Insulin Resistance in children on Sodium Valproate – A hospital based cross-sectional study in Indian children

Abstract

Our objective was to compare the point prevalence of insulin resistance (IR) in children taking sodium valproate (VPA) and phenytoin sodium (PS) monotherapy for >1 year. 150 children, aged 6–18 years, were categorized (50 each) into - group A (VPA), group B (PS) and group C (healthy controls age-sex matched with group A). Groups were compared for metabolic complications and risk factors assessed. The point prevalence of IR and non-alcoholic fatty liver disease was significantly higher in children on VPA (12% and 34% respectively) than on PS and healthy controls, regardless of age, sex, pubertal and nutritional status. The presence of central obesity, acanthosis, hypertension, dyslipidaemia was significantly associated with IR but none showed an independent association on multivariate analysis. Therapy with VPA makes children susceptible to metabolic complications. Close monitoring will facilitate early detection and timely intervention.

Keywords

Endocrine Physiology General Health Asia Location

Introduction

Sodium valproate (VPA) and phenytoin sodium (PS) are commonly used antiepileptic drugs (AED) in the management of childhood epilepsy in view of their broad spectrum activity. Children with epilepsy are, however, vulnerable to a poor metabolic profile owing to their sedentary life style compounded by the adverse effect of various AED.^1,2 Despite VPA being well tolerated, there is evidence to suggest an association with metabolic complications such as weight gain and insulin resistance. However, the pathophysiology and exact mechanism of this association is poorly understood. Literature reviews on this subject across the world have yielded conflicting results.^3,4 The effect of the VPA on lipid profile has also been inconsistent in published studies,⁵ which have reported an association of prolonged use of VPA with non-alcoholic fatty liver disease (NAFLD), especially in obese adolescents.⁶

The metabolic side effects of AEDs are most often overlooked as these children may have other pressing issues such as epilepsy control, learning disability, behavioural problems, personality changes and hyperactivity. There is a growing epidemic of obesity and metabolic syndrome in Indian children with an estimated prevalence of 22%.^7,8 In this setting, it becomes imperative to assess the metabolic adverse effects associated with these drugs. Indian studies on this subject are scarce.^9–11 To address this gap, our study was conceived. Other clinical and biochemical parameters that increase the risk for metabolic complications in these children were also assessed.

Methods

Our cross-sectional study was conducted on children aged 6–18 years attending the pediatric epilepsy clinic and paediatric out-patients in a tertiary care hospital at New Delhi between November 2015 and March 2017. The subjects were categorised into three groups- Group A and B being children on VPA monotherapy and PS monotherapy for at least 1 year, respectively. Group C being healthy children age and sex matched with Group A who attended OPD for minor complaints. Children with chronic diseases (chronic liver disease, chronic kidney disease, preexisting neurometabolic conditions), concomitant endocrine disorders, diseases that required steroid therapy during the previous year and non-ambulatory patients were excluded. Assuming the prevalence of insulin resistance to be 20% in VPA group¹² and 0.8% in healthy children (based on 22% prevalence of insulin resistance in overweight/obese children⁸), power 80% and α = 0.05, the sample size was determined as 49 in each group.

A written informed consent was taken from all parents/caregivers and additionally, assent was taken from children (> 8 years) prior to enrolment in the study.The study was approved by our institutional ethics committee.

Information on age, sex, type of seizures, duration and dose of the antiepileptic therapy, and family history of hypertension, diabetes mellitus, dyslipidaemia was recorded from all participants. Clinical evaluation was performed in all enrolled subjects which included assessment of anthropometric parameters, waist circumference, blood pressure, tanner staging, presence/absence of hepatomegaly and acanthosis nigricans. Central obesity was defined as waist circumference ≥90^th centile for corresponding age and sex,¹³ and the centiles were based on Indian data.¹⁴ The cutoff of BMI for age at 23^rd adult equivalent (71^st centile in boys and 75^th in girls) and 27^th adult equivalent (90^th centile in boys and 95^th in girls) was applied to classify the subjects as overweight and obese respectively, according to IAP 2015 reference charts.¹⁵ Hypertension was defined as systolic or diastolic blood pressure ≥ 95^th centile for age, sex and height percentile in children < 13 years and > 130/80 for children ≥13 years folowing the 2017 AAP guidelines.¹⁶

After an overnight fast, blood samples were obtained from all participants to determine plasma glucose, serum insulin, total cholesterol, HDL cholesterol (HDL-C), LDL cholesterol (LDL-C), triglycerides and liver function test Ultrasonographic scan of the abdomen was performed to detect fatty liver changes. Fasting plasma glucose levels were interpreted following recommendations of the IAP National Task Force for Childhood Prevention of Adult diseases, 2004.¹⁷ Hyperinsulinaemia was defined as fasting insulin level >15 µU/mL for pre-pubertal children and > 30µU/mL for children in Tanner stage 2 and above of pubertal development.¹⁸ Homeostasis Assessment Model for Insulin Resistance (HOMA-IR) scores were derived for all the subjects as the product of the fasting plasma insulin level (µU/mL) and the fasting plasma glucose level (mmol/L), divided by 22.5. Insulin resistance was defined as HOMA-IR ≥ 3.16.¹⁹ dyslipidaemia was diagnosed in presence of derangements in one or more parameters of lipid profile including Total Cholesterol, LDL-C, Triglycerides, HDL-C as defined by the Expert panel on integrated guidelines for cardiovascular health risk reduction in children and adolescents, 2011.²⁰ Screening for NAFLD was based on values greater than specific upper limits of normal alanine transaminase (ALT) level (22 U/L for girls and 26 U/L for boys) and ultrasonographic evidence of fatty liver.²¹

The analysis was performed using statistical package for social sciences software version 16.0. Categorical data was described as numbers (n) and percentages and compared using Chi-square/ Fisher exact test Quantitative data was presented as mean (S.D) and compared across groups using Student t-test (un-paired). ANOVA test was applied to compare quantitative variables in the three groups. Simple logistic regression was applied to determine the predictors of insulin resistance and NAFLD in children on valproate therapy. The odds ratio (ORs) with 95% CI was calculated for the same. A p-value <0.05 were considered as significant. A multivariate logistic regression analysis was done to look for the determinants of insulin resistance and fatty liver in children on VPA.

Results

A total of 150 children were enrolled with 50 in each group A (VPA), group B (PS) and group C (control). The clinical characteristics of the study groups were similar (Table 1). The BMI z scores, prevalence of central obesity and hypertension were similar in the three groups. The proportion of children with acanthosis was higher in group A (8%) than group B (2%) and the control (4%). The most common diagnosis for children on VPA was primary/idiopathic generalised epilepsy while that for PS was neurocysticerosis. The mean fasting plasma glucose among the three groups was similar and none had impaired fasting glucose or diabetes. The prevalence of insulin resistance was significantly higher in Group A (12%) as compared to group B (2%) and none in the control group (Table 2). The prevalence of dyslipidaemia was 42%, 34% and 26% in group A, B and C respectively. The mean LDL cholesterol was higher in children in group A and group B as compared to the controls. The proportion of children with ultrasonographic evidence of NAFLD was higher in group A (34%) when compared with those in group B (10%) and control (8%) (Table 2).

Table 1.

Clinical characteristics of children in the 3 study groups.

	GROUP A (n = 50)	GROUP B (n = 50)	GROUP C (n = 50)	P value
Age (years) (Mean ± SD)	11.5 ± 3.36	11.24 ± 3.44	11.44 ± 3.19	0.945
Sex: males n (%)	29(58)	26(52)	29(58)	0.784
Pubertal Status				0.248
Pre- Pubertal n (%)	20 (40)	28 (56)	22 (44)
Pubertal n(%)	30 (60)	22 (44)	28 (56)
Age at onset anti-epileptic therapy (years) (Mean ± SD)	7.52 ± 3.93	8.15 ± 3.23	-	0.389
Duration of therapy (years) (Mean ± SD)	2.81 ± 1.76	2.47 ± 1.68	-	0.32
Dose of drug (mg/kg/day) (Mean ± SD)	21.88 ± 10.34	6.02 ± 1.03	-	-
BMI z score (Mean ± SD)	0.003 ± 1.06	−0.10 ± 0.7	−0.07 ± 0.68	0.74
BMI category
Overweight n(%)	5 (10)	2 (4)	2 (4)	0.101
Obese n(%)	2 (4)	0	0	0.155
Central obesity n(%)	4 (8)	1 (2)	2 (4)	0.35
Acanthosis Nigricans n(%)	4 (8)	1 (2)	2 (4)	0.125*
Hypertension n(%)	2 (4)	0	1 (2)	0.399
Clinical Hepatomegaly n(%)	4(8)	1 (2)	0	0.05^

Group A- Children on Sodium Valproate.

Group B – Children on phenytoin sodium.

Group C- Healthy children.

(*Between Group A and B, p = 0.042; ^Between Group A and C, p = 0.042).

Table 2.

Comparison of biochemical parameters related to glucose homeostasis, lipid profile and NAFLD among children in 3 groups.

	GROUP A (n = 50)	GROUP B (n = 50)	GROUP C (n = 50)	P value
Fasting plasma glucose (mmol/L) (Mean ± SD)	4.78 ± 0.43	4.87 ± 0.43	4.97 ± 0.37	0.064
Fasting Insulin Levels (μU/mL) (Mean ± SD)	7.17 ± 3.17	5.36 ± 2.70	4.06 ± 1.92	<0.001
Hyperinsulinaemia n (%)	1 (2)	0	0	0.37
HOMA- IR score (Mean ± SD)	1.56 ± 0.85	1.20 ± 0.68	0.92 ± 0.47	<0.001
Insulin Resistance n (%)	6 (12)	1 (2)	0	0.01^#
Total Cholesterol (mmol/L) (Mean ± SD)	3.39 ± 0.68	3.36 ± 0.65	3.04 ± 0.51	0.031*
Triglycerides (mmol/L) (Mean ± SD)	0.80 ± 0.23	0.76 ± 0.23	0.73 ± 0.15	0.304
HDL- C (mmol/L) (Mean ± SD)	1.05 ± 0.26	1.11 ± 0.23	1.11 ± 0,16	0.316
LDL- C (mmol/L) (Mean ± SD)	1.94 ± 0.65	1.92 ± 0.62	1.59 ± 0.40	0.006^
Dyslipidaemia n (%)	21(42)	17(34)	13(26)	0.33
ALT level ((Mean ± SD) (U/L), Elevated ALT n(%)	20.78 ± 9.09, 14(28)	21.66 ± 7.72, 6(12)	23.66 ± 8.85, 3(6)	0.228, 0.007
Radiological fatty liver n (%)	17(34)	5(10)	4(8)	<0.001

# Between Group A and B, p = 0.051; and Group A and C, p = 0.012.

*p value between group B and C was 0.0291.

^p value between group A and C was 0.008 and group B and C was 0.027.

There was no difference in age, sex, pubertal status, dose and duration of VPA among children with and without insulin resistance in group A. However, concomitant central obesity, overweight, hypertension, fasting Hyperinsulinaemia, dyslipidaemia, elevated ALT and fatty liver on USG were significantly associated with higher odds of developing insulin resistance (Table 3). The occurrence of fatty liver in children on VPA was significantly associated with overweight, central obesity, acanthosis, hypertension, insulin resistance, dyslipidaemia, and elevated ALT (Table 4). However, the variables identified statistically significant on univariate analysis were not found to be independently associated with insulin resistance or fatty liver on performing multivariate logistic regression.

Table 3.

Determinants of insulin resistance in children on VPA monotherapy.

	Subjects with IR (n = 6)	Subjects without IR (n = 44)	p-value	Odds Ratio [95%CI]
Age (years) (Mean ± SD)	9.67 ± 2.94	11.75 ± 3.40	0.161
Sex (n% males)	2 (33.3)	27 (61.4)	0.193	-
Pubertal status
Pre-Pubertal n (%)	3 (50)	17 (38.6)	0.456	1.59 [0.29–8.79]
Pubertal n (%)	3 (50)	27 (61.6)
Dose of drug (mg/kg/day) (Mean ± SD)	17.50	22.48	0.278	-
Duration of VPA monotherapy (years) (Mean ± SD)	1.42 ± 0.38	3.01 ± 1.83	0.04*	-
Central obesity n (%)	3 (50)	1 (2.3)	0.004*	43 [3.36–549.35]
BMI category
Overweight + Obese n (%)	4 (66.7)	3 (6.8)	<0.001*	27.3 [3.47–215.06]
Acanthosis nigricans n (%)	3 (50)	1 (2.3)	0.004*	43 [3.36–549.35]
Prehypertension + Hypertension n (%)	3 (50)	0	<0.001*	-
Fasting plasma glucose (mmol/L) (Mean ± SD)	5.17 + 0.27	4.73 + 0.31	0.018*	-
Fasting Insulin (μU/mL) (Mean ± SD)	14.63 ± 2.36	6.15 ± 2.55	<0.001*	-
dyslipidaemia n (%)	5 (83.3)	16 (36.4)	0.030*	8.75 [0.95–81.63]
Deranged Liver Enzymes n (%)	5 (83.3)	9 (20.5)	0.005*	19.44 [2.01–187.44]
Fatty Liver n (%)	6 (100)	11(25)	0.0003*	-

*p value <0.05 – significant.

CI – Confidence intervals.

IR- Insulin resistance.

Table 4.

Determinants of non-alcoholic fatty liver disease in children on VPA monotherapy.

	Subjects with Fatty Liver (n = 17)	Subjects without fatty liver (n = 33)	P value	Odds Ratio[95%CI]
Age in years(Mean ± SD)	10.82 ± 3.23	11.85 ± 3.47	0.317	-
Sex n(%) males	9 (52.9)	20 (60.6)	0.412	-
Pubertal status
Pre-Pubertal n(%)	7 (41.2)	13 (39.4)	0.57	1.08 [0.33–3.55]
pubertal/ post pubertal n(%)	10 (58.8)	20 (60.6)
Dose of drug in mg/kg/day (Mean ± SD)	18.65 ± 9.04	23.55 ± 10.86	0.117	-
Duration of VPA monotherapy in years (Mean ± SD)	2.44 ± 1.30	3.01 ± 1.99	0.317	-
Central obesity n(%)	4 (23.5)	0	0.01*	-
BMI category
Overweight + Obese n(%)	5 (29.4)	2 (6.1)	0.026*	6.46 [1.1–37.92]
Acanthosis nigricans n(%)	4 (23.5)	0	0.01*	-
Pre-hypertension and Hypertension n (%)	3 (17.7)	0	0.013*	-
Fasting plasma glucose (mmol/L) (Mean ± SD)	4.89 ± 0.53	4.72 ± 0.37	0.197	-
Fasting Insulin (μU/mL) (Mean ± SD)	9.73 ± 4.92	5.85 ± 2.02	<0.001*	-
Hyperinsulinaemia n (%)	1 (5.9)	0	0.164	-
HOMA-IR score (Mean ± SD)	2.15 ± 1.10	1.25 ± 0.48	<0.001*	-
Insulin resistance n (%)	6 (35.3)	0	<0.001*	-
dyslipidaemia n (%)	11 (64.7)	10 (30.3)	0.020*	4.22 [1.22–14.59]
Deranged liver enzymes n (%)	10 (58.8)	4 (12.1)	0.001*	10.36 [2.5–42.99]

*p value <0.05 – significant.

CI – Confidence intervals.

Discussion

Weight gain in patients on valproate is a common reported side effect (10–70%) across multiple studies.^{2, 22} The mechanism of weight gain is still not clear and may be attributed to increased long chain fatty acid, high insulin levels, dysregulation of adipocytokines and leptin.²³ High insulin concentrations activate lipogenesis. However, we did not find significant difference in BMI z scores, prevalence of overweight/obesity and central obesity between children on VPA and PS. Similar observations have also been reported in studies comparing VPA and other antiepileptics in children and adults from India and elsewhere.^9,24 The lack of consistent relationship between VPA and weight gain in published studies may be because of a heterogeneity of the study subjects with respect to socio-economic strata, cultures, physical activity levels, duration of AED therapy and, most importantly food habits.

The prevalence of insulin resistance (measured by fasting Hyperinsulinaemia and HOMA IR score) observed in children on VPA therapy was higher as compared to controls in this study. This finding is consistent with other published studies across the world.^1,2 Higher insulin resistance in children on VPA was observed despite similar BMI status of children in the three groups and with no relation with dose and duration of therapy. The mechanisms proposed are interference with insulin metabolism in the liver resulting in Hyperinsulinaemia and down regulation of insulin receptors.²⁴ Normal fasting blood glucose levels in the presence of insulin resistance in our study favours the former mechanism. Other hypotheses for insulin resistance are increased plasma levels of free fatty acids (FFA), beta-cell dysfunction as a consequence of the oxidative stress and intrahepatic fat accumulation.²⁵ Although Hyperinsulinaemia and insulin resistance is often found in association with VPA induced adiposity,^1,2,26 a few studies have also reported this in non-obese subjects on VPA therapy.^4,27 The prevalence of dyslipidaemia reported in our study was similar in children on VPA and PS as compared to healthy controls, in accord with a systematic review on lipid profile derangements,²⁸ although a few studies have failed to show such abnormalities.^9,10 Hence the effect of antiepileptics on lipid profile remains unclear and would require further prospective data to draw meaningful inferences. We found increased evidence of fatty liver in VPA group in comparison to controls (group B and C) and this observation is consistent with studies published in children as well as adults.^6,29,30 The proposed mechanisms of fatty liver in patients on VPA are due to the direct effect of its metabolites on the liver parenchyma and /or secondary to VPA induced weight gain and insulin resistance.²⁹ The association of fatty liver in children on VPA monotherapy with overweight/obseity, central obesity, hypertension, insulin resistance and dyslipidaemia reported here is well supported by published literature.^6,30 The comparable anthropometric profile of children in the three groups and the lack of independent association of overweight/obesity with insulin resistance and fatty liver in children on VPA imply that the weight gain and adiposity alone are not responsible for these adverse effects. Further, large scale well designed prospective studies are needed for drawing firm conclusions.

The strength of our study is that it has assessed prevalence of insulin resistance and NAFLD in children receiving two commonly used broad spectrum antiepileptics (VPA and PS) and compared it with age and sex matched healthy children, where metabolic syndrome is an increasingly recognised problem. The main limitation of the study was its cross-sectional design that precluded us from drawing a causal relationship between insulin resistance and the risk factors. The unavailability of the baseline clinical, anthropometry and biochemical parameters was also perceived as a limitation to draw conclusions. Assessment of dietary habits and physical activity was furthermore not done in this study. Further, assessment of fatty liver was measured by ultrasound as against liver biopsy, which is the gold standard. Our study nonetheless highlights the need for a screening programme and lifestyle interventions in children on VPA therapy to prevent development of metabolic complications that could persist in adulthood.

Footnotes

Disclaimers

None,

Ethical clearance

Cleared by the Institutional Ethics Committee, Lady Hardinge Medical College on 30.10.2015, no. LHMC/ECHR/2015/52

Clinical trial registration no

Not applicable,

Details of contribution of each author

LJG: reviewed literature, collected and analysed the data, helped in drafting the manuscript; PS: drafted and finalized the manuscript; SA: helped in study design and supervised the collection of data; SRS: supervised the radiological investigations; RS: supervised the laboratory work; AS: conceived and designed the study, provided critical inputs in preparation and finalizing the manuscript.

All authors approved the final version of the manuscript, and are accountable for all aspects related to the study.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Preeti Singh

Anju Seth

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