Polypharmacy is a well-recognized challenge in chronic kidney disease (CKD) management, driving nonadherence and accelerating disease progression. In an interview with MIMS Doctor, Professor Takashi Yokoo of Jikei University, Japan, discussed how multifunctional sodium-glucose cotransporter-2 inhibitors (SGLT2i) help simplify treatment regimens based on his clinical experience with empagliflozin in patients with complex clinical profiles.
Vicious cycle of polypharmacy in CKD
Nearly all (98 percent) CKD patients have ≥1 comorbidity. With a mean of 3.4 comorbidities, patients take an average of 8 medications daily, highlighting a substantial pill burden in CKD. [Br J Gen Pract 2021;71:e243-e249; Sci Rep 2026;16:2653]
“Polypharmacy complicates CKD management as it creates a vicious cycle that is difficult to break,” noted Yokoo. As the disease progresses and treatment regimens become more complex, many patients begin skipping or refusing medications. Poor adherence leads to worsened clinical outcomes, which can be misinterpreted as insufficient treatment, resulting in an even higher pill burden and creating a vicious cycle that contributes to accelerated renal decline. [Kidney360 2024;5:841-850; Res Social Adm Pharm 2025;21:1090-1095; Am J Kidney Dis 2015;66:621-629]
“Single-pill treatment with SGLT2i such as empagliflozin addresses multiple clinical needs, including glucose control, oedema reduction, and uric acid reduction,” said Yokoo. “Using SGLT2i as first-line therapy simplifies medication regimens from the outset.” [Kidney Int 2022;102:S1-S127; Kidney Int 2024;105:S117-S314]
Real-world experience with empagliflozin in CKD
In the EMPA-KIDNEY trial, empagliflozin reduced the risk of kidney disease progression or cardiovascular (CV) death by 28 percent vs placebo (p<0.001) in patients with CKD. [N Engl J Med 2023;388:117-127]
Empagliflozin’s cardiorenal benefits are demonstrated across a range of real-world complex CKD patients, including frail elderly patients (case 1), patients with type 2 diabetes (T2D) and atherosclerotic cardiovascular disease (ASCVD) (case 2), and patients with multimorbidity (case 3).
Notably, across these cases, empagliflozin allowed dose reduction or discontinuation of ≥1 other agent.
Moreover, steep pretreatment estimated glomerular filtration rate (eGFR) decline consistently transformed into a near-horizontal trajectory following empagliflozin initiation, regardless of CKD aetiology or baseline eGFR, with an average eGFR slope attenuation of approximately 78 percent.
“While an initial eGFR dip was commonly seen at month 3, it was a transient and reversible haemodynamic change that did not necessitate treatment discontinuation,” emphasized Yokoo.
Additionally, a sustained decrease in urine albumin-to-creatinine ratio (UACR) was observed in all patients, showing an approximately 60–70 percent reduction over 3 years.
Use of SGLT2i in frail population
Overall, SGLT2i have a favourable safety profile with high levels of adherence observed in CKD patients. [Kidney Int 2024;105:S117-S314]
“SGLT2i should be avoided in severe frailty [CFS ≥7]. However, as demonstrated in case 1, frailty is not always a contraindication to SGLT2i use,” commented Yokoo. “The main concern is dementia, as SGLT2i must be withheld during sick days, which may present challenges for patients who cannot understand or follow sick-day rules.”
“With careful patient selection, sick-day education, and monitoring of diuretics and BP, empagliflozin can be used safely in frail patients with CKD,” Yokoo stated.
How to sequence therapies?
“While maximally-tolerated renin-angiotensin system inhibitors [RASi] remain the foundation of CKD management, I generally introduce SGLT2i early as part of first-line treatment in most patients due to their simple once-daily dosing and cardiorenal benefits, in line with Kidney Disease: Improving Global Outcomes [KDIGO] guideline recommendations,” said Yokoo. [Kidney Int 2022;102:S1-S127; Kidney Int 2024;105:S117-S314]
“For those with persistent albuminuria despite first-line treatment, nonsteroidal mineralocorticoid receptor antagonists may be added, with glucagon-like peptide-1 [GLP-1] receptor agonists considered in patients with obesity,” added Yokoo. [Kidney Int 2022;102:S1-S127; Kidney Int 2024;105:S117-S314]
Importance of early SGLT2i use in HK
“The incidence of dialysis initiation is higher in individuals aged ≥70 years, reflecting the typical functional lifespan of the kidneys. This is historically driven by diabetic nephropathy as well as a recent rising trend of nephrosclerosis associated with ageing and hypertension,” shared Yokoo. “As populations age, the gap between human lifespan and kidney functional lifespan further widens, leading to a growing number of dialysis cases.”
In a post hoc analysis of EMPA-KIDNEY, empagliflozin prolonged time to kidney failure vs placebo, highlighting the role of SGLT2i in helping to narrow this gap, with estimated benefit increasing with earlier empagliflozin initiation. [Clin Kidney J 2023;16:1187-1198]
“With Hong Kong recording one of the highest life expectancies at birth in the world [2024: males, 82.7 years; females, 88.2 years], active renal protection with early use of SGLT2i is crucial to reduce the risk of this long-living population spending their final years on dialysis,” Yokoo concluded.
