Our analyses demonstrated that administering simvastatin at dosages of 20 to 40 mg/day, adjusted based on cardiovascular disease presence and follow-up LDL-C levels, for an average duration of 4.9 years, significantly reduced the risk of CKD and renal failure compared to not using statin therapy in T2DM patients at elevated risk of cardiovascular disease, with a baseline median eGFR of 89.9 ml/min/1.73 m2. Furthermore, the analysis revealed significant variability in the treatment effect on CKD and renal failure based on baseline lipid levels, albuminuria, or eGFR levels, yet the risk of CKD consistently decreased across all subgroups. Additionally, LDL-C reduction appears to be a potential mediator of simvastatin’s protective effect on CKD.

This study represents a post hoc analysis of the ACCORD Trial. Uniquely, our analysis included a statin-free control group, a rarity in contemporary intervention studies due to the well-documented cardiovascular benefits of statin therapy in diabetes patients [9]. The absence of a placebo control group challenges the reliability and validity of findings. Furthermore, our study benefited from a large sample size and an extensive, nearly complete follow-up period.

Our findings suggest simvastatin’s beneficial effects on kidney function, particularly in reducing CKD and renal failure among T2DM patients. This study concentrated on the impact on clinically relevant renal events rather than solely on eGFR decline. Our results align with those from the Heart Protection Study (HPS), which found that simvastatin significantly mitigated the decrease in eGFR during follow-up in diabetic and non-diabetic individuals alike [10]. Similarly, the Scandinavian Simvastatin Survival Study (4 S) showed that simvastatin significantly reduced the frequency of a ≥ 25% decline in kidney function. However, it did not significantly affect kidney function in participants who developed CKD by the end of the follow-up [11]. Statins, including atorvastatin, pravastatin, and simvastatin, displayed a trend toward reducing the risk of kidney failure, with a combined risk reduction for renal failure of 6% (95% CI, 1–12%), whereas other statins did not exhibit similar effects [5]. Therefore, we advocate for the use of statins for their renal benefits, emphasizing the reduction of clinically relevant renal events and the thoughtful selection of statin type in T2DM patients.

Our subgroup analysis revealed that the protective effect of simvastatin on CKD and renal failure in patients with T2DM varies across different baseline lipid and renal profiles. Existing evidence indicates that diabetes and CKD are often associated with an altered lipid profile, typically characterized by low HDL-C and elevated triglyceride levels [12, 13]. Although in patients with typical diabetic or CKD lipid profiles—low HDL-C and high triglycerides—the protective effect of simvastatin on CKD appeared slightly less pronounced, its effect remained consistently beneficial across all subgroups. This finding supports the use of simvastatin to reduce the risk of CKD in T2DM patients, regardless of their lipid profile or renal function status.

Our mediator analyses suggest that LDL-C reduction mediates the protective effect of simvastatin on CKD. Indeed, high LDL-C levels have been both observationally and genetically associated with increased risks of CKD, indicating a potential causal role of LDL-C in the pathogenesis of the disease [14]. The mechanisms behind lipid-induced renal damage are centered on lipotoxicity, where excessive lipid accumulation leads to cellular dysfunction and injury, particularly affecting renal tubular epithelial cells, renal interstitial cells, and glomerular podocytes. This process is closely linked to the progression of diabetic nephropathy [15]. However, as previously mentioned, not all LDL-C -lowering statins offer renal protection. Our study shows that LDL-C reduction only partially mediates this protective effect, suggesting that simvastatin may have renal benefits independent of LDL-C reduction. Recent studies have demonstrated the senolytic activity of lipophilic statins—specifically simvastatin, lovastatin, and atorvastatin—on cultured human endothelial cells [16]. Further research is needed to explore the underlying mechanisms of simvastatin’s potential renal protective effects.

The limitation of our analysis is that most ACCORD participants had normal kidney function at baseline, leading to a limited number of renal failure events. Nevertheless, the significant effect of simvastatin on this outcome, even after comprehensive adjustments, warrants further investigation to confirm its robustness. Additionally, unlike the original ACCORD trial design, this study focused on assessing the renal effects of simvastatin, excluding patients on fenofibrate to avoid potential synergistic or confounding effects. While this approach allows for a more accurate evaluation of simvastatin’s impact, it also reduces the sample size and may introduce selection bias. These limitations should be considered when interpreting the findings.

In conclusion, using statins, particularly simvastatin, in individuals with T2DM at high risk of cardiovascular disease, is likely to offer additional renal benefits, especially in reducing clinically relevant renal events such as CKD and renal failure. These findings have important implications given the burden of diabetes and the urgent need for effective therapies to slow the progression of significant renal endpoints.