Sodium-Glucose Cotransporter 2 Inhibitors in Older Patients with CKD

The indication for sodium-glucose cotransporter 2 (SGLT2) inhibitors to slow the progression of kidney function decline has expanded from glucose lowering in patients with type 2 diabetes mellitus to include patients with CKD with or without type 2 diabetes mellitus.1,2 Unfortunately, despite this expanding indication, many patients with CKD who qualify for treatment with an SGLT2 inhibitor do not receive this drug. Low rates of utilization are particularly evident among older patients with CKD3,4 despite high rates of kidney failure and cardiovascular events in older patients. For instance, in a Canadian registry of patients with CKD and type 2 diabetes mellitus who were eligible for SGLT2 inhibitor prescription, the likelihood of prescription decreased steeply with age.3 Why are SGLT2 inhibitors underutilized in older patients? This may be in part due to employment-based drug coverage, as in some countries (e.g., the United States), retirement in older patients could affect drug coverage. However, underutilization of SGLT2 inhibitors among older patients has also been reported in countries where access to medication does not depend on employment status (e.g., Sweden).4 Safety-related and efficacy-related considerations also play an important role in underutilization of SGLT2 inhibitors among older patients. First, some clinicians may consider that SGLT2 inhibitors may be less safe in older patients. More specifically, some have expressed concern with respect to the risk of hypoglycemia and volume depletion in older patients because of the known mechanism of actions of SGLT2 inhibitors and diminished efficiency of counter-regulatory responses. Second, pharmacokinetics and pharmacodynamic changes in older patients add to the concern that the benefit–risk balance may be less favorable in older patients. Whether these concerns are justifiable is questionable. Fortunately, several of the large-scale randomized controlled trials performed with SGLT2 inhibitors in patients with CKD have reported their results by age. This information may help to guide evidence-based decision making in older patients with CKD. Data from key SGLT2 inhibitor trials in patients with CKD indicate that the SGLT2 inhibitors not only have an acceptable safety profile but the safety profile of SGLT2 inhibitors is also similar in older (≥70 years) and younger patients (<70 years) with CKD.5–7 In the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial (mean age 63 years), the rate of hypoglycemia was similar in the canagliflozin and placebo groups in older patients (9.6% versus 12.4%) and in younger patients (10.4% versus 10.4%). The same was observed for volume depletion that occurred in 8.7% versus 8.0% of patients in the canagliflozin and placebo groups among those ≥70 years and 5.9% versus 4.3% among patients <70 years, respectively.5 Rates of fracture, hospitalization, and kidney-related events, including AKI, were also similar in canagliflozin and placebo groups in older and younger patients. Myotic genital infections occurred more frequently in the canagliflozin compared with the placebo group in older and younger patients (2.3% versus 0.7% in those ≥70 years and 2.3% versus 0.5% in those <70 years). In the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial (mean age 62 years), major hypoglycemia events also did not occur more frequently with dapagliflozin compared with placebo in either age group. The rates of volume depletion in the DAPA-CKD trial appeared numerically higher in the dapagliflozin compared with placebo arm in both age groups (7.4% versus 5.3% in ≥70 years and 5.3% versus 3.7% in <70 years, respectively).6 Rates of diabetic ketoacidosis were not reported by age in the post hoc analyses of the CREDENCE trial because the low incidence of such events (<0.3% overall) did not allow a stratified analysis. In the DAPA-CKD trial, diabetic ketoacidosis did not occur in any dapagliflozin-treated patient. Moreover, in the EMPA-KIDNEY trial (mean age 64 years), no difference in safety was observed between empagliflozin and placebo among patients age ≥65 and <65 years.7 With respect to the efficacy of SGLT2 inhibitors, data from the three SGLT2 inhibitor kidney outcome trials also report consistency in the treatment efficacy for the primary end point across age subgroups. For instance, the CREDENCE, DAPA-CKD, and EMPA-KIDNEY trials observed no statistical heterogeneity by age in the effect of SGLT2 inhibitors on the primary composite end point of kidney disease progression, kidney failure, or death due to kidney or cardiovascular disease.5–7 The hazard ratio (HR) for the effect of SGLT2 inhibitors on the primary end point in those ≥70 years was 0.89 (95% confidence interval [CI], 0.61 to 1.29) (n=1072) in the CREDENCE trial, 0.52 (95% CI, 0.37 to 0.75) (n=1197) in the DAPA-CKD trial, and 0.65 (95% CI, 0.52 to 0.81) (n=2637) in the EMPA-KIDNEY trial (pooled HR, 0.66 [95% CI, 0.51 to 0.86]) (Figure 1). Similar HRs were observed in the younger age groups (Figure 1). The benefit of SGLT2 inhibitors in reducing the risk of hospitalization for heart failure and cardiovascular death was also similar across patients of different age groups.5,6 Of note, the treatment benefit on clinical outcomes was evident during a median follow-up of approximately 2.5 years, suggesting that even older patients with a relatively short life expectancy may benefit from treatment with SGLT2 inhibitors.Figure 1: The efficacy estimates for SGLT2 inhibitors on the composite outcome of incidence of kidney disease progression, kidney failure, or death due to kidney or cardiovascular disease by age in key SGLT2 inhibitors trials in patients with CKD. (A) age ≥ 70 years; (B) age 60–69 years; (C) age <60 years. CI, confidence interval; CREDENCE, Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation; DAPA-CKD, Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease; HR, hazard ratio; SGLT2, sodium-glucose cotransporter 2.The available data on major adverse cardiovascular events also indicate a similar propensity toward benefit in older and younger patients. The CREDENCE trial showed a 20% lower risk of incident major adverse cardiovascular events (a composite of myocardial infarction, stroke, or cardiovascular death) with canagliflozin compared with placebo and reported no effect modification by age.5 In the DAPA-CKD trial,6 the rates of major cardiovascular events were also numerically lower in those treated with SGLT2 inhibitors across age groups. It appears that the benefit of SGLT2 inhibitors on major cardiovascular events is driven mainly by the benefit on cardiovascular mortality.8 Regarding all-cause mortality, again, there was no effect modification by age. Rates were lower in the treatment arm compared with placebo in older and younger patients in the DAPA-CKD (7% versus 10.1% in patients ≥70 years and 3.8% versus 5.5% in <70 years, respectively) and CREDENCE trials (9.9% versus 11.0% in patients ≥70 years and 6.9% versus 8.5% in <70 years, respectively). In the EMPA-KIDNEY trial,7 an age-stratified effect on all-cause mortality has not been reported to date, but the trial demonstrated numerically lower rates of all-cause mortality in the empagliflozin compared with the placebo group (0.9 versus 2.1 per 100 patient-years). Given that the absolute risk of major cardiovascular events and all-cause mortality is generally higher in older patients, even a modest reduction in risk will be meaningful. The aforementioned subgroup analyses showing similar safety and efficacy were in general defined by an age < or ≥70 years. Some may object that the situation may be different in frail elderly or in the very old patients (i.e., aged ≥80 years). Frailty is common among older patients. Such patients are limited in their ability for physical mobility and self-care and have shorter life expectancy compared with nonfrail older patients. These patients are also known to be at a greater risk of disease and treatment complications. Therefore, physicians and other care providers often exhibit therapeutic nihilism in these patients. So far, only one study has investigated the effect of SGLT2 inhibitors on clinical outcomes by frailty levels (derived from comorbidities) in patients with CKD.9 Although this study did not specifically investigate frail older patients, the benefit–risk profile appeared similar across frailty levels. Of note, in frail older patients, it may be equally (if not more) important to understand the effect of SGLT2 inhibitors on a patient's quality of life, cognition, and other related outcomes (e.g., social participation). Data from observational studies suggest that SGLT2 inhibitors could improve cognitive functioning and prevent dementia.10 Unfortunately, data on the therapeutic value of SGLT2 inhibitors in frail older patients are limited, as are data among patients ≥80 years, because of few such patients in clinical trials. In the CREDENCE and DAPA-CKD trials, only 109 and 197 participants ≥80 years were included, respectively. In summary, on the basis of subgroup analyses of large randomized clinical trials, it appears as if older patients (age ≥70 years) experience similar (sizable) benefits and incur similar (modest) risks as younger patients. These data do not justify markedly lower rates of SGLT2 inhibitor prescription in older patients. However, because frailty was not formally assessed and few patients ≥80 years were enrolled in the CREDENCE, DAPA-CKD, and EMPA-KIDNEY trials, additional studies are required to better understand the effect of SGLT2 inhibitors in these patients. Finally, sex-related differences in rates of reported adverse events can be anticipated also among older patients and may affect prescription rates among older men and women. Unfortunately, data from clinical trials on possible sex differences in the safety profile of SGLT2 inhibitors among older patients are limited and warrant further study.

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