Cancer-Related Thyroidectomy Linked to Increased Diabetes Risk

People with thyroid cancer treated with thyroidectomy have as much as a 40% increased risk of developing type 2 diabetes, regardless of their age, with the elevated risk observed with low as well as high doses of postoperative levothyroxine, new research shows.

“This is the first population-based study to demonstrate an elevated risk of type 2 diabetes in post-thyroidectomy patients with thyroid cancer, compared with that in matched controls,” write the authors in research published recently in the Journal of Clinical Endocrinology & Metabolism.

“Notably, there was a U-shaped relationship between postoperative levothyroxine dosage, a surrogate marker of TSH suppression, and the risk of type 2 diabetes,” say Hye Jin Yoo, MD, of the Division of Endocrinology and Metabolism, Korea University College of Medicine, in Seoul, and colleagues.

While other studies have linked thyroidectomy for thyroid cancer with an elevated risk for other metabolic conditions, including coronary heart disease and ischemic stroke, the relatively high diabetes risk is unexpected, commented Tyler Drake, MD, an endocrinologist with the Minneapolis VA Health Care System.

“A 40% increased risk of diabetes is a big surprise,” he told Medscape Medical News.

“Diabetes is very common, with about one in 10 US adults having type 2 diabetes, but a 40% increased risk in thyroid cancer patients is higher than I see in my clinical practice. [However], it is important to note that the [highest] risk was predominantly among the groups on the lowest and highest doses of levothyroxine,” said Drake, who is also assistant professor of medicine at the University of Minnesota, Minneapolis.

U-Shaped Relationship Between Levothyroxine Dose and Diabetes Risk

The findings are from a study of 36,377 patients with thyroid cancer in the National Health Insurance Service (NHIS) database in Korea who had undergone a thyroidectomy between 2004 and 2013.

The patients were matched 1:1 with controls who had nonthyroid cancers. Their mean age was 46.6 years, about 30% were male, and their mean body mass index (BMI) was 23.8 kg/m².

Over a mean follow-up of 6.6 years, the patients with thyroid cancer had a significantly higher risk of developing type 2 diabetes, at a rate of 47.5% (10,812) compared with 36.9% (9414; HR, 1.43; P < .001) in the control group, after adjustment for factors such as age, sex, BMI, smoking, drinking, systolic blood pressure, and fasting glucose.

The risk of type 2 diabetes among those with thyroid cancer was higher among the 83.2% of patients who underwent a total thyroidectomy compared with the 16.8% who had a unilateral lobectomy (HR, 1.06; P < .001).

In addition, those with thyroid cancer who received the lowest as well as highest dosages of levothyroxine had significantly higher risks of type 2 diabetes compared with controls (HR, 1.50 and 1.39, respectively; both P < .001).

A closer look at quartiles of levothyroxine dosing showed the first (lowest) quartile (defined as a mean levothyroxine dosage of < 101 μg/day) was associated with an increased risk of type 2 diabetes compared with the second quartile group (101-127 μg/day; HR, 1.45), as was the fourth quartile (≥ 150 μg/day; HR, 1.37), while a decreased risk of type 2 diabetes was observed in the third quartile group (128-149 μg/day versus the second quartile group; HR, 0.91).

“This result suggests a U-shaped relationship between the mean levothyroxine dosage and risk of type 2 diabetes in post-thyroidectomy patients with thyroid cancer,” the authors say.

However, “consistent with previous studies, the present study showed that the highest risk of type 2 diabetes was observed in patients with thyroid cancer who were treated with the lowest mean dosage of levothyroxine,” they note.

“This result suggests that inadequate supplementation of thyroid hormones may worsen glucose metabolism and should therefore be avoided.”

Potential Mechanisms

Abnormal thyroid function, including hypo- and hyperthyroidism, following thyroidectomy and subsequent treatment with levothyroxine is known to have potentially detrimental effects on glucose regulation among patients with thyroid cancer.

The potential mechanisms linking hypothyroidism with diabetes specifically include the possibility that insulin becomes unable to promote the utilization of glucose by muscles and adipose tissue. However, thyroid hormone replacement has been associated with a normalization of insulin sensitivity, the authors note.

Meanwhile, glucose intolerance is common among patients with hyperthyroidism, largely due to an increase in hepatic glucose production, and likewise, the normalization of thyroid levels among those treated with methimazole has been linked to normalization of glucose and lipid metabolism alterations.

Drake noted that an important study limitation is that patients were analyzed based on their levothyroxine dose and not their TSH values, which the authors explain was due to the unavailability of the TSH values. 

“By looking at levothyroxine doses, and not TSH values, it is possible some patients were being improperly treated with either too much or too little levothyroxine,” Drake noted.

Control Group Should Have Had Hypothyroidism

Dr Anupam Kotwal

The findings nevertheless shed light on the risk of diabetes following thyroidectomy for thyroid cancer, Anupam Kotwal, MD, commented on the study.

“This study is significant because it addresses an important topic exploring the link between thyroid dysfunction and metabolic disease, in this case…hypothyroidism, due to surgery for thyroid cancer and type 2 diabetes mellitus,” Kotwal, an assistant professor of medicine in the Division of Diabetes, Endocrinology & Metabolism at the University of Nebraska Medical Center, in Omaha, told Medscape Medical News.

In terms of other limitations, Kotwal noted that the controls did not have hypothyroidism, therefore, “from this study, it is impossible to confirm whether hypothyroidism from any cause would be associated with higher incidence of diabetes or if it is specific to thyroid surgery for thyroid cancer.”

“It would have been useful to have a control group of autoimmune primary hypothyroidism to evaluate the rate of diabetes during a similar follow-up duration,” Kotwal said.

“Hence, cohort studies with more granular data such as degree of TSH suppression and having a control group of hypothyroid patients due to autoimmune thyroid disease are needed to better understand this risk.”

Kotwal and Drake have reported no relevant financial relationships.

J Clin Endocrinol & Metab. Published online October 28, 2021. Abstract

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