SGLT2 inhibitor treatment in an elderly patient with CKD and significant proteinuria despite well-controlled T2DM

Presentation and history
An 80-year-old woman with 1 year’s history of significant proteinuria presented in January 2022 with bilateral ankle swelling. Due to reduced walking ability and exercise tolerance, she became almost homebound and unable to go to the market, which she used to do every day.

The patient had a 30-year history of type 2 diabetes mellitus (T2DM) and hypertension (HTN), which were well controlled with medications. No diabetes or HTN-related complications were reported in her regular check-up in 2019. At presentation, she was taking two glucose-lowering agents (metformin, 500 mg BID; linagliptin, 5 mg QD) for T2DM, a calcium channel blocker (amlodipine, 5 mg QD) and an angiotensin-converting enzyme (ACE) inhibitor (lisinopril, 10 mg QD) for HTN.

Investigations, treatment and response
Physical examination showed severe bilateral lower-limb oedema extending up to the mid-calf. Laboratory tests revealed proteinuria of 3.5 g/day, urinary albumin-to-creatinine ratio (UACR) of 3,200 mg/g and estimated glomerular filtration rate (eGFR) of 47 mL/min/1.73 m². (Table) HbA_1c was 6.8–7.1 percent, and blood pressure (BP) was 120–130/70–80 mm Hg.

The patient’s medical history and assessment findings suggested a nondiabetic cause of chronic kidney disease (CKD). On balance of potential risks and benefits, renal biopsy was ruled out following discussion with the patient’s family. In March 2022, the patient was started on dapagliflozin (10 mg QD), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, which was added to her ACE inhibitor–containing regimen.¹

The patient responded well to dapagliflozin. At week 4, her UACR decreased from 3,200 mg/g to 1,700 mg/g, and her proteinuria dropped from 3.5 g/day to 1.9 g/day. At week 8, her proteinuria further decreased to 0.9 g/day, and eGFR improved to 55 mL/min/1.73 m². Notably, her oedema resolved in 4 months. (Table) She had resumed daily activities, including going to the market every day.

Neither an initial eGFR dip associated with SGLT2 inhibitors nor adverse events (AEs) associated with dapagliflozin were observed throughout treatment. However, after 2 months, the patient had an episode of COVID-19 infection and developed acute kidney injury, which necessitated suspending dapagliflozin for 1 week. After COVID-19 recovery, she had stable renal function and resumed dapagliflozin 10 mg QD. No dose adjustments of therapeutic agents in her regimen were needed.

At the time of writing, the patient has been on dapagliflozin-based therapy for 1.5 years. Her condition remains stable, with low-grade albuminuria (0.8–1.2 g/day), and good control of glycaemia and BP.

Discussion
CKD, a progressive condition and a leading cause of death worldwide, is common in elderly individuals and patients with diabetes or HTN.² Unlike our patient who presented with symptoms along with significant proteinuria, most CKD patients remain asymptomatic until the disease has progressed to later stages. Therefore, regular monitoring of renal markers (eg, eGFR and UACR) is important for early detection of CKD in high-risk patients. Initiating appropriate treatment upon CKD detection can prevent loss of kidney function and delay or prevent disease progression.^1,3

While renal biopsy can identify CKD aetiology and guide treatment decisions, this diagnostic procedure may carry an increased risk of major bleeding in elderly patients.^1,4 Even when CKD aetiology is known and can be treated with immunosuppressants, the risk of infection associated with immunosuppressants is an important clinical consideration.⁵ Thus, a renoprotective treatment that can reduce proteinuria is necessary for patients with multiple comorbidities.

SGLT2 inhibitors, such as dapagliflozin, are cardiorenal-protective agents recommended for T2DM patients irrespective of their proteinuria levels.¹ With emergence of clinical evidence on their cardiorenal benefits, SGLT2 inhibitors represent a major breakthrough in treatment of CKD with or without comorbid T2DM, following two decades of renin-angiotensin system (RAS) inhibitors (ie, ACE inhibitors and angiotensin-receptor blockers) being the only recommended drug class for this condition.⁶

The Clinical Practice Guideline of Kidney Disease: Improving Global Outcomes (KDIGO) 2023 recommends SGLT2 inhibitors as first-line therapy for patients with CKD and heart failure or eGFR ≥20 mL/min/1.73 m² with UACR ≥200 mg/g, with or without T2DM.¹ Combining an SGLT2 inhibitor with a RAS inhibitor may provide an additive effect on patients’ renal haemodynamic function, and is recommended as the first-line treatment for CKD patients with or without T2DM.^1,7,8

Dapagliflozin’s cardiorenal protective effects were demonstrated in the DAPA-CKD trial in 4,304 CKD patients with or without T2DM (>65 years of age, 42.2 percent; mean eGFR, 43.1 mL/min/1.73 m²; median UACR, 949 mg/g). These patients were randomized to receive either oral dapagliflozin 10 mg QD or placebo in addition to optimized background therapy with a RAS inhibitor. Among those with T2DM (n=2,906), 396 (13.6 percent) had nondiabetic CKD.^9-11

Results showed a significant reduction in the primary composite outcome of a sustained decline in eGFR of ≥50 percent, end-stage kidney disease, or death from renal or cardiovascular causes in the dapagliflozin vs placebo group (9.2 percent vs 14.5 percent; hazard ratio [HR], 0.61; 95 percent confidence interval [CI], 0.51–0.72; p<0.001) over a median follow-up of 2.4 years. This primary outcome improvement was consistent across subgroups, including patients aged ≤65 years and >65 years. The HR was 0.56 (95 percent CI, 0.45–0.68; p<0.001) for the renal-specific composite outcome and 0.69 (95 percent CI, 0.53–0.88; p=0.004) for all-cause mortality. Results were similar in patients with or without T2DM.⁹

In subsequent analyses of DAPA-CKD with median follow-up duration of 2.4 years, dapagliflozin significantly reduced geometric mean UACR by 29.3 percent (95 percent CI, -33.1 to -25.2; p<0.0001) and slowed total eGFR decline by 0.93 mL/min/1.73 m²/year (95 percent CI, 0.61–1.25) vs placebo in CKD patients with or without T2DM.^9,10 (Figure)

Patients with diabetes are at risk of CKD, and CKD in diabetes patients can be due to diverse aetiologies with varying levels of severity.^1,12,13 Early initiation of a cardiorenal-protective agent, such as SGLT2 inhibitor, may prevent CKD and slow disease progression in these patients.

Although our patient had good long-term glycaemic control while on a regimen containing glucose-lowering agents and an ACE inhibitor, she still developed CKD of uncertain aetiology. After adding dapagliflozin to her regimen, her proteinuria level decreased by 45.7 percent at 4 weeks and eGFR increased by 8 mL/min/1.73 m² at 8 weeks. Subsequently, she had resolution of oedema and was able to resume daily activity. It can be expected that the improvements would have occurred earlier had she not developed COVID-19.

Our patient tolerated dapagliflozin well, without any treatment-associated AEs. This is consistent with safety findings of the DAPA-CKD trial, which showed a similar incidence of AEs between the dapagliflozin and placebo groups in the overall study population as well as a similar safety profile between the two groups across all frailty categories.^9,14 While patients with higher frailty index (FI) at DAPA-CKD baseline were older and more likely to experience serious AEs, rates of serious AEs were numerically lower in the dapagliflozin vs placebo group across frailty categories (not frail to mildly frail [FI, ≤0.210]: 16.9 percent vs 20.1 percent) (moderately frail [FI, 0.211–0.310]: 26.3 percent vs 30.7 percent) (severely frail [FI, ≥0.311]: 42.9 percent vs 47.8 percent). No increased likelihood of serious AEs was observed between groups within each frailty category.¹⁴

In some elderly patients with CKD treated with an SGLT2 inhibitor, medication adjustments based on glycaemic and BP levels may be necessary.¹⁵ Providing patient education on signs of initial eGFR dip and urinary tract infection (UTI) may enhance treatment adherence. Education on UTI prevention, such as adequate hydration and personal hygiene, can help enhance tolerance to SGLT2 inhibitors.

Integrative care is essential for improving outcomes in patients with CKD and T2DM. This approach necessitates multidisciplinary team collaboration that involves nephrologists, endocrinologists, family physicians, pharmacists, and dietitians. Together, they can address aspects such as CKD management, diabetes control, medication reconciliation and counselling, and dietary counselling.^1,16

Early detection of CKD is key to its effective management. As demonstrated in our patient’s case and DAPA-CKD, dapagliflozin is a viable therapeutic option for CKD regardless of aetiology and presence or absence of T2DM.