SGLT2 Inhibitors and GLP-1 Agonists in the ICU

 

SGLT2 Inhibitors and GLP-1 Agonists in the ICU: Beyond Diabetes Management

Dr Neeraj Manikath , Claude.ai

Abstract

Background: Sodium-glucose co-transporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists have revolutionized diabetes management, but their pleiotropic effects extend far beyond glycemic control. These agents are increasingly encountered in the intensive care unit (ICU) setting, where their cardiovascular, renal, and metabolic benefits may be particularly relevant.

Objective: To provide a comprehensive review of SGLT2 inhibitors and GLP-1 agonists in critical care, focusing on their non-glycemic effects, perioperative considerations, and emerging applications in acute care settings.

Methods: We conducted a systematic review of literature published between 2015-2024, focusing on clinical trials, observational studies, and case series involving critically ill patients.

Results: SGLT2 inhibitors demonstrate significant benefits in acute heart failure, chronic kidney disease progression, and may have protective effects in various acute conditions. GLP-1 agonists show promise in cardiovascular protection, weight management, and potentially in acute inflammatory states. However, both drug classes present unique challenges in the ICU environment, including risks of euglycemic diabetic ketoacidosis, volume depletion, and drug interactions.

Conclusions: Understanding the expanded role of these agents beyond diabetes management is crucial for intensivists. Careful patient selection, monitoring protocols, and awareness of potential complications are essential for safe and effective use in critical care settings.

Keywords: SGLT2 inhibitors, GLP-1 agonists, critical care, heart failure, acute kidney injury, perioperative care

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Introduction

The landscape of diabetes management has been transformed by the introduction of sodium-glucose co-transporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists. These agents, initially developed for glycemic control, have demonstrated remarkable pleiotropic effects that extend well beyond their antidiabetic properties. In the intensive care unit (ICU), where patients often present with complex comorbidities and acute physiological derangements, understanding these medications' broader therapeutic potential and associated risks has become increasingly important.

SGLT2 inhibitors, including empagliflozin, dapagliflozin, and canagliflozin, work by blocking glucose reabsorption in the proximal tubule, leading to glucosuria and modest diuresis. GLP-1 agonists, such as liraglutide, semaglutide, and dulaglutide, enhance insulin secretion in a glucose-dependent manner while slowing gastric emptying and promoting satiety. However, their clinical utility in critical care extends far beyond these primary mechanisms.

This review aims to provide intensivists with a comprehensive understanding of these agents' role in acute care settings, focusing on their applications in heart failure management, renal protection, perioperative considerations, and potential complications unique to the ICU environment.

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SGLT2 Inhibitors in Critical Care

Mechanism of Action and Pleiotropic Effects

SGLT2 inhibitors exert their effects through multiple pathways beyond glucose regulation:

1. Hemodynamic Effects: Reduction in preload through mild diuresis and natriuresis
2. Metabolic Reprogramming: Enhanced ketone body production and improved myocardial energetics
3. Anti-inflammatory Properties: Reduction in inflammatory markers and oxidative stress
4. Direct Cardiac Effects: Improved calcium handling and reduced cardiac fibrosis
5. Renal Protection: Reduction in intraglomerular pressure and albuminuria

Acute Heart Failure Management

Evidence Base

The EMPEROR-Reduced and DAPA-HF trials demonstrated significant cardiovascular benefits in patients with heart failure with reduced ejection fraction (HFrEF), regardless of diabetes status. In the acute setting, several studies have explored SGLT2 inhibitor use in hospitalized heart failure patients.

Pearl 🔹: SGLT2 inhibitors can be safely initiated during hospitalization for acute heart failure, with benefits observed as early as 48-72 hours after initiation.

Clinical Applications in ICU

1. Acute Decompensated Heart Failure (ADHF)

   • Early initiation (within 24-48 hours of stabilization) shows improved diuresis
   • Synergistic effects with loop diuretics without electrolyte derangements
   • Reduction in readmission rates when initiated in-hospital

2. Cardiorenal Syndrome

   • Improved renal function through reduction in intraglomerular pressure
   • Preserved kidney function despite volume removal
   • Reduced need for renal replacement therapy in some cases

Practical Considerations

Monitoring Parameters:

• Volume status and blood pressure
• Electrolytes (particularly sodium and potassium)
• Renal function
• Ketone levels (urine or serum β-hydroxybutyrate)

Oyster ⚠️: Despite their diuretic effect, SGLT2 inhibitors can cause hypovolemia and hypotension, particularly in combination with other diuretics or in volume-depleted patients.

Renal Protection in Acute Settings

Acute Kidney Injury (AKI) Prevention

Recent evidence suggests SGLT2 inhibitors may have protective effects against AKI:

• Contrast-Induced Nephropathy: Potential reduction in contrast-induced AKI risk
• Sepsis-Associated AKI: Anti-inflammatory effects may attenuate kidney injury
• Post-Operative AKI: Emerging data on perioperative renal protection

Chronic Kidney Disease Progression

The CREDENCE, DAPA-CKD, and EMPA-KIDNEY trials established renal benefits in non-acute settings. In the ICU, continuation of SGLT2 inhibitors in CKD patients may:

• Maintain renoprotective effects during acute illness
• Reduce progression to end-stage renal disease
• Improve long-term outcomes post-ICU discharge

Hack 💡: For patients with eGFR 30-60 mL/min/1.73m², consider continuing SGLT2 inhibitors during mild-moderate acute illness, with careful monitoring.

Perioperative Considerations

Preoperative Management

Risk Assessment:

• Volume status evaluation
• Renal function assessment
• Diabetic ketoacidosis (DKA) risk stratification

Timing of Discontinuation:

• Major surgery: Hold 3-4 days preoperatively
• Minor procedures: May continue with close monitoring
• Emergency surgery: Check ketones immediately

Postoperative Considerations

Oyster ⚠️: Euglycemic DKA is a unique risk with SGLT2 inhibitors, presenting with normal or mildly elevated glucose levels but significant ketosis and metabolic acidosis.

Signs of Euglycemic DKA:

• Metabolic acidosis (pH < 7.30, HCO₃ < 15 mEq/L)
• Elevated ketones (β-hydroxybutyrate > 3.0 mmol/L)
• Anion gap > 12-14 mEq/L
• Glucose may be < 250 mg/dL (13.9 mmol/L)

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GLP-1 Agonists in Critical Care

Mechanism and Pleiotropic Effects

GLP-1 agonists exert multiple effects relevant to critical care:

1. Cardiovascular Protection: Anti-atherosclerotic and anti-inflammatory effects
2. Gastroparesis Risk: Delayed gastric emptying can complicate nutrition and aspiration risk
3. Weight Loss: Beneficial for obesity-related complications
4. Neuroprotection: Potential benefits in stroke and traumatic brain injury
5. Anti-inflammatory Effects: Reduction in systemic inflammatory markers

Cardiovascular Applications

Acute Coronary Syndromes

Evidence from LEADER, SUSTAIN-6, and REWIND trials:

• Reduced major adverse cardiovascular events (MACE)
• Lower rates of cardiovascular death
• Potential benefits in acute MI settings

ICU Applications:

• Continuation during acute coronary syndromes
• Potential cardioprotective effects during non-cardiac surgery
• Improved outcomes in diabetic patients with acute MI

Heart Failure Considerations

Unlike SGLT2 inhibitors, GLP-1 agonists have mixed evidence in heart failure:

• HFrEF: Neutral to modest beneficial effects
• HFpEF: Potential benefits through weight loss and metabolic improvements
• Caution: Risk of increased heart rate and potential arrhythmias

Gastroparesis and Aspiration Risk

Pearl 🔹: GLP-1 agonists significantly delay gastric emptying, which can persist for days after discontinuation.

Clinical Implications in ICU

1. Enteral Nutrition Challenges

   • Increased residual volumes
   • Risk of aspiration pneumonia
   • Need for post-pyloric feeding access

2. Procedural Considerations

   • Increased aspiration risk during intubation
   • Consider rapid sequence induction protocols
   • Gastric decompression may be necessary

3. Drug Absorption Issues

   • Delayed absorption of oral medications
   • Consider parenteral alternatives for critical medications

Hack 💡: For elective procedures, consider holding long-acting GLP-1 agonists for 1-2 weeks, and short-acting agents for 2-3 days to minimize gastroparesis risk.

Perioperative Safety

Preoperative Assessment

Risk Stratification:

• Duration since last dose
• Type of GLP-1 agonist (short vs. long-acting)
• Planned procedure complexity
• Baseline gastroparesis risk

Intraoperative Considerations

1. Anesthesia Implications

   • Increased aspiration risk
   • Consider awake intubation for high-risk cases
   • Gastric point-of-care ultrasound assessment

2. Hemodynamic Effects

   • Potential for hypotension
   • Interaction with anesthetic agents
   • Monitor for bradycardia or heart block

Postoperative Management

Monitoring Parameters:

• Gastric residuals
• Signs of gastroparesis
• Nutritional status
• Glycemic control during temporary discontinuation

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Drug Interactions and Monitoring in ICU

SGLT2 Inhibitor Interactions

Diuretic Synergy

• Enhanced diuresis with loop diuretics
• Risk of volume depletion and hypotension
• Electrolyte monitoring essential

Insulin and Hypoglycemic Agents

• Reduced insulin requirements
• Risk of hypoglycemia with intensive insulin protocols
• Adjust insulin dosing accordingly

Contrast Agents

• Potential nephroprotection vs. volume depletion risk
• Individual risk-benefit assessment needed

GLP-1 Agonist Interactions

Gastric Motility Agents

• Reduced efficacy of prokinetic agents
• May need alternative approaches for gastroparesis

Oral Medications

• Delayed absorption due to gastroparesis
• Consider timing of administration
• Switch to parenteral routes when necessary

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Monitoring Protocols for ICU

SGLT2 Inhibitors

Daily Assessments

• Volume Status: Input/output, daily weights, clinical examination
• Electrolytes: Na⁺, K⁺, Cl⁻, HCO₃⁻, anion gap
• Renal Function: Creatinine, eGFR, BUN
• Ketones: Urine ketones or serum β-hydroxybutyrate if indicated

Red Flag Symptoms

• Nausea, vomiting, abdominal pain
• Altered mental status
• Dyspnea, tachypnea
• Signs of volume depletion

Oyster ⚠️: Normal glucose levels do NOT rule out DKA in patients on SGLT2 inhibitors.

GLP-1 Agonists

Daily Assessments

• Gastrointestinal: Nausea, vomiting, gastric residuals
• Cardiovascular: Heart rate, blood pressure, rhythm monitoring
• Nutritional: Caloric intake, weight changes
• Glycemic Control: Blood glucose monitoring

Special Considerations

• Gastric ultrasound for high-risk procedures
• Consider prokinetic agents if severe gastroparesis develops
• Monitor for pancreatitis in high-risk patients

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Special Populations

Sepsis and Critical Illness

SGLT2 Inhibitors

Potential Benefits:

• Anti-inflammatory effects
• Improved hemodynamics in some patients
• Renal protection

Risks:

• Volume depletion in distributive shock
• Increased DKA risk during stress
• Drug-drug interactions with vasopressors

GLP-1 Agonists

Benefits:

• Continued cardiovascular protection
• Anti-inflammatory effects

Risks:

• Gastroparesis complicating nutrition
• Hemodynamic instability
• Reduced drug absorption

Post-Cardiac Surgery

SGLT2 Inhibitors

• Early reinitiation may improve diuresis
• Monitor for excessive volume loss
• Cardioprotective effects during recovery

GLP-1 Agonists

• High aspiration risk perioperatively
• Consider temporary discontinuation
• Resume once normal GI function returns

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Emerging Applications and Future Directions

Novel Indications Under Investigation

SGLT2 Inhibitors

1. Acute Respiratory Distress Syndrome (ARDS)

   • Anti-inflammatory effects
   • Improved pulmonary edema clearance
   • Early clinical trials ongoing

2. Traumatic Brain Injury

   • Metabolic neuroprotection
   • Reduced cerebral edema
   • Improved neurological outcomes

3. Acute Pancreatitis

   • Anti-inflammatory properties
   • Potential reduction in severity
   • Preliminary evidence promising

GLP-1 Agonists

1. Stroke Recovery

   • Neuroprotective effects
   • Improved functional outcomes
   • Ongoing clinical trials

2. Acute Kidney Injury

   • Anti-inflammatory effects
   • Improved renal recovery
   • Limited clinical data

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Clinical Decision-Making Algorithms

SGLT2 Inhibitor Decision Tree

Patient Presents to ICU on SGLT2 Inhibitor:

1. Assess Volume Status

   • Euvolemic/hypervolemic → Consider continuing
   • Hypovolemic → Hold temporarily

2. Check Ketones

   • Normal → Proceed with monitoring
   • Elevated → Investigate for DKA

3. Evaluate Renal Function

   • eGFR > 30 → Usually safe to continue
   • eGFR < 30 → Consider holding

4. Monitor for Complications

   • Daily ketones if high DKA risk
   • Frequent electrolyte monitoring
   • Volume status assessment

GLP-1 Agonist Decision Tree

Patient on GLP-1 Agonist Requires ICU Admission:

1. Assess GI Function

   • Normal → May continue with monitoring
   • Gastroparesis → Hold temporarily

2. Evaluate Aspiration Risk

   • Low risk → Continue with caution
   • High risk → Discontinue

3. Consider Procedure Requirements

   • Elective → Hold 2-3 days prior
   • Emergency → Assess individual risk

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Practical Pearls and Oysters

Pearls 🔹

1. SGLT2 Inhibitors:

   • Can improve diuresis in heart failure without worsening renal function
   • Benefits may appear within 48-72 hours of initiation
   • Euglycemic DKA risk is highest during periods of stress, dehydration, or reduced caloric intake
   • Consider continuing in stable patients with heart failure or CKD

2. GLP-1 Agonists:

   • Gastroparesis effects can persist for days after discontinuation
   • May provide cardiovascular protection during acute coronary syndromes
   • Weight loss benefits may improve outcomes in obese critically ill patients
   • Consider gastric decompression before high-risk procedures

Oysters ⚠️

1. SGLT2 Inhibitors:

   • Normal glucose levels do NOT exclude DKA
   • Volume depletion can occur rapidly, especially with concurrent diuretics
   • May mask typical DKA symptoms due to glucose-independent mechanism
   • Risk of acute kidney injury if combined with other nephrotoxins

2. GLP-1 Agonists:

   • Significant aspiration risk due to delayed gastric emptying
   • May cause hemodynamic instability in some patients
   • Drug absorption issues can affect critical medications
   • Risk of pancreatitis, especially in patients with risk factors

Practical Hacks 💡

1. Quick DKA Screen for SGLT2 Users:

   • Check anion gap and ketones, regardless of glucose level
   • If AG > 14 or ketones elevated, investigate further
   • Early recognition and treatment prevent complications

2. GLP-1 Gastroparesis Assessment:

   • Use gastric ultrasound to assess residual volume
   • Consider post-pyloric feeding access early
   • Prokinetic agents may have limited efficacy

3. Perioperative Planning:

   • SGLT2: Hold 3-4 days for major surgery, continue monitoring for 48 hours post-op
   • GLP-1: Hold long-acting agents 1-2 weeks, short-acting 2-3 days before elective procedures

4. ICU Monitoring Shortcuts:

   • Daily ketones for SGLT2 users with poor oral intake
   • Gastric residual checks q4h for GLP-1 users on enteral nutrition
   • Weight-based diuretic adjustments for SGLT2 users

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Contraindications and Precautions

Absolute Contraindications

SGLT2 Inhibitors

• Active diabetic ketoacidosis
• Severe renal impairment (eGFR < 30 mL/min/1.73m² for most agents)
• Severe hepatic impairment
• Known hypersensitivity

GLP-1 Agonists

• Personal or family history of medullary thyroid carcinoma
• Multiple endocrine neoplasia syndrome type 2
• Severe gastroparesis
• Known hypersensitivity

Relative Contraindications and Cautions

SGLT2 Inhibitors

• Volume depletion or hypotension
• Concurrent nephrotoxic drug use
• Elderly patients (increased fall risk)
• History of recurrent UTIs or genital infections

GLP-1 Agonists

• Severe renal or hepatic impairment
• History of pancreatitis
• Gastroparesis or severe GI disorders
• High aspiration risk procedures

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Cost-Effectiveness and Resource Utilization

Economic Considerations

SGLT2 Inhibitors

• High acquisition costs offset by reduced hospitalizations
• Fewer heart failure readmissions
• Reduced need for dialysis in CKD patients
• Shorter ICU stays in some populations

GLP-1 Agonists

• Expensive agents but potential for long-term savings
• Reduced cardiovascular events
• Weight loss benefits in obese patients
• May reduce overall diabetes management costs

Resource Optimization Strategies

1. Patient Selection: Focus on highest-risk patients likely to benefit
2. Monitoring Protocols: Standardized approaches to reduce complications
3. Staff Education: Comprehensive training on recognition and management of complications
4. Quality Metrics: Track outcomes to demonstrate value

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Conclusions

SGLT2 inhibitors and GLP-1 agonists represent a paradigm shift in our understanding of diabetes medications, with significant implications for critical care practice. Their pleiotropic effects extend well beyond glycemic control, offering potential benefits in heart failure, renal protection, and various acute conditions.

For intensivists, key considerations include:

1. SGLT2 Inhibitors: Excellent agents for heart failure and renal protection, but require vigilance for euglycemic DKA and volume depletion
2. GLP-1 Agonists: Valuable for cardiovascular protection but present significant challenges related to gastroparesis and aspiration risk
3. Perioperative Care: Both drug classes require careful perioperative planning and monitoring
4. Patient Selection: Not all ICU patients are appropriate candidates; careful risk-benefit analysis is essential

As our experience with these agents in acute care settings continues to grow, standardized protocols and monitoring strategies will be crucial for optimizing outcomes while minimizing risks. Future research should focus on defining optimal patient selection criteria, dosing strategies, and monitoring protocols specific to the ICU environment.

The integration of these agents into critical care practice requires a multidisciplinary approach involving intensivists, endocrinologists, pharmacists, and nursing staff. With appropriate knowledge and monitoring protocols, these medications can significantly improve outcomes for critically ill patients beyond their traditional role in diabetes management.

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