Use of an SGLT2i in a patient with cardiovascular-kidney-metabolic syndrome
20 Feb 2025
byDr. Chu-Pak Lau, Specialist in Cardiology, Honorary Clinical Professor, University of Hong Kong, Hong Kong
History and presentation
A 70-year-old Chinese male patient had an acute myocardial infarction (MI) at the age of 60 years and underwent a successful percutaneous coronary intervention. At the time of presentation in 2013, he had cardiovascular-kidney-metabolic (CKM) syndrome, including obesity with a body mass index (BMI) of 28 kg/m2, type 2 diabetes mellitus (T2DM) with HbA1c of 7.5 percent, chronic kidney disease (CKD) with estimated glomerular filtration rate (eGFR) of 50 mL/min/1.73 m2 and urine albumin-to-creatinine ratio (UACR) of 4 mg/mmol, and heart failure with reduced ejection fraction (HFrEF) and left ventricular ejection fraction (LVEF) of 40 percent.
Along with lifestyle changes to address obesity, he was prescribed several medications, including an angiotensin-converting enzyme inhibitor (ACEI), spironolactone, a beta-blocker, a statin, a sulphonylurea, and metformin.
The patient defaulted follow-up and revisited my clinic with worsened CKM syndrome in 2024. His HbA1c had increased to 9.0 percent, potassium level increased to 5.3 mmol/L, eGFR was reduced to 30 mL/min/1.73 m², UACR had increased to 40 mg/mmol, and his BMI had increased to 31 kg/m². His LVEF was now 35 percent. He had New York Heart Association (NYHA) functional class III symptoms, with marked limitation in his daily activities. (Table)
Treatment and response
In early 2024, the patient started taking a sodium-glucose cotransporter-2 inhibitor (SGLT2i), empagliflozin 10 mg daily, due to its triple benefits for HF, T2DM and CKD. Combination therapy with a statin and ezetimibe was used for lowering LDL-cholesterol level. He was advised to discontinue spironolactone, switched from an ACEI to an angiotensin receptor-neprilysin inhibitor (ARNI), and to add vericiguat to control his HF. Sulphonylurea was discontinued while metformin was continued to manage his T2DM. A glucagon-like peptide-1 receptor agonist (GLP-1 RA) was added, which was also useful for T2DM and weight management. A nonsteroidal mineralocorticoid receptor antagonist (ns-MRA) was added to control CKD with albuminuria.
After 6 months of treatment, the patient showed notable improvements in clinical symptoms. His NYHA functional class improved from III to II, enabling him to engage in more activities, including daily leisure activities and hiking. After 1 year of treatment, his LVEF improved to 40 percent, BMI decreased to 27kg/m2, and HbA1c improved to 7 percent. Despite a transient increase in creatinine, his kidney function stabilized with eGFR maintained at around 30 mL/min/1.73 m2 and UACR reduced to 20 mg/mmol. (Table) Potassium level remained stable throughout treatment.
As of November 2024, the patient remained well on the combination treatment without developing new cardiovascular (CV) or kidney events.
Discussion
Most patients in Hong Kong admitted for HF present with multiple comorbidities, including hypertension (69.8 percent), diabetes (35.9 percent), coronary artery disease (29.3 percent), and CKD (11.5 percent).1 These comorbidities are associated with an increased risk of CV events, with the risk of CV death doubling with T2DM alone, tripling with CKD, and increasing sixfold when both conditions coexist.2
Screening and early detection of CKM risk factors are essential for timely CKM treatment, which reduces the risk of adverse CV events and slows the progression of kidney disease. Without early intervention, kidney function may decline to an eGFR <15 mL/min/1.73 m², at which point renal replacement therapy often becomes the only treatment option.
To screen for CKM syndrome, N-terminal pro–B-type natriuretic peptide (NT-proBNP) measurement, echocardiography, and CT calcium score are useful for detecting subclinical cardiac disease.3 Traditional risk assessment for CKD should be expanded to include routine screening of UACR, as outlined in the 2023 American Heart Association’s PREVENT equations.4 Additionally, obesity, which is central to CKM syndrome, should be assessed by measuring both BMI and waist circumference.5
Given the interrelatedness of the CV, renal, and metabolic systems, it is important to optimize CKM management by treating it as a single disease rather than addressing each condition seperately.6 Due to their cardiorenal-protective effect, SGLTi’s (eg, empagliflozin) are a guideline-recommended first-line therapy for CKM conditions, including T2DM with CV disease (American Association of Clinical Endocrinology and American Diabetes Association), HF irrespective of LVEF (European Society of Cardiology), as well as CKD with T2DM and an eGFR ≥20 mL/min/1.73 m² (Kidney Disease: Improving Global Outcomes).7-11
In the EMPA-REG OUTCOME trial in T2DM patients with established CV disease, empagliflozin reduced CV death (relative risk reduction [RRR], 38 percent; p<0.001), HF hospitalization (RRR, 35 percent; p=0.002), and all-cause mortality (RRR, 32 percent; p<0.001) vs placebo.12 Additionally, empagliflozin lowered CV death or HF hospitalization risk vs placebo consistently in patients with HF irrespective of LVEF, with or without diabetes, in both the EMPEROR-Reduced and EMPEROR-Preserved trials, and reduced the risk of CKD progression or CV death vs placebo in EMPA-KIDNEY.13-15 (Figures 1 and 2) Similar benefits in HF patients with reduced, preserved or mildly reduced LVEF had been found with dapagliflozin.16,17
SGLT2i’s offer opportunities for integrated disease management when initiated early in the course of CKM syndrome. While adverse events of SGLT2i’s are usually easy to manage, patients with poor nutrition or undergoing surgery should be cautious of possible ketoacidosis risk. SGLT2i’s should be discontinued in such cases and resumed once the patients can maintain adequate hydration and nutrition.18
There are now significant advances in medical management of HF. SGLT2i’s are recommended now as first-line treatment for CKD and T2DM, and HF regardless of LVEF. GLP-1 RAs should be considered in patients with prior CV disease and a BMI >27 kg/m2, and as add-on therapy for obese patients with HF with mildly reduced ejection fraction and T2DM. ns-MRA can be considered in patients with CKD with albuminuria or those with HFmrEF or HF with preserved ejection fraction (HFmrEF) if these conditions are not optimally controlled. The recent availability of these new therapeutic medications calls for timely use of them, alone and/or in combination, to improve the prognosis of patients with HF.
