Surgery, Radioactive Iodine for Hyperthyroidism Up Survival

CHICAGO – Treatment of hyperthyroidism with surgery or radioactive iodine significantly extends survival compared to antithyroid medication, while surgery raises the risk for obesity, new data from a large cohort study suggest.

“I think this is something we need to take into our discussions with patients because treatment for hyperthyroidism is very much individualized decision-making…The effects on mortality are not usually one of the factors we discuss there. But now, we have strong data from a very large cohort of patients indicating that this is something that does need to be discussed,” lead author Kristien Boelaert, MD, who is the current president of the British Thyroid Association, told Medscape Medical News.

Boelaert presented the findings of the EGRET (Weight Changes, Cardio-Metabolic Risks and Mortality in Patients With Hyperthyroidism) study at ENDO 2023: The Annual Meeting of the Endocrine Society.

Other notable findings from EGRET were that the patients on antithyroid medication were thinner than expected, suggesting undertreatment and that no differences were found for major adverse cardiac events (MACE) across the treatment options leaving unexplained the reasons for the increased mortality in the medicated group.  

Asked to comment, session moderator Spyridoula Maraka, MD, told Medscape Medical News: “I think this is very important work because so far when we counsel our patients about the different treatment modalities we focus more on risk for recurrence and other short-term outcomes.”

“But these data give us a bigger perspective on mortality and cardiovascular outcomes…We haven’t had such good quality data to accurately counsel our patients,” added Maraka, of the University of Arkansas for the Medical Sciences, Little Rock.

Mortality Higher for Medication-Treated, but Why?

“Hyperthyroidism or an overactive thyroid gland is common, affecting up to 3% of the population, and is associated with long-term adverse cardiac and metabolic consequences. The optimal treatment choice remains unclear,” explained Boelaert, professor of endocrinology at the University of Birmingham, UK, outlining the reasons they conducted the EGRET study.

The study population was 55,318 patients (77% women) with newly diagnosed hyperthyroidism identified from a UK population-based primary care electronic health record database. Of those, 77.8% were treated with antithyroid medication, 14.6% with radioactive iodine, and 7.8% with surgery (total or hemithyroidectomy). The health records were linked with national mortality data and Health Survey England data on body mass index (BMI) for comparison.

Boelaert noted that the trial design “is the best we have” because a randomized clinical trial comparing hyperthyroid treatments would be extremely difficult given the need to individualize therapy and the impossibility of blinding. On the other hand, with the current study, “it’s certainly the largest patient group we’ve looked at.”

Over an average 12.1 years of follow-up, the proportion of patients who died was 14.1% in the medication group, 18.7% of those who had radioiodine therapy, and 9.2% of those who underwent surgery.

Compared with the number who would have been expected to die based on the general background population, the likelihood of reduced life expectancy for the treated groups was increased 2.10-fold for radioiodine, 2.13-fold for surgery, and 2.71-fold for medication. All were significantly higher than the general population (P < .0001).

After further adjustment for multiple confounders, mortality risk was reduced in patients treated with radioiodine (by 13%) or surgery (by 20%), compared with those treated with antithyroid medication, both significant reductions (P < .0001).

After exclusion of the 3.9% with baseline cardiovascular disease, MACE (defined as cardiovascular death or hospitalization for stroke or myocardial infarction) occurred in 9.9%, 13.4%, and 8.0% of the medication, radioiodine, and surgery groups, respectively.

After adjustments, there were no differences in MACE compared with medications, with hazard ratios of 1.00 (P = .94) for radioactive iodine and 0.97 for surgery (P = .61).

“We were expecting to see a reduction in cardiovascular events, as previous studies suggest that radioactive iodine patients have fewer cardiovascular deaths. We did not see that but our protocol wasn’t set up to get every single specific cause of death. That will require further ongoing analysis,” said Boelaert.

Weight Gain: Worth It for Longer Life

Compared with the background population, thyroidectomy was associated with an increased likelihood of developing obesity (BMI > 30 kg/m2) in both men (odds ratio [OR], 1.56; P < .001), and women (OR, 1.27; P < .001), while radioiodine increased obesity risk in women (OR, 1.12; P < .001) but not in men (OR, 1.03; P = .55). 

Among the women, those treated with antithyroid medications had an average 0.28 kg/m2 lower BMI compared with the background population, and those treated with surgery had a 0.83 kg/m2 higher BMI. Both differences were significant (P < .001).

The BMI differences were not significant for radioactive iodine in women and for medications and radioactive iodine in men, although the men treated surgically also had a significantly higher BMI (1.09 kg/m2P < .001).

“The patients on antithyroid drugs were lighter than we would expect. I think that’s ongoing hyperthyroidism. I strongly believe that…to get rid of hyperthyroidism you have to make patients hypothyroid…It’s really important that you get good control,” Boelaert commented.

Maraka, who is also endocrine section chief of the Arkansas Veteran’s Healthcare System, Little Rock, commented: “[Boelaert’s] concern is that the patients on anti-thyroid drugs are not adequately controlled, and we know very well that uncontrolled hyperthyroidism is associated with increased mortality and increased cardiovascular outcomes. This suggests that if patients are on antithyroid medications they should at least be monitored very well.”

Regarding the possible cause of the increased mortality, if not cardiovascular, Maraka also pointed out that typically once antithyroid medications are stopped, about half of patients will stay in remission and the other half will return to hyperthyroidism.

“It might be that this kind of ‘yo-yo’ is what’s actually leading to the increased mortality, compared to patients who had definitive treatment and this problem was taken care of. This is speculation but it might be what we’re seeing,” Maraka observed.

The BMI differences worked out to a weight gain with surgery of approximately 2.1 kg (4.6 lb) for a woman with a height of 160 cm and 2.4 kg for 170 cm. Among men, those differences were 3.2 kg and 3.5 kg for heights of 170 cm and 190 cm, respectively.

Boelaert said, “I think we should discuss this with patients. They will say they don’t want to get fat, but the absolute weight gain is…not that much.”

“I personally think that 2 kg is not a big price to pay to live longer. I hope that’s what we’ll be telling our patients in clinic in the next few years after we get this published.”

Boelaert and Maraka have reported no relevant financial relationships.

ENDO 2023. Presented June 17, 2023.

Miriam E. Tucker is a freelance journalist based in the Washington, DC, area. She is a regular contributor to Medscape, with other work appearing in The Washington Post, NPR’s Shots blog, and Diabetes Forecast magazine. She is on Twitter: @MiriamETucker.

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