Erfolgreich durch internationale Zusammenarbeit

Endocrinology and Metabolism

Cite as: Archiv EuroMedica. 2026. 16; 4. DOI 10.35630/2026/16/Iss.4.04

Received 11 June 2026;
Accepted 1 August 2026;
Published 6 August 2026

THE ROLE OF THE GUT MICROBIOTA IN STATIN ASSOCIATED DYSGLYCEMIA AND NEW ONSET DIABETES: A NARRATIVE REVIEW

Zuzanna Borecka¹ , Agnieszka Marta Sobczak² ,
Alicja Szymczak³ , Anna Jaworowicz⁴ ,
Joanna Piasecka³ , Bartosz Gołembiewski⁴ ,
Grzegorz Mulski² , Martyna Manicka³ ,
Michał Baranowicz⁵ , Weronika Mazurkiewicz⁴

¹ Regional Hospital in Poznan, Poland
² University Hospital in Poznan, Poland
³ Medical Center HCP, Poznan, Poland
⁴ MSWiA Hospital in Poznan, Poland
⁵ Poznan University of Medical Sciences, Poznan, Poland

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  zuzanna.borecka2912@gmail.com

ABSTRACT

Background

Statins are among the most widely prescribed lipid lowering agents and substantially reduce cardiovascular morbidity and mortality. However, accumulating evidence suggests that statin therapy may be associated with disturbances in glucose homeostasis and an increased risk of statin associated dysglycemia and new onset diabetes (SANOD). Alterations in the gut microbiota have emerged as a potential contributor to these metabolic effects.

Aim

This narrative review summarizes current evidence on the relationship between statin therapy, gut microbiota alterations, and statin associated dysglycemia and new onset diabetes, with emphasis on the underlying biological mechanisms and their potential clinical relevance.

Materials and methods

A literature search was conducted in PubMed/MEDLINE, Scopus, and Web of Science, with Google Scholar used as a supplementary source. Publications available up to July 20, 2026, were considered. Clinical, observational, experimental, and relevant review studies evaluating associations between statin therapy, gut microbiota, glucose homeostasis, and new onset diabetes were qualitatively synthesized. A total of 46 publications were included.

Results

Current evidence suggests that statins may alter gut microbiota composition and metabolic activity. Proposed mechanisms include modulation of bile acid metabolism, short chain fatty acid production, incretin signaling, intestinal barrier integrity, and inflammatory pathways. These microbiota mediated alterations may contribute to individual susceptibility to statin associated dysglycemia and new onset diabetes. However, the available evidence remains heterogeneous and is largely based on observational and experimental studies.

Conclusions

The gut microbiota represents a biologically plausible mediator of statin associated metabolic effects, but current evidence is insufficient to establish causality or support microbiota guided clinical decision making. Further well designed prospective and mechanistic studies are needed to clarify these interactions and their clinical significance.

Keywords: statins; gut microbiota; dysglycemia; new onset diabetes; type 2 diabetes mellitus; glucose homeostasis

INTRODUCTION

Type 2 diabetes mellitus is a common metabolic disorder whose prevalence continues to increase, accompanied by rising rates of complications and mortality, particularly from cardiovascular diseases [1,2]. The disease is characterized by chronic hyperglycemia, insulin resistance, and progressive pancreatic beta cell dysfunction, with inflammation, oxidative stress, and disturbances in glucose and lipid metabolism contributing to its progression [3–6]. The gut liver pancreas axis plays an important role in maintaining metabolic homeostasis, including the effects of the gut microbiota on short chain fatty acid production, bile acid metabolism, immune signaling, and incretin secretion [7–9].

Because individuals with T2DM are at very high cardiovascular risk, statins remain the cornerstone of lipid-lowering therapy and are widely recommended for both primary and secondary prevention of cardiovascular events [10–12]. Their efficacy in reducing cardiovascular morbidity and mortality has been consistently demonstrated in randomized clinical trials and meta-analyses [12,13]. Nevertheless, accumulating evidence indicates that statin therapy is associated with a modest but clinically relevant increase in the risk of dysglycemia and new-onset diabetes, particularly among individuals with pre-existing metabolic risk factors such as obesity, prediabetes, or metabolic syndrome [14–19]. Importantly, these diabetogenic effects do not outweigh the established cardiovascular benefits of statins, but they have prompted considerable interest in the biological mechanisms responsible for interindividual differences in metabolic responses to treatment [14–17].

The gut microbiota constitutes a complex microbial ecosystem that plays a fundamental role in maintaining host metabolic homeostasis [20]. Alterations in its composition and function, collectively referred to as dysbiosis, have been repeatedly linked to insulin resistance, impaired glucose regulation, and the development of T2DM [7–9,21,22]. More recently, evidence has emerged suggesting that statins may also influence the composition and metabolic activity of the gut microbiota. Population-based studies have demonstrated distinct microbial profiles among statin users [23], while prospective data from the FINRISK cohort identified specific bacterial taxa associated with an increased risk of statin-associated new-onset diabetes (SANOD) [24]. Experimental studies further suggest that microbiota-dependent alterations in bile acid metabolism, SCFA production, incretin signaling, and inflammatory pathways may contribute to impaired glucose homeostasis during statin therapy [25–28].

Previous reviews have addressed these topics from complementary but distinct perspectives. Reviews focusing on the gut microbiota have primarily discussed its role in metabolic diseases and T2DM [9,21,22], whereas reviews devoted to statin associated dysglycemia have summarized the clinical evidence and molecular mechanisms underlying the diabetogenic effects of statins [29,30]. Other recent reviews have explored bidirectional interactions between statins and the gut microbiota in the broader context of cardiovascular disease, drug response, and metabolic health [31]. However, a comprehensive synthesis specifically integrating clinical, observational, and mechanistic evidence on the role of the gut microbiota as a potential mediator of statin associated dysglycemia and new onset diabetes remains limited.

The relevance of this review is determined by the widespread use of statins and the occurrence of disturbances in glucose metabolism in some patients during treatment [14–19,29,30]. Direct clinical evidence is limited, study findings are heterogeneous, and a causal relationship has not been established [23–25,30,31]. A specific feature of this review is the focused integration of clinical, observational, and experimental evidence on possible microbiota mediated mechanisms underlying the metabolic effects of statins.

AIM

The aim of this review is to critically summarize current evidence on the role of the gut microbiota in the development of dysglycemia and new onset diabetes associated with statin therapy.

The objectives of the review are:

1. To summarize evidence on the effects of statins on glucose homeostasis, gut microbiota composition, and microbial functional activity.
2. To examine the proposed microbiota mediated mechanisms, including bile acid metabolism, short chain fatty acid production, GLP 1 secretion, intestinal barrier dysfunction, and inflammatory signaling pathways.
3. To assess the clinical significance of the identified associations, the limitations of the current evidence, and priorities for future research.

MATERIALS AND METHODS

This study was conducted as a narrative review based on publications retrieved from major international databases. The literature search was performed in PubMed/MEDLINE, Scopus, and Web of Science, with Google Scholar used as a supplementary source to identify additional relevant studies. The search covered publications available up to July 20, 2026. No strict time restrictions were applied. Older publications were included when they addressed relevant pathophysiological mechanisms or provided foundational evidence for the interpretation of more recent findings. Following title, abstract, and full text screening according to the predefined eligibility criteria, 46 publications were included in the final narrative synthesis.

The literature search was conducted using combinations of keywords related to three main areas of the review: statin therapy, gut microbiota, and statin-associated dysglycemia or new-onset diabetes. The primary search strategy included the following terms: (statins OR atorvastatin OR rosuvastatin OR simvastatin) AND (gut microbiota OR microbiome OR intestinal microbiota OR dysbiosis) AND (new-onset diabetes OR statin-associated new-onset diabetes OR dysglycemia OR glucose metabolism OR insulin resistance OR type 2 diabetes).

Additional searches included combinations of the terms: bile acids, GLP-1, short-chain fatty acids, insulin resistance, and microbiota-dependent mechanisms. The search was supplemented by manual screening of reference lists of selected articles to identify additional relevant publications.

The analysis included publications addressing the effects of statin therapy on gut microbiota composition or function and their potential contribution to disturbances in glucose metabolism, including dysglycemia and new-onset diabetes. Clinical trials, cohort studies, observational studies, systematic reviews, and meta-analyses were primarily considered, supplemented by selected translational and experimental studies providing mechanistic data relevant to clinical interpretation. Studies involving patients with type 2 diabetes mellitus, prediabetes, metabolic syndrome, hypercholesterolemia, or statin users without diabetes were included when they provided evidence regarding associations between statin therapy, alterations in gut microbiota, and glucose homeostasis. Publications were excluded if they were case reports, case series lacking an analytical component, conference abstracts, editorials, letters to the editor, or non-peer-reviewed publications. Studies not addressing gut microbiota, statin therapy, or metabolic outcomes relevant to the objectives of this review were also excluded. The screening of titles, abstracts, and full-text articles was performed independently by two authors. Any disagreements regarding study eligibility were resolved through discussion and consensus. Data on study design, population characteristics, statin therapy, methods of assessing the gut microbiota, and metabolic outcomes related to glucose homeostasis were extracted from the selected studies.

As this paper represents a narrative review, no formal protocol registration, standardized risk of bias assessment, meta analysis, or quantitative assessment of the methodological quality of individual studies was performed. The review was prepared and reported with consideration of the SANRA (Scale for the Assessment of Narrative Review Articles) checklist. Given the substantial heterogeneity of the available studies, including differences in study design, study populations, gut microbiota assessment methods, and evaluated metabolic outcomes, the results are presented as a narrative synthesis.

RESULTS

Gut microbiota and glucose homeostasis

The gut microbiota is now widely recognized as an important contributor to host metabolic homeostasis and the pathogenesis of metabolic disorders, including type 2 diabetes mellitus (T2DM) [9,22]. It forms a complex ecosystem of microorganisms involved in key metabolic processes, including the fermentation of undigested nutrients, the production of short-chain fatty acids (SCFAs), bile acid metabolism, and immune regulation [9,21,22,32]. Disruptions in its composition, collectively referred to as dysbiosis, have been implicated in the development of insulin resistance, impaired glucose homeostasis, and T2DM [7,9,33].

Early sequencing studies comparing the gut microbiota of patients with T2DM and healthy individuals demonstrated significant alterations in microbial composition and reduced bacterial diversity in diabetic subjects [7,8]. In particular, the abundance of SCFA-producing bacteria, including Faecalibacterium and Roseburia, was consistently reduced, whereas the relative abundance of potentially pro-inflammatory taxa was increased [7,34]. Subsequent metagenomic studies confirmed these observations and further demonstrated functional alterations within the microbiome, affecting pathways involved in carbohydrate, amino acid, and lipid metabolism [8,35]. A key mechanism linking dysbiosis to metabolic dysfunction is reduced SCFA production, particularly butyrate [21,36]. These microbial metabolites play a crucial role in maintaining intestinal barrier integrity, regulating inflammatory responses, and modulating glucose metabolism through effects on incretin secretion and insulin sensitivity [9,21,36]. Reduced SCFA availability has been proposed to increase intestinal permeability and promote the translocation of bacterial lipopolysaccharide (LPS) into the systemic circulation, leading to metabolic endotoxemia [37]. This process contributes to chronic low-grade inflammation and the development of insulin resistance, both of which are central to disturbances in glucose homeostasis and the pathogenesis of T2DM [5,37].

Beyond SCFA production, the gut microbiota also regulates bile acid metabolism and signaling through receptors such as farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5), which influence glucose and lipid metabolism [21,22,26]. Consequently, alterations in gut microbiota composition may affect multiple metabolic pathways involved in glucose regulation and insulin sensitivity [9,26]. Population-based studies have demonstrated associations between specific gut microbiota profiles and metabolic parameters, including fasting glucose, insulin resistance, and the future risk of developing T2DM [8,34,38].

Although numerous studies support a relationship between gut microbiota alterations and impaired glucose metabolism, the causal nature of these associations remains incompletely understood, as microbial composition is influenced by multiple factors, including diet, obesity, lifestyle, and pharmacological treatment [9,21,36,38]. Among these factors, increasing attention has been directed toward commonly prescribed medications capable of modifying the gut microbiota. This is particularly relevant for statins, whose effects extend beyond lipid lowering and may involve alterations in microbial composition and associated metabolic functions. These observations have raised the hypothesis that the gut microbiota may contribute to interindividual differences in glucose metabolism during statin therapy and potentially influence the risk of statin-associated dysglycemia and new-onset diabetes [23–25].

Effects of statins on glucose metabolism

Statins have become an integral component of cardiovascular disease prevention and remain the first-line lipid-lowering therapy for patients at high cardiovascular risk [10–12]. By competitively inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, they reduce hepatic cholesterol synthesis, increase LDL receptor expression, and effectively lower circulating LDL cholesterol levels [10,12]. Their efficacy in reducing cardiovascular morbidity and mortality has been consistently demonstrated in numerous randomized controlled trials and large meta-analyses [12,13]. Despite these well-established cardiovascular benefits, concerns regarding the potential effects of statins on glucose metabolism have emerged over the past decade following reports of a modest increase in the incidence of new-onset diabetes among statin-treated individuals [14,15].

Meta-analyses of randomized clinical trials have demonstrated that statin therapy is associated with a small but statistically significant increase in the risk of developing new-onset diabetes [14]. Subsequent studies confirmed that this risk is more pronounced with intensive statin therapy and in individuals with pre-existing metabolic risk factors, including obesity, prediabetes, and metabolic syndrome [15,16]. Observational studies and cohort analyses further suggest that diabetes developing during statin therapy occurs predominantly in metabolically susceptible individuals, indicating that statins may unmask or accelerate pre-existing disturbances in glucose regulation rather than acting as their sole cause [16,17]. This phenomenon, commonly referred to as statin-associated new-onset diabetes (SANOD), has been consistently documented across different populations [15,18]. Importantly, the modest increase in diabetes risk does not outweigh the substantial cardiovascular benefits of statin therapy, particularly in patients at elevated cardiovascular risk [12,13,18].

The mechanisms responsible for statin-associated dysglycemia remain incompletely understood, although several complementary pathways have been proposed. Experimental studies indicate that statins may reduce peripheral insulin sensitivity by impairing insulin signaling and decreasing GLUT4-mediated glucose transport in skeletal muscle [39]. Inhibition of the mevalonate pathway has also been implicated in mitochondrial dysfunction and reduced coenzyme Q10 biosynthesis, potentially affecting cellular energy metabolism and insulin responsiveness [29]. Additional evidence suggests that statins may impair pancreatic β-cell function, leading to reduced insulin secretion and higher fasting glucose concentrations, particularly during high-intensity treatment [16,29]. Although differences among individual statins remain incompletely resolved, several studies have suggested that high-intensity statins, particularly atorvastatin and rosuvastatin, may exert more pronounced effects on glucose metabolism [15,19].

Increasing evidence indicates that these mechanisms may also involve interactions with the gut microbiota. Population-based cohort studies have demonstrated that statin therapy is associated with measurable alterations in gut microbiota composition and a lower prevalence of gut microbiota dysbiosis [23]. Moreover, the FINRISK cohort identified specific bacterial taxa associated with an increased risk of statin-associated new-onset diabetes, suggesting that the intestinal microbiome may contribute to interindividual susceptibility to dysglycemia during statin therapy [24]. Experimental studies further indicate that statins may influence bile acid metabolism and glucagon-like peptide-1 (GLP-1) signaling through microbiota-dependent pathways, with potential downstream effects on microbial metabolic functions, including short-chain fatty acid metabolism [25]. These findings support the hypothesis that gut microbiota alterations represent one of several mechanisms potentially contributing to disturbances in glucose homeostasis observed during statin therapy and provide the rationale for further investigation of the gut microbiota-statin-glucose metabolism axis [25,30,31].

Effects of statin therapy on gut microbiota composition and function

Recent studies suggest that statins may influence the composition and function of the gut microbiota, potentially contributing to metabolic effects beyond lipid lowering [23,40]. This is particularly relevant in the context of glucose homeostasis, where the gut microbiota plays an important role in regulating bile acid metabolism, short-chain fatty acid production, inflammatory pathways, and incretin secretion [21,26,40]. Collectively, these observations support the hypothesis that statin-induced alterations in the gut microbiota may contribute to statin-associated dysglycemia and new-onset diabetes through microbiota-dependent metabolic pathways, although current evidence remains largely associative [23–25,30,31].

One of the first large population-based cohort studies linking statin therapy with changes in gut microbiota composition was conducted by Vieira-Silva et al. [23]. Compared with non-users, statin-treated individuals exhibited distinct microbial profiles and a lower prevalence of gut microbiota dysbiosis. In particular, differences were observed in the abundance of bacterial taxa belonging to the phyla Bacteroidetes and Firmicutes, both of which have previously been associated with metabolic homeostasis and glucose regulation [8,23]. Subsequent observational and experimental studies suggested that statin-associated microbiota alterations may extend beyond taxonomic composition and involve microbial metabolic pathways related to bile acid transformation and short-chain fatty acid metabolism [21,26,41]. Because these microbial metabolites regulate insulin sensitivity, inflammatory responses, and signaling through receptors such as FXR and TGR5, statin-induced alterations in gut microbiota composition may indirectly influence glucose metabolism [26,27].

Further evidence supporting this hypothesis was provided by the FINRISK cohort study [24], which demonstrated that specific gut microbiota signatures were associated with an increased risk of statin-associated new-onset diabetes (SANOD). These findings suggest that interindividual variation in gut microbiota composition may contribute to susceptibility to dysglycemia during statin therapy. Experimental studies have provided additional mechanistic support, demonstrating that statins may alter gut microbiota composition through modulation of bile acid metabolism and changes in the intestinal microenvironment [27,28]. In animal models, atorvastatin-induced alterations in gut microbiota were associated with reduced glucagon-like peptide-1 (GLP-1) secretion, increased insulin resistance, and impaired glucose tolerance, supporting a microbiota-dependent mechanism linking statin therapy with dysglycemia [25].

Despite these findings, the available evidence remains heterogeneous. The observed effects of statins on gut microbiota composition appear to depend on multiple factors, including statin type and dose, treatment duration, dietary habits, baseline microbiota composition, and individual comorbidities [9,40–43]. While several studies suggest that statins may improve gut microbial composition by reducing dysbiosis [23], others indicate that microbiota alterations may contribute to impaired glucose homeostasis in susceptible individuals [24,25]. These discrepancies likely reflect methodological differences between studies as well as the considerable interindividual variability of the human gut microbiome. Furthermore, most currently available data originate from observational studies or experimental models, limiting the ability to establish causal relationships in humans [30,31].

Overall, current evidence indicates that statins are capable of influencing both the composition and functional potential of the gut microbiota. Although the precise mechanisms remain incompletely understood, modulation of the microbiota-bile acid-GLP-1 axis represents one of the leading mechanistic hypotheses linking statin therapy with disturbances in glucose homeostasis. These findings provide the rationale for the mechanistic pathways discussed in the following section and support the need for further well-designed prospective human studies investigating the gut microbiota-statin-glucose metabolism axis [30,31]. The summary of the key studies evaluating relationships between statins, gut microbiota and metabolic outcomes is presented in Table 1.

Microbiota-mediated mechanisms underlying statin-associated dysglycemia and new-onset diabetes

Current evidence suggests that statins may influence glucose homeostasis not only through direct cellular mechanisms but also via microbiota-mediated pathways [9,23]. The gut microbiota regulates several metabolic processes involved in glucose homeostasis, including bile acid metabolism, short-chain fatty acid (SCFA) production, incretin secretion, and immune signaling [9,21,26]. Consequently, statin-induced alterations in gut microbiota composition may indirectly affect insulin sensitivity, pancreatic β-cell function, and the overall metabolic response to statin therapy, although the relative contribution of these pathways remains to be fully established [23–25,30,31]. Among the proposed mechanisms, the interaction between the gut microbiota and bile acid metabolism is one of the best characterized. By participating in bile acid deconjugation and biotransformation, intestinal bacteria regulate the activation of farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5), both of which play important roles in glucose and lipid metabolism [26,27]. Statins may influence this pathway both directly, by modifying hepatic cholesterol and bile acid metabolism, and indirectly through alterations in gut microbiota composition [27,28]. Consequently, disturbances within the microbiota-bile acid-FXR/TGR5 axis may impair insulin sensitivity and contribute to disturbances in glucose homeostasis [26,27].

Another proposed mechanism involves alterations in SCFA metabolism. Short-chain fatty acids, particularly butyrate, propionate, and acetate, are generated through bacterial fermentation of dietary fiber and exert multiple beneficial metabolic effects [9,21]. Acting through G protein-coupled receptors such as GPR41 and GPR43, SCFAs regulate GLP-1 secretion, insulin sensitivity, intestinal barrier integrity, and inflammatory responses [21,36]. Reduced abundance of SCFA-producing bacteria has been consistently associated with insulin resistance and chronic low-grade inflammation [9,36]. Although direct evidence that statins reduce SCFA production in humans remains limited, statin-induced alterations in gut microbiota composition may influence SCFA metabolism and thereby contribute to impaired glucose regulation in susceptible individuals [23,24,30].

The incretin axis represents another potential link between statin therapy, gut microbiota, and glucose metabolism. Glucagon-like peptide-1 (GLP-1) enhances glucose-dependent insulin secretion, suppresses glucagon release, and delays gastric emptying, improving glycemic control [44]. Experimental evidence indicates that gut microbiota composition may regulate GLP-1 secretion through both bile acid-dependent and SCFA-dependent mechanisms. A recent experimental study demonstrated that atorvastatin-induced alterations in gut microbiota reduced GLP-1 levels and aggravated insulin resistance through a microbiota-dependent pathway, providing direct mechanistic evidence linking statin therapy with impaired glucose homeostasis in an animal model [25].

Low-grade chronic inflammation may also contribute to statin-associated dysglycemia through microbiota-mediated mechanisms. Dysbiosis may impair intestinal barrier integrity, facilitating the translocation of bacterial lipopolysaccharide (LPS) into the systemic circulation, a phenomenon known as metabolic endotoxemia [37]. Increased circulating LPS activates Toll-like receptor signaling and promotes chronic inflammation, oxidative stress, and insulin resistance [5,37,45,46]. Although direct evidence linking statin-induced microbiota alterations with metabolic endotoxemia remains limited, this mechanism represents a biologically plausible pathway through which gut microbiota may modulate metabolic responses to statin therapy [21,23,30].

Overall, current evidence supports the concept that interactions between statins, the gut microbiota, bile acid metabolism, SCFAs, incretin signaling, and inflammatory pathways may collectively contribute to interindividual differences in glucose homeostasis during statin therapy.

While the relative contribution of each pathway remains to be established, these microbiota-mediated mechanisms provide a reasonable biological framework linking statin therapy with dysglycemia and new-onset diabetes. However, most available evidence is derived from observational studies and experimental models, highlighting the need for prospective human studies to clarify the clinical relevance of these mechanisms [30,31]. A summary of the proposed mechanisms is presented in Table 2.

DISCUSSION

This narrative review summarizes current evidence supporting a relationship between statin therapy, gut microbiota alterations, and disturbances in glucose homeostasis leading to statin-associated dysglycemia and new-onset diabetes (SANOD). Although the association between statin therapy and dysglycemia has been recognized for more than a decade, accumulating evidence suggests that this phenomenon cannot be explained solely by direct effects on insulin signaling or pancreatic β-cell function. Instead, interactions between statins and the gut microbiota may represent an additional mechanism contributing to interindividual differences in metabolic responses to treatment [23–25,30]. Among the mechanisms discussed in the available literature, alterations within the microbiota-bile acid-incretin axis appear to represent one of the most biologically plausible pathways linking statin therapy with disturbances in glucose homeostasis.

Gut microorganisms regulate bile acid transformation and influence FXR- and TGR5-mediated signaling, both of which play important roles in glucose and lipid metabolism [26,27]. Changes in the abundance of short-chain fatty acid-producing bacteria may influence insulin sensitivity, intestinal barrier integrity, and inflammatory activity. In addition, experimental studies suggest that microbiota-dependent regulation of GLP-1 secretion may provide another potential pathway linking statin therapy with glucose homeostasis [21,25,36,44].

Collectively, these observations support the hypothesis that microbiota-mediated mechanisms may partially explain why only a subset of statin-treated individuals develop dysglycemia despite receiving similar treatment.

Several recent reviews have summarized either the diabetogenic effects of statins or the interactions between statins and the gut microbiota separately [30,31]. However, an integrated discussion of current mechanistic and clinical evidence linking gut microbiota alterations with statin-associated dysglycemia and new-onset diabetes remains limited. By focusing specifically on microbiota-dependent mechanisms that may contribute to individual susceptibility to SANOD, the present review attempts to bridge this gap and provide an updated synthesis of the available evidence.

Nevertheless, the currently available evidence remains heterogeneous and should be interpreted with caution. The findings of the key studies are not directly comparable because they addressed different research questions. Vieira-Silva et al. [23] evaluated the overall prevalence of gut microbiota dysbiosis in statin users and reported a lower prevalence of dysbiosis. Koponen et al. [24] investigated specific gut microbiota signatures associated with the risk of statin-associated new-onset diabetes. She et al. [25] examined a microbiota-dependent mechanism of insulin resistance in an experimental animal model. Therefore, these findings should not be interpreted as directly contradictory. They reflect differences in study design, population, outcome measures, and methods of gut microbiota assessment. Most available evidence remains observational or experimental, and causal relationships between statin-induced microbiota alterations and disturbances in glucose metabolism cannot yet be established.

From a clinical perspective, these findings should always be interpreted in the context of the well-established cardiovascular benefits of statin therapy. Although statin-associated dysglycemia and new-onset diabetes have been reported, the absolute metabolic risk remains modest and is substantially outweighed by the reduction in cardiovascular morbidity and mortality achieved with statin treatment [12–16,18]. Therefore, the available evidence does not support withholding or discontinuing statins in patients with established indications for lipid-lowering therapy. Instead, current data support closer monitoring of glucose metabolism, particularly in individuals with obesity, prediabetes, metabolic syndrome, or other pre-existing metabolic abnormalities who appear to be at the highest risk of developing SANOD [15–17].

An emerging concept highlighted by the reviewed studies is that gut microbiota composition may contribute to interindividual variability in metabolic responses to statin therapy. The identification of microbiota signatures associated with increased susceptibility to SANOD raises the possibility that gut microbiota profiling could eventually contribute to individualized risk stratification before treatment initiation [23,24,30]. Likewise, microbiota-targeted interventions, including dietary modification, prebiotics, probiotics, or other microbiome-directed strategies, represent promising avenues for future research.

However, current evidence remains insufficient to recommend these approaches for the prevention or management of statin-associated dysglycemia in routine clinical practice, and no microbiota-based intervention can currently be recommended specifically for this purpose [21,44].

Taken together, the available evidence indicates that interactions between statin therapy, gut microbiota composition, bile acid metabolism, short-chain fatty acid production, incretin signaling, and inflammatory pathways represent a promising field of investigation with potential clinical relevance. Future well-designed prospective clinical studies integrating microbiome profiling with metabolic phenotyping are needed to clarify causal mechanisms, identify individuals at increased metabolic risk, and determine whether modulation of the gut microbiota can reduce statin-associated dysglycemia while preserving the well-established cardiovascular benefits of statin therapy.

Limitations of the current evidence

Despite the growing number of publications exploring interactions between statin therapy, the gut microbiota, and glucose metabolism, the evidence linking microbiota alterations specifically to statin-associated dysglycemia and new-onset diabetes (SANOD) remains limited. Most available studies are observational or based on experimental models, which precludes definitive conclusions regarding causality [9,23,24]. Consequently, it remains uncertain whether microbiota alterations directly contribute to the development of SANOD or reflect pre-existing metabolic disturbances and other host-related factors.

Another important limitation is the substantial heterogeneity across published studies. Differences in study populations, baseline metabolic status, dietary habits, duration and intensity of statin therapy, concomitant medications, sequencing methodologies, and bioinformatic pipelines all influence gut microbiota composition and reduce comparability between studies [21,23,41–43]. In particular, medications such as metformin, which independently modify the gut microbiome, represent an important source of confounding when interpreting microbiota changes in statin-treated individuals [9,21,38]. A major limitation of the current literature is the lack of prospective longitudinal studies evaluating gut microbiota before statin initiation and during follow-up. Most studies assess microbiota composition at a single time point after treatment has already been introduced, making it difficult to determine whether observed microbial alterations precede dysglycemia or develop as a consequence of metabolic deterioration. Similarly, randomized clinical trials investigating microbiota as a predefined endpoint remain largely unavailable.

Current studies also focus predominantly on taxonomic composition rather than microbial function. Although alterations in bacterial abundance have been consistently reported, relatively few investigations have integrated metagenomic, metabolomic, or transcriptomic analyses capable of evaluating functional pathways such as bile acid metabolism, short-chain fatty acid production, or incretin regulation [21,27,36]. Consequently, many of the proposed biological mechanisms remain hypothetical and require further experimental validation.

Finally, although recent studies have identified microbiota signatures associated with increased susceptibility to SANOD [24], the available evidence remains insufficient to support microbiota-guided prediction, prevention, or personalization of statin therapy in routine clinical practice. Validation in large prospective cohorts and mechanistic clinical studies is required before gut microbiota profiling can be considered a clinically useful tool for identifying individuals at increased metabolic risk.

Overall, current evidence provides biologically plausible mechanisms linking statin therapy, gut microbiota alterations, and dysglycemia, but substantial methodological limitations continue to restrict causal interpretation and clinical translation.

Future well-designed longitudinal studies integrating microbiome profiling with metabolic phenotyping will be essential to determine whether modulation of the gut microbiota can reduce the risk of statin-associated dysglycemia while preserving the cardiovascular benefits of statin therapy.

Future directions

Despite increasing interest in the interactions between statin therapy, the gut microbiota, and glucose metabolism, important knowledge gaps remain regarding the role of the gut microbiome in the development of statin-associated dysglycemia and new-onset diabetes (SANOD). Future progress will depend on studies capable of distinguishing causal microbiota-mediated mechanisms from secondary metabolic changes occurring during statin therapy. A major research priority should be the conduct of prospective longitudinal studies evaluating gut microbiota composition before statin initiation and throughout treatment. Such studies would help determine whether specific microbial signatures precede the development of dysglycemia and could serve as predictors of individual susceptibility to SANOD [23,24]. Randomized clinical trials incorporating gut microbiota as a predefined endpoint are also needed to clarify whether different statins exert distinct microbiota-mediated metabolic effects.

Future investigations should increasingly integrate multi-omics approaches, combining metagenomic, metatranscriptomic, metabolomic, and clinical data. Such strategies may provide a more comprehensive understanding of functional microbiome alterations induced during statin therapy and identify biological pathways involving bile acid metabolism, short-chain fatty acid production, incretin signaling, and inflammatory responses [21,27,36].

Another important direction is the validation of gut microbiota signatures as biomarkers of susceptibility to statin-associated dysglycemia. Although preliminary studies suggest that specific microbial profiles may influence metabolic responses to statin therapy [23,24], these findings require confirmation in large, ethnically diverse prospective cohorts before microbiota-based risk stratification can be considered for clinical application. Future studies should also carefully account for important confounding factors, including baseline metabolic status, obesity, dietary habits, concomitant medications, and lifestyle factors, all of which independently influence gut microbiota composition [9,21,38,42]. Standardization of microbiome sampling, sequencing methodologies, bioinformatic pipelines, and outcome definitions will also be essential to improve comparability between studies.

Finally, intervention studies investigating whether modulation of the gut microbiota through dietary interventions, prebiotics, probiotics, or other microbiome-directed approaches can reduce the risk of statin-associated dysglycemia while preserving the cardiovascular benefits of statin therapy represent an important future research priority. Although current evidence remains insufficient to recommend such strategies in clinical practice, this area offers considerable translational potential and warrants further investigation.

CONCLUSIONS

Accumulating evidence suggests that the gut microbiota may contribute to the development of statin-associated dysglycemia and new-onset diabetes (SANOD) by modulating several metabolic pathways involved in glucose homeostasis. Alterations in bile acid metabolism, short-chain fatty acid production, incretin signaling, intestinal barrier integrity, and inflammatory responses represent biologically plausible mechanisms through which gut microbiota may influence individual metabolic responses to statin therapy. However, the currently available evidence remains largely observational and experimental, preventing definitive conclusions regarding causality. Considerable heterogeneity in study design, patient characteristics, microbiome assessment methods, and potential confounding factors further limits the interpretation and clinical translation of existing findings. Consequently, current evidence does not support microbiota-guided prediction, prevention, or modification of statin therapy in routine clinical practice.

Nevertheless, the identification of gut microbiota as a potential mediator of interindividual susceptibility to SANOD provides a promising direction for future research. Well-designed prospective longitudinal studies integrating microbiome profiling with detailed metabolic phenotyping are needed to clarify causal mechanisms and determine whether modulation of the gut microbiota can reduce the risk of statin-associated dysglycemia while preserving the well-established cardiovascular benefits of statin therapy.

DISCLOSURE

Author contributions

Conceptualization: Zuzanna Borecka. Methods: Zuzanna Borecka, Agnieszka Marta Sobczak. Literature review and data extraction: Zuzanna Borecka, Agnieszka Marta Sobczak. Data analysis: Zuzanna Borecka, Agnieszka Marta Sobczak, Alicja Szymczak, Anna Jaworowicz, Joanna Piasecka, Bartosz Gołembiewski, Grzegorz Mulski, Martyna Manicka, Michał Baranowicz, Weronika Mazurkiewicz. Writing – original draft preparation: Bartosz Gołembiewski, Alicja Szymczak, Martyna Manicka, Weronika Mazurkiewicz, Michał Baranowicz, Joanna Piasecka. Writing – review and editing: Zuzanna Borecka, Agnieszka Marta Sobczak, Anna Jaworowicz, Grzegorz Mulski. Supervision: Zuzanna Borecka.

All authors contributed to the manuscript and approved its final version for publication.

Conflict of interests

The authors declare no conflict of interest.

Funding

This study received no external funding.

Declaration of the use of generative AI and AI assisted technologies

Artificial intelligence tools were not used for data collection, data analysis, or interpretation of the results presented in this article. AI tools were applied only for language editing and stylistic refinement of the manuscript text.

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