2Assistant Manager, Medical Services, Biocon Limited, Bangalore
3Junior Resident, Department Of General Medicine, Medical College, Kolkata
In the present study, we aim to observe the impact of metformin on serum TSH levels in hypothyroid patients who are on stable and adequate LT4 and found to have diabetes or prediabetes. We also intend to compare the above mentioned group with hypothyroid patients who are on adequate and stable LT4 replacement therapy without diabetes or prediabetes. Although there are many similar studies published on this research problem, this is the first study from Indian subcontinent population.
Descriptive statistical analysis was carried out in the present study. Results of continuous measurements were presented as mean ± standard deviation (Min-Max) and results of categorical measurements were presented in Number (%). Significance was assessed at the 5 % level. Unpaired t-test to find significant difference in the baseline and follow-up study parameters namely LT4 and TSH between two groups. Repeated measure ANOVA was used to observe the within group differences for the changes in LT4 and TSH. SAS (Statistical Analysis System) version 9.2 for windows, SAS Institute Inc. Cary, NC, USA and SPSS (Statistical Package for Social Sciences) version 20.0 was used for the analysis of the data and Microsoft word and Excel were used to generate graphs and tables.
In the study group (case cohort) after three months of on metformin, mean TSH was significantly lower than basal TSH (basal TSH: 4.018 ± 0.7207microUI/ml vs. three months after metformin TSH: 3.72 ± 0.6216 microUI/ml, P < 0.0001). Mean FT4 level changes during metformin administration (basal FT4: 1.344 ± 0.2514 ng/dl, three months after metformin FT4: 1.3405 ± 0.2437ng/dl, p= 0.691, which is non-significant. After six months of on metformin, mean TSH was significantly lower than basal TSH (basal TSH: 4.018±0.7207microUI/ml vs. six months after metformin TSH: 2.966 ± 0.7194microUI/ml; P < 0.0001). Mean FT4 level significantly increases during metformin administration (basal FT4: 1.344 ± 0.2514 ng/dl, six months after metformin FT4: 1.372 ± 0.238ng/dl; p=0.007). After 12 months of on metformin, mean TSH was significantly lower than basal TSH (basal TSH: 4.018±0.7207microUI/ml vs. 12 months after metformin TSH: 1.8788 ± 0.6055microUI/ml; p < 0.0001). Mean FT4 level increases during metformin administration (basal FT4: 1.344 ± 0.2514 ng/dl, 12 months after metformin FT4: 1.3848 ± 0.24305ng/dl; p= 0.001) which is once again strongly significant.
Dissimilarly to the case cohort, in control group after three months, mean TSH changes from basal TSH is non-significant (basal TSH: 2.7493 ±1.3579 microUI/ml versus three months after TSH is 2.7518 ±1.3342microUI/ml, p = 0.917). Mean FT4 level changes is also non-significant (basal FT4: 1.3182 ± 0.3080 ng/dl, three months after FT4 is 1.3288 ± 0.2980 ng/dl, p = 0.241). After six months in control group, mean TSH changes from basal TSH is also non-significant (basal TSH: 2.7493 ± 1.3579 microUI/ ml versus six months after TSH: 2.7250 ± 1.3266 microUI/ml, p = 0.358).(Figure 1) At six months, mean FT4 level changes is again non-significant in the control cohort (basal FT4: 1.3182 ± 0.3080 ng/dl, six months after FT4 is 1.327 ± 0.2894 ng/dl, p = 0.324). ).(Figure 2) After 12 months in control group , mean TSH
Paired Samples Statistics |
|||||
|
Mean |
N |
Std. Deviation |
Std. Error Mean |
|
Pair 1 |
tshm1 |
4.018 |
40 |
.7207 |
.1140 |
tshm3 |
3.720 |
40 |
.6216 |
.0983 |
|
Pair 2 |
tshm1 |
4.018 |
40 |
.7207 |
.1140 |
tshm6 |
2.966 |
40 |
.7194 |
.1137 |
|
Pair 3 |
tshm1 |
4.018 |
40 |
.7207 |
.1140 |
tshm12 |
1.8788 |
40 |
.60551 |
.09574 |
|
Pair 4 |
tshc1 |
2.7493 |
40 |
1.35798 |
.21472 |
tshc3 |
2.7518 |
40 |
1.33462 |
.21102 |
|
Pair 5 |
tshc1 |
2.7493 |
40 |
1.35798 |
.21472 |
tshc6 |
2.7250 |
40 |
1.32662 |
.20976 |
|
Pair 6 |
tshc1 |
2.7493 |
40 |
1.35798 |
.21472 |
tshc12 |
2.7690 |
40 |
1.35525 |
.21428 |
Paired Samples Test |
|||||||||
|
Paired Differences |
t |
df |
Sig. (2-tailed) |
|||||
Mean |
Std. Deviation |
Std. Error Mean |
95% Confidence Interval of the Difference |
||||||
Lower |
Upper |
||||||||
Pair 1 |
tshm1 - tshm3 |
.2975 |
.1806 |
.0285 |
.2398 |
.3552 |
10.421 |
39 |
<0.0001 |
Pair 2 |
tshm1 - tshm6 |
1.0520 |
.4241 |
.0671 |
.9164 |
1.1876 |
15.687 |
39 |
<0.0001 |
Pair 3 |
tshm1 - tshm12 |
2.13900 |
.43447 |
.06870 |
2.00005 |
2.27795 |
31.137 |
39 |
<0.0001 |
Pair 4 |
tshc1 - tshc3 |
-.00250 |
.15094 |
.02387 |
-.05077 |
.04577 |
-.105 |
39 |
.917 |
Pair 5 |
tshc1 - tshc6 |
.02425 |
.16481 |
.02606 |
-.02846 |
.07696 |
.931 |
39 |
.358 |
Pair 6 |
tshc1 - tshc12 |
-.01975 |
.09119 |
.01442 |
-.04891 |
.00941 |
-1.370 |
39 |
.179 |
Paired Samples Statistics |
|||||
|
Mean |
N |
Std. Deviation |
Std. Error Mean |
|
Pair 1 |
ftm1 |
1.344 |
40 |
.2514 |
.0398 |
ftm3 |
1.3405 |
40 |
.24378 |
.03855 |
|
Pair 2 |
ftm1 |
1.344 |
40 |
.2514 |
.0398 |
ftm6 |
1.376 |
40 |
.2386 |
.0377 |
|
Pair 3 |
ftm1 |
1.344 |
40 |
.2514 |
.0398 |
ftm12 |
1.3848 |
40 |
.24305 |
.03843 |
|
Pair 4 |
ftc1 |
1.3182 |
40 |
.30809 |
.04871 |
ftc3 |
1.3288 |
40 |
.29803 |
.04712 |
|
Pair 5 |
ftc1 |
1.3182 |
40 |
.30809 |
.04871 |
ftc6 |
1.327 |
40 |
.2894 |
.0458 |
|
Pair 6 |
ftc1 |
1.3182 |
40 |
.30809 |
.04871 |
ftc12 |
1.330 |
40 |
.2986 |
.0472 |
Paired Samples Test |
|
||||||||
|
Paired Differences |
|
|
|
|||||
Mean |
Std. Deviation |
Std. Error Mean |
95% Confidence Interval of the Difference |
||||||
Lower |
Upper |
t |
df |
Sig. (2-tailed) |
|||||
Pair 1 |
ftm1 - ftm3 |
.00375 |
.05917 |
.00936 |
-.01517 |
.02267 |
.401 |
39 |
.691 |
Pair 2 |
ftm1 - ftm6 |
-.0315 |
.0693 |
.0110 |
-.0537 |
-.0093 |
-2.875 |
39 |
.007 |
Pair 3 |
ftm1 - ftm12 |
-.04050 |
.06752 |
.01068 |
-.06209 |
-.01891 |
-3.794 |
39 |
.001 |
Pair 4 |
ftc1 - ftc3 |
-.01053 |
.05587 |
.00883 |
-.02839 |
.00734 |
-1.191 |
39 |
.241 |
Pair 5 |
ftc1 - ftc6 |
-.00875 |
.05543 |
.00876 |
-.02648 |
.00898 |
-.998 |
39 |
.324 |
Pair 6 |
ftc1 - ftc12 |
-.01200 |
.05317 |
.00841 |
-.02900 |
.00500 |
-1.427 |
39 |
.161 |
Other hypotheses include changes in the affinity of TH receptors, TH binding, bioavailability and metabolism, induced constitutive activation of the TSH receptor, and interference with the TSH assay. Additionally, it cannot be excluded that elevated TSH values may not necessarily reflect hypothyroidism, but could represent recovery from a nonthyroidal illness, mild resistance to TH, or obesity, as is the case in many patients with DM receiving metformin.8
Additionally, metformin treatment resulted in a significant decrease in the nodular size (30-55%) in insulin-resistant patients with thyroid nodules, possibly through its action on the insulin signalling pathway.12 The promising role of metformin as adjuvant therapy in the management of thyroid cancer, especially in diabetic patients is seen through various studies. Metformin has an antimitogenic and proapoptotic effect in thyroid carcinoma cell lines and augments the antiproliferative effect of chemotherapeutic agents, such as doxorubicin and cisplatin. Furthermore, it was found to inhibit insulin-induced growth stimulation via interference with the insulin/IGF signalling and the AMPK/mTOR pathway.13Similarly, treatment with metformin suppressed growth and metastatic potential in medullary thyroid carcinoma cells by down regulating the mTOR pathway.5
- Rotondi M, Cappelli C, Magri F, Botta R, Dionisio R, Iacobello C, et al. Thyroidal Effect of Metformin Treatment in Patients With Polycystic Ovary Syndrome. Clin Endocrinol (Oxf). 2011;75(3):378-81.
- Isidro ML, Penín MA, Nemiña R, Cordido F. Metformin reduces thyrotropin levels in obese, diabetic women with primary hypothyroidism on thyroxine replacement therapy. Endocrine. 2007;32(1):79-82.
- Cappelli C, Rotondi M, Pirola I, Agosti B, Gandossi E, Valentini U, et al. TSH-lowering effect of metformin in type 2 diabetic patients: differences between euthyroid, untreated hypothyroid, and euthyroid on L-T4 therapy patients. Diabetes Care. 2009;32(9):1589-90.
- Cappelli C, Rotondi M, Pirola I, Agosti B, Formenti A, Zarra E, et al. Thyreotropin levels in diabetic patients on metformin treatment. Eur J Endocrinol. 2012;167(2):261-5.
- Klubo-Gwiezdzinska J, Jensen K, Costello J, Patel A, Hoperia V, Bauer A, et al. Metformin inhibits growth and decreases resistance to anoikis in medullary thyroid cancer cells. Endocr Relat Cancer. 2012;19(3):447-56.
- Lim CT, Kola B and Korbonits M. AMPK as a mediator of hormonal signalling. J Mol Endocrinol. 2010;44(2):87-97.
- Bogachus LD and Turcotte, LP. Genetic downregulation of AMPK-alpha isoforms uncovers the mechanism by which metformin decreases FA uptake and oxidation in skeletal muscle cells. Am J Physiol Cell Physiol. 2010;299(6):C1549-61.
- López M1, Varela L, Vázquez MJ, Rodríguez-Cuenca S, González CR, Velagapudi VR, et al. Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance. Nat Med. 2010;16(9):1001-8
- Łabuzek K, Suchy D, Gabryel B, Bielecka A, Liber S, Okopień B et al. Quantification of metformin by the HPLC method in brain regions, cerebrospinal fluid and plasma of rats treated with lipopolysaccharide. Pharmacol Rep. 2010;62(5):956-65.
- Chau-Van C, Gamba M, Salvi R, Gaillard RC, Pralong FP. Metformin inhibits adenosine 5′-monophosphate-activated kinase activation and prevents increases in neuropeptide Y expression in cultured hypothalamic neurons.Endocrinology. 2007;148(2):507-11.
- Ortega-González C, Cardoza L, Coutiño B, Hidalgo R, Arteaga-Troncoso G, Parra A. Insulin sensitizing drugs increase the endogenous dopaminergic tone in obese insulin-resistant women with polycystic ovary syndrome.J Endocrinol. 2005;184(1):233-9.
- Rezzónico J, Rezzónico M, Pusiol E, Pitoia F, Niepomniszcze H. Metformin treatment for small benign thyroid nodules in patients with insulin resistance.Metab Syndr Relat Disord. 2011;9(1):69-75.
- Chen G, Xu S, Renko K, Derwahl M. Metformin inhibits growth of thyroid carcinoma cells, suppresses self-renewal of derived cancer stem cells, and potentiates the effect of chemotherapeutic agents.J Clin Endocrinol Metab. 2012;97(4):E510-20.