Association of inadequately controlled hypothyroidism with major adverse cardiovascular events in type 2 diabetes patients receiving levothyroxine: a retrospective cohort study.
In adults with type 2 diabetes, the increased risk of MACE observed in patients receiving LT4 appears to be driven by inadequately controlled hypothyroidism rather than the medication itself, underscoring the critical importance of achieving and maintaining euthyroidism through careful LT4 dosing and active thyroid-function monitoring.
Key Findings
Results
LT4 users with type 2 diabetes had a higher incidence of MACE compared with matched nonusers.
Study used a retrospective cohort design from the multi-institutional Chang Gung Research Database covering 2006–2017.
New LT4 users were matched 1:1 to nonusers by age, sex, and index date.
Patients with prior LT4 exposure or prior MACE were excluded.
Primary outcome was MACE defined as nonfatal myocardial infarction, nonfatal stroke, or heart failure hospitalization.
Cox proportional hazards models were used to estimate hazard ratios in the matched cohort.
Results
Among the components of MACE, LT4 users specifically showed higher rates of nonfatal stroke and heart failure hospitalization compared with nonusers.
The composite MACE outcome included nonfatal myocardial infarction, nonfatal stroke, and heart failure hospitalization.
Nonfatal myocardial infarction did not show the same differential pattern as stroke and heart failure.
Follow-up extended from the index date to the first MACE event or 31 December 2017.
Results
Subgroup analyses identified older age, male sex, hypertension, diabetic microvascular complications, and end-stage renal disease as factors associated with increased MACE risk among LT4 users.
These subgroup analyses were prespecified.
Subgroups examined included age, sex, hypertension status, presence of diabetic microvascular complications, and end-stage renal disease.
Each of these clinical characteristics was independently associated with increased MACE risk in the context of LT4 use.
These findings suggest that certain high-risk patient subgroups may be particularly vulnerable to cardiovascular events when hypothyroidism is inadequately controlled.
Discussion
The increased cardiovascular risk in LT4-treated type 2 diabetes patients was attributed to inadequately controlled hypothyroidism rather than to LT4 therapy itself.
The authors concluded that the observed MACE risk was driven by failure to achieve euthyroidism, not by the medication per se.
Baseline comorbidities, concomitant medications, and laboratory parameters were assessed as part of the analytical framework.
The authors emphasize the importance of careful LT4 dosing and active thyroid-function monitoring to mitigate cardiovascular risk.
The study population represents a high-risk group given the dual burden of type 2 diabetes and hypothyroidism.
Conclusions
Achieving and maintaining euthyroidism through optimized LT4 therapy was identified as critical for reducing cardiovascular risk in type 2 diabetes patients with hypothyroidism.
The authors underscore 'the critical importance of achieving and maintaining euthyroidism through careful LT4 dosing and active thyroid-function monitoring.'
This recommendation is directed at a population already at elevated cardiovascular risk due to type 2 diabetes.
The retrospective design using real-world data from 2006–2017 supports the clinical applicability of the findings.
The study design could not fully establish causality between inadequate thyroid control and MACE, as it is observational.
What This Means
This research suggests that people with type 2 diabetes who are taking levothyroxine (a thyroid hormone replacement medication) for hypothyroidism have a higher risk of serious cardiovascular events—including stroke and hospitalization for heart failure—compared to similar patients not taking the medication. The study followed thousands of patients in Taiwan between 2006 and 2017, carefully matching treated and untreated patients to make fair comparisons. Importantly, the researchers concluded that the elevated heart risk was not caused by the medication itself, but rather by the fact that many patients' thyroid levels were not being adequately controlled despite treatment.
The study also found that certain groups faced even greater cardiovascular risk: older patients, men, those with high blood pressure, those with diabetes-related kidney or nerve complications, and those with end-stage kidney disease were all at higher risk. These findings highlight that simply prescribing levothyroxine is not enough—patients need regular monitoring to ensure their thyroid hormone levels are actually reaching a normal, healthy range.
This research suggests that for people managing both type 2 diabetes and hypothyroidism, close attention to thyroid function through regular blood tests and medication adjustments may be an important but underrecognized way to reduce the risk of heart attack, stroke, and heart failure. The dual burden of diabetes and poorly controlled thyroid disease appears to create a particularly high-risk situation that warrants careful clinical management.
Lin Y, Hsu C, Liu P, Huang Y, Lin C. (2026). Association of inadequately controlled hypothyroidism with major adverse cardiovascular events in type 2 diabetes patients receiving levothyroxine: a retrospective cohort study.. Endocrine. https://doi.org/10.1007/s12020-026-04651-2