Weight loss;

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 history of gastric bypass surgery now presents with right upper quadrant pain and gallstones. Is there a connection between gastric bypass surgery and gallstones?

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

An increased risk of new gallstones following gastric bypass surgery (GBS) has been reported by several studies (1-5).  More specifically, a study involving patients with baseline normal gallbladder ultrasound found that at 6 months following GBS 36% of patients developed gallstones and 13% developed sludge (4).  Similarly, a gallstone formation rate of 32% has been reported after GBS among patients who did not receive prophylactic treatment (5). 

New cholelithiasis following GBS may be largely attributed to rapid weight loss following this procedure, not the surgery itself or its related anatomical changes. Of interest, rapid weight loss, even by dieting, has been shown to increase the risk of gallstones (6).

However, overweight patients also have an increased risk of developing cholelithiasis at baseline, in part related to increased cholesterol secretion resulting in bile supersaturation with cholesterol (1).  Though weight loss may be expected to decrease this risk, rapid weight loss is thought to change the bile composition towards higher concentrations of calcium and cholesterol and increased production of gallbladder mucin, contributing to the pathogenicity of gallstone formation (5). 

In light of these findings, some have recommended routine prophylactic cholecystectomy as part of the GBS (7,8),  while others have argued against it (9,10), largely due to different observed rates of post-GBS symptomatic gallstones requiring cholecystectomies in various studies. Of note, post-operative ursodiol (ursodeoxycholic acid) may also reduce the incidence of post-GBS cholelithiasis (5,11). 

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References

1. Everhart JE. Contributions of obesity and weight loss to gallstone disease. Ann Intern Med 1993;119(10):1029–35. https://www.ncbi.nlm.nih.gov/pubmed/8214980
2. Wudel LJ, Wright JK, Debelak JP, Allos TM, Shyr Y, Chapman WC. Prevention of gallstone formation in morbidly obese patients undergoing rapid weight loss: Results of a randomized controlled pilot study. J Surg Res 2002;102(1):50–6. https://www.ncbi.nlm.nih.gov/pubmed/11792152
3. Manatsathit W, Leelasincharoen P, Al-Hamid H, Szpunar S, Hawasli A. The incidence of cholelithiasis after sleeve gastrectomy and its association with weight loss: A two-centre retrospective cohort study. Int J Surg [Internet] 2016;30:13–8. Available from: http://dx.doi.org/10.1016/j.ijsu.2016.03.060 https://www.ncbi.nlm.nih.gov/pubmed/27063855
4. Shiffman M, Sugerman H, Kellum J, Brewer W, Moore E. Gallstone formation after rapid weight loss: a prospective study in patients undergoing gastric bypass surgery for treatment of morbid obesity. Am J Gastroenterol 1991;(86):1000–5. https://www.ncbi.nlm.nih.gov/pubmed/1858735
5. Sugerman H, Brewer W, Shiffman M, et al. A Multicenter, Placebo-Controlled, Randomized, Double-Blind, Prospective Trial of Prophylactic Ursodiol for the Prevention of Gallstone Formation Rapid Weight Loss. Am Jourmal Surg 1995;169(January):91–7. https://www.ncbi.nlm.nih.gov/pubmed/7818005

6. de Oliverira CIB, Chaim EA, da Silva BB. Impact of rapid weight reduction on risk of cholelithiasis after bariatric surgery. Obesity Surgery 2003;13:625-8.
7. Tarantino I, Warschkow R, Steffen T, Bisang P, Schultes B, Thurnheer M. Is routine cholecystectomy justified in severely obese patients undergoing a laparoscopic Roux-en-Y gastric bypass procedure? A comparative cohort study. Obes Surg 2011;21(12):1870–8. https://reference.medscape.com/medline/abstract/21863228
8. Amstutz S, Michel JM, Kopp S, Egger B. Potential Benefits of Prophylactic Cholecystectomy in Patients Undergoing Bariatric Bypass Surgery. Obes Surg 2015;25(11):2054–60. https://link.springer.com/article/10.1007%2Fs11695-015-1650-6
9. Karadeniz M, Gorgun M, Kara C. The evaluation of gallstone formation in patients undergoing Roux-en -Y gastric bypass due to morbid obesity. Turkish J Surg 2014;30(2):76–9. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4379817/
10. D’Hondt M, Sergeant G, Deylgat B, Devriendt D, Van Rooy F, Vansteenkiste F. Prophylactic Cholecystectomy, a Mandatory Step in Morbidly Obese Patients Undergoing Laparoscopic Roux-en-Y Gastric Bypass? J Gastrointest Surg 2011;15(9):1532–6. https://www.ncbi.nlm.nih.gov/pubmed/21751078
11. Miller K, Hell E, Lang B, Lengauer E. Gallstone Formation Prophylaxis after Gastric Restrictive Procedures for Weight Loss: A Randomized Double-Blind Placebo-Controlled Trial. Ann Surg 2003;238(5):697–702. https://www.ncbi.nlm.nih.gov/pubmed/14578732

Contributed by Kim Schaefer, Harvard medical student, Boston, MA. 

 

My patient with history of gastric bypass surgery now presents with right upper quadrant pain and gallstones. Is there a connection between gastric bypass surgery and gallstones?

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?

Why do patients with anorexia nervosa often experience bradycardia?

FA Manian MD, MPH, , Leave a comment

Cardiac complications are common in anorexia nervosa (AN), with sinus bradycardia occurring in up to 95% of patients1,2. The mechanism of bradycardia in AN has yet to be clearly elucidated.

The predominant hypothesis posits that bradycardia is due to an increased cardiac vagal tone3,4, with a direct relationship observed between vagal tone and percent weight loss4. Additionally, sympathetic response may be altered through down-regulation of cardiac beta-adrenoceptors5. The physiologic response of lowering the resting heart rate through an increase in parasympathetic activity and sympathetic down-regulation leads to energy conservation in the fasting state of AN.

Current guidelines recommend that patients with AN and “severe” sinus bradycardia—defined as heart rate <50 beats/min during the day or <45 beats/min at night—should be admitted to the hospital for cardiac monitoring and gradual weight gain6. Fortunately, bradycardia associated with AN is reversible with weight gain7,8.

 

References

  1. Portilla MG. Bradycardia: an important physical finding in anorexia nervosa. J Ark Med Soc 2011;107:206-208. https://www.ncbi.nlm.nih.gov/pubmed/21739848
  2. Katzman DK. Medical complications in adolescents with anorexia nervosa: a review of the literature. Int J Eat Dis 2005; 37:S52-S59. https://onlinelibrary.wiley.com/doi/full/10.1002/eat.20118
  3. Petretta M, et al. Heart rate variability as a measure of autonomic nervous system function in anorexia nervosa. Clin Card 1997; 20: 219-224. https://www.ncbi.nlm.nih.gov/pubmed/9068906
  4. Kollai M., et al. Cardiac vagal hyperactivity in adolescent anorexia nervosa. Eur Heart J 1994;15:1113-1118. https://www.ncbi.nlm.nih.gov/pubmed/7988604
  5. Kaye WH, et al. Isoproterenol infusion test in anorexia nervosa: Assessment of pre-and post-beta-noradrenergic receptor activity. Psychopharm Bull 1990.
  6. Golden NH, et al. Eating disorders in adolescents. J Adolesc Health 2003;33: 496-503. https://www.ncbi.nlm.nih.gov/pubmed/14642712
  7. Gottdiener JS, et al. Effects of self-induced starvation on cardiac size and function in anorexia nervosa. Circulation 1978;58: 425-433. https://www.ncbi.nlm.nih.gov/pubmed/679432
  8. Olivares JL, et al. Cardiac findings in adolescents with anorexia nervosa at diagnosis and after weight restoration. Eur J Pediatrics 2005;164:383-386. https://www.ncbi.nlm.nih.gov/pubmed/15909184

 

Contributed by Marissa K Shoji, Medical Student, Harvard Medical School

Why do patients with anorexia nervosa often experience bradycardia?

Routine screening of my patient suspected of having tuberculosis (TB) shows that he is HIV seropositive. Does HIV affect the clinical manifestation of TB?

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

Patients with newly-diagnosed TB are ~20 times more likely to be coinfected with HIV than those without TB. Unfortunately, the diagnosis of TB in HIV-infected patients is often delayed in part related to its atypical presentation1.

In HIV-infected patients with high CD4 counts, clinical manifestations of TB are usually similar to those without HIV infection (eg, subacute fever, weight loss, cough) with CXR often showing upper lobe infiltrates and/or cavitations typically seen in reactivation TB.

Lower CD4 counts, however, are associated with atypical CXR findings, including pleural effusions, lower or middle lobe infiltrates, mediastinal adenopathy, and lack of cavitary lesions1,2.  A normal CXR has been reported in 21% of patients with CD4 <200 cells/μl (vs 5% in those with higher counts)2.

Advanced immune suppression in HIV infection is also associated with negative sputum smears for acid-fast bacilli, concurrent extra-pulmonary disease, and immune reconstitution symptoms after initiation of anti-TB therapy1.

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References

  1. Kwan CK, Ernst JD. HIV and tuberculosis: a deadly human syndemic. Clin Microbiol Rev 2011;24:351-376. https://cmr.asm.org/content/24/2/351
  2. Greenberg, SD, Frager D, Suster B, et al. Active pulmonary tuberculosis in patients with AIDS: spectrum of radiographic findings (including a normal appearance). Radiology 1994;193:115-9. https://pubs.rsna.org/doi/abs/10.1148/radiology.193.1.7916467
Routine screening of my patient suspected of having tuberculosis (TB) shows that he is HIV seropositive. Does HIV affect the clinical manifestation of TB?