Comparison of major cardiovascular and kidney outcomes between women and men with chronic kidney disease receiving sodium-glucose co-transporter (SGLT-2) inhibitors

Chronic kidney disease (CKD) is a long-term condition where the kidneys do not work as well as they should. It is a progressive condition that affects >10% of the general population worldwide, amounting to >800 million individuals. CKD is more prevalent in older individuals, women, racial minorities, and in people experiencing diabetes mellitus (a condition where the blood sugar level is too high) and high blood pressure.

In recent years, research interest in sex and gender medicine concerning CKD has increased. Data has indicated sex differences in cardiovascular (CV) health both in the general population and among patients with CKD. In previous analysis we have shown an increased risk for CV events (conditions affecting the heart and blood vessels, such as heart attack or stroke) in women with CKD compared to men with CKD. More controversially, sex has been suggested to influence treatment response. Several analyses of large randomized controlled trials focusing on cardiovascular and kidney health provide evidence in this regard. However, most of these analyses have primarily focused on patients with heart failure, leaving a gap in understanding the sex-specific effects in CKD patients. CKD is well established as a major and independent risk factor for cardiovascular disease, as it is consistently associated with increased cardiovascular events and mortality. In recent years, sodium-glucose co-transporter-2 inhibitors (SGLT-2i) inhibitors have become a cornerstone therapy for CKD due to their significant effects in reducing cardiovascular events and slowing disease progression. SGLT-2i work by reducing blood sugar levels as they help the kidneys to remove excess sugar, which is passed out through the urine. Thus, exploring the response pattern in women and men is fundamental to improve individualized patient care.

Studies analyzing the sex-specific efficacy of SGLT-2i so far have primarily consisted of analyses of one or two trials or meta-analyses using summary data, both of which may introduce significant bias. In contrast, a meta-analysis combining the individual participant data from multiple trials can substantially improve both the quantity and quality of data while enabling more reliable results. It also offers greater flexibility in analyses, enabling the assessment of whether SGLT-2i are more or less effective in different subgroups of participants.

In addition, previous analyses on the interaction between sex, the efficacy of SGLT-2i and cardiovascular-kidney outcomes have mainly relied on data from randomized controlled trials. Evidence based on real-world data (data collected from patients not in clinical trials) is currently lacking, and it remains unknown whether findings from trial-level data can be translated to real-world settings.

Therefore, we will conduct an evaluation of the efficacy of SGLT-2i in women and men with CKD through an individual participant data meta-analysis to address the existing gap. Additionally, a parallel study using real-world data will enhance our understanding of sex-specific response patterns to SGLT-2i. Our findings will help clinicians provide individualized patient care and reduce unnecessary overtreatment in CKD patients.