To study effects of metformin on thyroid functions in type-2 diabetes mellitus in patients attending OPD at Government Medical College, Bidar

ABSTRACT

Introduction:

Metformin is one of the most used diabetes treating agents and has proved to be very effective, with a wide spectrum of efficacy, safety as well as being as agent that works at different spots in diabetes pathogenesis paradigm. Recently it has been reported that metformin is able to interfere with thyroid hormone profile, by decrease in the serum levels of thyrotropin (TSH) to subnormal levels in hypothyroid patients in stable levothyroxine (L-T4) treatment.

Objectives:

To study and compare the effect of metformin and non-metformin composed treatment of type-2 diabetes mellitus on thyroid functions.

Methods:

Comparative observational study was conducted among diabetic patients taking metformin as study and taking antidiabetic other than metformin as control group and analysed for the thyroid profile (TSH, fT3, fT4). Total 70 patients including both group from tertiary care teaching hospital were enrolled in to the study after taking informed verbal consent.

Observations:

The present study demonstrates that while the study group’s fT3 and fT4 levels were lower than those of the control group, diabetic patients on non-metformin medication had statistically higher TSH (2.05 ± 0.15 mIU/mL vs. 2.35 ± 0.18 mIU/mL) levels than those taking metformin.

Conclusion:

Thyroid-stimulating hormone (TSH) levels may be somewhat or not at all decreased by metformin. Thyroid function monitoring is crucial for diabetic patients using metformin, particularly if they already have thyroid problems.

Introduction

One of the most widely used oral hypoglycaemic medications for type-2 diabetes is metformin. By reducing hepatic gluconeogenesis and activating AMP-activated protein kinase (AMPK), this biguanide derivative works as an insulin sensitizer in the liver and enhances glucose absorption in the skeletal muscles. It does not have any clinically significant medication interactions and has comparatively low negative effects. As a result, it is often considered a safe medication.[1]

Both diabetes mellitus (DM) and hypothyroidism are chronic conditions that have a lasting impact on cardiovascular morbidity and death. Cardiovascular risk factors like hypertension and hyperlipidaemia are further elevated by hypothyroidism. Patients with type-2 diabetes are more likely to have hypothyroidism. According to the estimates, the prevalence of thyroid disorders in the general Indian population is 10%, however in the diabetic population, it is 24.8%.[2,3,4]

The effect of metformin on thyroid function has been the subject of numerous recent investigations. Studies that examined thyroid function in diabetic individuals taking metformin found little to no evidence that the medication increased the incidence of thyroid dysfunction in people with type 2 diabetes. Better diabetes treatment may help prevent thyroid-related problems, they said, adding that poor glycaemic control may be a contributing factor to thyroid dysfunction. Furthermore, studies showed that metformin reduced thyroid-stimulating hormone (TSH) levels in patients with subclinical hypothyroidism, especially in those with baseline TSH levels higher than 5 mIU/L and TPO-Ab positive results.[5,6,7,8]

Considering this, an observational study was designed to examine whether the Metformin therapy significantly affects thyroid function parameters like TSH, T3, T4 levels in patients with type-2 diabetes Mellitus attending the OPD at Government Medical College, Bidar.

Materials and Methods

Comparative observational study was conducted among diabetic patients taking metformin as study and taking antidiabetic other than metformin as control group. Patients with diabetes, who visited the Medicine Outpatient Department of the Tertiary Care Teaching Hospital in North Karnataka participated in the study. Prior to the study’s commencement, institutional ethics clearance and consent from known diabetic cases were obtained.

The study group consisted of known cases of type-2 diabetics taking tablets of Metformin for longer than 6 months, either by themselves or in conjunction with other anti-diabetic drugs. The control group consisted of known cases of diabetics taking tablets other than Metformin. The study excluded diabetic individuals with known thyroid conditions, those on antithyroid meds, those taking medications that alter thyroid function, pregnant women, and those with any other comorbidities.

A sample size of 70 is determined using n = Z²P (1 − P)/d², considering the prevalence of 9% thyroid dysfunction among diabetes patients with an admissible error of 5% with a 95% confidence interval. Of the 70, half (n = 35) were assigned to the metformin-using study group, while the remaining members were assigned to the non-metformin-using control group.

A proforma comprising the patient’s sociodemographic profile, diabetes treatment data, thyroid history, and other comorbidities was used to gather information. Thyroid profiles (TSH, fT3, fT4) of individuals with known type-2 diabetes mellitus are evaluated using these investigations. Following venipuncture, a 2 mL fasting venous blood sample was collected in a serum vacutainer. The hospital’s central laboratory conducted the TSH, fT3, and fT4 level testing. At the 6-month follow-up visit, the patient was monitored and a second sample was taken. SPSS software was used for the statistical analysis, and the test of association was applied correctly. Every statistical test was deemed significant if the P value was less than 0.05.

Results

Following verbal informed permission and an explanation of the study’s purpose, a total of 38 participants were enrolled in the study group and 38 in the control group.

The study group’s mean age was 40.5 years, while the control groups was 41.1 years, as shown in Table 1. Males outnumbered females, and most participants were between the ages of 41 and 50. The subjects’ Body Mass Index (BMI) fell within the typical range. Most participants held salaried positions (private more than government) and were educated and read. Other than diabetes, most patients had no other associated morbidities. The individuals’ distribution across the different factors was not deemed statistically significant [Table 1].

Table 1.

Distribution of the participants according to socio-demographic details

Variables	Study group (n=38)		Control group (n=38)		Chi-square (P)
	Number	%	Number	%
Age group
Mean±SD	40.5±09		41.1±08		0.722 (0.65)
41 to 50 years	22	58%	24	63%
51 to 60 years	11	29%	08	21%
>60 years	05	13%	06	16%
Gender
Male	24	63%	27	71%	0.238 (0.62)
Female	14	37%	11	29%
BMI
<18.5	06	15%	07	18%	0.951 (0.09)
18.5 to 25	23	61%	22	58%
>25	09	24%	09	24%
Education
Illiterate	11	29%	15	39%	0.935 (0.33)
Literate	27	71%	23	61%
Occupation
Non-working/Retired	08	21%	07	18%	0.51 (0.91)
Salaried job	16	42%	19	50%
Business	04	11%	03	08%
Housemaker	10	26%	09	24%
Morbidity status
Present	09	24%	11	29%	0.27 (0.60)
Absent	29	76%	27	71%

Table 2 shows that the mean age at which diabetes first appeared in each group was 42 years for the study group and 43 years for the control group. Most patients were between the ages of 41 and 50 when their diabetes first appeared, and the total duration for both groups was at least 5 years and up to 10 years. Twenty-one percent of the study group and twenty-four percent of the control group had a history of any systemic problem brought on by diabetes. The study’s mean HbA1c was 6.4%, while the control groups was 6.1%. Neither group’s distinctive distribution was deemed statistically significant.

Table 2.

Distribution of the participants according to diabetes profile

	Study group (n=38)		Control group (n=38)		Tests of significance (P)
	Number	%	Number	%
Age of onset
Mean±SD	42±07		43±05		Chi-square 0.477 (0.78)
Before 30 years	06	16%	05	13%
31 to 40 years	13	34%	11	29%
41 to 50 years	19	50%	22	58%
Total duration
1 to 5 years	03	08%	06	16%	Chi-square 1.243 (0.53)
5 to 10 years	25	66%	24	63%
>10 years	10	26%	08	21%
h/o systemic complications
Yes	30	79%	29	76%	Chi-square 0.075 (0.783)
No	08	21%	09	24%
HbA1c
Mean±SD	6.4%±1.4		6.1%±1.2		t-1.003 (0.31)

In Table 3 thyroid profile for both groups indicates that the control group’s blood TSH level was noticeably higher than that of the study group. Also, the TSH level of study group found significantly increased compared to baseline levels. Although the control group had lower levels of free T3 and free T4 than the study group, the difference was not deemed statistically significant. There are no significant variations among the control group baseline levels and after six-month levels.

Table 3.

Thyroid profile of the participants in both groups

Variables	Mean±SD		t-test, (P)
	Study group (n=38)	Control group (n=38)
Serum TSH (mIU/L)
Baseline	2.01±0.10	2.31±0.07	3.946 (0.002)
After 6 months	2.09±0.15	2.35±0.18
t-test (P)	2.736 (0.007)	1.277 (0.20)
Free T3 (pmol/L)
Baseline	4.56±0.51	4.40±0.90	1.225 (0.22)
After 6 months	4.54±0.71	4.32±0.85
t-test (P)	0.953 (0.343)	0.398 (0.69)
Free T4 (pg/mL)
Baseline	14.03±45.10	14.04±1.09	0.075 (0.93)
After 6 months	14.82±55.19	14.14±2.01
t-test (P)	0.952 (0.06)	0.269 (0.788)

Discussion

The present study demonstrates that while the study group’s fT3 and fT4 levels were lower than those of the control group, diabetic patients on non-metformin medication had statistically higher TSH levels than those taking metformin.

According to a review by Sharma et al.,[9] metformin has very little influence on thyroid function in people with type-2 diabetes. People with hypothyroidism have mild changes in their thyroid hormone levels. Although metformin is typically safe for thyroid function, regular thyroid tests and customized treatment are still necessary. They also talked about how difficult it is to distinguish between the effects of metformin and the progression of thyroid disorders in diabetic populations.

According to a review by Green et al.,[10] most patients’ thyroid function does not seem to be adversely impacted by metformin, a medication that is frequently used to treat diabetes. Mild changes in thyroid levels in people, who already have thyroid illness. They also underlined the necessity of closely monitoring thyroid function in diabetes individuals using metformin and the need for longer-term research to completely comprehend its effects.

To assess the impact of metformin on thyroid hormone levels in diabetic patients, Li et al.,[11] reviewed data from numerous cohort studies. Metformin may have an impact on peripheral thyroid hormone metabolism, although it does not appear to directly change thyroid hormone production or secretion. Additionally, they advise patients using metformin to have regular thyroid function tests, especially if their baseline thyroid function has disturbed.

According to a review by Patel et al.,[12] metformin does not appear to have a substantial impact on thyroid function in diabetics. However, the authors also talked about how treating diabetes may become more difficult in the Indian population if thyroid dysfunction and diabetes coexist. Additionally, it was underlined how important it is to periodically check thyroid function, especially in patients with diabetes, who have had the condition for a longer period or who have thyroid illness because metformin might change insulin sensitivity, which may have an impact on peripheral thyroid hormone metabolism.

According to a systematic analysis by Jafari et al.,[13] metformin typically had no significant effects on TSH levels or thyroid function in general. Additionally, they pointed out that metformin may occasionally affect the bioavailability or absorption of thyroid drugs, making it more difficult to treat hypothyroid individuals receiving combination therapy. Emphasized the significance of routinely evaluating thyroid functions to spot any minute variations in thyroid activity when using metformin.

In their review, Anderson et al.,[14] discovered conflicting evidence: some reported a modest drop in TSH levels in diabetes individuals using metformin, while others showed no discernible change in thyroid function indicators. Additionally, it was hypothesized that the way metformin affects thyroid hormone metabolism is probably indirect and could be impacted by age, gender, and thyroid conditions.

According to Wang et al.’s[15] meta-analysis, there is not enough proof to establish that metformin alters thyroid hormone levels in most diabetic patients in a way that is clinically meaningful. The authors also noted that thyroid indicators may fluctuate slightly in certain individuals, such as those with chronic diabetes or those on other drugs. Additionally, it was indicated that while routine screening is not required for all metformin users, it should be taken into consideration for individuals, who have signs of thyroid disease or known thyroid dysfunction.

Since the study is observational in nature, it is unable to prove a link between the use of metformin and variations in thyroid parameter levels, which could be impacted by several confounding variables. Multicentre randomized clinical studies are therefore necessary to support the study’s conclusions.

Conclusion

TSH levels were statistically greater, while fT3 and fT4 levels were lower in diabetic individuals on non-metformin medication than in those on metformin. In conclusion, since diabetes and thyroid dysfunction are both endocrine disorders, they may have an impact on one another. Thyroid function is somewhat impacted by metformin, a medication that is frequently used to treat type-2 diabetes. TSH levels may be somewhat or not at all decreased by metformin. Thyroid function monitoring is crucial for diabetic patients using metformin, particularly if they already have thyroid problems. This helps to ensure that both illnesses are managed as best they can. To elucidate the long-term consequences and develop protocols for tracking thyroid function in these patients, more investigation is needed.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.