Awareness of statin–food interactions using grapefruit as an example: a cross-sectional study in Eastern Province of Saudi Arabia

Abstract

Objectives

The purpose of this study is to assess patients’ knowledge regarding statin–grapefruit interactions, to identify any pertinent demographic characteristics that may influence knowledge of this drug–food interaction, and to identify preferred patient sources of health information.

Methods

A cross-sectional study was conducted to collect data from statins users about the awareness regarding drug interaction with foods. Self-administered questionnaires have been distributed to collect data from statins users regardless of the type and the reason they administer these medications. Respondents were statins users visiting the King Fahd Hospital’s outpatient clinic (KFHU) and community pharmacies in the Eastern province of Saudi Arabia.

Key findings

Our study revealed that 62% of statin users never heard about the statin–grapefruit interaction. Only 11% have correctly recognized the interaction effect. Only 11, 21 and 6% of users have reported that they often/always received information on drug–food interaction from pharmacists, physicians and nurses, respectively. Users aged above 60 years had lower awareness than those aged <40 (6.0% vs. 14.1%). Similarly, the proportion was lower among users who had primary or lower educational attainment, unemployed or had income lower than 5000 SAR compared with that among the contrary groups. However, only income showed a statistically significant association (P = 0.007).

Conclusions

The majority of statin users have never heard about their interaction with food. Geriatrics, low-income and less educated patients had a lower level of awareness compared with their counterparts. Many patients may end up discontinuing their medications because of that interaction and the consequent side effects. Pharmacists are requested to play their expected role in providing adequate patient counselling to help improve patients’ awareness regarding safety concerns of statins medication.

clinical pharmacist, statins, drug interactions, rational medication use, awareness

Introduction

Dyslipidemia is a broad term that refers to several lipid disorders. It has long been recognized as one of the highest leading causes of death worldwide. Dyslipidemia refers to the abnormal amounts of lipids (e.g. triglycerides, cholesterol and fat phospholipids) in the blood. However, dyslipidemia is classified as a modifiable risk factor for the incidence and development of cardiovascular diseases (CVD). Furthermore, the World Health Organization reports indicated that in 2030, the number of deaths could reach 23.6 million from CVD.^[1] Previous studies suggested that the financial ‘direct and indirect’ cost of lipid stiffness places a heavy burden on health service financing sources worldwide.^[2–5] It was estimated that the total cost of CVD and stroke associated with dyslipidemia – exceeds $400 million in a study conducted in the USA in 2006.^[6]

However, several pharmacological and non-pharmacological approaches have been recommended to treat and reduce hyperlipidaemia’s risk during the past three decades. As a non-pharmacological treatment, Jena et al. reported that lifestyle modification could also help this aspect.^[7] Lifestyle modifications and other pharmacological interventions that lower blood cholesterol (such as statins) have been shown to reduce the incidence and frequency of major coronary artery events and overall mortality associated with dyslipidemia. However, numerous comprehensive studies support the use of statins in coronary heart disease (CHD) patients for the treatment of dyslipidemia and secondary prevention.^[8–10]

Statins as drug therapy inhibit the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase are considered the most effective class of drugs for the treatment of dyslipidemia.^[11–13] Statin drugs include (Atorvastatin, Simvastatin, Pravastatin, Pitavastatin, Lovastatin and Rosuvastatin) and are perceived to have a favourable safety profile.^[14–16]

Furthermore, statins inhibit the enzyme HMG-CoA reductase at a stage early in the mevalonate pathway. This pathway generates a range of other products in addition to cholesterol.^[15]

Despite the recognized effectiveness in managing dyslipidemia and the proven safety record of statins, like other drugs in general, they interact with many drugs and foods. Statins are metabolized in a variety of ways; for example, Atorvastatin, Simvastatin and Lovastatin are metabolized via the cytochrome P450 CYP3A4 pathway, whereas Pravastatin and Rosuvastatin are not. Therefore, concurrent administration of statins with CYP3A4 inhibitors (drugs or foods) may elevate statins concentrations and toxicity risk.^[17] Similarly, several organic compounds have been found in citrus and specifically in grapefruit juice exert an inhibitory action on statins metabolism. Previous studies reported that the metabolism of some statins such as Atorvastatin (Lipitor), Lovastatin (Mevacor) and Simvastatin (Zocor) was found to be highly affected by grapefruit juice. In contrast, Pravastatin (Pravachol), Fluvastatin (Lescol) and Rosuvastatin (Crestor) are lacking such interaction with grapefruit.^{[18, 19]} The statin rhabdomyolysis experienced by statin users upon grapefruit juice’s concurrent use has been attributed to grapefruit juice inhibition of CYP3A4 responsible for some statins’ metabolism.^{[20, 21]} As a result of changes in all societies’ lifestyles worldwide due to the drastic shift in information technology, there is an increase in demand and the use of natural materials as one of the therapeutic alternatives. In order to enhance and reduce drug-related problems, it is imperative to counsel the patients and educate them about their medication use, mechanism of action, role in their therapy, drug and food interactions and possible side effects. Since statins are highly prescribed drugs and the chance to co-administer them with grapefruit is high, the drug–food interactions are expected and the consequent adverse effects might lead to discontinuation of statins putting patients’ health at higher risk. Unfortunately, this problem has not been studied before in Saudi Arabia where the prevalence of obesity and CVD is high. This study has been performed to evaluate statins users’ awareness regarding the drug–food interactions, their expectations about the consequences of the interactions and the sources of such information.

Ethics Approval

The study has been exempted from ethical review after application to the institutional review board (IRB) of Alain University, as it is an observational, non-interventional survey-based study.

Methods

Study design and setting

A cross-sectional study was conducted to collect data from statins users about their awareness regarding their interaction with foods. The data collection was done using self-administered questionnaires distributed among statins users regardless of the type and the reason they administer these medications. Study participants were statins users visiting the King Fahd Hospital’s outpatient clinic (KFHU) and in community pharmacies in the Eastern province of Saudi Arabia. Study investigators who are pharmacists verify if the patient is a statin user after checking their prescription and asking them about current statins use, their willingness to participate in a research study about the topic, in addition to the direct questions at the beginning of the survey about the current administration of different statin medications. Recruiting those patients to participate in the study was done by randomly asking those statin users to self-administer the study survey. All users are eligible to participate, but only those who gave consent for voluntary participation were included in the study. Statin users who did not have enough time to fill the survey and those who did not consent to participate in the study were excluded (non-responders).

Sample size calculation

A minimum of 385 participants was required to estimate the proportion of statin users aware of the statin–food interaction with a margin of error of 5% at 95% confidence level. In the absence of the expected proportion from previous studies, we assumed that 50% of the study population are expected to be aware of the interaction. The selected proportion yields the largest sample size with the given margin of error and confidence level

Data collection instrument

To develop the questionnaire, an in-depth literature review was carried out to assess statin users’ awareness regarding the potential interactions with regularly consumed foods. Among few sets of adapted questionnaires, an initial version of a structured questionnaire was drafted by compiling and adopting relevant questions from previously validated questionnaires in published literature.^[22–24] The expert panel input involving three pharmacy academicians, including a statistician, was considered to develop the final draft. Expert’s comments and suggestions were addressed accordingly to ensure the questionnaire fulfils the study objectives and the requirements of the quality assessment domain and gain insights into its appropriateness. The expert panel ensured the content validity with the full agreement of all experts. The whole questionnaire was divided into three parts. First, part A includes respondents’ socio-demographic characteristics, including gender, age, marital status, educational level, occupation, average income and co-morbidities, to describe the population and correlate these characteristics with the awareness of statins interactions. Second, part B includes the used statin, the given dose, how they obtain the medications if they are consuming any of the foods known to interact with statins, in addition to the frequency of administering such foods. A favorable source of drug information was also requested. Third, part C includes questions about the participants’ awareness of the potential interaction between grapefruit and statins, the consequences of that interaction, whether they receive counseling from physicians, nurses or pharmacists about these interactions, and the perceived effectiveness used awareness improvement tools. Statins have been classified based on patient-reported medications and doses according to statin dosing and the American College of Cardiology (ACC) and American Heart Association (AHA) Classification of Intensity.^[25] The questionnaire was piloted to address all the corrections about wording and feasibility to ensure face validity. The reliability of the instrument was assessed in this phase. However, data gathered from the pilot study were not included in the final analysis. The data were gathered on one occasion to ease the capture of responses. Closed-ended questions were deliberately chosen for the survey design to reduce the risk of unintentional bias in interpreting responses.

Statistical analysis

Descriptive statistics were used to describe the study variables, items, frequencies and corresponding percentages. Chi-square test was carried out to test the association between patient characteristics and awareness of statin–grapefruit interaction. A P-value <0.05 was considered statistically significant. Data management and analysis were done using SPSS Statistics (Version 24.0. Armonk, NY: IBM Corp.).

Results

Characteristics of study participants

A total of 400 surveys were distributed; however, only 289 statin users (75% of the targeted sample) had completed the study questionnaire. Socio-demographic characteristics are presented in Table 1. Majority of participants were male (61.9%; n = 179), aged 40 years or more (77.8%; n = 224) and married (77.2%; n = 223). More than 60% had elementary or higher education (n = 237), employed (n = 189) and earning a monthly income of 5000 SAR or more (n = 180). Around one-half of the study participants (n = 143) had three or more co-morbidity conditions (Table 1).

Table 1

Socio-demographic details of study participants (N = 289)

Variables	Frequency	%
Gender
Male	179	61.9
Female	110	38.1
Age (in years)
18–39	64	22.2
40–59	140	48.6
≥60	84	29.2
Marital status
Single	66	22.8
Married	223	77.2
Education level
Primary or lower	52	18.0
Elementary-secondary	106	36.7
University education	131	45.3
Occupation
Not working	100	34.6
Working	189	65.4
Average monthly income (SAR)
<5000	105	36.8
5000–10 000	85	29.8
10 001–20 000	74	26.0
Above 20 000	21	7.4
Co-morbidity conditions
Dyslipidaemia	252	87.2
Hypertension	190	65.7
Heart disease	55	19.0
Diabetes	164	56.7
Obesity	46	15.9

Table 2 represents the pattern of Statin use among the participants. The most commonly used statin types among the participants were Atorvastatin (57.8%), Simvastatin (21.8%) and Rosuvastatin (15.9%). In terms of statin intensity, 62 and 30% were on moderate and high intensity, respectively. The data have shown that a substantial proportion (40.8%; n = 118) of moderate-/high-intensity statin users were regularly co-administering grapefruits (Figure 1).

Table 2

Statin use among the participants (N = 289)

Variables	Frequency	%
Medication
Atorvastatin	167	57.8
Simvastatin	63	21.8
Rosuvastatin	46	15.9
Lovastatin	5	1.7
Fluvastatin	3	1.0
Pitavastatin	2	0.7
Pravastatin	3	1.0
Dose of statin (mg)
10	77	26.6
20	131	45.3
40	69	23.9
80	12	4.2
Statin intensity
Low intensity	23	8.0
Moderate intensity	179	61.9
High intensity	87	30.1

Figure 1

Frequency of grapefruit use among statin users.

Awareness of statin–grapefruit interaction

As shown in Figure 2, 62% of statin users never heard about the statin–grapefruit interaction. Surprisingly, only 11% have correctly recognized the interaction effect. Only 11, 21 and 6% of users have reported that they often/always received information on drug–food interaction from pharmacists, physicians and nurses, respectively (Figure 3). The proportion varied by the users’ characteristics (Table 3). Gender showed no difference in terms of awareness regarding the abovementioned interaction. Users aged above 60 years had lower awareness than those younger than 40 (6.0% vs. 14.1%). Marital status did not reflect any difference in awareness, where single and married statin users had almost the same proportion of awareness regarding the interaction. On the other hand, the proportion was lower among users who had primary or lower educational attainment, unemployed or had income lower than 5000 SAR compared with that among the contrary groups indicating that higher education, employment and higher-income statin users had higher awareness regarding the aforementioned interaction between statins and grapefruits. However, only income showed a statistically significant association. Surprisingly, the awareness regarding that interaction was higher among those who do not or rarely administer grapefruits. This might indicate that the awareness was reflected in minor use for grapefruits among those users, as shown in Table 3.

Table 3

Association between socio-demographic and clinical characteristics with the awareness of statin–grapefruit interaction

Variable	Not aware, n (%)	Aware, n (%)	P-value
Gender
Male	158 (88.3)	21 (11.7)	0.649
Female	99 (90)	11 (10)
Age (in years)
18–39	55 (85.9)	9 (14.1)	0.196
40–59	122 (87.1)	18 (12.9)
≥60	79 (94)	5 (6)
Marital status
Single	59 (89.4)	7 (10.6)	0.891
Married	198 (88.8)	25 (11.2)
Education level
Primary or lower	50 (96.2)	2 (3.8)	0.068
Elementary-secondary	96 (90.6)	10 (9.4)
University education	111 (84.7)	20 (15.3)
Occupation
Not working	93 (93)	7 (7)	0.109
Working	164 (86.8)	25 (13.2)
Average income (SAR)
<5000	95 (90.5)	10 (9.5)	0.007*
5000–10 000	81 (95.3)	4 (4.7)
10 001–20 000	58 (78.4)	16 (21.6)
>20 000	19 (90.5)	2 (9.5)
Statin intensity
Low intensity	19 (82.6)	4 (17.4)	0.601
Moderate intensity	160 (89.4)	19 (10.6)
High intensity	78 (89.7)	9 (10.3)
Frequency of grapefruit use
No/rarely	139 (86.9)	21 (13.1)	0.349
One or two fruits per day	95 (90.5)	10 (9.5)
More than two fruits per day	23 (95.8)	1 (4.2)

Chi-square test was used; *P-value <0.05.

Figure 2

Awareness of statin–grapefruit interaction.

Figure 3

Source of information on statin–grapefruit interaction.

Figure 4 shows the users’ preferred source of information on drug–food interaction. More than two-third were believing that healthcare practitioners should educate the patients about the interaction through consultations.

Figure 4

Recommended source of information on drug–food interaction.

Discussion

Patterns of statins use

The findings highlighted that atorvastatin was the most prescribed statins, and ~62% of the cases have received moderate-intensity regimens. Similarly, a previous drug formulary review has highlighted atorvastatin as the preferred statin therapy.^[26] In contrast, previous research reported a prevalent use of moderate-intensity regimen was reporting simvastatin as the most commonly prescribed statin.^[27] It is expected to witness variations in prescribing patterns of statin, which could be attributed to diversity in prescribing setting, primary or secondary CVD indications. Generally, the more prevalent use of atorvastatin is anticipated at relatively higher intensity dosing regimens among patients with higher CVD risk profiles as in this study population.

Prevalence of statin interactions

It is worthy to note that not all statin therapies have the same susceptibility to drug interactions. In a study conducted to investigate and compare the general safety profile of various statin medications, the potential profile of drug interactions was affected by the inter-differences between statin therapies.^[28] For instance, some statin therapies influenced by cytochrome P450, including simvastatin and lovastatin, were more prone to interactions. On the other hand, atorvastatin is not affected by this metabolic pathway. Interestingly, pravastatin and rosuvastatin are the least likely statin therapies associated with significant drug interactions.^[29]

As one of the most widely prescribed medication categories, concerns on safety associated with statin therapy have imposed clinical significance for more investigations related to drug interactions and adverse effects. Although several reports underpinned the prevalence and degree of significance of a wide range of interactions involving statin and other medications.^{[29, 30]} Statin–food interactions are still not well significantly covered. The findings reported an overall (40%) concomitant consumption of grapefruit among statin users. Previous research reported that about one-third of overall possible drug–drug interactions.^[30] These figures denote that potential food–drug interactions are possibly more common and must be carefully considered.

Grapefruit juice has been reported to increase statin levels, increase the effective dose and potentially increase safety concerns.^[31] However, Lee et al. have emphasized the potential benefit of co-administering the grapefruit with statins, increasing effective doses and boosting the LDL-c reduction with a minimal impact on the risk of rhabdomyolysis.^[31] A further opinion suggests considering this drug–food interaction in designing a low statin–grapefruit combination that could serve as a better economic choice for patients with dyslipidemia.^[32] On the other hand, the therapeutic use of this drug interaction was refuted by another perspective that focuses on the potential unnecessary harm that might have emerged as a result of this drug interaction with no significant difference in the overall regimen effectiveness compared with statin monotherapy.^[33] The scenario will be more worrying if patients consume a more significant amount of grapefruit juice with <8–12 h apart from statin therapy. Therefore, it seems that the claims for therapeutic benefits to support the recommendation for using grapefruit concomitantly with statin therapy are not well established. Furthermore, by following ‘do no harm’ therapeutic principle, it is better to address this scenario to assure patient safety.

Awareness and sources of information

This section’s findings were alarming, where the majority of participants were not aware of the statin–grapefruit interaction. Sadly, only a few (11%) of the study participants had correct information concerning the impact of this interaction on statin levels. The results did not show statistically significant differences in the awareness levels with social, employment, educational status. However, a better economic status/higher monthly income was associated significantly with higher awareness levels. In contrast, similar previous research conducted in the USA has highlighted that overall grapefruit consumption was more common among those with higher education levels.^[34] In concordance with previous research, our study participants have reported that a direct consultation with healthcare professionals, for example, physicians and pharmacists, is a recommended source for their information concerning statin–food interactions. Other relatively less preferred information sources were media and reading medication package inserts. It is worthy of highlighting that media could have an adverse impact on communicating healthcare information, especially those related to medication-related warnings, side effects or precautions.^[35]

Regarding the use of statin therapy, it is crucial to recognize that although various statin therapies share the exact mechanism, they have different metabolic pathways that enhance certain statins’ susceptibility to specific interactions compared with other agents.^[36] This point should be carefully considered while promoting awareness among healthcare providers about effective statin-related drug and food interactions. Previous research has highlighted the impact of such educational intervention targeted healthcare providers on improving their knowledge regarding statin therapy and its potential safety concerns and drug interactions.^[37] With comprehensive expertise regarding statin drug and food interactions, healthcare providers would be an excellent source of information in the community and contribute to ensure patient safety. In addition, pharmacists should play the expected role that is expanded day after day in improving rational medication use.

One of our study’s limitations is that the reliance of this study on data collected from the participants on the survey may be subject to biases, such as non-response bias and reporting or recall bias. In addition to this, caution should be considered while interpreting the study findings, and generalizability cannot be taken for granted given the sample size of study participants. However, the study highlighted a deficient awareness level among statins users regarding this common interaction with food. Moreover, healthcare providers should expand their role in raising patients’ awareness regarding medication safety, especially after the reported patients’ high level of trust.

Conclusion

The majority of statin users have never heard about their interaction with food, which may put them at risk of undergoing severe adverse effects. Only a small proportion of patients have a fair knowledge about this potential drug–food interaction. Our findings revealed that geriatrics, low-income and less educated patients had a lower awareness level than their counterparts. Pharmacists are requested to play their expected role in ensuring rational medication use and providing adequate patient counseling to help improve patients’ awareness regarding safety concerns of statins medication.

Author Contributions

Conceptualization: M.A.B., M.H.E., R.E., A.S., A.A.E., R.J.C., A.H.A. and M.M.A.M.; collected data: M.A.B. and A.H.A.; data analysis and interpretation: M.A.B., M.H.E., R.E., A.S., A.A.E., R.J.C., A.H.A. and M.M.A.M.; writing—original draft preparation: M.A.B., M.H.E., R.E., A.S., A.A.E., R.J.C., A.H.A. and M.M.A.M.; writing—review and editing, M.A.B., M.H.E., R.E., A.S., A.A.E., R.J.C., A.H.A. and M.M.A.M. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

Conflict of Interest

The authors declare they have no conflict of interest.

Data Availability

The datasets and any results produced from the study are available from the corresponding author on reasonable request.