Expanding the Impact of SGLT2 Inhibitors in Chronic Kidney Disease

Individuals with chronic kidney disease (CKD) have an increased risk of estimated glomerular filtration rate (eGFR) decline, end-stage kidney disease (hereafter referred to as CKD progression), and heart failure (HF) compared to the general population [1]. Landmark clinical trials have demonstrated that sodium-glucose cotransporter-2 (SGLT2) inhibitors reduce the risk of not only CKD progression but also HF hospitalization and cardiovascular (CV) death in people with CKD and urine albumin-to-creatinine ratio (UACR) greater than 200 mg/g (moderately increased albuminuria) or eGFR of 20 to less than 45 mL/min per 1.73 m², regardless of type 2 diabetes (T2D) status [2‒4]. SGLT2 inhibitors have benefits on HF outcomes in both primary and secondary prevention among people with CKD [5, 6]. SGLT2 inhibitors also have demonstrated significant reductions in HF hospitalization among people with T2D and established atherosclerotic CV disease or atherosclerotic CV risk factors [7‒10] and in people with HF with reduced or preserved ejection fraction [11‒14].

SGLT2 inhibitors stand poised to have an immense impact on the management of CV and kidney disease. Previous reports of potential SGLT2 inhibitor use in people with type 2 diabetes mellitus or a single SGLT2 inhibitor indication have estimated the number of potentially avoidable events [15‒18]. Due to the frequent coexistence of CKD with T2D, atherosclerotic CV disease, and HF, individuals with CKD may have an SGLT2 inhibitor indication due to concomitant T2D or HF independent of UACR or eGFR levels. Based on data in the National Health and Nutrition Examination Survey (NHANES) study [19], a nationally representative, cross-sectional study of people in the USA, an estimated 10.4 million adults with CKD in the USA would be eligible for an SGLT2 inhibitor due to albuminuria (>200 mg/g) or comorbid T2D or HF. In the absence of SGLT2 inhibitor treatment, an estimated 1.18 million CKD progression events and 1.21 HF hospitalization events would occur over a 3-year period among people with CKD in the USA. Based on relative risk reductions in landmark clinical trials, full adoption of SGLT2 inhibitor treatment could prevent 377,000 CKD progression events and 283,000 HF events (181,000 primary prevention HF events among people without a history of HF) (Fig. 1).

Completed SGLT2 inhibitor clinical trials enriched the study population with individuals at the highest levels of risk. These individuals account for a disproportionately high number of adverse kidney and HF events among the CKD population. Despite lower absolute event rates, individuals with moderately increased albuminuria who remain ineligible for landmark CKD trials may account for a large proportion of all CKD progression and HF events due to the size of this group. SGLT2 inhibitors have strong safety profiles and may have the potential to serve as a preventative option for people with moderately increased albuminuria, but without type 2 diabetes mellitus or HF. An estimated 4.4 million adults in the US have elevated cardio-kidney risk as indicated by UACR 30–200 mg/g and do not meet criteria for an SGLT2 inhibitor indication according to NHANES-based calculations. Within this group, an estimated 691,000 CKD progression events and 292,000 HF events would occur over a 3-year period [20, 21]. Applying the relative effects of SGLT2 inhibitors on the risk of CKD progression and HF events observed in landmark CKD trials of higher risk participants, full SGLT2 inhibitor inhibition among those with elevated cardio-kidney risk and no current indication for an SGLT2 inhibitor could potentially prevent 219,000 CKD progression events and 73,000 HF events (Fig. 1).

Research on alternative pharmacological and non-pharmacological interventions to reduce cardio-kidney risk in people with moderately increased albuminuria could address this gap. Indeed, people with CKD and moderate cardio-kidney risk may accept the long-term use of pharmacologic or non-pharmacologic therapies to reduce cardio-kidney risk. A survey of 1,029 adults with CKD suggests that upward of 50–60% of the CKD population is likely or very likely to take a medication that reduces their risk of developing kidney failure, whether that benefit accrues over a 5- or 20-year horizon [22]. The FIGARO-DKD trial enrolled participants with moderately (UACR of 30 to less than 300 mg/g) and severely elevated albuminuria (300–5,000 mg/g) and did not find evidence supporting differential effects of finerenone on the primary composite outcome across albuminuria categories [23]. Pragmatic and adaptive study designs, which have been used to study blood pressure-lowering [24], cholesterol-lowering [25], and aspirin dosing regimens [26], may help enable such clinical trials for SGLT2 inhibitors or other pharmacologic or non-pharmacologic interventions in a cohort of people with moderately increased albuminuria alone.

Widespread SGLT2 inhibitor adoption among adults with CKD in the USA has the potential to prevent hundreds of thousands of CKD progressions and HF events. Clinicians and healthcare systems should prioritize the use of SGLT2 inhibitors among appropriate people. Research on the effects of SGLT2 inhibitors in individuals with elevated cardio-kidney risk without a current SGLT2 inhibitor indication is warranted.