|Year : 2022 | Volume
| Issue : 4 | Page : 349-354
|The effects of acitretin on insulin resistance, glucose metabolism, and lipid levels in patients with psoriasis
Satnam Singh Sachdev1, Adawiyah Jamil2, Preamala Gunabalasingam1, Najeeb Ahmad Safdar1
1 From the Dermatology Department, Hospital Tuanku Jaafar, Jalan Rasah, Bukit Rasah, Seremban, Negeri Sembilan, Malaysia
2 Dermatology Unit, Department of Medicine, University Kebangsaan Malaysia Medical Center, Bandar Tun Razak, Cheras, Kuala Lumpur, Malaysia
|Date of Web Publication||2-Nov-2022|
Derpartment of Medicine, University Kebangsaan Malaysia Medical Center, Bandar Tun Razak, Cheras, Kuala Lumpur - 56000
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Context: Acitretin increases serum lipids. Data on its effects on insulin resistance and glucose metabolism are sparse and contradicting. Aims: The aim of this study is to investigate the effects of acitretin on insulin resistance, glucose metabolism, and lipids. Methods: Dermatology clinic in a public tertiary hospital. A cross sectional study involving chronic plaques psoriasis patients on acitretin plus topical therapy or topical therapy alone was performed. Fasting blood glucose (FBG), serum lipids, serum insulin, and glucose tolerance test (GTT) were performed. Homeostatic model of insulin resistance (HOMA-IR) was calculated. Psoriasis severity was evaluated using Psoriasis Area and Severity Index. Chi square and t-tests determined differences between cases and controls. Pearson's correlation coefficient test determined the relationship between continuous variables. Results: A total of 60 patients participated, 30 were on acitretin while 30 were on topical therapy. Psoriasis duration, disease severity, BMI, presence of metabolic syndrome, and other comorbidities between the two groups were similar. There were no significant differences in GTT, FBG, HOMA-IR, and serum lipids. Patients on acitretin >25 mg daily had lower FBG [4.4 (0.8) versus 4.9 (0.9), P = 0.04] and triglyceride [1.05 (0.33) versus 1.57 (1.03), P = 0.02] compared with doses ≤25 mg. Higher acitretin dose correlated with lower FBG (r = −0.36, P = 0.05) and triglycerides (r = −0.37, P = 0.05) while longer therapy duration correlated with lower total cholesterol (r = −0.37, P = 0.05). HOMA-IR showed inverse correlation with acitretin dose and duration (r = −0.10, P = 0.61 and r = −0.12, P = 0.53, respectively). Conclusion: Acitretin therapy resulted in increased triglyceride. The effect of acitretin on glucose metabolism and insulin resistance maybe dependent on the dose and duration of therapy.
Keywords: Acitretin, glucose, insulin resistance, metabolic syndrome
|How to cite this article:|
Sachdev SS, Jamil A, Gunabalasingam P, Safdar NA. The effects of acitretin on insulin resistance, glucose metabolism, and lipid levels in patients with psoriasis. Indian J Dermatol 2022;67:349-54
|How to cite this URL:|
Sachdev SS, Jamil A, Gunabalasingam P, Safdar NA. The effects of acitretin on insulin resistance, glucose metabolism, and lipid levels in patients with psoriasis. Indian J Dermatol [serial online] 2022 [cited 2022 Dec 8];67:349-54. Available from: https://www.e-ijd.org/text.asp?2022/67/4/349/360327
| Introduction|| |
Psoriasis is a chronic relapsing skin disorder that has no permanent cure to date. Psoriasis is characterized by plaques with thick scales that resulted from accelerated epidermal proliferation due to a chronic immune mediated process involving the interplay of genetic, immunological, psychological, and environmental factors. Psoriasis is not limited to skin, joints, and nails, mucous membranes maybe involved and there are multiple systemic associations. Obesity, insulin resistance, diabetes mellitus, hypertension, metabolic syndrome, and atherosclerosis are common comorbidities.,, Metabolic syndrome is an important comorbidity of psoriasis.,
Psoriasis is treated according to disease severity. Treatment options ranged from topical therapy to physical or systemic therapy, and a combination of these modalities. Presence of comorbidities often complicates treatment choice. Most systemic agents are immunosuppressants that carry short and long-term adverse effects. Oral retinoid is a systemic treatment that has been used for many years. Retinoids are non-immunosuppressive and has an acceptable safety profile., The first oral synthetic retinoid used in the treatment of psoriasis and other disorders of keratinization in the 1970s was etretinate. Acitretin is the free and active metabolite of etretinate. Acitretin became the most widely used systemic retinoid in psoriasis management due to improved pharmacokinetic profile. Acitretin is cheap, easily available in many countries, and is a relatively safer option for patients requiring systemic therapy. Acitretin may increase serum lipid levels and affect glucose metabolism. Data on glucose metabolism are inconsistent.,,, Acitretin therapy induces severe hypoglycaemia and remission of type 2 diabetes in a case report, while another report described acitretin-induced reversible hyperglycaemia.
We aimed to investigate the effects of acitretin therapy on glucose metabolism and lipid levels in patients with chronic plaque psoriasis. Glucose metabolism was assessed with fasting blood glucose (FBG), homeostatic model of insulin resistance (HOMA-IR), and glucose tolerance test (GTT). Lipid levels include triglycerides, low density lipoprotein-cholesterol (LDL-cholesterol), and high density lipoprotein-cholesterol (HDL-cholesterol). We further evaluated the effects of lower doses of acitretin versus higher doses and whether duration of therapy has a significant effect on sugar or lipid metabolism.
| Subjects and Methods|| |
An observational study involving patients with chronic plaque psoriasis was performed using cross sectional study design at a dermatology clinic in a public tertiary heath facility. Informed consent was obtained. Inclusion criteria were adult patients aged ≥18 years and on acitretin therapy ≤50 mg daily for at least a month or topical therapy alone. Exclusion criteria included patients on phototherapy or other systemic agents, pregnant, diagnosed with diabetes prior to commencing on acitretin, BMI >30 kg/m2, or on medications that may interfere with glucose metabolism.
Blood pressure, weight, height, and waist circumference were measured. Psoriasis Area and Severity Index (PASI) was determined by a single investigator. Venous blood was taken for evaluation of FBG, fasting serum lipid, aspartate transaminase, alanine transaminase, and fasting serum insulin. GTT was performed with 75 gm of oral glucose diluted in 200 ml of water and serum glucose was obtained at 60 and 120 min. HOMA-IR was determined by multiplying fasting serum glucose with serum insulin and dividing the total by a constant of 22.5. HOMA-IR determines the degree of insulin resistance, and higher HOMA-IR indicates a higher insulin resistance. A healthy range of HOMA-IR is 0.5 to 1.4. Value of HOMA-IR <1.0 means insulin-sensitive which is optimal, >1.9 indicates early insulin resistance and >2.9 indicates significant insulin resistance.
Sample size was calculated based on the results from Corbetta et al. where HOMA-IR was 1.53 ± 0.73 in cases and 2.59 ± 1.41 in controls. Sample size was calculated using PS: Power and Sample Size Calculation software. The calculated sample size was 58 subjects with alpha value 0.05, power 80%, ratio 1, and 20% drop out rate.
Statistical analysis was performed using IBM SPSS Statistics 26.0. Chi square and t-tests determined the differences between two variables. Pearson's correlation coefficient test determined the relationship between continuous variables. All hypotheses were tested with a statistical significance of 0.05. This study was approved by Medical Research and Ethics Committee, Ministry of Health Malaysia, research registration number NMRR-19-3907-52268(IIR).
| Results|| |
A total of 60 patients with chronic plaque psoriasis on regular follow-up at the clinic were recruited, half were on acitretin treatment, and the rest were on topical treatment only. The mean age of patients on acitretin was 47.97 ± 13.20 and 41.63 ± 17.33 for those on topical therapy, P = 0.11. There were 22 (73.3%) males and 8 (26.7%) females in acitretin group, with 16 (53.3%) males and 14 (46.7%) females in topical therapy group with mean age of psoriasis onset was 34.5 ± 13.15 and 31.07 ± 17.94, respectively. Disease duration was 13.63 ± 9.72 years for patients on acitretin and 13.03 ± 12.54 for patients on topical therapy, P = 0.83. Mean acitretin dose was 33.83 ± 11.94, while mean duration of acitretin therapy was 22.35 ± 27.38 months. The mean weight and waist circumference of both groups were not statistically different, while the mean BMI were the same, 26 kg/m2. Three patients on acitretin and two patients on topical therapy had metabolic syndrome. Comorbidities documented were hypertension, dyslipidaemia, and coronary artery disease with no significant differences between the two groups. Disease severity was comparable, PASI was 15.34 ± 8.51 in acitretin group versus 13.24 ± 9.0 in topical therapy group, P = 0.36. There was no significant difference in Dermatology Life Quality Index (DLQI), 10.11 ± 6.18 versus 9.17 ± 6.43, P = 0.57. Demographic data and clinical characteristics of the study population with comparison between acitretin and topical therapy groups are presented in [Table 1].
|Table 1: Demographic and clinical characteristics of the study population|
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The results of GTT, fasting lipids, fasting glucose, serum insulin, and HOMA-IR are presented in [Table 2]. There were equal number 7 (50%) of patients in both groups with normal and impaired GTT. The values of total cholesterol, LDL and HDL cholesterols, and triglyceride in both groups were within normal limits. Total cholesterol and LDL-cholesterol were slightly higher in acitretin group, while HDL-cholesterol was higher in topical therapy group with P = 0.56, 0.79, and 0.09, respectively. Triglyceride was significantly higher in patients on acitretin 1.62 ± 0.85 compared with topical therapy 1.24 ± 0.61, P = 0.05. Fasting blood sugar results were within normal range, 4.91 ± 0.62 versus 4.85 ± 0.65, P = 0.74. Serum insulin was above the normal limit for topical therapy group 11.49 ± 7.26, while just at the upper limit of normal for acitretin group 10.14 ± 8.63, P = 0.52. HOMA-IR among was higher in acitretin group 3.70 ± 5.90 versus 2.55 ± 1.72 among topical therapy group, P = 0.31.
|Table 2: Comparison of insulin resistance, glucose metabolism, and cholesterol levels between cases and controls|
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[Table 3] illustrates the GTT, fasting lipids, fasting glucose, serum insulin, and HOMA-IR results with acitretin dose ≤25 mg versus >25 mg and therapy duration of ≤6 months or >6 months. About 19 (63.3%) patients received acitretin ≤25 mg daily and 11 (36.67%) received >25 mg daily; 14 patients (46.7%) were treated for ≤6 months while 16 (53.3%) was on therapy for >6 months. There were no significant differences in the number of patients with normal or impaired GTT in terms of acitretin dose or therapy duration. Acitretin at higher dose showed significantly lower FBG 4.4 (0.8 mmol/L) versus 4.9 (0.9 mmol/L), P = 0.05, and triglyceride 1.05 (0.33 mmol/L) versus 1.57 (1.03), P = 0.02, compared with lower dose. Higher values of total, LDL-, and HDL-cholesterols were observed with higher dose acitretin, but results were not statistically significant. Duration of acitretin therapy did not significantly affect cholesterol and fasting blood sugar profiles. There were no significant differences in serum insulin and HOMA-IR with acitretin dose or duration. Serum insulin was higher while HOMA-IR is lower in patients on lower acitretin dose. Shorter duration of acitretin therapy showed higher serum insulin and HOMA-IR.
|Table 3: Effect of acitretin dose and duration on insulin resistance, glucose metabolism, and cholesterol levels. Comparison between patients on acitretin dose ≤25 mg and >25 mg, and therapy duration ≤6 months and >6 months|
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Correlation analyses to determine the relationship between acitretin dose and duration with insulin resistance, glucose metabolism, and cholesterol levels in cases are shown in [Table 4]. There were negative correlations between triglyceride and fasting blood sugar with higher acitretin dose, with P values approaching significance for both (P = 0.05). Positive non-significant correlations were observed for the remaining parameters except blood glucose at 60 min GTT and HOMA-IR. Total, LDL and HDL cholesterols, triglycerides, serum insulin, and HOMA-IR were inversely correlated with acitretin dose. The relationships were non-significant except for total cholesterol which approached significance with P = 0.05.
|Table 4: Correlations between acitretin dose and duration with insulin resistance, glucose metabolism, and cholesterol levels|
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Relationship between psoriasis severity with insulin resistance, glucose metabolism, and cholesterol levels in both groups were further analyzed. In acitretin group, blood glucose at 60 min GTT, triglycerides, HOMA-IR, and FBG were inversely correlated with PASI with only FBG achieving statistical significance 0.03. Other parameters showed non-significant positive correlations except for total cholesterol with P value approaching significance at 0.05 and LDL cholesterol with P value 0.04. In topical therapy group, significant positive correlations were observed for total cholesterol (P = 0.03), LDL-cholesterol (P = 0.01), and HOMA-IR (P = 0.04). Positive non-significant correlations were seen for fasting blood sugar, serum insulin, and triglycerides. Blood glucose at 60 min GTT and HDL-cholesterol showed inverse relationship. However, these are not statistically significant.
| Discussion|| |
Effect of acitretin on insulin resistance and glucose metabolism
In our study population, acitretin therapy did not seem to affect glucose metabolism and insulin resistance as there were no significant differences noted in GTT, FBS, and HOMA-IR between patients on acitretin and topical therapy. However, a trend of higher HOMA-IR was observed in patients on acitretin therapy. Insulin resistance is an important characteristic of metabolic syndrome which is common in psoriasis patients., Psoriasis patients had higher adiponectin, serum insulin, and HOMA-IR indicating insulin resistance compared with healthy volunteers with similar BMI. The number of psoriasis patients with metabolic syndrome in our patients on acitretin and topical therapy were comparable, which may explain the similarities in parameters of insulin resistance with inclination toward higher values in patients on acitretin.
The effect of acitretin on insulin resistance is most likely dependant on the dose and duration of therapy. Acitretin at lower doses of 10 to 25 mg reduced RBP-4, insulin, C peptide, and HOMA-IR following 3 months of therapy in 34 patients. On the other hand, Acitretin 35 mg daily resulted in an increased insulin and HOMA-IR after 1 month in another cohort of 10 patients. However, all values improved with no significance difference compared with baseline after 3 months of therapy. In comparison, we observed significantly higher FBG with acitretin ≤25 mg, while higher dose correlated with a lower FBS and better GTT. With usage of acitretin for >6 months duration, we noted HOMA-IR and FBS were lower, while GTT were almost comparable. Serum insulin and HOMA-IR values inversely correlated with duration of acitretin therapy.
Acitretin >25 mg consumption did not show significant differences in glucose levels at 60 and 120 min GTT despite a lower FBG. The initial response to a glucose meal involves pancreatic release of insulin which stimulates glucose uptake from blood. This results in reduction in blood sugar that occurs in both cases and controls, thus there is no difference in glucose level measured at 60 and 120 min GTT. Insulin stimulates the liver to convert glucose to glycogen by inducing hepatocyte glucokinase enzyme production during the second stage of the glucose metabolism. Retinoids acts synergistically with insulin in upregulating glucokinase through the activation of hepatic retinoic acid receptor (RAR) and retinoid X receptor (RXR). Glucokinase switches hepatic carbohydrate metabolism from fasting to fed state when blood glucose level is high, this cause further convertion of glucose to glycogen over the next few hours and results in blood glucose reduction 4 to 6 h from the last meal. Hence, a significantly lower fasting glucose was observed in our patients who were treated with higher doses of acitretin. Increased insulin sensitivity was demonstrated in 6 healthy volunteers who were subjected to intravenous GTT before and after an 8 days course of acitretin 50 mg daily.
Effect of acitretin on lipid levels
Psoriasis patients on acitretin demonstrated a significant increase in serum triglyceride compared with controls. Although increased, triglyceride levels remained within upper borders of normal limit. Acitretin is known to increase triglycerides, and serum lipids should be determined before and monitored few weeks after starting acitretin., RAR and RXR are involved in adipogenesis; however, the role of retinoids in inducing hypertrigliceridaemia is unclear. Triglyceride were significantly lower with acitretin at doses >25 mg and higher doses correlated significantly with lower triglyceride in our cohort. Longer duration of acitretin therapy showed lower triglyceride values as well albeit non-significant. These results are consistent with a previous study where 34 patients received acitretin 10 to 50 mg had a significant increase of triglyceride after 3 months of therapy although triglyceride values remained just above the upper limit of normal. A smaller cohort with 10 patients treated with acitretin 35 mg showed an increase in triglycerides but not significant at 1 and 3 months of therapy. Although increased, the serum triglyceride levels remain within normal range.
Relationship between psoriasis severity with insulin resistance, glucose metabolism, and lipid levels
Higher PASI correlated with lower fasting glucose in our patients on acitretin while patients on topical therapy showed higher insulin resistance with more severe psoriasis. Higher PASI associated with lower fasting glucose reflects the effect of acitretin in glucose metabolism as discussed earlier. Patients with more severe diseases were on higher doses of acitretin. Acitretin therapy may have additional systemic benefits in improving the metabolic syndrome which is commonly associated with psoriasis. Patients with severe psoriasis are more affected with metabolic syndrome compared with patients with mild disease as observed in our patients on topical therapy alone, where higher HOMA-IR were significantly correlated with more severe psoriasis.
Severe psoriasis significantly correlated with higher total cholesterol and LDL-cholesterol in both our cases and controls. Patients with psoriasis had a higher prevalence of dyslipidaemia as part of the metabolic syndrome., Acitretin increases triglyceride and LDL-cholesterol levels, therefore regular monitoring with lifestyle changes are advised for patients on acitretin therapy.
Interpretation of this study results is limited by its cross-sectional design as there is no longitudinal information on insulin resistance, glucose metabolism, and lipid levels. Causal inference cannot be made; however, our results showed a few aspects of acitretin therapy which directs further investigation.
| Conclusion|| |
Acitretin therapy resulted in higher triglyceride. The effect of acitretin on insulin resistance is possibly dependent on dose and duration of therapy. Higher doses maybe beneficial in improving insulin resistance and has a glucose reducing effect. Further research is required to confirm these observations. We recommend evaluating patients' comorbidities when considering acitretin therapy. Patients should have their serum glucose and lipids monitored before and during therapy.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Acitertin cause elevation of triglyceride level. Acitretin does not affect insulin resistance and glucose metabolism in general; however, higher doses maybe beneficial in improving insulin resistance and has a glucose reducing effect. Serum lipid and blood glucose monitoring is recommended during acitretin therapy.
The authors would like to thank Sister Thamil Selvi for her assistance in patient recruitment and data collection and all the participants of the study who were very patient and cooperative.
Financial support and sponsorship
This work was supported by a grant from the Dermatological Society of Malaysia.
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]
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