Prevalence of substances with OATP1B1 inhibitory properties in individual case safety reports of suspected statin-associated myopathy – an analysis of Swiss pharmacovigilance data

Abstract

Purpose

Statin associated musculoskeletal symptoms (SAMS) are common adverse drug reactions reported by 20% of statin users and are assumed to be dose dependent. The organic anion transporting polypeptide 1B1 (OATP1B1), a hepatocellular uptake transporter, modulates the systemic exposure of statins. The concurrent use of OATP1B1 inhibitors can increase systemic statin exposure and thus increase the risk of SAMS.

Methods

Individual case safety reports (ICSRs) of suspected adverse drug reactions (ADRs), like SAMS, are an important data source to monitor the safety of marketed drugs. We used the Swissmedic database to analyse the prevalence of potential OATP1B1 involving interactions in cases of suspected SAMS.

Results

In 54% of the ICSRs analysed, at least one substance with OATP1B1 inhibiting properties was used together with a statin. Antidiabetic and cardiovascular drugs were the most commonly reported substances with OATP1B1 inhibiting properties.

Conclusion

Our findings could indicate clinically relevant OATP1B1 involving interactions in SAMS, which should be further investigated.

Supplementary Information

The online version contains supplementary material available at 10.1007/s00228-025-03968-7.

Introductions

Transmembrane transport by the organic anion transporting polypeptide 1B1 (OATP1B1) facilitates the hepatocellular uptake of various endogenous and xenobiotic substrates including certain drugs [1]. Statins (ATC code C10AA), a group of drugs indicated to treat hypercholesterolemia and to prevent cardiovascular events, are well-known OATP1B1 substrates, albeit with varying affinity [1, 2]. Today, several drug agencies, including the Swiss Agency for Therapeutic Products (Swissmedic), consider statins, such as pitavastatin, pravastatin, and rosuvastatin, as OATP1B1 probe substrates. It is advised to use such probe substrates when testing for OATP1B1 involving drug-drug interactions (DDI) in vitro or clinical studies, which are required for drug authorization under certain circumstances [3]. Importantly, the concurrent use of OATP1B1 inhibitors can increase systemic statin exposure and thus increase the risk of dose-dependent adverse drug reactions (ADRs). For example, gemfibrozil, a lipid-lowering drug of the fibrate class, was found to significantly increase the exposure of several statins in clinical studies [4–6]. The combination of gemfibrozil and statins was further found to significantly increase the risk to experience rhabdomyolysis, a severe musculoskeletal toxicity, in cases of adverse events reported to the United States Food and Drug Administration (FDA) [7, 8]. This interaction has been attributed, in part, to the inhibition of OATP1B1 by gemfibrozil, which represents one of the underlying mechanisms [9]. Today, the Swiss drug label of gemfibrozil contains a special warning, and the combination with simvastatin or rosuvastatin (40 mg) is contraindicated due to the increased risk of myopathy [10]. Although all statins are transported by OATP1B1, they are also subject to several other transporters and enzymes that influence their pharmacokinetic behavior including the transporter breast cancer resistance protein (BCRP, e.g. rosuvastatin), the enzymes cytochrome p450 3A4 (CYP3A4, e.g. simvastatin and atorvastatin) and CYP2C9 (e.g. fluvastatin) [11, 12]. DDIs involving those and other transporters and enzymes can also relevantly affect statin exposure and should be taken into account when evaluating statin associated DDIs in clinical practice. Statin-associated musculoskeletal symptoms (SAMS), occurring with varying severity, are frequently reported and are expected to be dose-dependent [13]. In clinical studies, myalgia without relevant creatine kinase (CK) elevation, meaning without muscular damage, is found in around 10% of patients treated with statins. Myopathy with relevant CK elevation and thus likely muscular damage is less frequently reported for about 0.05%. In rare cases, about 0.01%, the intake of statins leads to rhabdomyolysis, a severe muscle damage with the risk of kidney failure [14]. In clinical practice however, SAMS seem more frequently and are reported by over 20% of statin users [15]. In Switzerland, an analysis of health insurance drug claims data found that over 35% of first-time statin users changed their therapy (e.g. switch to a different statin or different lipid-lowering drug, discontinuation of statin therapy) within the first 18 month, which could indicate the extent of statin intolerance in clinical practice [16]. Notably, even comparatively mild myalgia is assumed to have a negative influence on the patients’ adherence to statin therapy and thus could increase the risk for atherosclerotic cardiovascular diseases (ASCVD). Amongst over 100’000 adults starting statin therapy for secondary prophylaxis after a myocardial infarction (MI), those with statin intolerance had an around 40% higher rate of recurrent coronary heart events [17]. Another cohort study amongst over 200’000 adults could even associate all-cause mortality with reduced adherence to statin therapy [18]. Consequently, understanding the cause of SAMS could help develop strategies to reduce its occurrence, ultimately improving statin adherence and potentially lowering ASCVD risk and related mortality.

Spontaneous reporting is an important tool for drug agencies to monitor drug safety once a product is on the market. In many countries, including Switzerland, health care professionals and pharmaceutical companies are legally obliged to report suspected ADRs, especially if serious or unlabeled in the respective product information. Swissmedic maintains a pharmacovigilance database of such individual case safety reports (ICSRs), recording Swiss cases of suspected ADRs. To analyze the potential role of the previously described OATP1B1 involving interactions with statins in clinical practice, this study aimed to explore the prevalence of coadministered OATP1B1-inhibitors in ICSRs of suspected SAMS reported to Swissmedic.

Methods

Case selection

We selected ICSRs from the Swissmedic database filed between 1992 and 2023 that reported muscular ADRs and concurrent intake of statins. To identify these cases, we searched the database for reported reactions containing the Medical Dictionary for Regulatory Activities (MedDRA) preferred terms “myalgia”, and/or “myopathy”, and/or “rhabdomyolysis”, associated with a statin (ATC: C10AA) as suspected or concomitant drug. Duplicates and cases that reported statin use without additional medication were excluded from further analysis.

OATP1B1-inhibitor analysis

We identified OATP1B1 inhibitors from literature by analysing pharmacokinetic (PK) data gathered in the Drug Interaction Database (DIDB^®, Copyright Certara, USA). As previously published [19], we included substances based on predefined PK threshold values, indicating OATP1B1 inhibition in vitro (IC₅₀ ≤ 10 µM) and/or in vivo (AUCR ≥ 1.25). To make this list of identified OATP1B1 inhibitors applicable to our study setting, we further selected those substances, which have been marketed in Switzerland between 1992 and 2023 based on information published by Swissmedic online (www.swissmedicinfo.ch).

We then compared the list of identified OATP1B1 inhibitors from the DIDB^® with the reported suspected and concomitant drugs of the selected ICSRs from the Swissmedic database. As endpoints, we analysed (1) the number of ICSRs involving OATP1B1 inhibitors, and (2) the prevalence of individual OATP1B1 inhibitors, using the statistics software RStudio (version 4.5, Posit Software, USA) and Excel (version 2016, Microsoft Corporation, USA). Additionally, the software OriginPro (version 2023, OriginLab Corporation, USA) was used for generating figures.

Results

ICSR selection and characteristics

In total we retrieved 588 ICSRs reported between 1992 and 2023 to Swissmedic, which recorded muscular adverse events with statins as suspected or concomitant drugs (see Fig. 1). From further analysis of the reported additional medication, we excluded 103 ICSRs that have not recorded any medication in addition to statins, and 43 duplicated ICSRs.

Fig. 1.

Overview of the selection process of individual case safety reports (ICSRs) from the Swissmedic database for analysis. ICSR: individual case safety report

The majority of patients in the analysed 442 ICSRs were male, senior adults, and treated with polypharmacy, with a reported median intake of 5 different drug substances (see Table 1). Part of these were 7 different statins, of which some ICSRs reported more than one. Statins were reported with different frequencies as follows: Atorvastatin (41.3%) > Simvastatin (27.3%) > Rosuvastatin (17.6%) > Pravastatin (11.5%) > Fluvastatin (3.6%) > Pitavastatin (1.6%) > Cerivastatin (1.1%).

Table 1.

Overview of selected demographic and treatment characteristics

Characteristic	Type/Description	Number (n), Percentage (%) or Median [IQR]
ICSR analysed, n	-	442
Sex, %	Male	63.8
	Female	34.6
	Not reported	1.6
Age in years, median [IQR], (minimum, maximum)	Reported for n = 379	65 [55–72], (22, 95)
Reported number of substances, median [IQR]	-	5 [3–8]
ICSR with polypharmacy, %	≥ 5 reported substances	58.5

Prevalence of OATP1B1-inhibitors

The systematic search of the DIDB^® yielded 125 substances with inhibitory effects on OATP1B1 in vitro and/or in vivo, which have been marketed in Switzerland between 1992 and 2023 (see Supplementary Information). Based on this list, we identified 238 ICSRs (53.8%) that reported concomitant use of at least one OATP1B1 inhibitor and one statin. Of these, 65 (15.2%) and 14 (3.2%) ICSRs reported the use of at least two and three OATP1B1 inhibitors, respectively. Primary reporters of almost half of the identified ICSRs (n = 112), rated the reported OATP1B1 inhibitor as suspected/interacting drug in the respective ICSRs. Overall, 41 different OATP1B1 inhibitors were reported, which comprise a wide range of substance classes, including: antivirals, antibiotics, antimycotics, antidiabetics, immunosuppressants, antineoplastics, antithrombotics and antihypertensives. For 15 of these, there are clinical (in vivo) data in the DIDB^®, indicating OATP1B1 inhibitory effects (see Fig. 2). The four most frequently reported substances with OATP1B1 inhibiting potential, which were mentioned a total of 160 times, are metformin, ezetimibe, clopidogrel and cyclosporine. Those were mostly reported together with atorvastatin (35.8%), simvastatin (28.3%) and rosuvastatin (15.0%).

Fig. 2.

Overview of the prevalence of individual OATP1B1 inhibitors in the analysed ICSRs. Legend: ICSR = individual case safety report; (*) = in vivo data indicating OATP1B1 inhibition available

Discussion

Overall, the prevalence of OATP1B1 inhibitors in the analysed ICSRs recording suspected SAMS in the Swissmedic database is considerable. More than half of the ICSRs reported at least one concurrently administered OATP1B1 inhibitor. Thereof, the antidiabetic metformin was recorded most frequently, in almost 11% of the ICSRs (n = 47) followed by ezetimibe (n = 42), clopidogrel (n = 39) and cyclosporine (n = 32). The statins atorvastatin (35.8%) and simvastatin (28.3%) were reported most frequently in association with these four OATP1B1 inhibitors. Notably, it is known that lipophilic statins such as atorvastatin and simvastatin have a higher affinity for the OATP1B1 transporter, compared to more hydrophilic statins like rosuvastatin or pravastatin [2], which could suggest that their exposure is more strongly affected by OATP1B1 involving DDIs, possibly explaining their observed high frequency.

Antidiabetics

The blood sugar lowering drug metformin is recommended first line for the treatment of type 2 diabetes [20] and was among the 20 most claimed prescription drugs in 2022 in Switzerland [21]. However, there is limited clinical data indicating potential OATP1B1 inhibition by metformin. In a recent analysis of a drug transporter probe cocktail containing rosuvastatin as OATP1B1 substrate and three additional active substances including metformin, as probes for other drug transporters, it was found that plasma exposure of rosuvastatin increased by around 40% when the cocktail was applied compared to when rosuvastatin was taken alone [22]. This finding led to further investigations by the authors, who mainly attributed the increased plasma exposure to an interaction with metformin.This effect seems to be dose-dependent and was eliminated when the metformin dose was reduced from 500 mg to 50 mg [23]. Notably, in clinical practice, metformin is dosed up to 3000 mg daily. The authors state that the underlying mechanism of the observed DDI between rosuvastatin and metformin remains unclear. However, rosuvastatin is a probe substrate for the transporters OATP1B1 and BCRP, which makes their involvement possible. In our study, the analysed ICRs reported metformin most frequently together with atorvastatin followed by rosuvastatin, pravastatin, simvastatin and fluvastatin. All of them are subject to OATP1B1 mediated transport, with a higher affinity of the lipophilic statins like atorvastatin, simvastatin and fluvastatin for OATP1B1 [2]. BCRP however, mainly plays a role in the transport of rosuvastatin [12], and perhaps to a lesser extent atorvastatin [24]. There is currently no indication of an interaction with OATP1B1 in the Swiss (Swissmedic), German (European Medicines Agency, EMA) or U.S. (FDA) drug label of metformin [10, 25, 26]. Further investigations are needed to evaluate the main DDI mechanism of metformin with different statins. However, we identified further oral antidiabetics in the analysed ICSRs including sulfonylureas (glimepiride and glibenclamide), glitazones (pioglitazone and rosiglitazone) and glinides (repaglinide), for all of which only in vitro studies indicating OATP1B1 inhibition are documented in the DIDB^® e.g [27–29]. Concerning their current drug label (rosiglitazone is not authorized anymore), the in vitro OATP1B1 substrate available from Swissmedic, EMA and FDA [10, 25, 26]. Lastly, the glucagon-like Peptide-1 (GLP-1) agonist semaglutide, which is not only widely used as an antidiabetic, but also as a therapy for obesity, was identified in two ICSRs. In vitro data from a market approval study for subcutaneously applied semaglutide indicated inhibition of OATP1B1 based on its effect on the cellular accumulation of estradiol-17-beta-glucuronide. The same study, as referenced in the DIDB^® (NDA 209637) and the Swiss, German and U.S. drug labels, found that semaglutide did not appear to affect the exposure of a single dose of atorvastatin in vivo [10, 25, 26]. For this reason, the respective Swiss and U.S. drug labels (i.e. Ozempic^®, and Rybelsus^®) mention, that there is only limited potential for drug transporter inhibition by semaglutide [9, 22]. However, another clinical study found a 41% increase in exposure of rosuvastatin when combined with oral semaglutide [30].

Lipid-lowering drugs

Apart from statins, also other lipid lowering drugs interact with OATP1B1. Ezetimibe, a cholesterol uptake inhibitor often added to an established statin therapy, was reported in 9.5% of the analysed ICSRs (n = 42). Ezetimibe has been found to inhibit OATP1B1 in vitro in multiple studies [31, 32]. However, ezetimibe did not significantly change rosuvastatin AUC in two clinical studies in a limited number of Korean men (n = 25) [33, 34]. A more recently published study, not yet referenced by the DIDB^®, indicates relevant in vivo and in vitro OATP1B1 inhibition by the active metabolite ezetimibe-glucuronide quantified by measuring the accumulation of the OATP1B1 biomarker coproporphyrin I (CPI) [35]. Another lipid-lowering drug reported to be an in vivo OATP1B1 inhibitor and identified in two of our analysed ICSRs is gemfibrozil, a fibrate. As mentioned before, the Swiss drug label of gemfibrozil contraindicates a combination with certain statins due to the increased risk of myopathy attributed to OATP1B1 inhibition [10]. The same applies for the respective German and U.S. drug label [25, 26]. A combination of gemfibrozil with the no longer approved cerivastatin, leading to an interaction attributed to OATP1B1 and CYP2C8, was even contraindicated due to the increased risk of rhabdomyolysis reported post marketing [7]. Apart from OATP1B1 and CYP2C8, gemfibrozil has also been shown to inhibit the renal organic anion transporter 3 (OAT3), which is involved in the renal elimination of rosuvastatin and pravastatin [12, 36]. Bempedoic acid, another lipid lowering drug, is a known OATP1B1 inhibitor, e.g. as noted in the “Interaction” section of the according Swiss drug label [10]. However, it was not reported in the analysed ICSRs, possibly because it was only authorised in Switzerland in 2022.

Cardiovascular drugs

Clopidogrel was recorded in 39 (9%) of the analysed ICSRs. For this platelet aggregation inhibitor, which is together with statins primarily indicated for secondary prevention of myocardial infarction and stroke, a limited number of in vitro and in vivo studies suggest that it inhibits OATP1B1. In detail, a clinical study in 12 healthy volunteers reported moderate OATP1B1 inhibition shown by an increase of simvastatin AUC of around 27% [37]. Another clinical study in 8 Japanese volunteers indicated a stronger effect by an increase in repaglinide AUC of 149% [38]. The stronger signal in the latter DDI study can most likely be attributed to the additional CYP2C8 inhibitory effect of clopidogrel, via which repaglinide is metabolized [38]. Additionally, the simultaneous administration of pioglitazone, another drug with reported in vitro OATP1B1 inhibitory capacity as described before, could have further increased repaglinide exposure in this study [38]. The current Swiss and German drug labels of Plavix^® (Clopidogrel) references data from an additional DDI study not curated in the DIDB^®, that showed 2.0-1.3.0.3 times higher rosuvastatin AUC without further interpretation or recommendation for clinical practice [10, 25]. In addition to OATP1B1, clopidogrel has also been associated with the inhibition of BCRP, mainly involved in the transport of rosuvastatin [39]. Therefore, the increased rosuvastatin exposure could most likely be attributed to the inhibition of both OATP1B1 and BCRP. Further drugs with cardiovascular indications, which were recorded in the analysed ICSRs include several antihypertensives, namely angiotensin receptor blockers (ARB - irbesartan, losartan, and telmisartan), angiotensin-converting enzyme (ACE) inhibitors (ramipril, fosinopril), phosphodiesterase 5 (PDE5) inhibitor (sildenafil) and calcium channel blocker (nisoldipine), as well as the cardiac glycoside digoxin, and the antiarrhythmic dronedarone. For all these substances, the data indicating OATP1B1 inhibition is based on in vitro studies, i.a [40–43]., except for sildenafil, where in vivo data from a placebo controlled double blind study in 35 healthy male volunteers, is indicating OATP1B1 inhibition by a relevant change in bosentan AUC [44]. For the neprilysin inhibitor sacubitril there is data from a PBPK modelling study indicating relevant OATP1B1 inhibition by the increase of the substrate pemafibrate (AUCR ≥ 1.25) [45]. A similar effect, indicated by the accumulation of atorvastatin, was also found in a clinical study with co-administration of sacubitril and valsartan, which is the fixed combination in which sacubitril is marketed (Entresto^®) [46]. This study is referred to in the current Swiss and German drug label of Entresto^®, indicating an OATP1B1 involving interaction and to therefore be cautious when combining statins with Sacubitril [10, 25]. The current U.S. drug label of Entresto^® however, only mentions in vitro data indicating OATP1B1 inhibition, without any warning concerning the use of statins [26].

Immunosuppressants

Cyclosporine is an immunosuppressant indicated to prevent transplant rejection, and a well-studied OATP1B1 inhibitor used as probe inhibitor for in vitro and clinical DDI studies for marketing authorization as recommended by drug agencies including Swissmedic [3]. In our analysis, cyclosporine was recorded in 32 ICSRs (7.2%) with suspected SAMS. There is data from various clinical DDI studies indicating a strong accumulation of several statins in combination with cyclosporine (AUCR ≥ 2), which is associated with the inhibition of OATP1B1 but for certain statins also the potent inhibition of other pathways including CYP3A, MRPs and BCRP is of relevance, i.a [47–49]. The association between SAMS and the use of cyclosporine, due to reduced statin clearance, is described in the Swiss, the German as well as the U.S. cyclosporine drug label [10, 25, 26]. Further immunosuppressants, which have been associated with OATP1B1 inhibition and were detected in two single cases of our analysis, are sirolimus and tacrolimus. In the DIDB^®, only data from a single clinical DDI study was available for Sirolimus that demonstrated this association in vivo [50]. Information on possible OATP1B1-inhibiting effects of sirolimus and tacrolimus is currently not included in the corresponding Swiss, German or U.S. drug labels [10, 25, 26].

Levothyroxine

Levothyroxine is a thyroid hormone indicated for substitution in cases of hypothyroidism [10]. In our analysed ICSRs of suspected SAMS levothyroxine was recorded in 22 cases (5%). Levothyroxine was also commonly used in patients of a study retrospectively analysing 122 cases of cerivastatin-induced rhabdomyolysis. Therefore, the authors screened levothyroxine and 14 other commonly used drugs of those cases for their OATP1B1 inhibiting potential using cerivastatin and estrone-3-sulfate as OATP1B1 probe substrates. They found levothyroxine to relevantly inhibit the OATP1B1 mediated uptake of cerivastatin and estrone-3-sulfate in vitro with IC₅₀ values of 0.88 µM and 2.04 µM respectively [28]. So far, the DIDB^® references no clinical studies that found levothyroxine to inhibit OATP1B1 in vivo. Interestingly however, the condition that is treated with levothyroxine, hypothyroidism itself is associated with increased risk for SAMS and myopathy in general [51, 52].

Antiinfectives

The antibiotics clarithromycin and trimethoprim were recorded in 13 (3%) and 7 (2%) of the analysed ICSRs. Clarithromycin is commonly used in atypical pneumonia and trimethoprim is indicated for urinary tract infections [10]. For both substances there is data curated in the DIDB^®, indicating OATP1B1 inhibition in vivo. Clarithromycin as an example was administered in a clinical study together with a probe drug cocktail containing 6 different substances including the known OATP1B1 substrates pitavastatin, rosuvastatin and atorvastatin in 12 healthy volunteers. The coadministration of clarithromycin increased the AUC of all three statins to varying extents (pitavastatin 24%, rosuvastatin 56%, atorvastatin 245%). The significantly greater accumulation of atorvastatin can be explained by the additional strong CYP3A4 inhibitory effect of clarithromycin. In contrast to atorvastatin, both pitavastatin and rosuvastatin are not substrates of CYP3A4 [53], further supporting the suggestion ofa OATP1B1 interaction. For trimethoprim, the second antibiotic in our analysis, there is only very limited data on potential OATP1B1 inhibition available. Only a single in vitro and in vivo study each has been annotated in the DIDB^® investigating the effect of trimethoprim on OATP1B1. In vitro it was found that trimethoprim inhibited the OATP1B1 mediated uptake of estradiol-17-beta-glucuronide by 25% [54]. In a clinical study trimethoprim was tested together with the OATP1B1 substrates pitavastatin and repaglinide. For pitavastatin no change in exposure could be detected, however the AUC of repaglinide was increased by 80% when applied together with trimethoprim. This difference may be explained by repaglinide also being a substrate of CYP2C8, which is inhibited by trimethoprim [38]. At this point, based on this single study, the relevance of OATP1B1 inhibition in vivo by trimethoprim is questionable. Our analysis depicted in Fig. 2 includes several substances indicated for infections with the human immunodeficiency virus (HIV), mainly protease inhibitors. Except for ritonavir and the booster cobicistat, the data indicating OATP1B1 inhibition of the listed substances (elvitegravir, darunavir, indinavir, lopinavir, nelfinavir) mainly comes from in vitro studies. However, in most cases, additional information from in vivo studies would be available for the above mentioned substances, but these were coadministered with other antivirals as marketed and used in the clinic [55]. This makes it challenging to distinguish the OATP1B1 inhibiting effects of the individual substance. Therefore, this data was not included in our analysis. However, it is known that people living with HIV tend to have dyslipidemia due to the underlying pathophysiology and adverse reactions of some antiviral substances [56]. Furthermore, various antiviral substances used to treat HIV infections show relevant interactions with statins, increasing the risk to develop statin intolerance [10, 56]. Most drug labels of the respective antivirals warn of interactions with statins, providing recommendations for the selection and dosing of specific statins, however, without mentioning the underlying mechanisms of the interaction [10, 25, 26]. Still, based on in vitro assessments these interaction mechanisms could include OATP1B1, as well as BCRP in the case of rosuvastatin [57].

Limitations

We analysed Swiss ICSRs of muscular adverse drug reactions in association with the intake of statins. Although the primary reporters considered the statin to be causative for the reported symptoms, this is not a conclusive evaluation. Therefore, reasons for the reported myopathy other than the use of statins cannot be excluded. In order not to miss any cases of statin-associated myopathies, we also included ICSRs in which the statins were only recorded as concomitant medication, but reporters did not suspect them as causative. Furthermore, since adverse reactions are generally underreported, our analysis is not comprehensive and probably misses cases with other potentially interacting OATP1B1 inhibitors [58]. In 2019 around 11% of the Swiss population (ca. 940’000) have been treated with a statin [21]. Assuming that about 20% of them experienced SAMS [15], it becomes clear that the analysed 442 ICSRs represent only a very small fraction of the total number of cases. However, it should be considered that not all SAMS are subject to the Swiss reporting obligation, since they are known adverse reactions and are not serious in every case. Moreover, the analysed cases exhibit deviations from today’s prescribing patterns, because we included reports dating back to the early 1990s. For example, cerivastatin is no longer marketed and the prescription of simvastatin has decreased due to the availability of newer and more potent statins like rosuvastatin. Today, atorvastatin (50%) and rosuvastatin (29%) are the most frequently claimed statins in Switzerland [21]. Therefore, we might over- or underweight certain interactions and prevalences of OATP1B1 inhibitors. Overall, the analysed ICSRs show a polymedicated population. Therefore, the consideration of DDI causing increased statin exposure like OATP1B1 inhibition seems to be of specific relevance. However, since the main concern of this study was to identify the prevalence of potential OATP1B1 involving DDIs, other potentially causative interactions unrelated to OATP1B1 like CYP3A4- or BCRP inhibition may have been missed and cannot be excluded. Furthermore, the risk to experience SAMS is assumed to be affected by multiple additional factors, including but not limited to statin dose, physical activity, genetic predisposition, hypothyroidism, and sex [59].

Conclusions

Still, our findings indicate a clinically relevant role of OATP1B1 involving interactions in SAMS. For example, our study showed a decent prevalence of already well-studied OATP1B1 inhibitors such as cyclosporine (7%) and clarithromycin (3%). However, further investigations are necessary to confirm these associations and to elucidate their clinical relevance in statin therapy. Those should also consider individual genetic predispositions. Genetic polymorphisms of SLCO1B1 (encoding OATP1B1) have been linked to altered activity of OATP1B1, reduced hepatic uptake and therefore increased exposure of statins associated with an increased risk of SAMS [60–62]. Today, pharmacogenetic guidelines can be used in clinical practice to optimize statin selection and dosing based on SLCO1B1 polymorphisms, to reduce the risk of SAMS [11, 63]. However, it is currently unclear whether and how a combination of drug-gene-interactions and drug-drug-interactions, so called drug-drug-gene interactions (DDGI), should be considered in the evaluation and prevention of SAMS. Still, it seems plausible that there is an interplay of genetic and non-genetic factors affecting the activity of OATP1B1, as indicated in a very limited number of clinical studies [64–66]. Based on the prevalence of antidiabetic and cardiovascular drugs in our analysis, and the importance to prevent ASCVD in patients with preexisting cardiovascular diseases and diabetes, those patients represent an important group to further investigate the impact of DDGI in SAMS.

Supplementary Information

Below is the link to the electronic supplementary material.

Author contributions

Conceptualization, methodology and investigation, C.K.S., V.T., T.S., S.S.A. and H.E.MzS; Formal analysis and data interpretation, C.K.S. and V.T.; writing—original draft preparation, C.K.S.; writing—additional content, critical review and editing, V.T., T.S., S.S.A. and H.E.MzS; visualization, C.K.S.; supervision, H.E.MzS. All authors have read and agreed to the published version of the manuscript.

Funding

No funding was received for conducting this study or to assist with the preparation of this manuscript.

Data availability

The data presented in this study are available on request from the corresponding author. Data originate from the Swissmedic Database and the Drug Interaction Database and are not publicly available.

Declarations

Ethics approval

This study did not fulfill the criteria for research according to the Swiss Human Research Act and therefore was exempt from ethics approval from a competent cantonal ethics committee. This research study was conducted retrospectively from anonymously collected data of individual case safety reports obtained from the Swissmedic database. It was ensured that all data collected was fully anonymized and handled in compliance with Swiss data protection regulations, thereby adhering to ethical research standards.

Consent

Consent was not required as all information analysed and reported is fully anonymized and not traceable to an individual.

Clinical trial number

Not applicable.

Competing interests

The authors declare no competing interests.