Going with the Flow: Updates in Diabetes and Chronic Kidney Disease

Abstract

Diabetes is a chronic condition that, if not managed appropriately, can lead to chronic kidney disease (CKD). As sustained hyperglycemia results in irreversible damage to renal microvasculature, thus leading to CKD, glycemic control optimization remains imperative to minimizing the incidence of CKD and promoting favorable participant outcomes.

Image credit: neirfy | stock.adobe.com

Recent American Diabetes Association (ADA) and Kidney Disease Improving Global Outcomes (KDIGO) guideline updates have provided more emerging evidence for the management of CKD in the setting of type 2 diabetes (T2D), including sodium-glucose co-transporter 2 (SGLT2) inhibitors, glucagon-like peptide 1 (GLP-1) agonists, and nonsteroidal mineralocorticoid receptor antagonists (ns-MRAs), which show promise in reducing CKD progression and cardiovascular events.

We aim to compare the current guidelines and supporting literature to further guide optimal treatment options and approaches when it comes to selecting appropriate pharmacotherapy.

Introduction

The prevalence of diabetes has been increasing in the US. In 2021, approximately 38.4 million (11.6%) of the US population had diabetes.¹ Due to chronic hyperglycemia and insulin resistance, many individuals with diabetes develop macrovascular complications such as heart disease, stroke, and peripheral vascular disease and microvascular complications such as retinopathy, nephropathy, and neuropathy.² Diabetes is a leading risk factor for chronic kidney disease (CKD) due to sustained hyperglycemia, which damages renal microvasculature. This impairment leads to compromised filtration and renal dysfunction. It is estimated that 1 in 3 people with diabetes will develop CKD, which has raised significant public health concern.^3,4

CKD is diagnosed based upon several lab factors, including estimated glomerular filtration rate (eGFR) and albuminuria. If not controlled, CKD can progress to kidney failure or the need for a kidney transplant. Per guidelines, it is recommended to optimize glucose management to reduce the risk or slow the progression of CKD. For anti-glycemic agents, there is emerging data regarding the use of sodium-glucose co-transporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 (GLP-1) agonists to reduce CKD progression and cardiovascular (CV) events. ⁵ There is also data supporting the use of nonsteroidal mineralocorticoid receptor antagonists (ns-MRAs) such as finerenone in reducing the risk of CV disease and CKD progression. ⁶

Pharmacists are the most accessible health care professionals.⁷ Therefore, it is imperative that they understand new evidence regarding type 2 diabetes (T2D) and CKD. The purpose of this article is to provide pharmacists with resources regarding T2D and CKD, including the most up-to-date guidelines and supporting literature review.

2025 American Diabetes Association (ADA) Guidelines

The 2025 ADA guidelines emphasize a holistic approach to improving outcomes in individuals with T2D and CKD. Following lifestyle modifications, SGLT2 inhibitors are recommended for individuals with eGFR ≥20 mL/min/1.73 m² and T2D, as they slow CKD progression and reduce heart failure risk independent of glucose management. The 2025 ADA guideline update additionally recommends the use of GLP-1 agonists with demonstrated benefit to reduce CV risk and kidney disease progression. For individuals with CKD (eGFR ≥ 25 mL/min/1.73 m²) and albuminuria, ns-MRA can be used to reduce CV events and CKD progression, with emphasis on potassium monitoring while receiving therapy. For non-pregnant individuals with hypertension and a urinary albumin-to-creatinine ratio (UACR) of 30–299 mg/g, renin-angiotensin system inhibitors (RASi) are recommended as first-line therapy, which should be titrated to the maximally tolerated dose. With the initiation of pharmacotherapy, the goal is to slow progression of CKD, as evidenced by a reduction of urinary albumin by ≥30%. Of note, there have been no studies directly comparing ns-MRAs, SGLT2 inhibitors, and GLP-1 agonists. As per ADA guidelines, health care professionals should utilize their best judgment as to which agent(s) to utilize.⁵

2024 Kidney Disease Improving Global Outcomes (KDIGO) Guidelines

The 2024 KDIGO guidelines review treatment and risk modifications in delaying CKD progression and managing complications. Similar to the 2025 ADA guidelines, KDIGO also emphasizes a holistic approach with lifestyle modifications followed by first-line therapy of SGLT2 inhibitors. KDIGO aims for systolic blood pressure of <120 mmHg with an RASi and targeted therapies for complications. SGLT2 inhibitors are recommended for people with T2D, CKD, and an eGFR ≥ 20 mL/min/1.73 m². Several pivotal randomized controlled trials, including Empagliflozin in Patients with Chronic Kidney Disease (EMPA-KIDNEY), Dapagliflozin in Patients with Chronic Kidney Disease (DAPA-CKD), and Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy (CREDENCE), have shown that SGLT2 inhibitors reduce the risk of kidney failure, CV mortality, and heart failure (HF) in people with CKD. It is important to note that the guidelines emphasize that once an SGLT2 inhibitor is initiated, it is reasonable to continue an SGLT2 inhibitor even if the eGFR falls below 20 mL/min/1.73 m², unless it is not tolerated or a kidney replacement therapy is initiated. Angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARB), if tolerated, are strongly recommended for people with CKD and moderately to severely increased albuminuria with or without diabetes. Regarding targeted therapies complications, an ns-MRA, such as Finerenone, is suggested with proven kidney or CV benefit for adults with T2D, an eGFR >25 mL/min/1.73 m², normal serum potassium concentration, and albuminuria (>30 mg/g) despite maximum tolerated dose of RASi. Lastly, in adults with T2D and CKD who have not achieved individualized glycemic targets despite the use of metformin and SGLT2 inhibitors or who are unable to use those medications, a long-acting GLP-1 agonist is recommended.⁶

Literature review

Non-steroidal mineralocorticoid receptor antagonist (MRA)

Finerenone (Kerendia)

Finerenone is an ns-MRA. Finerenone blocks MR-mediated sodium reabsorption and MR overactivation in both epithelial and nonepithelial tissues.⁸ Finerenone is the only ns-MRA with proven kidney and CV benefits, as demonstrated by two large clinical trials—Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD) and Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD). Finerenone is dosed as 10 mg or 20 mg taken by mouth once daily based on eGFR and potassium levels.⁸ Common side effects of finerenone include hyperkalemia, hypotension, and hyponatremia.

• In FIDELIO-DKD, a randomized, double-blind, placebo-controlled trial, participants with CKD and T2D who received finerenone had a significantly lower incidence of the primary composite outcome of kidney failure, a sustained decrease of at least 40% in the eGFR from baseline, or death from renal causes as compared to placebo. Participants in the finerenone group also had a significantly lower risk of death from CV causes, nonfatal myocardial infarction (MI), nonfatal stroke, or hospitalization from heart failure (HHF).⁹
• FIGARO-DKD, a randomized, double-blind, placebo-controlled trial, demonstrated that participants with CKD and T2D who received finerenone had a significantly lower incidence of death from CV causes, nonfatal MI, nonfatal stroke, or HHF as compared with placebo. The incidence of HHF was lower in the finerenone group as compared with placebo.¹⁰

SGLT2 inhibitors

SGLT2 inhibitors block the action of SGLT2 protein in the kidneys, which in turn leads to reduced glucose reabsorption in the kidney and increased glucose excretion in the urine. Empagliflozin and dapagliflozin are FDA approved for the treatment of HF and T2D, and canagliflozin is approved for the treatment of T2D.^11,12,13 More recently, data from 3 large clinical trials, EMPA-KIDNEY, DAPA-CKD, and CREDENCE have shown benefits in CKD. SGLT2 inhibitors are dosed once a day and are generally well tolerated. When initiating SGLT2 inhibitors, individuals with diabetes should be counseled to monitor for side effects such as increased urination and signs and symptoms of urinary tract infections and genital mycotic infections.

Empagliflozin (Jardiance)

In the EMPA-KIDNEY trial, an international, randomized, parallel-group, double-blind, placebo-controlled clinical trial, the progression of kidney disease or death from CV causes was lower in the empagliflozin group vs the placebo group. Furthermore, the rate of hospitalization from any cause was lower in the empagliflozin group than in the placebo group, but there were no significant between-group differences with respect to the composite outcome of hospitalization for HF or death from CV causes or death from any cause.¹⁴

Dapagliflozin (Farxiga)

DAPA-CKD is a randomized, double-blind, placebo-controlled, multicenter clinical trial. This trial included participants with and without diabetes. The primary outcome, which was a composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or CV causes, occurred in 197 of 2152 participants (9.2%) in the dapagliflozin group and 312 of 2152 participants (14.5%) in the placebo group.¹⁵

Canagliflozin (Invokana)

CREDENCE, a double-blind, randomized trial, demonstrated that the relative risk of the primary outcome composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m²), a doubling of the serum creatinine level, or death from renal or cardiovascular causes, was 30% lower in the canagliflozin group than in the placebo group. The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% and the relative risk of end-stage kidney disease was lower by 32%. The canagliflozin group also had a lower risk of CV death, myocardial infarction, or stroke and hospitalization for heart failure.¹⁶

GLP 1 Agonist

Semaglutide (Ozempic)

Semaglutide is a GLP-1 agonist which reduces blood glucose by stimulating insulin secretion and lowering glucagon secretion in a glucose-dependent manner.¹⁷Semaglutide also slows down gastric emptying which can lead to increased fullness and satiety after eating. Semaglutide is available as a weekly subcutaneous injection. It’s recommended as one of the first line agents for T2D and has proven highly effective in weight loss. Common side effects of this medication include gastrointestinal issues such as nausea, vomiting, diarrhea, constipation. More serious but rare side effects include pancreatitis and gallbladder disease. GLP-1 agonists carry a boxed warning for risk of thyroid c-cell tumors and is contraindicated in persons with personal or family history of medullary thyroid carcinoma or in persons with Multiple Endocrine Neoplasia syndrome type 2. Additionally, routine monitoring of thyroid is recommended.

In the FLOW trial (Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes), an international randomized double-blind, placebo-controlled trial, it demonstrated that participants with CKD and T2D in the semaglutide group had fewer incidence of major kidney disease as well as reduced risk of CV events and death from any cause.¹⁸

Discussion

These large clinical trials collectively support the use of ns-MRA, SGLT2 inhibitors, and GLP-1 agonists for individuals with CKD. FIDELIO-DKD demonstrated finerenone’s ability to reduce the risk of primary kidney outcomes while FIGARO-DKD demonstrated finerenone’s ability to reduce the cardiovascular composite primary outcomes and were complementary trials of each other.^8,9 The CREDENCE trial led to the US FDA approval to reduce the risk of end stage renal disease (ESRD) and CV events in adults with T2D and CKD with albuminuria. Additionally, this trial led to the DAPA-CKD trial which expanded to include adults with or without T2D.¹⁵ Lastly, the EMPA-CKD trial aimed to further include a large population of participants without diabetes and with low levels of albuminuria.¹⁴ The FLOW trial is the first trial to demonstrate major renal outcomes for GLP-1 agonists.¹⁸ However, limitations that exist among these trials, such as differing definitions of CKD, inclusion/exclusion criteria, and diagnosis of diabetes, can affect generalizability across clinical settings. Populations such as those with nonalbuminuric CKD, lower risk of CKD, no diabetes, comorbidities who were excluded, and did not identify as white remain underrepresented.

These trials advanced management of CKD in individuals with or without diabetes. There are several opportunities for future investigation and tailored therapies. Ns-MRA could be favorable in people with CKD and T2D who have new-onset or preexisting heart failure. Given the promising results from the FLOW trial and its demonstration of reduced risk of major kidney disease, future studies could explore other GLP-1 agonists. Additionally, KDIGO guidelines could include use of GLP-1 agonist in people with CKD and T2D with greater confidence. Furthermore, future studies could also include variations of combinations between finerenone, SGLT2 inhibitors, and GLP-1 agonists.

Conclusion

The 2025 ADA and 2024 KDIGO Guidelines both emphasize the importance of lifestyle modifications as first line management followed by the use of SGLT2 inhibitors, which carries proven benefit in the setting of CKD. The use of finerenone continues to be noted in both guidelines as an add-on to CKD management in T2D, with pivotal trials showing benefits in reducing CV events and CKD progression. GLP-1 agonist use remains of interest, as illustrated in the FLOW trial, which demonstrated the benefit of semaglutide use in this population as an add-on if people with CKD and T2D are not meeting their glycemic goals. Guideline updates provide more insight into the use of GLP-1s and their benefit in CKD. The future of CKD treatment in the setting of diabetes is promising. Currently there are future trials in the works on the renal outcomes of GLP-1 therapy and other novel agents.¹⁹ In the clinical setting, agent selection should be driven by the mechanism of action of the agent, CKD and CV benefit, and tolerability. Routine follow-ups and lab monitoring will help to ensure safe and effective agent selection.

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