A Meta-analysis About The Effects Of Levothyroxine On Blood Lipids In Patients With Subclinical Hypothyroidism

Purpose:Subclinical Hypothroidism(SCH)is a common endocrine disease.The prevalence of SCH is between 4%and 10%in the general population.According to the elevated levels of serum thyroid-stimulating hormone(TSH),subclinical hypothyroidism can be divided into two categories:mild SCH(4.0～10.0 m IU/L)and more severe SCH(>10 m IU/L).Studies have shown that SCH is associated with dyslipidemia,suggesting that SCH may be an independent risk factor for cardiovascular disease.However,the effect of levothyroxine(LT4)replacement therapy on dyslipidemia is still controversial.Therefore,we conducted this meta-analysis in order to use updated research data to more comprehensively evaluate the lipid modulations of levothyroxine replacement therapy in patients with SCH,so as to provide reference for clinical practice.Methods:A comprehensive search was performed on the electronic databases PubMed,Cochrane Library,Dutch Medical Abstracts Database(Embase),China National Knowledge Infrastructure(CNKI),Wanfang Academic Database,China Biology Medicine(CBM).Literatures on the effects of levothyroxine replacement therapy on blood lipids in patients with SCH were retrieved as of 7 January,2020.Two researchers independently conducted literature screening based on inclusion and exclusion criteria.All included studies were randomized controlled trials,and the control group was set as placebo group or blank control group.The Cochrane bias risk assessment tool was used to evaluate the quality of the included literatures.Stata/SE 12.0 software was used for statistical analysis.According to the results of the heterogeneity test,random effect models(P≤0.1 or I~2>50%)or fixed effect models were used(P>0.1 and I~2≤50%)to calculate the combined effect size.The statistical results of the meta-analysis were represented by the Forest plot,and the combined effect size was SMD(Standardized Mean Difference).Subgroup analysis,sensitivity analysis,and meta-regression were used to explore the likely sources of heterogeneity,and the Funnel plot and Egger’s test were used to detect publication bias.The main outcome indicators were serum total cholesterol(TC),low density lipoprotein(LDL),high density lipoprotein(HDL),and triglyceride(TG).Results:A total of 21 studies,1739 participants were included,and all SCH patients were over 15 years old.Among them,there were 6 Chinese literatures and 15 English literatures.The overall quality assessment of the included literatures was moderate.The results showed that levothyroxine replacement therapy led to significant reductions of TC,LDL,and TG in patients with SCH.SMD and its 95%confidence interval were:-0.554(-0.764,-0.345),-0.554(-0.775,-0.334),-0.388(-0.589,-0.188),separately,P<0.05 for all of them,the heterogeneity test results were:I~2=73.1%,73.6%,68.4%,severally.The results of the subgroup analysis indicated that replacement therapy was equally effective for patients with mild SCH,and the difference in different regions might be the source of heterogeneity.Compared with foreign studies,the effects of LT4replacement therapy were more significantly on reducing TC and TG in the Chinese study subgroup(P values were 0.023 and 0.041,respectively).For LDL,the Chinese study subgroup also showed a stronger reduction trend,but it had no statistical significance(P=0.079).For HDL,although the overall SMD was-0.225(P=0.045),the further results of subgroup analysis and sensitivity analysis entirely showed that the statistical results were not robust,so it was hardly to conduct that LT4 replacement therapy of SCH patients had an effect on HDL.Conclusions:Our study results suggest that levothyroxine replacement therapy can reduce TC,LDL,and TG levels in patients with SCH,even in those with mild SCH.This result provides a basis for the application of L-T4 to improve the abnormal increase of TC,LDL,and TG levels in patients with SCH,and the improvements of blood lipids are likely to have cardiovascular benefits.However,due to the large heterogeneity of the included studies,more large rigorously designed high-quality randomized controlled trials are needed to verify this result,and further explore the clinical value and best options of replacement therapy for SCH patients.