In addition, breaking down these patients according to serum TSH levels revealed that increased statin utilization was observed even in patients with a normal serum TSH, in other words the patients had reached biochemical euthyroidism.
The data obtained in sites 2 and 3 support the idea that the association between LT4 and statins was not a limited finding, restricted to 1 academic medical setting. On the contrary, it was also observed in millions of individuals outside an academic medical center. The present findings need to be considered in the light of the following important points:.
Impact of healthcare exposure: in most patients, hyperlipidemia is unrelated to hypothyroidism; so that when assessment of serum lipids is triggered by identification of hypothyroidism it is conceivable that the hyperlipidemia will not be responsive to treatment with LT4, which would likely provoke statin therapy.
While these are critical points, we note that site 1 consisted of regular patients, followed at the University of Chicago for at least 3 years prior to LT4 therapy was initiated.
Control for healthcare exposure is less straightforward in sites 2 and 3. In site 2 we looked at coprescriptions by primary care physicians, so that all patients were under active ambulatory medical care as they were taking at least 1 prescription medication.
An additional important limitation of site 1 is that we could not conduct a before—after statistical analysis on a suitable control population due to lack of a proper definition of an index encounter and the presence of time-varying confounders.
However, an ad hoc analysis demonstrates that on average, 3-year statin utilization decreased in a smaller set of control patients that were age and sex matched to case patients who were on both statins and LT4. Nonetheless, all patients included in this study were under ongoing medical care, which makes it less likely they were undertreated. It is unlikely that LT4-treated hypothyroid patients monitored for lipids would not be monitored for TSH levels as well, which would prompt an adjustment of the LT4 dose rather than initiation of statin therapy.
Indeed, it is recommended that hypothyroid patients be treated with LT4 for 3 to 4 months before starting lipid-lowering therapy, such as statins [ 30 ]. The small number of covariates analyzed in sites 2 and 3: Given the nature of the databases, their level of detail did not allow further refinement of the data. Thus, we could not directly consider body mass index or other confounding metabolic comorbidities, which could have affected statin utilization. In addition, it is accepted that even when potential confounders have not been ruled out by design, a large observed effect can also outweigh the combined effects of confounders [ 31 ].
Indeed, the OR for LT4 and statin co-utilization reached 1. Alternatively, the impact of confounders in observational studies has also been addressed by assigning each participant a propensity score [ 31 ].
In this subgroup as well, the association of LT4 and statins coprescription still persisted. LT4 is considered a safe and effective medication.
Two large studies have found that, provided hypothyroid patients achieve normal TSH levels, mortality is similar to the background population [ 32 , 33 ]. However, in these studies the use of lipid-lowering drugs was either not assessed [ 33 ] or no direct comparison in outcomes between those on and off lipid-lowering drugs was provided [ 32 ]. The present data indicate that by virtue of being more frequently coprescribed with LT4, statins might play a role in these excellent outcomes reported by these studies.
We considered the underlying factors that explain the relationship between LT4 therapy and statins. One possibility is that patients with unsuspected hypothyroidism develop hypercholesterolemia and are treated with statins, only to be diagnosed and treated for hypothyroidism at a later time. An alternative possibility is that treatment with LT4 normalizes TSH levels but fails to restore thyroid hormone signaling in metabolically relevant tissues, including the liver, such as seen in our preclinical model [ 10 ].
Clinical evidence that normal TSH levels do not necessarily reflect normalization of thyroid hormone signaling in all tissues was obtained in hypothyroid patients treated with replacement therapy. Whereas parameters reflecting thyroid status in the heart and skeletal muscle were promptly normalized, energy expenditure and serum cholesterol levels were not, despite near normal TSH levels [ 35 ]. An unexpected finding of the present investigation was the association between utilization of LT4 and DM medications.
At face value, it suggests that the residual metabolic fingerprint of hypothyroidism could be broader than anticipated, placing LT4-treated patients at a higher risk of disruptions in energy and carbohydrate metabolism. Alternatively, we cannot exclude that medical attention, and concomitant testing, such as screening both TSH and lipid profiles at the same time, is the driver for coprescription of T4 diabetes medications. Nonetheless, patients on statins have been found to be at a higher risk of developing DM [ 36 ].
While this could be a confounding factor in the present studies, the M-H analysis indicated that the LT4 -effect on statin utilization was independent of medications for DM. The present studies were conducted in 3 different sites, in 2 continents, and involved millions of prescribed medications and patients. The consistency of the results across the 3 sites was remarkable, supporting the idea that the present conclusions can be generalized to a larger adult population, independent of sex and age group.
The retrospective study of 3 independent and relatively large cohorts indicate that patients of both sexes and all adult ages on LT4 were more likely to be treated with statins. These findings call for further studies to explore whether LT4 treatment is associated with residual hypercholesterolemia to the extent intervention is required. We are grateful to Ms. Disclosures: A.
All data presented in this manuscript are contained within the figures and tables presented in the manuscript. Google Scholar. Guidelines for the treatment of hypothyroidism: prepared by the American Thyroid Association task force on thyroid hormone replacement.
Paradigms of dynamic control of thyroid hormone signaling. Endocr Rev. Clin Endocrinol Oxf. Fine adjustment of thyroxine replacement dosage: comparison of the thyrotrophin releasing hormone test using a sensitive thyrotrophin assay with measurement of free thyroid hormones and clinical assessment.
Roberts ND. Psychological problems in thyroid disease. BTF Newsletter. Google Preview. An online survey of hypothyroid patients captured predominantly dissatisfied individuals. Differences in hypothalamic type 2 deiodinase ubiquitination explain localized sensitivity to thyroxine. J Clin Investig. Biochemical markers reflecting thyroid function in athyreotic patients on levothyroxine monotherapy. Association between thyroid-stimulating hormone level after total thyroidectomy and hypercholesterolemia in female patients with differentiated thyroid cancer: a retrospective study.
J Clin Med. Systemic thyroid hormone status during levothyroxine therapy in hypothyroidism: a systematic review and meta-analysis.
J Clin Endocrinol Metab. No effect of the Thr92Ala polymorphism of deiodinase-2 on thyroid hormone parameters, health-related quality of life, and cognitive functioning in a large population-based cohort study. A systematic review of prescription pattern monitoring studies and their effectiveness in promoting rational use of medicines.
Perspect Clin Res. Modified prescription-event monitoring studies: a tool for pharmacovigilance and risk management. Drug Saf. These include cholesterol-lowering medications such as:. Treating hyperthyroidism can help raise too-low cholesterol levels.
Possible treatments include:. If your entire thyroid gland is removed, you'll need to take thyroid replacement hormone such as levothyroxine for the rest of your life. This is sometimes the case with partial removal and radioiodine therapy as well. An overactive thyroid and low cholesterol can both be improved with medication, radioiodine therapy, or surgery directed at stunting the overproduction of thyroid hormone.
Cholesterol treatments can affect thyroid disease and treatment in several ways. Drugs classified as bile acid resins may prevent your body from absorbing levothyroxine. They're prescribed for hyperthyroidism and include:. You should take these drugs at least four hours after taking levothyroxine to sidestep this concern. Muscle pain is a common side effect of statins, such as:. If you have hypothyroidism, you're especially likely to have this side effect.
Niacin is one treatment for increasing HDL "good cholesterol" levels. Its side effects, such as flushing, can closely mimic the symptoms of hyperthyroidism. That might make you think your thyroid treatments aren't working properly. On the plus side, a study found that treating high cholesterol with statin medications reduced the risk of Grave's orbitopathy.
Drugs used to lower cholesterol can produce side effects that mimic symptoms of thyroid disease and interfere with thyroid medication absorption. Those with thyroid disease may also be more likely to experience side effects of cholesterol drugs than others.
Lifestyle changes can help you manage cholesterol and thyroid problems. Your healthcare provider may recommend the following:. Thyroid hormones and cholesterol levels are connected. If your cholesterol is high or drops suddenly, get your thyroid checked. Thyroid treatments cannot only help you reduce your risk of complications such as heart attack and stroke, but they can also help you manage cholesterol. If you are on cholesterol drugs, know that they can affect your thyroid disease and treatments.
You don't necessarily have to have your thyroid condition managed by an endocrinologist—a healthcare provider who specializes in treating hormone issues. Many healthcare providers feel confident managing these conditions themselves. However, if you have other health issues or your healthcare provider is not comfortable treating you, seeing a specialist may be best.
Losing weight with thyroid disease can be a struggle. Our thyroid-friendly meal plan can help. Sign up and get yours free! The correlation between serum free thyroxine and regression of dyslipidemia in adult males: A 4. Medicine Baltimore. National Institutes of Health, U. National Library of Medicine: MedlinePlus. Updated June 16, The lipid-lowering effect of levothyroxine in patients with subclinical hypothyroidism: A systematic review and meta-analysis of randomized controlled trials.
Clin Endocrinol Oxf. Relation of subclinical hypothyroidism is associated with cardiovascular events and all-cause mortality in adults with high cardiovascular risk. Am J Cardiol.
Systemic thyroid hormone status during levothyroxine therapy in hypothyroidism: A systematic review and meta-analysis [published online ahead of print, Aug 15]. However, you should not drink more than 14 units of alcohol a week. For full details of cautions and interactions relating to your specific medicine, check the patient information leaflet that comes with it. Page last reviewed: 19 November Next review due: 19 November Pregnancy and breastfeeding Statins should not be taken by anyone who is pregnant or breastfeeding, as there's no firm evidence on whether it's safe to do so.
Contact a GP for advice if you become pregnant while taking statins. People at an increased risk of side effects Statins should be taken with caution if you're at an increased risk of developing a rare side effect called myopathy, which is where the tissues of your muscles become damaged and painful.
Things that can increase this risk include: being over 70 years old having a history of liver disease regularly drinking large quantities of alcohol having a history of muscle-related side effects when taking a statin or fibrate another type of medicine for high cholesterol having a family history of myopathy or rhabdomyolysis If one or more of these apply to you, you may need to be frequently monitored to check for complications.
Read more about the side effects of statins. Accordingly, the serum TSH levels at the end of follow-up were significantly lower in the statin group compared with the control group 2. Figure 2 The changes of total cholesterol levels and thyroid function in the statin group and the control group in total population A—C , euthyroid subjects at baseline D—F and subjects with subclinical hypothyroidism SCH at baseline G—I. A Changes of serum total cholesterol levels from baseline to the end of follow-up in each group in total population.
B The percentage of subjects with euthyroidism at the end of follow-up in each group in total population. C Changes of serum thyroid-stimulating hormone TSH levels from baseline to the end of follow-up in each group in total population. D Changes of serum total cholesterol levels from baseline to the end of follow-up in each group in euthyroid subjects at baseline. E The incidence rate of SCH during follow-up in each group in euthyroid subjects at baseline.
F Changes of serum TSH levels from baseline to the end of follow-up in each group in euthyroid subjects at baseline. G Changes of serum total cholesterol levels from baseline to the end of follow-up in each group in subjects with SCH at baseline.
We further did subgroup analyses according to the thyroid status of subjects at baseline. In both euthyroid subjects and subjects with SCH at baseline, serum TC levels were significantly lower in the statin group than those in the control group at the end of follow-up Figures 2D, G.
Among subjects with normal thyroid function at baseline, the incidence rate of SCH during follow-up was significantly lower in the statin group compared with the control group 6. Consistently, the serum TSH levels in the statin group significantly reduced from 4. Besides, there were two subjects in the control group and one subject in the statin group developed OH during follow-up.
Together, subjects in the statin group had better outcomes of thyroid function than the control group in both euthyroid and SCH subjects. To evaluate the relationship between statin use and the outcomes of thyroid function and if it was independent of confounding factors, we utilized the logistic regression models. As presented in Table 2 , subjects with statin use had higher odds of normal thyroid function at the end of follow-up compared with the control group OR 2.
Table 2 Logistic regression analysis of statin use and normal thyroid function at the end of follow-up. We also performed logistic regression analysis with normal thyroid function as dependent variable and statin use as independent variable in euthyroid subjects and subjects with SCH at baseline, respectively.
We found that statin use was significantly associated with normal thyroid function at the end of follow-up in both subgroups Table 2. After adjusting for confounding factors, the association remained significant. Compared with individuals without statin use, the odds of maintenance of normal thyroid function for statin use increased 2. The results remained similar after further adjustment for the presence of CVD and follow-up time.
These results suggested that statin use was independently associated with a better chance of normal thyroid function at the end of follow-up in both SCH and euthyroid participants at baseline. As TSH is a more sensitive marker of thyroid dysfunction, we further performed linear regression analysis to examine the relationship between statin use and serum TSH levels at the end of follow-up. The results remained similar after further adjustment for the presence of CVD and follow-up time Table 3.
Table 3 Linear regression analysis of statin use and log-transformed thyroid-stimulating hormone TSH levels at the end of follow-up. Similar results are achieved in the subgroup analysis of euthyroid subjects at baseline. In subjects with SCH at baseline, statin use also suggested the trend of a negative association with serum log-transformed TSH levels at the end of follow-up Table 3.
These results demonstrated that statin use was associated with a decrease in TSH levels, even in euthyroid subjects. Since previous studies suggested that cholesterol may influence thyroid function and we already found an association between statin use and benefits of thyroid function, we performed a mediation analysis to test if TC changes mediated the relationship between statin use and TSH levels at the end of follow-up.
A similar mediation effect was also found in euthyroid subjects at baseline Supplementary Figure 2 and Supplementary Table 2. Table 4 Mediation analysis of total cholesterol changes in the relationship between statin use and log-transformed thyroid-stimulating hormone TSH levels at the end of follow-up. Figure 3 The mediation effect of total cholesterol changes in the relationship between statin use and log-transformed thyroid-stimulating hormone TSH levels at the end of follow-up.
The independent variable was statin use, the dependent variable was serum TSH levels at the end of follow-up, and the mediator was the changes of serum total cholesterol levels during follow-up. Age, sex, free triiodothyronine, free thyroxine, thyroid stimulating hormone, thyroid autoimmunity, body mass index, systolic blood pressure, fasting plasma glucose, alanine aminotransferase and evaluated glomerular filtration rate at baseline were adjusted in the analysis.
In path a, the mediator was regressed onto the independent variable. In path b, the dependent variable was regressed onto the mediator. In path c, the dependent variable was regressed onto the independent variable without the adjustment of mediator.
In our present study, we investigated whether statin use is associated with a beneficial effect on thyroid function in a community-based population. We found that the percentage of euthyroid subjects was higher in the statin group at the end of follow-up. In multivariable regression analyses, statin use was independently associated with normal thyroid function and lower TSH levels at the end of follow-up.
Furthermore, the mediation analysis showed that the relationship between statin use and lower TSH levels was mediated by TC declines. Collectively, our results suggest that statin use is indeed associated with benefits of thyroid function, and TC changes serve as a mediator.
The prevalence of SCH has significantly increased in China in the past decades 2 , which suggests the importance of identifying the potential risk factors. At the same time, dyslipidemia is also a concerning problem in the world Both SCH and hypercholesteremia increase the risk of cardiovascular events 3 , 22 , and these two conditions can present simultaneously in many cases 3.
Evidence from animal study has suggested that hypercholesteremia could influence thyroid function 23 , and our previous population study also found that higher TC level was an independent risk factor of progression to OH in SCH patients If the control of TC levels could also benefit thyroid function, this could be important to clinical practice and may be valuable to our management strategy of hypothyroidism.
On the basis of previous studies, we found that the cholesterol-lowering effect of statin was associated with better outcomes of thyroid function in both SCH and euthyroid subjects. Our findings provide additional evidence for the hypothesis that the disturbance of lipid metabolism may cause thyroid dysfunction, and stress the importance of controlling TC levels.
SCH including mild SCH was related to a higher risk of cardiovascular events and mortality, even after adjusting for other cardiovascular risk factors including LDL-C LDL-C is a known independent risk factor for cardiovascular diseases. If LDL-C lowering agents, like statins, can not only lower LDL-C levels, but also maintain normal thyroid function, this study may provide additional evidence for the use of statins to prevent cardiovascular disease.
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