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Correspondence: Address to Susanne B. Nicholas, MD, MPH, PhD, David Geffen School of Medicine at University of California, Los Angeles, 7-155 Factor Bldg, 10833 LeConte Blvd, Los Angeles, CA 90095-7073.
Affiliations
David Geffen School of Medicine at University of California, Los Angeles
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.
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.
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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.
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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.
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The delivery of health care by a multidisciplinary team affords the potential to achieve truly integrated care for patients with DKD.
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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.
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.
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).
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.
Kidney Disease: Improving Global Outcomes Diabetes Work Group KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease.
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
—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.
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.
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.
Higher albuminuria levels and lower eGFR are independently and additively associated with an increased risk for cardiovascular (CV) and all-cause mortality.
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.
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.
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.
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.
Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: results from the International Diabetes Federation Diabetes Atlas, 9th edition.
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.
Lixisenatide and renal outcomes in patients with type 2 diabetes and acute coronary syndrome: an exploratory analysis of the ELIXA randomised, placebo-controlled trial.
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.
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
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
American Diabetes Association Professional Practice Committee 11. Chronic kidney disease and risk management: standards of medical care in diabetes—2022.
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 Diabetes Work Group KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Table 1Summary of International Guideline Recommendations for Monitoring of Kidney Function and Risk Factor Management in Patients with Diabetes and DKD
American Diabetes Association Professional Practice Committee 11. Chronic kidney disease and risk management: standards of medical care in diabetes—2022.
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.
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.
At 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
<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.
Kidney Disease: Improving Global Outcomes Diabetes Work Group KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease.
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.
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.
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.
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.
Kidney Disease: Improving Global Outcomes Diabetes Work Group KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease.
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.
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.
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.
). 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.
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.
Conversely, in later stages of DKD, levels of HbA1c may be falsely increased by metabolic acidosis, carbamylation, and advanced glycation end-product formation.
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.
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.
American Diabetes Association Professional Practice Committee 11. Chronic kidney disease and risk management: 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.
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.
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.
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
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.
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.
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 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
Initially, 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
Glucose 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
Glucose 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 daily
Glucose lowering
Initially, 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
Glucose-lowering effect blunted with reduced kidney function.
Oral; once daily
Glucose 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 needed
Not 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
Glucose-lowering effect blunted with reduced kidney function.
Oral; once daily
Glucose 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 needed
Not 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
Glucose-lowering effect blunted with reduced kidney function.
Oral; once daily
Glucose 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 needed
Not 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.
Kidney Disease: Improving Global Outcomes Diabetes Work Group KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease.
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.
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.
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.
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).
American Diabetes Association Professional Practice Committee 11. Chronic kidney disease and risk management: standards of medical care in diabetes—2022.
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.
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.
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.
American Diabetes Association Professional Practice Committee 11. Chronic kidney disease and risk management: standards of medical care in diabetes—2022.
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.
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.
Cardiorenal protection with the newer antidiabetic agents in patients with diabetes and chronic kidney disease: a scientific statement from the American Heart Association.
Circulation.2020; 142 (Published correction appears in Circulation. 2020;142(17):e304): e265-e286
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.
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.
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.
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.
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.
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.
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.
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).
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.
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.
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.
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.
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.
Factors that can trigger diabetic ketoacidosis include intercurrent illness, reduced food and fluid intake, reduced insulin doses, and alcohol consumption.
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.
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).
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.
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.
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.
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).
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.
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.
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.
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.
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.
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.
Nomenclature for kidney function and disease—executive summary and glossary from a Kidney Disease: Improving Global Outcomes (KDIGO) consensus conference.
Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: results from the International Diabetes Federation Diabetes Atlas, 9th edition.
Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis.
Lixisenatide and renal outcomes in patients with type 2 diabetes and acute coronary syndrome: an exploratory analysis of the ELIXA randomised, placebo-controlled trial.
KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Definition, identification, and prediction of CKD progression.
Holistic review of people with diabetes and chronic kidney disease reveals important multimorbidity and unmet clinical need: the ENHIDE diabetes renal telehealth pilot study.
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.
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).
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.
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.
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.
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.
Cardiorenal protection with the newer antidiabetic agents in patients with diabetes and chronic kidney disease: a scientific statement from the American Heart Association.
Circulation.2020; 142 (Published correction appears in Circulation. 2020;142(17):e304): e265-e286
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.
Insights from CREDENCE trial indicate an acute drop in estimated glomerular filtration rate during treatment with canagliflozin with implications for clinical practice.
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.
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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