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<div class="figure-label">Figure 1. PRISMA Flow Diagram</div><a id="ioi220009f1" class="figure-table-anchor"> </a>
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<p class="para">GLP-1 RAs denotes glucagon-like peptide-1 receptor agonists; RCTs, randomized clinical trials; and T1D, type 1 diabetes.</p>
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<div class="figure-label">Figure 2. Risks of Cholelithiasis, Cholecystitis, and Biliary Diseases in Patients Randomized to GLP-1 RA Treatment Compared With Controls in All Trials</div>
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<p class="para">ARD denotes the absolute risk difference and GLP-1 RA, glucagon-like peptide-1 receptor agonist.</p>
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<div class="figure-label">Figure 3. Risks of Gallbladder or Biliary Diseases Associated With Individual GLP-1 RA Drugs</div><a id="ioi220009f3" class="figure-table-anchor"> </a>
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<p class="para">GLP-1 RA indicates glucagon-like peptide-1 receptor agonist; and SC, subcutaneous.</p>
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<div class="table-label">Table. Factors and Risks of Gallbladder or Biliary Diseases in 76 Randomized Clinical Trials of GLP-1 RA Drug Use</div><a class="figure-table-anchor" id="ioi220009t1"> </a>
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<div class="supplement-title"><span class="title-label">Supplement.</span><p class="para"><strong>eMethods 1.</strong> Data sources and search strategies</p><p class="para"><strong>eMethods 2</strong>. Identification of the outcomes</p><p class="para"><strong>eTable 1.</strong> Eligibility criteria of included studies</p><p class="para"><strong>eTable 2.</strong> Baseline characteristics of studies and participants included</p><p class="para"><strong>eTable 3.</strong> Assessments of risks of bias of eligible studies according to revised Cochrane risk-of-bias tool for randomized trials</p><p class="para"><strong>eTable 4.</strong> Grade summary of findings for each outcome in the meta-analysis</p><p class="para"><strong>eTable 5.</strong> Effects of factors on the risks of gallbladder or biliary diseases with GLP-1 RAs in trials with treatment for diabetes</p><p class="para"><strong>eTable 6.</strong> Effects of factors on the risks of gallbladder or biliary diseases with GLP-1 RAs in trials with treatment for weight loss</p><p class="para"><strong>eFigure 1.</strong> Summary of risks of bias of all included studies</p><p class="para"><strong>eFigure 2.</strong> Risks of cholelithiasis, cholecystitis, and biliary diseases in patients with GLP-1 RAs treatments compared with controls</p><p class="para"><strong>eFigure 3.</strong> Risks of the composite of gallbladder or biliary diseases, cholelithiasis, cholecystitis, and biliary diseases with glp-1 ras compared with controls in trials with treatment for diabetes</p><p class="para"><strong>eFigure 4.</strong> Overall risks of cholelithiasis, cholecystitis, and biliary diseases in patients with GLP-1 RAs compared with controls in trials with treatment for diabetes</p><p class="para"><strong>eFigure 5.</strong> Risks of the composite of gallbladder or biliary diseases, cholelithiasis, cholecystitis, and biliary diseases with GLP-1 RAs compared with controls in trials with treatment for weight loss</p><p class="para"><strong>eFigure 6.</strong> Overall risks of cholelithiasis, cholecystitis, and biliary diseases in patients with GLP-1 RAs compared with controls in trials with treatment for weight loss</p><p class="para"><strong>eFigure 7.</strong> Risks of cholecystectomy in patients with GLP-1 RAs compared with controls</p><p class="para"><strong>eFigure 8.</strong> Risks of biliary tract cancer in patients with GLP-1 RAs compared with controls</p><p class="para"><strong>eFigure 9.</strong> Risks of gallbladder or biliary diseases in patients with different GLP-1 RAs individuals compared with controls in all trials</p><p class="para"><strong>eFigure 10.</strong> Risks of gallbladder or biliary diseases in patients with different GLP-1 RAs medications compared with controls in trials with treatment for diabetes</p><p class="para"><strong>eFigure 11.</strong> Risks of gallbladder or biliary diseases in patients with different GLP-1 RAs medications compared with controls in trials with treatment for weight loss</p><p class="para"><strong>eFigure 12.</strong> Effects of doses and duration of treatments on the association between GLP-1 RAs and gallbladder or biliary diseases in all trials</p><p class="para"><strong>eFigure 13.</strong> Effects of doses and duration of treatments on the association between GLP-1 RAs and gallbladder or biliary diseases in trials with treatment for diabetes</p><p class="para"><strong>eFigure 14.</strong> Effects of baseline bmi and types of control on the association between GLP-1 RAs and gallbladder or biliary diseases in all trials, trial for diabetes or weight loss</p><p class="para"><strong>eFigure 15.</strong> Effects of types of trials on the risks of gallbladder or biliary diseases in trials with treatment for diabetes</p><p class="para"><strong>eFigure 16.</strong> Sensitivity analyses by omitting each trial one by one and removing studies with albiglutide</p><p class="para"><strong>eFigure 17.</strong> Sensitivity analyses by using random-effect models</p><p class="para"><strong>eFigure 18.</strong> Funnel plot of all eligible studies</p><p class="para"><strong>eResults.</strong> Risks of gallbladder or biliary diseases in patients with GLP-1RAs treatments compared with controls</p><p class="para"><strong>eReferences</strong></p></div>
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<div class="comment-item--date-submitted">May 8, 2022</div>
<div class="comment-item--title thm-col fw-b sb-pc">Possible confound</div>
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<span class="author-name fw-b">David Karpf, MD</span> | Stanford University School of Medicine
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<span class="comment-item--text-limited ellipsis">It might be a little too soon to attribute the HR of 1.37 to the GLP-1 RAs. It has been known for some time that both obesity and significant weight loss increase the risk of
gall bladder disease, including that of gallstones. See, for example, just a few references<br><br>1. R L Weinsier, et al. Gallstone formation and weight loss. Obes Res. 1993 Jan;1(1):51-56.<br>2. Gebhard RL, et al. The role
of gallbladder emptying in gallstone formation during diet-induced rapid weight loss. Hepatology. 1996 Sep;24(3):544-548.<br>3. Festi D, et al. Gallbladder motility and gallstone formation in</span>
<span class="comment-item--text-remaining"> obese patients following very low calorie diets. Use it (fat) to lose it (well). Int J Obes Relat Metab Disord. 1998 Jun;22(6):592-600.<br>4. Festi D, et al. Review: low caloric intake
and gall-bladder motor function. Aliment Pharmacol Ther. 2000 May;14 Suppl 2:51-53.<br>5. Marks JW, et al. The sequence of biliary events preceding the formation of gallstones in humans. Gastroenterology. 1992
Aug;103(2):566-570. <br>6. Hofmann AF. Et al. Primary and secondary prevention of gallstone disease: implications for patient management and research priorities. Am J Surg. 1993 Apr;165(4):541-548. <br> <br>It seems entirely
plausible that at least some of the risk, if not all, can be attributed to the often profound and substantial weight loss due to the the GLP-1 RA therapy.<br><br>David B. Karpf, MD<br>Adj. Clinical professor of Endocrinology,
Gerontology & Metabolism<br>Stanford University School of Medicine</span>
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<div class="comment-item--date-submitted">June 8, 2022</div>
<div class="comment-item--title thm-col fw-b sb-pc">Question about the "Data Synthesis and Analysis" Section of the Methods</div>
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<span class="author-name fw-b">Ting Zhang, Resident</span> | Department of Family Medicine & Division of General Internal Medicine, Department of Medicine, Peking Union Medical College Hospital
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<p>In the Methods, the authors state: " Random-effects models with the DerSimonian-Laird method were used when there was no significant heterogeneity (Q tests, P < .05; I2 > 50%); otherwise, Mantel-Haenszel methods and
fixed-effects models were used."</p>
<p> Can the authors explain the rationale? It is my understanding that generally, 50% heterogeneity is taken as the dividing line between fixed effect and random effect. That is, < 50% heterogeneity choose a fixed-effect
model, >= 50% choose a random effect model. </p>
<p> Reference: (Rothstein, 2010, Res Synth Methods[IF:5.273, PMID:26061376])</p>
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<span class="meta-authors--remaining"><span class="wi-fullname brand-fg"><a href="/searchresults?author=Na+Yang&q=Na+Yang" rel="nofollow" target="_blank">Na Yang, MM<sup>1</sup></a></span><span class="al-author-delim">;
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<div class="meta-author-name"><sup>1</sup>Department of Endocrinology, Key Laboratory of Endocrinology of the National Health Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking
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<span class="meta-citation-journal-name">JAMA Intern Med. </span><span class="meta-citation"> 2022;182(5):513-519. doi:10.1001/jamainternmed.2022.0338</span>
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<span class="heading-text thm-col h3 cb section-type-keyPoints decorated-hed sb-sc ">Key Points</span>
<p><strong>Question</strong> <span>What is the association of glucagon-like peptide-1 receptor agonist (GLP-1 RAs) use with the risk of gallbladder or biliary diseases?</span></p>
<p><strong>Findings</strong> <span>This systematic review and meta-analysis of 76 randomized clinical trials found that use of GLP-1 RAs was associated with increased risk of gallbladder or biliary diseases, especially when used
at higher doses, for longer durations, and for weight loss.</span></p>
<p><strong>Meaning</strong> <span>The findings of this systematic review and meta-analysis indicate that physicians and patients should be concerned about the risks of gallbladder or biliary diseases with using GLP-1 RAs for
treatment in clinical practice; future studies should report on associated gallbladder and biliary diseases.</span></p> <a class="article-section-id-anchor" id="248371865"></a>
<div class="h3 cb section-type-abstract decorated-hed ">
<div class="heading-text thm-col sb-sc"> Abstract </div>
</div>
<p><strong>Importance</strong> <span>Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been widely recommended for glucose control and cardiovascular risk reduction in patients with type 2 diabetes, and more recently,
for weight loss. However, the associations of GLP-1 RAs with gallbladder or biliary diseases are controversial.</span></p>
<p><strong>Objective</strong> <span>To evaluate the association of GLP-1 RA treatment with gallbladder and biliary diseases and to explore risk factors for these associations.</span></p>
<p><strong>Data Sources</strong> <span>MEDLINE/PubMed, EMBASE, Web of Science, and Cochrane Library (inception to June 30, 2021), websites of clinical trial registries (July 10, 2021), and reference lists. There were no language
restrictions.</span></p>
<p><strong>Study Selection</strong> <span>Randomized clinical trials (RCTs) comparing the use of GLP-1 RA drugs with placebo or with non−GLP-1 RA drugs in adults.</span></p>
<p><strong>Data Extraction and Synthesis</strong> <span>Two reviewers independently extracted data according to the PRISMA recommendations and assessed the quality of each study with the Cochrane Collaboration risk-of-bias tool.
Pooled relative risks (RRs) were calculated using random or fixed-effects models, as appropriate. The quality of evidence for each outcome was assessed using the GRADE (Grading of Recommendations Assessment, Development, and
Evaluation) framework.</span></p>
<p><strong>Main Outcomes and Measures</strong> <span>The primary outcome was the composite of gallbladder or biliary diseases. Secondary outcomes were biliary diseases, biliary cancer, cholecystectomy, cholecystitis, and
cholelithiasis. Data analyses were performed from August 5, 2021, to September 3, 2021.</span></p>
<p><strong>Results</strong> <span>A total of 76 RCTs involving 103 371 patients (mean [SD] age, 57.8 (6.2) years; 41 868 [40.5%] women) were included. Among all included trials, randomization to GLP-1 RA treatment was associated
with increased risks of gallbladder or biliary diseases (RR, 1.37; 95% CI, 1.23-1.52); specifically, cholelithiasis (RR, 1.27; 95% CI, 1.10-1.47), cholecystitis (RR, 1.36; 95% CI, 1.14-1.62), and biliary disease (RR, 1.55; 95% CI,
1.08-2.22). Use of GLP-1 RAs was also associated with increased risk of gallbladder or biliary diseases in trials for weight loss (n = 13; RR, 2.29; 95% CI, 1.64-3.18) and for type 2 diabetes or other diseases (n = 63; RR, 1.27;
95% CI, 1.14-1.43; <i>P</i> <.001 for interaction). Among all included trials, GLP-1 RA use was associated with higher risks of gallbladder or biliary diseases at higher doses (RR, 1.56; 95% CI, 1.36-1.78) compared with lower
doses (RR, 0.99; 95% CI, 0.73-1.33; <i>P</i> = .006 for interaction) and with longer duration of use (RR, 1.40; 95% CI, 1.26-1.56) compared with shorter duration (RR, 0.79; 95% CI, 0.48-1.31; <i>P</i> = .03 for
interaction).</span></p>
<p><strong>Conclusions and Relevance</strong> <span>This systematic review and meta-analysis of RCTs found that use of GLP-1 RAs was associated with increased risk of gallbladder or biliary diseases, especially when used at
higher doses, for longer durations, and for weight loss.</span></p>
<p><strong>Trial Registration</strong> <span>PROSPERO Identifier: <a href="https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=271599">CRD42021271599</a></span></p>
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<a class="article-section-id-anchor" id="248371870"></a>
<div class="h3 cb section-type-section ">
<div class="heading-text thm-col sb-sc"> Introduction </div>
</div>
<a class="article-section-id-anchor" id="248371871"></a>
<p class="para">Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are recommended for patients with type 2 diabetes to control glycemia and reduce cardiovascular risk, and for patients with obesity to reduce
weight.<sup><a href="#ioi220009r1" class="ref-link section-jump-link" data-tab-toggle=".tab-nav-references">1</a></sup><sup>-<a href="#ioi220009r1" class="ref-link section-jump-link" data-tab-toggle=".tab-nav-references">4</a></sup>
Given the widespread use of these drugs,<sup><a href="#ioi220009r3" class="ref-link section-jump-link" data-tab-toggle=".tab-nav-references">3</a></sup> potential safety concerns deserve attention.</p>
<a class="article-section-id-anchor" id="248371872"></a>
<p class="para">Several randomized clinical trials (RCTs) have shown a higher rate of gallbladder disorders in patients who were randomized to GLP-1 RAs vs a
placebo.<sup><a href="#ioi220009r5" class="ref-link section-jump-link" data-tab-toggle=".tab-nav-references">5</a></sup><sup>-<a href="#ioi220009r5" class="ref-link section-jump-link" data-tab-toggle=".tab-nav-references">7</a></sup>
However, whether increased risk of gallbladder-related events is a class effect of GLP-1 RAs has not been
established,<sup><a href="#ioi220009r8" class="ref-link section-jump-link" data-tab-toggle=".tab-nav-references">8</a></sup><sup>,<a href="#ioi220009r9" class="ref-link section-jump-link" data-tab-toggle=".tab-nav-references">9</a></sup>
and prescribing information for all GLP-1 RA medications does not provide a warning regarding increased risk of gallbladder
disorders.<sup><a href="#ioi220009r10" class="ref-link section-jump-link" data-tab-toggle=".tab-nav-references">10</a></sup><sup>,<a href="#ioi220009r11" class="ref-link section-jump-link" data-tab-toggle=".tab-nav-references">11</a></sup>
In addition to gallbladder-related events, a post hoc analysis of the LEADER trial<sup><a href="#ioi220009r8" class="ref-link section-jump-link" data-tab-toggle=".tab-nav-references">8</a></sup> found significantly increased risks
of acute biliary obstruction in patients randomized to liraglutide compared with placebo. Because GLP-1 RAs are generally prescribed at higher doses for weight loss rather than for control of type 2 diabetes, there may be
differential effects on risk for gallbladder or biliary diseases depending on dose.</p> <a class="article-section-id-anchor" id="248371873"></a>
<p class="para">In response to these knowledge gaps, we conducted a systematic review and meta-analysis to evaluate the associations of GLP-1 RA use with the risk for gallbladder or biliary diseases. We also sought to determine if
risks differ by indication (for diabetes vs weight loss), dose, or duration of treatment.</p> <a class="article-section-id-anchor" id="248371874"></a>
<div class="h3 cb section-type-section ">
<div class="heading-text thm-col sb-sc"> Methods </div>
</div>
<a class="article-section-id-anchor" id="248371875"></a>
<p class="para">The protocol of this systematic review and meta-analysis was prospectively registered in the International Prospective Register of Systematic Reviews
(<a href="https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=271599">CRD42021271599</a>). The study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses
(<a href="http://www.equator-network.org/reporting-guidelines/prisma/">PRISMA</a>) reporting guideline statement.<sup><a href="#ioi220009r12" class="ref-link section-jump-link" data-tab-toggle=".tab-nav-references">12</a></sup>
Ethical review and informed consent were waived because the study used secondary data from previous studies.</p> <a class="article-section-id-anchor" id="248371876"></a>
<div class="h4 cb section-type-section ">
<div class="heading-text "> Data Sources and Searches </div>
</div>
<a class="article-section-id-anchor" id="248371877"></a>
<p class="para">The literature search was conducted of MEDLINE (via PubMed), Cochrane Library, EMBASE, and Web of Science, from inception to June 30, 2021, with no language restrictions (details are available in eMethods 1 in the
<a class="supplement-link section-jump-link" data-tab-toggle=".tab-nav-supplemental" href="#note-IOI220009-1">Supplement</a>). The search was supplemented by screening the reference lists of relevant systematic reviews and manually
searching for gray literature on clinical trial registries.</p> <a class="article-section-id-anchor" id="248371878"></a>
<div class="h4 cb section-type-section ">
<div class="heading-text "> Study Selection </div>
</div>
<a class="article-section-id-anchor" id="248371879"></a>
<p class="para">Two reviewers (H.L.Y., Z.H.B.) independently searched for randomized clinicals trials of GLP-1 RA medications (albiglutide, dulaglutide, exenatide, liraglutide, lixisenatide, or semaglutide) that also reported adverse
events of gallbladder or biliary diseases according to predefined inclusion and exclusion criteria available in eTable 1 in the
<a class="supplement-link section-jump-link" data-tab-toggle=".tab-nav-supplemental" href="#note-IOI220009-1">Supplement</a>. Eligible studies were identified and selected by 2 reviewers (H.L.Y., W.J.L.) who screened titles,
abstracts, and citations, and evaluated full-text records. Disagreements were resolved through discussions with other team members.</p> <a class="article-section-id-anchor" id="248371880"></a>
<div class="h4 cb section-type-section ">
<div class="heading-text "> Outcome Measures </div>
</div>
<a class="article-section-id-anchor" id="248371881"></a>
<p class="para">The primary outcome was a composite of gallbladder or biliary diseases, including gallbladder disorders and biliary-related events. Secondary outcomes were 3 subcategories of gallbladder and biliary diseases, including
bile duct obstruction, stenosis, and stone; biliary colic, cyst, and fistula; biliary tract cancer; cholecystectomy, cholecystitis, and cholelithiasis; and cholangitis. Definitions of outcomes are shown in eMethods 2 in the
<a class="supplement-link section-jump-link" data-tab-toggle=".tab-nav-supplemental" href="#note-IOI220009-1">Supplement</a>.</p> <a class="article-section-id-anchor" id="248371882"></a>
<div class="h4 cb section-type-section ">
<div class="heading-text "> Data Extraction and Quality Assessments </div>
</div>
<a class="article-section-id-anchor" id="248371883"></a>
<p class="para">Data extraction was performed independently by 2 reviewers (H.L.Y., H.J.Y.) using a standardized predefined data extraction form. Extracted data included first author or trial name, publication year, indication for
treatment, duration of treatments, GLP-1 RA administrations, comparator drugs, incidence of gallbladder or biliary disease outcomes, and characteristics of trial participants (ie, age, weight, body mass index [BMI, calculated as
weight in kilograms divided by height in meters squared], and glycated hemoglobin [HbA<sub>1c</sub>] levels).</p> <a class="article-section-id-anchor" id="248371884"></a>
<p class="para">The risk of bias in each of the studies included was assessed independently by 3 reviewers (H.L.Y., Z.H.B., W.J.L.) using the revised Cochrane risk-of-bias tool for randomized clinical
trials.<sup><a href="#ioi220009r13" class="ref-link section-jump-link" data-tab-toggle=".tab-nav-references">13</a></sup> Disagreements were resolved by discussion with other team members.</p>
<a class="article-section-id-anchor" id="248371885"></a>
<div class="h4 cb section-type-section ">
<div class="heading-text "> Data Synthesis and Analysis </div>
</div>
<a class="article-section-id-anchor" id="248371886"></a>
<p class="para">Pooled relative risks (RR) and 95% CIs were calculated using random or fixed-effects models. Statistical heterogeneity was assessed using Q tests and <i>I</i><sup>2</sup>
statistic.<sup><a href="#ioi220009r14" class="ref-link section-jump-link" data-tab-toggle=".tab-nav-references">14</a></sup> Random-effects models with the DerSimonian-Laird method were used when there was no significant
heterogeneity (<i>Q</i> tests, <i>P</i> < .05; <i>I</i><sup>2</sup> > 50%); otherwise, Mantel-Haenszel methods and fixed-effects models were used. Absolute risks were estimated based on the calculated RR and mean event rate
across control groups for each outcome, and the event rates derived from different treatment durations for each outcome were converted into annual
incidences.<sup><a href="#ioi220009r15" class="ref-link section-jump-link" data-tab-toggle=".tab-nav-references">15</a></sup><sup>,<a href="#ioi220009r16" class="ref-link section-jump-link" data-tab-toggle=".tab-nav-references">16</a></sup>
</p> <a class="article-section-id-anchor" id="248371887"></a>
<p class="para">In subgroup analyses, we evaluated associations with gallbladder or biliary diseases of specific GLP-1 RA medications, higher and lower doses, shorter and longer treatment durations (≤26 or >26 weeks), indication
for treatment (type 2 diabetes/other diseases or obesity), type of control (placebo or active comparator), and baseline BMI. High doses of GLP-1 RAs were defined as equal to or greater than: albiglutide, 50 mg once weekly;
dulaglutide, 1.5 mg once weekly; liraglutide, 1.8 mg once daily; subcutaneous semaglutide, 1.0 mg once weekly; and oral semaglutide, 7 mg once daily. Low doses were defined as: albiglutide, 30 mg (<50 mg) once weekly;
dulaglutide, 0.75 mg (<1.5 mg) once weekly; liraglutide, 0.6 to 1.2 mg (<1.8 mg) once daily; subcutaneous semaglutide, 0.5 mg (<1.0 mg) once weekly; and oral semaglutide, 3.0 mg (<7.0 mg) once daily. Exenatide and
lixisenatide as single doses were not included to assess the dosage-dependent effects. Significant differences between subgroups were estimated using metaregression with the residual maximum likelihood method.</p>
<a class="article-section-id-anchor" id="248371888"></a>
<p class="para">Sensitivity analyses were conducted by omitting eligible trials 1 by 1 and removing studies with albiglutide. Random-effects models were also used to pool results for sensitivity analysis.</p>
<a class="article-section-id-anchor" id="248371889"></a>
<p class="para">Publication bias was assessed visually using funnel plots and statistically using the Egger test. Certainty of the evidence for each outcome in the analysis was evaluated using the GRADE (Grading of Recommendations,
Assessment, Development and Evaluations) framework,<sup><a href="#ioi220009r17" class="ref-link section-jump-link" data-tab-toggle=".tab-nav-references">17</a></sup> which considers risk of bias, imprecision, inconsistency,
indirectness, and publication bias of the included studies.</p> <a class="article-section-id-anchor" id="248371890"></a>
<p class="para">Analyses were repeated and restricted to trials for control of type 2 diabetes or weight loss. Subgroup analyses by dose or duration of treatment were only performed in trials for control of diabetes owing to the small
number of trials that included lower doses or shorter duration for weight loss. Finally, among the trials of treatment for diabetes, we assessed risk of gallbladder and biliary diseases according to whether the trial aimed to assess
cardiovascular outcome or not.</p> <a class="article-section-id-anchor" id="248371891"></a>
<p class="para">Statistical analyses were conducted from August 5, 2021, to September 3, 2021, using R, version 4.0.2 (R Foundation for Statistical Computing). Tests were 2-tailed, and <i>P</i> values <.05 were considered
statistically significant.</p> <a class="article-section-id-anchor" id="248371892"></a>
<div class="h3 cb section-type-section ">
<div class="heading-text thm-col sb-sc"> Results </div>
</div>
<a class="article-section-id-anchor" id="248371893"></a>
<div class="h4 cb section-type-section ">
<div class="heading-text "> Trial Identification and Characteristics </div>
</div>
<a class="article-section-id-anchor" id="248371894"></a>
<p class="para">The literature search identified 7214 potentially relevant studies (<a href="#ioi220009f1" class="figure-link section-jump-link" data-tab-toggle=".tab-nav-figure-table">Figure 1</a>), of which 76 randomized clinical
trials with 77 data sets were included in the meta-analysis—the complete list is available in the eReferences of the
<a class="supplement-link section-jump-link" data-tab-toggle=".tab-nav-supplemental" href="#note-IOI220009-1">Supplement</a>. The included studies had a combined total of 103 371 participants (mean [SD] age, 57.8 [6.2] years; 41 868
[40.5%] women; mean BMI, 32.6; mean HbA<sub>1c</sub>, 7.8%). Most of the trials included participants with type 2 diabetes (84.4%). The baseline characteristics of eligible trials and participants are shown in eTable 2 in the
<a class="supplement-link section-jump-link" data-tab-toggle=".tab-nav-supplemental" href="#note-IOI220009-1">Supplement</a>.</p> <a class="article-section-id-anchor" id="248371896"></a>
<p class="para">Stratified by indication for treatment, there were 60 trials (including 61 data sets) with 91 599 participants randomized to GLP-1 RAs for diabetes, 13 trials with 11 281 participants randomized for weight loss, and 3
trials for nonalcoholic steatohepatitis, polycystic ovary syndrome, and schizophrenia. Three trials conducted in participants with type 2 diabetes were classified with weight loss trials because their primary outcome was change in
weight and GLP-1 RA doses were in the weight-loss range. The mean BMI of patients in trials for treatment of diabetes and obesity was 31.6 and 36.9, respectively.</p> <a class="article-section-id-anchor" id="248371897"></a>
<div class="h4 cb section-type-section ">
<div class="heading-text "> Risk of Bias and GRADE Rating </div>
</div>
<a class="article-section-id-anchor" id="248371898"></a>
<p class="para">The risk of bias for each study is shown in eTable 3 and eFigure 1 in the <a class="supplement-link section-jump-link" data-tab-toggle=".tab-nav-supplemental" href="#note-IOI220009-1">Supplement</a>. Most of the
studies had a low risk or some concern of bias across all 5 domains evaluated.</p> <a class="article-section-id-anchor" id="248371899"></a>
<p class="para">The overall quality of evidence for the comparisons of GLP-1 RAs vs control groups for increased risk of the combined outcome of gallbladder or biliary disease was rated high. For the secondary outcomes of
cholelithiasis, cholecystitis, and biliary disease, the quality of evidence was rated high or moderate (eTable 4 in the
<a class="supplement-link section-jump-link" data-tab-toggle=".tab-nav-supplemental" href="#note-IOI220009-1">Supplement</a>).</p> <a class="article-section-id-anchor" id="248371900"></a>
<div class="h4 cb section-type-section ">
<div class="heading-text "> Association of GLP-1 RAs With Gallbladder or Biliary Disease </div>
</div>
<a class="article-section-id-anchor" id="248371901"></a>
<p class="para">Randomization to GLP-1 RAs treatment was associated with a significantly increased risk of gallbladder or biliary diseases (RR, 1.37; 95% CI, 1.23-1.52; <i>I</i><sup>2</sup> = 0%) compared with controls (eResults in
the <a class="supplement-link section-jump-link" data-tab-toggle=".tab-nav-supplemental" href="#note-IOI220009-1">Supplement</a>); the absolute risk difference (range) was an additional 27 (17-38) events per 10 000 patients per year
(<a href="#ioi220009f2" class="figure-link section-jump-link" data-tab-toggle=".tab-nav-figure-table">Figure 2</a>). Treatment with GLP-1 RAs was associated with increased risks of cholelithiasis (RR, 1.27; 95% CI, 1.10-1.47;
<i>I</i><sup>2</sup> = 0%), cholecystitis (RR, 1.36; 95% CI, 1.14-1.62; <i>I</i><sup>2</sup> = 0%), and biliary disease (RR, 1.55; 95% CI, 1.08-2.22; <i>I</i><sup>2</sup> = 0%) compared with controls
(<a href="#ioi220009f2" class="figure-link section-jump-link" data-tab-toggle=".tab-nav-figure-table">Figure 2</a>; eFigure 2 in the
<a class="supplement-link section-jump-link" data-tab-toggle=".tab-nav-supplemental" href="#note-IOI220009-1">Supplement</a>). The results from trials of diabetes or weight-loss treatment are presented in eFigures 3 to 6 in the
<a class="supplement-link section-jump-link" data-tab-toggle=".tab-nav-supplemental" href="#note-IOI220009-1">Supplement</a>.</p> <a class="article-section-id-anchor" id="248371903"></a>
<p class="para">In all of the included trials, GLP-1 RAs was associated with a higher risk of cholecystectomy compared with controls (RR, 1.70; 95% CI, 1.25-2.32; <i>I</i><sup>2</sup> = 0%; eFigure 7 in the
<a class="supplement-link section-jump-link" data-tab-toggle=".tab-nav-supplemental" href="#note-IOI220009-1">Supplement</a>); there was no increase in risk of biliary tract cancer (RR, 1.43; 95% CI, 0.80-2.56;
<i>I</i><sup>2</sup> = 0%; eFigure 8 in the <a class="supplement-link section-jump-link" data-tab-toggle=".tab-nav-supplemental" href="#note-IOI220009-1">Supplement</a>).</p> <a class="article-section-id-anchor" id="248371904"></a>
<div class="h4 cb section-type-section ">
<div class="heading-text "> Specific GLP-1 RA Drugs and Gallbladder or Biliary Disease </div>
</div>
<a class="article-section-id-anchor" id="248371905"></a>
<p class="para">Compared with the control group, randomization to liraglutide (RR, 1.79; 95% CI, 1.45-2.25) or dulaglutide (RR, 1.35; 95% CI, 1.06-1.73) treatment was associated with increased risk for gallbladder or biliary diseases.
Randomization to subcutaneous semaglutide (RR, 1.28; 95% CI, 0.99-1.65) and exenatide (RR, 1.23; 95% CI, 1.00-1.52) was associated with increased risk, although the increase was not statistically significant. However, oral
semaglutide, lixisenatide, and albiglutide did not increase risk (<a href="#ioi220009f3" class="figure-link section-jump-link" data-tab-toggle=".tab-nav-figure-table">Figure 3</a>; eFigure 9 in the
<a class="supplement-link section-jump-link" data-tab-toggle=".tab-nav-supplemental" href="#note-IOI220009-1">Supplement</a>); higher doses of subcutaneous semaglutide (≥1.0 mg) were associated with increased gallbladder or biliary
diseases (RR, 1.58; 95% CI, 1.13-2.22). The results in trials with treatment for diabetes or weight loss are presented in eFigures 10 to 12 in the
<a class="supplement-link section-jump-link" data-tab-toggle=".tab-nav-supplemental" href="#note-IOI220009-1">Supplement</a>.</p> <a class="article-section-id-anchor" id="248371907"></a>
<div class="h4 cb section-type-section ">
<div class="heading-text "> Dose, Duration, and Indication for Treatment </div>
</div>
<a class="article-section-id-anchor" id="248371908"></a>
<p class="para">Use of GLP-1 RAs was significantly associated with increased risks of gallbladder or biliary disease at higher doses (RR, 1.56; 95% CI, 1.36-1.78) but not at lower doses (RR, 0.99; 95% CI, 0.74-1.33; <i>P</i> = .006
for interaction; <a href="#ioi220009t1" class="table-link section-jump-link" data-tab-toggle=".tab-nav-figure-table">Table</a>). Longer duration of treatment with GLP-1 RAs (>26 weeks) was associated with increased risk for
gallbladder or biliary disease (RR, 1.40; 95% CI, 1.26-1.56), but shorter duration (≤26 weeks) of treatment was not (RR, 0.79; 95% CI, 0.48-1.31; <i>P</i> = .03 for interaction;
<a href="#ioi220009t1" class="table-link section-jump-link" data-tab-toggle=".tab-nav-figure-table">Table</a>). Restricted to trials for diabetes, the effect of dose (<i>P</i> = .08 for interaction) and duration of treatment
(<i>P</i> = .07 for interaction) were similar (supporting data reported in eTable 5 and eFigure 13 in the <a class="supplement-link section-jump-link" data-tab-toggle=".tab-nav-supplemental" href="#note-IOI220009-1">Supplement</a>).
</p> <a class="article-section-id-anchor" id="248371910"></a>
<p class="para">Use of GLP-1 RAs for weight loss showed stronger effects on the risk of gallbladder or biliary disease than the other indications (ie, diabetes/other diseases; <i>P</i> <.001 for interaction;
<a href="#ioi220009t1" class="table-link section-jump-link" data-tab-toggle=".tab-nav-figure-table">Table</a>). No significant association of baseline BMI or type of control (placebo or active comparators) were observed (Table;
eTables 5 and 6 and eFigure 14 in the <a class="supplement-link section-jump-link" data-tab-toggle=".tab-nav-supplemental" href="#note-IOI220009-1">Supplement</a>). In trials for diabetes, there were no significant differences in
effects in trials for cardiovascular or noncardiovascular outcomes (eFigure 15 in the <a class="supplement-link section-jump-link" data-tab-toggle=".tab-nav-supplemental" href="#note-IOI220009-1">Supplement</a>).</p>
<a class="article-section-id-anchor" id="248371911"></a>
<div class="h4 cb section-type-section ">
<div class="heading-text "> Sensitivity Analyses </div>
</div>
<a class="article-section-id-anchor" id="248371912"></a>
<p class="para">After the iterative omission of each trial, removal of all trials of albiglutide or which used random-effects models, the pooled results did not change. Additional details are available in eFigures 16 and 17 in the
<a class="supplement-link section-jump-link" data-tab-toggle=".tab-nav-supplemental" href="#note-IOI220009-1">Supplement</a>.</p> <a class="article-section-id-anchor" id="248371913"></a>
<div class="h4 cb section-type-section ">
<div class="heading-text "> Publication Bias </div>
</div>
<a class="article-section-id-anchor" id="248371914"></a>
<p class="para">There was no evidence of publication bias for studies of gallbladder or biliary diseases (<i>P</i> = .83), cholelithiasis (<i>P</i> = .19), cholecystitis (<i>P</i> = .20), or biliary diseases (<i>P</i> = .57) by the
Egger test (supporting data are eFigure 18 in the <a class="supplement-link section-jump-link" data-tab-toggle=".tab-nav-supplemental" href="#note-IOI220009-1">Supplement</a>). Visually, funnel plots did not demonstrate publication
bias.</p> <a class="article-section-id-anchor" id="248371915"></a>
<div class="h3 cb section-type-section ">
<div class="heading-text thm-col sb-sc"> Discussion </div>
</div>
<a class="article-section-id-anchor" id="248371916"></a>
<p class="para">This systematic review and meta-analysis of 76 randomized clinical trials found that randomization to treatment with GLP-1 RAs compared with placebo or active controls was associated with increased risk of the
composite outcome of gallbladder or biliary diseases and for cholelithiasis, cholecystitis, and biliary diseases. Risk was increased in trials of patients treated for diabetes and for weight loss and was higher in the trials for
weight reduction. Higher doses and longer duration of GLP-1 RAs treatment were also associated with increased risk of gallbladder or biliary diseases, although the association was not statistically significant.</p>
<a class="article-section-id-anchor" id="248371917"></a>
<p class="para">Previous systematic reviews have reported an increased risk of cholelithiasis with GLP-1 RA
use,<sup><a href="#ioi220009r18" class="ref-link section-jump-link" data-tab-toggle=".tab-nav-references">18</a></sup><sup>,<a href="#ioi220009r19" class="ref-link section-jump-link" data-tab-toggle=".tab-nav-references">19</a></sup>
but these reviews were limited to trials with restrictions on populations and duration of treatment and did not include several important studies that have been published
recently.<sup><a href="#ioi220009r6" class="ref-link section-jump-link" data-tab-toggle=".tab-nav-references">6</a></sup><sup>,<a href="#ioi27" class="ref-link section-jump-link" data-tab-toggle=".tab-nav-references">7</a>,<a href="#ioi220009r20" class="ref-link section-jump-link" data-tab-toggle=".tab-nav-references">20</a></sup>
</p> <a class="article-section-id-anchor" id="248371918"></a>
<p class="para">Use of GLP-1 RAs may be associated with increased risk of gallbladder or biliary diseases because GLP-1 inhibits gallbladder motility and delays gallbladder emptying by suppressing the secretion of
cholecystokinin.<sup><a href="#ioi220009r8" class="ref-link section-jump-link" data-tab-toggle=".tab-nav-references">8</a></sup><sup>,<a href="#ioi220009r21" class="ref-link section-jump-link" data-tab-toggle=".tab-nav-references">21</a></sup><sup>-<a href="#ioi220009r21" class="ref-link section-jump-link" data-tab-toggle=".tab-nav-references">24</a></sup>
In addition, marked weight loss, which occurs in some patients using GLP-1 RAs, has been associated with a high risk of gallbladder
disorders.<sup><a href="#ioi220009r9" class="ref-link section-jump-link" data-tab-toggle=".tab-nav-references">9</a></sup><sup>,<a href="#ioi220009r25" class="ref-link section-jump-link" data-tab-toggle=".tab-nav-references">25</a></sup>
</p> <a class="article-section-id-anchor" id="248371919"></a>
<p class="para">Gallbladder disease has been reported as an adverse event in the published reports and/or the supplemental materials of most of the randomized clinical trials of GLP-1
RAs<sup><a href="#ioi220009r6" class="ref-link section-jump-link" data-tab-toggle=".tab-nav-references">6</a></sup><sup>,<a href="#ioi220009r20" class="ref-link section-jump-link" data-tab-toggle=".tab-nav-references">20</a></sup><sup>,<a href="#ioi220009r26" class="ref-link section-jump-link" data-tab-toggle=".tab-nav-references">26</a></sup><sup>-<a href="#ioi220009r26" class="ref-link section-jump-link" data-tab-toggle=".tab-nav-references">28</a></sup>;
however, to our knowledge, biliary diseases have seldom been reported. Only 20 of the 76 trials eligible for this systematic review clearly reported biliary-related events, suggesting potential underreporting. Given the findings of
this review and analysis, studies of GLP-1 RAs should fully report biliary-related events.</p> <a class="article-section-id-anchor" id="248371920"></a>
<p class="para">The risk of gallbladder or biliary diseases was higher in trials using GLP-1 RAs for weight loss than for diabetes control. The increased risk of gallbladder or biliary diseases in weight loss trials may be associated
with weight loss produced by GLP-1 RAs, but these trials also used higher doses and/or longer treatment durations than the diabetes control trials used. Liraglutide (3.0
mg)<sup><a href="#ioi220009r28" class="ref-link section-jump-link" data-tab-toggle=".tab-nav-references">28</a></sup> and subcutaneous semaglutide (2.4
mg)<sup><a href="#ioi220009r29" class="ref-link section-jump-link" data-tab-toggle=".tab-nav-references">29</a></sup> have been approved by the US Food and Drug Administration (FDA) for weight
management,<sup><a href="#ioi220009r9" class="ref-link section-jump-link" data-tab-toggle=".tab-nav-references">9</a></sup><sup>,<a href="#ioi220009r29" class="ref-link section-jump-link" data-tab-toggle=".tab-nav-references">29</a></sup>
suggesting that GLP-1 RA drugs will increasingly be used at high doses for weight control; the increased risk for gallbladder and biliary diseases should be of concern in these patients.</p>
<a class="article-section-id-anchor" id="248371921"></a>
<p class="para">Liraglutide has drawn the most attention concerning the increased risk of gallbladder-related
events,<sup><a href="#ioi220009r7" class="ref-link section-jump-link" data-tab-toggle=".tab-nav-references">7</a></sup><sup>-<a href="#ioi220009r7" class="ref-link section-jump-link" data-tab-toggle=".tab-nav-references">9</a>,<a href="#ioi220009r30" class="ref-link section-jump-link" data-tab-toggle=".tab-nav-references">30</a></sup>while
other GLP-1 RA medications have received limited attention.<sup><a href="#ioi220009r9" class="ref-link section-jump-link" data-tab-toggle=".tab-nav-references">9</a></sup> Previous
studies<sup><a href="#ioi220009r18" class="ref-link section-jump-link" data-tab-toggle=".tab-nav-references">18</a></sup><sup>,<a href="#ioi220009r19" class="ref-link section-jump-link" data-tab-toggle=".tab-nav-references">19</a></sup>
did not notice a high risk of gallbladder or biliary disease in patients randomized to dulaglutide treatment, and current prescribing information for dulaglutide does not contain warnings about the risks of gallbladder or biliary
diseases.<sup><a href="#ioi220009r31" class="ref-link section-jump-link" data-tab-toggle=".tab-nav-references">31</a></sup><sup>,<a href="#ioi220009r32" class="ref-link section-jump-link" data-tab-toggle=".tab-nav-references">32</a></sup>
The prescribing information from the FDA and the European Medicines Agency mention the possible increased risk of cholelithiasis for
exenatide<sup><a href="#ioi220009r33" class="ref-link section-jump-link" data-tab-toggle=".tab-nav-references">33</a></sup><sup>,<a href="#ioi220009r34" class="ref-link section-jump-link" data-tab-toggle=".tab-nav-references">34</a></sup>
and subcutaneous
semaglutide<sup><a href="#ioi220009r35" class="ref-link section-jump-link" data-tab-toggle=".tab-nav-references">35</a></sup><sup>,<a href="#ioi220009r36" class="ref-link section-jump-link" data-tab-toggle=".tab-nav-references">36</a></sup>
compared with placebo. Our findings showed that GLP-1 RA medications, including dulaglutide, exenatide, and subcutaneous semaglutide (≥1.0 mg), increased the risk of gallbladder or biliary diseases. Given the similar efficacy and
effectiveness of oral and subcutaneous
semaglutide,<sup><a href="#ioi220009r37" class="ref-link section-jump-link" data-tab-toggle=".tab-nav-references">37</a></sup><sup>,<a href="#ioi220009r38" class="ref-link section-jump-link" data-tab-toggle=".tab-nav-references">38</a></sup>
the association of the oral formulation with the risk of gallbladder or biliary diseases requires further evaluation. Although in this meta-analysis, albiglutide and lixisenatide were not associated with a statistically significant
increased risk, these findings may have been influenced by low power owing to a small number of studies or to inadequate reporting of gallbladder or biliary diseases in these
trials.<sup><a href="#ioi220009r39" class="ref-link section-jump-link" data-tab-toggle=".tab-nav-references">39</a></sup><sup>-<a href="#ioi220009r39" class="ref-link section-jump-link" data-tab-toggle=".tab-nav-references">42</a></sup>
</p> <a class="article-section-id-anchor" id="248371922"></a>
<p class="para">Higher risk of gallbladder or biliary diseases was associated with higher doses of GLP-1 RAs in weight loss trials compared with lower doses in diabetes control trials; however, there was a similar trend to increased
risk with higher doses in the diabetes trials. Increasing doses of GLP-1 RAs may be recommended for patients who do not achieve glycemic control goals with lower
doses<sup><a href="#ioi220009r43" class="ref-link section-jump-link" data-tab-toggle=".tab-nav-references">43</a></sup>; therefore, increased risks of gallbladder or biliary diseases should be considered when the doses are
escalated.</p> <a class="article-section-id-anchor" id="248371923"></a>
<p class="para">A previous observational study reported that gallbladder or biliary diseases tended to occur in the first 6 months of GLP-1 RA
treatment.<sup><a href="#ioi220009r25" class="ref-link section-jump-link" data-tab-toggle=".tab-nav-references">25</a></sup> In contrast, the present meta-analysis found that GLP-1 RA use increased the risk of gallbladder or biliary
disease only with longer durations of treatment. Given that GLP-1 RAs may need to be used for the long term, both for control of diabetes and weight, an increased risk associated with long-duration treatment could be clinically
important.</p> <a class="article-section-id-anchor" id="248371924"></a>
<p class="para">Although this meta-analysis showed that the RRs for gallbladder and biliary diseases were elevated, the overall absolute risk increase was small (an additional 27 cases per 10 000 persons treated per year). This
absolute risk increase should be weighed against the benefits of treatment with GLP-1 RA drugs.</p> <a class="article-section-id-anchor" id="248371925"></a>
<div class="h4 cb section-type-section ">
<div class="heading-text "> Strengths and Limitations </div>
</div>
<a class="article-section-id-anchor" id="248371926"></a>
<p class="para">This systematic review and meta-analysis was strengthened by the incorporation of recently published studies, by addressing the increased risks of biliary diseases with GLP-1 RA use separately from gallbladder
disorders, and by highlighting the increased risk associated with other GLP-1 RA medications, in addition to liraglutide. The present study revealed that GLP-1 RAs used at higher doses for weight control may contribute to a higher
risk of gallbladder or biliary diseases. However, this study had several limitations. Information on biliary-related events may not have been fully reported because they were not a predefined safety outcome in most of the included
trials. These studies were not specifically designed to evaluate the risk of gallbladder or biliary diseases associated with GLP-1 RAs treatment. Also, because this was a meta-analysis of randomized trials, we were unable to use
patient-level data to evaluate outcomes. Finally, the small number of events in subgroups may have allowed for underpowered subgroup analyses.</p> <a class="article-section-id-anchor" id="248371927"></a>
<div class="h3 cb section-type-section ">
<div class="heading-text thm-col sb-sc"> Conclusions </div>
</div>
<a class="article-section-id-anchor" id="248371928"></a>
<p class="para">The findings of this systematic review and meta-analysis indicate that physicians should be concerned about the increased risk of gallbladder or biliary disease associated with GLP-1 RA use, especially at the higher
doses recommended for weight loss. In addition, future trials should prespecify gallbladder and biliary diseases as potential adverse events, and fully test for and report on these outcomes.</p>
<a class="article-section-id-anchor" id="248371929"></a>
<div class="h3 cb section-type-acknowledgements has-back-to-top">
<a href="#top" class="section-jump-link back-to-top" data-tab-toggle=".tab-nav-full-text">Back to top</a>
<div class="heading-text thm-col sb-sc"> Article Information </div>
</div>
<p class="para"><strong>Accepted for Publication:</strong> January 28, 2022.</p>
<p class="parapublished-online"><strong>Published Online:</strong> March 28, 2022. doi:10.1001/jamainternmed.2022.0338</p>
<p class="authorInfoSection"><strong>Corresponding Author:</strong> Huabing Zhang, MD, Department of Endocrinology, Key Laboratory of Endocrinology of the National Health Commission, Peking Union Medical College Hospital, Chinese
Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing, Dongcheng District, Beijing, China 100730 (<a href="mailto:huabingzhangchn@163.com" target="_blank">huabingzhangchn@163.com</a>).</p>
<p class="paraauthor-contributions"><strong>Author Contributions:</strong> Dr Zhang had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.</p>
<p class="para"><i>Concept and design:</i> He, Zhang.</p>
<p class="para"><i>Acquisition, analysis, or interpretation of data:</i> All authors.</p>
<p class="para"><i>Drafting of the manuscript:</i> He, Zhang.</p>
<p class="para"><i>Critical revision of the manuscript for important intellectual content:</i> All authors.</p>
<p class="para"><i>Statistical analysis:</i> He, Wang, Ping, Yang, Zhang.</p>
<p class="para"><i>Obtained funding:</i> Y. Li, Zhang.</p>
<p class="para"><i>Administrative, technical, or material support:</i> He, Wang, Yang, Huang, Xu, Y. Li, W. Li.</p>
<p class="para"><i>Supervision:</i> Ping, Xu, Y. Li, W. Li, Zhang.</p>
<p class="parafinancial-disclosure"><strong>Conflict of Interest Disclosures:</strong> None reported.</p>
<p class="parafunding-statement"><strong>Funding/Support:</strong> This work was supported by grants from the National Natural Science Foundation of China (No. 91846106), the Beijing Municipal Natural Science Foundation (No. M22014),
the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (No. 2019XK320029), the CAMS Innovation Fund for Medical Sciences (No. 2021-1-I2M-002), and the Training Program for Excellent Talents in
Dongcheng District (No. TPETDD2018).</p>
<p class="para"><strong>Role of the Funder/Sponsor:</strong> The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the
manuscript; and decision to submit the manuscript for publication.</p>
<p class="para"><strong>Additional Contributions:</strong> The authors are grateful to the staff of the Peking Union Medical College Hospital and all who actively participated and provided statistical support to the study.</p>
<a class="article-section-id-anchor" id="248371930"></a>
<div class="h3 cb section-type-references ">
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[Skip to Navigation] Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast JAMA+ AI JOURNALS JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2024 American Medical Association. All Rights Reserved Search All * Search All * JAMA * JAMA Network Open * JAMA Cardiology * JAMA Dermatology * JAMA Forum Archive * JAMA Health Forum * JAMA Internal Medicine * JAMA Neurology * JAMA Oncology * JAMA Ophthalmology * JAMA Otolaryngology–Head & Neck Surgery * JAMA Pediatrics * JAMA Psychiatry * JAMA Surgery * Archives of Neurology & Psychiatry Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Subscribe to the JAMA Internal Medicine journal full text icon Full Text contents icon Contents figure icon Figures / Tables multimedia icon Multimedia attach icon Supplemental Content references icon References related icon Related comments icon Comments Download PDF Comment Top of Article * Key Points * Abstract * Introduction * Methods * Results * Discussion * Conclusions * Article Information * References Figure 1. PRISMA Flow Diagram View LargeDownload GLP-1 RAs denotes glucagon-like peptide-1 receptor agonists; RCTs, randomized clinical trials; and T1D, type 1 diabetes. Figure 2. Risks of Cholelithiasis, Cholecystitis, and Biliary Diseases in Patients Randomized to GLP-1 RA Treatment Compared With Controls in All Trials View LargeDownload ARD denotes the absolute risk difference and GLP-1 RA, glucagon-like peptide-1 receptor agonist. Figure 3. Risks of Gallbladder or Biliary Diseases Associated With Individual GLP-1 RA Drugs View LargeDownload GLP-1 RA indicates glucagon-like peptide-1 receptor agonist; and SC, subcutaneous. Table. Factors and Risks of Gallbladder or Biliary Diseases in 76 Randomized Clinical Trials of GLP-1 RA Drug Use View LargeDownload Supplement. eMethods 1. Data sources and search strategies eMethods 2. Identification of the outcomes eTable 1. Eligibility criteria of included studies eTable 2. Baseline characteristics of studies and participants included eTable 3. Assessments of risks of bias of eligible studies according to revised Cochrane risk-of-bias tool for randomized trials eTable 4. Grade summary of findings for each outcome in the meta-analysis eTable 5. Effects of factors on the risks of gallbladder or biliary diseases with GLP-1 RAs in trials with treatment for diabetes eTable 6. Effects of factors on the risks of gallbladder or biliary diseases with GLP-1 RAs in trials with treatment for weight loss eFigure 1. Summary of risks of bias of all included studies eFigure 2. Risks of cholelithiasis, cholecystitis, and biliary diseases in patients with GLP-1 RAs treatments compared with controls eFigure 3. Risks of the composite of gallbladder or biliary diseases, cholelithiasis, cholecystitis, and biliary diseases with glp-1 ras compared with controls in trials with treatment for diabetes eFigure 4. Overall risks of cholelithiasis, cholecystitis, and biliary diseases in patients with GLP-1 RAs compared with controls in trials with treatment for diabetes eFigure 5. Risks of the composite of gallbladder or biliary diseases, cholelithiasis, cholecystitis, and biliary diseases with GLP-1 RAs compared with controls in trials with treatment for weight loss eFigure 6. Overall risks of cholelithiasis, cholecystitis, and biliary diseases in patients with GLP-1 RAs compared with controls in trials with treatment for weight loss eFigure 7. Risks of cholecystectomy in patients with GLP-1 RAs compared with controls eFigure 8. Risks of biliary tract cancer in patients with GLP-1 RAs compared with controls eFigure 9. Risks of gallbladder or biliary diseases in patients with different GLP-1 RAs individuals compared with controls in all trials eFigure 10. Risks of gallbladder or biliary diseases in patients with different GLP-1 RAs medications compared with controls in trials with treatment for diabetes eFigure 11. Risks of gallbladder or biliary diseases in patients with different GLP-1 RAs medications compared with controls in trials with treatment for weight loss eFigure 12. Effects of doses and duration of treatments on the association between GLP-1 RAs and gallbladder or biliary diseases in all trials eFigure 13. Effects of doses and duration of treatments on the association between GLP-1 RAs and gallbladder or biliary diseases in trials with treatment for diabetes eFigure 14. Effects of baseline bmi and types of control on the association between GLP-1 RAs and gallbladder or biliary diseases in all trials, trial for diabetes or weight loss eFigure 15. Effects of types of trials on the risks of gallbladder or biliary diseases in trials with treatment for diabetes eFigure 16. Sensitivity analyses by omitting each trial one by one and removing studies with albiglutide eFigure 17. Sensitivity analyses by using random-effect models eFigure 18. Funnel plot of all eligible studies eResults. Risks of gallbladder or biliary diseases in patients with GLP-1RAs treatments compared with controls eReferences 1. Kalyani RR. Glucose-lowering drugs to reduce cardiovascular risk in type 2 diabetes. N Engl J Med. 2021;384(13):1248-1260. doi:10.1056/NEJMcp2000280PubMedGoogle ScholarCrossref 2. Liuzzo G, Galiuto L. GLP-1 receptor agonists: fighting obesity with an eye to cardiovascular risk. Eur Heart J. 2021;42(17):1652-1653. doi:10.1093/eurheartj/ehab175PubMedGoogle ScholarCrossref 3. Marx N, Davies MJ, Grant PJ, et al. Guideline recommendations and the positioning of newer drugs in type 2 diabetes care. Lancet Diabetes Endocrinol. 2021;9(1):46-52. doi:10.1016/S2213-8587(20)30343-0PubMedGoogle ScholarCrossref 4. Marx N, Grant PJ, Cosentino F. Compelling evidence for SGLT2 inhibitors and GLP-1 receptor agonists as first-line therapy in patients with diabetes at very high/high cardiovascular risk. Eur Heart J. 2020;41(2):329-330. doi:10.1093/eurheartj/ehz853PubMedGoogle ScholarCrossref 5. Wadden TA, Bailey TS, Billings LK, et al; STEP 3 Investigators. Effect of subcutaneous semaglutide vs placebo as an adjunct to intensive behavioral therapy on body weight in adults with overweight or obesity: the STEP 3 randomized clinical trial. JAMA. 2021;325(14):1403-1413. doi:10.1001/jama.2021.1831 ArticlePubMedGoogle ScholarCrossref 6. Wilding JPH, Batterham RL, Calanna S, et al; STEP 1 Study Group. Once weekly semaglutide in adults with overweight or obesity. N Engl J Med. 2021;384(11):989-1002. doi:10.1056/NEJMoa2032183PubMedGoogle ScholarCrossref 7. Lundgren JR, Janus C, Jensen SBK, et al. Healthy weight loss maintenance with exercise, liraglutide, or both combined. N Engl J Med. 2021;384(18):1719-1730. doi:10.1056/NEJMoa2028198PubMedGoogle ScholarCrossref 8. Nauck MA, Muus Ghorbani ML, Kreiner E, Saevereid HA, Buse JB; LEADER Publication Committee on behalf of the LEADER Trial Investigators. Effects of liraglutide compared with placebo on events of acute gallbladder or biliary disease in patients with type 2 diabetes at high risk for cardiovascular events in the LEADER randomized trial. Diabetes Care. 2019;42(10):1912-1920. doi:10.2337/dc19-0415PubMedGoogle ScholarCrossref 9. Christensen RM, Juhl CR, Torekov SS. Benefit-risk assessment of obesity drugs: focus on glucagon-like peptide-1 receptor agonists. Drug Saf. 2019;42(8):957-971. doi:10.1007/s40264-019-00812-7PubMedGoogle ScholarCrossref 10. US Food and Drug Administration. Drugs@FDA: FDA approved drug products. Accessed February 22, 2022. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm 11. European Medicines Agency. Medicines. Accessed February 22, 2022. https://www.ema.europa.eu/en/medicines 12. Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Ann Intern Med. 2009;151(4):W65-94. doi:10.7326/0003-4819-151-4-200908180-00136PubMedGoogle ScholarCrossref 13. Sterne JAC, Savović J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366:l4898. doi:10.1136/bmj.l4898PubMedGoogle ScholarCrossref 14. Higgins JPT, Thomas J, Chandler J, et al, eds. Cochrane Handbook for Systematic Reviews of Interventions version 6.2 (updated February 2021). Accessed February 22, 2022. www.training.cochrane.org/handbook. 15. Cai T, Abel L, Langford O, et al. Associations between statins and adverse events in primary prevention of cardiovascular disease: systematic review with pairwise, network, and dose-response meta-analyses. 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Cholelithiasis in patients treated with glucagon-like peptide-1 receptor: an updated meta-analysis of randomized controlled trials. Diabetes Res Clin Pract. 2020;161:108087. doi:10.1016/j.diabres.2020.108087PubMedGoogle ScholarCrossref 20. Davies M, Færch L, Jeppesen OK, et al; STEP 2 Study Group. Semaglutide 2·4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial. Lancet. 2021;397(10278):971-984. doi:10.1016/S0140-6736(21)00213-0PubMedGoogle ScholarCrossref 21. Shaddinger BC, Young MA, Billiard J, Collins DA, Hussaini A, Nino A. Effect of albiglutide on cholecystokinin-induced gallbladder emptying in healthy individuals: a randomized crossover study. J Clin Pharmacol. 2017;57(10):1322-1329. doi:10.1002/jcph.940PubMedGoogle ScholarCrossref 22. Rehfeld JF, Knop FK, Asmar A, Madsbad S, Holst JJ, Asmar M. 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(12):1429-1432. doi:10.1080/00365521.2018.1530297PubMedGoogle ScholarCrossref 23. Nexøe-Larsen CC, Sørensen PH, Hausner H, et al. Effects of liraglutide on gallbladder emptying: A randomized, placebo-controlled trial in adults with overweight or obesity. Diabetes Obes Metab. 2018;20(11):2557-2564. doi:10.1111/dom.13420PubMedGoogle ScholarCrossref 24. Gether IM, Nexøe-Larsen C, Knop FK. New Avenues in the regulation of gallbladder motility-implications for the use of glucagon-like peptide-derived drugs. J Clin Endocrinol Metab. 2019;104(7):2463-2472. doi:10.1210/jc.2018-01008PubMedGoogle ScholarCrossref 25. Faillie JL, Yu OH, Yin H, Hillaire-Buys D, Barkun A, Azoulay L. Association of bile duct and gallbladder diseases with the use of incretin-based drugs in patients with type 2 diabetes mellitus. JAMA Intern Med. 2016;176(10):1474-1481. doi:10.1001/jamainternmed.2016.1531 ArticlePubMedGoogle ScholarCrossref 26. Lundgren JR, Janus C, Jensen SBK, et al. Healthy weight loss maintenance with exercise, liraglutide, or both combined. N Engl J Med. 2021;384(18):1719-1730. doi:10.1056/NEJMoa2028198PubMedGoogle ScholarCrossref 27. Álvarez-Villalobos NA, Treviño-Alvarez AM, González-González JG. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(18):1797-1798. doi:10.1056/NEJMc1611289PubMedGoogle ScholarCrossref 28. Holman RR, Bethel MA, Mentz RJ, et al; EXSCEL Study Group. Effects of once weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2017;377(13):1228-1239. doi:10.1056/NEJMoa1612917PubMedGoogle ScholarCrossref 29. US Food and Drug Administration. FDA approves new drug treatment for chronic weight management, first since 2014. Accessed February 23, 2022. https://www.fda.gov/news-events/press-announcements/fda-approves-new-drug-treatment-chronic-weight-management-first-2014 30. Tak YJ, Lee SY. Long-term efficacy and safety of anti-obesity treatment: where do we stand? Curr Obes Rep. 2021;10(1):14-30. doi:10.1007/s13679-020-00422-wPubMedGoogle ScholarCrossref 31. European Medicines Agency. Trulicity. Accessed February 23, 2022. https://www.ema.europa.eu/en/medicines/human/EPAR/trulicity 32. US Food and Drug Administration. Drug approval package Trulicity (dulaglutide) injection. NDA No. 125469. Accessed February 23, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/125469Orig1s000TOC.cfm 33. AstraZeneca. Bydureon BCise full prescribing information. Accessed February 23, 2022. http://www.azpicentral.com/pi.html?product=bydureon_bcise 34. European Medicines Agency. Bydureon, annex I: summary of product characteristics. Accessed February 23, 2022. https://www.ema.europa.eu/en/documents/product-information/bydureon-epar-product-information_en.pdf 35. US Food and Drug Administration. Ozempic. NDA No. 209637. Accessed February 23, 2022. http://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&varApplNo=209637 36. European Medicines Agency. Ozempic: EPAR product information. Accessed February 23, 2022. https://www.ema.europa.eu/en/medicines/human/EPAR/ozempic#product-information-section 37. Meier JJ. Efficacy of semaglutide in a subcutaneous and an oral formulation. Front Endocrinol (Lausanne). 2021;12:645617. doi:10.3389/fendo.2021.645617PubMedGoogle ScholarCrossref 38. Davies M, Pieber TR, Hartoft-Nielsen ML, Hansen OKH, Jabbour S, Rosenstock J. Effect of oral semaglutide compared with placebo and subcutaneous semaglutide on glycemic control in patients with type 2 diabetes: a randomized clinical trial. JAMA. 2017;318(15):1460-1470. doi:10.1001/jama.2017.14752 ArticlePubMedGoogle ScholarCrossref 39. Pinget M, Goldenberg R, Niemoeller E, Muehlenbartmer I, Aronson R. Efficacy and safety of lixisenatide once daily versus placebo in patients with type 2 diabetes insufficiently controlled on pioglitazone (GetGoal-P). Abstracts of the 48th EASD Annual Meeting of the European Association for the Study of Diabetes. Diabetologia. 2012;55:S334. doi:10.1007/s00125-012-2688-9Google ScholarCrossref 40. Ratner RE, Hanefeld M, Shamanna P, et al. Efficacy and safety of lixisenatide once daily versus placebo in patients with type 2 diabetes mellitus insufficiently controlled on sulfonylurea ± metformin (GetGoal-S). Abstracts of the 48th EASD Annual Meeting of the European Association for the Study of Diabetes. Diabetologia. 2011;54:S317. doi:10.1007/s00125-011-2276-4Google ScholarCrossref 41. Reusch J, Stewart M, Perkins C, et al. HARMONY 1 results at week 52 primary endpoint: once weekly albiglutide vs placebo in patients with type 2 diabetes mellitus not controlled on pioglitazone ± metformin. Abstracts of the 48th EASD Annual Meeting of the European Association for the Study of Diabetes. Diabetologia. 2013;56:S359-S360. doi:10.1007/s00125-013-3012-zGoogle ScholarCrossref 42. Green JB, Hernandez AF, D’Agostino RB, et al. Harmony outcomes: a randomized, double-blind, placebo-controlled trial of the effect of albiglutide on major cardiovascular events in patients with type 2 diabetes mellitus: rationale, design, and baseline characteristics. Am Heart J. 2018;203:30-38. doi:10.1016/j.ahj.2018.03.030PubMedGoogle ScholarCrossref 43. Frías JP, Auerbach P, Bajaj HS, et al. Efficacy and safety of once weekly semaglutide 2·0 mg versus 1·0 mg in patients with type 2 diabetes (SUSTAIN FORTE): a double-blind, randomised, phase 3B trial. Lancet Diabetes Endocrinol. 2021;9(9):563-574. doi:10.1016/S2213-8587(21)00174-1PubMedGoogle ScholarCrossref * GLP-1 Agonists and Gastrointestinal Adverse Events JAMA Research Letter November 14, 2023 This database study examines the association between glucagon-like peptide 1 agonists (eg, semaglutide, liraglutide) used for weight loss and reports of gastrointestinal adverse events. Mohit Sodhi, MSc; Ramin Rezaeianzadeh, BSc; Abbas Kezouh, PhD; Mahyar Etminan, PharmD, MSc * GLP-1 Receptor Agonist Use and Risk of Postoperative Complications JAMA Research Letter May 21, 2024 This cohort study evaluates the risk of postoperative respiratory complications among patients with diabetes undergoing surgery who had vs those who had not a prescription fill for glucagon-like peptide 1 receptor agonists. Anjali A. Dixit, MD, MPH; Brian T. Bateman, MD, MS; Mary T. Hawn, MD, MPH; Michelle C. Odden, PhD; Eric C. Sun, MD, PhD * Safety of Glucagon-Like Peptide-1 Receptor Agonists JAMA Internal Medicine Invited Commentary May 1, 2022 Shanzay Haider, MD; Kasia J. Lipska, MD, MHS SEE MORE ABOUT Clinical Pharmacy and Pharmacology Hepatobiliary Disease Adverse Drug Events Pharmacoepidemiology Gastroenterology and Hepatology Diabetes Diabetes and Endocrinology TRENDING * Severe Acute Liver Injury After Hepatotoxic Medication Initiation JAMA Internal Medicine Research June 24, 2024 * Abdominal Pain After Roux-en-Y Gastric Bypass JAMA Surgery Review August 2, 2023 * Laparoscopic Liver Resection for Benign Disease JAMA Surgery Research December 1, 2007 -------------------------------------------------------------------------------- SELECT YOUR INTERESTS SELECT YOUR INTERESTS Customize your JAMA Network experience by selecting one or more topics from the list below. * Academic Medicine * Acid Base, Electrolytes, Fluids * Allergy and Clinical Immunology * American Indian or Alaska Natives * Anesthesiology * Anticoagulation * Art and Images in Psychiatry * Assisted Reproduction * Bleeding and Transfusion * Cardiology * Caring for the Critically Ill Patient * Challenges in Clinical Electrocardiography * Climate and Health * Climate Change * Clinical Challenge * Clinical Implications of Basic Neuroscience * Clinical Pharmacy and Pharmacology * Coaching * Complementary and Alternative Medicine * Consensus Statements * Coronavirus (COVID-19) * Critical Care Medicine * Cultural Competency * Dental Medicine * Dermatology * Diabetes and Endocrinology * Diagnostic Test Interpretation * Digital Health * Drug Development * Emergency Medicine * End of Life, Hospice, Palliative Care * Environmental Health * Equity, Diversity, and Inclusion * Ethics * Facial Plastic Surgery * Gastroenterology and Hepatology * Genetics and Genomics * Genomics and Precision Health * Geriatrics * Global Health * Guide to Statistics and Methods * Guidelines * Hair Disorders * Health Care Delivery Models * Health Care Economics, Insurance, Payment * Health Care Quality * Health Care Reform * Health Care Safety * Health Care Workforce * Health Disparities * Health Inequities * Health Policy * Health Systems Science * Hematology * History of Medicine * Humanities * Hypertension * Images in Neurology * Implementation Science * Infectious Diseases * Innovations in Health Care Delivery * JAMA Forum * JAMA Infographic * Law and Medicine * Leading Change * Less is More * LGBTQIA Medicine * Lifestyle Behaviors * Medical Coding * Medical Devices and Equipment * Medical Education * Medical Education and Training * Medical Journals and Publishing * Melanoma * Narrative Medicine * Nephrology * Neurology * Neuroscience and Psychiatry * Notable Notes * Nursing * Nutrition * Nutrition, Obesity, Exercise * Obesity * Obstetrics and Gynecology * Occupational Health * Oncology * Ophthalmology * Orthopedics * Otolaryngology * Pain Medicine * Palliative Care * Pathology and Laboratory Medicine * Patient Care * Patient Information * Pediatrics * Performance Improvement * Performance Measures * Perioperative Care and Consultation * Pharmacoeconomics * Pharmacoepidemiology * Pharmacogenetics * Pharmacy and Clinical Pharmacology * Physical Medicine and Rehabilitation * Physical Therapy * Physician Leadership * Poetry * Population Health * Primary Care * Professional Well-being * Professionalism * Psychiatry and Behavioral Health * Public Health * Pulmonary Medicine * Radiology * Regulatory Agencies * Reproductive Health * Research, Methods, Statistics * Resuscitation * Rheumatology * Risk Management * Scientific Discovery and the Future of Medicine * Sexual Health * Shared Decision Making and Communication * Sleep Medicine * Sports Medicine * Stem Cell Transplantation * Substance Use and Addiction Medicine * Surgery * Surgical Innovation * Surgical Pearls * Teachable Moment * The Art of JAMA * The Arts and Medicine * The Rational Clinical Examination * Tobacco and e-Cigarettes * Toxicology * Translational Medicine * Trauma and Injury * Treatment Adherence * Ultrasonography * Urology * Users' Guide to the Medical Literature * Vaccination * Venous Thromboembolism * Veterans Health * Violence * Women's Health * Workflow and Process * Wound Care, Infection, Healing Save Preferences Privacy Policy | Terms of Use OTHERS ALSO LIKED Comment 2 Comments for this article EXPAND ALL May 8, 2022 Possible confound David Karpf, MD | Stanford University School of Medicine It might be a little too soon to attribute the HR of 1.37 to the GLP-1 RAs. It has been known for some time that both obesity and significant weight loss increase the risk of gall bladder disease, including that of gallstones. See, for example, just a few references 1. R L Weinsier, et al. Gallstone formation and weight loss. Obes Res. 1993 Jan;1(1):51-56. 2. Gebhard RL, et al. The role of gallbladder emptying in gallstone formation during diet-induced rapid weight loss. Hepatology. 1996 Sep;24(3):544-548. 3. Festi D, et al. Gallbladder motility and gallstone formation in obese patients following very low calorie diets. Use it (fat) to lose it (well). Int J Obes Relat Metab Disord. 1998 Jun;22(6):592-600. 4. Festi D, et al. Review: low caloric intake and gall-bladder motor function. Aliment Pharmacol Ther. 2000 May;14 Suppl 2:51-53. 5. Marks JW, et al. The sequence of biliary events preceding the formation of gallstones in humans. Gastroenterology. 1992 Aug;103(2):566-570. 6. Hofmann AF. Et al. Primary and secondary prevention of gallstone disease: implications for patient management and research priorities. Am J Surg. 1993 Apr;165(4):541-548. It seems entirely plausible that at least some of the risk, if not all, can be attributed to the often profound and substantial weight loss due to the the GLP-1 RA therapy. David B. Karpf, MD Adj. Clinical professor of Endocrinology, Gerontology & Metabolism Stanford University School of Medicine CONFLICT OF INTEREST: None Reported READ MORE June 8, 2022 Question about the "Data Synthesis and Analysis" Section of the Methods Ting Zhang, Resident | Department of Family Medicine & Division of General Internal Medicine, Department of Medicine, Peking Union Medical College Hospital In the Methods, the authors state: " Random-effects models with the DerSimonian-Laird method were used when there was no significant heterogeneity (Q tests, P < .05; I2 > 50%); otherwise, Mantel-Haenszel methods and fixed-effects models were used." Can the authors explain the rationale? It is my understanding that generally, 50% heterogeneity is taken as the dividing line between fixed effect and random effect. That is, < 50% heterogeneity choose a fixed-effect model, >= 50% choose a random effect model. Reference: (Rothstein, 2010, Res Synth Methods[IF:5.273, PMID:26061376]) CONFLICT OF INTEREST: None Reported This Issue Views 47,093 Citations 88 236 Comments 2 View Metrics * Download PDF * X Facebook More LinkedIn * Cite This CITATION He L, Wang J, Ping F, et al. Association of Glucagon-Like Peptide-1 Receptor Agonist Use With Risk of Gallbladder and Biliary Diseases: A Systematic Review and Meta-analysis of Randomized Clinical Trials. JAMA Intern Med. 2022;182(5):513–519. doi:10.1001/jamainternmed.2022.0338 MANAGE CITATIONS: Ris (Zotero) EndNote BibTex Medlars ProCite RefWorks Reference Manager Mendeley © 2024 * Permissions Original Investigation March 28, 2022 ASSOCIATION OF GLUCAGON-LIKE PEPTIDE-1 RECEPTOR AGONIST USE WITH RISK OF GALLBLADDER AND BILIARY DISEASES: A SYSTEMATIC REVIEW AND META-ANALYSIS OF RANDOMIZED CLINICAL TRIALS Liyun He, MM1; Jialu Wang, MM1; Fan Ping, MD1; et al Na Yang, MM1; Jingyue Huang, MM1; Yuxiu Li, MD1; Lingling Xu, MD1; Wei Li, MD1; Huabing Zhang, MD1 Author Affiliations Article Information * 1Department of Endocrinology, Key Laboratory of Endocrinology of the National Health Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China JAMA Intern Med. 2022;182(5):513-519. doi:10.1001/jamainternmed.2022.0338 visual abstract icon Visual Abstract editorial comment icon Editorial Comment related articles icon Related Articles author interview icon Interviews multimedia icon Multimedia audio icon Listen to this article * Invited Commentary Safety of Glucagon-Like Peptide-1 Receptor Agonists Shanzay Haider, MD; Kasia J. Lipska, MD, MHS JAMA Internal Medicine * Research Letter GLP-1 Agonists and Gastrointestinal Adverse Events Mohit Sodhi, MSc; Ramin Rezaeianzadeh, BSc; Abbas Kezouh, PhD; Mahyar Etminan, PharmD, MSc JAMA * Research Letter GLP-1 Receptor Agonist Use and Risk of Postoperative Complications Anjali A. Dixit, MD, MPH; Brian T. Bateman, MD, MS; Mary T. Hawn, MD, MPH; Michelle C. Odden, PhD; Eric C. Sun, MD, PhD JAMA Key Points Question What is the association of glucagon-like peptide-1 receptor agonist (GLP-1 RAs) use with the risk of gallbladder or biliary diseases? Findings This systematic review and meta-analysis of 76 randomized clinical trials found that use of GLP-1 RAs was associated with increased risk of gallbladder or biliary diseases, especially when used at higher doses, for longer durations, and for weight loss. Meaning The findings of this systematic review and meta-analysis indicate that physicians and patients should be concerned about the risks of gallbladder or biliary diseases with using GLP-1 RAs for treatment in clinical practice; future studies should report on associated gallbladder and biliary diseases. Abstract Importance Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been widely recommended for glucose control and cardiovascular risk reduction in patients with type 2 diabetes, and more recently, for weight loss. However, the associations of GLP-1 RAs with gallbladder or biliary diseases are controversial. Objective To evaluate the association of GLP-1 RA treatment with gallbladder and biliary diseases and to explore risk factors for these associations. Data Sources MEDLINE/PubMed, EMBASE, Web of Science, and Cochrane Library (inception to June 30, 2021), websites of clinical trial registries (July 10, 2021), and reference lists. There were no language restrictions. Study Selection Randomized clinical trials (RCTs) comparing the use of GLP-1 RA drugs with placebo or with non−GLP-1 RA drugs in adults. Data Extraction and Synthesis Two reviewers independently extracted data according to the PRISMA recommendations and assessed the quality of each study with the Cochrane Collaboration risk-of-bias tool. Pooled relative risks (RRs) were calculated using random or fixed-effects models, as appropriate. The quality of evidence for each outcome was assessed using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) framework. Main Outcomes and Measures The primary outcome was the composite of gallbladder or biliary diseases. Secondary outcomes were biliary diseases, biliary cancer, cholecystectomy, cholecystitis, and cholelithiasis. Data analyses were performed from August 5, 2021, to September 3, 2021. Results A total of 76 RCTs involving 103 371 patients (mean [SD] age, 57.8 (6.2) years; 41 868 [40.5%] women) were included. Among all included trials, randomization to GLP-1 RA treatment was associated with increased risks of gallbladder or biliary diseases (RR, 1.37; 95% CI, 1.23-1.52); specifically, cholelithiasis (RR, 1.27; 95% CI, 1.10-1.47), cholecystitis (RR, 1.36; 95% CI, 1.14-1.62), and biliary disease (RR, 1.55; 95% CI, 1.08-2.22). Use of GLP-1 RAs was also associated with increased risk of gallbladder or biliary diseases in trials for weight loss (n = 13; RR, 2.29; 95% CI, 1.64-3.18) and for type 2 diabetes or other diseases (n = 63; RR, 1.27; 95% CI, 1.14-1.43; P <.001 for interaction). Among all included trials, GLP-1 RA use was associated with higher risks of gallbladder or biliary diseases at higher doses (RR, 1.56; 95% CI, 1.36-1.78) compared with lower doses (RR, 0.99; 95% CI, 0.73-1.33; P = .006 for interaction) and with longer duration of use (RR, 1.40; 95% CI, 1.26-1.56) compared with shorter duration (RR, 0.79; 95% CI, 0.48-1.31; P = .03 for interaction). Conclusions and Relevance This systematic review and meta-analysis of RCTs found that use of GLP-1 RAs was associated with increased risk of gallbladder or biliary diseases, especially when used at higher doses, for longer durations, and for weight loss. Trial Registration PROSPERO Identifier: CRD42021271599 Introduction Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are recommended for patients with type 2 diabetes to control glycemia and reduce cardiovascular risk, and for patients with obesity to reduce weight.1-4 Given the widespread use of these drugs,3 potential safety concerns deserve attention. Several randomized clinical trials (RCTs) have shown a higher rate of gallbladder disorders in patients who were randomized to GLP-1 RAs vs a placebo.5-7 However, whether increased risk of gallbladder-related events is a class effect of GLP-1 RAs has not been established,8,9 and prescribing information for all GLP-1 RA medications does not provide a warning regarding increased risk of gallbladder disorders.10,11 In addition to gallbladder-related events, a post hoc analysis of the LEADER trial8 found significantly increased risks of acute biliary obstruction in patients randomized to liraglutide compared with placebo. Because GLP-1 RAs are generally prescribed at higher doses for weight loss rather than for control of type 2 diabetes, there may be differential effects on risk for gallbladder or biliary diseases depending on dose. In response to these knowledge gaps, we conducted a systematic review and meta-analysis to evaluate the associations of GLP-1 RA use with the risk for gallbladder or biliary diseases. We also sought to determine if risks differ by indication (for diabetes vs weight loss), dose, or duration of treatment. Methods The protocol of this systematic review and meta-analysis was prospectively registered in the International Prospective Register of Systematic Reviews (CRD42021271599). The study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline statement.12 Ethical review and informed consent were waived because the study used secondary data from previous studies. Data Sources and Searches The literature search was conducted of MEDLINE (via PubMed), Cochrane Library, EMBASE, and Web of Science, from inception to June 30, 2021, with no language restrictions (details are available in eMethods 1 in the Supplement). The search was supplemented by screening the reference lists of relevant systematic reviews and manually searching for gray literature on clinical trial registries. Study Selection Two reviewers (H.L.Y., Z.H.B.) independently searched for randomized clinicals trials of GLP-1 RA medications (albiglutide, dulaglutide, exenatide, liraglutide, lixisenatide, or semaglutide) that also reported adverse events of gallbladder or biliary diseases according to predefined inclusion and exclusion criteria available in eTable 1 in the Supplement. Eligible studies were identified and selected by 2 reviewers (H.L.Y., W.J.L.) who screened titles, abstracts, and citations, and evaluated full-text records. Disagreements were resolved through discussions with other team members. Outcome Measures The primary outcome was a composite of gallbladder or biliary diseases, including gallbladder disorders and biliary-related events. Secondary outcomes were 3 subcategories of gallbladder and biliary diseases, including bile duct obstruction, stenosis, and stone; biliary colic, cyst, and fistula; biliary tract cancer; cholecystectomy, cholecystitis, and cholelithiasis; and cholangitis. Definitions of outcomes are shown in eMethods 2 in the Supplement. Data Extraction and Quality Assessments Data extraction was performed independently by 2 reviewers (H.L.Y., H.J.Y.) using a standardized predefined data extraction form. Extracted data included first author or trial name, publication year, indication for treatment, duration of treatments, GLP-1 RA administrations, comparator drugs, incidence of gallbladder or biliary disease outcomes, and characteristics of trial participants (ie, age, weight, body mass index [BMI, calculated as weight in kilograms divided by height in meters squared], and glycated hemoglobin [HbA1c] levels). The risk of bias in each of the studies included was assessed independently by 3 reviewers (H.L.Y., Z.H.B., W.J.L.) using the revised Cochrane risk-of-bias tool for randomized clinical trials.13 Disagreements were resolved by discussion with other team members. Data Synthesis and Analysis Pooled relative risks (RR) and 95% CIs were calculated using random or fixed-effects models. Statistical heterogeneity was assessed using Q tests and I2 statistic.14 Random-effects models with the DerSimonian-Laird method were used when there was no significant heterogeneity (Q tests, P < .05; I2 > 50%); otherwise, Mantel-Haenszel methods and fixed-effects models were used. Absolute risks were estimated based on the calculated RR and mean event rate across control groups for each outcome, and the event rates derived from different treatment durations for each outcome were converted into annual incidences.15,16 In subgroup analyses, we evaluated associations with gallbladder or biliary diseases of specific GLP-1 RA medications, higher and lower doses, shorter and longer treatment durations (≤26 or >26 weeks), indication for treatment (type 2 diabetes/other diseases or obesity), type of control (placebo or active comparator), and baseline BMI. High doses of GLP-1 RAs were defined as equal to or greater than: albiglutide, 50 mg once weekly; dulaglutide, 1.5 mg once weekly; liraglutide, 1.8 mg once daily; subcutaneous semaglutide, 1.0 mg once weekly; and oral semaglutide, 7 mg once daily. Low doses were defined as: albiglutide, 30 mg (<50 mg) once weekly; dulaglutide, 0.75 mg (<1.5 mg) once weekly; liraglutide, 0.6 to 1.2 mg (<1.8 mg) once daily; subcutaneous semaglutide, 0.5 mg (<1.0 mg) once weekly; and oral semaglutide, 3.0 mg (<7.0 mg) once daily. Exenatide and lixisenatide as single doses were not included to assess the dosage-dependent effects. Significant differences between subgroups were estimated using metaregression with the residual maximum likelihood method. Sensitivity analyses were conducted by omitting eligible trials 1 by 1 and removing studies with albiglutide. Random-effects models were also used to pool results for sensitivity analysis. Publication bias was assessed visually using funnel plots and statistically using the Egger test. Certainty of the evidence for each outcome in the analysis was evaluated using the GRADE (Grading of Recommendations, Assessment, Development and Evaluations) framework,17 which considers risk of bias, imprecision, inconsistency, indirectness, and publication bias of the included studies. Analyses were repeated and restricted to trials for control of type 2 diabetes or weight loss. Subgroup analyses by dose or duration of treatment were only performed in trials for control of diabetes owing to the small number of trials that included lower doses or shorter duration for weight loss. Finally, among the trials of treatment for diabetes, we assessed risk of gallbladder and biliary diseases according to whether the trial aimed to assess cardiovascular outcome or not. Statistical analyses were conducted from August 5, 2021, to September 3, 2021, using R, version 4.0.2 (R Foundation for Statistical Computing). Tests were 2-tailed, and P values <.05 were considered statistically significant. Results Trial Identification and Characteristics The literature search identified 7214 potentially relevant studies (Figure 1), of which 76 randomized clinical trials with 77 data sets were included in the meta-analysis—the complete list is available in the eReferences of the Supplement. The included studies had a combined total of 103 371 participants (mean [SD] age, 57.8 [6.2] years; 41 868 [40.5%] women; mean BMI, 32.6; mean HbA1c, 7.8%). Most of the trials included participants with type 2 diabetes (84.4%). The baseline characteristics of eligible trials and participants are shown in eTable 2 in the Supplement. Stratified by indication for treatment, there were 60 trials (including 61 data sets) with 91 599 participants randomized to GLP-1 RAs for diabetes, 13 trials with 11 281 participants randomized for weight loss, and 3 trials for nonalcoholic steatohepatitis, polycystic ovary syndrome, and schizophrenia. Three trials conducted in participants with type 2 diabetes were classified with weight loss trials because their primary outcome was change in weight and GLP-1 RA doses were in the weight-loss range. The mean BMI of patients in trials for treatment of diabetes and obesity was 31.6 and 36.9, respectively. Risk of Bias and GRADE Rating The risk of bias for each study is shown in eTable 3 and eFigure 1 in the Supplement. Most of the studies had a low risk or some concern of bias across all 5 domains evaluated. The overall quality of evidence for the comparisons of GLP-1 RAs vs control groups for increased risk of the combined outcome of gallbladder or biliary disease was rated high. For the secondary outcomes of cholelithiasis, cholecystitis, and biliary disease, the quality of evidence was rated high or moderate (eTable 4 in the Supplement). Association of GLP-1 RAs With Gallbladder or Biliary Disease Randomization to GLP-1 RAs treatment was associated with a significantly increased risk of gallbladder or biliary diseases (RR, 1.37; 95% CI, 1.23-1.52; I2 = 0%) compared with controls (eResults in the Supplement); the absolute risk difference (range) was an additional 27 (17-38) events per 10 000 patients per year (Figure 2). Treatment with GLP-1 RAs was associated with increased risks of cholelithiasis (RR, 1.27; 95% CI, 1.10-1.47; I2 = 0%), cholecystitis (RR, 1.36; 95% CI, 1.14-1.62; I2 = 0%), and biliary disease (RR, 1.55; 95% CI, 1.08-2.22; I2 = 0%) compared with controls (Figure 2; eFigure 2 in the Supplement). The results from trials of diabetes or weight-loss treatment are presented in eFigures 3 to 6 in the Supplement. In all of the included trials, GLP-1 RAs was associated with a higher risk of cholecystectomy compared with controls (RR, 1.70; 95% CI, 1.25-2.32; I2 = 0%; eFigure 7 in the Supplement); there was no increase in risk of biliary tract cancer (RR, 1.43; 95% CI, 0.80-2.56; I2 = 0%; eFigure 8 in the Supplement). Specific GLP-1 RA Drugs and Gallbladder or Biliary Disease Compared with the control group, randomization to liraglutide (RR, 1.79; 95% CI, 1.45-2.25) or dulaglutide (RR, 1.35; 95% CI, 1.06-1.73) treatment was associated with increased risk for gallbladder or biliary diseases. Randomization to subcutaneous semaglutide (RR, 1.28; 95% CI, 0.99-1.65) and exenatide (RR, 1.23; 95% CI, 1.00-1.52) was associated with increased risk, although the increase was not statistically significant. However, oral semaglutide, lixisenatide, and albiglutide did not increase risk (Figure 3; eFigure 9 in the Supplement); higher doses of subcutaneous semaglutide (≥1.0 mg) were associated with increased gallbladder or biliary diseases (RR, 1.58; 95% CI, 1.13-2.22). The results in trials with treatment for diabetes or weight loss are presented in eFigures 10 to 12 in the Supplement. Dose, Duration, and Indication for Treatment Use of GLP-1 RAs was significantly associated with increased risks of gallbladder or biliary disease at higher doses (RR, 1.56; 95% CI, 1.36-1.78) but not at lower doses (RR, 0.99; 95% CI, 0.74-1.33; P = .006 for interaction; Table). Longer duration of treatment with GLP-1 RAs (>26 weeks) was associated with increased risk for gallbladder or biliary disease (RR, 1.40; 95% CI, 1.26-1.56), but shorter duration (≤26 weeks) of treatment was not (RR, 0.79; 95% CI, 0.48-1.31; P = .03 for interaction; Table). Restricted to trials for diabetes, the effect of dose (P = .08 for interaction) and duration of treatment (P = .07 for interaction) were similar (supporting data reported in eTable 5 and eFigure 13 in the Supplement). Use of GLP-1 RAs for weight loss showed stronger effects on the risk of gallbladder or biliary disease than the other indications (ie, diabetes/other diseases; P <.001 for interaction; Table). No significant association of baseline BMI or type of control (placebo or active comparators) were observed (Table; eTables 5 and 6 and eFigure 14 in the Supplement). In trials for diabetes, there were no significant differences in effects in trials for cardiovascular or noncardiovascular outcomes (eFigure 15 in the Supplement). Sensitivity Analyses After the iterative omission of each trial, removal of all trials of albiglutide or which used random-effects models, the pooled results did not change. Additional details are available in eFigures 16 and 17 in the Supplement. Publication Bias There was no evidence of publication bias for studies of gallbladder or biliary diseases (P = .83), cholelithiasis (P = .19), cholecystitis (P = .20), or biliary diseases (P = .57) by the Egger test (supporting data are eFigure 18 in the Supplement). Visually, funnel plots did not demonstrate publication bias. Discussion This systematic review and meta-analysis of 76 randomized clinical trials found that randomization to treatment with GLP-1 RAs compared with placebo or active controls was associated with increased risk of the composite outcome of gallbladder or biliary diseases and for cholelithiasis, cholecystitis, and biliary diseases. Risk was increased in trials of patients treated for diabetes and for weight loss and was higher in the trials for weight reduction. Higher doses and longer duration of GLP-1 RAs treatment were also associated with increased risk of gallbladder or biliary diseases, although the association was not statistically significant. Previous systematic reviews have reported an increased risk of cholelithiasis with GLP-1 RA use,18,19 but these reviews were limited to trials with restrictions on populations and duration of treatment and did not include several important studies that have been published recently.6,7,20 Use of GLP-1 RAs may be associated with increased risk of gallbladder or biliary diseases because GLP-1 inhibits gallbladder motility and delays gallbladder emptying by suppressing the secretion of cholecystokinin.8,21-24 In addition, marked weight loss, which occurs in some patients using GLP-1 RAs, has been associated with a high risk of gallbladder disorders.9,25 Gallbladder disease has been reported as an adverse event in the published reports and/or the supplemental materials of most of the randomized clinical trials of GLP-1 RAs6,20,26-28; however, to our knowledge, biliary diseases have seldom been reported. Only 20 of the 76 trials eligible for this systematic review clearly reported biliary-related events, suggesting potential underreporting. Given the findings of this review and analysis, studies of GLP-1 RAs should fully report biliary-related events. The risk of gallbladder or biliary diseases was higher in trials using GLP-1 RAs for weight loss than for diabetes control. The increased risk of gallbladder or biliary diseases in weight loss trials may be associated with weight loss produced by GLP-1 RAs, but these trials also used higher doses and/or longer treatment durations than the diabetes control trials used. Liraglutide (3.0 mg)28 and subcutaneous semaglutide (2.4 mg)29 have been approved by the US Food and Drug Administration (FDA) for weight management,9,29 suggesting that GLP-1 RA drugs will increasingly be used at high doses for weight control; the increased risk for gallbladder and biliary diseases should be of concern in these patients. Liraglutide has drawn the most attention concerning the increased risk of gallbladder-related events,7-9,30while other GLP-1 RA medications have received limited attention.9 Previous studies18,19 did not notice a high risk of gallbladder or biliary disease in patients randomized to dulaglutide treatment, and current prescribing information for dulaglutide does not contain warnings about the risks of gallbladder or biliary diseases.31,32 The prescribing information from the FDA and the European Medicines Agency mention the possible increased risk of cholelithiasis for exenatide33,34 and subcutaneous semaglutide35,36 compared with placebo. Our findings showed that GLP-1 RA medications, including dulaglutide, exenatide, and subcutaneous semaglutide (≥1.0 mg), increased the risk of gallbladder or biliary diseases. Given the similar efficacy and effectiveness of oral and subcutaneous semaglutide,37,38 the association of the oral formulation with the risk of gallbladder or biliary diseases requires further evaluation. Although in this meta-analysis, albiglutide and lixisenatide were not associated with a statistically significant increased risk, these findings may have been influenced by low power owing to a small number of studies or to inadequate reporting of gallbladder or biliary diseases in these trials.39-42 Higher risk of gallbladder or biliary diseases was associated with higher doses of GLP-1 RAs in weight loss trials compared with lower doses in diabetes control trials; however, there was a similar trend to increased risk with higher doses in the diabetes trials. Increasing doses of GLP-1 RAs may be recommended for patients who do not achieve glycemic control goals with lower doses43; therefore, increased risks of gallbladder or biliary diseases should be considered when the doses are escalated. A previous observational study reported that gallbladder or biliary diseases tended to occur in the first 6 months of GLP-1 RA treatment.25 In contrast, the present meta-analysis found that GLP-1 RA use increased the risk of gallbladder or biliary disease only with longer durations of treatment. Given that GLP-1 RAs may need to be used for the long term, both for control of diabetes and weight, an increased risk associated with long-duration treatment could be clinically important. Although this meta-analysis showed that the RRs for gallbladder and biliary diseases were elevated, the overall absolute risk increase was small (an additional 27 cases per 10 000 persons treated per year). This absolute risk increase should be weighed against the benefits of treatment with GLP-1 RA drugs. Strengths and Limitations This systematic review and meta-analysis was strengthened by the incorporation of recently published studies, by addressing the increased risks of biliary diseases with GLP-1 RA use separately from gallbladder disorders, and by highlighting the increased risk associated with other GLP-1 RA medications, in addition to liraglutide. The present study revealed that GLP-1 RAs used at higher doses for weight control may contribute to a higher risk of gallbladder or biliary diseases. However, this study had several limitations. Information on biliary-related events may not have been fully reported because they were not a predefined safety outcome in most of the included trials. These studies were not specifically designed to evaluate the risk of gallbladder or biliary diseases associated with GLP-1 RAs treatment. Also, because this was a meta-analysis of randomized trials, we were unable to use patient-level data to evaluate outcomes. Finally, the small number of events in subgroups may have allowed for underpowered subgroup analyses. Conclusions The findings of this systematic review and meta-analysis indicate that physicians should be concerned about the increased risk of gallbladder or biliary disease associated with GLP-1 RA use, especially at the higher doses recommended for weight loss. In addition, future trials should prespecify gallbladder and biliary diseases as potential adverse events, and fully test for and report on these outcomes. Back to top Article Information Accepted for Publication: January 28, 2022. Published Online: March 28, 2022. doi:10.1001/jamainternmed.2022.0338 Corresponding Author: Huabing Zhang, MD, Department of Endocrinology, Key Laboratory of Endocrinology of the National Health Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing, Dongcheng District, Beijing, China 100730 (huabingzhangchn@163.com). Author Contributions: Dr Zhang had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: He, Zhang. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: He, Zhang. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: He, Wang, Ping, Yang, Zhang. Obtained funding: Y. Li, Zhang. Administrative, technical, or material support: He, Wang, Yang, Huang, Xu, Y. Li, W. Li. Supervision: Ping, Xu, Y. Li, W. Li, Zhang. Conflict of Interest Disclosures: None reported. Funding/Support: This work was supported by grants from the National Natural Science Foundation of China (No. 91846106), the Beijing Municipal Natural Science Foundation (No. M22014), the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (No. 2019XK320029), the CAMS Innovation Fund for Medical Sciences (No. 2021-1-I2M-002), and the Training Program for Excellent Talents in Dongcheng District (No. TPETDD2018). Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Additional Contributions: The authors are grateful to the staff of the Peking Union Medical College Hospital and all who actively participated and provided statistical support to the study. 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