The use of SGLT2 inhibitors and GLP-1 receptor agonists in older patients: a debate on approaches in CKD and non-CKD populations

ABSTRACT

The management of CKD in older patients presents a significant challenge in modern medicine. As the global population ages, the prevalence of CKD among older adults is increasing, which demands effective and safe treatment strategies. The introduction of sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists has revolutionized the treatment of CKD, offering potential benefits beyond traditional therapies. However, their use in the older population raises essential questions about safety and efficacy, given the unique physiological changes and comorbidities associated with aging. In this CKJ controversy paper, Roberto Minutolo (PRO) and Sophie Liabeuf (CON) debate on the use of SGLT2 inhibitors and GLP-1 receptor agonists in older patients with CKD. Roberto Minutolo advocates the benefits of these medications, highlighting their role in improving cardiovascular outcomes and slowing CKD progression in older patients. He emphasizes the importance of personalized treatment plans based on the patient's cardio-renal risk profile and preferences. In contrast, Sophie Liabeuf expresses concerns about the safety of these drugs in older adults, citing risks such as fractures, acute kidney injury, and urinary tract infections. She argues that treatment decisions should be guided by patient frailty rather than chronological age, as frail individuals are more vulnerable to adverse drug effects. Both contenders agree on the need for more inclusive clinical trials to better understand the impact of these treatments on older populations. While Roberto Minutolo and Sophie Liabeuf present differing perspectives on the use of SGLT2 inhibitors and GLP-1 receptor agonists in older patients with CKD, their views can be seen as complementary rather than strictly opposing. Minutolo's focus on the benefits of these drugs underscores their potential to improve outcomes. Liabeuf's emphasis on caution and the consideration of frailty highlights the need for careful

patient assessment. Both agree on the importance of personalized treatment and the inclusion of older patients in future clinical trials, suggesting a shared goal of optimizing care for this vulnerable population. Their debate underscores the complexity of treatment decisions and the necessity of balancing risks and benefits in managing CKD in older adults.

INTRODUCTION

In recent decades, the global aging population has led to a significant increase in the prevalence of chronic diseases, including diabetes and hypertension, which are primary risk factors for CKD. This rise has resulted in a parallel increase in the incidence of CKD, along with related mortality and disability. CKD is particularly concerning in older patients, as kidney function tends to decline with age, and the presence of comorbidities further complicates the clinical management of these patients.

Addressing CKD in the elderly is crucial because old age is associated with a high risk of cardiovascular events and mortality. Additionally, CKD can lead to a reduced quality of life due to debilitating symptoms, cognitive defects and the need for complex treatments such as dialysis. Therefore, effective management of CKD in the elderly is essential to improve clinical outcomes and reduce the overall healthcare burden.

Recently, sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists have emerged as promising therapies for delaying CKD progression and improving cardiovascular outcomes in patients with type 2 diabetes. The latest 2024 KDIGO guidelines recommend the use of SGLT2 inhibitors as a first-line strategy for delaying CKD progression, while GLP-1 receptor agonists should be preferred as a second-line treatment in diabetic kidney disease (DKD) when glycemic control is not achieved despite the use of SGLT2 inhibitors or in patients unable to use SGLT2 inhibitors [1].

However, applying these guidelines to older patients remains a matter of debate. The elderly and in particular frail older patients are commonly underrepresented in randomized clinical trials (RCTs), making it difficult to assess the efficacy and safety of these drugs in this population compared with younger adults. Additionally, concerns about potential adverse effects in older patients, such as fracture risk, acute kidney injury, and urinary tract infections, further complicate therapeutic decision-making.

This debate between Sophie Liabeuf and Roberto Minutolo explores differing perspectives on using SGLT2 inhibitors and GLP-1 receptor agonists in older patients with and without CKD. Minutolo presents the PRO position, emphasizing the potential benefits and advocating for broader use. Sophie Liabeuf advocates the CON position, highlighting safety concerns and the need for cautious implementation. Both authors agree that it is essential to include a sufficient number of older patients in clinical trials to better understand the safety and efficacy of these treatments in this vulnerable population.

PRO POSITION, ROBERTO MINUTOLO

In the last 25 years, population growth, aging, and the related expanding prevalence of diabetes and hypertension have led to a marked increase in the incidence of CKD worldwide with a parallel increment in related death and disability. Most recent guidelines recommend the use of SGLT2 inhibitors (SGLT2is) as first-line strategy for delaying progression of CKD. GLP-1 receptor agonists (GLP-1-RAs) should be preferred as second line in DKD when, despite the use of SGLT2is, glycemic control is not achieved or in patients who are unable to use SGLT2is. The efficacy data of these new classes of drugs as well as their safety profile have not been extensively investigated in older patients with CKD and a correct placement of these drugs in the older population remains a matter of debate (Table 1).

Table 1:

Decision for prescribing either SGLT2i or GLP-1 RA for optimization of cardiac and kidney protection in patients with diabetic kidney disease.

SGLT2is and GLP-1-RAs have considerable cardio-renal benefits and are currently indicated as preferred agents in patients with CKD [1]. However, despite the remarkable clinical results provided by RCTs, the uptake of these classes of drugs remains, low especially in older patients [2]. This may be due to the low representation of older adults in RCTs, implying difficulties in assessing their efficacy in older patients compared with younger adults as well as to concerns relating to potential adverse effects and polypharmacy in older patients. It is important to remember that guidelines serve as a general reference for populations, but physicians must tailor treatments to individual patients based on their specific clinical conditions and preferences. Therefore, it is critical to disentangle from the current literature the efficacy and safety data in older populations.

SGLT2 inhibitors

In terms of efficacy, a recent meta-analysis of 13 RCTs testing SGLT2is in >90 000 patients with and without type 2 diabetes (T2DM) demonstrated a reduced risk of kidney progression versus placebo [hazard ratio (HR) 0.63, 95% confidence interval (CI) 0.58–0.69] irrespective of primary kidney disease [3]. In addition, SGLT2is significantly reduced the risk of cardiovascular death or hospitalization for heart failure, cardiovascular death alone, and all-cause death by 23%, 14%, and 11%, respectively. These data, therefore, provide the most solid evidence supporting the use of SGLT2is to improve the global outcome (cardiovascular, kidney, and mortality risk) in a large spectrum of clinical conditions (at high risk of atherosclerotic cardiovascular disease, heart failure, and CKD) [1]. However, when implementing these findings, it is important to consider that RCTs usually enroll selected populations not always representative of the population followed in daily clinical practice. This has been proven in the case of the DAPA-CKD trial, whose generalizability to patients regularly seen in renal clinics did not exceed 20% [4]. Consequently, it is particularly important to consider whether the beneficial effects are modified by age because the older population is growing in renal clinics. Such data are provided by subgroup analyses of RCTs in the CKD population evaluating the effect of SGLT2is on kidney outcome in older patients [5–7]. They consistently found that age does not act as a modifier of the protective effect of SGLT2is. Indeed, the subgroup of older CKD patients exhibited a renal risk reduction not different from that in younger participants (Fig. 1A). Similarly, in those studies no heterogeneity was reported when patients were stratified by eGFR level (Fig. 1B); patients with higher eGFR were protected from renal events to the same extent as that reported in patients with more advanced CKD, thus supporting the use of these drugs across the whole CKD spectrum. Similarly, when CKD progression was assessed using the eGFR slope, no difference in SGLT2i benefits depending on age were detected [5–8].

Figure 1:

Risk of primary kidney outcome by age (A) and by eGFR (B) in patients receiving SGLT2is in large randomized clinical trials.

The greater kidney protection with SGLT2is reported in the elderly must be balanced with adverse events. In particular, genito-urinary infections (mycotic and bacterial) and volume depletion are relevant in older populations because the incidence of urinary tract infection is high in patients with T2DM and increases with age [9]. On the other hand, the impaired ability for urine concentration occurring with aging may potentially expose the older population to volume depletion [9]; this must be considered because older patients, particularly if CKD coexists [10], usually receive diuretics more frequently due to a higher burden of cardiovascular comorbidities [11]. Indeed, in the CREDENCE trial the incidence of urinary tract infections as well as the incidence of volume depletion was higher in elderly patients receiving either canagliflozin or placebo [6]. However, the risk of mycotic genital infections with canagliflozin as compared with placebo significantly increased only in older subjects (HR 2.38, 95% CI 0.91–6.19, HR 7.56, 95% CI 2.28–25.11, and 3.11 95% CI 1.00–9.64 in patients aged <60 years, 60–69 years and ≥70 years, respectively [6].

GLP-1 receptor agonists

GLP-1-RAs are less extensively studied in CKD patients. Indeed, major RCTs with this class of drugs are placebo-controlled cardiovascular outcome trials (CVOTs) that mainly focused on cardiovascular events rather than on kidney outcomes. In a meta-analysis including eight CVOTs with 60 000 participants with T2DM, the risk of major atherosclerotic cardiovascular events (MACEs) was significantly reduced (by 14%; HR 0.86, 95% CI 0.80–0.93), as were the single components of the composite MACE endpoint (death from cardiovascular causes, myocardial infarction, and stroke were reduced by 13%, 10%, and 17%, respectively) [12]. The beneficial effect of GLP-1-RAs extended to all-cause mortality (HR 0.88, 95% CI 0.82–0.94, P = 0.0001) and, more importantly, it was similar in patients without established cardiovascular disease (primary prevention) and in those with cardiovascular disease at baseline (secondary prevention) [12]. The analysis of a composite kidney outcome disclosed a significant protective effect of GLP-1-RAs (HR 0.79, 95% CI 0.73–0.87, P < 0.0001); however, this result was mainly driven by the reduced risk of developing increased albuminuria (macroalbuminuria). Indeed, when restricting the kidney outcome to the worsening of kidney function, the protective effect of GLP-1-RAs was non-significant (HR 0.86, 95% CI 0.72–1.02, P = 0.09) [12]. This discrepancy likely relates to the fact that studies with GLP-1-RAs included in this meta-analysis enrolled patients with T2DM and relatively preserved kidney function (mean eGFR of participants ranged from 72 to 80 mL/min per 1.73 m²).

More recently, the FLOW trial tested the effect of semaglutide on a primary kidney outcome (composite of dialysis, transplantation, eGFR of <15 mL/min per 1.73 m², eGFR reduction from baseline ≥50%, or death from kidney-related or cardiovascular causes) in a typical CKD population with T2DM (i.e. eGFR 25–75 mL/min per 1.73 m² and albuminuria 100–5000 mg/g) [13]. In comparison with placebo, patients receiving semaglutide had a 24% lower risk of a renal event (HR 0.76, 95% CI 0.66–0.88, P = 0.0003) and a slower decrease of the eGFR slope by 1.16 mL/min/year (95% CI 0.86–1.47). Subgroup analyses evidenced that the protective effect of semaglutide was irrespective of eGFR level and occurred similarly across age groups (HR 0.71, 0.85, and 0.63 in patients aged <65, 65–74 and ≥75 years, respectively) [13].

The metabolic effects of GLP-1-RA apparently are similar in older and younger patients. In a pooled analysis of six trials testing dulaglutide versus placebo in 5171 patients with T2DM, no difference was found between younger (<65 years) and older (≥65 years) patients in the decline in HbA1c and body weight, and in the incidence of gastrointestinal side effects [14]. A post hoc analysis of the REWIND trial expanded the similarity between younger and older patients to the protective effects of dulaglutide on the risk of MACEs (P for interaction 0.797) and mortality (P for interaction 0.329), with a similar occurrence of side effects (severe hypoglycemic events, incidence of serious renal or urinary events, serious gastrointestinal events, serious cardiac conduction disorders) [15]. Again, taking into account the potential differences between the trial setting and the real world, a closer follow-up is required in older patients; indeed, the reduced intake of nutrients observed with GLP-1-RA therapy obviously includes salt and therefore may expose them to a higher risk of volume depletion.

The choice between SGLT2 inhibitors and GLP1 receptor agonists

A direct comparison between these two classes of drug would help physicians in deciding the most effective strategy, but unfortunately, RCTs comparing SGLT2is and GLP-1-RAs head-to-head are lacking. Three recent observational analyses shed some light on the difference between SGLT2is and GLP-1-RAs in kidney outcomes. Fadini et al. retrospectively evaluated the eGFR decline and albuminuria changes in 10 402 patients with T2DM starting either SGLT2i or GLP-1-RA matched by propensity score; the mean age was 61 years and eGFR was 87 mL/min per 1.73 m² (23% with CKD) [16]. Over 2.1 years of follow-up, they found a slower eGFR decline in patients treated with SGLT2is as compared with GLP-1-RAs (−1.1 and −1.6 mL/min/year, respectively) and a 36% lower risk of creatinine doubling with SGLT2is [16]. These results were unchanged after the removal of patients with CKD at baseline. A second retrospective study evaluated 29 146 veterans with T2DM and baseline eGFR >20 mL/min per 1.73 m² initiating SGLT2is or GLP-1-RAs matched by propensity score [17]. During an observation period of up to 36 months, they confirmed a better outcome with SGLT2is versus GLP-1-RAs (HR 0.65, 95% CI 0.62–0.68, P < 0.001) for the composite endpoint (≥40% decline in eGFR, ESKD and all-cause mortality), as well as for the single components. In addition, eGFR was better preserved in patients receiving SGLT2is. Finally, a real-world study using a population-based database of patients with T2DM in Hong Kong compared SGLT2is and GLP-1-RAs after propensity-score matching [18]. The authors found that SGLT2i users had a significantly 23% lower risk of composite kidney outcomes (mainly dependent on a reduction in ESKD) and a slower eGFR decline than GLP-1-RA users (−1.19 versus −1.95 mL/min/year, P < 0.01). A nationwide, longitudinal study in Taiwan in which 320 210 patients were stratified according to frailty index rather than by age further supports a lower risk of ESKD with SGLT2is versus GLP-1-RAs in all frailty categories [19]. Overall, these findings suggest that SGLT2is could be considered as preferred agents for kidney protection in patients with T2DM and preserved kidney function. This hypothesis will be verified by the PREvention of CardIovascular and DiabEtic kidNey Disease in Type 2 Diabetes (PRECIDENTD) trial, which will randomize 6000 patients with T2DM, established atherosclerotic cardiovascular disease, or CKD stage 3 to receive SGLT2is or GLP-1-RAs to compare the risk of first and recurrent cardiovascular, kidney, and death events during a mean follow-up of 3 years (https://clinicaltrials.gov/study/NCT05390892).

While waiting for the results of this trial, expected in early 2029, the preferential use of either SGLT2is or GLP-1-RAs can be established based on the patient's cardio-renal risk profile and the different metabolic effects of these two classes of drugs. GLP-1-RAs provide better control of HbA1c and larger body weight reductions than SGLT2is [20], thus supporting their use as the preferred drug in obese patients and in those with poor glycemic control. Patients at higher risk of heart failure may benefit more from SGLT2is than from GLP-1-RAs for their superior ability to prevent hospitalization for heart failure, while GLP-1-RAs provide advantages in protecting from the risk of stroke [21]. When kidney measures (eGFR and albuminuria) are considered, impaired kidney function predicts a better cardiovascular risk reduction with SGLT2is. At the same time, GLP-1-RAs could be preferred for patients with normal eGFR because they confer better cardiovascular protection than SGLT2is [22]. Regarding CKD progression, SGLT2is seem preferable for reducing the risk of faster eGFR decline or ESKD. The presence of an anti-albuminuric effect with both classes of drugs may suggest the use of GLP-1-RAs in albuminuric patients with low eGFR when SGLT2is are contraindicated. It is important to note, however, that in patients with T2DM and increased albuminuria the combination of these two classes is a feasible option and it may provide better results in term of cardio-renal protection as compared with the use of each drug alone [23].

CON POSITION, SOPHIE LIABEUF

SGLT2is and GLP-1-RAs offer significant benefits for older patients with CKD, but their use raises specific safety concerns. Certain safety signals may be more pronounced or more complex to manage in older patients with CKD compared with those without, such as the potential fracture risk associated with SGLT2is, acute kidney injury linked to GLP-1-RAs, and early declines in eGFR with SGLT2is. These concerns about possible complications may lead to suboptimal adherence to treatment guidelines in older patients with CKD compared with those without CKD.

Traditionally, chronological age has been considered a critical factor in determining treatment plans, including drug prescriptions. However, emerging evidence suggests that frailty, rather than age alone, plays a more crucial role in how individuals respond to medications. Frailty is a multidimensional syndrome that involves a decline in physiological reserves and increased vulnerability to stressors. It affects multiple systems, including the musculoskeletal, cardiovascular, and immune systems, leading to an increased risk of adverse outcomes such as falls, hospitalization, and mortality. Frailty is more prevalent among individuals with CKD than in the general population. Studies suggest that up to 40% of patients with CKD exhibit some degree of frailty, with the prevalence increasing as kidney function declines. For those undergoing dialysis, frailty rates can be as high as 70% [24]. In CKD patients, polypharmacy poses a particular challenge due to the delicate balance needed to manage multiple comorbidities while minimizing the risk of drug toxicity. Even though SGLT2is and GLP-1-RAs have shown promising results in CKD patients, their prescription must consider polypharmacy and patient frailty.

In addition, the magnitude of expected health benefits varies greatly by age and health status. While GLP-1-RAs and SGLT2is have substantial health benefits for many older adults with T2DM and CKD, for patients with limited life expectancy the focus often shifts toward improving quality of life through CKD or cardiovascular prevention. Therefore, life expectancy and patient preferences are important considerations when prescribing these newer diabetes medications.

To determine if a drug is safe and effective for use in older adults and patients with CKD, it is essential to include a sufficient number of these individuals in clinical trials. Excluding them may prevent identifying safety concerns and effectiveness outcomes specific to this population, making it challenging to assess the overall risk-to-benefit ratio. Several SGLT2i- and GLP-1-RA-specific trials (DAPA-CKD, EMPA-KIDNEY, CREDENCE, FLOW, SUSTAIN-6) have included CKD patients; however, the number of patients with CKD included may not be sufficient to reveal rare adverse drug reactions (ADRs). Indeed, some ADRs associated with these medications could warrant particular attention in older patients with CKD compared with those without CKD. Moreover, to date, patients with an eGFR <20 mL/min per 1.73 m², those receiving dialysis, and kidney transplant recipients have not been included in clinical trials, which excludes these individuals from receiving prescriptions based on their marketing authorization and may potentially deprive them of an adequate treatment opportunity.

The implementation of these new antidiabetic medications for CKD patients, particularly SGLT2i guidelines, has encountered challenges in clinical practice, especially among those without concurrent T2DM [25]. Indeed, a recent cross-sectional study in a real-world setting of adults with advanced CKD registered with UK primary care practices had shown that, of those indicated for treatment, SGLT2is were prescribed to 22% with co-existing CKD and type 2 diabetes, and <0.1% with CKD without T2DM. The lack of implementation of these treatments in the CKD population may be attributed to concerns about adverse effects. Below, we will discuss the specific safety signals that may be more pronounced and challenging to manage in older patients with CKD than those without CKD.

Fracture risk with SGLT2 inhibitors

The effects of SGLT2is on the risk of fractures remain controversial. They may vary across different agents. In the Canagliflozin Cardiovascular Assessment Study (CANVAS), canagliflozin treatment was associated with a 26% higher overall fracture rate than placebo (HR 1.26, 95% CI 1.04–1.52). Most of these fractures were low-trauma and were balanced between the upper and lower limbs [26]. Following the interim results of the CANVAS trial, the US Food and Drug Administration (FDA) issued a warning in 2015 regarding the increased risk of bone fractures associated with canagliflozin [27]. In individuals over 65 who have both T2DM and CKD—conditions that independently contribute to increased skeletal fragility—introducing a treatment that might raise the risk of fractures could appear risky. Among the proposed mechanisms for the increased fracture risk, the most discussed are a higher risk of falls due to hypoglycemia, volume depletion, or postural hypotension, and increased bone turnover linked to weight loss. Additionally, SGLT2is influence multiple interconnected mineral and bone metabolism pathways. These include effects on electrolyte and calcium/phosphorus metabolism, increased PTH levels, and reduced 1,25-(OH)-vitamin D levels. These factors are especially significant in individuals with CKD, who are more prone to alterations in bone quality given the highly prevalent CKD-related mineral and bone disorder, in particular in advanced CKD. However, evidence of increased fracture risk was not confirmed in real-world studies involving diabetic patients [28] or in those with CKD [29]. Nevertheless, a bone mineral density (BMD) and fracture risk evaluation should be considered for CKD patients, especially older CKD patients, before prescribing canagliflozin. For other molecules in the same class, clinical studies and meta-analyses have not clearly demonstrated a significant increase in the risk of fractures.

Acute kidney injury/decline in eGFR

The increasing utilization of GLP-1-RAs in the management of diabetes, obesity, and cardiovascular and kidney protections have been accompanied by an increase in reports of kidney-related adverse events. Specifically, there have been documented cases associating GLP-1 agonists with acute interstitial nephritis (AIN) [30]. The possible risk factors for GLP-1 agonist-induced AIN include CKD, advanced age, obesity, and concurrent administration of medications that cause AIN (such as proton pump inhibitors) [30]. As with many other potentially nephrotoxic drugs, patients with pre-existing CKD are at an increased risk of developing acute kidney injury, necessitating cautious use of these agents.

The major SGLT2i outcome trials have reported an early decline in eGFR (around 3–6 mL/min per 1.73 m²) shortly after initiating these drugs compared with placebo controls. These early declines were typically observed at 2–4 weeks after initiation of the SGLT2i, with subsequent partial recovery of the eGFR curve by week 12. In patients with CKD, the management of this sudden decline in eGFR could be more complicated with modifications to concomitant medications to prevent the risk of accumulation and associated adverse effects. So, this decline in eGFR may pose a more significant barrier to prescription for older patients with CKD than those without. Indeed, a recent report in CKD patients presented a discontinuation rate with SGLT2is reaching ∼10% at 6 months, surpassing rates in trial contexts. The decline in eGFR was the principal cause of discontinuation, observed in two-thirds of the instances [31]. Nephrologists play a pivotal role in discerning the underlying causes of GFR decline and optimizing concomitant medications such as RAS inhibitors and diuretics. Note that among older adults with type 2 diabetes with or without CKD, initiation of an SGLT2i was associated with a reduced risk of AKI compared with initiation of a DDP-4 inhibitor or a GLP-1-RA [32].

Other safety issues

Different safety signals have been additionally discussed with the use of GLP-1-RAs, such as the risk of suicidal thoughts and thoughts of self-harm, and pancreatic and thyroid cancers. However, these concerns remain controversial and none of these potential risks have explicitly been reported to be increased in the context of CKD [33].

One of the most frequently reported ADRs of SGLT2is is an increased risk of urinary tract infections [34]. The mechanism behind this is related to the increased urinary glucose excretion, which creates an environment conducive to the growth of pathogens. In a recent report among US veterans with diabetes from the Veterans Affairs healthcare system, compared with DPP4i use, SGLT2i use was associated with lower infection-related and genitourinary infection hospitalization risk. Analyses in non-CKD patients and CKD showed similar findings [35].

SGLT2is are rarely associated with euglycemic diabetic ketoacidosis, resulting in a US FDA warning in 2015. In the clinical trials including CKD patients, in CREDENCE the incidence of diabetic ketoacidosis was higher with canagliflozin treatment, although absolute rates were low (2.2 vs 0.2 per 1000 patient-years). In DAPA-CKD no cases of DKA were reported with dapagliflozin treatment; however, all patients should receive counseling regarding ‘sick day’ medication management upon SGLT2i prescription.

A rare but serious genital infection known as Fournier's gangrene has been reported in patients taking SGLT2is. Once again, we are unaware of any reports comparing the frequency of this kind of event between older CKD patients and non-CKD patients.

In conclusion, the safety profile of GLP-1-RAs and SGLT2is appears to be close between older patients with and without CKD. However, greater caution is warranted in patients with CKD. First, collective post-marketing safety surveillance should be conducted, as some rare adverse events may not have been detected due to the limited number of CKD patients included in the trials. At the prescribing level, several precautions should be more specific to CKD patients, such as assessing fracture risk before prescribing specific SGLT2is and reassessing concomitant medications in cases of early decline in eGFR in moderate stages. Furthermore, concerns about potential complications with these drugs may lead to poorer implementation of guidelines in older patients with CKD compared with those without.

CONCLUSION

The debate between Dr Minutolo and Dr Liabeuf underscores the complexity of treating older patients with CKD. While Liabeuf's concerns about safety and frailty are valid, Minutolo's emphasis on the potential benefits and the need for individualized treatment plans highlights the importance of balancing risks and rewards (Fig. 2). Both perspectives agree that including older patients in clinical trials is necessary to understand better these treatments' safety and efficacy in this demographic. Even more important will be real-world data in such patients, whenever they receive both SGLT2i plus GLP-1-RA.

Figure 2:

Benefit–risk balance of SGLT2i and GLP-1 agonist treatments in older patients with CKD.

CONFLICT OF INTEREST STATEMENT

R.M. has been a member of advisory boards for Amgen, Astellas, Bayer, and GSK and has received fees for lectures from these companies, as well as from Astra Zeneca, Bayer, Boehringer-Lilly, and Vifor Pharma. S.L. and C.Z. reported no disclosure. J.F. reported lecture and/or consultancy honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, and CSL Vifor; he also served on data safety monitoring boards of trials by NovoNordisk and currently AstraZeneca.