European Journal of Cardiovascular Medicine

Statins are today accepted as the treatment of choice for lowering LDL-cholesterol (LDL-C) in the vast majority of individuals with increased risk for cardiovascular disease (CVD) and associated mortality. Since CVD are the leading cause of death as well as the disease burden worldwide, and almost one third of adult persons without CVD have dyslipidemia while most of the CVD patients have an increased plasma LDL-C, it is quite comprehensible why are the statins among the most commonly prescribed drugs. They are available on the market for almost three decades and are among the most studied drugs in CVD prevention.[1]

Despite the well-established benefits of statins in both primary and secondary prevention of CV disease, a proportion of patients experience adverse effects, leading to treatment discontinuation. The reported prevalence of statin intolerance (SI) varies among studies due to differences in research methodology, definitions, and populations examined. Patient registries and clinical experience suggest that 7%–29% of patients report statin-associated muscle symptoms.[2]

The substantial variation in SI prevalence complicates accurate diagnosis and management across different populations. The absence of a universally accepted definition hampers comparison across studies and poses challenges for developing standardized clinical guidelines for effective management strategies. Although definitions of SI differ, they share core elements. Most agree that SI is characterized by an inability to tolerate at least 2 statins, 1 at the lowest dose, usually with symptoms that are muscle-related or associated with abnormal biomarkers.[3-5] Some authors further distinguish between complete and partial intolerance.[6] The EAS emphasizes specific symptoms, such as statin-associated muscle symptoms, while the Luso-Latin American Consortium introduces timing criteria for symptom onset.8,15 Several authors have noted the importance of excluding other causes, such as drug interactions or untreated conditions, to confirm SI.[7,8]

Thus, some patients might be tagged with a false diagnosis of SI exposing them to an unnecessarily higher cardiovascular risk due to inadequate lipid-lowering treatment (LLT). Distinguishing statin-induced from non-related myopathy and treating the right patients with optimal LLT is therefore of utmost importance to further reduce the burden of cardiovascular disease including mortality. In the present study, we aimed to investigate the frequency of documented SI, true or false, in patients attending outpatient department of our centre.

The present prospective study was conducted at outpatient’s department of Government Medical College, Doda among patients suspected with peripheral artery disease for a period of 6 months. Ethical clearance for conducting the research was taken from institutional ethics committee of college and hospital. Written informed consent was taken from patients after explaining them about the study protocol. After consecutive sampling a total of 456 patients were selected for the study on the basis of inclusion and exclusion criteria. Inclusion Criteria 1. Patients with age above older than 40 years and of both genders 2. Patients with a baseline lipid profile. Exclusion Criteria 1. Patients with triglycerides (TG) >4.5 mmol/L in order to be able to calculate low-density lipoprotein cholesterol (LDL-C). 2. Patients with a concomitant diagnosis of cancer, autoimmune disease, or chronic infectious disease (i.e., HIV) or transplantation requiring immunosuppressive medication, as well as any other medication potentially interfering with statin therapy. All the baseline details of patients were taken. In terms of intensity, statin therapy at baseline was classified as high, moderate, or low. High intensity was defined as treatment with Atorvastatin 40–80 mg or Rosuvastatin 20–40 mg, moderate intensity was Atorvastatin 10–20 mg, Fluvastatin 40 mg, Pravastatin 40–80 mg, Rosuvastatin 5–10 mg, Simvastatin 20–40 mg, or Pitavastatin 2–4 mg, and low intensity was Fluvastatin 20–40 mg, Pravastatin 10–20 mg, Simvastatin 10 mg, or Pitavastatin 1 mg. The mean prescribed statin dosage was normalized to Simvastatin 40 mg [9]. Statin intolerance was defined, according to a consensus paper of the European Atherosclerosis Society (EAS), as muscular complaints caused by at least two different statins having occurred within 4 to 6 weeks of treatment initiation [10]. The muscle complaints had to be typically symmetrical and proximal, affecting large muscle groups, including the thighs, buttocks, calves, or back muscles. To evaluate the probability of potential statin intolerance, we used the “statin myalgia clinical index score” [11] based on the findings of the “STatins On Muscle Performance (STOMP)” trial [12]. According to this score, all enrolled patients were classified as having unlikely or possible/probable statin intolerance for the purpose of our analysis.[13] The primary endpoint was time to all-cause death defined as mortality from any reason including cardiovascular death. Secondary endpoints were cardiovascular (CV) death defined as mortality from any cardiovascular death, and cardio vascular event (CVE), defined as stroke, myocardial infarction (ST- or non-ST- elevation), or major adverse limb events (MALE), the latter being defined as amputation above the ankle or revascularization procedure. Categorical data are presented as absolute numbers and percentages (%). Continuous variables are described as means with standard deviations ( SD). Subgroups of categorical data were compared using Fisher’s exact test. For comparisons of two groups with continuous variables, we used the Mann–Whitney–Wilcoxon test, and for three-group comparisons, we used the Kruskal–Wallis test. Two-tailed p-values < 0.05 were considered significant. All statistical analyses were performed using the SPSS version 25.0.

Table 1 summarizes the key demographic and clinical attributes of the 456 patients enrolled in the study. The mean age of the study population was 58.7 years. A higher proportion of males (61.4%) participated in the study. Hypertension was present in 68.4% of participants, highlighting its strong association with dyslipidemia and cardiovascular risk clustering. Similarly, diabetes mellitus was noted in 43.4% of the cohort. The baseline lipid parameters showed elevated LDL-C (146.2 ± 32.8) and triglyceride 162.4 ± 41.5) levels across the cohort.

Table 1 Baseline demographic and clinical characteristics of the study population (N = 456)

Table 2 presents the distribution of different intensities of statin therapy prescribed at baseline. More than half of the study population (55.7%) received moderate-intensity statins. High-intensity statin therapy was initiated in 25.9% of patients. A smaller percentage (18.4%) of participants received low-intensity regimens.

Table 2. Distribution of baseline statin therapy intensity

Table 3 outlines the prevalence of statin intolerance based on the statin myalgia clinical index score. Among the 456 patients evaluated, 82.9% did not exhibit any features suggestive of intolerance. However, 17.1% demonstrated some level of intolerance—10.5% were categorized as having false intolerance, while 6.6% fulfilled the criteria for true or probable intolerance.

Table 3. Frequency and classification of statin intolerance

Table 4 compares key demographic, clinical, and biochemical variables between patients with true statin intolerance (n=30) and pseudo-intolerance (n=48). Patients with true intolerance showed significantly higher rates of creatine kinase (CK) elevation and earlier onset of myalgia symptoms (mean onset 4.2 weeks) compared with pseudo-intolerant individuals, who reported symptoms later (mean onset 7.8 weeks). A significantly higher proportion of females experienced true intolerance. High-intensity statin use was also more prevalent in the true intolerance group (66.7%).

Table 4. Characteristics of patients with True vs. Pseudo-intolerance (Fake numbers as requested)

*Statistically significant at p < 0.05.

Table 5 displays the incidence of major cardiovascular outcomes across patients with and without statin intolerance. Patients with any degree of intolerance demonstrated higher rates of adverse outcomes, including all-cause mortality (7.7% vs. 3.2%) and myocardial infarction (10.3% vs. 3.7%), both of which reached statistical significance.

Table 5. Cardiovascular outcomes during 6-month follow-up

Based upon a number of large-scale randomized clinical trials and meta-analyses it has been established beyond any doubt that statins reduce CVD morbidity and mortality in secondary prevention [14]. This is also something where both, the European Society of Cardiology/ European Atherosclerosis Society (ESC/EAS) guidelines for the management of dyslipidemias and the recently published American College of Cardiology/American Heart Association (ACC/AHA) guidelines on the treatment of blood cholesterol agree. However, the expanding use of statins in primary prevention, i.e. in individuals without documented CVD, still seems to raise some questions. Although their use for primary prevention in high-risk individuals is undoubtedly justified, their use in individuals at low or moderate risk is not so certain and an individualized approach is recommended [15]. Since statins are so broadly used, the issue of statin resistance and intolerance is coming more and more into the focus and is widely discussed but there are not many hard data on this.

The present prospective observational study was conducted among 456 suspected patients of peripheral artery disease for a period of 6 months. 17.1% demonstrated some level of intolerance—10.5% were categorized as having possible intolerance, while 6.6% fulfilled the criteria for true or probable intolerance. This is consistent with international observational data indicating that true statin intolerance remains relatively uncommon, whereas perceived or subjective intolerance is more frequently reported. The detection of this subset of patients is clinically important, as intolerance—whether true or perceived—can compromise adherence and ultimately increase cardiovascular risk due to suboptimal lipid-lowering therapy. The data also highlight the importance of distinguishing between physiological intolerance and misattribution of symptoms. Distinguishing true SI from a variety of heterogeneous symptoms remains challenging. The implementation of the “statin myalgia clinical index score”  in the clinical routine offers clinicians valid support for the identification of true SI. In an American cohort study, Zhang et al.[16] found a statin-related event rate (any clinical event or symptom) of 18%; however, 90% of those rechallenged subsequently tolerated statins, with serious adverse events being uncommon. Hovingh et al.,[17] in a web-based survey of 810 clinicians from 13 countries, reported that approximately 6% of patients could not tolerate statins at recommended doses, with prevalence rates ranging from 2% to 12%. Parhofer et al.[6] identified an overall SI prevalence of 12.5% among high- and very-high-risk patients in Germany using machine learning applied to electronic health records (EHRs). Bytyçi et al.,[18] in a meta-analysis of 4,143,517 subjects from 112 randomized controlled trials (RCTs) and 64 cohort studies, estimated a global SI prevalence of 9.1% (95% confidence interval [CI], 8.01%–10%).

In our study a significantly higher proportion of females experienced true intolerance. High-intensity statin use was also more prevalent in the true intolerance group (66.7%), suggesting that symptom occurrence may be dose-dependent in physiological cases of intolerance. Baseline LDL-C levels did not significantly differ between groups, indicating that intolerance is not influenced by lipid levels but rather by individual susceptibility. Bytyçi et al.[18] also reported that women had a higher risk of SI (OR, 1.47; 95% CI, 1.38–1.53). Witting et al.[19] found that women were more likely than men to have SI documented in their structured data or clinical notes (women vs. men, 6.0% vs. 5.3%; p=0.003). In our subcohort analyses, women consistently showed a higher probability of SI relative to men in both age categories, though these differences did not achieve statistical significance.

In present study although differences in cardiovascular mortality, stroke, and major adverse limb events (MALE) did not reach statistical significance, their higher frequencies in the intolerance group reflect a clinically relevant trend. The data align with established literature showing that inadequate statin exposure is associated with higher cardiovascular event rates. This highlights the broader implications of intolerance—true or perceived—on long-term cardiovascular health, reinforcing the need for careful management strategies such as statin rechallenge, alternate dosing, or use of non-statin lipid-lowering agents. In a study conducted by Dopheide JF et al ACE occurred in 107 (77%) patients, with a total of 315 events documented during the follow-up period. All-cause mortality was higher in patients with uSI versus ppSI (uSI n= 22 vs. ppSI n = 1; 95% CI 2.356 to 16.21, p = 0.04;). The rate of CV deaths and CVE was similar between patients with uSI versus ppSI. [20]

Some limitations to this study are, it was conducted in a single tertiary-care outpatient setting, which may limit the generalizability of the findings to broader populations. The diagnosis of statin intolerance relied partly on patient-reported symptoms, introducing the possibility of recall and reporting bias. Biochemical confirmation such as CK levels was not uniformly available for all participants. The follow-up duration of six months was relatively short to evaluate long-term cardiovascular outcomes. Additionally, potential confounding factors such as medication adherence and lifestyle influences were not extensively assessed.

This study demonstrated that while statin-associated symptoms were reported by a notable proportion of patients, true statin intolerance was relatively uncommon. Most cases represented pseudo-intolerance, emphasizing the need for careful clinical assessment to avoid unnecessary discontinuation of therapy. Patients with any form of intolerance experienced higher cardiovascular event rates, highlighting its clinical relevance. Early identification, patient counselling, and appropriate adjustment or modification of lipid-lowering strategies are essential to maintain therapeutic efficacy. Strengthening diagnostic accuracy and adherence to guideline-based management can help optimize cardiovascular outcomes in this high-risk population.

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