Isotretinoin-Induced Dyslipidemia: a Single-Center Study in Saudi Arabia

Introduction

Acne is a chronic inflammatory skin disease. The factors that lead to lesion formation include increased sebum production, hyperkeratinization, Cutibacterium acnes colonization, and the subsequent inflammatory reactions are the main therapeutic targets.¹ In Saudi Arabia, the prevalence of acne vulgaris in 2022 was 53%. About 54% of the female and 50% of the male participants both had acne vulgaris.² Acne had a significant negative impact on the quality of life for young ladies, with 85.5% prevalence in the eastern region of Saudi Arabia.³ Substantial mental health burden is associated with treatment-resistant acne during isotretinoin therapy and the potential impact of medication side effects.⁴

Isotretinoin is a retinoic acid derivative taken orally for the treatment of moderate to severe, nodulocystic acne that is resistant to conventional medications. It primarily works by decreasing the number of sebaceous glands, the amount of the produced sebum, and the bacterial skin microflora.⁵

The possible side effects of isotretinoin including joint discomfort, headache, mucosal dryness, and nose bleeds were the most frequent side effects of isotretinoin treatment, along with lipid profile and liver enzyme changes.^6,7 Interestingly, a study conducted in Al-Ahsa, Saudi Arabia, showed that more than half of participants (58.7%) did not consider lipid profile changes as a risk of using isotretinoin.⁸

Following isotretinoin treatment, changes in lipid profile (total cholesterol and triglycerides) and liver enzymes (aspartate transaminase and alanine transaminase) have been recorded.^6,9 A recent study done during 2021 in Qassim University Medical City, Saudi Arabia, showed triglyceride levels and total cholesterol were elevated at the end of treatment course, 12.7% and 9%, respectively. Obesity was the major factor associated with high triglyceride levels, with a significant association between body weight and elevation of triglyceride levels.¹⁰ Our aim in this study is to identify the prevalence of increased lipid levels during and after isotretinoin use in polyclinic patients of King Faisal University, Al-Ahsa, Saudi Arabia.

Materials and Methods

A retrospective cohort design study tobtained the patient data and laboratory test results from the King Faisal University polyclinic records system. Patients of all ages diagnosed with acne vulgaris who were treated with oral isotretinoin in the years of 2021–2022 and who had baseline and follow-up laboratory readings of total cholesterol (TC) and triglycerides (TG) during the treatment course were included in this study. Participants who used isotretinoin for other medical conditions than acne or those with not enough laboratory readings were excluded from the sample population.

Parameters included: age, gender, weight, age of onset of acne, age of start of isotretinoin, commercial type of isotretinoin, the dose of isotretinoin (starting dose, ending dose), duration of treatment, previous use of isotretinoin, baseline laboratory tests, and follow-up laboratory results (second and last reading) of TC and TG. Analysis of TC and TG was based on:

• total cholesterol (TC) is classified as normal (100–200 mg/dL) and high (> 200 mg/dL);

• triglycerides (TG) is classified as normal (37–150 mg/dL) and high (> 150 mg/dL).

The study was approved by the institutional review board committee in King Faisal University.

Statistical Analysis

Categorical variables were presented using numbers and percentages. The relationship between the last triglycerides and cholesterol readings among the demographic and clinical characteristics of patients has been performed using Fischer's exact test. A P-value of ≤ 0.05 was considered statistically significant. The data were analyzed using Statistical Packages for Social Sciences (SPSS) version 26 (IBM Corp., Armonk, NY, USA).

Results

We found 132 patients were treated with isotretinoin. Due to lack of the needed laboratory investigations, we recruited 88 patients.

Sociodemographic Characteristics

Nearly half (48.9%) were aged between 21 and 23 years, with females being dominant (70.5%). A total of 50.7% weighed 51 to 70 kg. Approximately 48.9% had been diagnosed with acne at age of more than 19 years. The use of isotretinoin started at the age of 20 years or less (47.7%). The starting dose mostly ranged from 10 to 20 mg (87.5%), while the ending dose ranged between 30 and 40 mg (51.1%). Half of the respondents (50%) had 5 months or more duration of treatment. The prevalence of patients who had previous use of isotretinoin was 6.8% (Table 1).

Table 1 Demographic and Clinical Characteristics of the Lipid Profile Patients (n=88)

Pre, Second, and Last Cholesterol and Triglyceride Reading Levels

Most patients had normal pre-treatment cholesterol (87.5%) and triglycerides (90.9%). The second readings (first to third month) of cholesterol and triglycerides were also mostly normal, with 81.8% and 95.5%, respectively. The last readings (fourth to sixth month) of cholesterol and triglycerides were also normal among 77.3% and 94.3% (Table 2).

Table 2 Lipid Parameters (n=88)

Factors Affecting the Reading of Triglyceride Levels

It was observed that a high pre-treatment triglyceride level was significantly more common among the older age group (p=0.047), increasing age of start of isotretinoin (p=0.003) and increasing ending dose (p=0.016) while the last high triglyceride levels were significantly more common among male patients (p=0.025) and those who previously used isotretinoin (p=0.036). No significant relationships were observed between the last triglyceride levels in terms of age group, age of onset of acne, age of start of isotretinoin, starting dose, ending dose, duration of treatment, and weight group (p>0.05) (Table 3).

Table 3 Relationship Between First and Last Triglyceride Reading Among the Demographic and Clinical Characteristics of the Patients (n=88)

Factors Affecting the Reading of Cholesterol Levels

It was revealed that high pre-treatment cholesterol levels were significantly more common among the older age group (p=0.025) and previous usage of isotretinoin (p=0.024). On the other hand, the prevalence of patients with high cholesterol levels at the last readings was significantly more common among the older age group (p=0.042) (Table 4).

Table 4 Relationship Between First and Last Cholesterol Reading Among the Demographic and Clinical Characteristics of the Patients (n=88)

Discussion

Oral isotretinoin treatment might induce a significant rise in lipid profiles indicating the importance of careful monitoring during the duration of therapy. A meta-analysis done in 2016 does not recommend monthly laboratory testing for acne patients who used isotretinoin therapy.¹¹ However, a recent study demonstrated that although abnormal laboratory results are rare and often do not affect management, the practice of regular laboratory monitoring is still common.¹²

In this study, the lipid profile alterations (TG and TC) were assessed in acne patients treated with oral isotretinoin. The prevalence rates of high levels of cholesterol before treatment and at the first, and at the second follow-ups were 12.5%, 18.2%, and 22.7%, respectively. TG was less affected by isotretinoin therapy than cholesterol. The prevalence rates of high levels before treatment and at the first and second follow-ups for TG levels were 4.5%, 3.4% and 5.7%.

In our study, half of the patients (48.9%) were aged between 21 and 23 years, with females being dominant (70.5%). A similar finding of 200 patients reported that 75% of the patients were female with a mean age of 22–24 years.¹³

Regarding cholesterol level readings, we found that most of the patients had normal pre-treatment (baseline) cholesterol and both second and last follow-up readings (87.5%, 81.8%, and 77.3%, respectively). A retrospective study in Al Qassim, Kingdom of Saudi Arabia (KSA) produced results that corroborate our findings. There were 407 patients with baseline, follow-up, and the end of treatment course laboratory results. TC was normal at baseline with 89.5% of patients and follow-up with 88.6%.¹⁰ On the other hand, a retrospective study in Al Riyadh, KSA of 386 patients had high TC baseline readings as well as 2 follow-up readings (12.1%, 21.8%, and 18.7%, respectively).¹⁴ Also, a study done in Sakarya University, Turkey, found no relation statistically between the third and sixth months of treatment in all parameters including cholesterol and TG.¹⁵

Regarding triglyceride level readings, we noticed that almost all the patients had a normal baseline (90.9%) and both second (95.5%) and last (94.3%) follow-up readings. The same study done in Al Qassim, KSA showed that TG levels were normal at baseline of patients at 93.5% and at follow-up 83.7%.¹⁰ In contrast, Al Riyadh, KSA study demonstrated high TG levels over time (1.6%, 3.8%, and 4.4%) at baseline and first and second readings, respectively.¹⁴ Another retrospective study of 415 patients also supported significant differences between TG measurements mostly between the second month (23.9%) and the fourth month (27.2%).¹⁶ Many studies supported that high TG levels were associated with the third and sixth months of treatment.^17,18

In our study, we found that high cholesterol levels of pre-treatment and last readings had a significant relation with the older age group. In contrast, a study of 143 patients revealed that age and oral isotretinoin had no significant effect on cholesterol in the third month of treatment.¹⁹ Abd-Elaziz et al showed that the dose and duration of the treatment had a significant association with higher levels of cholesterol which was not found in our study.²⁰ Alajaji et al concluded that body weight had no significant effect on cholesterol levels at follow-up and last visit levels which is a similar result in our study.¹⁰

No significant relationships were observed in our study between the last TG levels in terms of weight group. However, a retrospective study of 204 patients showed that subjects with higher body weight had significantly higher levels of TG.²¹ In addition, a previous study showed that triglyceride levels compared with body weight were statistically significant for follow-up and last-visit levels.¹⁰ No relation was found between high TG levels and the dose of isotretinoin in our study, which is similar finding in the previous study.²²

Strengths

This study compares the following variables: age, gender, weight, dose, duration of treatment, and isotretinoin previous use with lipid parameters, which have not been discussed in previous studies.

Limitations

The limited sample size of the study, and the retrospective character leading to elimination of a number of patients due to lack of regular investigation and recruitment criteria.

Conclusion

Almost all acne patients who were treated with isotretinoin in our study have normal levels of total cholesterol and triglyceride at baseline, second, and last readings. The incidence of higher laboratory alterations of lipid profiles is low. The older age group has a high pre-treatment reading of both total cholesterol and triglyceride levels. Also, older patients have high last-reading cholesterol levels. In addition, previous usage of isotretinoin is associated with high pre-treatment cholesterol levels. High pre-treatment readings of triglyceride have a significant association with an increasing ending dose. While high last-reading triglyceride levels have a significant association with the male gender and those who previously used isotretinoin. Additional confirmatory studies with a larger patient sample will be recommended.