Beyond bariatrics: A systematic review and meta-analysis of glucagon-like peptide-1 receptor agonists and novel anti-obesity medications in critical care settings

INTRODUCTION

The global obesity epidemic has resulted in a significant increase in critically ill patients with obesity-related comorbidities, presenting unique challenges in intensive care management.^[1] Traditional approaches to managing these patients often involve insulin-based protocols for glycemic control, which carry substantial risks of hypoglycemia and high glucose variability.^[2] The advent of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and novel dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 RAs has transformed outpatient obesity management, with medications such as semaglutide, liraglutide, and tirzepatide demonstrating unprecedented efficacy in weight reduction.^[3,4]

While primarily indicated for chronic weight management and type 2 diabetes, emerging evidence suggests that these medications may have valuable applications in acute care settings.^[5] The physiological mechanisms of GLP-1 RAs extend beyond appetite suppression to include effects on inflammation, cardiovascular function, and glucose homeostasis – all highly relevant to critical illness.^[6,7] As critical care practitioners increasingly encounter patients using these medications before admission or consider their implementation during intensive care unit (ICU) stays, understanding their multifaceted effects becomes essential.^[8]

This systematic review and meta-analysis examines the application of GLP-1 RAs in critical care settings, evaluating the current evidence for their efficacy, safety considerations, practical implementation challenges, and future research directions.

MATERIALS AND METHODS

We conducted a comprehensive systematic review of studies investigating GLP-1 RA use in critical care settings published between January 2018 and February 2024. Electronic databases including PubMed, EMBASE, and the Cochrane Library were searched using the terms “GLP-1 receptor agonist,” “semaglutide,” “liraglutide,” “exenatide,” “tirzepatide,” “critical care,” “intensive care,” and “ICU.” We included randomized controlled trials, prospective cohort studies, retrospective analyses, and systematic reviews that evaluated GLP-1 RA use in adult patients (≥18 years) in ICU settings.

Two independent reviewers screened titles and abstracts for relevance, followed by full-text review of potentially eligible studies. Disagreements were resolved by consensus with a third reviewer.^[9]

Data extraction focused on:

• Type of GLP-1 RA used and dosing strategy

• Primary indication for use (glycemic control, organ protection, etc.)

• Comparative interventions

• Primary and secondary outcomes

• Adverse events and safety data

• Patient population characteristics

Studies were evaluated for methodological quality using the Cochrane Risk of Bias tool for randomized trials and the Newcastle-Ottawa Scale for observational studies.^[10] We conducted a narrative synthesis of findings along with meta-analysis where appropriate data were available.

Implementation protocols were developed based on synthesis of the available evidence, expert opinion, and consideration of practical aspects specific to critical care environments.

RESULTS

DISCUSSION

The application of GLP-1 RAs in critical care represents a significant paradigm shift in metabolic management for critically ill patients with obesity.^[27] Our findings suggest that these agents offer comparable glycemic control to traditional insulin therapy while substantially reducing hypoglycemia risk – a major safety advantage in vulnerable ICU populations.^[2] The glucose-dependent mechanism of action of GLP-1 RAs provides an inherent safety feature not present with insulin therapy, potentially reducing the resource-intensive monitoring requirements currently necessary for standard glycemic management protocols.^[28]

The observed improvements in cardiovascular parameters, particularly in post-cardiac surgery patients and those with cardiogenic shock, align with established cardioprotective effects of GLP-1 RAs in outpatient settings.^[29] The RESILIENT trial’s finding of improved cardiac index and reduced inotropic requirements suggests these agents may offer supportive benefits beyond metabolic control in selected cardiovascular critical illness, though the mechanisms – whether direct myocardial effects or secondary to improved metabolic state – require further elucidation.^[30]

Similarly, the respiratory benefits observed in the RECOVERY-GLP trial suggest potential applications in obesity-associated respiratory failure, a growing challenge in critical care.^[31] The improvement in oxygenation parameters without significant mortality benefit indicates potential physiological advantages that may translate to clinical benefit in appropriately selected populations or with optimized protocols.^[32]

The anti-inflammatory effects observed across multiple studies provide a mechanistic rationale for broader applications beyond glycemic control.^[33] The consistent reductions in inflammatory markers align with preclinical evidence of GLP-1 receptor signaling attenuating inflammatory responses, potentially offering additive benefits in conditions characterized by dysregulated inflammation, such as sepsis and ARDS.^[34]

However, significant implementation challenges remain.^[35] Most GLP-1 RAs require subcutaneous administration, which may be problematic in patients with significant edema, coagulopathy, or those receiving anticoagulation. The traditional approach of gradual dose escalation used in outpatient settings is impractical during short ICU stays, yet starting with higher doses increases the risk of gastrointestinal side effects.^[36] These gastrointestinal effects, while manageable in outpatient settings, pose particular challenges in critically ill patients at risk for aspiration or those requiring enteral nutrition.^[37]

Patient selection emerges as crucial, with certain populations likely to derive greater benefit while others face heightened risks.^[38] The favorable outcomes in liver failure and cardiac surgery suggest that these may be priority populations for further investigation, while patients with significant gastrointestinal compromise may face prohibitive risks of adverse effects.^[39]

The economic implications of GLP-1 RA use in the ICU require careful evaluation.^[40] These medications typically incur higher acquisition costs than conventional therapies, though potential reductions in complications, ICU length of stay, or readmissions might offset these expenses. Comprehensive cost-effectiveness analyses incorporating both short and long-term outcomes are essential to inform resource allocation decisions.^[41-44]

CONCLUSION

This systematic review and meta-analysis demonstrates that GLP-1 RAs represent a promising innovation in the management of critically ill patients with obesity, offering comparable glycemic control to insulin with reduced hypoglycemia risk and potential pleiotropic benefits including cardiovascular protection, reduced inflammation, and improved outcomes in specific populations. However, practical challenges related to administration, gastrointestinal effects, and limited evidence from large trials necessitate a cautious, selective approach to implementation.

Future research should focus on identifying optimal patient populations, establishing critical care-specific dosing protocols, investigating alternative administration routes, and evaluating long-term outcomes and cost-effectiveness. As our understanding evolves, these agents may become valuable tools in the complex care of critically ill patients with obesity, representing a meaningful innovation at the intersection of endocrinology and critical care medicine.