SGLT2 Inhibitors in ICU Patients: Risks and Benefits

 

Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors in ICU Patients: Risks and Benefits

Dr Neeraj Manikath , claude.ai

Abstract

Background: Sodium-glucose cotransporter-2 (SGLT2) inhibitors have revolutionized diabetes management and demonstrated cardiovascular and renal benefits. However, their use in critically ill patients presents unique challenges and considerations.

Objective: To evaluate the risks and benefits of SGLT2 inhibitors in intensive care unit (ICU) patients, with particular focus on euglycemic diabetic ketoacidosis (euDKA) risk versus potential renal and cardiovascular protection.

Methods: Comprehensive review of current literature, case reports, and clinical guidelines regarding SGLT2 inhibitor use in critical illness.

Results: SGLT2 inhibitors carry significant risk of euDKA in critically ill patients, particularly during periods of stress, dehydration, and reduced caloric intake. However, their renoprotective and cardioprotective effects may benefit select ICU populations when used judiciously.

Conclusions: SGLT2 inhibitors require careful risk-benefit analysis in ICU settings. Discontinuation is often warranted during acute illness, though continuation may be considered in hemodynamically stable patients with close monitoring.

Keywords: SGLT2 inhibitors, critical care, diabetic ketoacidosis, acute kidney injury, intensive care

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Introduction

Sodium-glucose cotransporter-2 (SGLT2) inhibitors, including empagliflozin, dapagliflozin, canagliflozin, and ertugliflozin, have transformed diabetes management since their introduction. These medications work by inhibiting glucose reabsorption in the proximal tubule, leading to glucosuria and modest glucose lowering independent of insulin action¹. Beyond glycemic control, landmark trials have demonstrated significant cardiovascular and renal benefits, establishing SGLT2 inhibitors as cornerstone therapy for patients with diabetes and cardiovascular or chronic kidney disease²⁻⁴.

However, the management of SGLT2 inhibitors in critically ill patients presents unique challenges. The ICU environment, characterized by physiological stress, altered metabolism, fluid shifts, and polypharmacy, creates conditions that may amplify both the risks and potential benefits of these agents. This review examines the current evidence surrounding SGLT2 inhibitor use in ICU patients, focusing on the critical balance between the risk of euglycemic diabetic ketoacidosis (euDKA) and potential organ-protective effects.

Mechanism of Action and Physiological Effects

Normal Physiology

The SGLT2 transporter, located in the S1 segment of the proximal tubule, is responsible for approximately 90% of filtered glucose reabsorption⁵. Under normal conditions, virtually all filtered glucose is reabsorbed, with the glucose threshold typically around 180 mg/dL (10 mmol/L).

SGLT2 Inhibitor Effects

SGLT2 inhibitors reduce the renal threshold for glucose excretion to approximately 40-60 mg/dL, resulting in:

• Glucosuria (30-80g glucose/day)
• Osmotic diuresis and natriuresis
• Modest weight loss (2-4 kg)
• Reduction in blood pressure (2-4 mmHg systolic)
• Increased ketogenesis due to volume contraction and altered metabolism⁶

Metabolic Adaptations

The osmotic diuresis triggers several compensatory mechanisms:

• Activation of the renin-angiotensin-aldosterone system
• Increased sympathetic nervous system activity
• Enhanced lipolysis and ketogenesis
• Improved insulin sensitivity
• Altered renal hemodynamics with reduced hyperfiltration⁷

Clinical Benefits in Stable Patients

Cardiovascular Protection

The EMPA-REG OUTCOME trial demonstrated a 14% reduction in major adverse cardiovascular events (MACE) with empagliflozin, driven primarily by cardiovascular death reduction². Subsequent trials with canagliflozin (CANVAS) and dapagliflozin (DECLARE-TIMI 58) confirmed cardiovascular benefits across the SGLT2 inhibitor class³⁻⁴.

Proposed Mechanisms:

• Reduction in preload and afterload
• Improved myocardial energetics
• Anti-inflammatory effects
• Reduced arterial stiffness
• Favorable effects on epicardial fat⁸

Renal Protection

SGLT2 inhibitors consistently demonstrate renoprotective effects:

• Reduced progression of chronic kidney disease
• Lower risk of end-stage renal disease
• Decreased albuminuria
• Preservation of estimated glomerular filtration rate (eGFR) over time⁹

The CREDENCE trial specifically in patients with diabetic nephropathy showed a 30% reduction in the primary composite renal outcome with canagliflozin¹⁰.

Heart Failure Benefits

Recent trials have established SGLT2 inhibitors as effective heart failure therapy, even in non-diabetic patients:

• DAPA-HF: 26% reduction in cardiovascular death or heart failure hospitalization with dapagliflozin¹¹
• EMPEROR-Reduced: 25% reduction in primary composite endpoint with empagliflozin¹²

Risks in Critical Illness

Euglycemic Diabetic Ketoacidosis (euDKA)

Definition and Incidence EuDKA is defined as diabetic ketoacidosis with blood glucose levels <250 mg/dL (13.9 mmol/L). While rare in stable outpatients (0.1-0.2% annually), the incidence appears higher in hospitalized patients and may reach 1-2% in high-risk populations¹³⁻¹⁴.

Pathophysiology in Critical Illness The ICU environment creates a "perfect storm" for euDKA development:

1. Increased Ketogenesis

   • Stress-induced catecholamine release
   • Reduced caloric intake
   • Volume depletion
   • Concurrent illness promoting lipolysis¹⁵

2. Reduced Ketone Clearance

   • Acute kidney injury
   • Dehydration
   • Altered renal perfusion

3. Precipitating Factors

   • Surgery and anesthesia
   • Infections and sepsis
   • Dehydration
   • Alcohol use
   • Reduced carbohydrate intake¹⁶

Clinical Presentation EuDKA may be difficult to recognize in ICU patients due to:

• Normal or mildly elevated glucose levels
• Nonspecific symptoms (nausea, vomiting, altered mental status)
• Overlap with other causes of metabolic acidosis
• Delayed recognition due to normal glucose levels¹⁷

Volume Depletion and Hemodynamic Instability

SGLT2 inhibitors cause predictable volume loss through osmotic diuresis. In critically ill patients, this may lead to:

• Exacerbation of pre-existing volume depletion
• Hypotension requiring vasopressor support
• Acute kidney injury
• Electrolyte abnormalities (hyponatremia, hyperkalemia)¹⁸

Genitourinary Infections

The glucosuric effect of SGLT2 inhibitors increases the risk of:

• Urinary tract infections
• Genital mycotic infections
• Rarely, necrotizing fasciitis of the perineum (Fournier's gangrene)¹⁹

In immunocompromised ICU patients, these risks may be amplified.

Drug Interactions and Altered Pharmacokinetics

Critical illness may alter SGLT2 inhibitor pharmacokinetics through:

• Reduced renal clearance
• Altered protein binding
• Drug-drug interactions with common ICU medications
• Variable absorption in patients with gastroparesis or enteral feeding²⁰

Special ICU Populations

Post-Surgical Patients

Perioperative SGLT2 inhibitor management is controversial:

Risks:

• Increased euDKA risk (up to 5-10x higher perioperatively)
• Volume depletion complicating anesthetic management
• Delayed wound healing due to glucosuria
• Interaction with contrast agents²¹

Current Recommendations:

• Discontinue 3-4 days before elective surgery
• Hold for 24-48 hours before emergency surgery if possible
• Monitor ketones perioperatively
• Resume only when hemodynamically stable and tolerating oral intake²²

Sepsis and Shock

Theoretical Benefits:

• Anti-inflammatory effects may be beneficial in sepsis
• Renal protection during acute kidney injury
• Improved microvascular function²³

Practical Concerns:

• Volume depletion may worsen shock
• Increased infection risk
• Difficult to distinguish euDKA from sepsis-related acidosis
• Potential for delayed recognition of deterioration²⁴

Pearl: In septic patients on SGLT2 inhibitors, always check serum ketones if unexplained metabolic acidosis is present, even with normal glucose levels.

Acute Kidney Injury (AKI)

SGLT2 inhibitors present a paradox in AKI management:

Protective Mechanisms:

• Reduced glomerular hyperfiltration
• Improved renal oxygenation
• Anti-inflammatory effects
• Reduced albuminuria²⁵

Risk Factors:

• Volume depletion may precipitate AKI
• Reduced drug clearance in established AKI
• Potential for hyperkalemia
• Uncertain dosing in renal impairment²⁶

Hack: Consider continuing SGLT2 inhibitors in patients with mild AKI (stage 1) if hemodynamically stable, but hold in moderate-severe AKI or if volume depleted.

Heart Failure Exacerbations

SGLT2 inhibitors may be beneficial in acute heart failure:

Potential Benefits:

• Rapid diuresis without electrolyte depletion
• Improved cardiac energetics
• Reduced preload
• Natriuretic effects independent of loop diuretics²⁷

Clinical Evidence: Limited data exist for acute settings, but SGLT2 inhibitors appear safe to initiate during heart failure hospitalizations when patients are hemodynamically stable²⁸.

Oyster: Don't assume SGLT2 inhibitors will replace traditional diuretics in acute heart failure - they work synergistically and have different mechanisms.

Monitoring and Management Strategies

Pre-ICU Assessment

When ICU patients are receiving SGLT2 inhibitors:

1. Risk Stratification

   • Assess for euDKA risk factors
   • Evaluate volume status
   • Review recent surgical procedures
   • Identify concurrent medications

2. Laboratory Monitoring

   • Complete metabolic panel
   • Serum ketones (beta-hydroxybutyrate preferred)
   • Arterial blood gas
   • Urinalysis²⁹

ICU Management Protocol

Daily Assessment:

• Volume status and hemodynamic stability
• Acid-base status
• Electrolyte balance
• Caloric intake
• Signs of infection

Laboratory Monitoring:

• Serum ketones if acidosis present (anion gap >12)
• Daily basic metabolic panel
• Blood glucose monitoring
• Urinalysis if infection suspected³⁰

Decision-Making Framework

Continue SGLT2 Inhibitors If:

• Hemodynamically stable
• Adequate oral/enteral intake
• No signs of volume depletion
• No metabolic acidosis
• Clear clinical benefit (e.g., heart failure)

Hold SGLT2 Inhibitors If:

• Hemodynamic instability
• Volume depletion
• NPO status >24 hours
• Metabolic acidosis (pH <7.3 or HCO₃ <18)
• Active infection with systemic signs
• Planned surgery within 48 hours³¹

Treatment of SGLT2 Inhibitor-Related Complications

EuDKA Management

Recognition:

• High index of suspicion in patients on SGLT2 inhibitors
• Check ketones in any patient with unexplained acidosis
• Consider even with normal glucose levels

Treatment:

1. Discontinue SGLT2 inhibitor immediately
2. Fluid resuscitation - Normal saline initially
3. Dextrose administration - Even with normal glucose levels
4. Insulin therapy - Low-dose continuous infusion (0.1 units/kg/hr)
5. Electrolyte replacement - Particularly potassium and phosphorus
6. Identify and treat precipitating factors³²

Hack: Start dextrose early in euDKA treatment (D5W or D10W) to prevent hypoglycemia while clearing ketones with insulin.

Volume Depletion

Assessment:

• Clinical examination
• Urine output monitoring
• Central venous pressure if available
• Lactate levels

Management:

• Balanced crystalloid solutions
• Avoid excessive diuretics
• Monitor electrolytes closely
• Consider temporary drug discontinuation³³

Future Directions and Research Priorities

Ongoing Studies

Several trials are investigating SGLT2 inhibitors in acute settings:

• EMPULSE: Empagliflozin in acute heart failure
• DARE-19: Dapagliflozin in COVID-19 patients with cardiovascular disease
• DEFENDER: Dapagliflozin in acute heart failure³⁴

Research Gaps

1. Optimal timing for drug discontinuation and resumption
2. Risk prediction models for euDKA in hospitalized patients
3. Role in specific ICU populations (trauma, burns, neurological patients)
4. Pharmacokinetics in critical illness
5. Cost-effectiveness in ICU settings³⁵

Emerging Applications

• Acute kidney injury prevention
• Sepsis-associated organ dysfunction
• Post-cardiac arrest care
• Diabetic emergencies beyond DKA³⁶

Clinical Pearls and Oysters

Pearls

1. Always check ketones in SGLT2 inhibitor users with unexplained acidosis, regardless of glucose level
2. Volume status is key - dehydrated patients should not receive SGLT2 inhibitors
3. Perioperative risk is highest - stop 3-4 days before elective surgery
4. EuDKA can occur with normal glucose - don't be falsely reassured by glucose <250 mg/dL
5. Dextrose is therapeutic in euDKA, even with normal glucose levels

Oysters

1. Ketones can be elevated in starvation - distinguish from pathological ketoacidosis by pH and clinical context
2. SGLT2 inhibitors don't prevent diabetic ketoacidosis - patients can still develop classic DKA
3. Renal benefits take time - don't expect immediate improvement in acute kidney injury
4. Infection risk is real but rare - don't withhold antibiotics, but maintain awareness
5. Drug interactions exist - particularly with diuretics and ACE inhibitors³⁷

Hacks

1. Use point-of-care ketone meters for rapid assessment in the ICU
2. Create standardized order sets for SGLT2 inhibitor management in your ICU
3. Establish clear holding criteria and communicate with primary teams
4. Consider pharmacist consultation for complex cases or drug interactions
5. Document reasoning clearly for continuation or discontinuation decisions³⁸

Conclusion

SGLT2 inhibitors represent a significant advancement in diabetes and cardiovascular care, but their use in critically ill patients requires careful consideration. The risk of euglycemic diabetic ketoacidosis, while rare, can be life-threatening and may be increased in the ICU environment. However, the potential cardiovascular and renal benefits of these agents may justify continued use in carefully selected, hemodynamically stable patients.

Critical care physicians must develop expertise in recognizing and managing SGLT2 inhibitor-related complications while understanding the potential benefits these medications may provide. A systematic approach to risk assessment, monitoring, and decision-making is essential for safe and effective use in the ICU setting.

The field would benefit from additional research specifically addressing SGLT2 inhibitor use in critical illness, including development of risk prediction tools, optimal monitoring strategies, and guidelines for specific ICU populations. Until such data are available, a conservative approach emphasizing patient safety while preserving potential benefits represents the most prudent strategy.

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Funding: None declared.

Conflicts of Interest: The authors declare no conflicts of interest.

Ethics Statement: This review article does not involve human subjects research.

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