Long-Term Levothyroxine Use May Reduce CV Risk In Older Adults

Levothyroxine has remained the cornerstone of hypothyroidism therapy for decades. The benefits of levothyroxine replacement are well established and typically evident on standard laboratory parameters within weeks of initiating therapy in most patients. However, the potential benefits of long-term levothyroxine therapy extend beyond correcting levels of the “low” thyroid hormone in the elderly. For certain older adults, it may serve to decrease the risk of cardiovascular disease. Thyroid hormone exerts wide-ranging effects on energy expenditure and parameters that are known to predict cardiovascular risk, including heart rate, lipid levels, blood pressure, and body temperature. However, optimizing levothyroxine therapy in elderly patients is not without risk, and both too little and too much of this hormone can have significant unwanted effects. While the symptoms of too little levothyroxine are typically more disabling, fewer immediate symptoms are apparent with too much, but its use is associated with an increased risk of atrial fibrillation, falls, frailty, and bone loss. A new message appears to be emerging regarding the treatment of individuals with thyroid abnormalities, including milder abnormalities. Contrary to previous warnings that every middle-aged or older person with even mild thyroid abnormalities should not receive vigorous thyroid hormone replacement therapy with levothyroxine on a long-term basis, such treatment appears to have health benefits that outweigh risks for many patients, provided the dose is appropriately individualized and overtreatment is avoided.

Why It Matters

Thyroid hormone has both direct and indirect effects on the cardiovascular system, and as a result, the time of initiation of thyroid hormone replacement therapy in the older patient is of considerable importance. Hypothyroidism is associated with decreased heart rate, decreased vascular compliance, increased cholesterol levels and decreased cardiac output. Each of these factors can be of particular concern in the older patient with additional hypertension, coronary artery disease, congestive heart failure, decreased functional reserve and other co-morbid diseases. Mild thyroid dysfunction may have significant effects on an individual’s energy level, exercise capacity, cognitive function and ability to recover from acute illness, affecting patients far beyond the parameters of a single laboratory test.

While the effect of continued levothyroxine on thyroid function tests is important to manage patient care, many clinicians are interested in the impact of continued levothyroxine on long-term clinical outcomes. Observational studies have addressed this clinical question and found that many older patients with subclinical hypothyroidism are at lower risk of future cardiovascular events. Importantly, these patients were on levothyroxine therapy with TSH levels above the age-referenced upper limit of normal. The hypothesis that long-term levothyroxine therapy can decrease risk of stroke, myocardial infarction, vascular disease, and decline in cardiovascular health is an exciting area of research.

While evidence supports the use of thyroid hormone replacement in the management of hypothyroidism, evidence is mixed regarding benefits of such treatment in older and even young patients. Previous studies including those that included older patients with mild subclinical hypothyroidism included numerous randomized clinical trials of patients with either overt or subclinical hypothyroidism in which treatment had no benefit in relieving hypothyroid symptoms or in improving either clinical or laboratory indicators of cardiac disease and, importantly, did not reduce the risk of myocardial infarction or other serious cardiovascular events during brief follow-up periods. However, more recent studies, including some cohort-based analyses of subclinical hypothyroidism, have suggested that patients with this condition may be at greater risk of adverse cardiovascular events with advancing age. Not all studies have found benefits of subclinical hypothyroidism treatment or results have been inconsistent. Additionally, some studies have suggested an increased risk of events such as fractures or even death in patients treated for subclinical hypothyroidism.

Although the long-term effects of levothyroxine therapy on the risk of cardiovascular disease remain uncertain, optimal therapy is paramount to avoid adverse effects of excessive levels of thyroid hormones. Patients may experience symptoms of excessive thyroid hormone such as palpitations, worsening of ischemic symptoms and development of new onset atrial fibrillation. In contrast, patients who are undertreated may experience continued elevated cholesterol levels and fatigue, in addition to a host of other symptoms including cognitive impairment, muscle weakness, muscle aches, dry skin, hair loss, poor digestion with constipation, and decreased physical capability. A more informed decision regarding the benefits of levothyroxine therapy and its potential risks and side effects must be made for the older, hyperthyroid patient. This issue serves as a guide to monitoring patients on levothyroxine replacement therapy in order to avoid undertreatment and overtreatment.

Thyroid hormone replacement can have a profound impact on the quality of life of older individuals with thyroid disease. However, the impact of appropriate thyroid hormone replacement does not stop there. It can also have a positive impact on the health-systems that serve older individuals with cardiovascular disease, which consumes a large proportion of costs, disabilities and hospital visits for this age group. Reducing cardiovascular events may seem like a modest goal, but avoiding arrhythmias and ischemic events could translate into fewer unscheduled visits to the emergency department and fewer hospitalizations. Many patients and their families, as well as physicians and health systems, would view such outcomes as very valuable, especially if they translate into improved ambulation and disability-free time. Even less expensive therapies have value when used appropriately and monitored.

The way in which subclinical hypothyroidism is perceived by the clinician managing the patient in older age also needs consideration. Mildly elevated TSH levels are a common finding in the elderly. Not all abnormal results, however, reflect disease that requires treatment. Some of the mildly elevated TSH levels encountered in the elderly are best regarded as a feature of normal aging and not as thyroid failure of significance. The interpretation of results of TSH measurement therefore has to take account of age. If the threshold for starting and continuing thyroid replacement is set too low, many patients will be placed on long-term therapy without benefit. It is clearly important not to set the threshold too high and miss the opportunity to treat patients for whom there really is an increased thyroid-related risk of cardiovascular disease. However, the knowledge that longer term levothyroxine suppression may further reduce risk of cardiovascular disease makes this a particularly important decision.

Who It Affects

Patients with diagnosed hypothyroidism will likely be the oldest group affected by these developments. Currently, they take levothyroxine on a daily basis and can expect their discussions with their clinicians regarding this medication to take on a new perspective. Many patients will be pleased to learn that levothyroxine is indicated for the treatment of fatigue, cold intolerance, constipation, cognitive slowing and the weight-related metabolic changes associated with hypothyroidism. Patients on optimal doses of thyroid hormone may also benefit from reduced risk of cardiovascular disease. Therefore, patients will gain a better understanding of the benefits of their current treatment.

In addition to the elderly patient with established hypothyroidism, the older adult with subclinical hypothyroidism is an important group, especially for the 65 year old and older patient. Many of these patients have thyroid test results that suggest normal aging versus mild disease. Such patients’ treatment decisions are often very individualized and sometimes surprising to the patient and the physician. Many of these patients report feeling sick because of their thyroid, while others are discovered to have the condition during preanesthesia evaluation or as a result of a routine health maintenance physical examination. New research is helping to clarify management of the patient with subclinical hypothyroidism and their observation versus further thyroid testing or treatment. The research may also provide insight into the appropriate interval between thyroid function tests and the rate of thyroid hormone replacement medication adjustment.

For many patients with thyroid disease, the impact of these developments will be felt first by the clinicians who administer most of the thyroid hormone replacement therapy in the community, primarily primary care physicians and other clinicians such as general practitioners, family physicians, internists, and nurse practitioners. These health care providers will be responsible for identifying abnormal TSH levels, starting and titrating doses of levothyroxine to optimal levels, scheduling and interpreting follow-up TSH lab values and monitoring for both beneficial and adverse effects of thyroid hormone replacement over time. For the clinician caring for the growing elderly population, future studies identifying the long-term effects of levothyroxine on the cardiovascular system will provide guidance in using age-adjusted TSH levels to appropriate thyroid hormone replacement and determining an appropriate interval for thyroid monitoring in patients with multiple comorbidities.

Future research is needed to translate these findings to clinical practice, requiring the input of endocrinologists and geriatricians. Endocrinologists will be needed to decide whether a patient’s symptoms are related to thyroid function and to advise on the treatment of the elderly person with a fluctuating TSH; with possible impaired thyroid hormone absorption; with drug interactions; with symptoms that cannot be explained by TSH; or with difficulties in up-titrating thyroid hormone replacement. The geriatrician needs to weigh the benefits of thyroid treatment against the background of frailty, risk of falls, cognitive impairment, polypharmacy, renal impairment and life expectancy. In very old people the aim of treatment might not be to strive for perfect biochemical normalisation of thyroid function but to achieve stable euthyroidism with minimal treatment and minimal harm.

As more elderly patients with a variety of concurrent cardiovascular conditions require medical attention, patients and doctors alike can anticipate that specialists such as cardiologists will become increasingly involved in the administration of thyroid replacement therapy, a field in which they may not be fully experienced. In patients with atrial fibrillation, coronary artery disease, heart failure, and a history of stroke, both the overtreatment of hyperthyroidism and the undertreatment of hypothyroidism may result in serious and potentially life-threatening complications. Therefore, it is anticipated that the management of the dose of thyroid hormone for the elderly patient with significant heart disease will require increased cooperation among the primary care physician, endocrinologist, and cardiologist.

In addition to affecting the patient, thyroid treatment and its management can have an impact on their family members and caregivers. Family members and caregivers of older patients on levothyroxine may assist with treatment, accompany them to appointments and drive them to specialist visits. Patients and their families( caregivers) need to have a clear understanding of the reasons for ongoing levothyroxine therapy, the timing and amount of the levothyroxine dose(s) each day, and potential side effects such as palpitations or dizziness. Additionally, patients and their families need to have a clear understanding of the signs and symptoms that require medical assessment.

Payers and health systems are eager to determine the bottom line for the ongoing management of hypothyroidism with levothyroxine. The cost of levothyroxine is modest but the long-term management of hypothyroidism incurs many other expenditures such as laboratory tests, clinical visits, dose adjustments and occasional referral to a specialist in thyroid disease. On the positive hand, evidence indicates that ongoing management of the older hypothyroid patient can be cost-effective by preventing major cardiovascular disease. On the negative hand, the consequences of inadequate, unsupervised therapy include increased rates of arrhythmias, osteoporotic fractures, hospitalization for thyroid-related problems and inappropriate dose of levothyroxine.

What Changes

• Clinicians may place greater emphasis on individualized, evidence-based continuation of levothyroxine in older patients, balancing cardiovascular benefits against risks like atrial fibrillation and bone loss.
• Monitoring practices could shift toward more consistent, targeted TSH testing and dose adjustments with clear thresholds for when to aim for tighter control versus a more conservative approach.
• Health systems may reassess screening and treatment thresholds for mild thyroid dysfunction in seniors, with potential implications for primary care workflows and referrals to endocrinology.
• Policymakers and payers might evaluate coverage and quality metrics to support sustained, safe thyroid replacement — including access to medication, patient education, and systems that reduce inappropriate dose changes from drug interactions or generic-switch confusion.

Why clinicians should pay attention

Levothyroxine is used to “replace” deficient thyroid hormone levels to relieve hypothyroid symptoms in patients, but its effect on long-term outcomes of older patients with hypothyyroidism is less clear. This question is pertinent to the clinician, and can guide management of mildly elevated TSH levels, the need for frequent monitoring of patients on replacement therapy, and the complicating factors of polypharmacy, alterations in absorption of oral thyroid hormone with age, and decreased health status in the decision to continue or discontinue levothyroxine therapy.

A number of safety considerations should be kept in mind when providing levothyroxine to older adults. Dosing should begin at a conservative level and then increased based on clinical findings. Providers should check the TSH after any change in the dose of levothyroxine and check the TSH level on occasion to assure that the patient is within the therapeutic range. Both providers and patients should be aware of the symptoms of overtreatment (i.e., palpitations, unexplained weight loss, increased risk of osteoporotic fractures). Patients should have a good understanding of how to take their levothyroxine appropriately (on an empty stomach in the morning), and be aware of which of their current or past supplements or medications might interfere with levothyroxine absorption (e.g., calcium and iron).

Patient experience and practical concerns

Many of your patients are already on multiple medications and multiple visits for multiple conditions. They likely see the continued levothyroxine to prevent cardiac events as a fair tradeoff for the increase in pill burden and the fatigue of managing their therapy for a life-long condition. A discussion of levothyroxine therapy in the context of overall health, including the role of thyroid hormone in heart health, will help them understand the physician’s decision to continue their life-long therapy.

While cost and access to levothyroxine are concerns in some situations, levothyroxine is generally inexpensive and readily available. A more difficult issue is distinguishing brand name from generic forms, the dispensing pharmacist substituting one levothyroxine preparation for another, and different strengths of levothyroxine. A system for ascertaining whether a dose change has occurred and for educating patients about their levothyroxine medication, as well as for involving pharmacists in the process of communication and dispensing, can help to prevent harm.

System-level trade-offs and policy considerations

Scaling up treatment to address risk of cardiovascular events in postmenopausal women at low cost might be very attractive to payers and public health planners at large scale. However, implementation in real-world practice would need to thoughtfully address increases in monitoring and specialist visits as well as the need for quality measures and clinical pathways. Specifically, any efforts to use hormone therapy in older women to potentially prevent cardiovascular events must be balanced with potential safety concerns.

Future workforce implications include the need for increased endocrinology consultation for more complex cases and the need to educate primary care physicians and staff about age appropriate thyroid care. There is also a future opportunity to use telemedicine to safely provide follow-up care to patients and their families while potentially decreasing in person visits. This model must address payment and equity of access and be implemented and supported specifically for older adults.

Looking ahead

Translating these findings into clinical practice is crucial and warrants further research on 1) development of clear recommendations for initiation and continued levothyroxine treatment in older adults; 2) proposal for reasonable frequency of monitoring of levothyroxine treatment in older adults; and 3) decision-aiding instruments for clinicians and their patients to weigh the potential risks and benefits of levothyroxine treatment. Future research includes longitudinal studies of healthy and diseased older white and non-white populations as well as studies assessing functional status and real-world adherence.

It is time for updated and practical clinical guidelines to be implemented in our daily practice and considered by policymakers. For them the question will be: is a modest investment in monitoring and coordination of hypothyroid patients in due time going to pay off by preventing cardiovascular events? Patients with hypothyroidism have a right to be well managed and to understand that with appropriate levothyroxine replacement on time and a reality-based understanding of current aging therapy options, they can promote heart health while maintaining quality of life.

Hypothyroidism treatment involves the use of levothyroxine and recent studies suggest that long-term suppression of hypothyroidism may have cardiovascular benefits. Safe translation of these studies into improved health outcomes of older adults with hypothyroidism will require informed clinical decisions, systems of care for adult treatment of hypothyroidism, and continued identification of benefits and harms.

References:

https://pmc.ncbi.nlm.nih.gov/articles/PMC8173189/