Clinical Endocrinology (2015) 83, 746–749
LETTERS TO THE EDITOR
Statins and thyroid-stimulating hormone concentrations in patients with type 2 diabetes
We have had the opportunity to compare serum TSH concentration in euthyroid diabetic patients classified according to the lipid-lowering therapy (statins, fibrates or no drug). Furthermore, in the group of diabetic patients with hypothyroidism under replacement therapy, we compared serum TSH and free thyroxine (FT4) concentrations in the same subgroups. Results are summarized in Table 1. We could not find any significant difference in TSH levels in the three groups of euthyroid diabetic patients. Furthermore, in hypothyroid patients under replacement therapy, TSH and FT4 levels were comparable in patients taking statins, fibrates or no drugs (Table 1). We also analysed the group of 47 patients with newly diagnosed hypothyroidism (15 men, 32 women; three overt and 44 subclinical hypothyroidism). In this group, there were 31 subjects (660%) taking statins, 4 (85%) treated with fibrates and 12 (255%) without lipid-lowering agents. Serum TSH concentrations in these three subgroups [721 (602–1080), 1002 (639– 1892) and 917 (792–1290) mU/l, respectively] were not significantly different (P = 0106, Kruskal–Wallis test). We performed a multiple regression analysis with TSH as dependent variable and gender, age, body mass index, statin therapy, fibrates and insulin therapy as independent variable. No significant relationships were found among TSH values and the considered covariates both in the group of euthyroid subjects and in the group of hypothyroid patients. When adding metformin therapy to this analysis, results were similar, that is, we found no significant relationship among TSH and the covariates in the two groups of studied subjects. Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) are commonly drugs prescribed for hyperlipidaemia in diabetic patients and also are frequently co-administered with levothyroxine in hypothyroid patients. Results herein reported show that serum levels of TSH in euthyroid hyperlipidaemic diabetic patients under treatment with statins were not different to those found in patients treated with fibrates or without lipid-lowering
Dear Editor, We have read with interest the recently published article by Dr Irving et al.1 These authors have performed a retrospective population analysis with the aim to evaluate drug interactions affecting levothyroxine bioavailability. They have evaluated changes in thyroid-stimulating hormone (TSH) following initiation of study drugs. Interestingly, they found that there was a significant decrease of 017 mU/l in TSH concentration for those patients on statins.1 We previously performed a screening programme for thyroid dysfunction in patients with type 2 diabetes who attended our clinic during 2004–2010.2 From a total population of 1112 patients, there were 828 subjects with euthyroidism and 204 with primary hypothyroidism. In the euthyroid group, 483 subjects had hyperlipidaemia. This group was formed by 271 women and 212 men with a mean age of 662 117 year, median (interquartile range) duration of diabetes of 10 (5–16) year, and mean haemoglobin A1c concentration of 632 177 mmol/mol. Insulin therapy was used by 565%, and metformin therapy was used by 360% of these patients. In this group of euthyroid subjects, 281 (582%) were treated with statins, 47 (97%) with fibrates and 2 (04%) with statins plus fibrates. In 153 patients (317%), no lipid-lowering agent was prescribed. In the group of 204 patients with hypothyroidism, there were 126 with hyperlipidaemia. Of these, 47 patients had incident hypothyroidism (diagnosed at screening) and 79 had prevalent hypothyroidism. Sixty-eight of these 79 patients were on replacement therapy with levothyroxine. This group was formed by 59 women and nine men [age, 673 105 year; duration of diabetes, 7 (3–13) year; haemoglobin A1c, 558 152 mmol/mol; insulin therapy, 368%; metformin therapy, 382%]. In this group of hypothyroid patients, 43 (632%) were treated with statins, 5 (74%) with fibrates and 20 (204%) were without lipid-lowering agents.
Table 1. Serum thyrotropin (TSH) and free thyroxine (FT4) concentrations in hyperlipidaemic diabetic patients classified according to thyroid function status (euthyroidism or levothyroxine replaced hypothyroidism) and therapy for hyperlipidaemia (statins, fibrates or no drug) Euthyroid patients
Statins Fibrates No drug P*
Hypothyroid patients on levothyroxine
n
TSH (mU/l)
n
TSH (mU/l)
n
FT4 (ng/dl)
281 47 153
150 (106–214) 173 (110–229) 154 (103–222) 0784
43 5 20
137 (073–296) 155 (095–448) 137 (041–364) 0917
30 5 16
130 020 122 035 133 028 0676
Data are expressed as median (interquartile range) for TSH concentration (nonparametric variable) and as mean SD for FT4 (normally distributed variable). *Kruskal–Wallis nonparametric test for differences in TSH concentrations; repeated measures ANOVA for differences in FT4 concentrations.
746
© 2015 John Wiley & Sons Ltd
Letters to the Editor 747 drugs. Similar results were obtained in hypothyroid diabetic patients under chronic levothyroxine replacement therapy, and in patients with newly diagnosed hypothyroidism, although in this latter case, TSH value are mainly conditioned by the degree of loss of thyroid function at the moment of our screening. In our cohort of patients with diabetes, we could not find any relationship between TSH and statins, although we recognize that our study was not designed to study this relationship. We could not assess the effects of the type of drug, dose and duration of statin treatment on TSH values in our patients. We also acknowledge that, in the group of hypothyroid patients on replacement therapy, it is theoretically possible that any effect of statin therapy on TSH may have been offset by a compensatory change in levothyroxine dosage. The relationships between statin therapy, levothyroxine bioavailability and TSH concentrations have been scarcely evaluated. A limited number of case reports have suggested a reduction of the efficacy of levothyroxine after starting lovastatin.3,4 Demke et al.3 reported a reversible increase in TSH levels after the addition of lovastatin to levothyroxine in a hypothyroid patient. Kisch & Segall4 reported elevation of TSH in two elderly hypothyroid patients after starting simvastatin therapy. A recent cross-sectional study in 41 hypothyroid patients receiving levothyroxine and simvastatin showed no significant difference between TSH and FT4 before and after 3 months of simultaneous treatment.5 No aggravation of any sign or symptom of hypothyroidism was reported in this study. Results obtained in the population study by Irving et al.1 are surprising because, to our knowledge, no clinical report or prospective study has shown decrease in TSH levels by statins. Interestingly, a study on radioiodine uptake showed that, in patients with a low TSH concentration, normal radioiodine uptake and scans were much more common in the patients who were taking statins (16 of 29, 55%) than in patients who were not (45 of 278, 16%). The authors suggest that statins may falsely lower serum TSH without altering thyroid function.6 A reduction in the absorption or an acceleration of the liver catabolism of levothyroxine has been postulated as possible mechanism of the statin-induced elevation of TSH levels in some patients.3,4 However, the mechanism of action of statins causing the modest, but significant, decrease in TSH levels in the population study by Irving et al.1 is unclear, although it could involve a putative direct pituitary action of these drugs. A similar effect of reduction in TSH levels has been reported with metformin,7,8 although it could not be confirmed in diabetic patients with intact pituitary–thyroid axis.9,10 In brief, our data on diabetic patients with hyperlipidaemia suggest that statin therapy is not accompanied by significant changes in serum TSH levels, both in euthyroid and in hypothyroid subjects with levothyroxine replacement therapy. Further investigations are needed to clarify the biological significance and clinical relevance of the possible effects of statins on TSH secretion.
Disclosure The authors have nothing to declare. © 2015 John Wiley & Sons Ltd Clinical Endocrinology (2015), 83, 746–749
Juan J. Dıez*,† and Pedro Iglesias* *Department of Endocrinology, Hospital Ramon y Cajal, †Universidad de Alcala de Henares, Madrid, Spain E-mail: [email protected] doi: 10.1111/cen.12752
References 1 Irving, S.A., Vadiveloo, T. & Leese, P. (2015) Drugs that interact with levothyroxine: an observational study from the Thyroid Epidemiology, Audit and Research Study (TEARS). Clinical Endocrinology (Oxford), 82, 136–141. 2 Dıez, J.J. & Iglesias, P. (2012) An analysis of the relative risk for hypothyroidism in patients with type 2 diabetes. Diabetic Medicine, 29, 1510–1514. 3 Demke, D.M., Gormley, G.J. & Tobert, J.A. (1989) Drug interaction between thyroxine and lovastatin. New England Journal of Medicine, 321, 1341–1342. 4 Kisch, E. & Segall, H.S. (2005) Interaction between simvastatin and L-thyroxine. Annals of Internal Medicine, 143, 547. 5 Abbasinazari, M., Nakhjavani, M. & Gogani, S. (2011) The effects of simvastatin on the serum concentrations of thyroid stimulating hormone and free thyroxine in hypothyroid patients treated with levothyroxine. Iranian Journal of Medical Sciences, 36, 80–83. 6 Yandell, S.D., Harvey, W.C., Fernandes, N.J. et al. (2008) Radioiodine studies, low serum thyrotropin, and the influence of statin drugs. Thyroid, 18, 1039–1042. 7 Vigersky, R.A., Filmore-Nassar, A. & Glass, A.R. (2006) Thyrotropin suppression by metformin. Journal of Clinical Endocrinology & Metabolism, 91, 225–227. 8 Isidro, M.L., Penın, M.A., Nemi~ na, R. et al. (2007) Metformin reducs thyrotropin levels in obese, diabetic women with primary hypothyroidism on thyroxine replacement therapy. Endocrine, 32, 79–82. 9 Cappelli, C., Rotondi, M., Pirola, I. et al. (2009) TSH-lowering effect of metformin in type 2 diabetic patients. Diabetes Care, 32, 1589–1590. 10 Dıez, J.J. & Iglesias, P. (2013) Relationship between serum thyrotropin concentrations and metformin therapy in euthyroid patients with type 2 diabetes. Clinical Endocrinology, 78, 505– 511.
The Authors’ Reply: Statins and thyroid-stimulating hormone Our recent publication showed that for patients on long-term thyroxine, their serum TSH concentration dropped by a median of 0.21 mU/l after starting a statin.1 The paper also showed changes in TSH after starting iron, calcium, proton pump inhibitors and possibly oestrogens. Diez and Iglesias showed that in patients with diabetes, statins did not seem to affect serum TSH in patients with newly diagnosed hypothyroidism, or in euthyroid patients.2 No relationship could be identified between serum TSH and statin use on multiple regression analysis. It is likely that difference in study size (n = 1944 vs n = 47) may explain the dissimilar findings. However, the latter study
LETTERS TO THE EDITOR
Statins and thyroid-stimulating hormone concentrations in patients with type 2 diabetes
We have had the opportunity to compare serum TSH concentration in euthyroid diabetic patients classified according to the lipid-lowering therapy (statins, fibrates or no drug). Furthermore, in the group of diabetic patients with hypothyroidism under replacement therapy, we compared serum TSH and free thyroxine (FT4) concentrations in the same subgroups. Results are summarized in Table 1. We could not find any significant difference in TSH levels in the three groups of euthyroid diabetic patients. Furthermore, in hypothyroid patients under replacement therapy, TSH and FT4 levels were comparable in patients taking statins, fibrates or no drugs (Table 1). We also analysed the group of 47 patients with newly diagnosed hypothyroidism (15 men, 32 women; three overt and 44 subclinical hypothyroidism). In this group, there were 31 subjects (660%) taking statins, 4 (85%) treated with fibrates and 12 (255%) without lipid-lowering agents. Serum TSH concentrations in these three subgroups [721 (602–1080), 1002 (639– 1892) and 917 (792–1290) mU/l, respectively] were not significantly different (P = 0106, Kruskal–Wallis test). We performed a multiple regression analysis with TSH as dependent variable and gender, age, body mass index, statin therapy, fibrates and insulin therapy as independent variable. No significant relationships were found among TSH values and the considered covariates both in the group of euthyroid subjects and in the group of hypothyroid patients. When adding metformin therapy to this analysis, results were similar, that is, we found no significant relationship among TSH and the covariates in the two groups of studied subjects. Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) are commonly drugs prescribed for hyperlipidaemia in diabetic patients and also are frequently co-administered with levothyroxine in hypothyroid patients. Results herein reported show that serum levels of TSH in euthyroid hyperlipidaemic diabetic patients under treatment with statins were not different to those found in patients treated with fibrates or without lipid-lowering
Dear Editor, We have read with interest the recently published article by Dr Irving et al.1 These authors have performed a retrospective population analysis with the aim to evaluate drug interactions affecting levothyroxine bioavailability. They have evaluated changes in thyroid-stimulating hormone (TSH) following initiation of study drugs. Interestingly, they found that there was a significant decrease of 017 mU/l in TSH concentration for those patients on statins.1 We previously performed a screening programme for thyroid dysfunction in patients with type 2 diabetes who attended our clinic during 2004–2010.2 From a total population of 1112 patients, there were 828 subjects with euthyroidism and 204 with primary hypothyroidism. In the euthyroid group, 483 subjects had hyperlipidaemia. This group was formed by 271 women and 212 men with a mean age of 662 117 year, median (interquartile range) duration of diabetes of 10 (5–16) year, and mean haemoglobin A1c concentration of 632 177 mmol/mol. Insulin therapy was used by 565%, and metformin therapy was used by 360% of these patients. In this group of euthyroid subjects, 281 (582%) were treated with statins, 47 (97%) with fibrates and 2 (04%) with statins plus fibrates. In 153 patients (317%), no lipid-lowering agent was prescribed. In the group of 204 patients with hypothyroidism, there were 126 with hyperlipidaemia. Of these, 47 patients had incident hypothyroidism (diagnosed at screening) and 79 had prevalent hypothyroidism. Sixty-eight of these 79 patients were on replacement therapy with levothyroxine. This group was formed by 59 women and nine men [age, 673 105 year; duration of diabetes, 7 (3–13) year; haemoglobin A1c, 558 152 mmol/mol; insulin therapy, 368%; metformin therapy, 382%]. In this group of hypothyroid patients, 43 (632%) were treated with statins, 5 (74%) with fibrates and 20 (204%) were without lipid-lowering agents.
Table 1. Serum thyrotropin (TSH) and free thyroxine (FT4) concentrations in hyperlipidaemic diabetic patients classified according to thyroid function status (euthyroidism or levothyroxine replaced hypothyroidism) and therapy for hyperlipidaemia (statins, fibrates or no drug) Euthyroid patients
Statins Fibrates No drug P*
Hypothyroid patients on levothyroxine
n
TSH (mU/l)
n
TSH (mU/l)
n
FT4 (ng/dl)
281 47 153
150 (106–214) 173 (110–229) 154 (103–222) 0784
43 5 20
137 (073–296) 155 (095–448) 137 (041–364) 0917
30 5 16
130 020 122 035 133 028 0676
Data are expressed as median (interquartile range) for TSH concentration (nonparametric variable) and as mean SD for FT4 (normally distributed variable). *Kruskal–Wallis nonparametric test for differences in TSH concentrations; repeated measures ANOVA for differences in FT4 concentrations.
746
© 2015 John Wiley & Sons Ltd
Letters to the Editor 747 drugs. Similar results were obtained in hypothyroid diabetic patients under chronic levothyroxine replacement therapy, and in patients with newly diagnosed hypothyroidism, although in this latter case, TSH value are mainly conditioned by the degree of loss of thyroid function at the moment of our screening. In our cohort of patients with diabetes, we could not find any relationship between TSH and statins, although we recognize that our study was not designed to study this relationship. We could not assess the effects of the type of drug, dose and duration of statin treatment on TSH values in our patients. We also acknowledge that, in the group of hypothyroid patients on replacement therapy, it is theoretically possible that any effect of statin therapy on TSH may have been offset by a compensatory change in levothyroxine dosage. The relationships between statin therapy, levothyroxine bioavailability and TSH concentrations have been scarcely evaluated. A limited number of case reports have suggested a reduction of the efficacy of levothyroxine after starting lovastatin.3,4 Demke et al.3 reported a reversible increase in TSH levels after the addition of lovastatin to levothyroxine in a hypothyroid patient. Kisch & Segall4 reported elevation of TSH in two elderly hypothyroid patients after starting simvastatin therapy. A recent cross-sectional study in 41 hypothyroid patients receiving levothyroxine and simvastatin showed no significant difference between TSH and FT4 before and after 3 months of simultaneous treatment.5 No aggravation of any sign or symptom of hypothyroidism was reported in this study. Results obtained in the population study by Irving et al.1 are surprising because, to our knowledge, no clinical report or prospective study has shown decrease in TSH levels by statins. Interestingly, a study on radioiodine uptake showed that, in patients with a low TSH concentration, normal radioiodine uptake and scans were much more common in the patients who were taking statins (16 of 29, 55%) than in patients who were not (45 of 278, 16%). The authors suggest that statins may falsely lower serum TSH without altering thyroid function.6 A reduction in the absorption or an acceleration of the liver catabolism of levothyroxine has been postulated as possible mechanism of the statin-induced elevation of TSH levels in some patients.3,4 However, the mechanism of action of statins causing the modest, but significant, decrease in TSH levels in the population study by Irving et al.1 is unclear, although it could involve a putative direct pituitary action of these drugs. A similar effect of reduction in TSH levels has been reported with metformin,7,8 although it could not be confirmed in diabetic patients with intact pituitary–thyroid axis.9,10 In brief, our data on diabetic patients with hyperlipidaemia suggest that statin therapy is not accompanied by significant changes in serum TSH levels, both in euthyroid and in hypothyroid subjects with levothyroxine replacement therapy. Further investigations are needed to clarify the biological significance and clinical relevance of the possible effects of statins on TSH secretion.
Disclosure The authors have nothing to declare. © 2015 John Wiley & Sons Ltd Clinical Endocrinology (2015), 83, 746–749
Juan J. Dıez*,† and Pedro Iglesias* *Department of Endocrinology, Hospital Ramon y Cajal, †Universidad de Alcala de Henares, Madrid, Spain E-mail: [email protected] doi: 10.1111/cen.12752
References 1 Irving, S.A., Vadiveloo, T. & Leese, P. (2015) Drugs that interact with levothyroxine: an observational study from the Thyroid Epidemiology, Audit and Research Study (TEARS). Clinical Endocrinology (Oxford), 82, 136–141. 2 Dıez, J.J. & Iglesias, P. (2012) An analysis of the relative risk for hypothyroidism in patients with type 2 diabetes. Diabetic Medicine, 29, 1510–1514. 3 Demke, D.M., Gormley, G.J. & Tobert, J.A. (1989) Drug interaction between thyroxine and lovastatin. New England Journal of Medicine, 321, 1341–1342. 4 Kisch, E. & Segall, H.S. (2005) Interaction between simvastatin and L-thyroxine. Annals of Internal Medicine, 143, 547. 5 Abbasinazari, M., Nakhjavani, M. & Gogani, S. (2011) The effects of simvastatin on the serum concentrations of thyroid stimulating hormone and free thyroxine in hypothyroid patients treated with levothyroxine. Iranian Journal of Medical Sciences, 36, 80–83. 6 Yandell, S.D., Harvey, W.C., Fernandes, N.J. et al. (2008) Radioiodine studies, low serum thyrotropin, and the influence of statin drugs. Thyroid, 18, 1039–1042. 7 Vigersky, R.A., Filmore-Nassar, A. & Glass, A.R. (2006) Thyrotropin suppression by metformin. Journal of Clinical Endocrinology & Metabolism, 91, 225–227. 8 Isidro, M.L., Penın, M.A., Nemi~ na, R. et al. (2007) Metformin reducs thyrotropin levels in obese, diabetic women with primary hypothyroidism on thyroxine replacement therapy. Endocrine, 32, 79–82. 9 Cappelli, C., Rotondi, M., Pirola, I. et al. (2009) TSH-lowering effect of metformin in type 2 diabetic patients. Diabetes Care, 32, 1589–1590. 10 Dıez, J.J. & Iglesias, P. (2013) Relationship between serum thyrotropin concentrations and metformin therapy in euthyroid patients with type 2 diabetes. Clinical Endocrinology, 78, 505– 511.
The Authors’ Reply: Statins and thyroid-stimulating hormone Our recent publication showed that for patients on long-term thyroxine, their serum TSH concentration dropped by a median of 0.21 mU/l after starting a statin.1 The paper also showed changes in TSH after starting iron, calcium, proton pump inhibitors and possibly oestrogens. Diez and Iglesias showed that in patients with diabetes, statins did not seem to affect serum TSH in patients with newly diagnosed hypothyroidism, or in euthyroid patients.2 No relationship could be identified between serum TSH and statin use on multiple regression analysis. It is likely that difference in study size (n = 1944 vs n = 47) may explain the dissimilar findings. However, the latter study
