What are the contraindications for sodium‑glucose co‑transporter‑2 (SGLT‑2) inhibitors such as canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin?

SGLT2 Inhibitor Contraindications

The only absolute contraindication to SGLT2 inhibitors is a history of serious hypersensitivity reaction (including anaphylaxis or angioedema) to the specific agent or its excipients. 1, 2

Absolute Contraindication

• Serious hypersensitivity reactions to dapagliflozin, canagliflozin, empagliflozin, or ertugliflozin—including anaphylaxis and angioedema—represent the sole FDA-labeled contraindication across this drug class 1, 2

Critical Clinical Situations Requiring Extreme Caution or Avoidance

Type 1 Diabetes Mellitus

• SGLT2 inhibitors are NOT indicated for glycemic control in type 1 diabetes and significantly increase the risk of life-threatening diabetic ketoacidosis (DKA) beyond background rates in this population 1
• In Europe, dapagliflozin carries approval as adjunct to insulin in type 1 diabetes, but this indication does not exist in North America and requires intensive patient education about DKA risk 3

Severe Renal Impairment (Context-Dependent)

• For glycemic control in type 2 diabetes: SGLT2 inhibitors are not recommended when eGFR <45 mL/min/1.73 m² because they become ineffective at lowering glucose due to reduced filtered glucose load 1, 4
• For cardiorenal protection (heart failure, CKD): Initiation is not recommended when eGFR <25 mL/min/1.73 m², but continuation is appropriate if eGFR falls below 25 while on therapy, as cardiovascular and renal benefits persist independent of glycemic effects 1, 4

High-Risk DKA Scenarios

• Pancreatic disorders (history of pancreatitis or pancreatic surgery) substantially increase ketoacidosis risk and warrant extreme caution 1
• Precipitating conditions that mandate temporary discontinuation include:
  • Under-insulinization (insulin dose reduction or missed doses)
  • Acute febrile illness
  • Severe volume depletion or dehydration
  • Ketogenic diet
  • Major surgery or prolonged fasting (withhold ≥3 days before procedure) 1, 5
  • Alcohol abuse 1

Important Clinical Warnings (Not Absolute Contraindications)

Volume Depletion Risk

• Use caution in patients on concurrent diuretics, ACE inhibitors, or ARBs, as SGLT2 inhibitors exert osmotic diuresis that may precipitate hypotension, orthostasis, or acute kidney injury 5, 6
• Frail older adults with baseline orthostasis or urinary incontinence require careful risk-benefit assessment 6

Amputation and Fracture Risk

• Canagliflozin specifically showed increased lower-limb amputation risk (6.3 vs 3.4 per 1,000 patient-years; HR 1.97) and fracture risk (15.4 vs 11.9 per 1,000 patient-years; HR 1.26) in one trial, though this has not been consistently observed with other SGLT2 inhibitors 5
• Whether this represents a class effect or canagliflozin-specific risk remains uncertain 5

Genital Mycotic Infections

• Increased glucosuria creates a favorable environment for genital mycotic infections, which are the most common adverse event but typically mild and treatable 5, 7
• Patients should be counseled to seek medical attention for severe or worsening infections 5

Key Clinical Pitfalls to Avoid

• Do not discontinue SGLT2 inhibitors solely because of the initial eGFR dip (3-5 mL/min decline) that occurs within weeks of initiation—this is hemodynamic, reversible, and does not indicate kidney injury 5, 4
• Do not stop SGLT2 inhibitors when glucose-lowering efficacy declines at lower eGFR levels, as cardiorenal benefits persist down to eGFR 20-25 mL/min/1.73 m² 4
• Recognize euglycemic DKA: Ketoacidosis may present with blood glucose <200 mg/dL and nonspecific symptoms (nausea, vomiting, abdominal pain, malaise); assess ketones in any patient with metabolic acidosis regardless of glucose level 5, 1
• Adjust insulin and sulfonylurea doses: When initiating SGLT2 inhibitors, reduce insulin by 10-20% and consider stopping sulfonylureas (especially if HbA1c <8.5%) to prevent hypoglycemia 8