History and presentation
A 36-year-old male with young-onset type 2 diabetes (T2D), hypertension, and stage 4 chronic kidney disease (CKD) presented on 31 March 2023. He was an ex-smoker of 15 years and an ex-drinker, with a family history of diabetes, hypertension, and familial hypercholesterolaemia.
The patient was initially diagnosed with T2D and hypertension in 2008. However, he did not receive any treatment for 10 years, which led to the development of proliferative diabetic retinopathy and stage 3b CKD with macroalbuminuria. In 2018, the patient was started on basal-bolus insulin, losartan, amlodipine, and vildagliptin at a public clinic. During the COVID-19 pandemic, he only refilled medications and defaulted follow-up appointments.
On 17 March 2023, the patient was hospitalized for acute-on-chronic kidney failure (estimated glomerular filtration rate [eGFR], 22 mL/min/1.73 m2). (Figure 1) Amlodipine was discontinued, and losartan was withheld.
Treatment and response
After discharge from hospital, the patient sought consultation at our clinic on 31 March 2023. Given his current eGFR of 22 mL/min/1.73 m2, vildagliptin was switched to a fixed-dose combination (FDC) of empagliflozin/linagliptin 10/5 mg QD for cardiorenal protection and glycaemic control. Losartan was restarted at a lower dose of 25 mg QD. Basal-bolus insulin was switched to insulin degludec (IDeg) 3 U.
The patient experienced an initial dip in kidney function, which stabilized and returned to baseline value in the next few months. Notably, his kidney function deterioration rate (1/ creatinine slope) became markedly slower after adding the empagliflozin/linagliptin FDC. (Figure 1) His HbA1c (5.6–6.4 percent), blood pressure (BP; <130/85 mm Hg), and body weight (body mass index, 19–22 kg/m2) remained well controlled.
Atorvastatin 10 mg QD was added in May 2023 because of the patient’s high cardiovascular (CV) risk, and his LDL-cholesterol level remained <1.4 mmol/L since then. Blood tests in January 2024 showed normal lipoprotein a and C-reactive protein levels. Calcitriol 0.25 mcg QD and calcium 600 mg were added to increase calcium levels.
Prior to consultation at our centre, the patient had experienced 2–3 episodes of hypoglycaemia. With the treatment given at our centre, along with continuous glucose monitoring and intensive dietary intervention from our dietitian, the patient did not experience any hypoglycaemia or hyperkalaemia.
Last seen on 22 October 2024 (1.5 years since first consultation), the patient remained free from dialysis, additional cardiorenal events, or hospitalizations despite his baseline stage 4 CKD.
Discussion
T2D has become increasingly prevalent in young populations.1 In Hong Kong, 21.3 percent of diabetic patients have young-onset diabetes (ie, onset at <40 years of age). Due to longer disease duration, this patient group has higher risks of cardiorenal complications at any given age.2 Our patient, who was diagnosed with T2D at the age of 22 years, developed stage 4 CKD by the age of 36 years.
Accumulating evidence shows strong interconnections between cardio-kidney-metabolic (CKM) conditions, including T2D, CKD, and CV disease.3 Prevention of T2D complications has focused on modifiable risk factors (ie, reduction of body weight, HbA1c, BP, and LDL-cholesterol levels). Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are evidence-based treatments that do not merely lower blood glucose, body weight and BP, but also offer cardiorenal protection, which can delay or prevent the development of long-term complications.4,5
Our case illustrates the tolerability and efficacy of empagliflozin in patients with advanced CKD. Extrapolation of long-term eGFR slope data from the EMPA-KIDNEY trial indicated that initiating empagliflozin at an eGFR of 20 mL/min/1.73 m² may delay the need for kidney replacement therapy (KRT) by 1.9 years vs placebo.6 (Figure 2) Consistent with this finding, our patient’s kidney function deterioration rate became markedly slower after initiation of empagliflozin, and he remained dialysis-free for 1.5 years despite a baseline eGFR of only 22 mL/min/1.73 m².
As early cardiorenal protection is key to preventing CKM syndrome in the long term, SGLT2i (eg, empagliflozin) are started by default at our clinic in patients with T2D at their initial presentation, unless contraindicated. In retrospect, the above patient should have been treated with empagliflozin when first diagnosed with T2D at the age of 22 years, as his family history and early-onset T2D heightened his risk of cardiorenal complications.
When empagliflozin is started at an eGFR of 85 mL/min/1.73 m², it is estimated to delay KRT by 26.6 years vs placebo, suggesting that early initiation of empagliflozin could lead to better outcomes.6 (Figure 2)
In EMPA-KIDNEY, empagliflozin significantly reduced the risk of the primary composite outcome of kidney disease progression or CV death (hazard ratio [HR], 0.72; 95 percent confidence interval [CI], 0.64–0.82; p<0.001), and all-cause hospitalizations (HR, 0.86; 95 percent CI, 0.78– 0.95; p=0.003), vs placebo.7 These findings are consistent with the experience of our patient, who was not hospitalized and did not encounter any further cardiorenal events after starting empagliflozin.
In a pooled analysis of 19 randomized, placebo-controlled trials, empagliflozin was found to reduce the incidence of hyperkalaemia vs placebo (1.2 vs 1.8 percent) without increasing the risk of hypokalaemia (20.3 vs 21.3 percent) in patients with T2D and moderate-to-severe CKD.8
Comprehensive management of T2D should not only focus on glycaemic levels, but also address modifiable risk factors to prevent or delay CKM complications.9 The kidney function and serum electrolyte (eg, potassium, calcium) levels of patients with comorbid CKD should be closely monitored.10 An FDC of empagliflozin and linagliptin provides a convenient approach to optimize patients’ glycaemic control and offers cardiorenal protection, without concern for hyperkalaemia and hypoglycaemia.
