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Cardiovascular diseases (CVDs) are the leading cause of global morbidity and mortality. According to the World Health Organization (WHO), the global burden of CVDs is remarkable, with an estimated 17.9 million deaths annually, accounting for approximately 32% of all global deaths (WHO) []. Dyslipidemia is a major contributor to CVDs, with statins as the gold-standard treatment for dyslipidemia and consequently playing a crucial role in the prevention of both primary and secondary CVDs []. However, despite their established safety and general tolerability, several studies have indicated a moderate, dose-dependent increase in the risk of new-onset type 2 diabetes mellitus (NO-T2DM) following statin therapy initiation [].

Ezetimibe is another prominent cholesterol-lowering drug that has been in use since 2002 []. It is the most commonly prescribed non-statin agent, effectively reducing low-density lipoprotein cholesterol (LDL-C) levels by 13% to 20% []. Unlike statins, which inhibit cholesterol synthesis through the mevalonate pathway, ezetimibe works by inhibiting the intestinal absorption of cholesterol []. Ezetimibe is usually combined with a statin when the cholesterol levels are not adequately controlled by statin monotherapy. Ezetimibe has also been used alone in cases where statins are contraindicated or not tolerated. Guidelines from the European Society of Cardiology [] and the American Heart Association [] recommend ezetimibe as a second-line lipid-lowering therapy in addition to statins when LDL-C treatment goals are not achieved, or as a monotherapy for patients with statin intolerance. A couple of studies have investigated the efficacy and side effects of statins and ezetimibe [,]. While the impact of statins on the development of NO-T2DM has been extensively documented in the literature [] The specific association of ezetimibe, either a standalone medication or as dual therapy with statins, remains relatively unexplored and therefore warrants further investigation using the systematic review and meta-analysis research methodologies.

This is a systematic review and meta-analysis aimed at providing a comprehensive summary of the impact of adding ezetimibe to statin therapy on the development of NO-T2DM. The study evaluated the risk of NO-T2DM associated with ezetimibe in combination with statins compared to statin monotherapy. Using the quantified weighted effect estimates, the study also estimated the proportion of patients who could potentially avoid developing NO-T2DM by adding ezetimibe to a moderate-intensity statin regimen, rather than increasing the statin dose.

A comprehensive search was conducted across five databases (PubMed, Scopus, Embase, CINAHL, and Web of Science) up to April 1, 2024. The search strategy, which included various search terms and Medical Subject Headings (MeSH) related to lipid-lowering agents, ezetimibe, and statins, was developed and refined by the expert librarian (G.A) (detailed in Supplementary File 2 ). To incorporate any recently published and eligible studies, a brief database search was conducted before manuscript preparation for submission on February 1, 2025. One more eligible study [] was identified and subsequently incorporated into our analysis ().

All retrieved citations were imported into the Covidence software [], a web-based collaboration platform used for record management in systematic and literature reviews, and duplicate citations were removed. Two reviewers independently screened the titles and abstracts of the retrieved citations. Full-text screening was conducted for eligible and potentially eligible studies, independently by two reviewers.

From eligible studies, data were extracted using a predefined form that captured key study characteristics, including the first author’s name, year of publication, study design, sample size, follow-up duration, intervention details (dual or monotherapy, dosage, and duration), and control conditions (placebo, standard care, or treatment modality). If available, crude and adjusted effect estimates with 95% confidence intervals (CIs) were extracted. Otherwise, raw data was used to calculate the relative risk (RR) of NO-T2DM by treatment modality, with corresponding 95% CIs. The extracted study-specific raw data and calculated RRs are provided in Supplementary File 3 .

The risk of bias (RoB) in observational studies was assessed using the Newcastle-Ottawa Quality Assessment Scale (NOS) []. The scale employs a ‘star system’ to evaluate studies across three domains: the representativeness of the study group selection, the comparability of groups, and the ascertainment of the exposure or outcome. Each of the nine items addressed receives one star, with a total score ranging from 0 to 9, where a higher score signifies better study quality. If any of the items are not reported in the study, a score of zero is allocated for that item. The quality of the RCTs was assessed using the Jadad scale []. This five-point scoring system evaluates key methodological features, including randomization, blinding, and reporting of withdrawals. A study is awarded one point for mentioning each of these three criteria. An additional point may be added or subtracted depending on the suitability of the methods employed for randomization and blinding. Any discrepancies in citation screening and data extraction were resolved through mutual discussion or consultation with a senior author (R.H.A.).

Due to heterogeneity in study design, comparators, and dosage, two independent meta-analyses were conducted using estimates from studies with similar designs, comparable comparison groups, and dosage. Of the ten identified cohort studies, weighted crude effect estimates were pooled and generated from only seven studies. The remaining three cohort studies [] as well as the four clinical trials [] were excluded from the meta-analysis due to heterogeneity in treatment modalities. In four [,] of the seven studies, ezetimibe plus moderate-intensity statin dual therapy was compared with high-intensity statin monotherapy, while in the other three studies [], the dual therapy was compared with moderate-intensity statin monotherapy. Estimates of association from these studies were pooled in two meta-analyses according to the comparison treatment modality ( and ). The weighted effect estimates of association and their corresponding 95% CIs were calculated using a random-effects model, employing the DerSimonian and Laird method. The estimate of heterogeneity was derived from the inverse-variance fixed-effect model.

Pooled estimates were visually assessed using forest plots. Heterogeneity among studies was evaluated using Cochran’s Q statistic, while the I -squared ( I 2 ) statistic was estimated to quantify the proportion of variability attributable to between-study heterogeneity. Additionally, Tau-squared (τ 2 ) was computed to estimate the between-study variance in the true association between treatment modality and NO-T2DM. A 95% prediction interval was also calculated to assess the expected distribution of the true effect size across the included studies [].

Of 1,617 citations retrieved from the five databases (PubMed, Scopus, Embase, CINAHL, and Web of Science), 11 studies met the inclusion criteria. An additional two studies were identified through hand-searching bibliographies, and one more was found through an updated database search conducted on February 1, 2025 (). Among the 14 included studies, ten were cohort studies and four were clinical trials.

The cohort studies followed 150,996 patients for 1 to 17 years. The effect of ezetimibe plus moderate-intensity statin on the risk of NO-T2DM was examined in comparison to: (1) moderate- or high-intensity statins in one study [] (2) moderate-intensity statins in three studies [] and (3) high-intensity statins in four studies [,]. In two studies [,], ezetimibe plus statin was compared to statin therapy without specifying intensity. In another study [], ezetimibe plus a low-intensity statin was compared to a moderate-intensity statin. Ezetimibe was administered at a dose of 10 mg in all cohort studies, except for two studies [,] where the dose was not reported. presents the characteristics of these ten observational cohort studies.

In four clinical trials, ezetimibe monotherapy was compared with either alirocumab or double-dose atorvastatin in two studies (ODYSSEY OPTIONS I trial []; ODYSSEY OPTIONS II trial []). One study [] compared moderate-intensity statin plus ezetimibe with moderate-intensity statin alone, while another [] compared moderate-intensity statin plus ezetimibe with moderate- or high-intensity statin. In none of the four trials was ezetimibe use associated with an increased risk of NO-T2DM, regardless of the comparison group. Nevertheless, the strength of evidence from these RCTs may be limited by insufficient statistical power to detect modest effects of ezetimibe on diabetes risk, as indicated by the wide confidence intervals in some trials. presents the characteristics of these four clinical trials. The calculated trial-specific estimate of associations is presented in the Supplementary File 5 .

Patients treated with moderate-intensity statin plus ezetimibe therapy had a 4.0% increased, but not statistically significant, risk of developing NO-T2DM compared to those on moderate-intensity statin monotherapy (weighted RR: 1.04; 95% CI: 0.94–1.14; I 2 = 0.0%) (). In contrast, patients treated with moderate-intensity statin plus ezetimibe had a statistically significant 18% lower risk of NO-T2DM compared to those on high-intensity statin monotherapy (weighted RR: 0.82; 95% CI: 0.77–0.87; I 2 = 0.0%) ().

Utilizing the generated weighted RR of 0.82 presented in , the ARF of NO-T2DM for moderate-intensity statin plus ezetimibe compared to high-intensity statin monotherapy was estimated at −22.0% (95% CI: −0.28 to −0.16). This indicates that 22% of NO-T2DM cases could potentially be averted with dual therapy (moderate-intensity statin plus ezetimibe). In the four cohort studies, among the 5,072 patients on high-intensity statin who developed NO-T2DM, 1,115 (range: 812–1,420) patients could potentially be protected from developing NO-T2DM. Calculations are presented in Supplementary File 3 .

The overall risk of bias was rated as low across all included observational studies (the NOS score ranged from 6 to 8); one study [] was categorized as having a moderate risk of bias. An additional four studies [,,,] raised concerns in at least one domain of the NOS, indicating some risk of bias. Most of the included studies, specifically five [,,,,] were judged to have a low risk of bias according to the NOS criteria. Full assessment presented in Supplementary File 4-Table S1 . The risk of bias for each of the four included RCTs was assessed using the Jadad Scale. Based on this assessment, two studies (ODYSSEY OPTIONS I trial [,] were categorized as having a low risk of bias, achieving the maximum score of 5. One study (ODYSSEY OPTIONS II trial []) scored 4, indicating a moderate risk of bias due to limitations in the description of the withdrawals and dropouts. One study [] scored three, suggesting a high risk of bias owing to the lack of description of double-blinding methods. Full assessment presented in Supplementary File 4-Table S2 .

This systematic review and meta-analysis examined the association between lipid-lowering treatments, specifically ezetimibe and statins, and the risk of developing NO-T2DM. By synthesizing data from multiple cohort studies, the study clarifies how different treatment regimens, including statin monotherapy and statin-ezetimibe combination therapies, influence the development of NO-T2DM. The findings contribute valuable insights into the potential benefits of adding ezetimibe to moderate-intensity statins in reducing the risk of NO-T2DM when compared to high-intensity statin monotherapy, while maintaining the desired lipid-lowering efficacy and overall cardiovascular benefits of statin therapy. These results have important implications for clinical decision-making and patient management in populations at risk for both dyslipidemia and NO-T2DM.

Ezetimibe is a non-statin lipid-lowering drug that has been reported to result in an additional 22 mg/dL reduction in LDL-C in patients with atherosclerotic cardiovascular disease (ASCVD) when combined with statin therapy, compared with patients receiving statin therapy alone []. This finding is consistent with the study by Toyota et al. which showed that intensifying lipid-lowering therapy with ezetimibe has the potential to enhance clinical outcomes (major adverse cardiovascular events, MACE) among individuals with ASCVD []. In line with this, a systematic review of randomized clinical trials comparing an alternative LDL-C-lowering strategy of using a moderate-intensity statin with ezetimibe versus a high-intensity statin strategy suggested that the combination therapy demonstrated comparable efficacy regarding 3-year death or cardiovascular events, with an associated reduction in LDL-C levels, risk for NO-T2DM, and intolerance [].

This approach could potentially achieve comparable cardiovascular benefits while minimizing the risk of NO-T2DM, as demonstrated by a recent meta-analysis showing that alternative LDL-C-lowering strategies are comparable in efficacy to high-intensity statins in patients with ASCVD []. Clinical trials and real-world practice have shown that moderate-intensity statin therapy combined with ezetimibe can achieve non-inferiority to high-intensity statin therapy in reducing LDL-C levels and CVD risk []. In observational studies, moderate-intensity statin therapy combined with ezetimibe achieved LDL-C reductions comparable to high-intensity statin monotherapy. Specifically, Choo et al. [] reported similar LDL-C lowering with the combination therapy, which was additionally associated with a lower risk of NO-T2DM, without differences in cardiovascular outcomes over 3 years. Similarly, Lee S.J. et al. [] demonstrated that LDL-C lowering with the combination therapy was non-inferior to high-intensity statins, while also reducing the risk of NO-T2DM, without compromising cardiovascular outcomes. These findings indicate that the benefit of lower diabetes risk with ezetimibe plus moderate-intensity statin therapy is not offset by a weaker effect on LDL-C or cardiovascular risk, supporting its use as an effective and safer alternative to high-intensity statin monotherapy. This is further supported by landmark trials such as RACING and IMPROVE-IT, which demonstrated that combination therapy can achieve non-inferiority to high-intensity statin monotherapy in reducing CVDs risk and achieving LDL-C goals [,]. Furthermore, the increasing utilization of moderate-intensity statin plus ezetimibe in clinical practice reflects this evidence, with use rising from 10.7% in 2015 to 20.4% in 2016 and further to 30.4% in 2017 []. Taken together, this body of evidence suggests that the combination of a moderate-intensity statin with ezetimibe could provide an equally effective LDL-C-lowering strategy while reducing the risk of NO-T2DM.

Current evidence on the effects of ezetimibe on glucose metabolism and diabetes risk remains limited. The findings of this systematic review indicate that adding ezetimibe to moderate-intensity statin therapy did not significantly alter the risk of NO-T2DM compared with moderate-intensity statin therapy alone. As supported by previous research demonstrating no significant impact of ezetimibe on glucose homeostasis. Wu and colleagues found that ezetimibe treatment does not lead to dysregulation of glucose metabolism. The authors also indicated that ezetimibe with low-dose statin therapy for more than 3 months may improve glycemic control []. Similarly, pooled data support this finding that adding ezetimibe to statin monotherapy did not increase fasting blood glucose levels for up to 96 weeks of treatment []. Together, these findings suggest a largely neutral, or even slightly favorable, impact of ezetimibe on glucose metabolism.

Ezetimibe’s ability to modify diabetes risk when combined with statins is believed to be due to two main mechanisms. First, the indirect mechanism: Ezetimibe works by inhibiting the absorption of cholesterol in the intestine. When it is combined with a moderate-intensity statin, the combination therapy can achieve the same degree of LDL-C lowering as a high-intensity statin monotherapy. By allowing patients to avoid the higher statin dose, this combination therapy effectively mitigates the dose-related increase in diabetes risk that would come from a high-intensity statin alone []. Second, the direct mechanism, ezetimibe, can improve endothelial function and reduce both postprandial triglycerides and insulin levels in patients with metabolic syndrome. This suggests that ezetimibe has vascular protective effects by reducing insulin resistance and postprandial hyperlipidemia [,].

Several mechanisms have been suggested to explain statin-associated NO-T2DM; however, the central proposed mechanism involves the low-density lipoprotein receptor (LDLR) pathway []. Specifically, that upregulation of LDLR not only mediates lipid-lowering effects but also increases cholesterol uptake in pancreatic β-cells, leading to lipotoxicity and β-cell dysfunction; this is supported by clinical observations in familial hypercholesterolemia, where reduced LDLR activity is associated with a lower prevalence of type 2 diabetes []. Experimental evidence from LDLR-deficient mouse models also shows protection of β-cells from cholesterol accumulation, further supporting this mechanism. Collectively, impaired insulin secretion appears to be the key driver of statin-induced type 2 diabetes, with insulin resistance contributing when β-cell compensation is insufficient [].

Nevertheless, a large genetic study examining life-long exposure to lower LDL-C levels due to NPC1L1 genetic variants—the target of ezetimibe—reported an increased risk of diabetes, suggesting that interference with glucose homeostasis may represent a class effect of LDL-C–lowering agents [], additionally, a meta-analysis of genome-wide association studies (GWAS) in statin-treated individuals identified two genetic loci, APOE and HNF1A , significantly associated with reductions in C-reactive protein (CRP), an inflammatory marker. These findings indicate that these genes, which are also linked to cholesterol metabolism and other diseases, may modulate individual responses to statin therapy, with the HNF1A locus specifically associated with diabetes risk []. Limited clinical data currently exist regarding the long-term impact of ezetimibe combination therapy on the incidence of NO-T2DM. Further research is warranted to investigate the long-term effects of this therapeutic strategy.

Interestingly, the results suggest a potential protective effect of ezetimibe against NO-T2DM when combined with moderate-intensity statins compared to high-intensity statin monotherapy in secondary prevention. This observation may be related to the dose-dependent increased risk of NO-T2DM associated with statin therapy. In a post-hoc analysis of the LODESTAR trial, the risk of NO-T2DM did not differ significantly between rosuvastatin and atorvastatin among patients receiving high-intensity statin therapy. However, when very low LDL-C levels (<70 mg/dL) were achieved, rosuvastatin was associated with a significantly higher risk of new-onset diabetes compared with atorvastatin []. meta-analyses confirm this trend, as Low-intensity or moderate-intensity regimens resulted in a 10% relative increase in NO-T2DM compared with placebo, and high-intensity statin regimens resulted in a 36% relative increase []. Preiss and coworkers reported that high-intensity statin therapy increased the incidence of NO-T2DM by 12% more than moderate-intensity statin therapy []. Indeed, a recent meta-analysis for randomized controlled trials assessing the Safety of ezetimibe revealed that ezetimibe was not associated with NO-T2DM (relative risk 0.88; 95% confidence interval 0.61 to 1.28) []. Moreover, Chiu and coworkers found that using ezetimibe does not appear to impact the risk of NO-T2DM when added to guideline-directed medical therapy []. It is important to note that previous meta-analyses often pooled data across different background therapies, potentially masking the nuanced effects observed in this study. The findings of this study suggest that considering the intensity of statin therapy, alongside the addition of ezetimibe, may be crucial for optimizing both lipid-lowering efficacy and the risk of NO-T2DM.

Statin therapy has been associated with an increased risk of developing NO-T2DM. Nevertheless, this elevated diabetes risk does not outweigh the substantial cardiovascular benefits of statin use, as the overall reduction in cardiovascular risk remains significant []. Maintaining long-term LDL-C levels at or below 100 mg/dL has been shown to reduce the incidence of major cardiovascular events by approximately 40% []. In light of these findings, a combined LDL-C–lowering approach using moderate-intensity statin therapy with ezetimibe may represent a more favorable strategy for individuals at high risk of developing type 2 diabetes compared to high-intensity statin monotherapy.

Previous meta-analyses have demonstrated that ezetimibe, compared to placebo, standard care, or other lipid-lowering agents, does not significantly increase the risk of NO-T2DM in individuals requiring lipid-lowering therapy. However, these analyses often lack specificity and insufficient detail to investigate these findings in-depth, as they typically compare ezetimibe across various treatment contexts without considering comparable homogeneity, including placebo, which is rarely utilized in clinical practice. A more nuanced understanding of ezetimibe’s impact on NO-T2DM risk requires dedicated analyses focusing on ezetimibe as an add-on to statin therapy, a more clinically relevant scenario. This study provides evidence that adding ezetimibe to moderate-intensity statin is associated with a lower risk of NO-T2DM compared with high-intensity statin in secondary prevention. It has a neutral effect when added to a moderate-intensity statin in either primary or secondary prevention.