Sodium-glucose cotransporter-2 (SGLT2) inhibitors
Sodium-glucose cotransporter-2 (SGLT2) inhibitors block renal glucose reabsorption to lower blood glucose, and independently reduce cardiovascular death, heart failure hospitalization, and kidney disease progression in high-risk patients with type 2 diabetes. Empagliflozin, canagliflozin, or dapagliflozin 10 mg (canagliflozin 100 mg) PO once daily is added early, regardless of hemoglobin A1c, in patients with established or high-risk atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease, with dose held during acute illness, prolonged fasting, or perioperatively to avoid euglycemic diabetic ketoacidosis.
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What this article covers
- Overview
Definition: SGLT2 inhibitors (empagliflozin, canagliflozin, dapagliflozin, ertugliflozin) are oral antihyperglycemic drugs that block sodium-glucose cotransporter 2 in the kidney, increasing urinary…
- Epidemiology
SGLT2 inhibitors are used across the large population of patients with type 2 diabetes who have comorbid ASCVD, heart failure, or chronic kidney disease, a group that makes up a substantial share of the overall type 2 diabetes population.
- Risk factors
Established or high risk for ASCVD, heart failure, or chronic kidney disease is the strongest indication for early SGLT2 inhibitor use.
- Pathophysiology
SGLT2 inhibitors block sodium-glucose cotransporter 2 in the proximal renal tubule, the transporter responsible for the majority of filtered glucose reabsorption, causing glucosuria and a modest…
- Clinical features
Most patients on an SGLT2 inhibitor are asymptomatic from the drug itself, with the medication used for its glucose-lowering and cardiorenal-protective effects rather than symptom control.
- Differential diagnosis
Standard hyperglycemic diabetic ketoacidosis: presents with markedly elevated glucose (typically above 250 mg/dL), unlike euglycemic DKA from SGLT2 inhibitor use, in which glucose is near-normal despite anion gap acidosis and ketosis.
- Diagnosis
Euglycemic diabetic ketoacidosis is diagnosed by an anion gap metabolic acidosis with elevated beta-hydroxybutyrate in a patient with a near-normal or only mildly elevated glucose, in the setting of…
- Management
First, confirm the indication: add an SGLT2 inhibitor after metformin (or as an early addition regardless of metformin status) in patients with established or high-risk ASCVD, established chronic…
- Complications
Euglycemic diabetic ketoacidosis is the most dangerous class-wide complication, potentially fatal if unrecognized because the near-normal glucose delays diagnosis.
- Prognosis
Empagliflozin reduces cardiovascular death and all-cause mortality in high-risk patients with type 2 diabetes (EMPA-REG OUTCOME), and reduces incident or worsening nephropathy.
- Prevention
Hold the SGLT2 inhibitor 3-4 days before elective surgery to prevent perioperative euglycemic diabetic ketoacidosis, resuming only once the patient is eating and hemodynamically stable.
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Related articles
- Noninsulin antihyperglycemic drugs in type 2 diabetes mellitus
Noninsulin antihyperglycemic drugs are the oral and injectable agents used to lower glucose in type 2 diabetes mellitus once lifestyle modification alone is insufficient, chosen in a patient-centered stepwise sequence built around metformin. Metformin, titrated to 850-1000 mg PO twice daily (max 2550 mg/day), is first-line for essentially every patient; an SGLT2 inhibitor or GLP-1 receptor agonist is added next for established or high-risk atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease, with further agents layered by hypoglycemia risk, weight effect, and cost.
- Type 2 diabetes mellitus
Type 2 diabetes is hyperglycemia from insulin resistance with progressive relative insulin deficiency, diagnosed by a hemoglobin A1c of 6.5% or higher, a fasting glucose of 126 mg/dL or higher, or a 2-hour oral glucose tolerance test value of 200 mg/dL or higher. First-line treatment is lifestyle modification plus metformin, with an SGLT2 inhibitor or GLP-1 receptor agonist added early for patients with atherosclerotic disease, kidney disease, or heart failure.
- Diabetic ketoacidosis
Diabetic ketoacidosis is a life-threatening hyperglycemic crisis of near-absolute insulin deficiency, most common in type 1 diabetes, producing an anion-gap ketoacidosis from unrestrained lipolysis and osmotic diuresis from severe hyperglycemia. It is diagnosed by hyperglycemia, ketonemia, and an anion-gap metabolic acidosis, and treated with intravenous isotonic saline, an intravenous regular insulin bolus and infusion, and aggressive potassium repletion guided by frequent electrolyte monitoring.
- Insulin therapy in diabetes mellitus
Insulin therapy replaces or supplements endogenous insulin to control hyperglycemia, and is lifelong and mandatory in type 1 diabetes because of absolute beta-cell failure, while in type 2 diabetes it is added when oral and noninjectable agents fail to reach glycemic goals. First-line therapy is a basal-bolus regimen started at 0.4-1.0 units/kg/day in type 1 diabetes, or basal insulin glargine 10 units/day (or 0.1-0.2 units/kg/day) in type 2 diabetes, titrated to a fasting glucose target.