From Glucocentricity to a Multi-Risk Strategy: An Updated Approach to Managing Chronic Kidney Disease

By Frank Lavernia, MD, and Jack Johnson, BS

Executive Summary

Chronic kidney disease (CKD) affects more than one-third of patients with diabetes. This issue emphasizes a shift to a multi-risk approach, highlighting four pillars of treatment: renin-angiotensin-aldosterone blockers, sodium-glucose cotransporter-2 inhibitors, nonsteroidal mineralocorticoid receptor antagonists, and glucagon-like peptide 1 receptor agonists.

• Nearly all patients in the earlier stages of CKD have virtually no symptoms, therefore screening for albuminuria and reduced estimated glomerular filtration rate (eGFR) is important.
• Risk factors include increased albuminuria, hyperglycemia, hypertension, dyslipidemia, obesity, and smoking.
• Depression, psychological distress, cognitive impairment, and anxiety frequently are found in patients with CKD, with depression three to four times more common when compared to the general population.
• With advancing reduction in eGFR, many medications require significant dose adjustments.
• The accuracy of hemoglobin A1c can be affected as the result of multiple factors. Options for alternative testing include fructosamine and glycated albumin levels, as well as continuous glucose monitoring glucose management indicator.
• Criteria for referral to nephrology include rapidly declining eGFR, nephrotic syndrome, and disproportionate proteinuria.

This issue is the first of a two-part discussion of complications of diabetes. Part I will discuss the management of chronic kidney disease in people with diabetes. Part II will discuss additional microvascular and macrovascular complications of diabetes, including diabetic peripheral neuropathy and peripheral artery disease. We hope these two issues will be useful to your clinical practice.

— Gregory R. Wise, MD, FACP, Editor

Diabetes mellitus (DM) continues to assume pandemic proportions worldwide and is increasing at an alarming rate, which likely will drive an increase in both its related micro- and macrovascular complications. This article will discuss an important microvascular complication of DM, chronic kidney disease (CKD), which affects more than one-third of patients with diabetes. There is substantial evidence that early diagnosis and management can delay or prevent the progression of CKD, making its prevention, diagnosis, and treatment a priority for the primary care clinician.

In addition to strict blood glucose control and appropriate guideline-directed management of blood pressure and lipid levels for all patients with diabetes, this review will discuss four important therapeutic tools for the prevention and treatment of diabetic kidney disease (DKD), also called diabetic nephropathy, in patients with type 2 diabetes mellitus (T2DM). These tools, or “pillars of treatment,” include renin-angiotensin-aldosterone system (RAAS) blockers; sodium-glucose cotransporter-2 (SGLT2) inhibitors; a novel nonsteroidal selective mineralocorticoid receptor antagonist (nsMRA), finerenone; and glucagon-like peptide 1 receptor agonists (GLP-1 RAs).

Etiology

CKD has become a major global public health problem. It is characterized by elevated urine albumin excretion or reduced glomerular filtration rate, or both. Although CKD in type 1 diabetes mellitus (T1DM) most often is secondary to microvascular disease, there is a whole spectrum of CKD etiologies in T2DM.¹ Several studies have verified that kidney disease in T2DM may be a more compounded entity than what is seen in T1DM, likely because the development of CKD in people with T2DM can be related to conditions commonly seen in this population, such as hypertension, dyslipidemia, obesity, intrarenal vascular disease, acute kidney injury, glomerular atherosclerosis, or age-related kidney loss.¹

DKD typically develops after a diabetes duration of 10 years in patients with T1DM (the most common presentation is five to 15 years after the diagnosis of T1DM) but may be present at the time of diagnosis of T2DM.²

Risk factors for the development of DKD include increased albuminuria, hyperglycemia, hypertension, dyslipidemia, obesity, and smoking.³ The primary care clinician should be mindful of these risk factors when choosing pharmacologic treatment for the patient with diabetes, since new treatment paradigms are moving from a glucocentric approach to a multi-risk strategy, which includes the use of new antidiabetic agents that, in addition to managing glucose, also provide cardiorenal protection.

Epidemiology

Diabetes is among the leading causes of CKD and end-stage kidney disease in the Western world.¹ DKD develops in nearly half of patients with T2DM and in one-third of those with T1DM during their lifetime.⁴ It was the most common diagnosis for the initiation of renal replacement therapy in the United States in 2018, accounting for 47% of the cases.⁵

The true incidence and prevalence of CKD in diabetes has been challenging to determine because of many factors, including the asymptomatic nature of the early to moderate stages of the disease as well as the fact that in patients with diabetes there are other factors, in addition to diabetes, that may contribute to CKD. According to the Centers for Disease Control and Prevention (CDC), the most recent data from the National Health and Nutritional Examination Survey (2017-2020) show that the prevalence of CKD in patients with diabetes is nearly 40%.

A 2022 study in the New England Journal of Medicine concluded that despite a recent decline in the incidence of CKD from 81.6 cases per 1,000 person-years (95% confidence interval [CI], 78.0 to 85.2) during 2015 and 2016 to 64.0 cases per 1,000 person-years (95% CI, 62.2 to 65.9) during 2019 and 2020, the persistently high incidence of CKD in the United States is troubling, given the large increase in the prevalence of diabetes and its accompanying high rates of kidney failure.⁶ Going forward, the number of individuals worldwide with DKD is expected to rise, mirroring the increasing prevalence of T2DM.⁴

CKD has emerged as one of the leading noncommunicable causes of death worldwide and is one of only a few to show an increase since 1990.⁷ In fact, the global all-age mortality rate attributed to CKD increased by 41.5% between 1990 and 2017.⁸ It is projected that CKD will affect an increasing number of individuals over time, further rising in importance among the various global causes of death.⁷

Pathophysiology

CKD in young and middle-aged patients with T1DM most commonly is attributed to diabetes-related microvascular disease; however, in patients with T2DM, there is a spectrum of causes. Patients with T2DM typically are older at the time of diagnosis and kidney disease from other causes already may have occurred in these patients, making kidney disease more likely to be multifactorial in patients with T2DM as compared to patients with T1DM. One study that evaluated kidney biopsies of T2DM patients with CKD observed typical diabetic microvascular changes in 36% of cases, nondiabetic kidney disease in 37% of cases, and a mix of diabetic and nondiabetic causes in the other 27% of cases.¹

Similar to diabetic peripheral neuropathy, the pathophysiologic mechanisms that lead to impaired renal function in T1DM involve hyperglycemia, altered hemodynamics, and metabolic and inflammatory pathways.¹ CKD in patients with T1DM is characterized initially by hyperfiltration, which manifests clinically as an elevated glomerular filtration rate (GFR). One proposed mechanism of this phenomenon states that hyperglycemia-dependent hyperfiltration upregulates sodium and glucose back-transportation in the renal tubular system.¹ After the initial hyperfiltration period ends, nephrons subsequently are lost, resulting in a steadily declining GFR (~3 mL/min/year to 6 mL/min/year). At this rate, renal failure requiring replacement intervention may occur within 20-25 years.¹ During this vicious cycle, the remaining nephrons compensate for lost nephrons by hyper-filtrating urine because of a combination of hyperglycemia and reduced filtration surface area.¹ Clinically, this can be seen as an elevated estimated glomerular filtration rate (eGFR) between 130 mL/min per 1.73 m² and 140 mL/min per 1.73 m². This phenomenon also can be seen in patients with T2DM.

Clinical Features

Nearly all patients, at least in the earlier stages of CKD, will have virtually no symptoms. Therefore, it is important for the clinician to be vigilant and screen for signs of early kidney disease, such as albuminuria and reduced eGFR as per evidence-based guidelines, because CKD is a clinical diagnosis made based on these findings in the absence of signs or symptoms of other primary causes of kidney damage.²

The goal of early and vigilant screening is, of course, to prevent progression to advanced CKD. In the later stages of CKD, signs and symptoms indeed will be present. Symptoms such as nausea, vomiting, loss of appetite, fatigue and weakness, sleep disturbance, muscle cramps, persistent pruritus, and shortness of breath may occur. Additionally, signs such as peripheral edema, hypertension, changes in urine output (increased during the hyperfiltration stage but eventually becoming decreased [oliguria]), and foamy or bloody urine may be present, as well as signs consistent with uremia, which may include skin changes (hyperpigmentation, pallor, a slate-gray discoloration, and a yellow skin hue), hyperreflexia, palpitations, dysgeusia (altered or distorted sense of taste), a pericardial friction rub (caused by uremic pericarditis), and even uremic frost (which occurs when high levels of blood urea nitrogen [BUN] cause urea in sweat to crystallize into fine, white powder, which is visible on the skin).

Diagnostic Studies

With the goal of early detection and prevention of disease progression, the American Diabetes Association (ADA) recommends that patients with diabetes be screened annually for CKD using two tests: the eGFR and the urine albumin-creatinine ratio (uACR). The uACR can be thought of as an “injury marker” and the eGFR as a “function indicator.” It is important to note that kidney disease is diagnosed when an abnormality is seen in either of these tests. Screening should start in people with T1DM when the duration of diabetes is ≥ 5 years and in people with T2DM screening should start at the time of diagnosis.² After a patient is diagnosed with CKD, uACR and eGFR should be monitored one to four times per year depending on the stage of the kidney disease.² (See Figure 11.1 here: https://diabetesjournals.org/care/article/47/Supplement_1/S219/153938/11-Chronic-Kidney-Disease-and-Risk-Management.)

Estimated Glomerular Filtration Rate

Traditionally, eGFR is calculated from serum creatinine using a validated equation and routinely is reported by laboratories along with serum creatinine on a metabolic panel. Most estimating equations become less accurate as eGFR decreases. An eGFR persistently < 60 mL/min/1.73 m² for at least three months is considered abnormal.⁹ It should be noted that estimating equations that include a race coefficient no longer are recommended. However, because the race-free equations may yield slightly different eGFR values compared to other equations, trends in eGFR should be assessed using results from a single equation.⁹

When clinicians are screening for CKD, sometimes the eGFR is not reduced but instead it is noted to be quite elevated. This supraphysiologic elevation in eGFR can be observed early in the natural history of T1DM and T2DM as much as 67% and 73% of the time, respectively.¹⁰ If the clinician is unaware of this natural history, they may miss the opportunity of an early warning signal for development of kidney disease. This supraphysiologic elevation of eGFR occurs because of glomerular hyperfiltration. The renal hemodynamic alterations can be caused by an adaptation to a reduction in functional nephron mass and/or in response to prevailing metabolic (high blood glucose) and neurohormonal stimuli, such as with obesity. Body weight also augments GFR (by about 15% in obese to about 56% in severely obese nondiabetic subjects).¹¹ This most likely is caused by various cytokines and growth factors in response to hyperglycemia.¹² From the onset of diabetes, the kidneys grow large due to the expanded nephron size (particularly hypertrophy of the proximal tubule).¹³ This may increase glomerular hydraulic pressure and transcapillary convective flux of ultrafiltrate and macromolecules (proteins). The prevailing hypothesis is that hyperfiltration in diabetes precedes the onset of albuminuria and/or decline in renal function.¹⁰ Identifying hyperfiltration can be clinically advantageous because this phenomenon is an early warning signal to future deterioration of renal function if strict glycemic and blood pressure targets are not met. Unfortunately, identification of hyperfiltration in clinical practice can be complicated by intra- and interday GFR fluctuations and the inaccuracy of available serum creatinine-based GFR estimates. With this in mind, reported thresholds to define hyperfiltration vary between 130 mL/min per 1.73 m² and 140 mL/min per 1.73 m².

Urine Albumin-to-Creatinine Ratio and Urine Protein-to-Creatinine Ratio

Microalbuminuria is defined as urinary excretion of albumin greater than or equal to 30 mg/day (and less than 300 mg/day) and is the earliest sign of diabetic nephropathy.¹⁴ Although 24-hour urine collection is considered the gold standard for assessment of microalbuminuria, quantification of microalbumin to creatinine ratio in a random spot urine has been shown to be comparable to 24-hour collection and is less cumbersome.¹⁴ Although the uACR typically is reported as mg/g, it can also be reported in mg/mmol. A urine albumin excretion rate > 30 mg/24 hours corresponds to a uACR of > 30 mg/g (> 3 mg/mmol).

Professional care standards for diabetes specifically endorse the use of uACR to screen for the development of hypertensive or diabetic nephropathy, and the sensitivity of uACR is higher than that of urine protein to creatinine ratio (uPCR) for low levels of proteinuria.^2,15

It should be remembered that uACR is a screening test and, as such, clinicians should note that there are a few things to consider when interpreting the uACR results in patients with diabetes. First, older age can cause false-positives and, second, elevations in the uACR, which are not related to diabetic nephropathy, can be seen, such as in the case of overt hyperglycemia, urinary infections, and other causes of renal disorders.¹⁴ In addition, heavy exertion can increase protein in the urine transiently; therefore, it is best that the patient has not engaged in this sort of activity immediately prior to sampling. Repetitive measurements (at least three) of first morning void urines provide a more accurate assessment of uACR. In cases of overt hyperglycemia, reassessment of uACR after the glucose is under better control is prudent.

Another factor for the primary care clinician to consider is the need to detect other etiologies of proteinuric kidney disease that may be superimposed on nephropathy because of diabetes. If the clinician suspects this, a uPCR as well as a uACR can be evaluated, since the uPCR will measure all of the urinary proteins, not just albumin. The clinical significance of differences between uACR and uPCR relate to the fact that albumin loss is more likely to be associated with injuries to the glomerular filtration apparatus (as seen in diabetic and hypertensive nephropathy), whereas total protein loss (albumin and other proteins that are measured in the uPCR) represents a broader spectrum of kidney injuries, such as tubulointerstitial injury, or systemic diseases, such as multiple myeloma.¹⁵ Thus, elevation of the uPCR out of proportion to the uACR may warrant a referral to a nephrologist.

Additionally, active urinary sediment (containing red or white blood cells or cellular casts), rapidly increasing albuminuria or total proteinuria, the presence of nephrotic syndrome, rapidly decreasing eGFR, or the absence of retinopathy (in T1DM) suggests alternative or additional causes of kidney disease. For individuals with these features, and/or if the eGFR is < 30 mL/min/1.73 m², referral to a nephrologist for further diagnostic procedures, including the possibility of kidney biopsy, should be considered.² Of note, in patients who have increased plasma levels of low molecular-weight proteins or in whom immunoglobulin light chains are present, it is essential to assess urine protein electrophoresis.

Treatment

Staging of CKD

The staging of CKD is done using both the eGFR and uACR. The “Kidney Function Heat Map” represents the risk for CKD progression according to the patient’s eGFR and albuminuria categories. (See “Prognosis of CKD by GFR and Albuminuria Categories” here: https://www.kidney.org/quick-reference-guide-kidney-disease-screening.) It is helpful for the patient to be empowered with an understanding of the natural progression of CKD and, thus, can be a visual aid for the clinician to use with the patient. The patient’s results can be plotted and then discussed with them to enhance their understanding.

Early identification of patients with CKD is essential to promote adequate strategies to prevent and slow its progression. Regardless of kidney disease etiology, strict blood glucose control is, on a group level, the single most important intervention to prevent the development of CKD in patients with T1DM and T2DM.¹ Additionally, optimizing blood pressure control and reducing blood pressure variability is important to lower the risk or slow the progression of CKD.²

Management of CKD in patients with diabetes has evolved alongside the growing understanding of the multiple interrelated pathophysiological mechanisms that involve the hemodynamic, metabolic, and inflammatory pathways, which contribute to its development. An emerging treatment strategy, recently discussed at the European Association for the Study of Diabetes (EASD) in Madrid, Spain, in 2024, promotes a four-pillared approach to the prevention and management of CKD, with three established pillars of therapy and a fourth, emerging pillar in the management of CKD in people with T2DM (see Table 1).¹⁶ This pillared treatment approach for cardiorenal protection in people with CKD and T2DM is similar to the pillared approach used in heart failure treatment in that both aim to maximize the benefits of currently available disease-modifying therapies. Using this pillared approach ensures that each drug class focuses on a specific aspect of the disease’s pathophysiology. (See https://pmc.ncbi.nlm.nih.gov/articles/PMC10547606/figure/FGA/.)

The First Pillar: Blockade of the Renin-Angiotensin-Aldosterone System

The first pillar of treatment is the blockade of RAAS, which, since its initial discovery, has remained a cornerstone of DKD management. In (nonpregnant) patients with diabetes and hypertension, either an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) is recommended for patients with moderately increased albuminuria (30 mg/g to 299 mg/g) and is strongly recommended for those with severely increased albuminuria (≥ 300 mg/g) and/or eGFR < 60 mL/min/1.73 m² to prevent the progression of kidney disease and reduce cardiovascular events. Importantly, an ACE inhibitor or an ARB is not recommended for the primary prevention of CKD in people with diabetes who have normal blood pressure, normal uACR (< 30 mg/g creatinine), and normal eGFR.²

Of clinical significance, RAAS blockers are known to variably cause increased serum creatinine of up to 30% in patients with CKD during the first two months of treatment initiation and, for this reason, it is recommended that the clinician periodically monitor for increased serum creatinine and potassium levels. Although a rise in the creatinine of up to 30% generally is acceptable, if this threshold or higher is reached, it is recommended to discontinue the RAAS blocker, understanding that the rise generally is reversible after drug discontinuation. (The RAAS blocker also should be discontinued if hyperkalemia develops, i.e., a serum potassium level of 5.6 mmol/L or greater.¹⁷) Dual therapy (using an ACE inhibitor together with an ARB) is never indicated because of the additive risk of decreasing eGFR or causing hyperkalemia.

The Second Pillar: Sodium-Glucose Cotransporter-2 Inhibition

The second pillar is treatment with SGLT2 inhibitors, which recently have emerged as a key disease-modifying therapy to prevent the progression of CKD. The ADA 2025 Standards of Care recommend that for people with T2DM and CKD, use of an SGLT2 inhibitor with demonstrated benefit is recommended to reduce CKD progression and cardiovascular events in individuals with eGFR ≥ 20 mL/min/1.73 m².¹⁸

SGLT2 inhibitors are proteins expressed in the proximal convoluted tubules of the kidneys that exert their physiologic function by reabsorbing filtered glucose from the tubular lumen. SGLT2 inhibitors reduce the reabsorption of filtered glucose, decrease the renal threshold for glucose, and promote urinary glucose excretion. These agents prevent decline in kidney function through reduction in glomerular hypertension mediated through tubuloglomerular feedback, independent of their effect on glycemic control.¹⁹ It has been hypothesized that SGLT2 inhibitors’ natriuretic and osmotic diuretic effects mediate their cardioprotective benefit, but there is some recent evidence that SGLT2 inhibitors do not produce a durable natriuretic effect or alleviate objective signs of congestion in randomized controlled trials.²⁰ One of the key mechanisms proposed for their cardioprotective effects is the alteration of myocardial energy metabolism, including enhanced ketone use. In congestive heart failure (CHF), myocardial energy efficiency declines, and the heart’s normal ability to use fatty acids and glucose is impaired. Ketones, such as beta-hydroxybutyrate, are a more energy-efficient fuel source as compared to fatty acids and glucose. SGLT2 inhibitors induce mild ketosis by promoting lipolysis and hepatic ketogenesis. This results in elevated circulating ketone bodies, even in nondiabetic individuals, shifting the myocardial substrate use from fatty acids and glucose to ketones.

Although studies to elucidate the mechanism of action responsible for the cardioprotective effect of SGLT2 inhibitors are ongoing, the fact remains that regardless of the reason for their benefit, SGLT2 inhibitors are revolutionizing the treatment of CHF as well as of CKD. In fact, the EMPA-KIDNEY trial was stopped early in March 2022 because of a finding of efficacy suggesting that SGLT2 inhibitors soon may be indicated for patients with CKD without albuminuria, so it is prudent for the primary care clinician to be mindful of updates to indications for these medications in the near future.²¹

Similar to RAAS inhibitors, SGLT2 inhibitors are recognized to cause an acute but transient reduction in GFR through a reduction in glomerular hypertension. In most cases, when this transient reduction occurs (typically two to four weeks after initiation), patients should be maintained on the SGLT2 inhibitor given the medication’s cardiorenal benefits. It might be encouraging to both the patient and the clinician that a larger magnitude of dip in eGFR may correlate with greater long-term benefit and, therefore, should be viewed as evidence of a positive hemodynamic effect.²¹ However, if the reduction in eGFR is greater than 30%, or if other risk factors for acute kidney injury (such as a volume-contracting illness or initiation of other medications that may affect kidney hemodynamic) have occurred, this should prompt a clinical review to evaluate the risk vs. the benefit of continued use of the SGLT2 inhibitor.

Most patients tolerate SGLT2 inhibitors quite well, with minimal (if any) side effects, but there are some clinical considerations. Owing to glucosuria, SGLT2 inhibitors are associated with an increased risk of genital mycotic infections. These infections are noted to be most common during the first month after initiation and also are noted to be more common in women and in those who have a prior history of infections. Personal hygiene advice should be provided for all patients initiating SGLT2 inhibitor therapy to decrease the risk of developing genital mycotic infections and thereby improve adherence with this clinically beneficial treatment.

Additionally, there is a small but real risk of diabetic ketoacidosis (DKA) in patients taking SGLT2 inhibitors. The literature reveals that DKA has occurred more frequently in patients with T1DM than in patients with T2DM taking SGLT2 inhibitors, although it should be strongly emphasized that while sometimes prescribed, the use of SGLT2 inhibitors in patients with T1DM is not currently approved by the U.S. Food and Drug Administration (FDA). There also is a risk of euglycemic diabetic ketoacidosis (EDKA) with the use of SGLT2 inhibitors, which is a clinical syndrome occurring both in T1DM and T2DM characterized by euglycemia (blood glucose less than 250 mg/dL) in the presence of severe metabolic acidosis (arterial pH less than 7.3, serum bicarbonate less than 18 mEq/L) and ketonemia.²² Although there are relatively few studies that specifically describe events of EDKA in association with SGLT2 inhibitors, the fact remains that EDKA is a life-threatening and challenging diagnostic dilemma that is becoming more widespread with the growing use of SGLT2 inhibitor drugs.²³ Therefore, the clinician must remain vigilant and educate patients on the risks and warning signs of EDKA to reduce instances of missed diagnosis.

To decrease the risk of possibly developing DKA or EDKA, all patients should be counseled to stop taking their SGLT2 inhibitors during episodes of acute illness, prolonged fasting, or when experiencing persistent vomiting or diarrhea. Additionally, clinicians should consider pausing SGLT2 inhibitors for three to four days prior to surgery. Patients who participate in intense endurance exercise competitions should consider not taking their SGLT2 inhibitor when they are participating in such events because of the associated prolonged exertion and stress.²³

Patients taking SGLT2 inhibitors also should be informed that if they start to feel unwell, with nausea and vomiting, they should check their blood glucose and consider using a urinary glucose and ketone strip, even in the absence of hyperglycemia. When discussing the utility of urine strips in evaluating for ketones (acetoacetic acid, beta-hydroxybutyric acid, and acetone) with patients, it should be emphasized that urine screening for ketones with nitroprusside reagent does not measure beta-hydroxybutyrate but detects only acetone and acetoacetate and, therefore, if clinical suspicion is high, even if the screen is negative, the patient should be evaluated with serum testing for EKDA.

The Third Pillar: Treatment with Nonsteroidal Mineralocorticoid Receptor Antagonists

The third pillar is treatment with nsMRAs. In 2020, trials with finerenone (the only selective nsMRA that currently is FDA-approved in the United States) demonstrated that in patients with CKD and T2DM, treatment with finerenone resulted in lower risks of CKD progression and cardiovascular events than placebo.²⁴ Finerenone works by inhibiting the effects of mineralocorticoids such as aldosterone and cortisol when the mineralocorticoid receptor (MR) is overactivated, possibly reducing inflammation and fibrosis in the heart and kidney. Finerenone has a high degree of selectivity and a more favorable adverse effect profile than other MR inhibitors.²⁵

The 2025 ADA Standards of Care recommend that to reduce cardiovascular events and CKD progression in people with CKD and albuminuria, an nsMRA that has been shown to be effective in clinical trials (finerenone) should be prescribed as long as the patient’s eGFR is ≥ 25 mL/min/1.73 m².¹⁸ Although the risk of hyperkalemia with finerenone is low, it is important to periodically monitor the patient’s potassium. If the potassium rises above 4.7, it is recommended to discontinue the finerenone.

Thus, the first three pillars of treatment of CKD in patients with T2DM incorporate the use of SGLT2 inhibitors and the nsMRA finerenone, and have given clinicians two evidence-based medications, which, when combined with RAAS inhibition, have been proven to slow DKD progression to approximately 2.5 mL/min/year to 3 mL/min/year, provided blood pressure and glucose levels are at guideline goals.²⁶ It should be mentioned that there has not been a direct comparison of MRAs and SGLT2 inhibitors in the literature. At this time, they can be used interchangeably or together for the goal of slowing progression of CKD and providing cardiovascular protection. As noted, all these studies included participants taking either an ACE inhibitor or an ARB, often at maximally tolerated doses.¹⁸

The Fourth Pillar: The Glucagon-Like Peptide 1 Receptor Agonist Semaglutide

Additionally, there is a fourth pillar of therapy: treatment with the GLP-1R agonist semaglutide. The literature has been growing in recent years regarding the role of GLP-1R agonists in the treatment of CKD in patients with diabetes. A meta-analysis published in Lancet Diabetes Endocrinology in 2021 concluded that GLP-1 receptor agonists, regardless of structural homology, reduced the risk of individual major adverse cardiac event components, all-cause mortality, hospital admission for heart failure, and worsening kidney function in patients with T2DM.²⁷ These findings expand on previous research, which revealed that GLP-1R agonists reduce the risk of myocardial infarction.

The 2025 ADA guidelines recommend that to reduce cardiovascular risk and kidney disease progression in people with T2DM and CKD, a GLP-1R agonist with demonstrated benefit in this population should be prescribed.¹⁸ This evidence-based guideline takes into consideration results from the FLOW (Evaluate Renal Function with Semaglutide Once Weekly) trial, published in the New England Journal of Medicine in May 2024, which showed that semaglutide (approved in 2017 for treating T2DM and in 2021 for chronic weight management in adults with obesity or overweight with at least one weight-related condition) reduced the risk of clinically important kidney outcomes and death from cardiovascular causes in patients with T2DM and chronic kidney disease.²⁸ It also should be noted here that recently (Jan. 28, 2025), after review of the FLOW trial, the FDA granted approval for the use of semaglutide in treating CKD in patients with T2DM.

In contrast to the SGLT2 inhibitors and finerenone, GLP-1R agonists have not been shown to confer protection from heart failure.²⁷ Therefore, the anti-atherosclerotic cardiovascular protection from GLP-1R agonists appears to be complementary to the SGLT2 inhibitors’ benefit in heart failure.¹⁶ Additionally, GLP-1R agonists are critically important for glycemic control, especially in people with more advanced CKD, because in patients with more advanced CKD and eGFRs < 30, SGLT2 inhibitors lose efficacy and metformin may be contraindicated.

However, despite their benefits, clinicians need to be mindful when prescribing GLP-1R agonists. Contraindications to the use of GLP-1R agonists include pregnancy (as a result of potential developmental abnormalities in the fetus) and a known hypersensitivity to GLP-1R agonists. Additionally, a complete history should be obtained because a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2 (MEN2) syndrome also is a contraindication to GLP-1R agonist therapy. Lastly, the clinician may want to avoid using a GLP-1R agonist in patients who have a history of gastroparesis or inflammatory bowel disease. If a patient has a history of acute pancreatitis, a definitive etiology and timeline should be ascertained before contemplating the use of a GLP-1R agonist.

The clinician should be aware that the most common side effects of GLP-1R agonists typically are mild to moderate, and often are transient gastrointestinal disturbances. Nausea can affect up to half of patients. Vomiting and diarrhea also can occur, especially during the first weeks of usage. Constipation may be noted in some patients, and this may persist longer than other gastrointestinal side effects. It should be stressed that, in general, these gastrointestinal side effects are mild to moderate and often transient, occurring more frequently at the start of treatment and/or after dose increases.

It is helpful to know that many of these side effects can be minimized by instructing patients to “start low and go slow.” By starting at the lowest weekly dosage of the GLP-1R agonist or GIP (glucose-dependent insulinotropic peptide)/GLP-1R agonist and increasing the dose slowly (waiting until after the patient has been taking the new or recently increased dose for at least four weeks), many of the gastrointestinal symptoms may be diminished. The patient should be reassured that their symptoms, if they experience any, are likely to dissipate within the first week or two. They should be instructed to drink plenty of water throughout the day to prevent dehydration (especially if they are experiencing some vomiting and/or diarrhea). If they are feeling full, the recommendation to have smaller meals and to avoid high-fat and spicy foods can be helpful. For constipation and diarrhea, the patient should monitor their fiber content and adjust accordingly. If symptoms do not improve, they should call their provider.

In patients with underlying kidney disease, if diarrhea and vomiting develop, close monitoring to prevent acute kidney injury (AKI) is critical. If acute, severe abdominal pain occurs with GLP-1R agonist or GIP/GLP-1R agonist therapy, the patient should be instructed to stop the medication and call their provider immediately to determine the etiology.

Treatment with statins also is critically important in patients with diabetes, since cardiovascular diseases are the leading cause of mortality in CKD, especially in end-stage renal disease patients. Although the incidence and prevalence of cardiovascular events already is significantly higher in patients in the early stages of CKD (stages 1-3) compared with the general population, patients in advanced CKD stages (stages 4-5) exhibit a markedly elevated risk. CKD causes a systemic, chronic proinflammatory state contributing to vascular and myocardial remodeling processes resulting in atherosclerotic lesions, vascular calcification, and vascular senescence as well as myocardial fibrosis and calcification of cardiac valves.²⁹

Thus, therapies to reduce cardiovascular risk are a priority in patients with CKD. Dyslipidemia in this population is characterized by high triglycerides, low high-density lipoprotein (HDL) cholesterol levels, and altered lipoprotein composition. Interestingly, the emerging data suggest that the composition of the lipoprotein particle size is altered, with increased small, dense low-density lipoprotein (LDL) and decreased larger LDL particles in people with CKD.

Robust evidence from clinical trials has shown the use of statins to be safe and effective in lowering LDL cholesterol and of benefit in reducing CVD events in individuals with pre-end stage CKD. However, it should be emphasized that statin therapy does not reduce cardiovascular events in dialysis patients, nor does statin therapy confer any protection against the progression of renal disease.

The various available agents (statins and non-statins) have different clearance routes, and some statins need dose adjustments in CKD.³⁰ Tables 2 and 3 list both statin and non-statin treatments for dyslipidemia and include the important dose adjustments in patients with CKD.

CKD and Patients with T1DM

Despite the tremendous progress that has been made in the treatment of CKD in patients with T2DM, management of CKD in T1DM continues to center mostly on glycemic control, RAAS inhibition, and optimization of risk factors (blood pressure, lipids, and body weight). Although these therapeutic approaches have significantly improved outcomes among people with T1DM and CKD, this population remains at a substantial elevated risk for adverse kidney and cardiovascular events, with limited improvements in medical management over the last few decades.

Unfortunately, people with T1DM have not been able to benefit from the four-pillared approach reviewed earlier and, therefore, remain at unacceptably high risk of kidney and cardiovascular complications.

It is hoped that in years to come the treatment armamentarium for patients with T1DM and CKD will expand, but in the meantime the cornerstone for prevention and treatment of CKD in these patients continues to be good glycemic, lipid, blood pressure, and weight management as well as judicious use of RAAS inhibition in the appropriate patients.

Additional Aspects of CKD and Cardiovascular Disease

In addition to its use as a biomarker of the progression of CKD, albuminuria also is recognized as a biomarker for the risk of cardiovascular disease. Albuminuria is associated with an increased risk of coronary artery disease (CAD), stroke, CHF, and arrhythmias, as well as microvascular disease.³¹ Urinary albumin excretion reflects widespread endothelial dysfunction, inflammation, myocardial capillary disease, and systemic vascular damage, which contributes to increased arterial stiffness and atherosclerosis and, thus, poor cardiovascular outcomes. This increased risk has been shown to be proportional to the level of albuminuria, and in some studies the cardiovascular risk is increased even at levels that are not considered to be abnormal.³² Despite this fact, screening for albuminuria still is low. Considering the importance of multidisciplinary management of patients with cardiovascular disease, it is crucial that clinicians managing such patients are aware of the benefits of albuminuria surveillance and management.³¹

Guidelines recommend that since patients with diabetes and albuminuria are at an increased risk for cardiovascular disease, measuring a serum brain natriuretic peptide (BNP) or a N-terminal pro-brain natriuretic peptide (NT-proBNP) level for select patients in whom a suspicion of heart failure exists may be prudent. (These markers are peptides secreted by the ventricular musculature in response to fluid or volume overload and have emerged as an important biomarker in the diagnosis of CHF). Thus, clinicians who encounter patients presenting with complaints consistent with CHF may consider proactively testing a BNP or an NT-proBNP to determine whether an echocardiogram to evaluate for CHF and/or a cardiology referral is warranted.¹⁸

Iron Deficiency in CKD

Iron deficiency in patients with CKD often is multifactorial. It is well known that CKD is associated with chronic inflammation. This inflammation can lead to elevated levels of the hormone hepcidin, a peptide hormone produced by the liver that plays a crucial role in iron homeostasis. Hepcidin blocks the absorption of iron from the gut and prevents the release of iron from storage sites in the liver and macrophages. Thus, the chronic inflammation and resultant elevated levels of hepcidin can result in a functional iron deficiency in patients with CKD.

A secondary effect of CKD is reduced hormone erythropoietin (EPO) production. This hormone, produced by the kidneys, stimulates the bone marrow to produce red blood cells (RBCs). In CKD, the diseased kidneys produce less EPO, leading to fewer RBCs, which can worsen iron deficiency.

Additionally, chronic blood loss can contribute to the iron deficiency often observed in CKD. Blood loss in this patient population can be from the gastrointestinal tract, from frequent blood testing, and/or from hemodialysis. During hemodialysis, there can be residual blood loss from the procedure itself (including blood retained in the dialyzer and blood tubing at the end of each dialysis treatment) or blood loss from puncture or insertion and/or removal of needles from hemodialysis vascular access. Couple this with the iron loss that can occur during dialysis (from exposure to dialysis tubing) and the decreased iron absorption that can occur as the result of elevated hepcidin levels and the uremic environment, and the patient can quickly develop iron deficiency.

Vitamin D in CKD

The 25-hydroxyvitamin D (25(OH)D) level is the most accurate way to measure vitamin D levels in patients with CKD. The Kidney Disease Outcomes Quality Initiative (KDOQI) recommends measuring these levels in CKD patients if they have plasma intact parathyroid hormone (PTH) levels above the target range for their stage of CKD. Vitamin D deficiency and insufficiency are common in CKD patients and are associated with poor outcomes and increased morbidity.

Mineral Bone Disorder in CKD

In CKD, the kidneys lose the ability to filter and excrete phosphate efficiently, leading to its accumulation. The kidneys are responsible for converting vitamin D into its active form, vitamin D3 calcitriol. In CKD, this process becomes impaired and leads to reduced intestinal absorption of calcium. The body, in turn, compensates by increasing PTH levels, which promotes phosphate release from bones, further contributing to hyperphosphatemia. Secondary hyperparathyroidism is caused by reduced calcium levels and high phosphate levels, which further stimulate the parathyroid glands, resulting in the secretion of more PTH. This, in turn, causes the bones to release both calcium and phosphate, further decreasing their levels in the bone. Fibroblast growth factor-23 (FGF-23) helps regulate phosphate metabolism by promoting its excretion and reducing calcitriol production. In CKD, the effectiveness of FGF-23 decreases, impairing phosphate regulation. All these in combination can result in hyperphosphatemia in CKD. Phosphate binders, both over-the-counter and prescription, are available to attempt to keep the phosphate level at 2.8 mg/dL to 4.5 mg/dL.

Hemoglobin A1c Considerations

CKD can affect the accuracy and interpretation of hemoglobin A1c (HbA1c) for many reasons. Some of the factors affecting this accuracy and interpretation include reduced RBC lifespan, iron deficiency (or iron therapy), dialysis, carbamylated hemoglobin (formed when hemoglobin reacts with cyanate, a byproduct of urea dissociation), the effect of erythropoiesis-stimulating agents, and metabolic acidosis. Some options for alternative testing to HbA1c include fructosamine and glycated albumin levels, which measure two to three weeks of glycemic control. Similarly, a continuous glucose monitor’s (CGM) glucose management indicator (GMI) value, which is calculated using the average glucose level as detected by the CGM, can be helpful.

Medication Considerations in Patients with Diabetes and CKD

Managing glucose in patients with diabetes who have a low eGFR requires careful monitoring and often adjusting or avoiding certain medications to prevent adverse effects, particularly hypoglycemia and lactic acidosis. In this section, some of the medications most commonly prescribed for glucose control to patients with diabetes are reviewed and necessary dose adjustments are discussed.

Metformin: Metformin is contraindicated if the eGFR is less than 30 mL/min. Dose adjustment is necessary for eGFR 30 mL/min to 45 mL/min to a maximal dose of 500 mg twice per day. This adjustment is necessary because of the increased risk of lactic acidosis at a lower eGFR, since metformin is renally excreted. Metformin-induced toxicity undoubtedly causes lactic acidosis; thus, an inappropriate dosage of metformin for the patient with CKD will increase the risk of lactic acidosis.

SGLT2 inhibitors: Most SGLT2 inhibitors are not recommended if the eGFR is < 30 mL/min/1.73 m². The reason that they are not recommended at this level is because SGLT2 inhibitors work by increasing glucose excretion via the kidneys, thus their glucose-lowering effects diminish with worsening kidney function. However, they may be prescribed with an eGFR < 30 mL/min/1.73 m² in certain cases for their renal-protective benefits.

GLP-1R agonists: The GLP-1R agonists generally have been considered safe to use in patients with mild to moderate kidney disease, and the FLOW trial has confirmed this.²⁸ However, because of their propensity to cause gastrointestinal upset, be wary if the patient develops nausea, vomiting, anorexia, and/or diarrhea or worsening renal function since acute-on-chronic renal disease can occur in this setting.

Dipeptidyl peptidase 4 (DPP-4) inhibitors: Dose adjustment is required for all the medications in this class based on the patient’s eGFR. (The exception is linagliptin, because it is metabolized through the liver.)

Insulin: Insulin may need to be adjusted as the result of impaired insulin clearance in patients with CKD. This impaired clearance can alter the action of insulin and increase the risk of dysregulated glucose levels.

Sulfonylureas: Glyburide should be avoided because of its prolonged half-life and the risk of hypoglycemia. For the same reason, glimepiride may need adjustment if the eGFR is < 60 mL/min/1.73 m².

Thiazolidinediones (TZDs) (pioglitazone): TZDs generally are safe to use with no dose adjustment in patients with decreased eGFR. Caution is needed in CHF patients (which often is associated with CKD) because as a class TZDs can cause fluid retention and may worsen CHF, so caution should be used.

Team Approach to Patients with CKD

In patients with CKD, a team approach to care can be quite beneficial. Consideration should be given to both the physiologic and psychologic effects that this disease has on the patient. Dietary referral can be quite helpful for patients both in the early and later stages of CKD, since diet has an effect on both the development and progression of the disease, especially as it relates to glucose management. Later, diet becomes critical as electrolyte abnormalities related to declining renal function begin to occur. In end-stage CKD, the patient may enter a catabolic state, and expert advice regarding protein is necessary.

Depression, psychological distress, cognitive impairment, and anxiety frequently affect CKD patients. The prevalence of depression in CKD patients is three to four times higher when compared to the general population and two to three times higher compared to patients with other chronic diseases; thus, referral to a social worker, psychologist, or psychiatrist often is necessary.³³

As mentioned previously, because of the need for further workup in some cases or for later stage management of CKD progression in others, referral to nephrology may become necessary. Lastly, timely consideration of referral to a vascular team is important when the need for vascular access becomes imminent as the patient enters CKD stage 4.

Summary

Chronic kidney disease, defined as an abnormality in either the uACR and/or in the eGFR, has become a major global public health problem with significant associated morbidity and mortality. Risk factors for the development of CKD in patients with diabetes include increased albuminuria, hyperglycemia, hypertension, dyslipidemia, obesity, and smoking. It should be emphasized that regardless of kidney disease etiology, strict blood glucose control is, on a group level, the single most important intervention to prevent the development of CKD in patients with T1DM and T2DM.¹

Management of the patient with diabetes and potential CKD starts with evidence-based screening for early diagnosis and prevention. This includes lifestyle modification, treatment of hyperglycemia, hypertension, and lipid abnormalities, as well as implementing the emerging treatment strategy promoting a four-pillared approach to the prevention and management of CKD in patients with T2DM. This approach has four established pillars of therapy (RAAS inhibition and the use of SGLT2 inhibitors, selective nsMRAs, and the GLP-1R agonist semaglutide) in the management of CKD in people with T2DM. For patients with T1DM, current treatment centers on good glucose control and management of blood pressure, lipids, and weight.

A team approach is important for all patients with diabetes for the long-term management of CKD and its sequelae because of the profound physiological and psychological effects of this chronic disease.

Frank Lavernia, MD, is a Volunteer Diabetologist at Caridad Center, Boynton Beach, FL.

Jack Johnson, BS, is a student at Florida Atlantic University.

The authors would like to thank Karla J. Holt, BS, and Sophie Pharand Dias, BS, for their graphics and illustrations contributions to this manuscript.

References

1. Nordheim E, Jenssen TG. Chronic kidney disease in patients with diabetes mellitus. Endocr Connect. 2021;10(5):R151-R159.

2. American Diabetes Association Professional Practice Committee. 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes—2024. Diabetes Care. 2024;47(Suppl 1):S219-S230.

3. Hussain S, Jamali MC, Habib A, et al. Diabetic kidney disease: An overview of prevalence, risk factors, and biomarkers. Clin Epidemiol Glob Health. 2021;9:2-6. https://doi.org/10.1016/j.cegh.2020.05.016

4. Hoogeveen EK. The epidemiology of diabetic kidney disease. Kidney Dial. 2022;2(3):433-442.

5. United States Renal Data System. 2019 USRDS Annual Data Report: Epidemiology of Kidney Disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2019.

6. Tuttle KR, Jones CR, Daratha KB, et al. Incidence of chronic kidney disease among adults with diabetes, 2015-2020. N Engl J Med. 2022;387(15):1430-1431.

7. Kovesdy CP. Epidemiology of chronic kidney disease: An update 2022. Kidney Int Suppl (2011). 2022;12(1):7-11.

8. GBD Chronic Kidney Disease Collaboration. Global, regional, and national burden of chronic kidney disease, 1990-2017: A systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2020;395(10225):709-733.

9. National Institute of Diabetes and Digestive and Kidney Diseases. Estimated glomerular filtration rates calculators. https://www.niddk.nih.gov/health-information/professionals/clinical-tools-patient-management/kidney-disease/laboratory-evaluation/estimated-gfr-calculators

10. Tonneijck L, Muskiet MH, Smits MM, et al. Glomerular hyperfiltration in diabetes: Mechanisms, clinical significance, and treatment. J Am Soc Nephrol. 2017;28(4):1023-1039.

11. Chagnac A, Weinstein T, Korzets A, et al. Glomerular hemodynamics in severe obesity. Am J Physiol Renal Physiol. 2000;278(5):F817-F822.

12. Bak M, Thomsen K, Christiansen T, Flyvbjerg A. Renal enlargement precedes renal hyperfiltration in early experimental diabetes in rats. J Am Soc Nephrol. 2000;11(7):1287-1292.

13. Vallon V, Komers R. Pathophysiology of the diabetic kidney. Compr Physiol. 2011;1(3):1175-1232.

14. Amin R, Ahn SY, Moudgil A. Kidney and urinary tract disorders. In: Dietzen D, Bennett M, Wong E, Haymond S, eds. Biochemical and Molecular Basis of Pediatric Disease, Fifth Edition. Academic Press; 2021:167-228.

15. Chang DR, Yeh HC, Ting IW, et al. The ratio and difference of urine protein-to-creatinine ratio and albumin-to-creatinine ratio facilitate risk prediction of all-cause mortality. Sci Rep. 2021;11(1):7851.

16. Agarwal R, Fouque D. The foundation and the four pillars of treatment for cardiorenal protection in people with chronic kidney disease and type 2 diabetes. Nephrol Dial Transplant. 2023;38(2):253-257.

17. Bakris GL, Weir MR. Angiotensin-converting enzyme inhibitor-associated elevations in serum creatinine: Is this a cause for concern? Arch Intern Med. 2000;160(5):685-693.

18. American Diabetes Association Professional Practice Committee. 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes—2025. Diabetes Care. 2025;48(Supplement_1):S239-S251.

19. Yau K, Dharia A, Alrowiyti I, Cherney DZI. Prescribing SGLT2 inhibitors in patients with CKD: Expanding indications and practical considerations. Kidney Int Rep. 2022;7(7):1463-1476.

20. Packer M. Lack of durable natriuresis and objective decongestion following SGLT2 inhibition in randomized controlled trials of patients with heart failure. Cardiovasc Diabetol. 2023;22(1):197.

21. Yau K, Dharia A, Alrowiyti I, Cherney DZI. Prescribing SGLT2 inhibitors in patients with CKD: Expanding indications and practical considerations. Kidney Int Rep. 2022;7(7):1463-1476.

22. Plewa MC, Bryant M, King-Thiele R. Euglycemic diabetic ketoacidosis. StatPearls [Internet]. StatPearls Publishing; 2024. https://www.ncbi.nlm.nih.gov/books/NBK554570/

23. Chow E, Clement S, Garg R. Euglycemic diabetic ketoacidosis in the era of SGLT-2 inhibitors. BMJ Open Diabetes Res Care. 2023;11(5):e003666.

24. Bakris GL, Agarwal R, Anker SD, et al. Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes. N Engl J Med. 2020;383(23):2219-2229.

25. Marcath LA. Finerenone. Clin Diabetes. 2021;39(3):331-332.

26. Naaman SC, Bakris GL. Diabetic nephropathy: Update on pillars of therapy slowing progression. Diabetes Care. 2023;46(9):1574-1586.

27. Sattar N, Lee MMY, Kristensen SL, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: A systematic review and meta-analysis of randomised trials. Lancet Diabetes Endocrinol. 2021;9(10):653-662.

28. Perkovic V, Tuttle KR, Rossing P, et al. Effects of semaglutide on chronic kidney disease in patients with type 2 diabetes. N Engl J Med. 2024;391(2):109-121.

29. Jankowski J, Floege J, Fliser D, et al. Cardiovascular disease in chronic kidney disease: Pathophysiological insights and therapeutic options. Circulation. 2021;143(11):1157-1172.

30. Rosenstein K, Tannock LR. Dyslipidemia in chronic kidney disease. In: Feingold JR, Anawalt B, Blackman MR, et al, eds. Endotext [Internet]. MDText.com, Inc.; 2024. https://www.ncbi.nlm.nih.gov/books/NBK305899/

31. Barzilay JI, Farag YM, Durthaler J. Albuminuria: An underappreciated risk factor for cardiovascular disease. J Am Heart Assoc. 2024;13(2):e030131.

32. Lessey G, Stavropoulos K, Papademetriou V. Mild to moderate chronic kidney disease and cardiovascular events in patients with type 2 diabetes mellitus. Vasc Health Risk Manag. 2019;15:365-373.

33. Simoes E, Silva AC, Miranda AS, et al. Neuropsychiatric disorders in chronic kidney disease. Front Pharmacol. 2019;10:932.