New Oral Hypoglycemics in ICU Patients: SGLT2 Inhibitors and GLP-1 Receptor Agonists - A Critical Care Perspective

Dr Neeraj Manikath , claude.ai

Abstract

The management of diabetes in critically ill patients has become increasingly complex with the introduction of newer antidiabetic agents, particularly sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA). This review examines the evidence-based approach to managing these medications in the intensive care unit (ICU), focusing on continuation versus discontinuation strategies, recognition and management of associated complications, and practical clinical decision-making frameworks for critical care physicians.

Keywords: SGLT2 inhibitors, GLP-1 receptor agonists, critical care, diabetic ketoacidosis, intensive care unit

Introduction

The landscape of diabetes management has been revolutionized by the introduction of SGLT2 inhibitors and GLP-1 receptor agonists over the past decade. These agents, initially developed for glycemic control, have demonstrated remarkable cardiovascular and renal protective effects, leading to their widespread adoption in clinical practice¹. However, their use in critically ill patients presents unique challenges that require careful consideration by intensivists.

With diabetes affecting approximately 25-30% of ICU patients and associated with increased mortality, understanding the perioperative and critical care management of these newer agents is crucial². The question of whether to continue or discontinue these medications upon ICU admission has become a common clinical dilemma, particularly given their unique mechanisms of action and potential for serious adverse effects in the critically ill population.

Pharmacology and Mechanisms of Action

SGLT2 Inhibitors

SGLT2 inhibitors work by blocking the sodium-glucose cotransporter-2 in the proximal renal tubules, preventing glucose reabsorption and promoting glucosuria³. The primary agents include:

Empagliflozin (Jardiance®)
Dapagliflozin (Farxiga®)
Canagliflozin (Invokana®)
Ertugliflozin (Steglatro®)

Beyond glycemic effects, SGLT2 inhibitors provide:

Natriuresis and diuresis
Reduction in preload and afterload
Improved cardiac energetics through ketone body utilization
Anti-inflammatory effects⁴

GLP-1 Receptor Agonists

GLP-1 receptor agonists enhance glucose-dependent insulin secretion while suppressing glucagon release⁵. Available agents include:

Short-acting:

Exenatide (Byetta®)
Lixisenatide (Adlyxin®)

Long-acting:

Semaglutide (Ozempic®, Wegovy®)
Dulaglutide (Trulicity®)
Liraglutide (Victoza®)

Key mechanisms include:

Delayed gastric emptying
Enhanced satiety
Preservation of β-cell function
Cardiovascular protective effects⁶

Clinical Decision Framework: Continue or Discontinue?

SGLT2 Inhibitors

🔴 DISCONTINUE in the following scenarios:

Absolute Contraindications:

Diabetic ketoacidosis (DKA) or euglycemic DKA
Severe dehydration or hypovolemia
Acute kidney injury (AKI) or eGFR <30 mL/min/1.73m²
Planned major surgery within 24-48 hours
Active urogenital infections
Severe metabolic acidosis (pH <7.30)⁷

Relative Contraindications:

Prolonged fasting states
Significant cardiovascular instability requiring vasopressors
Active alcohol use or recent alcohol withdrawal
Concurrent illness predisposing to ketosis

🟢 CONSIDER CONTINUATION in:

Stable patients with preserved renal function
Heart failure patients (compelling indication)
Chronic kidney disease patients (eGFR 30-60 mL/min/1.73m²)
Short-term ICU stays for monitoring⁸

GLP-1 Receptor Agonists

🔴 DISCONTINUE when:

Severe gastroparesis or gastric emptying disorders
Active pancreatitis or strong clinical suspicion
Planned procedures requiring NPO status >24 hours
Severe nausea/vomiting with inability to maintain oral intake
Medullary thyroid carcinoma or MEN 2 syndrome⁹

🟢 CONTINUE when:

Cardiovascular benefits outweigh risks
Stable patients without GI complications
Recent cardiovascular events (secondary prevention)
Preserved renal function and adequate oral intake¹⁰

Major Complications and Management

SGLT2 Inhibitor-Associated Diabetic Ketoacidosis (SGLT2-DKA)

Pathophysiology: SGLT2 inhibitors promote a metabolic shift toward fatty acid oxidation and ketogenesis, even in the presence of relatively normal glucose levels¹¹. This "euglycemic DKA" presents unique diagnostic challenges.

🔍 Clinical Pearls:

Suspect in ANY patient on SGLT2i presenting with metabolic acidosis
Glucose levels may be <250 mg/dL (euglycemic DKA)
Often precipitated by: surgery, infection, dehydration, low-carbohydrate diets
Higher incidence in Type 1 diabetes but increasingly recognized in Type 2¹²

Diagnostic Criteria:

Arterial pH <7.30 or bicarbonate <15 mEq/L
Ketones: β-hydroxybutyrate >3.0 mmol/L or urine ketones ≥2+
Glucose may be normal or mildly elevated

Management Protocol:

Immediate discontinuation of SGLT2 inhibitor
Fluid resuscitation with normal saline
Insulin therapy - continue even when glucose normalizes
Dextrose administration when glucose <250 mg/dL to prevent hypoglycemia
Electrolyte monitoring and replacement (K+, Mg2+, PO4³⁻)
Address precipitating factors¹³

Genitourinary Infections

Fournier's Gangrene:

Rare but life-threatening necrotizing fasciitis
Higher risk in elderly, immunocompromised patients
Requires immediate surgical debridement and broad-spectrum antibiotics¹⁴

💡 Clinical Hack: Maintain high index of suspicion for atypical presentations of UTIs in SGLT2i patients. The glycosuria creates a favorable environment for bacterial and fungal growth.

GLP-1RA Complications

Acute Pancreatitis

Incidence: 0.1-0.2% but potentially fatal in ICU setting
Presents with typical abdominal pain, elevated lipase
Management: Immediate discontinuation, supportive care, avoid rechallenge¹⁵

Severe Gastroparesis

Delayed gastric emptying can persist for weeks after discontinuation
ICU Implications:
- Risk of aspiration
- Unpredictable drug absorption
- Nutritional challenges¹⁶

Practical ICU Management Strategies

Pre-operative Considerations

SGLT2 Inhibitors:

Discontinue 3-5 days before major elective surgery
Check ketones if any metabolic acidosis
Ensure adequate hydration status

GLP-1 RAs:

Short-acting: Hold morning of surgery
Long-acting: Consider holding 24-48 hours pre-op
Monitor for delayed gastric emptying¹⁷

Monitoring Parameters

Daily Assessments:

Arterial blood gas analysis
Ketone levels (blood preferred over urine)
Renal function and electrolytes
Volume status
Signs of infection (especially genitourinary)

🎯 Oyster Alert: Normal glucose levels do NOT exclude SGLT2-associated ketoacidosis. Always check ketones in patients with unexplained metabolic acidosis.

Drug Interactions in ICU

SGLT2i Interactions:

Loop diuretics: Additive volume depletion risk
ACE inhibitors/ARBs: Increased AKI risk
Insulin: May mask DKA symptoms¹⁸

GLP-1RA Interactions:

Delayed absorption of oral medications
Enhanced hypoglycemic effects with insulin
Reduced efficacy of oral contraceptives due to gastroparesis¹⁹

Special Populations

Heart Failure Patients

SGLT2i Considerations:

Strong evidence for mortality benefit in HFrEF and HFpEF
Continue if hemodynamically stable
Monitor closely for volume depletion
Consider temporary discontinuation during acute decompensation²⁰

Chronic Kidney Disease

Risk-Benefit Analysis:

SGLT2i: Proven nephroprotective effects but AKI risk
GLP-1RA: Generally safe with dose adjustments
Monitor eGFR closely during critical illness²¹

Post-Surgical Patients

Enhanced Recovery Protocols:

Early reinitiation post-operatively when appropriate
Coordinate with surgical teams
Consider bridging with insulin protocols²²

Evidence-Based Guidelines and Recommendations

Professional Society Recommendations

American Diabetes Association (2024):

Discontinue SGLT2i 3-4 days before planned surgery
Resume when patient stable and eating regularly
Monitor ketones in high-risk situations²³

Society of Critical Care Medicine:

Individual risk-benefit assessment required
Consider cardio-renal benefits vs. acute risks
Maintain high suspicion for atypical presentations²⁴

Emerging Evidence

Recent studies suggest potential benefits of continuing SGLT2 inhibitors in selected ICU patients with heart failure, but more research is needed to establish clear guidelines²⁵.

Clinical Decision Support Algorithm

ICU Admission with SGLT2i/GLP-1RA
            ↓
    Assess Stability
    • Hemodynamics
    • Renal function  
    • Acid-base status
    • Planned procedures
            ↓
    High Risk Features Present?
    • AKI, pH <7.30
    • Major surgery planned
    • Severe infection
    • Gastroparesis (GLP-1RA)
            ↓
    YES → DISCONTINUE
    NO → Consider continuation with close monitoring
            ↓
    Daily reassessment and monitoring

Teaching Points and Clinical Pearls

💎 Pearls for Practice:

The "Normal Glucose Trap": Euglycemic DKA can occur with glucose <200 mg/dL in SGLT2i patients
Ketone Monitoring: Blood β-hydroxybutyrate is more reliable than urine ketones
Volume Status: SGLT2i cause osmotic diuresis - maintain vigilance for dehydration
Drug Absorption: GLP-1RA-induced gastroparesis affects ALL oral medications
Infection Screening: Always examine genitourinary tract in SGLT2i patients with sepsis

🦪 Oysters (Hidden Dangers):

Delayed Recognition: Symptoms of SGLT2-DKA may be subtle and attributed to primary illness
False Security: Continuing insulin while stopping SGLT2i may mask ketoacidosis development
Rebound Effects: Rapid discontinuation may precipitate rebound hyperglycemia
Drug Persistence: Long-acting GLP-1RA effects persist days after discontinuation
Interaction Complexity: Multiple drug interactions not immediately apparent

🔧 Clinical Hacks:

Ketone Protocol: Check ketones in ANY SGLT2i patient with unexplained symptoms
Volume Assessment: Use passive leg raise test to assess volume responsiveness
GI Function: Test gastric residuals before resuming oral medications post-GLP-1RA
Preemptive Monitoring: Start q6h ketone checks if discontinuing SGLT2i perioperatively
Communication Tool: Use structured handoff protocol when transferring these patients

Future Directions and Research Needs

Ongoing Clinical Trials

Several randomized controlled trials are investigating the safety and efficacy of continuing these agents in critically ill patients, including:

SGLT2 inhibitors in cardiogenic shock
GLP-1RA in post-operative cardiac surgery patients
Combination therapy effects in diabetic ICU patients²⁶

Emerging Technologies

Point-of-care ketone monitoring and continuous glucose monitoring systems are being evaluated for their role in managing these patients in the ICU setting²⁷.

Conclusion

The management of SGLT2 inhibitors and GLP-1 receptor agonists in ICU patients requires a nuanced understanding of their mechanisms, benefits, and risks. While these agents offer significant cardiovascular and metabolic benefits, their potential for serious complications in critically ill patients necessitates careful clinical decision-making.

The key principles for intensivists include: maintaining high clinical suspicion for atypical presentations, implementing robust monitoring protocols, and making individualized decisions based on the risk-benefit ratio for each patient. As our understanding evolves and more evidence emerges, these recommendations will continue to be refined.

Critical care physicians must stay current with the rapidly evolving evidence base while maintaining clinical vigilance for the unique complications associated with these newer therapeutic agents.

References

Zinman B, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-2128.
Umpierrez GE, et al. Management of hyperglycemia in hospitalized patients in non-critical care setting. Diabetes Care. 2012;35(6):1353-1364.
DeFronzo RA, et al. Characterization of renal glucose reabsorption in response to dapagliflozin in healthy subjects and subjects with type 2 diabetes. Diabetes Care. 2013;36(10):3169-3176.
Packer M. Cardiovascular and renal benefits of SGLT2 inhibitors and their mechanisms of action. J Am Coll Cardiol. 2017;69(20):2445-2447.
Drucker DJ. Mechanisms of action and therapeutic application of glucagon-like peptide-1. Cell Metab. 2018;27(4):740-756.
Marso SP, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311-322.
Burke KR, et al. SGLT2 inhibitors: a systematic review of diabetic ketoacidosis and related risk factors in the primary literature. Pharmacotherapy. 2017;37(2):187-194.
McMurray JJV, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381(21):1995-2008.
Nauck MA, et al. Cardiovascular outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes: a meta-analysis. Lancet Diabetes Endocrinol. 2017;5(2):105-113.
Gerstein HC, et al. Cardiovascular and renal outcomes with efpeglenatide in type 2 diabetes. N Engl J Med. 2021;385(10):896-907.
Blau JE, et al. Ketoacidosis associated with SGLT2 inhibitor treatment: analysis of FAERS data. Diabetes Metab Res Rev. 2017;33(8):e2924.
Erondu N, et al. Diabetic ketoacidosis and related events in the canagliflozin type 2 diabetes clinical program. Diabetes Care. 2015;38(9):1680-1686.
Danne T, et al. International consensus on risk management of diabetic ketoacidosis in patients with type 1 diabetes treated with sodium-glucose cotransporter (SGLT) inhibitors. Diabetes Care. 2019;42(6):1147-1154.
Bersoff-Matcha SJ, et al. Fournier gangrene associated with sodium-glucose cotransporter-2 inhibitors: a review of spontaneous postmarketing cases. Ann Intern Med. 2019;170(11):764-769.
Faillie JL. Drug-induced acute pancreatitis. Therapie. 2014;69(1):37-45.
Halawi H, et al. Effects of liraglutide on weight, satiation, and gastric functions in obesity. Gastroenterology. 2017;152(6):1367-1380.
American Society of Anesthesiologists. Practice guidelines for preoperative fasting and the use of pharmacologic agents to reduce the risk of pulmonary aspiration. Anesthesiology. 2017;126(3):376-393.
Goldenberg RM, et al. SGLT2 inhibitor-associated diabetic ketoacidosis: clinical review and practical considerations. Diabetes Ther. 2016;7(2):203-212.
Meier JJ. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nat Rev Endocrinol. 2012;8(12):728-742.
Packer M, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. 2020;383(15):1413-1424.
Heerspink HJL, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med. 2020;383(15):1436-1446.
Umpierrez GE, et al. Randomized study of basal-bolus insulin therapy in the inpatient management of patients with type 2 diabetes undergoing general surgery. Diabetes Care. 2011;34(2):256-261.
American Diabetes Association. Standards of medical care in diabetes—2024. Diabetes Care. 2024;47(Suppl 1):S1-S321.
Jacobi J, et al. Guidelines for the use of an insulin infusion for the management of hyperglycemia in critically ill patients. Crit Care Med. 2012;40(12):3251-3276.
Kosiborod MN, et al. Effects of dapagliflozin on prevention of major clinical events and recovery in patients with respiratory failure because of COVID-19. JAMA Cardiol. 2022;7(9):906-915.
ClinicalTrials.gov. Ongoing trials with SGLT2 inhibitors and GLP-1 agonists in critical care. Accessed January 2024.
Hirsch IB. Continuous glucose monitoring in the intensive care unit. J Diabetes Sci Technol. 2020;14(3):455-460.

Conflict of Interest: None declared
Funding: None

Word Count: ~3,200 words

Monday, September 8, 2025