| Background:Hypothyroidism is one of the most common endocrine disorders with low metabolic syndrome as the main manifestation.Depending on the severity of the disease,hypothyroidism is classified into overt hypothyroidism and subclinical hypothyroidism(SCH).SCH is an early manifestation of thyroid underactivity,which is characterized by elevated serum thyroid-stimulating hormone(TSH)levels,whereas serum-free thyroxine(FT4)levels within the normal range.According to the extent of elevation of TSH,SCH can be further defined as significant SCH(TSH ≥ 10.0 mIU/L)and mild SCH(TSH<10.0 mIU/L).Recent years,with the introduction of a hypersensitive assay method of TSH and FT4,the prevalence of SCH is progressively increasing.The worldwide prevalence of SCH was estimated ranging from 4%to 10%.In women over the age of 60,the prevalence of SCH is high to 20%.Previous studies have demonstrated that SCH can cause cardiac dysfunction,and is an independent risk factor for ischemic heart disease.In addition,about 2%-5%of SCH patients might progress to overt hypothyroidism.Therefore,prevention and treatment of SCH is an important task faced by endocrinologists.Levothyroxine(LT4)is the recommended medication for the treatment of SCH.However,the questions about whether SCH need positive LT4 supplement,as well as the target for treatment,have gone through a long period of argument.The most recent Clinical Practice Guidelines for Hypothyroidism in Adults(2012,Cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association)recommended that significant SCH patients should be given thyroid hormone replacement therapy.Although the majority of SCH patients are categorized as mild SCH,there were no clearly defined therapeutic recommendations due to the limited evidence from prospective,interventional studies.At the same time,this guideline stated out the issue that whether or not SCH patients could get cardiac benefit from LT4 treatment should be involved in the areas of future research.As we all know,hypercholesterolemia is an important risk factor for the occurrence and development of cardiovascular diseases.Lowering serum cholesterol levels can effectively reduce the morbidity and mortality of cardiovascular disease.Recent years,SCH has been shown to be associated with hypercholesterolemia.Our previous clinical study also found that serum TSH level was positively correlated with serum cholesterol levels,even after adjusted for other confounding factors.Moreover,hypercholesterolemia might be one of the important intermediate links for increased risk of cardiovascular disease induced by SCH.Therefore,when discussing the question of whether LT4 supplementation can bring cardiac benefit to patients with SCH,it should be clear first whether LT4 supplementation can improve serum cholesterol levels in SCH patients.There have been interventional studies explored this issue,but no consensus has been reached.Moreover,due to the small sample size,these studies failed to perform subgroup analyses in patients with different TSH or lipid levels,and could not answer the question that whether the effect of LT4 supplementation on serum cholesterol levels varied in patients with different basal serum TSH or cholesterol levels.The relatively small sample size and inconsistent conclusions may be the reason that why these studies did not provide enough strong evidence to guide clinical practice.Therefore,a large-sample,randomized,controlled trial was still necessary.In recent years,the relationship between SCH and non-alcoholic fatty liver disease(NAFLD)has attracted more and more attention.Both cross-sectional and prospective case-control studies have suggested that SCH is an independent risk factor for NAFLD.Our previous study also found that TSH can regulate hepatic triglycerides metabolism by affecting the expression of triglyceride de novo synthesis genes.Then,does the treatment of SCH patients to normalize elevated serum TSH levels via appropriate LT4 supplementation yield any benefits on NAFLD?No interventional study focusing on this issue is currently available.Objectives:We conducted a standardized clinical randomized controlled trial to observe the effect of LT4 supplementation on serum cholesterol levels in SCH patients.We further did a post hoc analysis of this randomized controlled trial to explore the effect of LT4 supplementation on NAFLD in SCH patients.The purpose of this study was to explore whether the LT4 supplementation therapy can bring lipid metabolism-related benefits to SCH patients from the above two perspectives,and thus to provide a reference for the management of SCH.Methods:1.Study Design and ParticipantsThis study was based on an open-label,randomized,controlled trial.37 significant and 378 mild SCH patients recruited from Ningyang County,Shandong Province were enrolled in the trial.The trial was registered at ClinicalTrials.gov(NCT01848171).2.RandomizationAccording to the guideline for hypothyroidism cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association,significant SCH patients were all treated with LT4(Euthyrox,50 μg per tablet,Merck Serono,Darmstadt,Germany).Mild SCH patients were randomized in a 1.5:1 fashion to LT4 supplement therapy or no treatment.3.Study endpointsIn the Part Ⅰ,we focused on the effect of LT4 supplement therapy on serum cholesterol levels through this randomized controlled trial.The primary outcome measure was the change in serum TC concentration;secondary outcome measures were other cholesterol indices,including changes in LDL and high-density lipoprotein cholesterol(HDL)levels during follow-up.In the Part Ⅱ,we explored the effect of LT4 supplement therapy on NAFLD in patients with SCH.The primary outcome was the prevalence of NAFLD.Secondary outcome were changes in serum alanine aminotransferase(ALT)and aspartate aminotransferase(AST)levels.4.Data CollectionBlood samples were drawn after an overnight fast for at least 10 hours.Chemiluminescent methods(Cobas E601;Roche)were used to quantitate thyroid function based FT3,FT4,and TSH levels.The serum lipid profile was determined using the ARCHITECT ci16200 Integrated System(Abbott).Non-HDL was calculated by subtracting HDL from total cholesterol.The intraassay and interassay coefficients of variation were always below 5%for all of the above parameters.Liver ultrasound was performed to assist the diagnosis of NAFLD.5.Statistical analysisQuantitative data are expressed as the mean 士 standard deviation or median(interquartile range)according to their distributions,and categorical data are presented as a number(percentage).Comparisons of variables among the groups were performed using one-way AN OVA,independent Student’s t-test.or the Mann-Whitney U test.A paired-samples t-test or Wilcoxon paired rank test was used for within-group comparisons(baseline and end-of-study variables in each group).Differences in categorical data were evaluated by chi-squared test.All statistical analyses were performed using SPSS version 22.0 for Windows(Chicago,IL,USA).Results:1-1 LT4 supplementation reduces serum TC and LDL levels in patients with SCHAfter LT4 treatment,significant SCH patients experienced significant decrease in serum TC(P = 0.004)and LDL(P = 0.016)levels.In addition,patients in mild SCH-LT4 group experienced a larger extent of reduction serum TC than that in the control group(P = 0.003).However,for serum LDL levels,Serum LDL decreased in mild SCH-LT4 group(P = 0.023),but was quite stable in the control group(P = 0.072).1-2 Effect of LT4 supplement on serum TC level was similar in mild SCH patients,regardless of the baseline TSH levelWhen stratify mild SCH patients according to TSH levels into three subgroups(i.e.,4.2 mIU/L≤TSH<5 mIU/L,5 mIU/L ≤ TSH<7 mIU/L,7 mIU/L≤ TSH<10 mIU/L)little change in serum TC level was observed in the control group.However,after the LT4 supplementation,serum TC levels decreased by 0.41 mmol/L,0.41 mmol/L,and 0.42 mmol/L(all P<0.001),respectively,in the three intervention subgroups defined above.In the 5 mlU/L≤TSH<7 mlU/L group,serum LDL also significantly decreased in the intervention subgroup(P = 0.033).1-3 The effect of LT4 supplement therapy on LDL was more pronounced in mild SCH patients with elevated basal LDLIn mild SCH patients with normal basal LDL(LDL<4.1 mmol/L),there were no significant changes in serum LDL levels during the study both in the intervention subgroup and in the control group.In mild SCH patients with elevated basal LDL level(LDL>4.1 mmol/L),serum LDL significantly decreased 4.55 ± 0.46 mmol/L to 4.07 ± 0.82 mmol/L(P<0.001)in the intervention group,while did not change significantly in the control group(P = 0.075).Regardless of the basal serum LDL level,serum TC decreased significantly in the two intervention subgroups defined above,while there was no significant change in the control group.2-1 In significant SCH patients,LT4 supplementation may ameliorate NAFLDIn the significant SCH group,the prevalence of NAFLD was reduced from 48.5%to 24.2%(P = 0.041)during the course of the study.Meanwhile,significant SCH patients experienced a decrease of 5.61 IU/L in serum AST(P<0.001)and a moderate but not statistically significant decrease in serum ALT-2-2 In mild SCH patients,LT4 supplementation could not ameliorate NAFLDIn mild SCH patients,there was no significant change in the prevalence of NAFLD in both the mild SCH-LT4 group and the mild SCH-Control group(P>0.05 for both).Patients in the mild SCH=LT4 group showed a marginally significant reduction in serum ALT from 19.09 IU/L to 17.95 IU/L(P,= 0.087),whereas serum ALT in the mild SCH-Control group was quite stable in the study.2-3 In mild SCH patients combined with dyslipidemia,LT4 supplementation might ameliorate NAFLDMild SCH patients with dyslipidemia who received LT4 treatment experienced decreases in the prevalence of NAFLD and serum ALT levels(P<0.05 for both).In contrast,these parameters remained comparably stable in patients who were not treated.Conclusion:1.LT4 supplementation reduces serum TC and LDL levels in patients with SCH2.Effect of LT4 supplementation on serum cholesterol level was similar in mild SCH patients,regardless of the baseline TSH or LDL level3.LT4 supplement therapy improves NAFLD in significant SCH patients,as well as in mild SCH patients combined with dyslipidemia.Background:With the rapid development in economy and changes in lifestyle,diabetes mellitus has become the third largest chronic non-communicable disease,seriously threatening humans’health.According to the data provided by the International Diabetes Federation(IDF),in 2017,there were 425 million people worldwide suffering from diabetes.Meanwhile,health-related expenditures due to diabetes were 723 billion dollars.In face of the unprecedented growth in the number of people with diabetes worldwide,preventing the onset of diabetes is indispensable in disposing the burden of diabetes.It has been well established that traditional cholesterol indexes,including higher low-density lipoprotein cholesterol(LDL)and lower high-density lipoprotein cholesterol(HDL)are important risk factors for diabetes.Recent years,non-high-density lipoprotein cholesterol(non-HDL)has been proved to be a more potent predictor of cardiovascular disease incidence than LDL:A prospective cohort study in 746 patients with type 2 diabetes showed that non-HDL is an independent risk factor for incident cardiovascular disease.In addition,a case-control study reported that for young people under the age of 36,non-HDL was the strongest indicator of myocardial infarction compared with other traditional risk factors.The 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults:A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines recommended non-HDL as the secondary monitoring target in the management of atherosclerotic cardiovascular disease risk.However,the performance of non-HDL in predicting incident diabetes,especially in comparison with routine cholesterol panels,has not been well documented.A prospective study conducted in 540 diabetes-free participants reported that non-HDL was a superior independent risk factor for type 2 diabetes than LDL or HDL in Aboriginal Canadians.Subsequently,a retrospective study further validated the superior role of non-HDL in predicting diabetes in people with normal glucose tolerance(NGT).On the contrary,there is also study that observed no solid association between non-HDL and development of diabetes.It can be seen that there are still deficiencies in the current researches about the relationship between non-HDL and diabetes.First of all,some of the studies did not clearly distinguish the basal glycemic status of the selected participants,that is either subjects with normal glucose tolerance(NGT)or pre-diabetic were involved,which might affect the results of the studies.On the other hand,for clinical practice and health promotion strategies,accurate estimate of cut-off of non-HDL to discriminate incident diabetes is necessary.What’s more,to direct precise preventive strategies,it is important to develop cut-offs according to the identification of similar risk levels across population.To the best of our knowledge,there is no longitudinal study available that estimated the threshold of non-HDL in predicting diabetes.Therefore,we conducted this prospective cohort study in people with NGT to explore the relationship between serum cholesterol indexes and incident diabetes,and to estimate the cut-offs of cholesterol parameters for discriminating incident diabetes in people with NGT.Objectives:The objective of this prospective study was to analyze the association between non-HDL and development of diabetes in comparison with traditional cholesterol indexes,and to estimate the cut-offs of cholesterol parameters for discriminating incident diabetes in people with NGT.Methods:1.Study Design and ParticipantsThe present article reports on the data from the Risk Evaluation of cAncers in Chinese diabeTic Individuals:a lONgitudinal(REACTION)study,which was a prospective observational cohort study and enrolled 259,657 Chinese(≥ 40 years of age)from 25 communities in mainland China between 2011 and 2012,with follow-up measurements planned 3,5 and 10 years later.In this study,baseline data were obtained from 7,068 residents of Ningyang County,Shandong Province.After exclusion,3,653 individuals with NGT were eligible for this study.At the 3-year follow-up evaluation conducted in 2014-2015,43 participants died and 443 lost to the follow-up,representing 1,025 men and 1,805 women remained in the present analysis.2.Data CollectionBlood samples were drawn after an overnight fast for at least 10 hours.Fasting total cholesterol(TC),LDL,HDL and triglyceride were measured using an auto-analyzer(ARCHITECT c16000 System,Abbott Laboratories,IL,USA).Non-HDL was calculated by subtracting HDL from TC.Participants without a known history of diabetes underwent the oral glucose tolerance test(OGTT),and plasma glucose was measured at 0 hours(FPG)and 2 hours(2hPG)by the glucose oxidase method.3.Definition of glycemic statusGlycemic status was evaluated by standardized OGTT and was defined based on the World Health Organization(WHO)1999 criteria:NGT,FPG<6.1 mmol/L and 2hPG<7.8 mmol/L;diabetes,FPG>7.0 mmol/L and/or 2hPG ≥11.1 mmol/L;pre-diabetes was defined as meeting either of the following two criteria:a)6.1 mmol/L≤ FPG<7.0 mmol/L and 2hPG<11.lmmol/L;b)FPG<7.0 mmol/L and 7.8 mmol/L:≤ 2hPG<11.1 mmol/L.4.Statistical analysisSPSS version 22.0 for Windows(Chicago,IL,USA)was used for statistical analyses.Multivariate Logistic regression analysis was used to estimate the odds ratios(ORs)and 95%confidence intervals(Cls)of incident diabetes according to different serum cholesterol levels.To compare the effect size of each cholesterol indexes on the development of diabetes,ORs per one SD increase in the cholesterol variables were calculated using univariate and multivariate Logistic regression analysis respectively.Receiver operating characteristic(ROC)analysis was used to compare the ability of each cholesterol index in discriminating incident diabetes.The optimal cut-off values were identified as the point at which the value of"sensitivity + specificity-1"(Youden index)was maximum.Results:1.In women,the risk of diabetes gradually increases along with increasing in TC,LDL,and non-HDL levelsThe study population was divided into 4 groups according to the quartiles of different serum cholesterol indexes.In women,incidence rate of diabetes increased significantly as the TC(from Quartile 1 to Quartile 4:3.5%,4.3%,5.9%,7.7%),,LDL(from Quartile 1 to Quartile 4:2.5%,5.3%,6.4%,7.3%),and non-HDL(from Quartile 1 to Quartile 4:3.2%,4.1%,5.7%,8.4%)increased from the first to the forth quartile.In the multivariable-adjusted model,compared with the lowest quartile,ORs of future diabetes for the higher quartiles were higher with a trend of dose-response relationship for serum TC,LDL,and non-HDL.The multivariable-adjusted ORs of incident diabetes in the highest quartile non-HDL were 2.39(95%CI,1.22-4.68;P = 0.011),higher than that of either TC(OR = 1.97;95%CI,1.04-3.76;P = 0.039)or LDL(OR = 2.32;95%CI,1.12-4.72;P = 0.012).In men,none of these four cholesterol indexes had significant linear relationship with development of diabetes.2.Non-HDL has a greater impact on the incident of diabetes than TC and LDLIn women,a one SD increment in serum non-HDL was associated with a 1.43(95%CI,1.14-1.79;P = 0.(002)fold higher risk of diabetes,while ORs for TC and LDL were 1.33(95%CI,1.06-1.67;P = 0.015)and 1.30(95%CI,1.04-1.64;P= 0.024),respectively.3.The cut-off of non-HDL for discriminating incident diabetes in people with NGTIn all female subjects,the cut-off for non-HDL with better properties for screening of incident diabetes was identified as 3.48 mmol/L(sensitivity 0.65,specificity 0.58).The discriminatory power and the optimal cut-off values of non-HDL for incident diabetes increased across BMI categories:in women with overweight(24 kg/m2<BMI<28 kg/m2)and obesity(BMI>28 kg/m2),the appropriate cut-offs of non-HDL for screening of diabetes were estimated as 3.39 mmo/L(sensitivity 0.73,specificity 0.51)and 3.51 mmo/L(sensitivity 0.83.The specificity is 0.50),respectively.Conclusion:1.Non-HDL associated with development of diabetes independent of age,BMI,blood pressure,FPG,family history of diabetes and lifestyle in women,but not in men.2.Compared with traditional cholesterol parameters,non-HDL highlighted higher risk for new-onset diabetes.3.The discriminatory power and the optimal cut-off values of non-HDL in predicting diabetes increased across BMI categories... |
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