Levothyroxine;

My patient with long standing hypertension and obesity with significant weight loss while on a glucagon-like peptide-1 receptor agonist (GLP-1RA), now has a “borderline” blood pressure. Should I consider adjusting his antihypertensive medication(s)?

FA Manian MD, MPH, , , , , , , , , , , , , , , , Leave a comment

Yes, you may very well need to adjust antihypertensive regimen of patients who have experienced significant weight loss while on GLP-1RAs.1,2  

In the STEP-1 trial evaluating the impact of semaglutide on cardiometabolic risk factors in adults who were overweight or obese, 34.3% of the group receiving semaglutide had either reduction in the dose or cessation of antihypertensive medications, compared to 15.6% in the placebo group.2  In SURMOUNT-1 trial examining the impact of tirzepatide on blood pressure reduction, a significant net reduction of 6.8 mm Hg systolic and 4.2 mm Hg diastolic blood pressure compared to placebo over 72 weeks was found; weight loss accounted for ~70% of systolic or diastolic blood pressure reduction. 2

The need to lower the dose of or discontinue antihypertensive medications in the setting of significant weight loss should not come as a surprise since this phenomenon predates the widespread use of GLP-1RA in obesity. 1,3 However, in addition to their impact on blood pressure through weight loss, GLP-1RAs may  lower blood pressure through alternative  mechanisms, including natriuresis, direct vasodilation and reduction in sympathetic nervous system activity.4  It’s also important to remember that GLP-1RAs may reduce both systolic and diastolic blood pressures in patients with hypertension even before significant weight loss is observed! 5

But it’s not just about antihypertensive medications!  The use of GLP-1RAs with its attendant weight loss may also require dosage adjustment or discontinuation of several other commonly prescribed medications (eg, insulin, levothyroxine, and anticonvulsants, phenytoin, warfarin, lithium carbonate, and digoxin).2 So don’t forget to regularly review the medication list of patients who have experienced recent weight loss on GLP-1RAs!

Bonus Pearl:  Did you know that the concept of incretin effect was first proposed in the 1970s based on observations that insulin secretion was 2-3 times higher after oral glucose intake than that after intravenous glucose administration? 5

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References

  1. Manian FA. Antihypertensive medications in patients with weight loss. JAMA Intern Med 2025;185:475. Antihypertensive Medications in Patients With Weight Loss | JAMA Internal Medicine | JAMA Network
  2. Karakus KE, Shah VN, Akturk HK. Tirzepatide-induced rapid weight loss-related thyrotoxicosis. JAMA Intern Med 2024;184:1246-1247. Tirzepatide-Induced Rapid Weight Loss–Related Thyrotoxicosis | Lifestyle Behaviors | JAMA Internal Medicine | JAMA Network
  3. Shantha GPS, Kumar AA, Kahan S, et al. intentional weight loss and dose reductions of antihypertensive medications: a retrospective cohort study. Cardiorenal Med 2013;3:17-25. Intentional weight loss and dose reductions of antihypertensive medications: a retrospective cohort study – PubMed
  4. Lingway I, Mosenzon O, Brown K, et al. Systolic blood pressure reduction with tirzepatide in patients with type 2 diabetes: insights from SURPASS clinical program. Cardiovasc Diabetol 2023;22:66. Systolic blood pressure reduction with tirzepatide in patients with type 2 diabetes: insights from SURPASS clinical program – PubMed
  5. Liu QK. Mechanisms of action and therapeutic applications of GLP-1 and dual GIP/GLP-1 receptor agonists. Front Endocrinol 2024; 15:1431292. Frontiers | Mechanisms of action and therapeutic applications of GLP-1 and dual GIP/GLP-1 receptor agonists

Disclosures/Disclaimers: Reference 1 was written by this contributor. The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis, Massachusetts General Hospital, Harvard Catalyst, Harvard University, their affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

My patient with long standing hypertension and obesity with significant weight loss while on a glucagon-like peptide-1 receptor agonist (GLP-1RA), now has a “borderline” blood pressure. Should I consider adjusting his antihypertensive medication(s)?

“My patient with severe hypothyroidism developed a large pericardial effusion. What is the pathophysiology underlying this process?”

FA Manian MD, MPH, , , , , , , , , , , , , Leave a comment

Pericardial effusion in hypothyroidism—responsible for up to 14% of all pericardial effusions¹⁻²—is thought to be related to an increase in permeability of the pericardial capillaries to serum proteins (eg, albumin) resulting in an exudative effusion.³   Increased capillary permeability may in turn be due to the release of histamine by mastocytes or a direct effect of thyroid hormone deficiency on vascular endothelial integrity. ¹⁻³ In addition, hypothyroidism can be associated with pulmonary hypertension and a decrease in catecholamines, both of which can impair lymphatic drainage and further exacerbate the effusion.¹

Of note, myxedema — the accumulation of acid mucopolysaccharides causing fluid retention –– by itself does not explain the accumulation of pericardial fluid, as there is a lack of acid mucopolysaccharide buildup in the pericardial space.¹⁻² Autoimmune processes also do not appear to play a role in this context as pericardial disease can occur in both autoimmune (eg, Hashimoto thyroiditis) and non-autoimmune hypothyroidism.¹ Thus, the pericardial effusion in hypothyroidism seems to be a direct consequence of the metabolic effects of thyroid hormone deficiency itself. 

Occasionally, pericardial effusion in hypothyroidism is not so “benign” and can be complicated by tamponade.¹ In addition to timely percutaneous or surgical drainage of the effusion, thyroid hormone supplementation should be initiated without delay. ¹⁻² Although most pericardial effusions resolve over several months with adequate thyroid supplementation, they may recur in severe or chronically untreated hypothyroidism due to persistent alterations in the pericardial vascular permeability and impaired lymphatic drainage. ¹⁻³ This is another reason to remind patients to not go off their thyroid supplementation!

Bonus pearl: Did you know that the attendant increase in metabolic demands, plasma volume and higher levels of thyroxine-binding globulin in pregnancy necessitates routine upward titration of levothyroxine in pregnant patients with hypothyroidism? ⁵

Contributed by: Sarah de la Serna, Ponce Health Sciences University, St. Louis, MO and Tony Hiran, MD, Mercy Hospital, St. Louis, MO

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References

  1. Chahine J, Ala CK, Gentry JL, Pantalone KM, Klein AL. Pericardial diseases in patients with hypothyroidism. Heart. 2019 Jul;105(13):1027-1033. doi: 10.1136/heartjnl-2018-314528. Epub 2019 Apr 4. PMID: 30948517. Pericardial diseases in patients with hypothyroidism – PubMed
  2. Chaker L, Papaleontiou M. Hypothyroidism: A Review. JAMA. Published online September 03, 2025. doi:10.1001/jama.2025.13559. Hypothyroidism: A Review | Endocrinology | JAMA | JAMA Network
  3. González Vílchez F, Castillo L, Pi J, Ruiz E. Manifestaciones cardíacas del hipotiroidismo primario. Factores determinantes y respuesta al tratamiento [Cardiac manifestations of primary hypothyroidism. Determinant factors and treatment response]. Rev Esp Cardiol. 1998 Nov;51(11):893-900. Spanish. PMID: 9859712. [Cardiac manifestations of primary hypothyroidism. Determinant factors and treatment response] – PubMed
  4. Kerber RE, Sherman B. Echocardiographic evaluation of pericardial effusion in myxedema. Incidence and biochemical and clinical correlations. Circulation. 1975 Nov;52(5):823-7. doi: 10.1161/01.cir.52.5.823. PMID: 126121. Echocardiographic evaluation of pericardial effusion in myxedema. Incidence and biochemical and clinical correlations – PubMed
  5. Alexander EK, Pearce EN, Brent GA, et al. 2017 Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and the Postpartum. Thyroid : Official Journal of the American Thyroid Association. 2017;27(3):315-389. doi:10.1089/thy.2016.0457. 2017 Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and the Postpartum – PubMed

Disclosures/Disclaimers: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis, Massachusetts General Hospital, Harvard Catalyst, Harvard University, their affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

“My patient with severe hypothyroidism developed a large pericardial effusion. What is the pathophysiology underlying this process?”

My elderly patient on chronic warfarin with recent hospitalization for soft tissue infection is now readmitted with gastrointestinal bleed and a newly-discovered supra-therapeutic INR? Why did her INR jump?

FA Manian MD, MPH, , , , , , , , , , , , , , , , , , , , Leave a comment

Assuming no recent changes in the dose of warfarin, one potential culprit may be her recent antibiotic exposure. Of the long list of antibiotics associated with elevated INR, quinolones (e.g. ciprofloxacin, levofloxacin), trimethoprim-sulfamethoxazole, macrolides (e.g. azithromycin), and azole antifungals (e.g. fluconazole) are generally thought to carry the highest risk of warfarin toxicity, while amoxacillin and cephalexin may be associated with a more modest risk. 1-3

Other drugs such as amiodarone (Did she have atrial fibrillation during her recent hospitalization?), acetaminophen (Has she been receiving at least 2 g/day for several consecutive days?), and increasing dose of levothyroxine (Was she thought to be hypothyroid recently?) should also be considered.3,4

Also remember to ask about herbal supplements (eg, boldo-fenugreek, dong quai, danshen) that may potentiate the effect of warfarin. 3 Of course, poor nutrition in the setting of recent illness might have also played a role.5

As far as the mechanisms for drug interaction with warfarin, some drugs act as cytochrome p450 inhibitors (thus reducing the metabolism of warfarin), while others influence the pharmacodynamics of warfarin by inhibiting the synthesis or increasing the clearance of vitamin K-2 dependent coagulation factors.3

Antibiotics may increase the risk of major bleeding through disruption of intestinal flora that synthesize vitamin K-2 with or without interference with the metabolism of warfarin through cytochrome p450 isozymes inhibition.

Check out a related pearl on P4P: https://pearls4peers.com/2015/06/25/is-there-anyway-to-predict-a-significant-rise-in-inr-from-antibiotic-use-in-patients-who-are-also-on-warfarin  

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References

  1. Baillargeon J, Holmes HM, Lin Y, et al. Concurrent use of warfarin and antibiotics and the risk of bleeding in older adults. Am J Med. 2012 February ; 125(2): 183–189. https://www.ncbi.nlm.nih.gov/pubmed/22269622
  2. Juurlink DN. Drug interactions with warfarin: what every physician should know. CMAJ, 2007;177: 369-371. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1942100/pdf/20070814s00018p369.pdf
  3. Ageno W, Gallus AS, Wittkowsky A, et al. Oral anticoagulant therapy: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e44S-e88S. doi:10.1378/chest.11-2292.  https://www.ncbi.nlm.nih.gov/pubmed/22315269
  4. Hughes GJ, Patel PN, Saxena N. Effect of acetaminophen on international normalized ratio in patients receiving warfarin therapy. Pharmacotherapy 2011;31:591-7. https://www.ncbi.nlm.nih.gov/pubmed/21923443
  5. Kumar S, Gupta D, Rau SS. Supratherapeutic international normalized ratio: an indicator of chronic malnutrition due to severely debilitating gastrointestinal disease. Clin Pract. 2011;1:e21. doi:10.4081/cp.2011.e21. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3981245

 

Contributed by Rachel Weitzman, Medical Student, Harvard Medical School, Boston, MA.

My elderly patient on chronic warfarin with recent hospitalization for soft tissue infection is now readmitted with gastrointestinal bleed and a newly-discovered supra-therapeutic INR? Why did her INR jump?