Generic vs Brand-Name Levothyroxine: Same Cardiac Event Risk?

Marlene Busko

July 02, 2019

Patients diagnosed with hypothyroidism (almost all with benign disease) who were prescribed levothyroxine (L-T4) had similar rates of short-term cardiovascular events whether they received a branded product or generic drug in a new study.

However, follow-up was limited and the study lacked information about hormone levels in the blood, the researchers caution.

Specifically, using a large national database, researchers matched almost 44,000 patients who filled an initial prescription for brand name L-T4 — Synthroid, Levoxyl, Levothroid, Unithroid, or Tirosint — with the same number of similar patients who were prescribed generic levothyroxine.  

After an average 1-year of follow-up, rates of hospitalization for atrial fibrillation, myocardial infarction, congestive heart failure, and stroke were similar in both treatment groups in the new study published in the July issue of Mayo Clinic Proceedings.

"There has been disagreement as to whether generic levothyroxine and branded thyroxine preparations are equivalent," says lead author Robert C. Smallridge, MD, Mayo Clinic, Jacksonville, Florida, in a press release issued by his institution. "These findings suggest that generic and brand levothyroxine therapy are similar as related to cardiovascular events risk."

Nevertheless, "this is just one other piece of information in a very large group of patients, [and] it needs follow-up studies," Smallridge told Medscape Medical News. 

Smallridge and colleagues say generic levothyroxine is normally half the price of branded products, but other studies have reported wider variation in pricing.

More Information Needed to Better Inform Clinical Practice

To better inform clinical practice, said Smallridge, it would be necessary to see blood test results for thyroid-stimulating hormone (TSH) and T4 for patients receiving the two types of drugs, information that the database used in this study lacked, he noted.

"It's possible if we had 5-year follow-up and...there were small but significant differences in the actual blood levels of thyroid hormones between generic and brand," he speculated, "then...we might see the evolution of atrial fibrillation, which subsequently could lead to some of these other complications."

Other study limitations include possible unknown confounders.

And the findings cannot be generalized to patients taking a combination of L-T4 and liothyronine L-T3 or thyroid extract — although most patients in clinical practice receive thyroxine monotherapy.

Importantly, "whether this recommendation could extend to patients with thyroid cancer, who often require higher doses of thyroid hormone with a narrower TSH target goal, would require further investigation," according to the researchers.

Patients with thyroid cancer are "an important group to study, and this is something we want to do in a follow-up study," Smallridge noted.

"If these observations are confirmed with longer-term follow-up, then either generic or brand L-T4 preparations may be used to treat hypothyroidism due to benign thyroid disorders, at least with respect to the risk of cardiovascular events," the researchers cautiously conclude.

Invited to comment on the clinical implications, Angela M. Leung, MD, David Geffen School of Medicine at UCLA, Los Angeles, California, who was not involved in the research, echoed this interpretation in an email to Medscape Medical News.  

"Using a large US database, the researchers demonstrated that the risks of hospitalization for cardiovascular events were similar among patients with newly diagnosed hypothyroidism who were prescribed either generic or brand-name levothyroxine,” she wrote.

This thus infers “that they are equivalent in terms of their short-term cardiovascular side effect profiles," she said, although "assessment of these outcomes at 1 year may not be sufficient time to study these endpoints."

Most Prescribed Drug in the United States 

Levothyroxine is the most frequently prescribed medication in the United States, and more than 23 million patients a year fill a prescription for the drug, Smallridge told Medscape Medical News.*

Similarly, in an October 2018 perspective article published in Medscape, Leung reported that "up to 7% of the general population [in the United States] has hypothyroidism" (Nat Rev Endocrinol. 2018;14:301-316) and "in 2016, approximately 123 million prescriptions for levothyroxine were dispensed."

However, "the type of thyroid hormone prescribed is under scrutiny by physicians, patients, and insurers," Smallridge and colleagues write.  

The US Food and Drug Administration "has declared that generics are equivalent (and are often less expensive)," they note, so "insurers may...require higher copayments for branded L-T4."  

Clinicians currently mainly prescribe generic rather than brand-name L-T4. For example, 63% of endocrinologists and 73% of family physicians prescribed generic L-T4 in 2013.

Some patients may request combined synthetic L-T4 and L-T3 or a porcine thyroid extract, they add, but these therapies have not been well studied.

Comparing Heart Outcomes With Generic vs Brand-Name Drugs

To investigate cardiovascular events in patients initiated on a generic versus brand-name L-T4, researchers performed a retrospective analysis using deidentified claims data from a large private US health plan (OptumLabs Data Warehouse).

They identified 201,056 US adults who filled a first prescription for L-T4 between December 31, 2004, and January 1, 2006, and had follow-up data for hospital admission until June 20, 2015 (0-9.3 years).

More than half of prescriptions were by a primary care physician (60%). The rest were by an endocrinologist (11%) or an obstetrician/ gynecologist, otorhinolaryngologist, registered nurse, surgeon, or cardiologist (10%). Prescriber information was missing for 19% of prescriptions.

Most patients (186,804, 93%) were prescribed L-T4 and few received a thyroid extract (5.5%) or L-T3 preparation (1.6%).  

Of patients who received L-T4, most (142,267, 76%) received generic L-T4, and the rest (44,537, 24%) received a brand-name drug.

Patients who received the brand-name versus generic drug were more likely to be women (79% vs 73%) or have thyroid cancer (3% vs 1.2%), but less likely to be 65 years and older (18% vs 30%).

Researchers matched 43,951 patients starting brand-name L-T4 with 43,951 patients starting generic L-T4 based on age range, sex, race, geographic region, Charlson/Deyo comorbidity score, prescription year, and 12 comorbidities.

In the matched sample, about 1% of patients had had a myocardial infarction, 4.4% had cerebrovascular disease, and 2.7% had congestive heart failure.  

Overall, there were no significant differences in cardiovascular outcomes (1.8-3.2 events/1000 patient-years) with generic versus name-brand L-T4.  


Cardiovascular Events, Patients Receiving Brand-Name vs Generic L-T4

  Events/1000 patient-years     
Outcome Brand L-T4 Generic L-T4 HR (95%CI)* P
AF 2.19 1.82 1.22 (0.90 - 1.65) .19
MI 1.83 2.12 0.86 (0.64 - 1.17) .35
CHF 2.00 2.27 0.88 (0.66 - 1.18) .41
Stroke 2.38 3.20 0.77 (0.59 - 1.00) .05
AF = atrial fibrillation, CHF = congestive heart failure, MI = myocardial infarction
*Risk of the event in the brand-name versus generic group. 

Rates of the four cardiovascular outcomes were roughly eight-fold higher in patients aged 65 years and older (6.3-9.8 events/1000 patient-years) than patients younger than 65 years (0.39-1.37 events/1000 patient-years).

But there were no significant differences in these event rates between brand-name versus generic L-T4 in either age subgroup.

The "average 30-day cost (both patient out-of-pocket and cost to the health plan) of brand medication was approximately twice that of generic L-T4," the researchers write, but cost, even for the same drug in nearby pharmacies, can vary.

In her October 2018 perspective article, Leung reported, "the lowest available prices for a bulk supply of common thyroid hormone formulations are $0.20/tablet for synthetic generic levothyroxine, $1.02/tablet for brand-name Synthroid, and $4.76/tablet for brand-name Tirosint." The perspective also addressed other things to take into account when making prescribing decisions.

*The article and a statement by the Mayo Clinic should state "> 23 million patients receiving prescriptions annually" instead of " > 23 million prescriptions annually," Smallridge said. (The 23 million patients are 7% of the US population of 327 million.)  

The study was funded by the Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery and by Alfred D. and Audrey M. Petersen. Leung is on the advisory board for Medscape Diabetes & Endocrinology. The authors have reported no relevant financial relationships.

Mayo Clin Proc. Published online April 26, 2019. Abstract

For more diabetes and endocrinology news, follow us on Twitter and on Facebook.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.