Chronic Kidney Disease: Implications for Cardiovascular Risk and Management in Patients With Type 2 Diabetes

Key Points

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Patients with diabetes mellitus (DM) need to be regularly (e.g., annually) screened for chronic kidney disease (CKD) or have their CKD staged using assessments of glomerular filtration rate (GFR) and albuminuria.
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CKD increases the risk of coronary artery disease, but is also particularly associated with structural heart disease, heart failure, arrhythmias, and sudden cardiac death. Most patients with CKD are more likely to die from cardiovascular disease (CVD) before progressing to the need for kidney replacement therapy.
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DM increases the risk of CVD mortality at any given level of GFR or albuminuria, and CKD appears to be a cause of CVD (directly or indirectly) independent of DM status.
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Additional complications of CKD commonly include effects on blood pressure, a characteristic atherogenic dyslipidemia, dysregulated salt-water balance and calcium-phosphate homeostasis, and renal anemia. These perturbations account for some of the links between CKD and CVD.
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Meta-analyses of trials of intensive glycemic control have suggested this strategy modestly reduces the risk of coronary artery disease and importantly reduces the risk of developing or worsening of diabetic nephropathy, but there may be no effect on the risk of heart failure, and effects on the risk of kidney failure are uncertain.
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In CKD, intensive statin-based regimens are safe and should be used to maximize the benefits. A meta-analysis has shown statin-based regimens safely reduce atherosclerotic CVD risk in CKD. Intensive regimens are recommended as in moderate-to-severe CKD (e.g., eGFR < 45 mL/min/1.73 m ²) a trend to smaller risk reductions per unit reduction in low-density lipoprotein cholesterol emerges when trial data are compared to patients without CKD. It is noteworthy that there is uncertainty about benefits in patients on dialysis among whom nonatherosclerotic CVD, including heart failure and sudden cardiac death, are common.
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A meta-analysis has shown intensive blood pressure regimens reduce the risk of CVD and albuminuria, but whether this translates into a reduced risk of kidney failure has not been demonstrated.
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Large placebo-controlled trials have shown renin-angiotensin-aldosterone system inhibitors, sodium-glucose cotransporter-2 inhibitors, and the nonsteroidal mineralocorticoid receptor antagonist finerenone may all reduce the risk of both kidney failure and CVD in patients with type 2 DM and proteinuric CKD. Most recently, the glucagon-like peptide-1 receptor agonist semaglutide has been shown to not only improve glycaemic control but also reduce cardiovascular risk and slow the rate of decline of kidney function in patients with type 2 DM and proteinuric CKD. These interventions should be started early and used in combination to prevent end-organ damage.
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In patients with DM and CKD, low-dose aspirin is indicated in patients with prior atherothrombotic CVD. In patients with type 2 DM and CKD but without CVD, the balance of CVD benefits versus major bleeding risk is finely balanced.
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Patients with DM and CKD are at high risk of stroke of all types. Intensive blood pressure control reduces the stroke risk, and statin-based therapy reduces the ischemic stroke risk. However, the optimum approach to thromboprophylaxis in atrial fibrillation in severe CKD is uncertain as the bleeding risk is high, warfarin may accelerate vascular calcification, and newer anticoagulants have been understudied in patients with severe CKD.
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Partial correction of dysregulated calcium-phosphate homeostasis with 1-alpha hydroxylated vitamin D and phosphate binders is a common clinical practice in nephrology but has not been shown to reduce CVD risk (and may even increase it).
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Partial correction of anemia caused by CKD with intravenous iron and erythropoiesis-stimulating agents is also common in nephrology practice as it reduces the need for blood transfusion and improves the quality of life. However, randomized trials have not confirmed that such practices prevent the development of structural heart disease, and aiming for a “normalized” hemoglobin increases the risk of stroke. Treating anemia in CKD therefore aims for partial correction and requires careful monitoring.

Chronic kidney disease (CKD) is defined as abnormalities of kidney structure or function, present for at least 3 months, with implications for health. It has a major impact on global morbidity and mortality due to its associations both with the risk of kidney failure and cardiovascular disease (CVD). For most patients with CKD, the risk of dying from CVD exceeds that of progression to the need for kidney replacement therapy in their lifetime, and so the management of both of these risks is a cornerstone of general nephrology practice.

Diabetic kidney disease is a leading cause of CKD globally, and is particularly common in regions where the prevalence of obesity is high. Diabetes mellitus (DM) and CKD both independently increase the risk of CVD, and their coexistence is associated with high risk, which can be extreme in severe CKD (i.e., eGFR < 30 mL/min/1.72 m ²). Population data show that even mild-to-moderate CKD is associated with the risk of coronary artery disease risk, which is equivalent to someone with established atherosclerotic CVD, but structural heart disease and heart failure, central and peripheral artery disease, arrhythmias, and sudden cardiac death are particular features of CVD in CKD. This chapter provides details of internationally agreed-upon definitions and staging for CKD; introduces its epidemiology, pathology, and associated complications; and provides an evidence-based approach to the management of risk of both CVD and kidney failure for patients with both DM and CKD.

CHRONIC KIDNEY DISEASE NOMENCLATURE AND STAGING

The kidney disease improving global outcomes (KDIGO) organization has coordinated the development of clinical practice guidelines in nephrology, including comprehensive “CKD evaluation and management” and specific “diabetes management in CKD” guidelines ( www.kdigo.org ). KDIGO “controversies conferences” also facilitate resolution of key nephrology-related issues, and have tackled its complex nomenclature ( Table 25.1 ). The use of the term “kidney” rather than “renal” is encouraged, with the term “kidney disease” encompassing both acute and chronic (i.e., present for >3 months) conditions.

Table 25.1

Summary of Kidney Disease-Related Nomenclature

CONCEPT OR TERM	RELATED TERMS	DEFINITION/MEANING
Glomerular filtration rate ( GFR )	Estimated GFR ( eGFR ) Measured GFR	A specific measure of glomerular kidney function, which is a key component of CKD staging. eGFR is normalized to body surface area and estimated from blood creatinine (eGFR _Cr), cystatin C (eGFR _cys), or both (eGFR _cr-cys) using estimating formulas assuming a steady state. GFR is directly measured using time-consuming clearance methods or exogenous filtration markers in selected circumstances when precise knowledge of GFR is important (e.g., living kidney donor assessment).
Albuminuria	Urinary albumin-to-creatinine ratio ( uACR ) Albumin excretion rate Historical terms: Normoalbuminuria Microalbuminuria Macroalbuminuria	Urine dipsticks can provide semiquantitative assessments of the amount of albumin in the urine and are useful for screening and predicting risk. More specific quantification of any urinary albumin can be performed by spot or timed urine collections. A ratio of urinary albumin-to-creatinine concentrations helps account for urine concentration in a spot sample and is practical for clinical practice. A uACR < 30 mg/g (about <3 mg/mmol) is considered normoalbuminuria (A1); 30–300 mg/g (about 3–30 mg/mmol) is equivalent to an albumin excretion rate of 30–300 mg per day and historically referred to as microalbuminuria (A2); while a uACR ≥300 mg/g (about ≥30 mg/mmol) is equivalent to ≥300 mg per day and considered macroalbuminuria (A3). (Note: To formally convert a uACR from mg/g to mg/mmol, divide by 8.84.)
Proteinuria	Urinary protein-to-creatinine ratio ( uPCR ) Protein excretion rate	Proteinuria includes urinary excreted albumin and nonalbumin proteins and may be used clinically, particularly when quantifying high urinary concentrations of albumin. Formulas for converting uPCR to estimates of uACR exist.
Chronic kidney disease ( CKD )	Historical terms: Chronic renal failure or chronic renal insufficiency	CKD is defined as eGFR <60 mL/min/1.73 m ² or markers of kidney damage present for at least 3 months (with implications for health). CKD is staged using GFR, albuminuria, and diagnosis.
Kidney failure	Historical terms: End-stage kidney disease End-stage renal disease	Kidney failure refers to patients with eGFR < 15 mL/min/1.73 m ² or treated with dialysis for at least 3 months, or kidney transplantation (i.e., CKD stage G5). The suffix D denotes dialysis status, and the suffix T denotes transplant status.
Kidney replacement therapy		Treatment with a long-term dialysis modality (i.e., stage G5D) or kidney transplantation (i.e., stages G1-5T).
Acute kidney injury ( AKI )	Historical term: Acute renal failure	AKI is defined clinically as oliguria for >6 hours, a rise in serum creatinine by >0.3 mg/dL in 2 days or by >50% in 1 week (Note: To convert serum creatinine from mg/dL to μmol/L, multiply by 88.4.)
Diabetes and kidney disease	Historical terms: Diabetic kidney disease ( DKD ) Diabetic nephropathy	The term “diabetic nephropathy” has been used to refer to patients with overt proteinuria (i.e., a uACR of ≥300 mg/g) attributed to traditional diabetic pathophysiology and/or histology. The term “diabetic kidney disease” recognizes the wider spectrum of renal pathological changes that DM and associated risk factors can cause. The term “diabetes and kidney disease” is suggested by KDIGO.

The original 2012 KDIGO framework for staging CKD is based principally on both categories of glomerular filtration rate (GFR) and level of albuminuria. Although GFR can be directly measured, it is more practical to estimate GFR using equations based on serum creatinine. An estimated GFR (eGFR) of at least 60 mL/min/1.73 m ² may be considered “normal” in older adults and, in the absence of albuminuria or other evidence of kidney disease with implication for health, does not constitute CKD.

Note that estimating formulas perform best below a GFR of about 60 mL/min/1.73 m ², so directly measuring GFR (referred to as mGFR) is generally reserved for scenarios where knowledge of a precise GFR is important (e.g., planning live kidney donation or certain chemotherapy drug dosing).

A persistent decrease in eGFR below 60 mL/min/1.73 m ² (i.e., stages G3–5) is sufficient to confirm CKD. Below this level of eGFR, the risk of kidney failure and CVD both progressively increases. An eGFR persistently less than 15 mL/min/1.73 m ² is referred to as “kidney failure” (in preference to the term “end-stage kidney disease”). This is the eGFR threshold below which maintenance (i.e., long-term) kidney replacement therapy may become clinically necessary.

Historical eGFR formulas developed by the CKD-Epidemiology (CKD-EPI) collaboration took account of race because previous studies indicated a higher average serum creatinine level for the same measured GFR in Black individuals. Race is not always available when laboratories report eGFR, and older formulas were more likely to be biased in Black individuals who suffer a disproportionate burden of kidney failure. The 2021 CKD-EPI eGFR formulas have been developed without race, share the bias more equitably between races, and were recommended for immediate implementation in the United States due to their potential to improve clinical decision-making for Black Americans.

Albuminuria is an early marker of CKD. A spot urine sample measuring albumin-to-creatinine ratio is a simple method to detect albuminuria and also estimates an approximate 24-hour albumin excretion rate. It is clinically more practical than timed (e.g., 8-hour or 24-hour) urine collections. The ratio estimate relies on an assumption that urinary creatinine excretion is generally constant, enabling daily variation in urinary tonicity to be accounted for. In patients with DM, a spot albumin-to-creatinine ratio is therefore an optimum method to regularly screen for, and quantify, albuminuria (e.g., annually).

Albuminuria predicts both risk of kidney failure and CVD independently of eGFR. CKD staging therefore incorporates both GFR (G1–5) and albuminuria (A1–3) into CKD risk categories. The KDIGO heat map depicts risk using green, yellow, orange, and red to represent low, moderately high, high, and very high risk ( Fig. 25.1 ). Low-risk CKD is estimated to have a 0.04/1000 patient-years risk of kidney failure in general population data, and in the absence of important abnormalities in kidney structure, stages G1A1 and G2A1 represent normal kidneys (i.e., no CKD). Relative to the low-risk category, moderately high-, high-, and very high-risk categories (i.e., yellow, orange, and red), represent increased relative risk of kidney failure by about ~5 times, ~20 times, and ~150 times, respectively.

A table with colored risk levels shows stages of estimated glomerular filtration rate against albuminuria stages. — Fig. 25.1

The CKD heat maps are also mirrored with respect to how decreased GFR and increased albuminuria independently predict a wide range of cardiovascular diseases, including myocardial infarction, stroke, heart failure, atrial fibrillation, and peripheral arterial disease. The 2024 KDIGO Clinical Practice Guideline for the Evaluation and Management of CKD provides for full details of how their CKD heat maps can be used clinically.

An individual’s absolute risk of kidney failure is estimated using validated Kidney Failure Risk Equations which, as a minimum, include age, sex, eGFR, and uACR. Any of the eGFR formulas used in these risk prediction equations provide excellent discrimination of risk. KFRE equations could help personalize CKD monitoring and treatment, but the KDIGO risk categories/heat map provides a general guide: low-risk CKD is suggested to have annual assessments, moderately high-risk, high-risk, and very high-risk recommend at least one, two, and three to four annual assessments, respectively.

Once kidney failure develops, nephrology services generally set up intensive multidisciplinary low clearance clinic systems to provide predialysis counseling and make the necessary preparations for an organized start of kidney replacement therapy or supportive care (aiming to avoid “crash-landing” onto dialysis). Historical trends in eGFR decline predicting a need to start kidney replacement therapy, and referrals for preparations are suggested about 1 year in advance.

PREVALENCE OF CHRONIC KIDNEY DISEASE

Globally, the crude prevalence of CKD in adults is about 9% to 12%, slightly higher in women and in low- and middle-income countries. In the United States, CKD prevalence appeared to plateau between 2004 and 2012 after years of increase, and has remained stable (although the recent change to 2021 CKD-EPI eGFR formulas could have an important implication for these prevalence estimates). Survey data from 2015 to 2018 show that the prevalence of an eGFR below 60 mL/min/1.73 m ² or albuminuria (i.e., uACR > 30 mg/g) is evident in 14.4% of US adults based on a single measurement from the National Health and Nutrition Examination Survey. This 14.4% prevalence estimate included ~6.3% of adults with CKD stages G3–5 and 0.12% with kidney failure (i.e., stage G5). The prevalence of DM among surveyed participants with CKD was 33%, increasing to 47% among those with CKD stages G4–5. The prevalence of DM among individuals without CKD was 10%.

DIAGNOSIS OF DIABETIC KIDNEY DISEASE

CKD prevalence data do not distinguish between CKD caused by DM versus another cause, and in patients with DM and CKD, the etiological diagnosis of CKD is often presumed. This is because a kidney biopsy is rarely performed in patients with DM and CKD to avoid the risk of procedural bleeding and because a tissue diagnosis is unlikely to alter the management. The 2020 KDIGO Clinical Practice Guideline for Diabetes Management in CKD recognized this diagnostic limitation and avoided diabetic nephropathy and diabetic kidney disease as terms, instead referring even more nonspecifically to “patients with diabetes and CKD.”

Historically, the term “diabetic nephropathy” has been used to refer to patients with overt proteinuria (i.e., ≥300 mg per day) attributed to traditional DM pathophysiology (i.e., glomerular hyperfiltration) and/or histology (i.e., classical glomerular features). Glomerular features of diabetic nephropathy range from mild glomerular capillary basement membrane thickening through mesangial expansion to classical nodular sclerosis. The term “diabetic kidney disease” recognizes the wider spectrum of renal pathological changes that DM and associated risk factors can cause. International pathological classifications include these vascular and interstitial features: vascular changes can include large-vessel arteriosclerosis and/or arteriolar hyalinosis. Interstitial changes may include interstitial fibrosis and tubular atrophy (known as IFTA) and/or interstitial inflammation.

A clinical diagnosis of diabetic kidney disease is presumed when there has been DM present for a sufficient duration (usually at least 5 years in patients with type 1 DM) and/or there is evidence of other microvascular involvement (e.g., retinopathy, neuropathy). Features suggestive of another cause of CKD may prompt a kidney biopsy if a tissue diagnosis is likely to change the management. Reasons to consider a tissue diagnosis may include a sudden decrease in GFR; a sudden substantial increase in albuminuria with the development of nephrotic syndrome (i.e., >3.5 g proteinuria per day with hypoalbuminemia); nephritic syndrome (i.e., microscopic hematuria with hypertension, edema, and progressively decreasing GFR); or clinical features of a systemic disease which can involve the kidney and which has specific immunological or other management which generally requires histology for confirmation and/or disease staging (e.g., lupus or vasculitis). The specific primary kidney diagnosis is, however, unlikely to modify approaches to CVD risk management.

ASSOCIATIONS BETWEEN CHRONIC KIDNEY DISEASE AND RISK OF DIFFERENT TYPES OF CARDIOVASCULAR DISEASE

Below an eGFR of about 60 mL/min/1.73 m ², CVD mortality risk increases progressively with a decreasing eGFR. This has been suggested as part of the justification for the staging eGFR threshold for stage G3 and the use of “disease” in the term “CKD” (although some nephrologists disagree with the use of the term “disease” given how common an eGFR of below 60 mL/min/1.73 m ² is at older age).

Patients with DM have a higher risk of kidney failure for a given level of eGFR or albuminuria, but the shape of associations between eGFR and CVD mortality risk is the same in patients with and without DM, emphasizing the importance of CKD as a predictor or, in fact, a cause of CVD.

The CVD mortality risk in CKD results from a range of different atherosclerotic and nonatherosclerotic CVD pathologies, with sudden cardiac death a particular feature in severe CKD. The presence of CKD appears to accelerate the presentation and progression of CVD, and CVD may accelerate CKD progression. The relationships between CKD and different types of CVD are introduced below.

Coronary and Central Artery Disease in Chronic Kidney Disease

Coronary artery disease is common in CKD, partly as a result of a characteristic dyslipidemia which is similar to that observed in patients with DM. In addition to lipid deposition, calcification of atherosclerotic plaque and the vascular intima is also a feature of severe CKD, with arterial disease also accompanied by accelerated vascular media calcification. Vascular calcification is attributed to disordered calcium-phosphate metabolism, referred to as CKD-mineral bone disorder (CKD-MBD). Management of the renal dyslipidemia and CKD-MBD are discussed in more detail later in this chapter.

A meta-analysis of observational studies shows that each 30% reduction in eGFR is associated with about a 30% increase in risk of atherosclerotic CVDs. At a population level, the risk of myocardial infarction among patients with CKD and an eGFR of 45 mL/min/1.73 m ² or more is similar to that of patients with established coronary artery disease or with DM, and exceeds that risk when eGFR declines to below 45 mL/min/1.73 m ². Furthermore, the risk of death after a myocardial infarction is increased three- to fourfold in patients with CKD compared to people free of both DM and CKD, and is increased fivefold in patients with both DM and CKD.

In CKD, the initial clinical manifestation of coronary artery disease is also more likely to be a myocardial infarction than exertional angina. Like in DM, myocardial infarction is more likely to present atypically, with less than half of patients with CKD reporting chest pain. Dyspnea and non-ST elevation electrocardiographic changes are common presentations.

In CKD, abdominal aortic aneurysm (AAA) risk is increased by about 30% compared to the general population (although this may be a bidirectional relationship with AAA and associated vascular disease causing CKD, as well as CKD and its associated-metabolic disturbances potentially causing AAAs). Experts suggest the indications for elective and emergent AAA repair are the same in people with and without CKD, although the risk of procedural complications is expected to be higher in CKD.

Two moderately large trials found no important additional benefits of revascularization for renovascular disease above optimal medical therapy (perhaps because proximal arterial disease represents a marker of more general ischemic nephropathy). Rare scenarios when revascularization may be considered have been proposed, but well-meaning attempts to dilate renal artery stenoses may result in important complications, including permanent worsening of kidney function from distal cholesterol emboli. The revascularization of renal arteries should generally only be considered by experts or in a research setting.

Heart Failure in Chronic Kidney Disease

Heart failure in CKD may result from a combination of chronic pressure overload, including hypertension and increased arterial stiffness, progressive volume overload (from dysregulated sodium and water homeostasis), direct alterations in myocardial structure and function, as well as the potential for CKD to cause coronary artery disease, atrial fibrillation, and valvular disease.

A recent cohort of patients with CKD and DM found a clinical history of heart failure to be apparent in about 14%, but evidence of subclinical structural heart disease is much more common. Left ventricular hypertrophy emerges in early CKD stages and also affects children with CKD ( Fig. 25.2 ). After adjustment for confounders, CKD stages G4–5 in adults are associated with double the odds of left ventricular hypertrophy compared to individuals with an eGFR of at least 60 mL/min/1.73 m ². About one-half of adults with CKD stages G3–4 have structural abnormalities, increasing to about three-quarters by the time kidney replacement therapy becomes indicated. In children with CKD, about two-fifths with an eGFR below 30 mL/min/1.73 m ² have evidence of left ventricular hypertrophy. Cardiomyocyte death and myocardial fibrosis are also apparent in CKD, predisposing to both systolic and diastolic cardiac dysfunction.

A bar graph compares the prevalence of left ventricular hypertrophy in adults and children across five levels of estimated glomerular filtration rate. — Fig. 25.2

Valvular Disease in Chronic Kidney Disease

The risk of valvular calcification is approximately doubled in patients with CKD, with about one-quarter of patients exhibiting evidence of mitral or aortic calcification (compared to about 11% of patients with DM). Progression of calcification is also often rapid in patients with CKD, with any subsequent development of symptomatic aortic stenosis with left ventricular pressure overload contributing to heart failure risk, and any mitral valve annular calcification potentially causing incompetence resulting in volume overload and increased risk of atrial fibrillation. As many as one in five patients with CKD may have a history of atrial fibrillation. In CKD, atrial fibrillation may particularly contribute to heart failure symptoms if left ventricular hypertrophy has resulted in left ventricular filling becoming more reliant on atrial contraction.

Optimal management of valvular heart disease in CKD remains uncertain. Statin-based therapy does not appear to influence valvular heart disease progression, or indeed risk of heart failure. Although valvular calcification is associated with arterial calcification, suggesting CKD-MBD is a common pathogenic mechanism, suppressing parathyroid hormone levels with cinacalcet also does not appear to modify risk of CVD. Furthermore, surgical interventions for aortic and mitral valve disease are associated with substantially higher risk of complications and mortality in CKD. Strategies for managing atrial fibrillation in CKD are considered below.

Sudden Cardiac Death

As GFR declines below about 45 mL/min/1.73 m ², nonatherosclerotic events begin to account for a relatively larger proportion of total CVD events than atherosclerotic CVD. Arrhythmias associated with both nonatherosclerotic and atherosclerotic disease contribute to the high risk of sudden death in CKD. The hemodialysis population is an extreme phenotype of CKD, where sudden cardiac death accounts for a third of deaths. Bradyarrythmias and asystole may be common, as well as ventricular tachyarrythmias. Rapid changes in volume and electrolytes which accompany hemodialysis may contribute to the excess risk of death after longer interdialytic intervals (e.g., before the first dialysis session of the week). As already introduced, multiple predisposing factors for an arrythmogenic heart exist in predialysis CKD, including left ventricular hypertrophy and myocardial fibrosis, fluid overload, and myocardial ischemia with vascular calcification. Decreased eGFR is a predictor of intracardiac conduction defects and also arrhythmias after a myocardial infarction. Although more data are needed to assess long-term risk-benefits, recent expert opinion suggests patients with CKD should be considered for implantable cardioverter defibrillators for secondary prevention, and for primary prevention in patients with a left ventricular ejection fraction of ≤35%.

Stroke and Atrial Fibrillation in Chronic Kidney Disease

CKD is also associated with increased risk of all forms of stroke, with incident stroke risk compared to the general population increased by three- to sevenfold through CKD stages G3–5. CKD is also associated with increased stroke severity, worse stroke outcomes, and vascular cognitive impairment.

The evidence base for stroke treatment and prevention in CKD is limited, particularly in severe CKD where risk is highest. Intravenous thrombolysis administered within the first 4.5 hours after onset of an ischemic stroke results in better functional outcomes. A meta-analysis shows this to be true even in patients over the age of 80 years, when CKD is common. Guidelines suggesting thrombolysis use in eligible patients with CKD without restriction are endorsed by expert opinion, despite some potential for increased risk of symptomatic intracerebral hemorrhage.

Atrial fibrillation is common in CKD, and CKD is also associated with increased risk of thromboembolism. Algorithms for rate versus rhythm control have been proposed, with rhythm control only suggested in CKD for those who are symptomatic with short duration of atrial fibrillation, with small left atrial size and/or reversible causes, with patient choice dictating medical versus catheter ablation approaches.

There is major scope to improve thromboembolic stroke risk prediction in CKD, but based on the currently available scores, most patients with DM and CKD will have a CHA ₂ DS ₂-VASc score of ≥2 and be considered for prophylactic anticoagulation. Down to an eGFR of about 25 mL/min/1.73 m ², direct oral anticoagulants (DOACs; e.g., apixaban) have been shown to be noninferior to warfarin with respect to ischemic stroke prevention, and may reduce the risk of intracranial hemorrhage compared to warfarin. With appropriate dose reduction, some DOACs have regulatory approval to be used in CKD stage 5 (including those on dialysis). DOACs also have the benefits of reduced need for monitoring and avoiding the potential for warfarin to accelerate vascular calcification through inhibition of phosphate scavenging by the vitamin K-dependent enzyme matrix gamma-carboxyglutamate Gla protein.

Intensive blood pressure lowering and LDL-cholesterol lowering are expected to reduce ischemic stroke risk in CKD (see next section). Primary prevention of ischemic stroke with low-dose aspirin in patients with DM and CKD has not been demonstrated to be of net benefit (see section on antiplatelet therapy below).

GENERAL MANAGEMENT STRATEGIES TO LOWER THE RISK OF KIDNEY FAILURE OR CVD IN PATIENTS WITH DM AND CKD

The management of CVD risk in patients with CKD and DM considers both traditional and CKD-specific risk factors which result from the associated-metabolic disturbances (summarized in Fig. 25.3 ). In this section, we describe the evidence base for lifestyle modification, management of dyslipidemia, and intensive glycemic and blood pressure control.

A treatment flowchart outlines risk-based interventions for managing cardiovascular and kidney failure risks in type 2 diabetes with chronic kidney disease. — Fig. 25.3

Lifestyle Recommendations in Chronic Kidney Disease

A raised body mass index is independently associated with risk of CKD, and a randomized trial of behavioral interventions to promote weight loss in patients with type 2 DM appeared to reduce the risk of developing very high-risk CKD over the long term. In addition, it has been recommended that all patients with DM and CKD receive standard advice on smoking, nutrition, and exercise.

Management of Hyperglycemia in Chronic Kidney Disease

Hyperglycemia is strongly associated with the risk of mortality from CVD and kidney failure, as are higher levels of glycosylated hemoglobin (HbA1c). A meta-analysis of four large-scale trials of intensive versus standard glycemic control which includes 27,049 patients with type 2 DM by the Collaborators on Trials of Lowering Glucose (CONTROL) group has shown that the ~0.9% achieved average difference in HbA1c (lowered from 7.7% to 6.8%) over about 5 years reduced the risk of any major cardiovascular event of about 9% (hazard ratio [HR], 0.91; 95% confidence interval [CI], 0.84–0.99). This included a 15% relative risk reduction for myocardial infarction (HR, 0.85; 95% CI, 0.76–0.94), but no clear effects on risk of heart failure or stroke. Five years of intensive glycemic control also reduced the risk of kidney events, particularly the risk of developing or worsening of “diabetic nephropathy” based on measures of albuminuria. Definitive evidence that this translates into the reduced risk of kidney failure is unavailable, but personalized HbA1c glycemic targets between <6.5% (48 mmol/mol) and <8.0% (64 mmol/mol) are suggested for patients with CKD and DM, with a target <7.0% (53 mmol/mol) still recommended particularly to reduce microvascular complications, wherever possible. How these targets might be safely achieved pharmacologically while maximizing CVD benefits is introduced later in this chapter.

In CKD, HbA1c monitoring may be less reliable at eGFRs below 30 mL/min/1.73 m ² because of shortened red cell life span, and suggestions have been made to increase the use of self-monitoring or continuous glucose monitoring if trying to safely achieve tight glycemic control in such patients.

Management of Dyslipidemia in Chronic Kidney Disease

The dyslipidemia in CKD is characterized by high circulating triglycerides with increased numbers of very-low-density lipoprotein and intermediate-density lipoprotein particles, plus low levels of high-density lipoprotein cholesterol. Low-density lipoprotein (LDL) cholesterol may not be particularly elevated, but an increased proportion of small oxidized LDL particles and increased apolipoprotein B are observed.

Meta-analyses by the Cholesterol Treatment Trialists’ Collaboration of large-scale trials of statin-based therapy including 183,419 participants have shown that the relative risk of major vascular events (i.e., coronary death, nonfatal myocardial infarction, ischemic stroke, and coronary revascularization) is reduced by 21% per 1.0 mmol/L (39 mg/dL) lower LDL-cholesterol in patients with or without DM (relative risk [RR], 0.79; 95% CI, 0.77–0.81). In moderate-to-severe CKD a trend toward smaller relative reductions per unit reduction in LDL-cholesterol on major vascular events emerges, but clear benefits remain in patients not on dialysis. The high baseline vascular risk at lower eGFR means that these smaller proportion reductions translate into important absolute risk reductions. The diminution in relative risk reduction as GFR declines and the high risk of atherosclerotic CVD in CKD despite relatively normal levels of LDL-cholesterol implies that intensive LDL-cholesterol-lowering regimens are required to maximize the LDL-cholesterol reduction and confer maximum benefits. The dyslipidemia management strategy in patients with CKD and DM should be to achieve the largest possible absolute reduction in LDL-cholesterol safely.

KDIGO suggests the use of a statin in patients with DM and CKD aged 18 to 49 years and recommends a statin or statin/ezetimibe in all adults with CKD aged ≥50 years. Several once-daily statin-based regimens have been shown to be safe in large trials in severe CKD, including patients on kidney replacement therapy: atorvastatin 20 mg, rosuvastatin 10 mg, fluvastatin 40 mg (in transplant recipients), and combining simvastatin 20 mg with ezetimibe 10 mg. There remains uncertainty about the presence of any clinically meaningful benefits on the risk of CVD among patients on dialysis, and LDL-cholesterol-lowering therapy has not been shown to prevent kidney failure.

The effects of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have not been studied in dedicated trials of moderate-to-severe CKD, but 10,081 patients with DM and 4443 patients with reduced eGFR (i.e., CKD stage G3+, median eGFR 51 mL/min/173 m ²) were randomized into the 27,563 participant FOURIER placebo-controlled trial of evolocumab. A CKD subgroup analysis of FOURIER showed that evolocumab safely reduced LDL-C by 58% (below 40 mg/dL), and the overall 15% relative risk reduction on atherosclerotic CVD events (RR, 0.85; 0.79–0.92) was similar in participants with and without evidence of a decreased eGFR.

Blood Pressure Lowering in Chronic Kidney Disease

Systemic hypertension usually accompanies decreased eGFR due to a range of mechanisms. These include shared causes, such as obesity, and CKD-associated changes in vascular biology, such as increased arterial stiffness and activation of the renin-angiotensin-aldosterone system with dysregulated salt and water homeostasis.

Increased systemic blood pressure is causally linked to the risk of CVD. Meta-analyses by the Blood Pressure Lowering Treatment Trialists’ Collaboration of 152,290 participants from large trials have shown that lowering blood pressure reduces the risk of major cardiovascular events (i.e., death from CVD, nonfatal myocardial infarction, stroke, or heart failure) by about 17% per 5 mm Hg lower systolic blood pressure (RR, 0.89; 0.93–0.95). These relative benefits appeared to be irrespective of the choice of antihypertensive drug and are apparent in the 30,295 included participants with an eGFR < 60 mL/min/1.73 m ².

In other meta-analyses restricted to 100,354 trial participants with type 2 DM, the CVD benefits of intensive blood pressure lowering have been demonstrated, with particularly large reductions in the risk of stroke. Relative risk reductions per 10 mm Hg lower systolic blood pressure on the risk of CVD were greater in those with a starting systolic value of at least 140 mm Hg, but reductions in the risk of stroke were evident with further reductions in systolic blood pressure among those with a baseline level of below 140 mm Hg.

The randomized trial data in patients with DM and CKD suggest that a systolic blood pressure target of below 130 mm Hg is clinically appropriate. The 2021 KDIGO Management of Blood Pressure in the CKD Clinical Practice Guideline update acknowledged that the benefits of intensive blood pressure lowering are less certain among patients with concomitant DM and CKD compared to patients with CKD without DM. Nevertheless the guideline suggests a systolic blood pressure target using standardized office methods of below 120 mm Hg should be considered in patients with CKD irrespective of DM status. This suggestion is a consequence of increasing confidence that the observational findings of clear positive log-linear relationships between blood pressure and CVD mortality above a systolic value of ~115 mm Hg represent causal associations (supported by genetic epidemiology), and achieving intensive blood pressure control is sufficiently safe. The SPRINT trial assessed a target of <120 versus <140 mm Hg in 9361 patients without DM, including 2446 patients with CKD. SPRINT reported a 25% reduction in the risk of major cardiovascular events (HR, 0.75; 0.64–0.89), with relative risk reductions which were similar in participants with and without CKD.

Higher blood pressure is observationally associated with risk of CKD progression and kidney failure. Accelerated phase hypertension causes histological glomerular arteriolar changes which can manifest as acute kidney injury and/or CKD. At such high levels of systemic blood pressure, protection from the kidney’s blood flow autoregulation systems begins to be lost.

In DM, the presence of hyperglycemia dysregulates homeostatic tubuloglomerular feedback, blunting kidney blood flow autoregulation and increasing the kidney’s susceptibility to moderate elevations in systemic blood pressure. The combination of DM and early hypertension may be sufficient to induce glomerular hyperfiltration and albuminuria. These changes are considered a precursor for the histological changes of diabetic kidney disease and later eGFR decline. Randomized trial data demonstrating that lowering systolic blood pressure below 140 mm Hg in patients with DM reduces albuminuria are consistent with this concept. Whether such reductions in albuminuria translate into long-term prevention of kidney failure has not been confirmed.

Prioritizing the use of blood pressure-lowering agents that favorably modify intraglomerular hemodynamics is recommended in patients with DM and CKD. Inhibitors of sodium-glucose cotransporter-2 (SGLT-2) reduce intraglomerular pressure through restoring tubuloglomerular feedback and reducing glomerular afferent arteriolar tone. Inhibitors of the renin-angiotensin-aldosterone system (RAAS) pathway act on the glomerular efferent arterioles, reducing tone and consequently also reducing intraglomerular pressure ( Fig. 25.4 ).

A schematic diagram shows the effects of R A A S inhibition, S G L T2 inhibition, and their combination on glomerular pressure and arteriole tone in chronic kidney disease. — Fig. 25.4

SPECIFIC PHARMACOLOGICAL AGENTS SHOWN TO LOWER THE RISK OF KIDNEY FAILURE AND/OR CVD IN PATIENTS WITH CKD AND DM

Large placebo-controlled trials that specifically recruited patients with type 2 DM and CKD have confirmed important kidney benefits of RAAS inhibitors (i.e., angiotensin-converting enzyme inhibitors or angiotensin-II receptor blockers), SGLT-2 inhibitors, and the nonsteroidal mineralocorticoid receptor antagonist, finerenone. Semaglutide also slows the rate of kidney function loss in diabetic kidney disease. These interventions could be started early to prevent the development and or progression of end-organ damage in those identified to be at risk (see Fig. 25.2 ).

Inhibitors of the Renin-Angiotensin-Aldosterone System in Chronic Kidney Disease

Three key randomized trials of inhibitors of the RAAS system with an angiotensin-converting enzyme inhibitor or angiotensin-receptor-2 blocker reduce the risk of kidney failure in patients with DM and overt nephropathy. Two moderately sized trials have demonstrated that angiotensin-receptor-2 blockers slow the progression from microalbuminuria to overt nephropathy in patients with DM with less degrees of albuminuria. RAAS inhibitors are therefore recommended for use in patients with DM as soon as the first clinical indication of CKD is evident and it is considered reasonable to treat patients with CKD with high blood pressure with a RAAS inhibitor in the absence of albuminuria. Combining an angiotensin-converting enzyme inhibitor with an angiotensin-receptor-2 blocker, or with a direct renin-inhibitor, however, is not currently recommended. Large trials have identified an increased risk of hyperkalemia and acute kidney injury without demonstrable additional benefits of this “dual-blockade” approach on the risk of kidney failure or CVD.

Neprilysin is an enzyme which cleaves peptides, including natriuretic peptides, and is particularly expressed in the kidney. Its inhibition results in both natriuresis and vasodilation, which lowers systemic blood pressure. As neprilysin inhibitors have the potential to activate the RAAS, they are combined with an ARB. The combined angiotensin receptor-nephrilysin inhibitor sacubitril-valsartan reduces the risk of death from CVD or hospitalization for heart failure in patients with heart failure with reduced ejection fraction. ARNis may be commonly used in heart failure clinics and are safe to use in CKD (down to at least 20 mL/min/1.73 m ²), but CKD is not an indication for ARNI prescription: in a phase 2 trial in CKD, sacubitril-valsartan safely reduced blood pressure and cardiac biomarkers, but there was no clear evidence that it offered nephroprotection above that provided by irbesartan alone.

Sodium-Glucose Cotransporter-2 Inhibitors in Chronic Kidney Disease

Combining an SGLT-2 inhibitor with an RAAS inhibitor clearly reduces the risk of kidney failure and hospitalization for heart failure patients with type 2 DM and CKD. The CREDENCE, DAPA-CKD, and EMPA-KIDNEY placebo-controlled trials were all stopped early for efficacy while testing cardiorenal primary outcomes with canagliflozin, dapagliflozin, and empagliflozin, respectively. CREDENCE recruited patients with diabetic kidney disease with an eGFR of 30 to 90 mL/min/1.73 m ² and a uACR of 300 to 5000 mg/g (mean eGFR 56 ± 18 mL/min/1.73 m ²; median uACR 927 mg/g), while DAPA-CKD recruited patients with CKD and an eGFR of 25 to 75 mL/min/1.73 m ² and a uACR of 200 to 5000 mg/g (mean eGFR 43 ± 18 mL/min/1.73 m ²; median uACR 949 mg/g), and EMPA-KIDNEY provided evidence at low levels of eGFR and uACR (eligibility 20–45 mL/min/1.73 m ² or 45–90 mL/min/1.73 m ² with a uACR of at least 200 mg/g; mean eGFR 37.3 ± 14.5 mL/min/1.73 m ²; median uACR 329 mg/g). Once meta-analyzed according to a composite kidney disease progression outcome based on at least a 50% decline in GFR from baseline, the need for maintenance kidney replacement therapy or death from kidney failure, SGLT-2 inhibitors have been shown to reduce such renal risk by 37% (HR, 0.63; 0.58–0.69). This reduction in relative risk was consistent irrespective of diabetes status and across the different types of kidney disease studied. EMPA-KIDNEY demonstrated renal benefits across the full range of GFR included, even at the lowest levels. This indicates that SGLT-2i should be prescribed widely in CKD to modify the risk of kidney failure and can be continued until the need to start kidney replacement therapy despite low eGFR substantially attenuating their HbA1c-lowering effect. Although the EMPA-KIDNEY trial was too short to demonstrate key benefits on its primary outcome directly in those with low uACR, the exploration of the annual rate of progression of kidney function suggests renoprotection is evident even in the absence of albuminuria. We recommend the initiation of an SGLT-2 inhibitor in patients with type 2 DM following the first clinical evidence of CKD. There are also clear benefits of SGLT-2i on the risk of hospitalization for heart failure ( Table 25.2 ) and CVD death. The effect on CVD death appears to reduce from reductions in the risk of heart failure death and sudden cardiac death, with less clear effect on myocardial infarction (once data from large trials are combined) and no effect on stroke.

Table 25.2

Estimates of Net Effects per 1000 Patient-Years of an SGLT-2 Inhibitor, by Types of Patient Recruited into Trials

Adapted from Staplin N, Roddick AJ, Emberson J, et al. Net effects of sodium-glucose co-transporter-2 inhibition in different patient groups: a meta-analysis of large placebo-controlled randomized trials. EClinicalMedicine . 2021;41:101163. doi:10.1016/j.eclinm.2021.101163

	ESTIMATED ABSOLUTE EFFECTS PER 1000 PATIENT-YEARS OF AN SGLT-2 INHIBITOR (STANDARD ERROR)
OUTCOMES	TYPE 2 DM AND HIGH CVD RISK TRIALS	PROTEINURIC CKD TRIALS (MAINLY TYPE 2 DM)
Benefits
Kidney disease progression	–3 (0.3)	–18 (1)
Heart failure hospitalization	–3 (0.2)	–6 (0.4)
Cardiovascular death	–2 (0.4)	–3 (0.6)
Acute kidney injury	–1 (0.2)	–5 (0.7)
Harms
Ketoacidosis	0.3 (0.1)	0.3 (0.1)
Amputation	0.7 (0.3)	1 (0.7)

Patient group-specific absolute effects estimated by applying the overall relative risk to the average event rate in the placebo arms.

SGLT-2 inhibitors also appear to reduce the risk of acute kidney injury, and so any acute decline in eGFR on commencing an SGLT-2 inhibitor should not routinely prompt their cessation (and we suggest checking kidney function shortly after commencing an SGLT-2 inhibitor is not routinely needed).

From a safety perspective, SGLT-2 inhibitors approximately double the risk of ketoacidosis in patients with diabetes, but as the absolute risk is low in patients with type 2 DM, there is a clear net benefit of SGLT-2 inhibitors. By virtue of their high absolute risk of cardiovascular death, heart failure complications, kidney disease progression, and acute kidney injury, the net absolute benefits may be particularly large in patients with type 2 DM and CKD, particularly if they have albuminuria (see Table 25.2 ).

In patients with type 1 DM and CKD, baseline ketoacidosis risk is high and so a doubling of an already high risk is a safety concern. There is an absence of large trials with sufficient follow-up time to assess whether any absolute benefits of SGLT-2 inhibitors on kidney failure and CVD outcomes are outweighed by the high absolute risk of ketoacidosis with SGLT-2 inhibitors. There is a pathophysiological rationale and supportive GFR slope data from EMPA-KIDNEY to propose that renal benefits of SGLT2 inhibitors would be retained in diabetic kidney disease in type 1 DM, but safety concerns means use of SGLT-2 inhibitors in type 1 DM is limited to specialists in selected patients, and requires availability of a ketone meter to facilitate rapid detection of ketosis.

Nonsteroidal Mineralocorticoid Receptor Antagonists in Chronic Kidney Disease

Steroidal mineralocorticoid receptor antagonists reduce blood pressure and albuminuria in patients with CKD but have not been definitively shown to slow kidney disease progression. Instead, placebo-controlled FIDELIO-DKD and FIGARO-DKD trials specifically tested a nonsteroidal mineralocorticoid receptor antagonist and demonstrated that finerenone reduced the risk of kidney failure and CVD in patients with CKD and type 2 DM already on maximal RAAS inhibition. FIDELIO-DKD demonstrated reductions in the risk of a categorical kidney outcome, a composite combining kidney failure and a sustained decline in an eGFR of ≥40%, in patients with an eGFR 25 to 60 mL/min/1.73 m ² and a uACR of 30 to 5000 mg/g, or an eGFR 60 to 75 mL/min/1.73 m ² with a uACR of 300 to 5000 mg/g. FIGARO-DKD demonstrated reductions in the risk of CVD, and particularly heart failure events, using a primary composite outcome of CVD death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure, in patients with eGFR 25 to 60 mL/min/1.73 m ² and a uACR of 30 to 5000 mg/g, or an eGFR over 60 mL/min/1.73 m ² with a uACR of 300 to 5000 mg/g. Pooling data from the two trials found the kidney failure risk was reduced by 16% (HR, 0.84; 0.71–0.99) and hospitalization for heart failure by 22% (HR, 0.78; 0.66–0.92; Fig. 25.5 ). Finerenone has not been studied in sufficient numbers of participants to confirm whether this translates into a reduced risk of death from CVD.

A comparison table presents outcomes between finerenone and placebo groups with hazard ratios and confidence intervals in pooled clinical trials. — Fig. 25.5

Information on the efficacy of combining mineralocorticoid receptor antagonists with SGLT-2 inhibitors in CKD are limited as only ~4% of FIDELIO-DKD, ~8% of FIGARO-DKD, ~5% of DAPA-CKD, and no CREDENCE participants were prescribed such a combination. Subgroup analyses from the SGLT-2 inhibitor trials in heart failure, where mineralocorticoid receptor antagonist coprescription was more common, found that mineralocorticoid receptor antagonist use did not modify key analyses’ findings.

FIDELIO-DKD and FIGARO-DKD excluded patients with a potassium of >4.8 mmol/L, as mineralocorticoid receptor antagonists cause hyperkalemia. Unlike dual RAAS blockade with an ACEi plus ARB, adding finerenone to a RAAS inhibitor did not increase the risk of serious acute kidney injury. The finerenone trials in proteinuric CKD attributed to type 2 DM implemented careful algorithmic potassium monitoring and found that whether based on laboratory data or investigator reports, the risk for hyperkalemia was approximately double compared to a placebo. Permanent withdrawal of finerenone versus a placebo for hyperkalemia was 1.7% versus 0.6%, but serious hyperkalemia was relatively rare, with a <1% excess risk for hospitalization for serious hyperkalemia over 3 years of follow-up. Risk factors for hyperkalemia were higher baseline potassium and lower eGFR. Concomitant diuretics or an SGLT-2 inhibitor were both associated with a lower risk for hyperkalemia. This observation is consistent with findings from trials of SGLT-2 inhibitors in heart failure populations where combining RAAS inhibitors and SGLT-2 inhibitors does not appear to cause hyperkalemia, and SGLT-2 inhibitors may reduce the risk of severe hyperkalemia among MRA users. Large trials combining an aldosterone synthase inhibitors and SGLT-2 inhibitors are planned.

In summary, large trial evidence supports the addition of finerenone to treatment with a RAAS inhibitor in patients with type 2 DM and proteinuria (i.e., urine albumin-to-creatinine ratio of at least 30 mg/g) provided the additional blood monitoring and the risk of serious hyperkalemia are acceptable. The trials of finerenone did not recruit patients with type 1 DM, but extrapolating the efficacy findings, the intervention may be useful in patients with type 1 DM at the risk of kidney disease progression, among whom the use of an SGLT-2 inhibitor may be considered unsafe.

CHOICE OF ANTIDIABETIC AGENTS IN PATIENTS WITH DIABETES MELLITUS AND CHRONIC KIDNEY DISEASE

GLUCAGON-LIKE PEPTIDE-1 RECEPTOR AGONIST (GLP-1 RA) IN CHRONIC KIDNEY DISEASE

SGLT-2 inhibitors should be prioritized for use in patients with type 2 DM and CKD. Their blood glucose-lowering effects are, however, substantially attenuated once eGFR falls below about 45 mL/min/1.73 m ² (despite beneficial effects on CVD and kidney failure risk are clearly preserved at low eGFR). We recommend prioritizing the use of GLP-1RA in diabetic kidney disease. Key evidence is provided by the FLOW trial which randomized 3533 participants with CKD at the risk of progression (mean body mass index is 32 kg/m ²) to subcutaneous semaglutide versus a matching placebo and was stopped early for efficacy. The prespecified composite primary outcome was kidney failure, a sustained decline of ≥50% in eGFR from the baseline, or death from kidney or cardiovascular causes. Over 3.4 years, the allocation to semaglutide resulted in a 24% (HR, 0.76; 0.88–0.66) reduction in the risk of the primary composite outcome. Semaglutide also reduced the risk of major cardiovascular events by 18% (HR, 0.82; 0.68–0.98), including cardiovascular death by 29% (HR, 0.71; 0.56–0.89). There were notable reductions in weight by an average of 4.1 kg and improvements in glycated hemoglobin by–0.81%. GLP-1RAs do cause nausea and other gastrointestinal disturbances, yet with the semaglutide dose studied in FLOW (1.0 mg/week initiated with an 8-week dose escalation), the medication was reasonably tolerated. Before FLOW, GLP1-RAs were already known to safely improve glycemic control and weight and reduce CVD risk in patients with type 2 diabetes and early CKD. The GLP-1RA dulaglutide has been tested in CKD stages G3–4 in patients with type 2 DM. It was shown to be as effective at lowering HbA1c as insulin glargine and to have lower rates of symptomatic hypoglycemia, reduced weight, and a slowed rate of eGFR decline compared to insulin glargine. These trials provide evidence to justify that GLP-1RAs are prioritized ahead of insulin in patients with type 2 DM and CKD (see Fig. 25.3 ), and semaglutide should be used for its effect on cardiorenal risk.

METFORMIN IN CHRONIC KIDNEY DISEASE

The evidence that metformin may favorably modify CVD risk comes from subgroup analyses and long-term follow-up of the United Kingdom Prospective Diabetes Study in a population of patients with newly diagnosed diabetes without CVD. Extrapolating these data, an argument for prioritizing the use of metformin ahead of other sulfonylureas and insulin has been made. However, below an eGFR of 30 mL/min/1.73 m ², metformin should generally be stopped to avoid the risk of lactic acidosis due to its accumulation. Above an eGFR of 30 mL/min/1.73 m ², metformin with an appropriate dose adjustment can still be used to manage hyperglycemia in CKD without the risk of hypoglycemia. If used at eGFRs between 30 and 45 mL/min/1.73 m ², a maximum daily dose of about 500 to 1000 mg per day is suggested based on pharmacokinetic considerations (and 500 mg per day for selected patients with an eGFR < 30 mL/min/1.73 m ²).

OTHER ANTIDIABETIC THERAPIES IN CHRONIC KIDNEY DISEASE

The dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin has been extensively studied in CKD and can be safely used even in severe CKD to lower blood glucose. Large-scale placebo-controlled trials show, however, that they do not meaningfully reduce the risk of CVD or kidney failure. Sulfonylurea treatment (e.g., gliclazide) is a potentially cheaper alternative to DPP-4 inhibitors to improve glycemic control in CKD, with an appropriate dose reduction to avoid hypoglycemia. Sulfonylurea therapy has not been shown to favorably modify CVD risk or slow kidney disease progression. Direct comparisons of the sulfonylurea glimepiride versus an SGLT-2 inhibitor in a trial using eGFR slopes have shown the importance of prioritizing the use of an SGLT-2 inhibitor.

THE USE OF ANTIPLATELET THERAPY IN CHRONIC KIDNEY DISEASE

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Tags: Diabeto-Cardiology: A Companion to Braunwald’s Heart Disease, Richard Haynes, William G. Herrington

May 17, 2026 | Posted by drzezo in CARDIOLOGY | Comments Off