Age-Related Kidney Function Decline: Implications for SGLT2 Inhibitor and GLP-1 RA Therapy

Abstract

This research report delves into the intricate relationship between age-related kidney function decline and the pharmacological considerations for Sodium-Glucose Cotransporter-2 (SGLT2) inhibitors and Glucagon-Like Peptide-1 Receptor Agonists (GLP-1 RAs). While these medications offer significant benefits in managing type 2 diabetes mellitus (T2DM) and cardiovascular disease, their efficacy and safety are critically dependent on renal function, a parameter that undergoes substantial changes with aging. The report will explore the specific physiological alterations in the aging kidney, encompassing structural and functional modifications. It will then examine how these alterations influence the pharmacokinetic profile of SGLT2 inhibitors and GLP-1 RAs, affecting drug metabolism, excretion, and overall drug exposure. We will analyze current guidelines for dosage adjustments based on varying degrees of renal impairment, highlighting the limitations of existing creatinine-based estimations and exploring the potential of novel biomarkers. Finally, the report will discuss strategies for mitigating kidney-related side effects and optimizing therapeutic outcomes in geriatric patients receiving these medications, advocating for a personalized approach that integrates comprehensive renal assessment and meticulous monitoring.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

1. Introduction

The global prevalence of both T2DM and chronic kidney disease (CKD) is increasing, creating a significant overlap, especially within the geriatric population [1]. The aging kidney undergoes a series of structural and functional changes that render it more susceptible to injury and less efficient in maintaining homeostasis. These changes have profound implications for drug pharmacokinetics, influencing absorption, distribution, metabolism, and excretion (ADME). This is particularly relevant for medications like SGLT2 inhibitors and GLP-1 RAs, which have become cornerstones in T2DM management and cardiovascular risk reduction [2].

SGLT2 inhibitors work by inhibiting glucose reabsorption in the proximal tubule of the kidney, leading to increased urinary glucose excretion and subsequent reduction in plasma glucose levels [3]. GLP-1 RAs, on the other hand, enhance glucose-dependent insulin secretion and suppress glucagon secretion, also contributing to improved glycemic control [4]. However, both drug classes rely on adequate renal function for their efficacy and safety. Reduced glomerular filtration rate (GFR), a hallmark of age-related kidney decline, directly impacts the glucose-lowering effect of SGLT2 inhibitors and can alter the elimination half-life of GLP-1 RAs. Moreover, geriatric patients are more prone to adverse effects, such as volume depletion, electrolyte imbalances, and acute kidney injury (AKI), when treated with these medications.

This report aims to provide a comprehensive overview of the age-related changes in kidney function, their impact on SGLT2 inhibitor and GLP-1 RA pharmacokinetics, and strategies for optimizing the use of these agents in older adults.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

2. Physiological Changes in the Aging Kidney

The aging kidney undergoes a constellation of structural and functional changes, leading to a progressive decline in renal reserve and an increased vulnerability to insults. These changes are not uniform and exhibit significant inter-individual variability, making it challenging to predict the exact impact on drug pharmacokinetics.

2.1 Structural Changes

The most prominent structural change is a reduction in kidney mass, typically starting around the fourth decade of life [5]. This reduction is primarily due to a decrease in the number of nephrons, the functional units of the kidney. Nephron loss is accompanied by glomerulosclerosis, a scarring process that impairs glomerular filtration [6]. The remaining glomeruli may undergo compensatory hypertrophy, leading to increased single-nephron GFR, which can mask the overall decline in renal function in early stages [7].

Other structural changes include:

• Cortical thinning: A decrease in the thickness of the renal cortex, the outer layer of the kidney containing the glomeruli and proximal tubules.
• Medullary fibrosis: An increase in the deposition of collagen and other extracellular matrix proteins in the renal medulla, the inner layer of the kidney responsible for urine concentration.
• Arteriosclerosis: Thickening and hardening of the renal arteries and arterioles, leading to reduced blood flow to the kidneys.
• Cyst formation: An increased prevalence of renal cysts, which can further impair kidney function.

2.2 Functional Changes

These structural changes translate into several functional impairments, most notably a decline in GFR. GFR typically decreases by approximately 1 mL/min/year after the age of 40, although the rate of decline can vary considerably [8]. This reduction in GFR is associated with impaired clearance of creatinine, a commonly used marker of renal function. However, creatinine production also decreases with age due to reduced muscle mass, which can lead to an overestimation of GFR when using creatinine-based equations [9].

Other functional changes include:

• Reduced tubular function: Impaired ability of the renal tubules to reabsorb solutes and water, leading to increased sodium excretion and a higher risk of dehydration and electrolyte imbalances.
• Decreased renin-angiotensin-aldosterone system (RAAS) activity: Reduced ability of the kidneys to regulate blood pressure and fluid balance, increasing the risk of orthostatic hypotension.
• Impaired vitamin D activation: Reduced ability of the kidneys to convert vitamin D to its active form, leading to increased risk of osteoporosis and other bone disorders.
• Reduced erythropoietin production: Decreased production of erythropoietin, a hormone that stimulates red blood cell production, leading to increased risk of anemia.
• Reduced ability to concentrate urine: Reduced response of the collecting ducts to antidiuretic hormone (ADH), leading to nocturia and an increased risk of dehydration.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

3. Impact of Age-Related Renal Changes on SGLT2 Inhibitor and GLP-1 RA Pharmacokinetics

The age-related decline in kidney function significantly impacts the pharmacokinetics of SGLT2 inhibitors and GLP-1 RAs, affecting their efficacy, safety, and overall therapeutic outcomes. Understanding these changes is crucial for optimizing dosage regimens and minimizing the risk of adverse effects.

3.1 SGLT2 Inhibitors

SGLT2 inhibitors are primarily eliminated through renal excretion, making their pharmacokinetics highly dependent on GFR. As GFR declines with age, the renal clearance of SGLT2 inhibitors is reduced, leading to increased plasma concentrations and prolonged half-lives [10]. This can potentially enhance the risk of adverse effects, such as hypoglycemia, volume depletion, and AKI. It also reduces the efficacy of the drugs, because reduced GFR also means less glucose is filtered by the glomerulus in the first place and therefore less available for the inhibitor to work on.

Specific impacts include:

• Reduced glucose-lowering efficacy: The glucose-lowering effect of SGLT2 inhibitors is directly proportional to the amount of glucose filtered by the glomeruli and subsequently reabsorbed by SGLT2 in the proximal tubule [11]. As GFR declines, less glucose is filtered, reducing the amount of glucose available for SGLT2 inhibition. This results in a diminished glucose-lowering effect, especially in patients with moderate to severe CKD. The current guidelines reflect this, recommending cessation of empagliflozin and dapagliflozin below certain GFR thresholds.
• Increased risk of volume depletion: SGLT2 inhibitors induce osmotic diuresis, leading to increased urinary water and sodium excretion [12]. In older adults with impaired tubular function and reduced RAAS activity, this can exacerbate the risk of volume depletion, leading to orthostatic hypotension, dizziness, and falls.
• Increased risk of acute kidney injury (AKI): While SGLT2 inhibitors have demonstrated renoprotective effects in some clinical trials, they can also paradoxically increase the risk of AKI in certain individuals, particularly those with pre-existing renal impairment or volume depletion [13]. The mechanism is thought to be related to a combination of factors, including reduced renal perfusion, increased tubular sodium concentration, and activation of tubuloglomerular feedback. This is a contentious point because there is data supporting renoprotection in patients with CKD.
• Altered drug interactions: Reduced renal clearance can also affect the interactions of SGLT2 inhibitors with other medications. For example, concomitant use of diuretics or ACE inhibitors/ARBs can further increase the risk of volume depletion and hypotension. Concomitant use of NSAIDs can blunt the diuretic effect of SGLT2 inhibitors and worsen renal hemodynamics.

3.2 GLP-1 RAs

GLP-1 RAs are primarily eliminated through renal metabolism and excretion, although the relative contribution of each pathway varies depending on the specific agent [14]. Some GLP-1 RAs, such as exenatide, are primarily cleared by the kidneys, while others, such as liraglutide and semaglutide, undergo more extensive metabolism [15]. The impact of age-related renal decline on GLP-1 RA pharmacokinetics is therefore more complex and agent-specific.

Specific impacts include:

• Prolonged half-life and increased drug exposure: Reduced renal clearance can prolong the half-life of GLP-1 RAs, leading to increased plasma concentrations and potentially enhanced pharmacological effects [16]. This can be beneficial in terms of glycemic control but may also increase the risk of gastrointestinal side effects, such as nausea, vomiting, and diarrhea.
• Altered dose-response relationship: The dose-response relationship of GLP-1 RAs may be altered in older adults with renal impairment. Some patients may require lower doses to achieve the same level of glycemic control, while others may be less responsive to the medication [17].
• Increased risk of gastrointestinal side effects: GLP-1 RAs slow gastric emptying, which can lead to nausea, vomiting, and abdominal discomfort [18]. These side effects can be more pronounced in older adults with renal impairment, potentially leading to dehydration and electrolyte imbalances.
• Potential for drug accumulation: In patients with severe renal impairment, GLP-1 RAs may accumulate in the body, potentially leading to unpredictable adverse effects. This is particularly concerning for agents that are primarily cleared by the kidneys.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

4. Dosage Adjustments and Guidelines for Renal Impairment

Given the impact of renal function on SGLT2 inhibitor and GLP-1 RA pharmacokinetics, dosage adjustments are often necessary in patients with CKD. Current guidelines from organizations such as the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) provide recommendations for dose adjustments based on estimated GFR (eGFR) [19].

4.1 SGLT2 Inhibitors

The guidelines generally recommend the following for SGLT2 inhibitors:

• Mild renal impairment (eGFR 60-89 mL/min/1.73 m2): No dose adjustment is typically required, but renal function should be monitored regularly.
• Moderate renal impairment (eGFR 30-59 mL/min/1.73 m2): Some SGLT2 inhibitors, such as canagliflozin, are not recommended for initiation in this range [20]. Others, such as empagliflozin and dapagliflozin, can be used with caution at reduced doses, but their glucose-lowering efficacy may be diminished. The cardiovascular benefit is generally retained despite the lower GFR.
• Severe renal impairment (eGFR <30 mL/min/1.73 m2): SGLT2 inhibitors are generally not recommended for use in patients with severe renal impairment or end-stage renal disease (ESRD) due to lack of efficacy and increased risk of adverse effects. A retrospective analysis of CREDENCE trial found no benefit for Canagliflozin at eGFR <30 mL/min/1.73 m2.

However, it’s crucial to note that eGFR estimates based on creatinine may be inaccurate in older adults due to reduced muscle mass and creatinine production. Cystatin C based GFR may be a more accurate alternative but is not routinely used. Regular monitoring of renal function and clinical assessment are essential to guide dose adjustments and prevent adverse effects.

4.2 GLP-1 RAs

The dosage adjustment recommendations for GLP-1 RAs are more variable and agent-specific:

• Mild to moderate renal impairment: Most GLP-1 RAs can be used without dose adjustment in patients with mild to moderate renal impairment. However, caution is advised, and renal function should be monitored regularly.
• Severe renal impairment: Some GLP-1 RAs, such as exenatide, are not recommended for use in patients with severe renal impairment or ESRD [21]. Others, such as liraglutide and semaglutide, can be used with caution at reduced doses, but their efficacy and safety have not been extensively studied in this population. There is some evidence that Semaglutide can be used safely at eGFR >15ml/min/1.73 m2 [22].

It is important to carefully review the prescribing information for each specific GLP-1 RA and consider the individual patient’s characteristics, including age, comorbidities, and concomitant medications, when determining the appropriate dose.

4.3 Limitations of Creatinine-Based Estimations and Potential of Novel Biomarkers

As previously noted, creatinine-based eGFR estimations can be inaccurate in older adults, leading to inappropriate dosage adjustments and potential adverse outcomes. Several alternative biomarkers have been proposed to improve the accuracy of renal function assessment, including cystatin C, beta-2 microglobulin, and kidney injury molecule-1 (KIM-1) [23].

• Cystatin C: A small protein produced by all nucleated cells that is freely filtered by the glomerulus and reabsorbed by the proximal tubules. Cystatin C levels are less affected by muscle mass and diet compared to creatinine, making it a potentially more accurate marker of GFR in older adults [24].
• Beta-2 microglobulin: Another small protein filtered by the glomerulus and reabsorbed by the proximal tubules. Beta-2 microglobulin levels can be elevated in patients with tubular dysfunction, making it a useful marker of early kidney damage.
• Kidney injury molecule-1 (KIM-1): A transmembrane protein expressed on renal proximal tubular cells in response to injury. KIM-1 levels are elevated in patients with AKI and CKD, making it a promising biomarker for early detection of kidney damage [25].

While these novel biomarkers hold promise, they are not yet widely available in clinical practice. Further research is needed to validate their accuracy and clinical utility in older adults with CKD. The development and implementation of more accurate and accessible methods for assessing renal function are crucial for optimizing the use of SGLT2 inhibitors and GLP-1 RAs in this vulnerable population.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

5. Strategies for Mitigating Kidney-Related Side Effects in Geriatric Patients

Given the increased susceptibility of older adults to kidney-related side effects from SGLT2 inhibitors and GLP-1 RAs, several strategies can be implemented to mitigate these risks and improve therapeutic outcomes.

5.1 Comprehensive Renal Assessment

A thorough assessment of renal function is essential before initiating treatment with SGLT2 inhibitors or GLP-1 RAs in geriatric patients. This should include:

• Measurement of eGFR: Using creatinine-based equations with caution, considering the limitations of these estimations in older adults. Cystatin C measurement may be considered if creatinine-based eGFR is borderline or discordant with clinical findings.
• Assessment of urine albumin-to-creatinine ratio (UACR): To detect early signs of kidney damage and assess the risk of CKD progression.
• Evaluation of blood pressure and volume status: To identify patients at risk of volume depletion and hypotension.
• Review of concomitant medications: To identify potential drug interactions that could affect renal function.

5.2 Careful Dose Titration

Initiating treatment with low doses and gradually titrating upwards can help minimize the risk of side effects. Patients should be closely monitored for changes in renal function, volume status, and glycemic control during dose titration.

5.3 Patient Education and Monitoring

Comprehensive patient education is crucial to ensure adherence to medication regimens and early detection of potential side effects. Patients should be educated about:

• The importance of adequate hydration: To prevent volume depletion and reduce the risk of AKI.
• The signs and symptoms of dehydration: Such as dizziness, lightheadedness, and decreased urine output.
• The need for regular monitoring of blood glucose and blood pressure: To detect hypoglycemia and hypotension.
• The importance of reporting any new or worsening symptoms to their healthcare provider.

5.4 Management of Comorbidities

Optimizing the management of other comorbidities, such as hypertension, heart failure, and hyperlipidemia, can help protect kidney function and reduce the risk of adverse events. This may involve adjusting medications, implementing lifestyle modifications, and addressing underlying risk factors.

5.5 Avoiding Nephrotoxic Medications

Concomitant use of nephrotoxic medications, such as NSAIDs, aminoglycosides, and intravenous contrast agents, should be avoided whenever possible. If these medications are necessary, renal function should be closely monitored.

5.6 Personalized Approach to Therapy

A personalized approach to therapy is essential to optimize the use of SGLT2 inhibitors and GLP-1 RAs in geriatric patients. This involves considering the individual patient’s characteristics, including age, comorbidities, renal function, and medication profile, when selecting the appropriate medication and dosage regimen. It also involves regular monitoring and adjustments to the treatment plan as needed to ensure optimal efficacy and safety. This includes consideration of frailty, cognitive impairment and social support.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

6. Conclusion

The age-related decline in kidney function has significant implications for the use of SGLT2 inhibitors and GLP-1 RAs in older adults. Understanding the specific physiological changes in the aging kidney and their impact on drug pharmacokinetics is crucial for optimizing dosage regimens, mitigating kidney-related side effects, and improving therapeutic outcomes. While current guidelines provide recommendations for dose adjustments based on eGFR, the limitations of creatinine-based estimations should be recognized, and novel biomarkers should be explored to improve the accuracy of renal function assessment. A personalized approach to therapy, incorporating comprehensive renal assessment, careful dose titration, patient education, and management of comorbidities, is essential to ensure the safe and effective use of these medications in geriatric patients. Further research is needed to address the gaps in knowledge and optimize the management of T2DM and CKD in this vulnerable population. There is a pressing need for prospective, randomized controlled trials specifically designed to evaluate the efficacy and safety of SGLT2 inhibitors and GLP-1 RAs in older adults with varying degrees of renal impairment, incorporating more accurate measures of renal function and assessing outcomes relevant to this population, such as frailty, cognitive function, and quality of life.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

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