Preventive Screening for GLP-1RA-Induced Gallstone Risks in Type 2 Diabetes
Editors:
- Dr. Praful B. Godkar (Ph.D)
Eminent Author, Medical Biochemist and Scientist, Technical Education consultant. AGD Biomedicals (Pvt) LTD. - Dr. Gauri Kulkarni MD (Pathology)
Vice President, AGD Biomedicals (Pvt) LTD.
Q1. What are GLP-1 receptor agonists?
ANS(2): GLP-1 receptor agonists are used for treating type 2 diabetes and obesity. These act by increasing insulin, suppressing glucagon, and slowing digestion, they effectively lower blood sugar and promote significant weight loss. Examples are: Liraglutide (Victoza), Semaglutide (Rybelsus), Dulaglutide (Trulicity), Exenatide (Byetta, Bydureon), Tirzepatide (Mounjaro, Zepbound) etc.
Q2. What is the mechanism of action of GLP-1 receptor agonists?
ANS(2): GLP-1 receptor agonists (RAs) mimic the natural GLP-1 hormone to manage diabetes and obesity by stimulating glucose-dependent insulin secretion, suppressing glucagon release, and slowing gastric emptying. They promote weight loss by increasing satiety and reducing appetite through central nervous system receptors.
Q3. What is GLP-1 hormone?
ANS(2): GLP-1 is a peptide hormone produced from proglucagon, mainly in intestinal L cells, in response to food. Upon release, it binds to GLP-1 receptors (GLP-1R) in tissues in organs such as the pancreas and brain to regulate glucose and appetite. However, it is rapidly degraded by the DPP-4 enzyme, giving it a one-two minute half-life.
NOTE(1,2)
(A) GLP-1 receptor agonist (RAs) drugs are synthetic versions of the natural GLP-1 hormone, modified to resist breakdown by the enzyme DPP-4. This structural change allows them to stay active in the body much longer than the natural version, providing a sustained therapeutic effect.
(B) GLP-1 receptor agonists increase relative risk, but absolute risk is low averaging 27 cases per 10,000 patients each year.
Q4. What are the symptoms of gall bladder, liver and biliary diseases caused due to prolonged use of GLP-1 receptor agonist (RAs) drugs?
ANS(1,5): The common symptoms related to gall bladder, liver and biliary diseases due to prolonged use of GLP-1 agonists are: Upper abdominal pain, nausea, vomiting, diarrhea, or constipation, post-hepatic jaundice, etc.
Q5. What are the basic tests recommended including Clinical laboratory IVD tests and related reasons to monitor GPL-1 RAs?
ANS(8): Refer Table 1 below:
Table 1: Basic tests and reasons for monitoring drug actions
| Test Type | Primary Markers | Why it is Monitored |
| Gallbladder Ultrasound | Gall stones | To check for cholelithiasis due to rapid weight loss. |
| Liver Function (LFTs) | Serum SGPT, SGOT, Bilirubin | To detect bile duct blockages or rare hepatic sensitivity. |
| Pancreatic Function | Serum Amylase, Lipase | To screen for or rule out drug-induced pancreatitis. |
NOTE : If the patient develops severe upper abdominal pain, nausea, or yellowing of the eyes while on these medications, it is necessary to consult a physician immediately.
CASE STUDY
A 69-year-old male presented with persistent, severe epigastric pain radiating to the back, nausea, loss of appetite, and yellow coloration of eyes.
He had a past medical history of uncontrolled type 2 diabetes mellitus on long-term use of insulin, metformin and victoza (liraglutide), as prescribed by his physician. No alcohol, tobacco, chronic fast-food intake, or recent acute illness (such as fever or infections) was reported. His clinical laboratory reports were as follows:
| PARAMETER | RESULT | REFERENCE RANGE |
| Serum total bilirubin | 8.6 mg/dl | Up to 1.0 mg/dl |
| Serum direct bilirubin | 4.7 mg/dl | Up to 0.5 mg/dl |
| Serum indirect bilirubin | 3.9 mg/dl | Up to 0.5 mg/dl |
| SGPT | 830 IU | 5-35 IU |
| SGOT | 950 IU | 8–40 IU |
| Alkaline phosphatase | 360 IU | 20–80 IU |
| Urine bile pigments | Present, ++ | Absent |
| Urine bile salts | Present | Absent |
| Urine urobilinogen | Present, Increased | Normal |
| Serum amylase | 560 IU | 30–110 IU |
| Serum lipase | 340 IU | > 200 IU |
INTERPRETATION(8)
Very high values of serum total bilirubin, direct bilirubin, indirect bilirubin, and the presence of bile salts, bile pigments in urine indicated that the patient was suffering from jaundice. Elevated levels of SGPT, SGOT, and markedly increased serum alkaline phosphatase are indicative of a posthepatic condition associated with obstructive jaundice. High values of serum amylase and lipase indicate pancreatic inflammation.
ADDITIONAL TEST
With reference to Blood test reports following addition test was advised:
Ultrasound examination report
An ultrasound of the right upper quadrant of the abdomen showed evidence of cholecystitis and biliary dilation.
FINAL DIAGNOSIS
Evidence from clinical trials and post-marketing reports points to Victoza (liraglutide) as the component associated with gallbladder-related issues like cholelithiasis (gallstones), cholecystitis, and obstructive (cholestatic) jaundice. While metformin and insulin are not typically linked to these specific biliary complications, liraglutide’s impact is well-documented(1).
NOTE
(1) Commonly observed laboratory findings: In pre-hepatic condition, indirect bilirubin and urine urobilinogen are very high, with normal SGPT and serum alkaline phosphatase. In hepatic condition, direct, indirect bilirubin, urine bile pigments and urobilinogen are very high, with very SGPT, SGOT and moderately increased serum alkaline phosphatase. Hence, on the basis of laboratory test results post-hepatic condition was diagnosed.
(2) It is necessary to find out the cause of obstructive jaundice by performing some of the following additional investigations as suggested by a gastroenterologists:
(A) Non-invasive: Abdominal ultrasound, hepatobiliary iminodiacetic acid scan (HIDA) Scan (Cholescintigraphy), Magnetic resonance cholangiopancreatography (MRCP), and CT Scan.
(B) Minimally invasive and endoscopic procedures: Endoscopic ultrasound (EUS).
Q6. Why does prolonged use of GLP-1 receptor agonists (GLP-1RAs) increase the risk of gallstones and inflammation of the liver, gallbladder, and pancreas?
ANS(2-4,7): This occurs primarily through following two mechanisms:
(A) GLP-1RAs are highly effective for weight reduction. Rapid weight loss increases the excretion of cholesterol into bile, leading to supersaturation of bile, which is likely to crystallize into stones.
(B) These medications also decrease gastrointestinal motility. Evidence suggests that these medications may also decrease gallbladder contractility, and bile remains in the gallbladder for longer phase, and provide more time for bile stone formation.
Q7. What necessary steps are required for periodic monitoring of long-term GLP-1RA use?
ANS: Although these medications are generally safe, healthcare providers often require following periodic performance of IVD clinical laboratory tests to ensure the body is tolerating the treatment correctly:
(A) Liver Function Tests (LFTs)
(B) Pancreatic Function Tests, and
(C ) Ultrasound examination: If a patient experiences severe abdominal pain.
Refer Table 1
References
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(3) Popoviciu MS, Pa˘duraru L, Yahya G, et al. Emerging role of GLP-1 agonists in obesity: a comprehensive review of randomised controlled trials. Int J Mol Sci 2023; 24: 10449.
(4) Gutzwiller JP, Drewe J, Göke B, et al. Glucagonlike peptide-1 promotes satiety and reduces food intake in patients with diabetes mellitus type 2.
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(5) Sodhi M, Rezaeianzadeh R, Kezouh A, et al. Risk of gastrointestinal adverse events associated with glucagon-like peptide-1 receptor agonists for weight loss. JAMA 2023; 330: 1795–1797.
(6) Sun H, Warren J, Yip J, et al. Factors influencing gallstone formation: a review of the literature. Biomolecules 2022; 12: 550.
(7) Rehfeld JF, Knop FK, Asmar A, et al. Cholecystokinin secretion is suppressed by glucagon-like peptide-1: clue to the mechanism of the adverse gallbladder events of GLP-1-derived drugs. Scand J Gastroenterol 2018; 53: 1429–1432.
(8) Godkar PB, Godkar DP. Textbook of Medical laboratory technology (4th edition, 2024), Bhalani Publishers, Mumbai. India.
