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Association between subclinical hypothyroidism and metabolic
cardiovascular disease risk factors in type 2 diabetic patients
Abstract
Objective The purpose of this study was to investigate the relationship
between subclinical hypothyroidism (SCH) and metabolic cardiovascular
disease risk factors at different levels of TSH in type 2 diabetic
patients.
Methods A cross-sectional survey of 937 patients who admitted to Wuhan
Central Hospital for treatment of type 2 diabetes was conducted. Blood
samples were collected to test total cholesterol(TC), LDL cholesterol
(LDL-C), high-density lipoprotein cholesterol(HDL-C) , triglyceride(TG),
glucose (Glu),Hemoglobin A1c (HbA1c),fasting plasma insulin, thyroid
-stimulating hormone(TSH),and free thyroxine(FT4).
Results The LDL-C level and HOMA-IR were significantly higher in the SCH
group. Serum LDL-C and TG were significantly higher, while HDL-C was
significantly lower in subjects with SCH-2 compared with the euthyroid
group. In total population TSH was positively correlated with
LDL-C(r=0.031;p= 0.012), TG (r=0.025; p=0.019) , HOMA-IR (r=0.017;
p=0.027);and negatively correlated with HDL-C (r=-0.037, p=0.028).FT4
was negatively correlated with LDL-C (r=-0.019, p=0.039). After adjusting
potential confounding factors, such as age, gender, HbA1c, BMI,duration
of diabetes, SCH remained significantly associated with LDL (OR:1.69,
95%CI: 1.04-2.34, P=0.03) and HOMA-IR (OR:1.47, 95%CI:1.10 -2.36,
P=0.02).
Conclusion There appears to be a significantly increase in dyslipidemia
and insulin resistance among type 2 diabetic patients with SCH.
Keywords subclinical hypothyroidism· type 2 diabetes mellitus· insulin
resistance· cardiovascular disease risk factors
Introduction
Subclinical hypothyroidism(SCH), defined as an increased serum TSH level
in normal free peripheral thyroid hormone concentrations, is relatively
common, occurring in 4-20% of the adult population[1-2].SCH has been
reported to be associated with an obvious increase in cardiovascular event
rates[3-4]. In a meta-analysis of individual participant data from 11
prospective cohort studies, SCH was associated with an increased risk of
coronary heart disease events and mortality [5].
Patients with type 2 diabetes mellitus are at an increased risk of
thyroid disease. Report documented a higher than normal prevalence of SCH
in the diabetic population. The association between type 2 diabetes and
1
SCH is well recognized. SCH could negatively impact diabetes and its
complications. Yasuda et al found SCH is independently associated with
albuminuria in people with type 2 diabetes[6]. Yang et al. demonstrated
that diabetic patients with SCH have more severe retinopathy than
euthyroid patients [7].Furthermore an increased risk of cardiovascular
disease was shown in type 2 diabetic patients with SCH[8].
SCH may impair metabolic control and add to cardiovascular disease risk
in type 2 diabetic patients. Metabolic cardiovascular disease (CVD) risk
factors have been intensively investigated in people with SCH,
particularly lipid profile. Several studies have found that individuals
with SCH have higher TC and LDL-C levels than euthyroid subjects [9], but
other studies did not confirm the association [10-11].However，little is known
of the relationship of SCH and metabolic cardiovascular disease risk
factors among type 2 diabetic patients. Therefore, this cross-sectional
study was conducted to explore the possible relationship between SCH and
metabolic cardiovascular disease risk factors at different levels of TSH
in Chinese type 2 diabetic patients.
Subjects and methods
Subjects
A total of 937 patients who admitted to Wuhan Central Hospital, Tongji
Medical College, Huazhong University of Science and Technology,
Wuhan,Hubei, China for treatment of type 2 diabetes from March 12, 2010
to August 24 ,2011 were screened for thyroid function. Individual with
overt hypothyroidism, overt or subclinical hyperthyroidism, or who were
taking thyroid function hormones were excluded. Furthermore patients with
type 1 diabetes mellitus, suffering from hepatic dysfunction, acute
illness, malignancy, pregnancy were also excluded. After excluding 241
individuals, 696 patients were included in the study. Those with normal
free triiodothyronine(FT3) ,free thyroxine(FT4),and an increased TSH (≥
4.8 mIU/L) level were diagnosed with SCH. We divided type 2 diabetic
patients into euthyroidism group and SCH group. SCH group was further
divided into two groups: group SCH-1 (TSH 4.5 to 10.0 mU/L, group SCH-2
(TSH≥10.0mU/L). The present study was approved by the Ethics Committee
of Wuhan Central Hospital.
Clinical examination and laboratory methods
Information concerning age, the duration of diabetes, and previous
history of hypertension was obtained from the patients’ medical records.
Current and past smokers were both categorized as smokers. Body mass index
(BMI) was measured as weight divided by height squared. Blood pressure
2
was measured in the sitting position after 10 minutes of rest.
Hypertension was defined as a systolic blood pressure ≥ 140mmHg or
diastolic blood pressure ≥90mmHg or taking antihypertensive medications.
Serum total cholesterol, LDL cholesterol, high-density lipoprotein (HDL)
cholesterol , triglyceride, glucose were measured by an automatic
biochemical analyzer (Roche Diagnostics, Manheim, Germany) . Hemoglobin
(Hb) A1c was measured by HPLC using an automated analyzer (Bio-Rad,
Hercules, CA, USA) .thyroid function was measured using a
chemiluminescence immunoassay system(Roche Diagnostics GmbH, Manheim,
Germany).Fasting plasma insulin(Bio-Rad, Hercules, CA, USA) were
measured by immunoradiometric assay. The homeostasis model assessment
index for insulin resistance(HOMA-IR) was calculated using the formula:
HOMA-IR =fasting plasma insulin ( μ U/ml) × fasting plasma glucose
(mmol/L)/22.5.
Statistical analysis
Statistical analyses were performed by the SPSS 13.0 software package
(SPSS, Inc., Chicago, IL).Continuous variables were expressed as mean ±
standard deviation. The variables which did not have normal distribution
were log-transformed prior to statistical analysis. Unpaired Student’s
t- tests were used to compare between-group differences. The chi-squared
test was used to compare frequencies. The relationships between variables
were studied with nonparametric test and with logistic regression
analysis. A P-value <0.05 was considered to indicated statistical
significance.
Results
Characteristics of type 2 diabetic patients in the euthyroid and SCH group
The clinical characteristics of the study participants are shown in Table
1.The 696 participants in the study included 349 males and 347 females.
Among them 609 had normal thyroid function; 75 had SCH-1 and 14 had
SCH-2.The SCH group had a higher proportion of women than the euthyroid
group. There were no significant differences between groups were found
in age, smoking status, duration of diabetes, BMI, total cholesterol, HDL
cholesterol, triglycerides or the prevalence of hypertension. The LDL
cholesterol level was significantly higher in the SCH group. Furthermore,
HOMA-IR value was higher in the SCH group than in the euthyroid group.
Moreover, No significant between-group difference was observed in the
fasting plasma glucose, HbA1c, systolic BP, or diastolic BP. In thyroid
function tests, as anticipated, TSH levels were elevated, and free T4
levels were lower in subjects in SCH group.
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A different effect of SCH-2 on the lipid parameters was observed. Serum
LDL cholesterol, triglycerides were significantly higher, while serum HDL
cholesterol was significantly lower in subjects with SCH-2 compared with
the euthyroid group. Moreover, the HOMA-IR level was higher in subjects
with SCH-2, while it did not achieve statistical significance in subjects
with SCH-1 compared with the euthyroid group.
Correlations of TSH and FT4 with CVD risk factors
In total population serum TSH was positively correlated with serum LDL
cholesterol(r=0.031;p= 0.012), triglycerides (r=0.025;p=0.019) , HOMAIR(r=0.017;p=0.027);and negatively correlated with serum HDL cholesterol
(r=-0.037,p=0.028).FT4 was negatively correlated with serum LDL
cholesterol (r=-0.019,p=0.039).
Multivariate analysis of the association between SCH and CVD risk factors
We investigated possible associations between subclinical hypothyroidism
and those metabolic CVD risk factors by adjusting potential confounding
factors, such as age,gender,HbA1c,BMI,duration of diabetes, SCH remained
significantly associated with, LDL (OR:1.69, 95%CI: 1.04-2.34, P=0.03)
and HOMA-IR (OR:1.47, 95%CI:1.10 -2.36, P=0.02).(Table 2)
Discussion
In the present study of type 2 diabetic patients, we demonstrated a
statistically significant association between SCH and a cluster of
metabolic CVD risk factors consisting of dyslipidaemia, insulin
resistance, although we did not observe an apparent relationship between
SCH and hypertension.
Thyroid hormone has multiple effects on the regulation of lipid
synthesis, absorption, and metabolism. Studies of serum lipid levels in
patients with SCH have been inconsistent. Among 8586 adults over age 40
from the National Health and Nutrition Examination Survey III database,
SCH was not associated with alterations in TC, LDL-C, TG, or HDL-C[12].By
contrast ,in a community-based sample of 2108 Australian participants,
serum TSH was positively correlated with TG, TC, and LDL-C [13].Among 1534
Chinese adults, individuals with SCH had higher TG and lower HDL-C than
euthyroid individuals[14].In a cross sectional study of 5343 Indian
subjects, serum TC, and LDL-C were significantly higher in adults with
TSH ＞10mIU/ml compared to controls[15]. In our study among type 2 diabetic
patients, the LDL-C level was significantly higher in the SCH group. Serum
LDL-C, TG were significantly higher, while serum HDL-C was significantly
lower in subjects with SCH-2 compared with the euthyroid group. In total
4
population, serum TSH was positively correlated with serum LDL-C, TG and
negatively correlated with serum HDL-C.FT4 was negatively correlated with
serum LDL-C. Studies showed that transfer of TG to HDL and phospholipids
was lower in patients with SCH than that in controls while transfer of
free and esterified cholesterol to HDL,HDL particle size, and paraoxonase
1 activity did not exhibit any difference[16].Such lipid abnormalities are
partly reversible with thyroixine treatment in patients with co-existent
diabetes[17].RCT studies investigating the effects of L-thyroxine therapy
in approximately 50 SCH subjects showed an improvement of the lipid
profile[18-19].
Insulin resistance is a prominent feature in type 2 diabetes. Thyroid
hormones are important determinants of glucose homeostasis .Our results
demonstrate that HOMA-IR value is higher in the SCH group than in the
euthyroid group. Serum TSH was positively correlated with HOMA- IR，this
association persisted after adjustment for age, gender, HbA1c, BMI,
duration of diabetes. There is no consistent data about insulin
sensitivity in patients with SCH from previous studies. Tuzcu et al found
higher fasting insulin level in patients with SCH in comparison to
controls, followed by an elevated serum level of high sensitive C reactive
protein, however HOMA-IR was not significantly different[20].Vaia et al
found thyroid hormones may contribute to the development of insulin
resistance in both fasting and postprandial state in the early stage of
type 2 diabetes[21]. Maratou et al[22] observed significantly higher HOMA-IR
in 12 hypothyroid and 13 SCH patients in comparison to the euthyroid group.
This observation is in line with the results of our study. They found a
decreased GLUT4 level in plasma membrane of monocytes in SCH patients and
impaired glucose transport in comparison to the euthyroid patients. The
authors concluded that the decreased translocation of glucose
transporters into plasma membrane caused an impairment of transportation
into the cell and thus reduced insulin action. In vivo and in vitro studies
have shown that this is due to impaired insulin stimulated glucose
utilization in peripheral tissues [23-24].
In our study, there was no significant difference between groups were
found in the prevalence of hypertension, systolic blood pressure(SBP),
or diastolic blood pressure(DBP). Our present data revealed that the
associations between SCH and hypertension were not well established.
Researchers still argued the relationship between SCH and hypertension.
Some researchers thought TSH positively correlated with SBP and /or
DBP[25,26],while some other researchers did not get such results[27]. Ittermann
et al[25] demonstrated there was a positive relationship between serum TSH
levels and hypertension in adolescents, suggesting that SCH is associated
with an increased risk of hypertension. Studies of Liu D et al[26] showed
the prevalence of hypertension in SCH group was significantly higher than
5
in euthyroid group in females. However ,Park et al reported there was no
difference between the euthyroid and SCH group[27].
Dependent on the size of the increase in serum TSH, SCH can be mild (serum
TSH concentrations of 4.5-9 mU/L) or severe(TSH≥10mU/L).Some experts
recommend that subclinical hypothyroidism even with TSH values ≤10mIU/L,
should be treated with thyroxine replacement[2]. However beneficial effect
of thyroxine replacement in subjects with SCH is controversial [28].In the
present study, we demonstrated that even mild SCH was associated with
LDL-C level. Our results suggested that the necessity of careful follow-up
in type 2 diabetic patients with mild SCH.
Our study has several limitations. First, this was a cross-sectional
analysis and could not clarify the longitudinal effects of subclinical
hypothyroidism on metabolic risk factors. Second, our study population
was a cohort of patients cared for at a single center. Thus, our results
may not generalizable to all patients with type 2 diabetes. Third, thyroid
function was evaluated at a single time point. It has been reported that
some patients with subclinical hypothyroidism develop overt thyroid
failure, while others may revert to euthyroid status during the follow-up
period.
Despite these limitations, the present study suggested that subclinical
hypothyroidism was associated with dyslipidaemia, insulin resistance.
Further lager prospective studies are required to confirm the association
between SCH and metabolic cardiovascular disease risk factors in type 2
diabetic patients.
Conflict of interest statement
We declare that we have no conflict of interest.
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