A total of 50 investigators from 43 institutions in Korea conducted a multicenter prospective observational study between January 1, 2016 and April 19, 2018. The study enrolled adult patients aged 19 years and older diagnosed with dyslipidemia (defined as low-density lipoprotein-cholesterol [LDL-C] levels ≥ 100 mg/dL) and T2DM, for whom pravastatin was indicated as per routine clinical practice. T2DM diagnosis followed the criteria outlined in the American Diabetes Association guidelines or the use of antidiabetic medications during the eligibility assessment [14, 15]. Patients who had not taken pravastatin within the 4 weeks before the enrollment date were enrolled in the study—additionally, patients who had been using statins other than pravastatin on the enrollment date switched to pravastatin. The investigators determined pravastatin doses (5, 10, 20, or 40 mg once daily orally) based on the usual standard of practice.

Patients were excluded from the study if they met any of the following criteria: hypersensitivity or a history of hypersensitivity to pravastatin; pregnancy, breastfeeding, or women of childbearing potential; active liver disease or elevation of transaminase levels (aspartate aminotransferase [AST] or alanine aminotransferase [ALT]) ≥ three times the upper limit of normal; end-stage kidney disease requiring dialysis; cholestasis; myopathy; hypercholesterolemia due to hyperalphalipoproteinemia accompanied by elevated high-density lipoprotein-cholesterol (HDL-C) levels; or genetic conditions such as galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

Baseline assessments included demographic characteristics, physical examination, medical history, underlying diseases, eGFR, fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c) levels, lipid profiles, and laboratory investigations (AST, ALT, and creatine kinase [CK]). The previous use of medications at baseline was defined as the usage of medications within the 4 weeks prior to the enrollment date. Hypertension was defined by a systolic blood pressure ≥ 140 mmHg, or a diastolic blood pressure ≥ 90 mmHg, or use of antihypertensive medications at baseline [16, 17].

Patients were monitored for a minimum of 24 weeks, with the option to extend the follow-up period to 48 weeks. Scheduled visits were planned at 12 weeks (optional), 24 weeks, and 48 weeks (optional). During these follow-up visits, concurrent medications such as antidiabetic and antihypertensive drugs and usage of statins were assessed. Additionally, adverse events (AEs) and laboratory data from blood and urine samples were also collected at each follow-up visit.

The study protocol and informed consent forms were approved by the institutional review board (IRB) of each participating institution, including Seoul National University Bundang Hospital, Republic of Korea: study no. B-1511-322-305 (detailed for each institution in Table S1). The study was registered with Clinicaltrials.gov (NCT05107063). The study was conducted in accordance with the principles of the Declaration of Helsinki 1964 and its later amendments, as well as the rules of each IRB. All patients voluntarily provided written informed consent before enrollment in the study. Data were de-identified to protect the privacy of the participating patients and to be fully compliant with locally applicable regulations.

The Modification of Diet in Renal Disease (MDRD) equation was used to calculate eGFR as follows [18]: eGFR (mL/min/1.73 m2) = 186 × (serum creatinine (Scr))−1.154 × age−0.203 × (0.742 if female) × (1.212 if African American).

The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) was also used to calculate eGFR as follows [18]: eGFR (mL/min/1.73 m2) = 141 × min(sCr/κ, 1)α × max(sCr/κ, 1)−1.209 × 0.993age × 1.018 (if female) × 1.159 (if African American), where κ is 0.7 for women and 0.9 for men, α is − 0.329 for women and − 0.411 for men, min indicates the minimum of sCr/κ or 1, and max indicates the maximum of sCr/κ or 1.

The primary endpoint at 24 weeks was percent change in eGFR from baseline. The percent change was calculated at each visit using the following equation: Percent change at follow-up visit = (measurement at a follow-up visit/measurement at baseline − 1 ) × 100.

Secondary endpoints were as follows: percent changes in eGFR at 12 and 48 weeks from baseline; change in eGFR at 12, 24, and 48 weeks from baseline; and percent changes and changes in lipid profile (total cholesterol [TC], LDL-C, triglyceride [TG], and HDL-C) and glycemic levels (FPG and HbA1c).

To assess the safety profile of pravastatin, both AEs and relevant laboratory parameters, such as ALT, AST, and CK levels, were collected and analyzed. The investigators conducted an assessment to determine if the observed laboratory parameters indicated clinically significant abnormalities. Additionally, all AEs were assessed to ascertain their seriousness and potential association with pravastatin treatment. Serious adverse events (SAEs) were categorized using the following criteria: adverse events that resulted in mortality; events deemed life-threatening; events necessitating initial or extended hospitalization; events leading to persistent or significant disability or incapacity or substantially disrupting normal life functions; and events identified by the investigator as congenital anomalies or birth defects. The investigator assessed the causality of reported AEs and classified adverse events as certain, probable/likely, possible, conditional/unclassified, or unassessable/unclassifiable, which were then regarded as adverse drug reactions (ADRs).

The safety set comprised patients who remained enrolled after excluding those who withdrew consent to participate in the study or had missed the initial pravastatin prescription record. The effectiveness set comprised patients from the safety set, excluding those who did not complete the study or meet the inclusion/exclusion criteria after the enrollment date, discontinued pravastatin, switched to another statin, had missing baseline eGFR measurement, or had missed all eGFR measurements during the follow-up period. The full eGFR set comprised patients from the effectiveness set with eGFR measurements at every follow-up interval (12, 24, and 48 weeks).

Demographics and clinical characteristics were summarized using descriptive statistics for patients in the effectiveness set. Continuous variables are presented using descriptive statistics such as mean and standard deviation (SD), whereas categorical variables are presented using frequencies or percentages (%).

The primary and secondary endpoints, including eGFR percent changes, were assessed for both the effectiveness and the full eGFR sets. Additionally, the secondary endpoints were assessed within the effectiveness set, focusing on percent changes and changes in lipid levels and glycemic levels. For comparison between two groups of primary and secondary endpoints (measurements at 12, 24, or 48 weeks vs baseline), the Shapiro–Wilk test was used to determine the normality of data distribution. Then, paired t tests were performed for continuous variables with normal distribution, whereas the Wilcoxon signed-rank test was performed for continuous variables without normal distribution. We also analyzed covariance (ANCOVA) to address potential confounders that could affect kidney function, including age, gender, duration of T2DM, baseline FPG, and HbA1c levels, changes in FPG and HbA1c levels during follow-up visits compared to baseline, and the presence of a history of hypertension. To address the influence of medications that could potentially affect kidney function, we conducted sensitivity analyses on patients who had not taken angiotensin receptor blockers (ARBs), angiotensin-converting enzyme inhibitors (ACEis), diuretics (DUs), or sodium-glucose cotransporter 2 (SGLT2) inhibitors from baseline to 24 weeks within the effectiveness set.

Subgroup analyses were conducted to investigate percent changes and changes in eGFR based on age group, gender, baseline eGFR and HbA1c, medical history of hypertension, T2DM duration, and previous statin treatments. The baseline eGFR was classified into four ranges as follows: eGFR ≥ 90, 60–89, 30–59, or < 30 mL/min/1.73 m2, referred to as CKD category G1, G2, G3, and G4/5, based on the 2012 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guidelines for CKD [19].

Furthermore, subgroup analyses were additionally conducted to assess metabolic profile changes in lipid and glycemic levels based on baseline eGFR and the changes in glycemic levels based on the modifying antidiabetic drugs during the follow-up period.

Safety analysis was conducted using the safety set. The number and incidence of AEs were assessed. Furthermore, the number and incidence of SAEs and ADRs were assessed. All AEs were coded using MedDRA version 18.1.

All statistical analyses were conducted using SAS ver. 9.4 (SAS Institute, Cary, NC, USA), and the level of significance was set at 5% (P < 0.05).