analyzed 3-point MACE as part of the primary analysis hierarchy in participants with T2DM and DKD.

      Solomon SD, Jhund P, Kosiborod M, et al. The Dapagliflozin in heart failure with reduced ejection fraction trial (DAPA-HF): outcomes in patients with CKD and effects on renal function. Oral presentation at: American Society of Nephrology-Kidney Week; November 8, 2019; Washington DC.

      CREDENCE participants were at high CVD risk, with 3-point MACE occurring in 16.1% and 8.3% during a mean of 2.6 years in those with and without established ASCVD, respectively.
      • Mahaffey K.W.
      • Jardine M.J.
      • Bompoint S.
      • et al.
      Canagliflozin and cardiovascular and renal outcomes in type 2 diabetes mellitus and chronic kidney disease in primary and secondary cardiovascular prevention groups.
      Risk for 3-point MACE was significantly reduced with canagliflozin versus placebo overall (HR, 0.80; 95% CI, 0.67-0.95) and in the primary prevention cohort for ASCVD (HR, 0.68; 95% CI, 0.49-0.94), and was numerically similar in the secondary prevention cohort (HR, 0.85; 95% CI, 0.69-1.06; Fig 2).
      Figure thumbnail gr2
      Figure 2Effects of canagliflozin on cardiovascular outcomes in the overall population. (A) Cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. (B) Fatal or nonfatal myocardial infarction. (C) Fatal or nonfatal stroke. (D) Hospitalization for heart failure. Reproduced from Mahaffey et al
      • Mahaffey K.W.
      • Jardine M.J.
      • Bompoint S.
      • et al.
      Canagliflozin and cardiovascular and renal outcomes in type 2 diabetes mellitus and chronic kidney disease in primary and secondary cardiovascular prevention groups.
      with permission of Wolters Kluwer Health, Inc; original graphic © 2019 by Mahaffey et al.

       Heart Failure

      In a systematic review and meta-analysis of the CVOTs with data from 34,322 patients with T2DM with or at high risk for ASCVD, relative risk for CVD death or hospitalization for HF was reduced by 23% in patients treated with an SGLT2 inhibitor versus placebo (HR, 0.77; 95% CI, 0.71-0.84).
      • Zelniker T.A.
      • Wiviott S.D.
      • Raz I.
      • 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.
      Reductions in hospitalizations for HF were seen in EMPA-REG OUTCOME, CANVAS, and DECLARE-TIMI 58, including patients with and without prevalent ASCVD and those with and without a history of HF. Results from these CVOTs and CREDENCE revealed more robust and consistent benefits on HF than on MACE with SGLT2 inhibitors.
      • Perkovic V.
      • Jardine M.J.
      • Neal B.
      • et al.
      Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.
      DAPA-HF was the first clinical trial of an SGLT2 inhibitor to assess HF events as the primary outcome and to include participants with and without diabetes.
      • Rawshani A.
      • Rawshani A.
      • Franzen S.
      • et al.
      Mortality and cardiovascular disease in type 1 and type 2 diabetes.
      DAPA-HF was conducted in 4,744 participants with New York Heart Association classes II to IV HF with an ejection fraction ≤ 40% who were treated by the standard of care, including β-blocker; ACE enzyme inhibitor, ARB, or sacubitril-valsartan; mineralocorticoid receptor antagonist; and cardiac device therapy (if indicated). The primary outcome of worsening HF or CVD death was significantly reduced, 16.3% versus 21.2% for dapagliflozin compared to placebo (HR, 0.74; 95% CI, 0.65-0.85). These results were consistent across subgroups including those with and without diabetes or CKD.
      In summary, all clinical trials to date have shown a consistent beneficial effect of the SGLT2 inhibitors on HF events. This observation has been also corroborated by real-world data from clinical practice that has found consistent associations between the use of SGLT2 inhibitors and lower risk for HF hospitalization across a broad spectrum of patients.
      • Kosiborod M.
      • Cavender M.A.
      • Fu A.Z.
      • et al.
      Lower risk of heart failure and death in patients initiated on sodium-glucose cotransporter-2 inhibitors versus other glucose-lowering drugs: the CVD-REAL Study (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors).
      ,
      • Patorno E.
      • Pawar A.
      • Franklin J.M.
      • et al.
      Empagliflozin and the risk of heart failure hospitalization in routine clinical care.

       Potential Mechanisms of Cardiovascular Benefits

      Patients with T2DM are at high risk for ASCVD and HF compared with nondiabetic individuals.
      • Rawshani A.
      • Rawshani A.
      • Franzen S.
      • et al.
      Mortality and cardiovascular disease in type 1 and type 2 diabetes.
      ,
      • Cavender M.A.
      • Steg P.G.
      • Smith Jr., S.C.
      • et al.
      Impact of diabetes mellitus on hospitalization for heart failure, cardiovascular events, and death: outcomes at 4 years from the Reduction of Atherothrombosis for Continued Health (REACH) Registry.
      However, glycemic control per se does not meaningfully reduce the risk for these events.
      • Ray K.K.
      • Seshasai S.R.
      • Wijesuriya S.
      • et al.
      Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomised controlled trials.
      • Turnbull F.M.
      • Abraira C.
      • Anderson R.J.
      • et al.
      Intensive glucose control and macrovascular outcomes in type 2 diabetes.
      • Udell J.A.
      • Cavender M.A.
      • Bhatt D.L.
      • Chatterjee S.
      • Farkouh M.E.
      • Scirica B.M.
      Glucose-lowering drugs or strategies and cardiovascular outcomes in patients with or at risk for type 2 diabetes: a meta-analysis of randomised controlled trials.
      The concept that benefits of SGLT2 inhibitors are mediated by nonglycemic mechanisms is further supported by observations that reduction in CVD events occurred irrespective of concomitant use of other glucose-lowering agents. Furthermore, the observed CVD risk reductions were not related to either baseline or achieved HbA1c levels in participants with diabetes.
      • Inzucchi S.E.
      • Kosiborod M.
      • Fitchett D.
      • et al.
      Improvement in cardiovascular outcomes with empagliflozin is independent of glycemic control.
      In DAPA-HF, dapagliflozin reduced the risk for worsening HF or CVD death irrespective of diabetes status.
      • McMurray J.J.V.
      • Solomon S.D.
      • Inzucchi S.E.
      • et al.
      Dapagliflozin in patients with heart failure and reduced ejection fraction.
      Thus, the mechanisms by which SGLT2 inhibitors reduce the risk for HF are not attributable to improved glycemic control.
      • Inzucchi S.E.
      • Zinman B.
      • Fitchett D.
      • et al.
      How does empagliflozin reduce cardiovascular mortality? Insights from a mediation analysis of the EMPA-REG OUTCOME Trial.
      A variety of potential mechanisms have been proposed to explain beneficial effects of SGLT2 inhibitors on CVD (Fig 3).
      • Heerspink 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.
      ,
      • Inzucchi S.E.
      • Zinman B.
      • Fitchett D.
      • et al.
      How does empagliflozin reduce cardiovascular mortality? Insights from a mediation analysis of the EMPA-REG OUTCOME Trial.
      • Georgianos P.I.
      • Agarwal R.
      Ambulatory blood pressure reduction with SGLT-2 inhibitors: dose-response meta-analysis and comparative evaluation with low-dose hydrochlorothiazide.
      • Lytvyn Y.
      • Bjornstad P.
      • Udell J.A.
      • Lovshin J.A.
      • Cherney D.Z.I.
      Sodium glucose cotransporter-2 inhibition in heart failure: potential mechanisms, clinical applications, and summary of clinical trials.
      • Verma S.
      • McMurray J.J.V.
      SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review.
      • Verma S.
      • McMurray J.J.V.
      The serendipitous story of SGLT2 inhibitors in heart failure.
      Those that appear particularly plausible include effects on volume status, natriuresis, expansion of red blood cell mass, and myocardial energetics.
      • Lambers Heerspink H.J.
      • de Zeeuw D.
      • Wie L.
      • Leslie B.
      • List J.
      Dapagliflozin a glucose-regulating drug with diuretic properties in subjects with type 2 diabetes.
      ,
      • Sano M.
      • Goto S.
      Possible mechanism of hematocrit elevation by sodium glucose cotransporter 2 inhibitors and associated beneficial renal and cardiovascular effects.
      ,
      • Inzucchi S.E.
      • Zinman B.
      • Fitchett D.
      • et al.
      How does empagliflozin reduce cardiovascular mortality? Insights from a mediation analysis of the EMPA-REG OUTCOME Trial.
      ,
      • Verma S.
      • McMurray J.J.V.
      SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review.
      ,
      • Mazer C.D.
      • Hare G.M.T.
      • Connelly P.W.
      • et al.
      Effect of empagliflozin on erythropoietin levels, iron stores, and red blood cell morphology in patients with type 2 diabetes mellitus and coronary artery disease.
      Figure thumbnail gr3
      Figure 3The kidney-heart connection for organ protection. Abbreviations: LV, left ventricular; NHE3, sodium–hydrogen exchanger 3. Reproduced courtesy of Emily J. Cox, PhD; original graphic © 2020 E.J. Cox.

       Future Research

      SGLT2 inhibitors reduce HF risks in broad cohorts of patients with T2DM and in those with reduced ejection fraction HF with or without diabetes.
      • Zelniker T.A.
      • Wiviott S.D.
      • Raz I.
      • 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.
      ,
      • McMurray J.J.V.
      • Solomon S.D.
      • Inzucchi S.E.
      • et al.
      Dapagliflozin in patients with heart failure and reduced ejection fraction.
      Results from post hoc analyses of the DECLARE-TIMI 58 trial and the CANVAS program have suggested that patients with reduced ejection fraction may have greater benefit.
      • Figtree G.A.
      • Radholm K.
      • Barrett T.D.
      • et al.
      Effects of canagliflozin on heart failure outcomes associated with preserved and reduced ejection fraction in type 2 diabetes mellitus.
      ,
      • Kato E.T.
      • Silverman M.G.
      • Mosenzon O.
      • et al.
      Effect of dapagliflozin on heart failure and mortality in type 2 diabetes mellitus.
      Whether HF benefits also apply to patients with preserved ejection fraction are being addressed in ongoing clinical trials evaluating empagliflozin and dapagliflozin (ClinicalTrials.gov identifiers NCT03057951 and NCT03619213, respectively). Despite robust evidence for CVD benefits of SGLT2 inhibitors, there remain important unanswered questions. Mechanistic studies will offer insights into the modes by which these agents improve CVD outcomes. Knowledge of mechanisms could help tailor therapy, identify additional populations who may benefit or may face enhanced risk for adverse effects, and elucidate new pathways or targets (Table 2).
      Table 2Proposed Research to Understand Effects of SGLT2 Inhibitors for CVD Safety or Benefit in Additional Populations
      StudyRationale/Objective
      Prediabetes and obesityHigh risk for ASCVD events
      Initial monotherapy in T2DMHigh risk for ASCVD and HF events
      T1DMHigh risk for ASCVD events
      Post–acute coronary syndrome, peripheral arterial diseaseHigh risk for ASCVD events
      Acute HF, HF with preserved ejection fractionHigh risk for HF events
      Atrial fibrillationHigh risk for ASCVD and HF events
      Hypertensive urgencyHigh risk for ASCVD and HF events
      Nondiabetic CKDHigh risk for ASCVD and HF events
      Abbreviations: ASCVD, atherosclerotic cardiovascular disease; CKD, chronic kidney disease; CVD, cardiovascular disease; HF, heart failure; SGLT2, sodium/glucose cotransporter 2; T2(1)DM, type 2 (1) diabetes mellitus.

      Kidney Protection by SGLT2 Inhibitors

       Kidney Disease Events

      EMPA-REG OUTCOME was the first CVOT to demonstrate that treatment with an SGLT2 inhibitor, empagliflozin, reduced the risk for a secondary kidney disease outcome (severely increased albuminuria, doubling of serum creatinine accompanied by eGFR ≤ 45 mL/min/1.73 m2, initiation of KRT, or death from kidney disease) to 12.7% versus 18.8% in the placebo group (HR, 0.61; 95% CI, 0.53-0.70).
      • Wanner C.
      • Inzucchi S.E.
      • Lachin J.M.
      • et al.
      Empagliflozin and progression of kidney disease in type 2 diabetes.
      Mean baseline eGFR was 74 mL/min/1.73 m2, 26% of participants had eGFR < 60 mL/min/1.73 m2, and 40% had albuminuria. Importantly, after the first 4 weeks of treatment during which eGFR declined with empagliflozin, eGFR stabilized in the empagliflozin groups and declined steadily in the placebo group. These findings were confirmed in the CANVAS program, in which mean baseline eGFR was 76 mL/min/1.73 m2, 20% had eGFR < 60 mL/min/1.73 m2, and 30% had albuminuria.
      • Neal B.
      • Perkovic V.
      • Mahaffey K.W.
      • et al.
      Canagliflozin and cardiovascular and renal events in type 2 diabetes.
      The secondary kidney disease outcome (sustained 40% reduction in eGFR, need for KRT, or death from kidney disease) occurred less frequently among participants in the canagliflozin group versus placebo (HR, 0.60; 95% CI, 0.47-0.77). DECLARE-TIMI 58 included participants with a mean baseline eGFR of 85 mL/min/1.73 m2, of whom 7.4% had eGFR < 60 mL/min/1.73 m2. The proportion with albuminuria was 30%, similar to other CVOTs. This trial demonstrated that dapagliflozin significantly decreased the risk for the secondary kidney disease outcome comprising 40% reduction in eGFR to <60 mL/min/1.73 m2, kidney failure, or death due to kidney disease (HR, 0.53; 95% CI, 0.43-0.66).
      CREDENCE was the first clinical trial to be stopped early for overwhelming efficacy proving the kidney protective effects of SGLT2 inhibition for DKD. The trial was conducted in 4,401 participants with T2DM and severely increased albuminuria (urinary albumin-creatinine ratio of >300 to <5,000 mg/g) with eGFR of 30 to <90 mL/min/1.73 m2 who were treated by the standard of care with either an ACE inhibitor or ARB.
      • Perkovic V.
      • Jardine M.J.
      • Neal B.
      • et al.
      Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.
      Starting at a mean baseline eGFR of 56 mL/min/1.73 m2, risk for the primary outcome (serum creatinine doubling, kidney failure treated by KRT, or death from kidney disease or CVD) was substantially reduced (HR, 0.70; 95% CI, 0.59-0.82). After 3 weeks of treatment, the mean rate of eGFR decline was significantly slower in patients receiving canagliflozin compared with placebo (−1.85 vs −4.59 mL/min/1.73 m2 per year; Figs 4 and 5). The number needed to treat with canagliflozin to prevent a primary outcome event was 22 during a mean of 2.6 years. These kidney-protective effects were accomplished with nominal between-group differences in HbA1c levels or blood pressure.
      Figure thumbnail gr4
      Figure 4CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) primary outcome: kidney failure, serum creatinine doubling, kidney or cardiovascular disease death. Adapted with permission from Perkovic et al
      • Perkovic V.
      • Jardine M.J.
      • Neal B.
      • et al.
      Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.
      with permission of the copyright holder; original graphic © 2019 Massachusetts Medical Society.
      Figure thumbnail gr5
      Figure 5CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation): summary forest plot. Post hoc analysis. Abbreviations: CV, cardiovascular; eGFR, estimated glomerular filtration rate; Scr, serum creatinine. Developed with data from Perkovic et al.
      • Perkovic V.
      • Jardine M.J.
      • Neal B.
      • et al.
      Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.

       Albuminuria

      In CREDENCE, urinary albumin-creatinine ratio was reduced by 31%.
      • Perkovic V.
      • Jardine M.J.
      • Neal B.
      • et al.
      Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.
      The CVOTs consistently showed a corresponding reduction in albuminuria by 30% to 40% in patients with albuminuria. Treatment with SGLT2 inhibitors also increases the likelihood to regress from severely to moderately increased albuminuria or normal albuminuria and from moderately increased albuminuria to normal albuminuria. The albuminuria-lowering effect occurs within weeks after initiation of treatment and is presumably due to glomerular hemodynamic effects. For prevention of new-onset albuminuria, CVOT results have been less consistent. This effect was observed in CANVAS
      • Neal B.
      • Perkovic V.
      • Mahaffey K.W.
      • et al.
      Canagliflozin and cardiovascular and renal events in type 2 diabetes.
      and DECLARE-TIMI-58,

      Raz I, Wiviott SD, Yanut I, et al. Effects of dapagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes: a predefined analysis from the DECLARE-TIMI 58 randomised, placebo-controlled trial. June 10, 2019; Oral presentation at: American Diabetes Association 79th Scientific Sessions, San Francisco, CA.

      but not in the EMPA-REG OUTCOME trial.
      • Wanner C.
      • Inzucchi S.E.
      • Lachin J.M.
      • et al.
      Empagliflozin and progression of kidney disease in type 2 diabetes.
      However, in the latter study, the absolute level of albuminuria in patients with normal albuminuria at baseline was lower in patients receiving empagliflozin compared with placebo by trial end.
      • Cherney D.Z.I.
      • Zinman B.
      • Inzucchi S.E.
      • et al.
      Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease: an exploratory analysis from the EMPA-REG OUTCOME randomised, placebo-controlled trial.

       Subgroup Responses

      In the CVOTs and CREDENCE, kidney-protective effects are consistent overall (Fig 6) and in participants with different levels of glycemic control (HbA1c < 7% or >9%) or eGFR strata (>90, 60-90, or 30-60 mL/min/1.73 m2).
      • Wanner C.
      • Inzucchi S.E.
      • Lachin J.M.
      • et al.
      Empagliflozin and progression of kidney disease in type 2 diabetes.
      ,
      • Neal B.
      • Perkovic V.
      • Mahaffey K.W.
      • et al.
      Canagliflozin and cardiovascular and renal events in type 2 diabetes.
      ,
      • Perkovic V.
      • Jardine M.J.
      • Neal B.
      • et al.
      Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.
      ,
      • Mosenzon O.
      • Wiviott S.D.
      • Cahn A.
      • et al.
      Effects of dapagliflozin on development and progression of kidney disease in patients with type 2 diabetes: an analysis from the DECLARE-TIMI 58 randomised trial.
      In CREDENCE, 29.8% (1,313/4,401) of participants had a baseline eGFR of 30 to 45 mL/min/1.73 m2, and kidney benefits did not differ from those in patients with higher eGFR.
      • Perkovic V.
      • Jardine M.J.
      • Neal B.
      • et al.
      Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.
      ,
      • Neuen B.L.
      • Young T.
      • Heerspink H.J.L.
      • et al.
      SGLT2 inhibitors for the prevention of kidney failure in patients with type 2 diabetes: a systematic review and meta-analysis.
      Given consistent effects over time and across stages of CKD, no particular eGFR subgroup appears to derive more prominent benefits than the others.
      • Wanner C.
      • Lachin J.M.
      • Inzucchi S.E.
      • et al.
      Empagliflozin and clinical outcomes in patients with type 2 diabetes mellitus, established cardiovascular disease, and chronic kidney disease.
      This observation is clinically relevant because in patients with eGFR < 45 mL/min/1.73 m2, SGLT2 inhibitors have nominal effects on glycemia, although reductions in eGFR decline, blood pressure, and body weight are maintained.
      • Kohan D.E.
      • Fioretto P.
      • Tang W.
      • List J.F.
      Long-term study of patients with type 2 diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but does not improve glycemic control.
      ,
      • Neuen B.L.
      • Ohkuma T.
      • Neal B.
      • et al.
      Cardiovascular and renal outcomes with canagliflozin according to baseline kidney function.
      The effects of SGLT2 inhibitors on kidney disease end points do not differ in patients with established ASCVD or those with multiple CVD risk factors.
      • Neal B.
      • Perkovic V.
      • Mahaffey K.W.
      • et al.
      Canagliflozin and cardiovascular and renal events in type 2 diabetes.
      ,
      • Perkovic V.
      • Jardine M.J.
      • Neal B.
      • et al.
      Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.
      ,
      • Mosenzon O.
      • Wiviott S.D.
      • Cahn A.
      • et al.
      Effects of dapagliflozin on development and progression of kidney disease in patients with type 2 diabetes: an analysis from the DECLARE-TIMI 58 randomised trial.
      The effects on kidney disease outcomes are also similar irrespective of background use of renin-angiotensin system blockade.
      • Perkovic V.
      • Jardine M.J.
      • Neal B.
      • et al.
      Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.
      Importantly, in all clinical trials of SGLT2 inhibitors reported to date, patients with baseline eGFR < 30 mL/min/1.73 m2 were excluded. Current studies will determine whether SGLT2 inhibitors have kidney benefits in patients with and without diabetes who have eGFR below this level (EMPA-KIDNEY: ClinicalTrials.gov identifier NCT03594110; DAPA-CKD: ClinicalTrials.gov identifier NCT03036150). Importantly, on March 30, 2020, DAPA-CKD was stopped early at the recommendation of an Independent Data Monitoring Committee due to overwhelming efficacy.
      Figure thumbnail gr6
      Figure 6Effects of sodium/glucose cotransporter 2 (SGLT2) inhibitors on chronic kidney disease end points in the cardiovascular disease outcome trials and CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation). Random effects meta-analysis. Abbreviations: ESKD, end-stage kidney disease; RR, relative risk. Reproduced from Neuen et al
      • Neuen B.L.
      • Young T.
      • Heerspink H.J.L.
      • et al.
      SGLT2 inhibitors for the prevention of kidney failure in patients with type 2 diabetes: a systematic review and meta-analysis.
      with permission of the copyright holder; original graphic © 2019 Elsevier Ltd.

       Future Research

      The influence of diuretic treatment on effects of SGLT2 inhibitors are unclear, although overall diuretics do not seem to have much effect on their kidney benefits.
      • Wanner C.
      • Inzucchi S.E.
      • Lachin J.M.
      • et al.
      Empagliflozin and progression of kidney disease in type 2 diabetes.
      ,
      • Neal B.
      • Perkovic V.
      • Mahaffey K.W.
      • et al.
      Canagliflozin and cardiovascular and renal events in type 2 diabetes.
      ,
      • Mosenzon O.
      • Wiviott S.D.
      • Cahn A.
      • et al.
      Effects of dapagliflozin on development and progression of kidney disease in patients with type 2 diabetes: an analysis from the DECLARE-TIMI 58 randomised trial.
      More research on this aspect is needed, especially differentiating thiazide and loop diuretics. The effects of other treatments that alter glomerular hemodynamics, for example, nonsteroidal anti-inflammatory drugs, remain to be clarified.
      • Mayer G.J.
      • Wanner C.
      • Weir M.R.
      • et al.
      Analysis from the EMPA-REG OUTCOME((R)) trial indicates empagliflozin may assist in preventing the progression of chronic kidney disease in patients with type 2 diabetes irrespective of medications that alter intrarenal hemodynamics.
      Better prediction of SGLT2 inhibitor response is needed because neither clinical characteristics nor various risk factors identify albuminuria responders (>30% reduction).
      • Heerspink H.J.L.
      • Sjostrom C.D.
      • Inzucchi S.E.
      • et al.
      Reduction in albuminuria with dapagliflozin cannot be predicted by baseline clinical characteristics or changes in most other risk markers.
      Only a subset of patients with T2DM and CKD have purely diabetic glomerulopathy (30%-50%), whereas others commonly have tubulointerstitial or vascular disease with or without diabetic glomerulopathy.
      • Ekinci E.I.
      • Jerums G.
      • Skene A.
      • et al.
      Renal structure in normoalbuminuric and albuminuric patients with type 2 diabetes and impaired renal function.
      ,
      • Fioretto P.
      • Mauer M.
      • Brocco E.
      • et al.
      Patterns of renal injury in NIDDM patients with microalbuminuria.
      Patients with different structural lesions may respond differently to SGLT2 inhibition, so their effects on structural lesions in DKD should be studied. Additionally, whether other patient groups (diabetes with glomerular hyperfiltration, T1DM, nondiabetic CKD, or post–kidney and post–heart transplant diabetes) benefit from SGLT2 inhibitors warrants study. Several glucagon-like peptide 1 (GLP1) receptor agonists have demonstrated ASCVD or CKD benefits in CVOTs for T2DM and in a clinical trial in moderate to severe CKD with T2DM.
      • Davies M.J.
      • D'Alessio D.A.
      • Fradkin J.
      • et al.
      Management of hyperglycemia in type 2 diabetes, 2018. a consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ,
      • Tuttle K.R.
      • Lakshmanan M.C.
      • Rayner B.
      • et al.
      Dulaglutide versus insulin glargine in patients with type 2 diabetes and moderate-to-severe chronic kidney disease (AWARD-7): a multicentre, open-label, randomised trial.
      Available data have shown additive benefits with an SGLT2 inhibitor and a GLP1 receptor agonist on glycemia, blood pressure, and weight.
      • Ludvik B.
      • Frias J.P.
      • Tinahones F.J.
      • et al.
      Dulaglutide as add-on therapy to SGLT2 inhibitors in patients with inadequately controlled type 2 diabetes (AWARD-10): a 24-week, randomised, double-blind, placebo-controlled trial.
      ,
      • Frias J.P.
      • Guja C.
      • Hardy E.
      • et al.
      Exenatide once weekly plus dapagliflozin once daily versus exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled with metformin monotherapy (DURATION-8): a 28 week, multicentre, double-blind, phase 3, randomised controlled trial.
      Therefore, combination therapy with these classes of agents could be studied for effects on clinical CKD and CVD outcomes (Table 3).
      Table 3Proposed Research to Understand Clinical Effects of SGLT2 Inhibitors on Kidney Disease
      StudyRationale/Objective
      Responder Status
      Identify responders and nonresponders to SGLT2 inhibition for kidney protection.Develop a precision approach to apply SGLT2 inhibition to patients most likely to benefit.
      Albuminuria and eGFR
      Determine whether the initial change in albuminuria or eGFR predicts subsequent GFR.Identifying so-called initial “decliners” vs “nondecliners” would be helpful for therapeutic applications.
      Structural Basis of Treatment Response
      Perform kidney biopsies, as well as measure corresponding urinary and blood biomarkers, to predict responsiveness to SGLT2 inhibition.Understanding structural basis of response to SGLT2 inhibition to advance therapeutic applications.
      Combination Treatments
      Test efficacy and safety of SGLT2 inhibitors and GLP-1 receptor agonists as a first-line agents in patients with diabetes and CKD for potential benefits of combination therapy.Determine benefits and risks of treatments and their combinations to optimize CKD and CVD outcomes.
      Benefits and Risks in Different Populations
      Identify additional groups who benefit from SGLT2 inhibitors for kidney protection.Learn whether SGLT2 inhibition provides similar benefits for patients with diabetes and glomerular hyperfiltration, T1DM, nondiabetic CKD, or post–kidney and post–heart transplant diabetes.
      Identify groups at high risk for SGLT2 inhibitor side effects such as ketoacidosis, genital mycotic infections, and volume depletion.More precisely characterize the clinical features of at-risk groups as well as categories and rates of adverse outcomes from SGLT2 inhibitors.
      Abbreviations: CKD, chronic kidney disease; CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate; GLP1, glucagon-like peptide 1; SGLT2, sodium/glucose cotransporter 2; T1DM, type 1 diabetes mellitus.

      Integration of SGLT Inhibition Into Clinical Practice

       Glycemic Control Regimens

      SGLT2 inhibitors were initially approved for T2DM as glucose-lowering agents without increased risk for hypoglycemia. Dapagliflozin and sotagliflozin also have regulatory approval in Europe as glucose-lowering agents adjunctive to insulin for T1DM. Although the glucose-lowering effect of SGLT2 inhibitors is attenuated with reduced eGFR, adjustment of concomitant glucose-lowering agents may be required to avoid hypoglycemia if administered with insulin, sulfonylureas, or glinides. Because the CKD and CVD benefits are largely independent of SGLT2 inhibitor dose, preservation of insulin dosing with SGLT2 inhibitor dose reduction is preferable to mitigate the risk for ketoacidosis.

       Prevention and Treatment of Kidney Disease and CVD

      The FDA granted regulatory approval for canagliflozin to reduce the risks for doubling of serum creatinine level, kidney failure, hospitalization for HF, and CVD death in adults with T2DM and CKD (urinary albumin-creatinine ratio, 300-5,000 mg/g and eGFR, 30-<90 mL/min/1.73 m2) based on CREDENCE. Most participants enrolled in the clinical trials of SGLT2 inhibitors were concomitantly treated with metformin, although some were not. For example, in the EMPA-REG OUTCOME trial, 1,827 (26%) participants were not treated with metformin.
      • Harrington J.L.
      • de Albuquerque Rocha N.
      • Patel K.V.
      • Verma S.
      • McGuire D.K.
      Should metformin remain first-line medical therapy for patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease? An alternative approach.
      Whether SGLT2 inhibitors should instead be used as first-line agents in people with T2DM for ASCVD, HF, or CKD is a point of debate.
      • Harrington J.L.
      • de Albuquerque Rocha N.
      • Patel K.V.
      • Verma S.
      • McGuire D.K.
      Should metformin remain first-line medical therapy for patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease? An alternative approach.
      Major national and international organizations are rapidly updating recommendations and guidelines (Table 4).
      Professional Practice Committee: Standards of Medical Care in Diabetes-2020.
      • Rangaswami J
      • Bhalla V
      • de Boer IH
      • et al.
      American Heart Association Council on the Kidney in Cardiovascular DiseaseCouncil on Arteriosclerosis, Thrombosis and Vascular BiologyCouncil on Cardiovascular and Stroke NursingCouncil on Clinical Cardiologyand Council on Lifestyle and Cardiometabolic Health
      Cardiorenal protection with the newer antidiabetic agents in patients with diabetes and chronic kidney disease: a scientific statement from the American Heart Association.
      • Cosentino F.
      • Grant P.J.
      • Aboyans V.
      • et al.
      2019 ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD.
      • de Boer IH
      • Caramori ML
      • Chan JCN
      • et al.
      Executive summary of the 2020 KDIGO diabetes management in CKD guideline: evidence-based advances in monitoring and treatment.
      All recommend SGLT2 inhibition for patients with T2DM and eGFR as low as 30 mL/min/1.73 m2, particularly if severely increased albuminuria is present. Moreover, SGLT2 inhibitor withdrawal is not required if eGFR decreases to <30 mL/min/1.73 m2, as per the CREDENCE protocol. Because DAPA-CKD was stopped early for overwhelming efficacy, the eGFR cutoff could be reduced to 25 mL/min/1.73 m2. If results are comparable in nondiabetic patients with CKD, they also may be recommended for SGLT2 inhibitor treatment.
      Table 4SGLT2 Guidelines for CKD and CVD in Diabetes
      Professional Group RecommendationsSGLT2i Recommended in CKDSGLT2i Recommended in ASCVDSGLT2i Recommended in HFSGLT2i Recommended Independent of Metformin
      European Society of Cardiology/European Association for the Study of Diabetes Guidelines 2019
      • Cosentino F.
      • Grant P.J.
      • Aboyans V.
      • et al.
      2019 ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD.
      Yes
      eGFR of 30 to<90mL/min/1.73m2.
      YesYesYes (patients drug naive for glucose-lowering agents)
      American Diabetes Association Standards of Medical Care in Diabetes 2020
      Professional Practice Committee: Standards of Medical Care in Diabetes-2020.
      Yes
      eGFR of 30 to 60mL/min/1.73m2 or urinary albumin-creatinine ratio> 30mg/g, particularly urinary albumin-creatinine ratio> 300mg/g.
      (if GFR adequate based on drug approval label)
      Yes (if GFR adequate based on drug approval label)Yes (if GFR adequate based on drug approval label)No
      Kidney Disease: Improving Global Outcomes Diabetes and CKD Guideline 2020
      • de Boer IH
      • Caramori ML
      • Chan JCN
      • et al.
      Executive summary of the 2020 KDIGO diabetes management in CKD guideline: evidence-based advances in monitoring and treatment.
      Yes
      eGFR ≥ 30 mL/min/1.73m2.
      (if GFR adequate based on drug approval label)
      Yes (if GFR adequate based on drug approval label)Yes (if GFR adequate based on drug approval label)No
      American Heart Association Scientific Statement on Cardiorenal Protection in Diabetes and CKD 2020
      • Rangaswami J
      • Bhalla V
      • de Boer IH
      • et al.
      American Heart Association Council on the Kidney in Cardiovascular DiseaseCouncil on Arteriosclerosis, Thrombosis and Vascular BiologyCouncil on Cardiovascular and Stroke NursingCouncil on Clinical Cardiologyand Council on Lifestyle and Cardiometabolic Health
      Cardiorenal protection with the newer antidiabetic agents in patients with diabetes and chronic kidney disease: a scientific statement from the American Heart Association.
      Yes
      eGFR ≥ 30 or≥45mL/min/1.73m2 depending on agent; for canagliflozin, eGFR of 30 to 45mL/min/1.73m2 and urinary albumin-creatinine ratio>300mg/g.
      (if GFR adequate based on drug approval label)
      Yes (if GFR adequate based on drug approval label)Yes (if GFR adequate based on drug approval label)No comment
      Abbreviations: ASCVD, atherosclerotic cardiovascular disease; CKD, chronic kidney disease; CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate; HF, heart failure; SGLT2, sodium/glucose cotransporter 2; SGLT2i, sodium/glucose cotransporter 2 inhibitor.
      a eGFR of 30 to <90 mL/min/1.73 m2.
      b eGFR of 30 to 60 mL/min/1.73 m2 or urinary albumin-creatinine ratio > 30 mg/g, particularly urinary albumin-creatinine ratio > 300 mg/g.
      c eGFR ≥ 30 mL/min/1.73 m2.
      d eGFR ≥ 30 or ≥45 mL/min/1.73 m2 depending on agent; for canagliflozin, eGFR of 30 to 45 mL/min/1.73 m2 and urinary albumin-creatinine ratio > 300 mg/g.

       Risks of SGLT2 Inhibitors

      Important risks of SGLT2 inhibitors include euglycemic ketoacidosis, genital mycotic infections, and volume depletion. For those with a history of these side effects, particularly if recent or recurrent, careful consideration should be given to the balance of benefits and harms of SGLT2 inhibitors. Inclusion of patients in shared decision making and counseling regarding use of an SGLT2 inhibitor are paramount to safe implementation. Whether to permanently discontinue SGLT2 inhibitor therapy following a single episode of ketoacidosis, a genital mycotic infection, or volume depletion should be individualized according to the clinical scenario, patient concerns, and potential for benefits. These risks occur across the SGLT2 inhibitor class.
      Euglycemic ketoacidosis with minimal to no elevation in blood glucose levels may occur in patients taking SGLT2 inhibitors due to increased fatty acid oxidation and glucagon release along with decreased insulin secretion.
      • Ogawa W.
      • Sakaguchi K.
      Euglycemic diabetic ketoacidosis induced by SGLT2 inhibitors: possible mechanism and contributing factors.
      ,
      • Rosenstock J.
      • Ferrannini E.
      Euglycemic diabetic ketoacidosis: a predictable, detectable, and preventable safety concern with SGLT2 inhibitors.
      Patients with either T1DM or T2DM taking insulin are at particular risk, with the greatest risk for ketoacidosis in T1DM. To mitigate risk, it is important to maintain insulin doses and pause SGLT2 inhibitor treatment during periods of acute illness or other stressors. Blood or urine ketone monitoring may be used for early detection of ketosis. Patients should be informed that if they experience signs or symptoms of ketoacidosis, such as nausea, vomiting, and abdominal pain, they should discontinue SGLT2 inhibitor therapy and immediately seek medical attention. Genital mycotic infections occur more often in SGLT2 inhibitor users (2%-4% in men and 3%-7% in women) than nonusers (<2% in both sexes).
      • Fitchett D.
      A safety update on sodium glucose co-transporter 2 inhibitors.
      In a recent report, advice given for daily rinsing of the genital area after voiding and before bedtime significantly lessened the risk for genital mycotic infections (6/125 vs 51/125; P = 0.015) and improved adherence to SGLT2 inhibitor treatment over a 3-year period.

      Williams SM, Ahmed SH. Improving compliance with SGLT2 inhibitors by reducing the risk of genital mycotic infections: the outcomes of personal hygiene advice. Poster presented at: American Diabetes Association 79th Scientific Sessions; June 9, 2019; San Francisco, CA.

      SGLT2 inhibitors may cause volume depletion due to their diuretic effect. However, stopping or reducing doses of other diuretics on SGLT2 inhibitor initiation is generally not necessary, but monitoring of electrolyte levels and kidney function is important for dose titration or adjustment of other antihypertensive or diuretic agents. To minimize risk for volume depletion, SGLT2 inhibitor treatment should be paused during periods of acute illness or other stressors.
      Among putative side effects of SGLT2 inhibitors, Fournier gangrene is rare (1 in 10,000 patients) but serious and has been reported in post–market approval safety reports to the FDA.
      • Dave C.V.
      • Schneeweiss S.
      • Patorno E.
      Association of sodium-glucose cotransporter 2 inhibitor treatment with risk of hospitalization for Fournier gangrene among men.
      It is unclear how much of this risk is attributable to SGLT2 inhibitors per se versus secular trends for increased rates of skin infections in diabetes.
      • Harding J.L.
      • Benoit S.R.
      • Gregg E.W.
      • Pavkov M.E.
      • Perreault L.
      Trends in rates of infections requiring hospitalization among adults with versus without diabetes in the U.S., 2000-2015.
      Despite theoretical concerns for acute kidney injury and urinary tract infection, SGLT2 inhibitors do not increase these risks and acute kidney injury is less common.
      • Neuen B.L.
      • Young T.
      • Heerspink H.J.L.
      • et al.
      SGLT2 inhibitors for the prevention of kidney failure in patients with type 2 diabetes: a systematic review and meta-analysis.
      ,
      • Donnan J.R.
      • Grandy C.A.
      • Chibrikov E.
      • et al.
      Comparative safety of the sodium glucose co-transporter 2 (SGLT2) inhibitors: a systematic review and meta-analysis.
      Higher risks for lower extremity amputation, mainly toe or metatarsal (6.3 vs 3.4 per 1,000 person-years), and fractures (15.4 vs 11.9 per 1,000 person-years) were reported for canagliflozin versus placebo in the CANVAS program.
      • Neal B.
      • Perkovic V.
      • Mahaffey K.W.
      • et al.
      Canagliflozin and cardiovascular and renal events in type 2 diabetes.
      Whether these are chance findings or they represent a class effect is uncertain. Higher risks for amputation and fracture were not observed in CVOTs of other SGLT2 inhibitors or with canagliflozin in the CREDENCE trial.
      • Perkovic V.
      • Jardine M.J.
      • Neal B.
      • et al.
      Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.
      ,
      • Neuen B.L.
      • Young T.
      • Heerspink H.J.L.
      • et al.
      SGLT2 inhibitors for the prevention of kidney failure in patients with type 2 diabetes: a systematic review and meta-analysis.
      ,
      • Donnan J.R.
      • Grandy C.A.
      • Chibrikov E.
      • et al.
      Comparative safety of the sodium glucose co-transporter 2 (SGLT2) inhibitors: a systematic review and meta-analysis.

       Optimizing Uptake of SGLT2 Inhibitors

      The clinical benefits provided by SGLT2 inhibition can only be realized with increased use. Nearly 20 years ago, similar expectations were held for ACE inhibitors and ARBs, but implementation of this standard of care for diabetes and CKD is strikingly low, in the range of 20% to 40%, even in contemporary reports from communities and health care systems.
      • Murphy D.P.
      • Drawz P.E.
      • Foley R.N.
      Trends in angiotensin-converting enzyme inhibitor and angiotensin II receptor blocker use among those with impaired kidney function in the United States.
      ,
      • Tuttle K.R.
      • Alicic R.Z.
      • Duru O.K.
      • et al.
      Clinical characteristics of and risk factors for chronic kidney disease among adults and children: an analysis of the CURE-CKD Registry.
      The newfound opportunity with SGLT2 inhibitors highlights the urgent need for better CKD screening and detection.
      • Wanner C.
      • Inzucchi S.E.
      • Lachin J.M.
      • et al.
      Empagliflozin and progression of kidney disease in type 2 diabetes.
      • Neal B.
      • Perkovic V.
      • Mahaffey K.W.
      • et al.
      Canagliflozin and cardiovascular and renal events in type 2 diabetes.
      • Wiviott S.D.
      • Raz I.
      • Bonaca M.P.
      • et al.
      Dapagliflozin and cardiovascular outcomes in type 2 diabetes.
      • Perkovic V.
      • Jardine M.J.
      • Neal B.
      • et al.
      Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.
      ,
      • Tuttle K.R.
      • Alicic R.Z.
      • Duru O.K.
      • et al.
      Clinical characteristics of and risk factors for chronic kidney disease among adults and children: an analysis of the CURE-CKD Registry.
      • Galbraith L.E.
      • Ronksley P.E.
      • Barnieh L.J.
      • et al.
      The See Kidney Disease targeted screening program for CKD.
      • Hellemons M.E.
      • Denig P.
      • de Zeeuw D.
      • Voorham J.
      • Lambers Heerspink H.J.
      Is albuminuria screening and treatment optimal in patients with type 2 diabetes in primary care? Observational data of the GIANTT cohort.
      Education and activation of patients regarding the benefits of receiving renin-angiotensin system inhibitors and SGLT2 inhibitors can be accomplished through focused discussion and information dispersed in clinical settings, communities of high-risk groups, and public media platforms. For example, the NKF and CVS Kidney Care have partnered on a campaign to promote kidney health and screening for CKD.
      National Kidney Foundation
      NKF and CVS Kidney Care have joined forces to promote kidney health.
      Even with greater awareness of the benefits of SGLT2 inhibitors, their high cost poses a barrier to use. Using a participant-level simulation model and United Kingdom health care costs, empagliflozin in addition to standard of care is projected to be cost-effective.
      • Kansal A.
      • Reifsnider O.S.
      • Proskorovsky I.
      • et al.
      Cost-effectiveness analysis of empagliflozin treatment in people with type 2 diabetes and established cardiovascular disease in the EMPA-REG OUTCOME trial.
      The model predicted that although patients would incur increased out-of-pocket cost, empagliflozin in addition to standard of care would result in longer survival by 2.1 life-years. Market exclusivity practice is another major barrier because brand name monopolies may delay widespread access to SGLT2 inhibitors.
      • Kesselheim A.S.
      • Avorn J.
      • Sarpatwari A.
      The high cost of prescription drugs in the United States: origins and prospects for reform.
      Patient advocacy and professional organizations can lead the education of clinicians and patients with concentrated efforts to increase SGLT2 inhibitor use in appropriate patients.
      • Cherney D.Z.
      • Udell J.A.
      Use of sodium glucose cotransporter 2 inhibitors in the hands of cardiologists: with great power comes great responsibility.
      ,
      • Nassif M.E.
      • Kosiborod M.
      Are we ready to bell the cat? A call for cardiologists to embrace glucose-lowering therapies proven to improve cardiovascular outcomes.
      Clinicians who provide care in nephrology, endocrinology, cardiology, and primary care must master competency in prescribing and managing SGLT2 inhibitors. Considering the broad indications for the treatment of T2DM, CKD, and CVD, dissemination and implementation science is needed to generate data that health care administrators and policy makers can use to support ready availability of SGLT2 inhibitors (Table 5).
      Table 5Proposed Research to Increase Uptake of SGLT2 Inhibitors
      StudyRationale/Objective
      Dissemination and Implementation
      Test whether multiprofessional clinics (in which patients are seen by nephrologist, cardiologist, diabetes care provider, and pharmacist) improve uptake of SGLT2 inhibitors.Identify new models of care to increase dissemination and implementation of SGLT2 inhibitor use.
      Availability of Insurance Coverage for SGLT2 Inhibitors
      Perform detailed risk-benefit and economic analyses using large claims databases.Encourage coverage for SGLT2 inhibitors for CKD and CVD from health insurers.
      Abbreviations: CKD, chronic kidney disease; CVD, cardiovascular disease; SGLT2, sodium/glucose cotransporter 2.

      Conclusions

      Diabetes is the leading cause of CKD worldwide, with high risks for kidney failure, ASCVD, HF, and premature mortality. The concept that benefits of SGLT2 inhibitors are mediated by nonglycemic mechanisms is supported by many observations that the CKD and CVD risk reductions in the clinical trials of these agents occurred irrespective of glycemic control or use of other glucose-lowering agents. SGLT2 inhibitors have numerous effects, from improving glomerular hemodynamics to modifying local and systemic mechanisms involved in the pathogenesis of CKD and CVD. More comprehensive understanding of these mechanisms is crucial for optimal application and to facilitate research that will elucidate actions of SGLT2 inhibitors. Clinicians have a responsibility to maximize the known benefits by prescribing and managing SGLT2 inhibitors in patients likely to benefit. Dedicated efforts are required to disseminate information, provide education, and ensure appropriate SGLT2 inhibitor use.

      Article Information

      Authors’ Full Names and Academic Degrees

      Katherine R. Tuttle, MD, Frank C. Brosius III, MD, Matthew A. Cavender, MD, MPH, Paola Fioretto, MD, Kevin J. Fowler, BS, BA, Hiddo J.L. Heerspink, PhD, Tom Manley, RN, Darren K. McGuire, MD, MHSc, Mark E. Molitch, MD, Amy K. Mottl, MD, MPH, Leigh Perreault, MD, Sylvia E. Rosas, MD, MSC, Peter Rossing, MD, DMSc, Laura Sola, MD, Volker Vallon, MD, Christoph Wanner, MD, and Vlado Perkovic, MBBS, PhD.

      Support

      The following companies provided a grant to the NKF to support the planning and conduct of the workshop: AstraZeneca, Boehringer Ingelheim, Janssen, Sanofi, Merck, and Metavant. The workshop sponsors had no role in the development of the workshop agenda or objectives. The sponsors were restricted from viewing any part of the workshop report manuscript until it was accepted for publication and therefore had no role in the content developed for this report.

      Financial Disclosure

      Dr Tuttle is supported by National Institutes of Health (NIH) grants and a Center for Disease Control and Prevention contract and has served as a consultant for Eli Lilly & Co, Boehringer Ingelheim, AstraZeneca, Gilead, Goldfinch Bio, Novo Nordisk, Bayer, and Janssen. Dr Cavender has received research support (nonsalary) from Amgen, AstraZeneca, Bristol Myers Squibb, Chiesi, CSL Behring, GlaxoSmithKline, and Novartis; research support (salary) from Novo-Nordisk; and consulting fees from AstraZeneca, Boehringer-Ingelheim, Boston Scientific, Edwards Lifesciences, and Merck. Dr Perreault has received personal fees from speaking and/or consulting from Novo Nordisk, Sanofi, AstraZeneca, Boehringer-Ingelheim, Janssen, Merck, and UpToDate. Dr Vallon reports grants from the NIH and has served as a consultant and received honoraria from Bayer, Boehringer Ingelheim, Eli Lilly & Co, Janssen Pharmaceutical, Merck, and Retrophin and grant support for investigator-initiated research from AstraZeneca, Bayer, Boehringer-Ingelheim, Fresenius, and Janssen Pharmaceutical. Dr Rossing reports having given lectures for AstraZeneca, Bayer, Novo Nordisk, and Boehringer-Ingelheim and has served as a consultant for AbbVie, AstraZeneca, Bayer, Eli Lilly & Co, Boehringer-Ingelheim, Astellas, Gilead, Mundipharma, Vifor, and Novo Nordisk, all fees given to Steno Diabetes Center Copenhagen. Dr Brosius reports grants from the NIH and the Juvenile Diabetes Research Foundation; the University of Michigan has contracted with Gilead for his consulting services. Dr Fioretto reports receiving personal fees for advisory boards or scientific presentations from AstraZeneca, Mundipharma, Boehringer-Ingelheim, Eli Lilly & Co, and Novartis. Mr Fowler is a consultant for Responsum Health, Bayer, Gilead, Chiesi, Talaris, Retrophin, Otsuka, and Veloxis. Dr Heerspink has served as a consultant for Abbvie, AstraZeneca, Boehringer-Ingelheim, Fresenius, Gilead, Janssen, Merck, Mundipharma, Mitsubishi-Tanabe, and Retrophin and received grant support from Abbvie, AstraZeneca, Boehringer-Ingelheim, and Janssen. Dr Mottl has contracts with Aurinia, Boehringer-Ingelheim, Calliditas, Duke Clinical Research Institute, and Pfizer; has been a member of the scientific advisory board for AstraZeneca; and has consultancy agreements with Proteomics Int. Dr Rosas reports grants from the NIH, Bayer, and Ironwood Pharmaceuticals and has participated in advisory boards for Reata and Bayer Healthcare. Dr Molitch reports grants from the National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Novartis, and NovoNordisk and consulting fees from Merck, Pfizer, and Janssen. Dr McGuire has received honoraria for clinical trial leadership from AstraZeneca, Sanofi Aventis, Janssen, Boehringer-Ingelheim, Merck & Co, Pfizer, Novo Nordisk, Lexicon, Eisai Inc, GlaxoSmithKline, Lilly USA, and Esperion and honoraria for consultancy from AstraZeneca, Sanofi Aventis, Lilly USA, Boehringer-Ingelheim, Merck & Co, Novo Nordisk, Metavant, Applied Therapeutics, and Afimmune. Dr Wanner has received honoraria from AstraZeneca, Sanofi, Boehringer Ingelheim, Merck, Eli Lilly & Co, and Mundipharma. Mr Manley is employed by the NKF. Dr Perkovic has received fees for advisory boards, steering committee roles, or scientific presentations from Abbvie, Astellas, AstraZeneca, Bayer, Baxter, BMS, Boehringer-Ingelheim, Chinook, Dimerix, Durect, Eli Lilly & Co, Gilead, GSK, Janssen, Merck, Mitsubishi Tanabe, Mundipharma, Novartis, Novo Nordisk, Pfizer, Pharmalink, Relypsa, Retrophin, Sanofi, Servier, Vifor, and Tricida.

      Acknowledgements

      We thank the conference participants, who aside from the authors of this article included: Amanda Adler, MD, PhD, Oxford, UK; Maryam Afkarian, MD, PhD, Sacramento, CA; Radica Alicic, MD, Spokane, WA; Meaghan Allain, Falls Church, VA; Pamela Anderson, MBA, Titusville, NJ; George Bakris, MD, Chicago, IL; Petter Bjornstad, MD, Aurora, CO; Jaime Blais, PhD, Titusville, NJ; Glenn Chertow, MD, MPH, Palo Alto, CA; Alfred Cheung, MD, Salt Lake City, UT; Mihye (Mia) Cmiel, PharmD, Philadelphia, PA; Stephanie Cogan, New York, NY; Mark Cooper, MBBS, PhD, Melbourne, Australia; Kerry Cooper, MD, Gaithersburg, MD; Ian de Boer, MD, MS, Seattle, WA; Luca De Nicola, MD, PhD, Naples, Italy; Ralph Defronzo, MD, San Antonio, TX; Tony Deluzio, Bridgewater, NJ; Barbara Gillespie, MD, MMS, Chapel Hill, NC; Anthony Gucciardo, New York, NY; Michelle Hangey, BBA, MBA, Philadelphia, PA; Raymond Harris, MD, Nashville, TN; Sibylle Hauske, MD, MBA, Ridgefield, CT; Richard Haynes, DM, MRCP, Oxford, UK; Will Herrington, MA, MBBS, MD, Oxford, UK; Donna Hodge, Titusville, NJ; Diana Jalal, MD, Iowa City, IA; Meg Jardine, MBBS, PhD, Sydney, Australia; Nichole Jefferson, Dallas, TX; Steven Kahn, MBChB, Seattle, WA; Mikhail Kosiborod, MD, Kansas City, MO; Liz Leff, New York, NY; Kerry Leigh, RN, Washington DC; Helen Looker, MBBS, MRCP, Phoenix, AZ; Julie Lovshin, MD, PhD, Ontario, Canada; Sally Marshall, MD, Tyne, UK; Julie Maurey, PharmD, Philadelphia, PA; Peter McCullough, MD, MPH, Dallas, TX; Jim McDermott, PhD, Gaithersburg, MD; Ciaran McMullan, MB BCh, MMSc, Philadelphia, PA; Elizabeth Montgomery, New York, NY; Marcel H. Muskiet, MD, Amsterdam, the Netherlands; Robert Nelson, MD, PhD, Phoenix, AZ; Joshua Neumiller, PharmD, Pullman, WA; Susanne Nicholas, MD, MPH, PhD, Los Angeles, CA; Gregorio Obrador, MD, MPH, Mexico City, Mexico; Milton Packer, MD, Dallas, TX; Sachin Paranjape, PhD, Bridgewater, NJ; Meda Pavkov, MD, PhD, Atlanta, GA; Pablo Pergola, MD, PhD, San Antonio, TX; Michaela Petrini, PA-C, MHS, Ridgefield, CT; Glenda Roberts, Seattle, WA; Motoaki Sano, MD, PhD, Tokyo, Japan; Jay Shubrook, DO, Vallejo, CA; Anna Solini, MD, PhD, Pisa, Italy; Christopher Sorli, MD, PhD, Bridgewater, NJ; Paul Strumph, MD, Durham, NC; Merlin Thomas, MBChB, PhD, Melbourne, Australia; Aliza Thompson, MD, Silver Spring, MD; Marcello Tonelli, MD, Edmonton, Alberta, Canada; Robert Toto, MD, Dallas, TX; Daniel van Raalte, MD, PhD, Amsterdam, the Netherlands; Joseph Vassalotti, MD, New York, NY; Mark West, PharmD, Pittsburgh, PA; Ernest W. Wright, PhD, DSci, FRS, Los Angeles, CA; Jason Wright, PharmD, Gaithersburg, MD; and Helen Yeh, PhD, Gaithersburg, MD. We thank Emily J. Cox, PhD (Providence Health Care, Providence Medical Research Center, Spokane, WA) who assisted in the development of Figure 3.

      Peer Review

      Received April 28, 2020, at Diabetes and AJKD. Evaluated by 3 external peer reviewers, with direct editorial input from the Diabetes Editor-in-Chief and an AJKD Associate Editor and Deputy Editor. Accepted in revised form by both journals August 4, 2020.

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