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Diabetic Kidney Disease Back in Focus: Management Field Guide for Health Care Professionals in the 21st Century

      Abstract

      Chronic kidney disease due to diabetes, or diabetic kidney disease (DKD), is a worldwide leading cause of chronic kidney disease and kidney failure and an increasingly important global public health issue. It is associated with poor quality of life, high burden of chronic diseases, and increased risk of premature death. Until recently, people with DKD had limited therapeutic options. Treatments have focused largely on glycemic and blood pressure control and renin-angiotensin system blockade, leaving patients with significant residual risk for progression of DKD. The availability of newer classes of glucose-lowering agents, namely, sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists, has changed the therapeutic landscape for these patients. These therapies have offered unprecedented opportunities to reduce the risk for progression of kidney disease and the risk of death that have led to recent updates to clinical guidelines. As such, the American Diabetes Association, the Kidney Disease: Improving Global Outcomes, and the European Association for the Study of Diabetes now recommend the use of sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists for patients with DKD to provide both kidney and cardiovascular protective benefits. This review highlights the importance of early detection of DKD and summarizes the latest recommendations in the clinical guidelines on management of patients with DKD with hope of facilitating their uptake into everyday clinical practice. An integrated approach to patient care with a multidisciplinary focus can help achieve the necessary shift in clinical care of patients with DKD.

      Abbreviations and Acronyms:

      ACEI (angiotensin-converting enzyme inhibitor), ADA (American Diabetes Association), ARB (angiotensin receptor blocker), ASCVD (atherosclerotic cardiovascular disease), CKD (chronic kidney disease), CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration), CV (cardiovascular), CVD (cardiovascular disease), DKD (diabetic kidney disease), eGFR (estimated glomerular filtration rate), GLP-1 RA (glucagon-like peptide 1 receptor agonist), HbA1c (glycated hemoglobin), KDIGO (Kidney Disease: Improving Global Outcomes), SGLT2 (sodium-glucose cotransporter 2), UACR (urinary albumin to creatinine ratio)
      Article Highlights
      • Diabetic kidney disease (DKD) is a worldwide leading cause of chronic kidney disease and kidney failure requiring kidney replacement therapy. It is associated with poor quality of life, increased risk of cardiovascular disease, infection, cancer, and premature death.
      • Because the health consequences of DKD are severe, it is crucial that clinicians ensure early detection and initiation of proven interventions that can prevent the progression of kidney disease and its complications.
      • The introduction of sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists into clinical practice will certainly reduce DKD progression, rates of cardiovascular disease, and risk of dying, thus providing a unique opportunity to achieve a paradigm shift in the care of DKD patients.
      • The delivery of health care by a multidisciplinary team affords the potential to achieve truly integrated care for patients with DKD.
      • This article provides a user-friendly summary of the latest clinical guidelines on the management of patients with DKD.
      Chronic kidney disease (CKD) is a common microvascular complication in patients with both type 1 and type 2 diabetes.
      US Department of Health and Human Services, Centers for Disease Control and Prevention
      National Diabetes Statistics Report 2020.
      It is defined as persistent albuminuria (urinary albumin excretion >30 mg/24 h or urinary albumin to creatinine ratio [UACR] >30 mg/g), persistent reduction in estimated glomerular filtration rate (eGFR) below 60 mL/min per 1.73 m2, or both, for at least 3 months.
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      • et al.
      Nomenclature for kidney function and disease—executive summary and glossary from a Kidney Disease: Improving Global Outcomes (KDIGO) consensus conference.
      Current estimates suggest that approximately 40% of patients with type 2 diabetes have CKD (stages 1 to 4), more than half of whom (52.5%) have moderate to severe disease (stage 3 and stage 4).
      Centers for Disease Control and Prevention
      National Diabetes Statistics Report.
      • Levin A.
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      • et al.
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      In referring to kidney disease in patients with diabetes, the terms diabetic kidney disease (DKD) and diabetic nephropathy are frequently used interchangeably. However, there are important differences between these terms. Diabetic kidney disease is a clinical diagnosis that describes the development of CKD in diabetes based on signs, symptoms, and laboratory values.
      Kidney Disease: Improving Global Outcomes Diabetes Work Group
      KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease.
      Diabetic nephropathy is a tissue diagnosis that refers to the characteristic pathologic glomerular lesions specific of CKD caused by diabetes.
      Kidney Disease: Improving Global Outcomes Diabetes Work Group
      KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease.
      ,
      • Tervaert T.W.
      • Mooyaart A.L.
      • Amann K.
      • et al.
      Pathologic classification of diabetic nephropathy.
      This distinction is important because up to 30% of patients with DKD may have other causes of CKD on kidney biopsy, and therefore their clinical presentation and management may differ
      • Anders H.J.
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      • Isermann B.
      • Schiffer M.
      CKD in diabetes: diabetic kidney disease versus nondiabetic kidney disease.
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      • Mauer M.
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      —thus the observation that the clinical presentation and progression of CKD in patients with diabetes, and particularly type 2 diabetes, are heterogeneous. Other kidney diseases with which patients with diabetes may present include minimal change disease, primary focal and segmental glomerulosclerosis, and polycystic kidney disease alone or combined with diabetic nephropathy.
      • Anders H.J.
      • Huber T.B.
      • Isermann B.
      • Schiffer M.
      CKD in diabetes: diabetic kidney disease versus nondiabetic kidney disease.
      This review focuses on the management of patients with CKD due to diabetes (without other known causes), which is referred to as DKD.
      As a consequence of the worldwide diabetes pandemic, recent decades have seen DKD become a global leading cause of kidney failure and the most frequent indication for kidney replacement therapy.
      United States Renal Data System
      USRDS annual data report. Chapter 1. CKD in the general population.
      • Jha V.
      • Garcia-Garcia G.
      • Iseki K.
      • et al.
      Chronic kidney disease: global dimension and perspectives.
      • Saeedi P.
      • Petersohn I.
      • Salpea P.
      • et al.
      Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: results from the International Diabetes Federation Diabetes Atlas, 9th edition.
      In contrast to the downward trends in other diabetes-related complications, including myocardial infarction, stroke, and limb amputation, the prevalence of DKD has not followed similar downward trends.
      • Harding J.L.
      • Pavkov M.E.
      • Magliano D.J.
      • Shaw J.E.
      • Gregg E.W.
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      ,
      • Gregg E.W.
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      • et al.
      Changes in diabetes-related complications in the United States, 1990-2010.
      Higher albuminuria levels and lower eGFR are independently and additively associated with an increased risk for cardiovascular (CV) and all-cause mortality.
      • Matsushita K.
      • van der Velde M.
      • Astor B.C.
      • et al.
      Chronic Kidney Disease Prognosis Consortium
      Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis.
      ,
      • Afkarian M.
      • Sachs M.C.
      • Kestenbaum B.
      • et al.
      Kidney disease and increased mortality risk in type 2 diabetes.
      For instance, the presence of kidney disease is associated with a sharp increase of 10-year cumulative all-cause mortality from 11.5% among individuals with diabetes and without kidney disease up to 31% among individuals with diabetes and kidney disease, indicating that most of the excess risk of all-cause and CV mortality for individuals with type 2 diabetes relates to the presence of DKD.
      • Afkarian M.
      • Sachs M.C.
      • Kestenbaum B.
      • et al.
      Kidney disease and increased mortality risk in type 2 diabetes.
      Overall, individuals with CKD have twice the risk of CV disease (CVD) compared with individuals without CKD, and death from CVD is more likely than progression to kidney failure.
      United States Renal Data System
      USRDS Annual data report. Chapter 4. Cardiovascular disease in patients with CKD.
      ,
      • Benjamin E.J.
      • Muntner P.
      • Alonso A.
      • et al.
      Heart Disease and Stroke Statistics—2019 Update: a report from the American Heart Association.
      From the patient’s perspective, the progression of kidney disease has been associated with reduced quality of life.
      • Tang E.
      • Bansal A.
      • Novak M.
      • Mucsi I.
      Patient-reported outcomes in patients with chronic kidney disease and kidney transplant—part 1.
      ,
      • Oh T.R.
      • Choi H.S.
      • Kim C.S.
      • et al.
      Association between health related quality of life and progression of chronic kidney disease.
      Until very recently, treatments to prevent the development and progression of DKD were limited to glycemic and blood pressure control and the use of renin-angiotensin system blockers, resulting in the significant residual risk that helped establish DKD as a growing major global public health problem.
      • Saeedi P.
      • Petersohn I.
      • Salpea P.
      • et al.
      Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: results from the International Diabetes Federation Diabetes Atlas, 9th edition.
      ,
      • Tuttle K.R.
      • Brosius 3rd, F.C.
      • Cavender M.A.
      • et al.
      SGLT2 inhibition for CKD and cardiovascular disease in type 2 diabetes: report of a scientific workshop sponsored by the National Kidney Foundation.
      The availability of newer classes of glucose-lowering agents, including sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide 1 receptor agonists (GLP-1 RAs), and the nonsteroidal mineralocorticoid receptor antagonist finerenone, will undoubtedly change this therapeutic landscape.
      Surprisingly, contemporary CV outcomes trials demonstrated reductions in not only CV events but also secondary kidney end points associated with the administration of SGLT2 inhibitors and GLP-1 RAs.
      • Marso S.P.
      • Bain S.C.
      • Consoli A.
      • et al.
      Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      • Marso S.P.
      • Daniels G.H.
      • Brown-Frandsen K.
      • et al.
      Liraglutide and cardiovascular outcomes in type 2 diabetes.
      • Muskiet M.H.
      • Tonneijck L.
      • Huang Y.
      • et al.
      Lixisenatide and renal outcomes in patients with type 2 diabetes and acute coronary syndrome: an exploratory analysis of the ELIXA randomised, placebo-controlled trial.
      • Neal B.
      • Perkovic V.
      • Mahaffey K.W.
      • et al.
      Canagliflozin and cardiovascular and renal events in type 2 diabetes.
      • Wanner C.
      • Inzucchi S.E.
      • Lachin J.M.
      • et al.
      Empagliflozin and progression of kidney disease in type 2 diabetes.
      • Wiviott S.D.
      • Raz I.
      • Bonaca M.P.
      • et al.
      Dapagliflozin and cardiovascular outcomes in type 2 diabetes.
      • Zinman B.
      • Wanner C.
      • Lachin J.M.
      • et al.
      Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
      Subsequently, dedicated kidney outcomes trials have confirmed benefits associated with SGLT2 inhibitors in terms of reductions in the progression of kidney disease and CV death.
      • Heerspink H.J.
      • Stefansson B.V.
      • Correa-Rotter R.
      • et al.
      Dapagliflozin in patients with chronic kidney disease.
      ,
      • Perkovic V.
      • Jardine M.J.
      • Neal B.
      • et al.
      Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.
      Similarly, in patients with DKD, finerenone was shown to mitigate the progression of kidney disease, CV risks, and death.
      • Bakris G.L.
      • Agarwal R.
      • Anker S.D.
      • et al.
      Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes.
      ,
      • Pitt B.
      • Filippatos G.
      • Agarwal R.
      • et al.
      Cardiovascular events with finerenone in kidney disease and type 2 diabetes.
      As a result, there is increased recognition of the historic opportunity to reshape the care and lives of patients with DKD. The aim of this article is to provide a succinct, user-friendly update on guidelines-recommended care, including the importance of early detection, as well as tailored follow-up with a focus on treatment that reduces the risk of kidney disease progression and CV death and improves overall clinical outcomes.

      Methods

      Recent guidelines for type 2 diabetes management are included for review, specifically, guidelines from the American Diabetes Association (ADA) and Kidney Disease: Improving Global Outcomes (KDIGO) in addition to joint guidelines from the American Association of Clinical Endocrinologists and the American College of Endocrinology and joint guidelines from the European Society of Cardiology and the European Association for the Study of Diabetes. Additional literature included CV outcomes trials with kidney outcomes data and prescribing information for guideline-recommended therapies. Also, the MEDLINE database was searched through PubMed to retrieve relevant articles on type 2 diabetes and GLP-1 RAs, SGLT2 inhibitors, and finerenone between 2010 and 2021 (limits: humans, English language). A total of 32 trials in patients with type 2 diabetes and GLP-1 RAs, 53 trials with SGLT2 inhibitors, and 9 trials with finerenone were identified. Of these identified trials, 20 trials were reviewed in detail. Other relevant literature was obtained on the basis of personal knowledge and experience. Manual assessment of retrieved references was used as the basis for a narrative overview of the literature.

      Diagnosis of DKD

      Diabetic kidney disease is generally diagnosed and classified as the presence of albuminuria or a reduction in eGFR in the absence of clinical indictors of other causes of kidney disease (Figure 1
      • Draznin B.
      • Aroda V.R.
      • Bakris G.
      • et al.
      American Diabetes Association Professional Practice Committee
      11. Chronic kidney disease and risk management: standards of medical care in diabetes—2022.
      ,
      KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Definition, identification, and prediction of CKD progression.
      ). Typically, DKD is manifested in a patient with long-standing (>10 years) type 2 diabetes in the presence of retinopathy, albuminuria without macroscopic hematuria, and progressive eGFR decline.
      Kidney Disease: Improving Global Outcomes Diabetes Work Group
      KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease.
      ,
      • Draznin B.
      • Aroda V.R.
      • Bakris G.
      • et al.
      American Diabetes Association Professional Practice Committee
      11. Chronic kidney disease and risk management: standards of medical care in diabetes—2022.
      Alternatively, in a subset of patients, evidence of DKD with reduced eGFR can be present at diagnosis of type 2 diabetes in the absence of retinopathy and without albuminuria.
      • Draznin B.
      • Aroda V.R.
      • Bakris G.
      • et al.
      American Diabetes Association Professional Practice Committee
      11. Chronic kidney disease and risk management: standards of medical care in diabetes—2022.
      Albuminuria is best assessed with spot urine samples (ideally, early morning samples) to calculate the UACR. Because DKD is usually asymptomatic until advanced stages, guidelines from the ADA and KDIGO recommend that all individuals with type 2 diabetes have eGFR and UACR measured at the time of diagnosis and annually thereafter.
      Kidney Disease: Improving Global Outcomes Diabetes Work Group
      KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease.
      ,
      • Draznin B.
      • Aroda V.R.
      • Bakris G.
      • et al.
      American Diabetes Association Professional Practice Committee
      11. Chronic kidney disease and risk management: standards of medical care in diabetes—2022.
      Individuals with type 1 diabetes should be screened within 5 years of diagnosis. Evaluation of DKD, especially at the time of initial diagnosis, should include careful medical and family history to look for other possible causes of kidney disease, such as family history of polycystic kidney disease, presence of chronic infections (such as HIV infection, hepatitis C), autoimmune disorders (systemic lupus erythematosus, vasculitis), malignant neoplasms (lymphoma, myeloma, solid tumors), episodes of acute kidney injury, frequent infections, and exposure to toxins.
      • Anders H.J.
      • Huber T.B.
      • Isermann B.
      • Schiffer M.
      CKD in diabetes: diabetic kidney disease versus nondiabetic kidney disease.
      Kidney function is assessed by a serum creatinine or cystatin C–based eGFR calculation, preferably with the CKD Epidemiology Collaboration (CKD-EPI) equation, which is more accurate than the Modification of Diet in Renal Disease study equation.
      • Matsushita K.
      • Mahmoodi B.K.
      • Woodward M.
      • et al.
      Comparison of risk prediction using the CKD-EPI equation and the MDRD study equation for estimated glomerular filtration rate.
      The serum creatinine–based CKD-EPI eGFR equation includes approximately 16% higher eGFR values for individuals self-identified as Black because of the use of a correction factor for self-reported Black race.
      • Levey A.S.
      • Stevens L.A.
      • Schmid C.H.
      • et al.
      A new equation to estimate glomerular filtration rate.
      Incorporation of the correction factor in the serum creatinine–based eGFR calculation was derived from findings of a small study that showed higher serum creatinine levels in Black vs White patients.
      • Jones C.A.
      • McQuillan G.M.
      • Kusek J.W.
      • et al.
      Serum creatinine levels in the US population: third National Health and Nutrition Examination Survey.
      Although the findings were not validated by direct measurements of glomerular filtration or lean body mass, the correction factor for race has subsequently been used inappropriately as a proxy for serum creatinine, which is derived primarily from skeletal muscle, in other eGFR equations.
      • Levey A.S.
      • Stevens L.A.
      • Schmid C.H.
      • et al.
      A new equation to estimate glomerular filtration rate.
      ,
      • Inker L.A.
      • Schmid C.H.
      • Tighiouart H.
      • et al.
      Estimating glomerular filtration rate from serum creatinine and cystatin C.
      However, serum creatinine values may reflect other conditions, such as dietary protein levels, vigorous exercise, or long-term glucocorticoid therapy, as well as changes in creatinine filtration.
      • Porrini E.
      • Ruggenenti P.
      • Luis-Lima S.
      • et al.
      Estimated GFR: time for a critical appraisal.
      On the other hand, the cystatin C–based CKD-EPI eGFR equation does not include a modifier for race
      • Inker L.A.
      • Schmid C.H.
      • Tighiouart H.
      • et al.
      Estimating glomerular filtration rate from serum creatinine and cystatin C.
      and appears to have a more linear association with CV events compared with the creatinine-based CKD-EPI equation.
      • Kalantar-Zadeh K.
      • Jafar T.H.
      • Nitsch D.
      • Neuen B.L.
      • Perkovic V.
      Chronic kidney disease.
      Given the approximately 4-fold higher prevalence of CKD in Blacks/African Americans,
      • Harding K.
      • Mersha T.B.
      • Vassalotti J.A.
      • Webb F.A.
      • Nicholas S.B.
      Current state and future trends to optimize the care of chronic kidney disease in African Americans.
      the National Kidney Foundation and the American Society of Nephrology created a Task Force to address the use of Black race in eGFR reporting
      • Delgado C.
      • Baweja M.
      • Burrows N.R.
      • et al.
      Reassessing the inclusion of race in diagnosing kidney diseases: an interim report from the NKF-ASN Task Force.
      in these vulnerable patients. As such, the Task Force has provided the following recommendations: use of the CKD-EPI creatinine-based equation without the race variable; use of cystatin C for eGFR confirmation in clinical decision-making; and research on new endogenous filtration markers that interventions may eliminate racial and ethnic disparities.
      • Delgado C.
      • Baweja M.
      • Crews D.C.
      • et al.
      A unifying approach for GFR estimation: recommendations of the NKF-ASN Task Force on reassessing the inclusion of race in diagnosing kidney disease.
      These approaches would advance unbiased assessments on informed decisions toward achieving health care equity for all individuals with CKD.
      Figure thumbnail gr1
      Figure 1Referral to nephrologist and number of visits in the first year after referral based on glomerular filtration rate (GFR) and albuminuria.
      KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Definition, identification, and prediction of CKD progression.
      The GFR and albuminuria grid shows the risk of progression, morbidity, and mortality by color, from best to worst (green, yellow, orange, red, dark red). The numbers in the boxes are a guide to the frequency of visits (number of times per year). Green can reflect chronic kidney disease with normal estimated GFR (eGFR) and albuminuria only in the presence of other markers of kidney damage, such as imaging showing polycystic kidney disease or kidney biopsy abnormalities, with follow-up measurements annually; yellow requires caution and measurements at least once per year; orange requires measurements twice per year; red requires measurements 3 times per year; and dark red requires measurements 4 times per year. These are general parameters only, based on expert opinion, and underlying comorbid conditions and disease state as well as the likelihood of having an impact on change in management for any individual patient must be taken into account. “Refer” indicates that nephrology services are recommended. aReferring clinicians may wish to discuss with their nephrology service, depending on local arrangements for treating or referring. Clinicians may wish to discuss with their nephrology service, depending on local arrangements for treating or referring for acute kidney injury, eGFR below 30 mL/min per 1.73 m2, consistent finding of significant albuminuria (urine albumin to creatinine ratio ≥300 mg/g), chronic kidney disease progression to new category of abrupt and sustained decline in eGFR of more than 5 mL/min per 1.73 m2 per year, persistent presence of urinary red cell casts, hypertension refractory to treatment with 4 or more antihypertensive agents, persistent abnormalities of serum potassium, recurrent or extensive nephrolithiasis, and hereditary kidney disease. From Kidney Int Suppl,
      KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Definition, identification, and prediction of CKD progression.
      with permission.
      When used together, eGFR and UACR improve risk stratification and diagnostic accuracy.
      • Draznin B.
      • Aroda V.R.
      • Bakris G.
      • et al.
      American Diabetes Association Professional Practice Committee
      11. Chronic kidney disease and risk management: standards of medical care in diabetes—2022.
      ,
      • Winocour P.H.
      • Moore-Haines K.
      • Sullivan K.
      • Currie A.
      • Solomon A.
      • Hardy D.
      Holistic review of people with diabetes and chronic kidney disease reveals important multimorbidity and unmet clinical need: the ENHIDE diabetes renal telehealth pilot study.
      More frequent testing is recommended for elevated UACR above 300 mg/g or eGFR of 30 to 60 mL/min per 1.73 m2.
      Kidney Disease: Improving Global Outcomes Diabetes Work Group
      KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease.
      ,
      • Draznin B.
      • Aroda V.R.
      • Bakris G.
      • et al.
      American Diabetes Association Professional Practice Committee
      11. Chronic kidney disease and risk management: standards of medical care in diabetes—2022.
      ,
      KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Definition, identification, and prediction of CKD progression.
      For instance, the ADA recommends twice-yearly monitoring for individuals with UACR of 300 mg/g or higher and CKD stage 3b and stage 4 (eGFR <45 mL/min per 1.73 m2) irrespective of therapy.
      • Draznin B.
      • Aroda V.R.
      • Bakris G.
      • et al.
      American Diabetes Association Professional Practice Committee
      11. Chronic kidney disease and risk management: standards of medical care in diabetes—2022.
      In addition, repeated testing should be performed if there is a change in clinical status (indicating rapid progression or advanced stages of DKD) or when new medications are started (such as an SGLT2 inhibitor, angiotensin-converting enzyme inhibitor [ACEI], or angiotensin receptor blocker [ARB]).
      Kidney Disease: Improving Global Outcomes Diabetes Work Group
      KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease.
      ,
      • Draznin B.
      • Aroda V.R.
      • Bakris G.
      • et al.
      American Diabetes Association Professional Practice Committee
      11. Chronic kidney disease and risk management: standards of medical care in diabetes—2022.
      Initiation of SGLT2 inhibitors or ACEI/ARBs may result in a transient reduction of up to 25% in eGFR, attributed to a change in glomerular hemodynamics rather than intrinsic renal disease, such as renal artery stenosis.
      Kidney Disease: Improving Global Outcomes Diabetes Work Group
      KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease.
      ,
      • Draznin B.
      • Aroda V.R.
      • Bakris G.
      • et al.
      American Diabetes Association Professional Practice Committee
      11. Chronic kidney disease and risk management: standards of medical care in diabetes—2022.
      Timely referral to a nephrologist may be considered for individuals with eGFR below 45 mL/min per 1.73 m2 for coordinated care to slow the progression of DKD, to improve the management of complications as the disease worsens, and to prepare patients adequately for kidney replacement therapy, as indicated.
      • Harding K.
      • Mersha T.B.
      • Vassalotti J.A.
      • Webb F.A.
      • Nicholas S.B.
      Current state and future trends to optimize the care of chronic kidney disease in African Americans.
      Referral to a nephrologist may also increase appropriate use of renin-angiotensin-aldosterone system blockers and optimal management of comorbidities, such as anemia, hypertension, and CKD mineral and bone disorders.
      • Harding K.
      • Mersha T.B.
      • Vassalotti J.A.
      • Webb F.A.
      • Nicholas S.B.
      Current state and future trends to optimize the care of chronic kidney disease in African Americans.
      Furthermore, referral to a nephrologist is strongly recommended once the eGFR drops below 30 mL/min per 1.73 m2, if there is consistent finding of significant albuminuria (UACR ≥300 mg/g), if DKD progresses to a new CKD category, or if there is an abrupt, sustained decline in eGFR of more than 5 mL/min per 1.73 m2 per year (Figure 1).

      Review of Key Points From Current Clinical Guidelines

      To slow the progression of kidney disease and to reduce CV events, individuals with DKD should receive comprehensive care. The foundation of this care includes a diabetes structured self-management education program, diet, exercise, and smoking cessation counseling, as well as treatment of hyperglycemia, optimization of blood pressure control using ACEIs or ARBs, and lipid management. The significant positive results of recent trials involving SGLT2 inhibitors, GLP-1 RAs, and finerenone on top of standard of care therapy with an ACEI or an ARB laid the foundation for new clinical guidelines recommending these agents in the treatment of DKD for their proven kidney and CV protective benefits (Table 1
      Kidney Disease: Improving Global Outcomes Diabetes Work Group
      KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease.
      ,
      • Draznin B.
      • Aroda V.R.
      • Bakris G.
      • et al.
      American Diabetes Association Professional Practice Committee
      11. Chronic kidney disease and risk management: standards of medical care in diabetes—2022.
      ,
      KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Definition, identification, and prediction of CKD progression.
      ,
      American Diabetes Association
      6. Glycemic targets: standards of medical care in diabetes—2022.
      Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure Work Group
      KDIGO 2021 Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease.
      • Garber A.J.
      • Handelsman Y.
      • Grunberger G.
      • et al.
      Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm—2020 executive summary.
      • 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.
      ).
      Table 1Summary of International Guideline Recommendations for Monitoring of Kidney Function and Risk Factor Management in Patients with Diabetes and DKD
      RecommendationADA 2022
      • Draznin B.
      • Aroda V.R.
      • Bakris G.
      • et al.
      American Diabetes Association Professional Practice Committee
      11. Chronic kidney disease and risk management: standards of medical care in diabetes—2022.
      ,
      American Diabetes Association
      6. Glycemic targets: standards of medical care in diabetes—2022.
      KDIGO 2020,
      Kidney Disease: Improving Global Outcomes Diabetes Work Group
      KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease.
      2021 (BP guideline)
      Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure Work Group
      KDIGO 2021 Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease.
      AACE/ACE
      • Garber A.J.
      • Handelsman Y.
      • Grunberger G.
      • et al.
      Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm—2020 executive summary.
      ESC/EASD 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.
      Screening and monitoring for DKDAt least annual UACR (preferably morning spot UACR) and eGFR in T1D ≥5 years and all T2D patients

      Monitor twice annually if UACR >300 mg/g and/or eGFR 30-60 mL/min per 1.73 m2
      At least annual UACR (preferably morning spot UACR) and eGFR

      Assess these more often if higher risk of progression or will have an impact on therapeutic decisions
      American Diabetes Association
      9. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes—2022.
      BP management<140/90 mm Hg for 10-year ASCVD risk of <15%

      <130/80 mm Hg for 10-year ASCVD risk of >15% if appropriate and can be achieved safely
      SBP <120 mm Hg for adults with T2D and CKD

      ACEI or ARB recommended if SBP >120 mm Hg, CKD, and moderately to severely increased albuminuria (G1-G4, A2 and A3; see Figure 1)
      <130/80 mm Hg for most patients

      Consider less stringent targets for patients with comorbidities

      <120/80 mm Hg may be appropriate for some patients (eg, those at risk of stroke)
      SBP to 130 mm Hg and, if well tolerated, <130 mm Hg (not <120 mm Hg)

      Individuals aged >65 years, target SBP: 130-139 mm Hg; DBP to <80 mm Hg (not <70 mm Hg)
      HbA1c targets<7.0% for most patients

      <8.0% if high risk of hypoglycemia or multiple comorbidities
      <6.5% to <8.0%, individualized target

      Higher target if risk of hypoglycemia, severe comorbidities, or limited life expectancy
      ≤6.5%

      Higher targets may be suitable for certain individuals and may change over time
      <7.0%

      Consider tighter control for younger patients.

      Less rigorous targets possible for elderly patients or those with severe comorbidities or advanced CVD
      AACE/ACE, American Association of Clinical Endocrinologists/American College of Endocrinology; ACEI, angiotensin-converting enzyme inhibitor; ADA, American Diabetes Association; ARB, angiotensin receptor blocker; ASCVD, atherosclerotic cardiovascular disease; BP, blood pressure; CKD, chronic kidney disease; CVD, cardiovascular disease; DBP, diastolic blood pressure; DKD, diabetic kidney disease; eGFR, estimated glomerular filtration rate; ESC/EASD, European Society of Cardiology/European Association for the Study of Diabetes; HbA1c, glycated hemoglobin; KDIGO, Kidney Disease: Improving Global Outcomes; SBP, systolic blood pressure; T1D, type 1 diabetes; T2D, type 2 diabetes; UACR, urine albumin to creatinine ratio.
      Current clinical guidelines advocate a patient-centered approach to management, with a focus on shared decision-making.
      Kidney Disease: Improving Global Outcomes Diabetes Work Group
      KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease.
      ,
      American Diabetes Association
      6. Glycemic targets: standards of medical care in diabetes—2022.
      ,
      • Garber A.J.
      • Handelsman Y.
      • Grunberger G.
      • et al.
      Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm—2020 executive summary.
      • 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.
      American Diabetes Association
      9. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes—2022.
      Table 1 summarizes the main recommendations from the clinical management guidelines for patients with type 2 diabetes from the ADA,
      American Diabetes Association
      6. Glycemic targets: standards of medical care in diabetes—2022.
      joint guidelines from the American Association of Clinical Endocrinologists and the American College of Endocrinology,
      • Garber A.J.
      • Handelsman Y.
      • Grunberger G.
      • et al.
      Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm—2020 executive summary.
      KDIGO guidelines on diabetes with CKD and blood pressure management,
      Kidney Disease: Improving Global Outcomes Diabetes Work Group
      KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease.
      ,
      Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure Work Group
      KDIGO 2021 Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease.
      and joint guidelines from the European Society of Cardiology and the European Association for the Study of Diabetes,
      • 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.
      as detailed here.

      Lifestyle Interventions

      Special emphasis in the approach to treatment of all DKD patients should be placed on adherence to a healthy diet high in vegetables, vegetable-based proteins, whole grains, unsaturated fat, fiber, and nuts. Sodium chloride intake should be limited to less than 5 g/d (equivalent to <2 g, or 90 mmol of sodium per day).
      Kidney Disease: Improving Global Outcomes Diabetes Work Group
      KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease.
      ,
      Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure Work Group
      KDIGO 2021 Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease.
      The recommended protein intake for all DKD patients, not on dialysis, is approximately 0.8 g/kg per day.
      Kidney Disease: Improving Global Outcomes Diabetes Work Group
      KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease.
      Lower levels of physical activity have been associated with higher risk of atherosclerotic CVD (ASCVD) and risk of dying.
      • Pandey A.
      • Garg S.
      • Khunger M.
      • et al.
      Dose-response relationship between physical activity and risk of heart failure: a meta-analysis.
      Therefore, it is recommended that patients with DKD undertake 150 minutes per week of moderate-intensity activity. Similarly, to achieve the glycemic target, the level and intensity of activity should be adjusted to individual CV and physical tolerance.
      Kidney Disease: Improving Global Outcomes Diabetes Work Group
      KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease.
      ,
      Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure Work Group
      KDIGO 2021 Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease.

      Glycemic Targets

      Achieving glycemic targets in individuals with DKD and especially advanced DKD is challenging primarily because of reduced kidney capacity for gluconeogenesis and altered metabolism and clearance of glucose-lowering therapies.
      • Neumiller J.J.
      • Alicic R.Z.
      • Tuttle K.R.
      Therapeutic considerations for antihyperglycemic agents in diabetic kidney disease.
      Consequently, patients with DKD may be at high risk for hypoglycemia and other adverse drug events.
      • Neumiller J.J.
      • Alicic R.Z.
      • Tuttle K.R.
      Therapeutic considerations for antihyperglycemic agents in diabetic kidney disease.
      ,
      • Galindo R.J.
      • Beck R.W.
      • Scioscia M.F.
      • Umpierrez G.E.
      • Tuttle K.R.
      Glycemic monitoring and management in advanced chronic kidney disease.
      Within the guidelines, there is agreement on the need for individualized glycemic targets for people with type 2 diabetes. The choice of tighter or less rigorous targets should be based on individual factors, including CKD stage, presence and severity of comorbidities, and age of the patient (Table 2
      Kidney Disease: Improving Global Outcomes Diabetes Work Group
      KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease.
      ,
      American Diabetes Association
      6. Glycemic targets: standards of medical care in diabetes—2022.
      ). Overall, the guidelines recommend a target glycated hemoglobin (HbA1c) level of less than 6.5% for patients at low risk of hypoglycemia and no comorbidities, less than 7.0% for most patients, and less than 8.0% for elderly patients and those with multiple comorbidities or advanced DKD.
      Table 2Factors That May Guide Decisions on Individualized HbA1c Targets in DKD
      Kidney Disease: Improving Global Outcomes Diabetes Work Group
      KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease.
      ,
      American Diabetes Association
      6. Glycemic targets: standards of medical care in diabetes—2022.
      Factor/considerationSupports more stringent HbA1c target (eg, <6.5% or 7.0%)Supports less stringent HbA1c target (eg, <8.0%)
      Severity of kidney diseaseEarly-stage DKD (eg, DKD G1-G3)Advanced-stage DKD (eg, DKD G4, G5)
      Macrovascular complicationsAbsent/minorPresent/severe
      Comorbidity burdenLowHigh
      Life expectancyLongShort
      Hypoglycemia riskLowHigh
      Hypoglycemia awarenessPresentImpaired
      Patient motivation/preference for treatment intensity/supportHighly motivated/available supportLow motivation/limited support
      DKD, diabetic kidney disease; HbA1c, glycated hemoglobin.

      Glycemic Monitoring

      The recommended biomarker for long-term monitoring of glycemia is HbA1c, with several important caveats to keep in mind. The HbA1c value may be decreased by factors that reduce the erythrocyte life span and are frequently present in patients with more advanced CKD, such as in the presence of anemia, after blood transfusion, and during the use of erythrocyte-stimulating agents or iron replacement therapy.
      • Galindo R.J.
      • Beck R.W.
      • Scioscia M.F.
      • Umpierrez G.E.
      • Tuttle K.R.
      Glycemic monitoring and management in advanced chronic kidney disease.
      These factors can decrease the precision and accuracy of HbA1c measurements in advanced CKD, particularly in patients undergoing dialysis.
      • Little R.R.
      • Rohlfing C.L.
      • Tennill A.L.
      • et al.
      Measurement of Hba1c in patients with chronic renal failure.
      Conversely, in later stages of DKD, levels of HbA1c may be falsely increased by metabolic acidosis, carbamylation, and advanced glycation end-product formation.
      • Galindo R.J.
      • Beck R.W.
      • Scioscia M.F.
      • Umpierrez G.E.
      • Tuttle K.R.
      Glycemic monitoring and management in advanced chronic kidney disease.
      ,
      • Little R.R.
      • Rohlfing C.L.
      • Tennill A.L.
      • et al.
      Measurement of Hba1c in patients with chronic renal failure.
      In these patients and in individuals undergoing hemodialysis, for whom the reliability of the HbA1c measurements is uncertain, self-monitoring of blood glucose concentration or continuous monitoring of glucose level is recommended to inform daily treatment decisions.
      Kidney Disease: Improving Global Outcomes Diabetes Work Group
      KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease.

      Antihyperglycemic Therapeutic Options

      The 2022 ADA standards of care specify that in individuals with or at high risk for ASCVD, heart failure, or kidney disease, SGLT2 inhibitors or GLP-1 RAs can be used as first line-therapy with and without metformin.
      • Draznin B.
      • Aroda V.R.
      • Bakris G.
      • et al.
      American Diabetes Association Professional Practice Committee
      11. Chronic kidney disease and risk management: standards of medical care in diabetes—2022.
      ,
      American Diabetes Association
      6. Glycemic targets: standards of medical care in diabetes—2022.
      Although SGLT2 inhibitors were initially developed as antihyperglycemic agents, at this point they are recommended for most patients with type 2 diabetes and eGFR below 60 mL/min per 1.73 m2 without albuminuria and for those with albuminuria of 200 mg/g or higher independent of the need for HbA1c lowering or individualized HbA1c target.
      • Draznin B.
      • Aroda V.R.
      • Bakris G.
      • et al.
      American Diabetes Association Professional Practice Committee
      11. Chronic kidney disease and risk management: standards of medical care in diabetes—2022.
      The GLP-1 RAs with proven CV benefits (long-acting GLP-1 RAs) can be used interchangeably with SGLT2 inhibitors in patients with eGFR below 60 mL/min per 1.73 m2 or in those with albuminuria who are intolerant of SGLT2 inhibitors.
      • Draznin B.
      • Aroda V.R.
      • Bakris G.
      • et al.
      American Diabetes Association Professional Practice Committee
      11. Chronic kidney disease and risk management: standards of medical care in diabetes—2022.
      The 2022 KDIGO guideline recommendations differ from the 2022 ADA guidance as the 2022 KDIGO guideline recommends the use of SGLT2 inhibitors in all patients with eGFR above 20 mL/min per 1.73 m2 independent of the presence of albuminuria. The GLP-1 RAs with proven CVD benefits can be used if SGLT2 inhibitors are not tolerated or are contraindicated.
      Kidney Disease: Improving Global Outcomes Diabetes Work Group
      KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease.
      The decision may be further informed by consideration of the individual preferences of the patient and balancing the risk of possible adverse effects with the risk of DKD progression.
      Kidney Disease: Improving Global Outcomes Diabetes Work Group
      KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease.
      If additional therapy is required for glycemic management, a GLP-1 RA is generally preferred.
      Kidney Disease: Improving Global Outcomes Diabetes Work Group
      KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease.
      The GLP-1 RAs with proven CVD benefit are the preferred choice for patients with type 2 diabetes and eGFR of 2 mL/min per 1.73 m2 or lower or UACR of 30 mg/g or higher (no dosage adjustments required), with existing or high risk of ASCVD, or in the presence of metabolic risk factors such as poorly controlled type 2 diabetes and obesity (Table 3
      Byetta (exenatide)
      Prescribing information. AstraZeneca.
      Bydureon BCise (exenatide extended-release) suspension autoinjector. Prescribing information. AstraZeneca.
      Adlyxin (lixisenatide) injection, for subcutaneous use. Highlights of prescribing information. Sanofi-Aventis U.S. LLC.
      Victoza (liraglutide) injection, for subcutaneous use. Highlights of prescribing information. Novo Nordisk A/S.
      Trulicity (dulaglutide) injection, for subcutaneous use. Highlights of prescribing information. Eli Lilly and Company.
      Ozempic (semaglutide) injection, for subcutaneous use. Highlights of prescribing information. Novo Nordisk.
      Jardiance (empagliflozin tablets), for oral use. Highlights of prescribing information. Boehringer Ingelheim Pharmaceuticals Inc.
      • Tantibanchachai C.
      US Food and Drug Administration
      FDA approves treatment for chronic kidney disease. Approval is first to cover many causes of disease.
      Farxiga (dapagliflozin) tablets, for oral use. Highlights of prescribing information. AstraZeneca Pharmaceuticals LP.
      Invokana (canagliflozin) tablets, for oral use. Highlights of prescribing information. Janssen Pharmaceutical Companies.
      ; Figure 2
      American Diabetes Association
      9. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes—2022.
      ,
      • 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).
      ).
      Kidney Disease: Improving Global Outcomes Diabetes Work Group
      KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease.
      ,
      • Winocour P.H.
      • Moore-Haines K.
      • Sullivan K.
      • Currie A.
      • Solomon A.
      • Hardy D.
      Holistic review of people with diabetes and chronic kidney disease reveals important multimorbidity and unmet clinical need: the ENHIDE diabetes renal telehealth pilot study.
      ,
      Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure Work Group
      KDIGO 2021 Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease.
      ,
      • Garber A.J.
      • Handelsman Y.
      • Grunberger G.
      • et al.
      Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm—2020 executive summary.
      ,
      American Diabetes Association
      9. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes—2022.
      ,
      • Li J.
      • Albajrami O.
      • Zhuo M.
      • Hawley C.E.
      • Paik J.M.
      Decision algorithm for prescribing SGLT2 inhibitors and GLP-1 receptor agonists for diabetic kidney disease.
      Furthermore, semaglutide is recommended as an effective therapy for weight management in people with type 2 diabetes.
      • Draznin B.
      • Aroda V.R.
      • Bakris G.
      • et al.
      American Diabetes Association Professional Practice Committee
      11. Chronic kidney disease and risk management: standards of medical care in diabetes—2022.
      Patients should be monitored for rare but serious possible adverse effects mentioned later. In addition, patients should receive advice on symptom recognition and mitigating strategies.
      Table 3Approved Indications and Recommended Kidney Dose Adjustments for GLP-1 RAs and SGLT2 Inhibitors in the United States
      BMI, body mass index; CKD, chronic kidney disease; CrCl, creatinine clearance (mL/min per 1.73 m2); CV, cardiovascular; CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate (mL/min per 1.73 m2); GLP-1 RA, glucagon-like peptide 1 receptor agonist; HF, heart failure; HFrEF, heart failure with reduced ejection fraction; MI, myocardial infarction; NYHA, New York Heart Association; SGLT2, sodium-glucose cotransporter 2; T2D, type 2 diabetes.
      AgentRoute and frequency of administrationApproved indicationsGeneral recommended dosing for glycemic controlRecommended kidney dose adjustment
      GLP-1 RAs
      Exenatide
      Byetta (exenatide)
      Prescribing information. AstraZeneca.
      Subcutaneous injection; twice dailyGlucose loweringInitially, 5 μg twice daily within the 60-minute period before the morning and evening meals

      Can increase to 10 μg twice daily after 1 month of therapy, based on clinical response
      Not recommended for patients with CrCl <30; caution recommended when initiating or escalating the dose in patients with CrCl 30-50
      Exenatide XR
      Bydureon BCise (exenatide extended-release) suspension autoinjector. Prescribing information. AstraZeneca.
      Subcutaneous injection; once weeklyGlucose lowering2 mg once weekly at any time of dayNot recommended for patients with eGFR <45 or with kidney failure
      Lixisenatide
      Adlyxin (lixisenatide) injection, for subcutaneous use. Highlights of prescribing information. Sanofi-Aventis U.S. LLC.
      Subcutaneous injection; once dailyGlucose loweringInitially, 10 μg once daily within the 60-minute period before the first meal of the day; on day 15, increase to 20 μg once dailyNot recommended for patients with CrCl <15
      Liraglutide
      Victoza (liraglutide) injection, for subcutaneous use. Highlights of prescribing information. Novo Nordisk A/S.
      Subcutaneous injection; once dailyGlucose lowering

      To reduce risk for MI, stroke, and CV death in adults with T2D who have established CVD

      Weight management among obese patients (BMI >30 kg/m2) aged >12 years
      Initially, 0.6 mg once daily at any time of day; after 1 week of 0.6-mg dose, increase to 1.2-1.8 mg once daily

      Obesity dose 3 mg once daily
      No dosage adjustments required
      Dulaglutide
      Trulicity (dulaglutide) injection, for subcutaneous use. Highlights of prescribing information. Eli Lilly and Company.
      Subcutaneous injection; once weeklyGlucose lowering

      To reduce risk of CV death, nonfatal MI, or nonfatal stroke in adults with T2D with CVD or with multiple CV risk factors
      Initially, 0.75 mg once weekly at any time of day; if additional glycemic control is required, can increase to 1.5 mg once weeklyNo dosage adjustments required
      Semaglutide
      Ozempic (semaglutide) injection, for subcutaneous use. Highlights of prescribing information. Novo Nordisk.
      Subcutaneous injection; once weeklyGlucose lowering

      Weight management among adult patients with BMI >30 kg/m2 or BMI >27 kg/m2 with at least one weight-related comorbidity (hypertension, high cholesterol level)
      Initially, 0.25 mg once weekly at any time of day; after 4 weeks on 0.25-mg dose, increase to 0.5 mg once weekly; if additional glycemic control is required, can increase to 1 mg once weekly after ≥4 weeks of treatment with the 0.5-mg dose

      Weight management dose 2.4 mg weekly
      No dosage adjustments required
      Oral; once dailyGlucose loweringInitially, 3 mg once daily at least 30 minutes before intake of first food, fluid, or other oral medications of the day; to be taken with no more than 120 mL of plain water only

      After 30 days on the 3-mg dose, increase to 7 mg once daily; if additional glycemic control is required, can increase to 14 mg once daily after ≥30 days of treatment with the 7-mg dose
      No dosage adjustments required
      SGLT2 inhibitors
      Empagliflozin
      Jardiance (empagliflozin tablets), for oral use. Highlights of prescribing information. Boehringer Ingelheim Pharmaceuticals Inc.
      Glucose-lowering effect blunted with reduced kidney function.
      Oral; once dailyGlucose lowering

      Reduce risk of CV death in patients with T2D and CVD

      Reduce risk of CV death plus hospitalization for HF in adults with HFrEF
      10 mg, may titrate up to 25 mg if neededNot recommended for glucose lowering in T2D patients with eGFR <30

      Data are insufficient to provide a dosing recommendation in patients with T2D and established CVD and eGFR <30 or who have HFrEF and eGFR <20

      Contraindicated in dialysis
      Dapagliflozin
      • Tantibanchachai C.
      US Food and Drug Administration
      FDA approves treatment for chronic kidney disease. Approval is first to cover many causes of disease.
      ,
      Farxiga (dapagliflozin) tablets, for oral use. Highlights of prescribing information. AstraZeneca Pharmaceuticals LP.
      Glucose-lowering effect blunted with reduced kidney function.
      Oral; once dailyGlucose lowering

      Risk reduction of sustained eGFR decline, kidney failure, CV death, and hospitalization for HF in adults with CKD

      Risk reduction of CV death and hospitalization for HF in adults with HFrEF (NYHA class II-IV)

      Risk reduction of hospitalization for HF in adults with T2D and established CVD or multiple CV risk factors
      5 mg, may titrate up to 10 mg if neededNot recommended for glucose lowering in T2D patients with eGFR <45

      Use for HF or CKD indications eGFR 25 to <45: 10 mg

      If eGFR <25, initiation not recommended; may continue 10 mg in patients with HF and CKD

      Contraindicated in dialysis
      Canagliflozin
      Invokana (canagliflozin) tablets, for oral use. Highlights of prescribing information. Janssen Pharmaceutical Companies.
      Glucose-lowering effect blunted with reduced kidney function.
      Oral; once dailyGlucose lowering

      Reduce risk of kidney failure, doubling of serum creatinine, CV death, and hospitalization for HF in adults with T2D and DKD with albuminuria >300 mg/d

      Reduce risk of CV death, nonfatal MI, and stroke in adults with T2D and established CVD
      100 mg before first meal, may titrate to 300 mg if neededNot recommended for glucose lowering in T2D patients with eGFR <30 eGFR ≥60: no dosage adjustment necessary

      eGFR 30 to <60: 100 mg/d

      eGFR <30 with albuminuria >300 mg/d: 100 mg/d

      eGFR <30 with no albuminuria: initiation not recommended
      a BMI, body mass index; CKD, chronic kidney disease; CrCl, creatinine clearance (mL/min per 1.73 m2); CV, cardiovascular; CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate (mL/min per 1.73 m2); GLP-1 RA, glucagon-like peptide 1 receptor agonist; HF, heart failure; HFrEF, heart failure with reduced ejection fraction; MI, myocardial infarction; NYHA, New York Heart Association; SGLT2, sodium-glucose cotransporter 2; T2D, type 2 diabetes.
      b Glucose-lowering effect blunted with reduced kidney function.
      Figure thumbnail gr2
      Figure 2Algorithm of glucose-lowering therapy for cardiorenal benefit.
      Kidney Disease: Improving Global Outcomes Diabetes Work Group
      KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease.
      ,
      American Diabetes Association
      9. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes—2022.
      ,
      • 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).
      ,

      Vaduganathan M, Docherty KF, Claggett BL, et al. SGLT2 inhibitors in patients with heart failure: a comprehensive meta-analysis of five randomised controlled trials. Lancet. Online ahead of print. DOI:10.11016/S0140-6736(22)01429-5.

      ASCVD, atherosclerotic cardiovascular disease; BMI, body mass index; CKD, chronic kidney disease; CV, cardiovascular; eGFR, estimated glomerular filtration rate; GLP-1 RA, glucagon-like peptide 1 receptor agonist; HbA1c, glycated hemoglobin; LVEF, left ventricular ejection fraction; LVH, left ventricular hypertrophy; PAD, peripheral artery disease; SGLT2, sodium-glucose cotransporter 2.

      Blood Pressure Control

      The 2022 ADA standard of medical care in diabetes recommends a target blood pressure below 140/90 mm Hg for patients with 10-year ASCVD risk of less than 15%. For patients at higher risk including existing ASCVD, 10-year ASCVD risk of 15% or higher, and mild to moderate albuminuria (UACR >30 to 300 mg/d), a target blood pressure below 130/80 mm Hg is appropriate if it can be achieved safely.
      • Draznin B.
      • Aroda V.R.
      • Bakris G.
      • et al.
      American Diabetes Association Professional Practice Committee
      11. Chronic kidney disease and risk management: standards of medical care in diabetes—2022.
      The 2021 KDIGO guideline recommended a blood pressure target that is lower. Specifically, for patients with hypertension and CKD, KDIGO recommends systolic blood pressure below 120 mm Hg, when tolerated.
      Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure Work Group
      KDIGO 2021 Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease.
      To achieve reductions in albuminuria development, DKD progression, and risk of kidney failure in patients with hypertension and mild to moderate (UACR of 30 to 300 mg/d) or severe albuminuria (UACR >300 mg/d), both KDIGO and ADA endorsed the initiation and subsequent up-titration to maximally tolerated doses of ACEIs and ARBs.
      Kidney Disease: Improving Global Outcomes Diabetes Work Group
      KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease.
      ,
      • Draznin B.
      • Aroda V.R.
      • Bakris G.
      • et al.
      American Diabetes Association Professional Practice Committee
      11. Chronic kidney disease and risk management: standards of medical care in diabetes—2022.
      In nonalbuminuric DKD patients, ACEIs and ARBs are not superior to other antihypertensive agents in slowing the progression of kidney disease. Importantly, they can be used as first-line therapy in patients with eGFR below 60 mL/min per 1.73 m2 and CV heart disease and may be considered in patients with proteinuria and normal blood pressure to ameliorate proteinuria (Table 1
      Kidney Disease: Improving Global Outcomes Diabetes Work Group
      KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease.
      ). The combination ACEI plus ARB therapy, however, is not recommended because of the lack of additive benefit and increased risks for hyperkalemia and acute kidney injury.
      Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure Work Group
      KDIGO 2021 Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease.
      The recently approved nonsteroidal mineralocorticoid receptor antagonist finerenone has lower rates of hyperkalemia compared with the steroidal mineralocorticoid receptor antagonists (eg, spironolactone, eplerenone).
      • Agarwal R.
      • Kolkhof P.
      • Bakris G.
      • et al.
      Steroidal and non-steroidal mineralocorticoid receptor antagonists in cardiorenal medicine.
      Finerenone is recommended to reduce progression of CKD and risk of CV events.
      • Draznin B.
      • Aroda V.R.
      • Bakris G.
      • et al.
      American Diabetes Association Professional Practice Committee
      11. Chronic kidney disease and risk management: standards of medical care in diabetes—2022.

      Lipid Management

      In 1998, the National Kidney Foundation Task Force on Cardiovascular Disease recommended that CKD patients be considered in the “highest risk group” for subsequent CV events.
      • Levey A.S.
      • Beto J.A.
      • Coronado B.E.
      • et al.
      Controlling the epidemic of cardiovascular disease in chronic renal disease: what do we know? What do we need to learn? Where do we go from here? National Kidney Foundation Task Force on Cardiovascular Disease.
      The landmark Study of Heart and Renal Protection showed a significant decrease in atherosclerotic events with simvastatin and ezetimibe compared with placebo in dialysis-dependent and non–dialysis-dependent patients and helped shape the KDIGO clinical practice guidelines for lipid management in CKD patients.
      Sharp Collaborative Group
      Study of Heart and Renal Protection (SHARP): randomized trial to assess the effects of lowering low-density lipoprotein cholesterol among 9,438 patients with chronic kidney disease.
      ,
      Kidney Disease: Improving Global Outcomes (KDIGO) Lipid Work Group
      KDIGO clinical practice guideline for lipid management in chronic kidney disease. Chapter 2: pharmacological cholesterol-lowering treatment in adults.
      Therefore, KDIGO recommends that at the time of CKD diagnosis, all adults with diabetes should have a lipid profile (total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides).
      Kidney Disease: Improving Global Outcomes (KDIGO) Lipid Work Group
      KDIGO clinical practice guideline for lipid management in chronic kidney disease. Chapter 2: pharmacological cholesterol-lowering treatment in adults.
      All adults aged 18 to 49 years not treated with long-term dialysis or kidney transplant should be treated with statin, and those 50 years of age and older should be treated with statin or statin/ezetimibe combination. Follow-up measurement of lipid levels after starting of a pharmacologic agent is not required for most patients. It could be considered to assess compliance with pharmacologic therapy. Because of concerns of increased toxicity, CKD-specific lipid management guidelines suggest using dose reduction of statins for individuals with an eGFR below 60 mL/min per 1.73 m2.
      Kidney Disease: Improving Global Outcomes (KDIGO) Lipid Work Group
      KDIGO clinical practice guideline for lipid management in chronic kidney disease. Chapter 2: pharmacological cholesterol-lowering treatment in adults.
      Unadjusted dosing used in the general population, including a high-intensity statin dosing, could be considered for individuals with eGFR of 45 to 59 mL/min per 1.73 m2 with acute coronary syndrome. In this scenario, unadjusted dosing could be considered with even lower eGFRs unless there are significant drug interactions with concomitant medications.
      • Sarnak M.J.
      • Bloom R.
      • Muntner P.
      • et al.
      KDOQI US commentary on the 2013 KDIGO clinical practice guideline for lipid management in CKD.

      Strategies to Overcome Key Clinical Concerns

      In view of the benefits of treatment with SGLT2 inhibitors and GLP-1 RAs, their incorporation into the clinical care of patients with type 2 diabetes and DKD is strongly encouraged.
      Kidney Disease: Improving Global Outcomes Diabetes Work Group
      KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease.
      ,
      • Tuttle K.R.
      • Brosius 3rd, F.C.
      • Cavender M.A.
      • et al.
      SGLT2 inhibition for CKD and cardiovascular disease in type 2 diabetes: report of a scientific workshop sponsored by the National Kidney Foundation.
      ,
      • Draznin B.
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      • Bakris G.
      • et al.
      American Diabetes Association Professional Practice Committee
      11. Chronic kidney disease and risk management: standards of medical care in diabetes—2022.
      ,
      • Garber A.J.
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      • et al.
      Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm—2020 executive summary.
      ,
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      • et al.
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      ,
      • Das S.R.
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      • et al.
      2020 Expert consensus decision pathway on novel therapies for cardiovascular risk reduction in patients with type 2 diabetes: a report of the American College of Cardiology Solution Set Oversight Committee.
      ,
      • Rangaswami J.
      • Bhalla V.
      • de Boer I.H.
      • et al.
      Cardiorenal protection with the newer antidiabetic agents in patients with diabetes and chronic kidney disease: a scientific statement from the American Heart Association.
      The existence of multiple clinical with similar yet not identical recommendations, compounded by the high cost and inconsistent insurance coverage may be contributing to the slow adoption of the new recommendations. Furthermore, concerns about the use of SGLT2 inhibitors, in particular with respect to possible adverse effects, such as euglycemic diabetic ketoacidosis and the risk of gangrene and genital fungal infections, may account for the restrained uptake of SGLT2 inhibitors in clinical practice.
      • Tuttle K.R.
      • Brosius 3rd, F.C.
      • Cavender M.A.
      • et al.
      SGLT2 inhibition for CKD and cardiovascular disease in type 2 diabetes: report of a scientific workshop sponsored by the National Kidney Foundation.
      ,
      • Li J.
      • Albajrami O.
      • Zhuo M.
      • Hawley C.E.
      • Paik J.M.
      Decision algorithm for prescribing SGLT2 inhibitors and GLP-1 receptor agonists for diabetic kidney disease.
      ,
      • Schernthaner G.
      • Shehadeh N.
      • Ametov A.S.
      • et al.
      Worldwide inertia to the use of cardiorenal protective glucose-lowering drugs (SGLT2i and GLP-1 RA) in high-risk patients with type 2 diabetes.
      Similarly, limited experience of primary care providers with GLP-1 RAs and concerns about tolerability, in particular gastrointestinal adverse effects, have contributed to slow uptake of these agents.
      • Schernthaner G.
      • Shehadeh N.
      • Ametov A.S.
      • et al.
      Worldwide inertia to the use of cardiorenal protective glucose-lowering drugs (SGLT2i and GLP-1 RA) in high-risk patients with type 2 diabetes.
      Discussion of the occurrence of adverse effects and strategies to mitigate them can assist clinicians and patients in balancing the risks and benefits of different treatment options, which are summarized here.

      SGLT2 Inhibitors

      Clinical studies with SGLT2 inhibitors have indicated that these agents are associated with an initial decrease in eGFR of 3 to 5 mL/min per 1.73 m2 in patients with type 2 diabetes and baseline eGFR above 30 mL/min per 1.73 m2.
      • Nespoux J.
      • Vallon V.
      SGLT2 inhibition and kidney protection.
      ,
      • Kraus B.J.
      • Weir M.R.
      • Bakris G.L.
      • et al.
      Characterization and implications of the initial estimated glomerular filtration rate 'dip' upon sodium-glucose cotransporter-2 inhibition with empagliflozin in the EMPA-REG OUTCOME trial.
      However, clinicians should be aware that after the initial “eGFR dip,” kidney function will generally return toward baseline in the following weeks and remain stable during SGLT2 inhibitor therapy or until drug discontinuation.
      • Nespoux J.
      • Vallon V.
      SGLT2 inhibition and kidney protection.
      Among more than 4000 participants of the CREDENCE trial, the initial decline in eGFR (>10% or <10%, and even >30%) had no influence on the subsequent course of eGFR, except in those with eGFR of 45 to 59 mL/min per 1.73 m2, in whom the initial dip was associated with a slower decline of eGFR.
      • Oshima M.
      • Jardine M.J.
      • Agarwal R.
      • et al.
      Insights from CREDENCE trial indicate an acute drop in estimated glomerular filtration rate during treatment with canagliflozin with implications for clinical practice.
      In an analysis of 6700 participants enrolled in the EMPA-REG OUTCOME trial, a decrease of more than 10% from baseline eGFR was found to be associated with more advanced DKD and diuretic use and did not raise safety concerns or have an impact on CV or kidney outcomes.
      • Kraus B.J.
      • Weir M.R.
      • Bakris G.L.
      • et al.
      Characterization and implications of the initial estimated glomerular filtration rate 'dip' upon sodium-glucose cotransporter-2 inhibition with empagliflozin in the EMPA-REG OUTCOME trial.
      Thus, the decline in eGFR is not a reason to discontinue treatment.
      Kidney Disease: Improving Global Outcomes Diabetes Work Group
      KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease.
      One of the more common adverse effects of SGLT2 inhibitor therapy is the development of genital fungal infections, occurring more frequently in women than in men (3% to 7% vs 2% to 4%, respectively, vs <2% in nonusers).
      • Fitchett D.
      A safety update on sodium glucose co-transporter 2 inhibitors.
      The risk of this event can be reduced by counseling patients on the practice of hygiene measures, including daily rinsing of the genital area after micturition and at bedtime.
      • Tuttle K.R.
      • Brosius 3rd, F.C.
      • Cavender M.A.
      • et al.
      SGLT2 inhibition for CKD and cardiovascular disease in type 2 diabetes: report of a scientific workshop sponsored by the National Kidney Foundation.
      Another common concern with the use of SGLT2 inhibitors is the development of volume depletion and hypovolemia due to their diuretic action, particularly among patients receiving concurrent diuretic therapy. However, it is not usually necessary to stop or to alter diuretic therapy with initiation of SGLT2 inhibitors, although monitoring of electrolyte levels is advised in adjusting the dose of diuretic or antihypertensive agents.
      • Tuttle K.R.
      • Brosius 3rd, F.C.
      • Cavender M.A.
      • et al.
      SGLT2 inhibition for CKD and cardiovascular disease in type 2 diabetes: report of a scientific workshop sponsored by the National Kidney Foundation.
      Furthermore, the risk of volume depletion can be minimized by pausing SGLT2 inhibitor therapy during periods of prolonged fasting, illness, or other sources of stress.
      • Tuttle K.R.
      • Brosius 3rd, F.C.
      • Cavender M.A.
      • et al.
      SGLT2 inhibition for CKD and cardiovascular disease in type 2 diabetes: report of a scientific workshop sponsored by the National Kidney Foundation.
      Alternatively, proactive reduction of diuretic therapy and monitoring for volume depletion can also help avoid an acute fall in eGFR.
      • Li J.
      • Albajrami O.
      • Zhuo M.
      • Hawley C.E.
      • Paik J.M.
      Decision algorithm for prescribing SGLT2 inhibitors and GLP-1 receptor agonists for diabetic kidney disease.
      In addition, home blood pressure monitoring may facilitate changes in diuretic dosing.
      Diabetic ketoacidosis is a rare but potentially serious adverse effect associated with SGLT2 inhibitor therapy that occurs with a minimal or absent increase in blood glucose concentration.
      • Palmer B.F.
      • Clegg D.J.
      Euglycemic ketoacidosis as a complication of SGLT2 inhibitor therapy.
      It is thought to be due to increased oxidation of fatty acids combined with reduced insulin secretion and generally occurs in patients with long-standing type 2 diabetes who are receiving insulin therapy.
      • Palmer B.F.
      • Clegg D.J.
      Euglycemic ketoacidosis as a complication of SGLT2 inhibitor therapy.
      Factors that can trigger diabetic ketoacidosis include intercurrent illness, reduced food and fluid intake, reduced insulin doses, and alcohol consumption.
      • Rosenstock J.
      • Ferrannini E.
      Euglycemic diabetic ketoacidosis: a predictable, detectable, and preventable safety concern with SGLT2 inhibitors.
      Clinicians and patients should also be aware that diabetic ketoacidosis may be manifested with normal or mildly elevated plasma glucose concentration (<200 mg/dL; “euglycemic diabetic ketoacidosis”) and nonspecific symptoms.
      • Palmer B.F.
      • Clegg D.J.
      Euglycemic ketoacidosis as a complication of SGLT2 inhibitor therapy.
      Therefore, the risk of this adverse outcome can be reduced by raising awareness and counseling patients on the potential triggers, advising them to seek immediate medical attention if symptoms develop (eg, malaise, nausea, vomiting, abdominal pain).
      • Zala A.
      • Maple-Brown L.J.
      • Shaw J.E.
      • Hare M.J.
      Current evidence and practical guidance for the use of sodium-glucose co-transporter-2 inhibitors in type 2 diabetes.
      An important consideration is discontinuation of the SGLT2 inhibitor 3 days before (for canagliflozin, dapagliflozin, and empagliflozin; or 4 days for ertugliflozin) any elective or anticipated invasive procedures.
      US Food and Drug Administration
      FDA Drug Safety Communication: FDA revises warnings regarding use of the diabetes medicine metformin in certain patients with reduced kidney function.
      Another rare but serious adverse effect is Fournier gangrene, a type of necrotizing fasciitis that affects the external genitalia and perineum.
      • Rad J.
      • Foreman J.
      Fournier gangrene
      StatPearls.
      This occurs more commonly in men than in women and has been reported in postmarket safety reports with a frequency of around 1 in 10,000 patients.
      • Dave C.V.
      • Schneeweiss S.
      • Patorno E.
      Association of sodium-glucose cotransporter 2 inhibitor treatment with risk of hospitalization for Fournier gangrene among men.
      Clinicians should retain a high index of suspicion for this rare adverse event and advise patients to seek urgent medical advice in the presence of a severe or worsening genital infection.
      Identification of another possible rare adverse event with SGLT2 inhibitor therapy has followed the observation of an increased risk of lower extremity amputation (6.3 vs 3.4 per 1000 person-years) and fractures (15.4 vs 11.9 per 1000 person-years) in a clinical trial with canagliflozin.
      • Neal B.
      • Perkovic V.
      • Mahaffey K.W.
      • et al.
      Canagliflozin and cardiovascular and renal events in type 2 diabetes.
      It is unclear whether this is a chance finding because higher risks of amputation and fractures have not been observed with 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.
      ,
      • 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.
      In addition to potential adverse events, an added barrier to the use of SGLT2 inhibitors can be their relatively high cost. However, the cost of treatment should be balanced against the significant savings achieved by reduction in CKD progression. A United Kingdom–based modeling study, based on the heart failure subpopulation of the EMPA-REG OUTCOME study, showed that adding empagliflozin to standard of care for patients with type 2 diabetes and heart failure would result in longer average life and overall health care savings and an overall increase in average life expectancy (by 1.2 years).
      • Reifsnider O.S.
      • Kansal A.R.
      • Franke J.
      • et al.
      Cost-effectiveness of empagliflozin in the UK in an EMPA-REG OUTCOME subgroup with type 2 diabetes and heart failure.

      GLP-1 RAs

      Delayed gastric emptying, due to the same mechanism that results in the robust postprandial antihyperglycemic effect of this class of medications, underlies the most common adverse effects of GLP-1 RAs of nausea, vomiting, and diarrhea.
      • Edwards C.M.
      • Stanley S.A.
      • Davis R.
      • et al.
      Exendin-4 reduces fasting and postprandial glucose and decreases energy intake in healthy volunteers.
      The risk of these effects may be reduced by starting treatment at the lowest possible dose and increasing the dose during several weeks.
      • Li J.
      • Albajrami O.
      • Zhuo M.
      • Hawley C.E.
      • Paik J.M.
      Decision algorithm for prescribing SGLT2 inhibitors and GLP-1 receptor agonists for diabetic kidney disease.
      Furthermore, patients’ adherence can be improved by advising that these effects are generally self-limited after 2 to 4 weeks of therapy. The GLP-1 RAs can also cause stimulation of the sympathetic nervous system, leading to an increase in heart rate, although no harmful effect of this increase has been reported to date.
      • Trujillo J.
      Safety and tolerability of once-weekly GLP-1 receptor agonists in type 2 diabetes.
      An increased risk of biliary tract–related events has been reported with liraglutide.
      • Nauck M.A.
      • Muus Ghorbani M.L.
      • Kreiner E.
      • Saevereid H.A.
      • Buse J.B.
      LEADER Publication Committee on behalf of the LEADER Trial Investigators
      Effects of liraglutide compared with placebo on events of acute gallbladder or biliary disease in patients with type 2 diabetes at high risk for cardiovascular events in the LEADER randomized trial.
      As a consequence, GLP-1 RAs should be used with caution in patients with a history of cholelithiasis.
      • Li J.
      • Albajrami O.
      • Zhuo M.
      • Hawley C.E.
      • Paik J.M.
      Decision algorithm for prescribing SGLT2 inhibitors and GLP-1 receptor agonists for diabetic kidney disease.
      In addition, concerns have been raised about a risk of pancreatitis with GLP-1 RA therapy, although the risk of this event appears to be low (≤1%).
      • Trujillo J.
      Safety and tolerability of once-weekly GLP-1 receptor agonists in type 2 diabetes.
      Nonetheless, GLP-1 RAs should be used cautiously or avoided in patients with a history of pancreatitis.
      • Garber A.J.
      • Handelsman Y.
      • Grunberger G.
      • et al.
      Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm—2020 executive summary.
      In animal studies, GLP-1 RAs have been linked with the development of medullary thyroid cancer.
      • Trujillo J.
      Safety and tolerability of once-weekly GLP-1 receptor agonists in type 2 diabetes.
      It is unclear whether GLP-1 RAs cause medullary thyroid cancer in humans, but they are contraindicated in patients with a medical history or family history of this cancer.
      Byetta (exenatide)
      Prescribing information. AstraZeneca.
      Bydureon BCise (exenatide extended-release) suspension autoinjector. Prescribing information. AstraZeneca.
      Adlyxin (lixisenatide) injection, for subcutaneous use. Highlights of prescribing information. Sanofi-Aventis U.S. LLC.
      ,
      Trulicity (dulaglutide) injection, for subcutaneous use. Highlights of prescribing information. Eli Lilly and Company.
      ,
      Jardiance (empagliflozin tablets), for oral use. Highlights of prescribing information. Boehringer Ingelheim Pharmaceuticals Inc.
      ,
      • Trujillo J.
      Safety and tolerability of once-weekly GLP-1 receptor agonists in type 2 diabetes.
      ,
      • Nauck M.A.
      • Muus Ghorbani M.L.
      • Kreiner E.
      • Saevereid H.A.
      • Buse J.B.
      LEADER Publication Committee on behalf of the LEADER Trial Investigators
      Effects of liraglutide compared with placebo on events of acute gallbladder or biliary disease in patients with type 2 diabetes at high risk for cardiovascular events in the LEADER randomized trial.
      After the occurrence of a single adverse event, the decision of whether to discontinue therapy should be individualized according to the clinical situation, the patient’s concerns, and the potential benefits of continued treatment.

      Conclusion

      The health consequences of DKD are severe. Early identification and initiation of interventions that can prevent progression of kidney disease combined with reduction in rates of CVD and the risk of dying are crucial. Until the introduction of SGLT2 inhibitors and GLP-1 RAs into clinical practice, even state-of-the-art standard of care resulted in a significant residual risk for DKD progression. For the very first time we have at our disposal therapeutic agents that offer promise to abate and ultimately to reverse the trend of DKD-associated morbidity and mortality and associated human suffering. Simultaneously we are increasingly becoming aware of the importance of the active role of patients in their own care, with treatment approaches tailored for their individual needs. Involving patients in shared clinical decision-making, including counseling about possible adverse effects, is key to optimizing treatment compliance with the new antihyperglycemic agents. To achieve this paradigm shift in care, we aspire to an integrated approach with a multidisciplinary focus that incorporates opportunities for primary care physicians and subspecialists, including nephrologists, cardiologists, and endocrinologists, to comanage treatments in the harmonized effort to reduce burden of disease and to improve quality of lives for patients with DKD. In parallel to medical care, there is a need for the reenergized legislative effort that will allow access to lifesaving therapies for all eligible individuals.

      Potential Competing Interests

      Dr Alicic reports consulting fees from Boehringer Ingelheim, grant research funding support from the Centers for Disease Control and Prevention, and Goldfinch Bio, the Kidney Company, and Bayer pharmaceuticals outside the submitted work. Dr Nicholas reports research funding support from the following entities: NIH/NCATS and NIH/NIMHD; UCLA DGSOM/Eli & Edythe BCRM and Stem Cell Research; Terasaki Institute of Biomedical Innovation; the Centers for Disease Control and Prevention, George Clinical Institute for Global Health, Goldfinch Bio, the Kidney Company, and Travere Pharmaceutical, Inc; and consulting fees from Janssen, Amgen, Boehringer Ingelheim/Lilly, AstraZeneca, and Bayer outside the submitted work. In addition, Dr Nicholas has a provisional patent on novel small-molecule drug to treat diabetic kidney disease.

      Acknowledgments

      Writing support was provided by Jennifer Garrett, MBBS, of Elevate Scientific Solutions, which was contracted and funded by Boehringer Ingelheim Pharmaceuticals, Inc. and Lily USA, LLC. Boehringer Ingelheim Pharmaceuticals, Inc was given the opportunity to review the manuscript for medical and scientific accuracy as well as for intellectual property considerations.
      Drs Alicic and Nicholas contributed equally to the manuscript.

      Supplemental Online Material

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      • In the Limelight: October 2022
        Mayo Clinic ProceedingsVol. 97Issue 10
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          This month’s feature highlights four articles that appear in the current issue of Mayo Clinic Proceedings. These articles are also featured on the Mayo Clinic Proceedings’ YouTube Channel ( https://youtu.be/tj-vwUQO0C0 ).
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