SGLT2 inhibitors confer cardiovascular, renal benefits in stage 4 CKM syndrome

In the treatment of patients with stage 4 cardiovascular–kidney–metabolic (CKM) syndrome, sodium–glucose cotransporter 2 (SGLT2) inhibitors appear to exert cardio- and renoprotective effects, as shown in a retrospective study.

Over 1-year follow-up, major adverse cardiovascular events (MACEs) occurred less frequently among SGLT2 inhibitor users vs never users (8.5 percent vs 13.1 percent). Similarly, the incidence of major adverse kidney events (MAKEs) was lower among SGLT2 inhibitor users (6.5 percent vs 10.2 percent), as was that of all-cause death (0.5 percent vs 1.8 percent). [J Am Heart Assoc 2025;doi:10.1161/JAHA.124.040382]

SGLT2 inhibitor use reduced the risk of MACE by 27.4 percent (hazard ratio [HR], 0.726, 95 percent confidence interval [CI], 0.575–0.917; p<0.05), driven primarily by its impact on cardiovascular death (HR, 0.876, 95 percent CI, 0.775–0.990; p<0.05) and heart failure readmission (HR, 0.673, 95 percent CI, 0.463–0.978; p<0.05).

SGLT2 inhibitor use was also associated with an 11.5-percent lower risk of MAKEs (HR, 0.885, 95 percent CI, 0.802–0.977; p<0.05), mostly due to a 19.7-percent reduction in the risk of worsening kidney function (HR, 0.803, 95 percent CI, 0.652–0.988; p<0.05). Finally, the risk of all‐cause mortality decreased by 11.3 percent with SGLT2 inhibitor use (HR, 0.887, 95 percent CI, 0.794–0.991; p=0.034).

Consistent cardiovascular and renal benefits were observed across a broad range of patient subgroups, including those defined by age, sex, BMI, HbA_1c, eGFR, coronary heart disease, atrial fibrillation, peripheral artery disease, stroke, type 2 diabetes (T2D), and chronic kidney disease, among others.

One-year changes in metabolic outcomes also favoured SGLT2 inhibitor use. Greater reductions were seen in HbA_1c levels (−0.63 percentage points vs −0.31 percentage points), BMI (−0.68 vs −0.22 kg/m²), systolic blood pressure (−4 vs −1.2 mm Hg), and high-sensitivity C-reactive protein (−0.67 vs −0.13 mg/L).

These findings are promising, given that patients with stage 4 CKM syndrome are at a very high risk of poor cardiovascular outcomes, the investigators said. Because the risk is so high, the main goal of medical treatment is to prevent cardiovascular events. [Circulation 2023;148:1606-1635; Cardiovasc Diabetol 2023;22:195; Diabetes Obes Metab 2022;24:2283-2296]

SGLT2 inhibitors protect the heart by acting on several different biological pathways. These drugs help reduce oxidative stress, inflammation, and endothelial dysfunction, all of which contribute to heart problems. Additionally, it can relieve heart strain by reducing cardiac preload and afterload. [Int J Mol Sci 2017;18:1-13; Front Immunol 2023;14:1163288; Cardiovasc Diabetol 2024;23:252; Cardiovasc Diabetol 2021;20:78]

Meanwhile, the renal benefit observed with SGLT2 inhibitors may be attributed to multiple mechanisms, including haemodynamic, metabolic, anti‐inflammatory, and direct renoprotective effects. [Biomedicine 2022;10:1-19; J Nephrol 2021;34:137-153; Annu Rev Physiol 2021;83:503-528]

The improvements in several metabolic outcomes may also explain why the drug reduced the risk of heart and kidney-related events, according to the investigators.

The analysis included a propensity-matched cohort of 1,624 patients (average age 63.8 years, average BMI 28.4 kg/m², average eGFR 75.4 mL/min per 1.83 m²) with stage 4 CKM syndrome who had been hospitalized at the Civil Aviation General Hospital in Beijing, China. Of these, 812 were actively taking an SGLT2 inhibitor during the follow‐up period and 812 had never received SGLT2 inhibitor therapy.

Of the patients, 91.4 percent had coronary heart disease, 43.3 percent had a heart failure, 15.9 percent had a stroke, 13.4 percent had peripheral artery disease, and 7.5 percent had atrial fibrillation. Most patients had a history of hypertension (63.5 percent), T2D (67.8 percent), metabolic syndrome (74 percent), and CKD (67.3 percent). Around half (50.6 percent) had hypertriglyceridemia.

The investigators acknowledged several study limitations, including its retrospective design and the short follow‐up period.