Introduction
Statins as the first-line treatment for dyslipidemia
Dyslipidemia is a major modifiable risk factor of cardiovascular disease (CVD), of which atherosclerotic cardiovascular disease (ASCVD) is a significant component [1]. ASCVD is responsible for more than four million deaths in Europe each year. It contributes to the death of more women (2.2 million) than men (1.8 million), but before the age of 65, deaths due to CVD are more common in men (490,000 vs. 193,000) [1].
Due to the high mortality from CVD, particular attention should be paid to reducing modifiable risk factors, such as dyslipidemia. Statins, 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors, remain the leader among the available forms of lipid-lowering drug (LLD) pharmacotherapy [2]. They lower cholesterol levels by reducing the synthesis of cholesterol in the liver. They are also known for the upregulation of hepatocyte surface low-density lipoprotein (LDL) receptors, increasing the uptake of LDL molecules by hepatocytes from the blood because of the lowered level of intracellular cholesterol [2].
Statins are the first-line treatment for dyslipidemia, and are used in primary and secondary CVD prevention. There is scientific evidence that they significantly reduce the prevalence of CVD and related mortality, for example, by slowing the progression and sometimes also causing regression of atherosclerotic changes in the coronary arteries. Reduction in LDL cholesterol levels by each one mmol/l through statin therapy has been shown to reduce the risk of major cardiovascular events (coronary deaths, myocardial infarctions, strokes and coronary revascularizations) by 22% [1]. Numerous clinical trials have demonstrated a reduction in cardiovascular risk with statins, in direct proportion to the degree of lipid reduction [3].
Adherence to statin therapy among women and men
One of the main problems in the treatment of dyslipidemia is delayed and insufficiently intensive treatment, as well as low adherence to statin therapy, especially among women [4–7].
A meta-analysis published in 2013 including 53 studies from diverse populations showed that women are at increased risk of nonadherence to statin treatment [8]. Only about 50% of men and 47% of women were adherent to statins, and women had a 10% greater odds of nonadherence (odds ratio 1.10, 95% CI) than men.
A Polish study revealed that, of people with hypercholesterolemia, 58.7% (61.5% of men and 56.0% of women) were not aware of its presence, 22.4% (20.1% of men and 24.5% of women) knew about it, but not treated, 8.1% (7.7% of men and 8.4% of women) were unsuccessfully treated, and only 10.9% (10.7% of men and 11.0% of women) achieved their therapeutic targets [9]. According to the WOBASZ II study conducted three years later, 61% of people above 19 years old with hypercholesterolemia were not diagnosed with the condition, 17% were not treated despite being diagnosed, and 15% were treated but without reaching the target level [10]. Also, the WOBASZ II study showed that more women than men with hypercholesterolemia did not undergo treatment. The number was higher especially in the group of patients who, despite being informed, did not undertake treatment (compared with the group that had not been informed or diagnosed), and was also higher in low- and moderate-risk groups [10].
The USAGE study (Understanding Statin Use in America and Gaps in Patient Education) from 2016, based on a self-administered, Internet-based questionnaire confirmed that women were less adherent to their statin treatment than men [11]. They were also less likely to be treated with statin therapy and with higher doses of more potent statins, and achieved fewer therapeutic goals than men.
A United States registry study based on the Patient and Provider Assessment of Lipids Management (PALM) Registry also found evidence of poorer statin adherence among women than men [12]. Women were less likely than men to be prescribed any statin therapy (67.0% vs. 78.4%; p < 0.001) or to receive a statin at the guideline-recommended intensity (36.7% vs. 45.2%; p < 0.001), and were more likely to report having never been offered statin therapy previously (18.6% vs. 13.5%; p < 0.001), having declined statin therapy (3.6% vs. 2.0%; p < 0.001), or having discontinued their statin (10.9% vs. 6.1%; p < 0.001). Women were also less likely than men to believe that statins were safe (47.9% vs. 55.2%; p < 0.001) or effective (68.0% vs. 73.2%; p < 0.001) and more likely to report discontinuing their statin because of a side effect (7.9% vs. 3.6%; p < 0.001). Gender-related differences were still consistent in primary and secondary prevention. Women were also more likely to report believing that statins can be responsible for side effects such as diabetes, statin-associated muscle symptoms, and liver damage [12].
Even at high cardiovascular risk, patients receive suboptimal statin doses, and have high discontinuation rates and low adherence rates. The median time to statin discontinuation was reported as 15 months in the moderate- to low-intensity statin regimen group and 21 months in the group with a high-intensity statin regimen [7]. An interesting study was published in 2019, describing poor statin persistence even among high-risk patients with dyslipidemia. Toth et al. [13] analyzed patients aged ≥ 45 years with diabetes and/or ASCVD who had a statin prescription filed in 2010. The results were extremely concerning: only 47% of patients after one year and 19% after five years were continuing statin therapy [13]. Statin persistence was worse among women than men and among younger than older patients (p < 0.001 for all comparisons).
Also in 2020, Olmastroni et al. [14] showed that women were less likely to adhere to statin therapy than men, and sex appeared to be a key determinant. The proportion of days covered with statin treatment > 0.80 after one year was found to be approximately 27% among men and 19% among women. Age also had an impact on adherence to treatment. Compared to patients aged 51–60 years, younger and older (> 70 years) patients were less likely to adhere to statin therapy. Adherence to statins was lower in women than in men, especially in the age group 41–50 years (tests of homogeneity for sex differences, p < 0.0001).
The adherence to statin therapy among women and men is summarized in Table 1.
Table 1
Adherence to statin therapy among women and men
| Reference | Study | Population | Results |
|---|---|---|---|
| Lewey et al. [8], 2013 | Meta-analysis including 53 studies | Diverse populations | 47% of women vs. 50% of men were adherent to statin therapy; women had a 10% greater odds of nonadherence than men |
| Zdrojewski et al.[9], 2016 | Cross-sectional observational study; the NATPOL 2011 survey | Representative sample of Polish men and women aged 18–79 years | 24.5% of women vs. 20.1% of men knew about the disease, but were not treated; 8.4% of women vs. 7.7% of men were unsuccessfully treated |
| Pajak et al. [10], 2016 | Cross-sectional survey; the WOBASZ II study | Random samples of the Polish population | 17.1% of women vs. 16.5% of men knew about the disease, but were not treated; 14.8% of women vs. 15.8% of men were unsuccessfully treated |
| Karalis et al.[11], 2016 | Understanding Statin Use in America and Gaps in Patient Education (USAGE) survey | The study population was derived from participants in the USAGE survey, a self-administered, Internet-based questionnaire | Women were less likely to be treated with statin therapy and with higher doses of more potent statins; women achieve fewer therapeutic goals than men |
| Nanna et al.[12], 2019 | Patient and Provider Assessment of Lipids Management (PALM) Registry | Patients of The United States – a nationwide registry of outpatients with or at risk for ASCVD | 36.7% of women vs. 45.2% of men received a statin at the guideline-recommended intensity; 3.6% of women vs. 2.0% of men declined statin therapy; 10.9% of women vs. 6.1% of men discontinued their statin |
| Toth et al. [13], 2019 | Observational retrospective administrative analysis of the Optum Research Database | Patients aged ≥45years with diabetes and/or ASCVD treated with a statin | Statin persistence was worse among women than men (p< 0.001) |
| Olmastroni et al.[14], 2020 | Observational retrospective analysis of the administrative databases of Lombardy region | Patients aged > 40 years, who have received a first prescription for statin medication, administrative databases of Lombardy region | 27% of men vs. 19% of women had the proportion of days covered with statin treatment > 0.80 after one year |
Adverse effects of statins and statin intolerance among women and men
Statin adverse events and statin intolerance appear to be the main cause of poor adherence to statin treatment.
The main serious side effects that can arise from statin therapy include myopathy, new-onset diabetes and hepatotoxicity defined as hepatic transaminase elevations. Less well-documented side effects include haemorrhagic stroke, cataracts, renal toxicity, neurological and neurocognitive effects, decreased energy levels, exertional fatigue, and reduced exercise capacity [15–17].
Statin toxicity most likely arises from HMG-CoA reductase inhibitory effects, direct cellular and subcellular effects, or a combination of both [15]. Other possible causes include genetic factors, drug interactions, vitamin D levels, and other metabolic effects. These factors alter the bioavailability and activity of the drug, which can lead to intolerance to it. Adverse reactions depend on class, dose, time, age, sex, and related coexisting conditions. The main factor contributing to the occurrence of side effects is age, most likely due to multiple comorbidities (renal or hepatic dysfunction), the use of multiple drugs and drug interactions, weight loss, and cognitive impairment. However, the mechanisms of documented and other potential side effects are still not well understood [15].
Women are found to be more likely than men to stop or switch their statin therapy because of side effects. As mentioned above, women were found less likely than men to believe that statins were safe (47.9% vs. 55.2%; p < 0.001) or effective (68.0% vs. 73.2%; p < 0.001) and more likely to report discontinuing their statin because of a side effect (7.9% vs. 3.6%; p < 0.001) [12]. Women were also more likely to report believing that statins can be responsible for side effects such as diabetes, statin-associated muscle symptoms, and liver damage.
Karalis et al. [11] found that more women than men report switching or stopping statin use because of side effects. Muscle symptoms (new or worsening) were reported in 31% of women compared with 26% of men. Women also complained more often about not being not well informed by their doctor about their heart disease risk. They were more likely to try three or more statins and to be dissatisfied with their statin or with how their clinician explained their cholesterol treatment, and were less adherent to statin therapy than men [11]. In a study by Zhang et al. [18], 27.1% of women, compared with 21.7% of men, reported an adverse reaction to a statin (p < 0.0001). Women were also less likely to be persisting with statin therapy at the end of follow-up (67.0% of women vs. 71.4% of men; p < 0.001) [18].
The definition of statin intolerance is a subject of debate and has undergone numerous modifications over the years [19, 20]. In 2015 the International Lipid Expert Panel suggested the definition: “Statin intolerance is the inability to tolerate at least two statins: one statin at the lowest starting daily dose and another statin at any daily dose, due to either objectionable symptoms (real or perceived) or abnormal laboratory determinations, which are temporally related to statin treatment and reversible upon statin discontinuation” [21].
In 2022, a meta-analysis was conducted on over 4 million patients to estimate the prevalence of statin intolerance according to the latest definitions [22]. The overall prevalence of SI was 9.1% (95% CI: 8.0–10%). The prevalence was similar when defined using NLA, ILEP, and EAS criteria, and was significantly lower in RCTs compared with cohort studies (4.9% [4.0–6.0%] vs. 17% [14–19%]). Risk factors for SI included age (odds ratio [OR] 1.33, p = 0.04), female gender (OR = 1.47, p = 0.007), Asian or black race (p < 0.05 for both), obesity (OR = 1.30, p = 0.02), diabetes (OR = 1.26, p = 0.02), hypothyroidism (OR = 1.37, p = 0.01), chronic hepatic and renal failure (p < 0.05 for both), antiarrhythmic drugs, calcium channel blockers, alcohol consumption, and increased statin dose.
The aim of the study was to summarize current knowledge and comprehensively discuss the lower adherence to statin treatment among women, especially when due to reported side effects, and to assess whether gender is associated with the incidence of statin side effects.
Methodology
A narrative review was conducted based on literature identified through systematic searches of the PubMed and Scopus databases. The search strategy included combinations of keywords related to statin adherence, statin adverse events, and gender. Although this review follows a narrative approach, efforts were made to enhance methodological transparency. Inclusion criteria encompassed peer-reviewed articles published in English that specifically addressed gender differences in adherence to statins or the incidence of statin-related side effects. Studies were excluded if they did not stratify data by gender or lacked relevance to either adherence or adverse events. In addition to the database search, relevant articles cited in the reference lists of the initially retrieved studies were also reviewed and included when appropriate. No formal quality assessment tool was used, which remains a limitation of this approach. Nevertheless, the review aimed to maintain rigor by clearly defining search terms, documenting the selection process, and focusing on high-quality sources. Although narrative reviews do not follow the strict protocols of systematic reviews, they offer the advantage of greater flexibility in exploring emerging themes and providing a broader context, especially in areas where the evidence is diverse or limited. The findings were synthesized thematically to identify recurring patterns and gaps in the literature.
Are the adverse reactions of statins related to gender differences?
Statin-associated muscle symptoms
Statin-associated muscle symptoms (SAMS) are the most frequently reported adverse reactions during statin therapy concerning about 7–29% of patients (in registries and observational studies) and the main reason for statin discontinuation [20, 23]. In turn, up to 72% of all statin adverse effects are muscle-related [24].
The most common SAMS are pain, heaviness, stiffness, cramps, and weakness. The symptoms involve mainly the leg muscles (thighs, calves), can also affect to the back, neck, and shoulders, and may be generalized [16]. 40% of complaints are identified after a triggering factor, such as unusual physical exertion or a new medication. In 25% of patients, the muscular complaints are permanent; in others, they are intermittent. The majority of SAMS are mild and cease after treatment is stopped of all cases of SAMS, 90% appear in the first six months of statin treatment, and in 75% in the first 10–12 weeks of statin treatment [25].
In a study assessing the incidence of myopathy in a usual care setting, 14% of patients developed myopathy, defined according to the ACC/AHA/NHLBI recommendations a general term referring to any disease of muscles [26]. The risk ratio for women compared with men was 1.52 (95% CI: 1.37–1.66). Most of the patients considered their pain severe, but importantly, the CK values were within the normal range. Muscular symptoms affected daily activities in women more than in men (80% vs. 43%, p = 0.001). Myopathy was the reason for statin withdrawal in the case of 70% of women and 25% of men who discontinued statin therapy. Dose dependency was confirmed only among men. Notably, of the myopathy patients, 76% reported other side effects, compared with 21% of those without myopathy. Other adverse drug reactions were also found more often among women than men (29% vs. 18%) [26].
Female sex among risk factors of statin-associated muscle symptoms
Female gender has been shown to increase the odds of myopathy by 2-fold [27]. Two interdependent mechanisms are implicated in the increased risk of SAMS: increased systemic exposure to statins due to clinical, pharmacokinetic, pharmacogenomic and pharmacogenomic factors, and co-increased skeletal muscle exposure and intracellular entry of skeletal myocytes leading to disruption of muscle function [28].
It is mostly clinical factors that lead to increased statin exposure. Listed among them are advanced age (> 80 years old), female sex, low body mass index; co-morbidities such as alcohol abuse, chronic kidney disease, chronic liver disease, diabetes, hypertension, hypothyroidism, vitamin D deficiency. Additional factors are physical exercise, personal or family history of muscle pain, higher statin dose, corticosteroids, CYP3A inhibitors, CYP2C9 inhibitors, high consumption of grapefruit juice, calcium disorders, Asian ethnicity (particularly women), and excessive physical activity [15]. Other risk factors for myopathy include a history of my opathy with other lipid-lowering drugs, high-dose statin therapy, history of unexplained spasms, history of elevated CK levels, family history of muscle symptoms during lipid-lowering therapy, and untreated hypothyroidism. The following factors are also mentioned: the dose or potency of statin, other interacting drugs and polypharmacy, surgery, infection, exertion, and genetic mutations associated with mitochondrial dysfunction [21, 29, 30]. Factors that put women at greater risk of statin-induced myalgia include lower metabolism, lower body mass index, plasma volume, and reduced muscle mass [31].
Women are also found to have higher exposure to most statins than men, except for rosuvastatin and atorvastatin. This can be attributed to higher hydroxylation metabolism [16]. The choice of these statins may reduce the risk of increased gender-specific exposure and, at the same time, lower the risk of side effects. The use of other drugs metabolized by cytochrome P450 may also be a predisposing factor. The muscular side effects of statins are dose-dependent, and the risk is increased by drug interactions that functionally enhance the potency of statins, often through inhibition of the cytochrome P450 3A4 system [32].
Statin concentrations in myocytes may be higher with increased systemic statin exposure, and the increased lipophilicity of statins may cause this phenomenon. This may explain the potential increased myotoxicity of lipophilic statins such as atorvastatin or simvastatin [33]. Lipophilic statins, through nonselective diffusion into extrahepatic tissues such as skeletal muscle, may also be responsible for greater penetration into myocytes. Hydrophilic statins show less muscle penetration and therefore carry a lower risk of SAMS [21].
However, not all reports consistently show a higher risk of myopathy in women than in men. Hippsley-Cox. [33] found a threefold increased risk of moderate/severe myopathy in women newly using statins, but nearly a six times greater risk in men. Women were more likely to develop myopathy when they took concomitant corticosteroids. The risk in that case increased threefold for women, and twofold for men. Hypothyroidism, type 1 diabetes, chronic liver disease, and treated hypertension were significant risk factors for myopathy in women, but not in men [33].
The likely mechanism of SAMS formation is similar to the general mechanisms producing side effects of statins, and is a complex process. Statins can alter the stability and fluidity of the muscle cell membrane as well as protein signaling and activity, affect the function of the mitochondria, and reduce the cholesterol content of the membranes [34].
Mitochondrial dysfunction may underlie many of the adverse events associated with statins [32]. Some additional risk factors for statin adverse events are those that enhance (or reflect) mitochondrial or metabolic susceptibility, such as metabolic syndrome factors, thyroid disease, and genetic mutations associated with mitochondrial dysfunction.
Research is being conducted on the involvement of mitochondria in the formation of SAMS. This appears important as skeletal muscles are closely dependent on the activity of the mitochondria due to the high energy consumption. According to reports, statins affect the mitochondria, with effects including reduction of coenzyme Q10 (CoQ10) level, inhibition of respiratory chain complexes, induction of mitochondrial apoptosis, dysregulation of Ca2+ metabolism and carnitine palmitoyltransferase-2 expression, mitochondrial depletion, lactone toxicity, and substrate overload [35, 36]. Upregulation of the expression of the muscle-specific ubiquitin-proteasome system is also considered a pathomechanism of statin-associated myopathy [37].
There are also studies on gender differences in mitochondrial functioning. According to previous reports, men mainly use proteins as a fuel source in their mitochondria, and women use mainly lipids [38]. These differences may affect the functioning of muscle cells in the event of the emergence of external factors disrupting the functioning of the mitochondria.
Mitochondria are susceptible to the influence of sex hormones, which, among others, show sexual dimorphism. These differences mainly include oxidative capacity, calcium metabolism, and resistance to oxidative stress. Estrogens affect mitochondria through many processes, including membrane and nuclear estrogen receptors (ERs), and more direct effects through signaling pathways [39].
This means that female gender may also predispose to a higher risk of SAMS at the mitochondrial level. Statins may slightly lower estrogen levels (a product of cholesterol), as they have been shown to lower testosterone levels in a similar way, and this will then lower levels of an essential antioxidant mediator in women that provides key mitochondrial protection [32].
It is also possible that the mitochondria function is worse in postmenopausal women. Studies have shown reduced antioxidant capacity and increased reactive oxygen species (ROS) production after menopause [40]. Most women treated with statins are postmenopausal. These mechanisms may explain the higher risk of SAMS among women. Further research into mitochondrial dysfunction in men and women using statins may help to understand the pathomechanisms underlying gender differences in adverse events.
Management
Due to the prevalence of SAMS and their significance as a factor in nonadherence to statins, especially among women, it is important to know which procedure should be implemented when SAMS occur. The physician should determine risk factors for statin-related myopathies (SRMs) and other causes of muscular complaints, and verify the indications for lipid-lowering therapy. There are also several alternative options when patients report SAMS or other statin intolerance: low-dosage drugs, intermittent doses using long half-life statins like atorvastatin or rosuvastatin, or switching to a different statin with another metabolism, solubility in monotherapy, or with a different hypolipidemic agent [37]. Patients should be treated with the maximum tolerated doses required for the indication [16]. Currently, CoQ10 and vitamin D supplementation is also suggested in treating myopathy [41].
New-onset diabetes
Another documented side effect of statins is new-onset diabetes. It is estimated that treatment of 10,000 patients for five years with an effective regimen (e.g., atorvastatin 40 mg daily) would lead to about 50–100 new cases of diabetes [42]. A meta-analysis of 13 placebo-controlled studies showed that after 4 years of statin treatment, the risk of new-onset diabetes increased by 9% [43].
The risk of diabetes appears to be higher among women and older adults – especially older women – and exhibits a dose-response effect [44]. In a study by Lee et al., women taking statins were more likely to develop new-onset diabetes than women not receiving statins (HR = 1.80, 95% CI: 1.58–2.06, p < 0.001). Such a dependence was not found in men [45]. In the JUPITER study, the risk of new-onset diabetes during rosuvastatin therapy was increased by 49% in women and only 14% in men compared to the placebo group [46].
The Australian Longitudinal Study on Women’s Health demonstrated that statin exposure was associated with a higher risk of treatment for new-onset diabetes among older women (HR = 1.33, 95% CI: 1.04–1.80; p = 0.024). The risk increased with a higher dose of statin [47].
Among the reported pathomechanisms for the development of diabetes is described increased cholesterol uptake by pancreatic bcells. Increased cholesterol uptake and concentration may damage insulin secretion, leading to bcell apoptosis [44]. Other possible mechanisms include the influence of statins on weight gain, adipocyte differentiation, blood glucose homeostasis via gluconeogenesis and the insulin signaling cascade, and changes in circulating free fatty acids or adipokines such as adiponectin and leptin [30, 48]. The presence of components of metabolic syndrome is also a risk factor [49]. The difference in the prevalence of diabetes between hydrophilic and lipophilic statins is not established [21].
The exact mechanism responsible for the higher risk of this side effect in women than in men is not described. The pathophysiological background may be similar to that of SAMS. However, it should be noted that despite the greater risk of side effects, the clinical benefits from statin therapy are significantly higher among older women than older men [50]. Therefore, statin therapy should not be given up but should be adjusted to the greater risk of side effects. More efforts should be made to prevent and monitor diabetes in patients treated with statins, especially those suffering from the abovementioned risk factors [51].
Hepatotoxicity
Asymptomatic increases in liver enzymes, with elevated transaminases > 3 times ULN, are a common adverse reaction that usually resolves with dose reduction and is not associated with histopathological changes or liver toxicity in the absence of elevated bilirubin or dysfunction. The prevalence is estimated at less than 3% of statin therapy patients [21].
Very rarely, hepatotoxicity has been reported as elevations (frequently asymptomatic) of transaminases, hepatitis, cholestasis or acute liver failure. Discontinuation of the statin is only necessary when the rise in transaminases is accompanied by hyperbilirubinemia. Patients with chronic liver disease, such as non-alcoholic fatty liver disease, chronic hepatitis, and primary biliary cirrhosis, are at greater risk of deterioration in liver function due to statin treatment [15], but the only contraindication to statin use is acute liver disease [17].
Reduction in the amount of mevalonate or one of its sterol intermediates may be the reason for transaminase activity. Asymptomatic increases without histopathological changes may also be due to changes in the lipid composition of the hepatocyte membrane, leading to increased permeability and leakage of liver enzymes [52]. Other reported potential pathomechanisms include induction of caspase activity, triggering of apoptosis, reduction of CoQ10, and generation of free radicals [21].
Increased liver metabolism, the lipophilicity of selected statins, and a high dose of the drug used may also contribute to hepatotoxicity [15]. Older patients are also at higher risk of liver injury, mostly due to concomitant therapies affecting pharmacokinetic profile and pharmacodynamic efficacy [17].
There is no evidence of a greater risk of liver dysfunction in women than in men when taking statins [33]. A gender-related difference was found in the return to normal liver functioning. The risk returned to normal within 1–3 years in women, and from three years in men [53].
Haemorrhagic stroke
Treatment of 10,000 patients for five years with an effective regimen (e.g., atorvastatin 40 mg daily) would cause 5–10 hemorrhagic strokes [42]. In the SPARCL study, in patients with a recent stroke or TIA and no known ischemic heart disease, 80 mg of atorvastatin daily reduced the overall incidence of ischemic strokes and cardiovascular events, while a slight increase in the incidence of hemorrhagic strokes was observed [54]. In 2020, the results of a large study in the Danish population assessing the risk of intracerebral hemorrhage in patients starting statin therapy after their first episode of stroke – both hemorrhagic and ischemic – were published [55]. The study found no evidence that statins increase the risk of intracerebral hemorrhage in people who have had a stroke, and the risk even appears to be even lower in the subgroup of ischemic stroke survivors. There were also no differences in the occurrence of hemorrhage between males and females.
A retrospective study has also been performed that assessed the risk of hemorrhagic stroke in older women receiving statins [56]. The study included 67,882 women with an average age of 63 ±7 years; the follow-up period was 12 years. There was no greater risk of hemorrhagic stroke in women receiving a statin than in women who did not. In contrast, the risk was more significant in women receiving concomitant statins and antiplatelet drugs than in women receiving only antiplatelet drugs.
Current recommendations do not support changing statin treatment in people with a history of cerebrovascular disease. On the other hand, US experts indicate that there may be a higher risk of hemorrhagic stroke with statin treatment for secondary stroke prevention, but the absolute risk is minimal, and the benefit of reducing the broad risk of strokes and other vascular events generally outweighs this risk [57]. In view of the study referred to above, more caution may be exercised when using statins in older women taking antiplatelet medications.
Sex differences in the side effects of statins are summarized in Table 2.
Table 2
Sex differences in the side effects of statins
| Side effects of statins | Results | References |
|---|---|---|
| SAMS | Muscle symptoms (new or worsening) were reported in 31% of women compared with 26% of men | Karalis et al.[11] |
| 70% of women vs. 43% of men discontinued statin therapy because of myopathy | Skilving et al.[26] | |
| New-onset diabetes | The risk of diabetes appears to be higher among women and older adults – especially older women | Cignarella et al.[44] |
| Women taking statins were more likely to develop new-onset diabetes than women not receiving statins, and such a dependence was not found in men | Lee et al.[45] | |
| Hepatotoxicity | There is no evidence of a greater risk of liver dysfunction in women than in men when taking statins | Hippisley-Cox et al.[53] |
| A gender-related difference was found in the return to normal liver function – the risk returned to normal within 1–3 years in women, and from 3 years in men | Hippisley-Cox et al.[33] | |
| Hemorrhagic stroke | No differences between women and men in the occurrence of hemorrhage | Ribe et al.[55] |
| No greater risk of hemorrhagic stroke in women receiving a statin than in women who did not | Salmoirago-Blotcher et al.[56] |
Differences in statin metabolism in women and men as a potential risk factor for adverse effects of statins among women
As described above, one of the factors for the increased risk of statin side effects is their increased systemic exposure in women compared to men [28]. Women tend to have a higher percentage of body fat, lower body weight, lower plasma volume, and lower organ blood flow than men, and these differences affect drug distribution [58]. These differences result in statin plasma concentrations generally 15–20% higher in women than in men, but no dose adjustment is required for this reason [58].
In general, women were found to be at higher risk of SAMS due to, among other things, lower body weight than men [31]. The volume of adipose tissue may also have an effect – it is usually larger in women than in men, resulting in a larger volume of distribution of lipophilic statins and an increased half-life. Prolonged statin exposure and higher risk of side effects in women may also be affected by a lower glomerular filtration rate than men [44]. Regardless of gender, the class of the statin also affects the risk of adverse events. Lipophilic statins diffuse to extrahepatic tissues to a greater extent than hydrophilic statins, possibly contributing to a greater risk of SAMS [15].
All statins except pravastatin are metabolized by hepatic cytochrome P450 (CYP), and simvastatin, lovastatin, and atorvastatin mainly by CYP 3A4 [44]. Woman have higher activity of cytochrome P450 3A4, which in theory should contribute to faster elimination of statins from the body and lower risk of SAMS [28]. On the other hand, the use of pitavastatin, rosuvastatin and pravastatin poses a lower risk of interactions with drugs metabolized by CYP 3A4 [44].
There may also be differences between women and men in the concentrations of additional enzymes involved in the conversion of statin prodrugs to their active forms, their uptake into hepatocytes and other cell types, and their degradation and elimination. These differences require further research to better identify and understand gender differences in side effects of statins [59].
Greater susceptibility to the nocebo and drucebo effect among women
The nocebo effect appears to be a significant factor in reports of side effects, especially those indicating statin intolerance. This is due to negative expectations about treatment outcomes resulting from the information provided by clinicians, drug package leaflets, the media, and online searches for possible side effects, leading to over-reporting of expected adverse events [21]. The ASCOT-LLA study investigated muscle symptoms among patients receiving 10 mg of atorvastatin and a placebo [60]. The study was divided into two stages: the first with blinding, in which both groups were randomly switched, and the second stage without randomization and blinding. Interestingly, in the blinded stage, no significant difference in the incidence of SAMS was found between the groups under study. However, a significant difference was found in the stage without blinding, when SAMS was reported significantly more often in the group receiving atorvastatin (1.26% vs. 1.0% per year). It should be emphasized, however, that this study was conducted on a low-dose statin, and as noted earlier, statin intolerance and SAMS are reported to be dose-dependent. In a review of 19 randomized clinical trials of statins vs. placebo, statin therapy was not associated with an increased risk of withdrawal due to adverse events [61].
In 2021 a retrospective, large-cohort study was conducted using the Food and Drug Administration Adverse Event Reporting System [62]. The aim was to evaluate differences between subjective and objective adverse effects (AEs) of statins. Subjective AEs included fatigue, as well as subjective muscular and nervous system AEs. Objective AEs included hepatic and objective muscular AEs. Among all reported AEs, there were more subjective than objective AEs (p < 0.0001). Women reported more subjective AEs than men and fewer objective muscular AEs than men. This suggests a greater prevalence of the nocebo effect among women [62].
The term drucebo effect has also recently been introduced; it refers to the beneficial or harmful effects of a drug (as opposed to a neutral substance) that arise from expectations rather than the drug’s pharmacological action [63]. A study investigating this phenomenon suggested a significant increase (38–78%) in the incidence of SAMS in outpatient therapy compared with a trial in which participants receiving the treatment were blinded [63].
Lowered confidence in the safety and effectiveness of statins may further exacerbate the nocebo and drucebo effects in women. The role of doctors in making women aware of the role of statins in primary prevention, and especially in secondary prevention, is critical.
Adjustment of therapy to gender differences
In an analysis of the literature on interventions aimed at improving adherence to cardiovascular drugs, no gender-specific interventions were found [64]. However, special procedures should be introduced to reduce the risk of side effects among women, for whom that risk is higher, and among those with other risk factors for adverse reactions.
First, it is imperative to talk to the patient and explain the purposefulness of treatment and the frequency of side effects. It would also be advisable to verify other risk factors, such as age and polypharmacy.
Treatment with a low dose of hydrophilic statin may be attempted in particularly predisposed patients with multiple risk factors.
Statins should be used with caution among older women, due to the higher risk of new-onset diabetes. A low-dose hydrophilic statin may also be considered. It will be especially important to monitor such patients to identify new-onset diabetes as quickly as possible.
In cases of statin intolerance, a statin switch may be considered. In a study to assess the tolerability of different statins, it was found that 92% of patients who were intolerant to the first statin responded well to a switch to a second statin. Another study found a 72.5% probability of tolerating a third prescribed statin [19].
Conclusions
The reports reviewed here indicate a higher prevalence of SAMS and new-onset diabetes among women than men. The risk also increases with age and is dose-dependent. Women were also shown to be more susceptible to the nocebo and drucebo effects of statins. It is important for these findings to be borne in mind, and also for recommendations to be introduced to improve adherence to statins, especially among women, and even more especially among older women.
The side effects of statins should not be underestimated. However, it is essential to define, recognize, explain, and monitor reported adverse reactions. Ensuring good, aware cooperation with the patient during treatment is also important.
Nevertheless, the absolute risk of adverse effects of statin therapy remains small in comparison with the absolute benefits. Physicians should remember that statins are usually well tolerated, effectively prevent cardiovascular events [21] and women diagnosed with CVD may even benefit more than men from statin treatment than men [65]. In clinical practice, however, most physicians will face reported statin intolerance and will need to attempt to determine the most effective treatment for dyslipidemia.
Greater awareness of gender-specific side effects may lead to better tailoring of therapy and consequently to better adherence to statins among women, and thus the achievement of therapeutic goals in finally reducing cardiovascular risk. Further research should be conducted to better understand the mechanisms of side effects, including those related to gender.
