Sodium-glucose cotransporter 2 (SGLT-2) inhibitors lower blood glucose by blocking renal tubular glucose reabsorption, forcing glycosuria independent of insulin secretion or action. This mechanism confers glucose-lowering efficacy across the full spectrum of type 2 diabetes mellitus (T2DM), including in patients with significant insulin deficiency, while simultaneously producing osmotic diuresis, natriuresis, weight loss, and blood pressure reduction through consequences of the glycosuric state.
The kidney filters approximately 180 grams of glucose per day through the glomerulus, and under normal circumstances nearly all of this filtered glucose is reabsorbed in the proximal tubule, with no glucose appearing in the urine. Glucose reabsorption is mediated by two sodium-glucose cotransporters: sodium-glucose cotransporter 2 (SGLT-2), expressed predominantly in the early proximal tubule (S1 and S2 segments), and sodium-glucose cotransporter 1 (SGLT-1), expressed in the late proximal tubule (S3 segment) and in the intestine. SGLT-2 has low affinity but high capacity for glucose transport and is responsible for approximately 90% of renal glucose reabsorption; SGLT-1 has high affinity but lower capacity and handles the remaining 10% as a salvage pathway when SGLT-2 is saturated. Both transporters couple glucose transport to the electrochemical sodium gradient established by the basolateral sodium-potassium adenosine triphosphatase (Na/K-ATPase), cotransporting one sodium ion per glucose molecule (SGLT-2) or two sodium ions per glucose molecule (SGLT-1) down the sodium gradient from lumen to cell, with glucose then exiting via facilitated glucose transporter 2 (GLUT2) on the basolateral membrane into the interstitium.1
SGLT-2 inhibitors competitively block SGLT-2 at the luminal surface of the early proximal tubule, reducing renal glucose reabsorption by approximately 30 to 50% of the filtered load. The unabsorbed glucose remains in the tubular fluid and is excreted in the urine, producing glycosuria of approximately 60 to 90 grams per day at therapeutic doses in patients with normal kidney function. Because the threshold for glucose appearance in the urine is normally about 10 millimoles per liter of plasma glucose, SGLT-2 inhibition lowers this threshold substantially, allowing glucose excretion even at near-normal plasma glucose concentrations and producing a glucose-lowering mechanism that is largely insulin-independent. The glycosuric caloric loss (approximately 240 to 360 kilocalories per day) contributes directly to weight reduction of 2 to 3 kg over 24 to 52 weeks. The glucose remaining in the tubular lumen exerts an osmotic effect that carries water into the tubular fluid (osmotic diuresis), reducing extracellular fluid volume by approximately 5 to 7% and producing reductions in blood pressure of approximately 3 to 5 millimeters of mercury systolic and 1 to 2 millimeters of mercury diastolic.1
SGLT-2 inhibition also produces natriuresis through a mechanism linked to tubuloglomerular feedback. In the proximal tubule, sodium and glucose are cotransported by SGLT-2; inhibiting SGLT-2 reduces proximal tubular sodium reabsorption, increasing sodium delivery to the macula densa of the juxtaglomerular apparatus. This increased distal sodium delivery activates tubuloglomerular feedback, producing afferent arteriolar vasoconstriction that reduces intraglomerular pressure (single-nephron glomerular filtration rate (GFR) decreases), which is the mechanism underlying the renoprotective effect of SGLT-2 inhibitors in diabetic kidney disease (DKD). This hemodynamic mechanism is analogous to the renoprotective mechanism of renin-angiotensin-aldosterone system (RAAS) blockade but acts on a different node of the glomerular pressure regulatory circuit: RAAS blockade dilates the efferent arteriole while SGLT-2 inhibition constricts the afferent arteriole, both reducing intraglomerular hypertension.2
SGLT-1 in the intestine mediates post-prandial glucose absorption. SGLT-1 in the late proximal tubule provides a salvage reabsorption pathway when SGLT-2 is inhibited. Highly selective SGLT-2 inhibitors (empagliflozin, dapagliflozin) spare intestinal SGLT-1, avoiding diarrhea. Canagliflozin at high doses has partial SGLT-1 inhibitory activity, transiently reducing intestinal glucose absorption post-meal and augmenting its glycosuric effect; this SGLT-1 contribution is modest at the 100 mg dose and more pronounced at 300 mg.
Four sodium-glucose cotransporter 2 (SGLT-2) inhibitors are approved in the United States: canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin. They share the core glycosuric mechanism but differ in their selectivity for sodium-glucose cotransporter 2 (SGLT-2) versus sodium-glucose cotransporter 1 (SGLT-1), their approved indications beyond type 2 diabetes mellitus (T2DM), and in their agent-specific and indication-specific estimated glomerular filtration rate (eGFR) floors for use, which differ substantially across agents and indications.
Canagliflozin was the first SGLT-2 inhibitor approved in the United States (March 2013) for glycemic control in T2DM. It is available at 100 mg and 300 mg orally once daily, taken before the first meal of the day. Canagliflozin has lower SGLT-2 selectivity than empagliflozin or dapagliflozin, with partial inhibitory activity at SGLT-1 at the 300 mg dose. Its oral bioavailability is approximately 65%, it is highly protein-bound (~99%), is metabolized primarily by glucuronidation (UGT1A9 and UGT2B4) with minimal cytochrome P450 (CYP450) involvement, and has a half-life of approximately 10 to 13 hours. The eGFR floor for its glycemic indication is 45 mL per minute per 1.73 m²; for its cardiovascular risk reduction indication in T2DM patients with established atherosclerotic cardiovascular disease (ASCVD), the eGFR floor is 30 mL per minute per 1.73 m²; for its diabetic kidney disease (DKD) indication (based on CREDENCE [Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation] trial data), the eGFR floor is 30 mL per minute per 1.73 m² with albuminuria.15
Dapagliflozin (approved January 2014 for T2DM) is a highly selective SGLT-2 inhibitor with minimal SGLT-1 activity, available at 5 mg and 10 mg once daily without regard to meals. Its bioavailability is approximately 78%, half-life approximately 12 hours, and it undergoes glucuronidation by UGT1A9. Dapagliflozin has the broadest range of approved indications of any SGLT-2 inhibitor as of 2024: T2DM (glycemic indication, eGFR floor 45 mL per minute per 1.73 m²), chronic kidney disease (CKD) regardless of T2DM status (DAPA-CKD [Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease] trial basis, eGFR floor 25 mL per minute per 1.73 m² with albuminuria), and heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF) regardless of T2DM status (DAPA-HF [Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure] and Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure (DELIVER) trial basis, eGFR floor 25 mL per minute per 1.73 m²).15
Empagliflozin (approved August 2014 for T2DM) is the most selective SGLT-2 inhibitor in the class with negligible SGLT-1 activity, available at 10 mg and 25 mg once daily. Its bioavailability is approximately 84%, half-life approximately 13 hours, and it undergoes glucuronidation primarily by uridine diphosphate glucuronosyltransferase enzymes with minimal cytochrome P450 involvement, similar to the glucuronidation pathway shared by dapagliflozin. Empagliflozin has three approved non-glycemic indications: cardiovascular risk reduction in T2DM with established ASCVD (the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) basis), heart failure regardless of T2DM status (HFrEF: the Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and a Reduced Ejection Fraction (EMPEROR-Reduced) trial; HFpEF: the Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction (EMPEROR-Preserved) trial), and chronic kidney disease regardless of T2DM status (EMPA-KIDNEY [Empagliflozin in Patients with Chronic Kidney Disease] trial basis). The eGFR floor for its HF indication is 20 mL per minute per 1.73 m²; for CKD, 20 mL per minute per 1.73 m².15
Ertugliflozin (approved December 2017 for T2DM) is available at 5 mg and 15 mg once daily and is the most recently approved and least studied agent of the four. It does not have approved non-glycemic indications beyond T2DM, and the Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes Trial (VERTIS-CV) cardiovascular outcome trial did not demonstrate superiority over placebo for the primary major adverse cardiovascular event (MACE) endpoint, though it met the non-inferiority criterion for cardiovascular safety. The eGFR floor for its glycemic indication is 45 mL per minute per 1.73 m². Ertugliflozin is less commonly used than the other three agents given its narrower indication profile and the lack of cardiovascular or renal outcome data supporting non-glycemic use.6
The eGFR threshold below which an SGLT-2 inhibitor should not be used varies by agent AND by the indication being treated. For glycemic control, most agents require eGFR ≥45 mL/min/1.73 m². For cardiovascular or renal indications, the floors are lower: dapagliflozin and empagliflozin can be used for HF or CKD indications down to eGFR 20–25 mL/min/1.73 m². Never apply a single eGFR floor across all agents and all indications. Always verify the current prescribing information for the specific agent and the specific indication being treated.
The cardiovascular outcome trial (CVOT) program for sodium-glucose cotransporter 2 (SGLT-2) inhibitors produced a paradigm shift in the management of type 2 diabetes mellitus (T2DM), heart failure, and atherosclerotic cardiovascular disease (ASCVD). In contrast to glucagon-like peptide-1 receptor (GLP-1R) agonist CVOTs where the dominant cardiovascular benefit is reduction in atherosclerotic events (myocardial infarction and stroke), the SGLT-2 inhibitor CVOTs demonstrated that their primary cardiovascular benefit is driven by reduction in heart failure hospitalizations, with more modest or absent effects on atherosclerotic endpoints in most trials.
The Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) was the landmark SGLT-2 inhibitor CVOT, enrolling 7,020 patients with T2DM and established ASCVD randomized to empagliflozin 10 mg, 25 mg, or placebo. At a median follow-up of 3.1 years, empagliflozin reduced the primary three-point major adverse cardiovascular event (MACE) composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke by 14% compared with placebo (hazard ratio 0.86, 95% confidence interval 0.74 to 0.99). The MACE reduction was driven almost entirely by a 38% reduction in cardiovascular death; rates of myocardial infarction and stroke were not significantly different between groups. Hospitalization for heart failure was reduced by 35%, establishing the heart failure hospitalization signal that would become the class signature. The rapidity of the cardiovascular mortality reduction (within weeks of drug initiation) was inconsistent with an atherosclerosis-slowing mechanism and instead suggested a hemodynamic mechanism operating through volume unloading and blood pressure reduction.7
The Canagliflozin Cardiovascular Assessment Study (CANVAS) program randomized 10,142 patients with T2DM and either established cardiovascular disease or multiple cardiovascular risk factors to canagliflozin or placebo. The primary three-point MACE composite was reduced by 14% (hazard ratio 0.86, 95% confidence interval 0.75 to 0.97), with hospitalization for heart failure reduced by 33%. The CANVAS program also identified two important safety signals: a 97% increased relative risk of lower extremity amputations (primarily toe amputations, hazard ratio 1.97, 95% confidence interval 1.41 to 2.75) and a significant increase in bone fractures with canagliflozin, particularly at the 100 mg dose. The amputation signal has not been consistently replicated across the class and is considered canagliflozin-specific by most authorities, though the mechanism remains uncertain; proposed explanations include volume depletion in susceptible patients and possible effects on bone metabolism through sodium-glucose cotransporter 1 (SGLT-1) inhibition in osteoclasts.3
The Dapagliflozin Effect on Cardiovascular Events – Thrombolysis in Myocardial Infarction 58 trial (DECLARE-TIMI 58) was the largest SGLT-2 inhibitor CVOT, enrolling 17,160 patients with T2DM, of whom only 40% had established ASCVD (the remainder had multiple risk factors only). Dapagliflozin did not significantly reduce the primary three-point MACE composite in the overall population (hazard ratio 0.93, 95% confidence interval 0.84 to 1.03, p=0.17 for superiority), though it did meet the cardiovascular safety (non-inferiority) criterion. In the pre-specified secondary composite of cardiovascular death or hospitalization for heart failure, dapagliflozin produced a significant 17% reduction, with the heart failure hospitalization component driving this benefit. The divergence between MACE (no significant reduction) and heart failure hospitalization (significant reduction) in DECLARE-TIMI 58 reinforced the conclusion that SGLT-2 inhibitors act primarily through heart failure mechanisms rather than atherosclerosis modification.9
GLP-1R agonists (liraglutide, semaglutide) reduce atherosclerotic MACE, particularly stroke, in established ASCVD patients, consistent with an anti-atherosclerotic mechanism. SGLT-2 inhibitors reduce heart failure hospitalizations and cardiovascular death, consistent with a hemodynamic mechanism (volume unloading, preload/afterload reduction). When a T2DM patient has both established ASCVD and heart failure, both drug classes are indicated and can be combined: GLP-1R agonist for atherosclerotic protection and SGLT-2 inhibitor for heart failure protection.
The most consequential advance in sodium-glucose cotransporter 2 (SGLT-2) inhibitor pharmacology has been the demonstration of heart failure and renal protective effects that are independent of glycemic lowering and operate across the full spectrum of ejection fraction, from heart failure with reduced ejection fraction (HFrEF) through heart failure with preserved ejection fraction (HFpEF), and in chronic kidney disease (CKD) regardless of type 2 diabetes mellitus (T2DM) status. These findings have transformed SGLT-2 inhibitors from anti-diabetic agents into cardiorenal protective drugs used across multiple disease states.
The Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure trial (DAPA-HF) enrolled 4,744 patients with HFrEF (left ventricular ejection fraction (LVEF) ≤40%) regardless of T2DM status, randomized to dapagliflozin 10 mg or placebo. The primary composite endpoint of worsening heart failure (hospitalization or urgent visit requiring intravenous therapy) or cardiovascular death was reduced by 26% with dapagliflozin (hazard ratio 0.74, 95% confidence interval 0.65 to 0.85), with consistent benefit in patients with and without T2DM (45% of the trial population did not have T2DM). Cardiovascular death was reduced by 18%, and worsening heart failure events by 30%. The Kansas City Cardiomyopathy Questionnaire (KCCQ) total symptom score improved significantly more with dapagliflozin, indicating meaningful symptom and quality-of-life benefit beyond the hard clinical outcomes.10
The Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and a Reduced Ejection Fraction (EMPEROR-Reduced) trial enrolled 3,730 HFrEF patients (LVEF ≤40%) randomized to empagliflozin 10 mg or placebo. The primary composite of cardiovascular death or hospitalization for heart failure was reduced by 25% (hazard ratio 0.75, 95% confidence interval 0.65 to 0.86), with a 30% reduction in total heart failure hospitalizations including recurrent events. The Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction (EMPEROR-Preserved) trial extended empagliflozin’s benefit to HFpEF (LVEF >40%), demonstrating a 21% reduction in the primary composite of cardiovascular death or hospitalization for heart failure (hazard ratio 0.79, 95% confidence interval 0.69 to 0.90) in 5,988 patients, making empagliflozin the first pharmacological agent to demonstrate superiority over placebo for this composite in HFpEF.8 Consistent with the SGLT-2 inhibitor heart failure mechanism, the benefit in both EMPEROR trials was driven primarily by reduced heart failure hospitalizations rather than cardiovascular mortality reduction.5
The mechanisms through which SGLT-2 inhibitors benefit heart failure are distinct from their glycemic mechanism and have been the subject of extensive investigation. The primary hemodynamic contributions are preload reduction (through osmotic diuresis and natriuresis reducing intravascular volume and ventricular filling pressures) and modest afterload reduction (through blood pressure lowering). These effects mirror those of loop diuretics and renin-angiotensin-aldosterone system (RAAS) blockers, but SGLT-2 inhibitors produce these changes without activating the neurohormonal compensatory responses (renin-angiotensin system activation, sympathetic activation) that typically accompany aggressive diuresis, possibly because the volume loss occurs gradually through urinary glucose and sodium excretion rather than abrupt loop diuretic-driven natriuresis. Additional proposed mechanisms include reduction in epicardial fat mass (which reduces pericardial constraint in HFpEF), anti-fibrotic effects in myocardial tissue, and a metabolic shift toward ketone body oxidation in the failing heart (the “thrifty substrate” hypothesis), where SGLT-2 inhibition raises circulating beta-hydroxybutyrate levels that may serve as a more oxygen-efficient fuel for the energy-depleted failing myocardium.11
The renal outcome trial program for SGLT-2 inhibitors has established their role as primary renoprotective agents in CKD. The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation trial (CREDENCE) enrolled 4,401 patients with T2DM and DKD (estimated glomerular filtration rate (eGFR) 30 to 90 mL per minute per 1.73 m² and urinary albumin-to-creatinine ratio (UACR) >300 mg per gram) receiving maximum tolerated RAAS blockade, randomized to canagliflozin 100 mg or placebo. The trial was stopped early at a median follow-up of 2.6 years due to overwhelming efficacy: canagliflozin reduced the primary renal composite (end-stage kidney disease, doubling of serum creatinine, or renal or cardiovascular death) by 30% (hazard ratio 0.70, 95% confidence interval 0.59 to 0.82).4 The Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease trial (DAPA-CKD) enrolled 4,304 patients with CKD (eGFR 25 to 75 mL per minute per 1.73 m² and UACR >200 mg per gram) regardless of T2DM status (33% without T2DM), demonstrating a 39% reduction in the primary renal composite.15 The Empagliflozin in Patients with Chronic Kidney Disease trial (EMPA-KIDNEY) further extended the renal protection evidence to patients with CKD down to eGFR 20 mL per minute per 1.73 m² using empagliflozin.12
Dapagliflozin and empagliflozin are approved for HFrEF and HFpEF regardless of T2DM status. Dapagliflozin and empagliflozin are approved for CKD regardless of T2DM status. Canagliflozin has a DKD indication but requires T2DM. For a patient with HF or CKD but without T2DM, dapagliflozin or empagliflozin can be prescribed for the cardiac or renal indication alone, without any glycemic indication or HbA1c threshold requirement.
The sodium-glucose cotransporter 2 (SGLT-2) inhibitor safety profile is well-characterized from large cardiovascular outcome trials and post-marketing surveillance. The clinically most significant risks are euglycemic diabetic ketoacidosis (DKA), Fournier gangrene, and volume depletion in vulnerable patients. Genital mycotic infections are the most common adverse effect. Understanding which risks are class-wide and which are agent-specific (particularly the canagliflozin amputation and fracture signals) is essential for appropriate agent selection and patient counseling.
Euglycemic diabetic ketoacidosis (DKA) is the most serious metabolic complication of SGLT-2 inhibitor therapy and occurs when ketoacidosis develops without markedly elevated plasma glucose, typically with glucose below 14 millimoles per liter (252 mg per deciliter), making it difficult to recognize clinically if glucose is not obviously elevated. The mechanism involves glucagon excess driving hepatic ketogenesis combined with the glycosuric effect of SGLT-2 inhibition that prevents glucose accumulation, resulting in ketone body production without hyperglycemia. Euglycemic DKA occurs more frequently in type 1 diabetes mellitus (T1DM) patients given SGLT-2 inhibitors (where none are FDA-approved for this indication) and in type 2 diabetes mellitus (T2DM) patients during periods of absolute or relative insulin deficiency: starvation, acute illness, surgery, excessive alcohol intake, or low-carbohydrate diets. The perioperative management protocol requires discontinuation of SGLT-2 inhibitors 3 to 4 days before planned major surgery and resumption only after the patient is eating and drinking normally with normal ketone levels. Any T2DM patient on an SGLT-2 inhibitor presenting with nausea, vomiting, or malaise should have serum or urine ketones measured regardless of glucose level.13
Fournier gangrene (necrotizing fasciitis of the perineum and genitalia) is a rare but life-threatening infection associated with SGLT-2 inhibitor use. The FDA issued a warning in 2018 after identifying 12 cases in the first 5 years of class availability, with subsequent post-marketing data confirming a class effect, though absolute risk remains very low (estimated at approximately 1 per 10,000 patient-years). The proposed mechanism is that glucosuria in the perineal area creates a nutrient-rich environment for polymicrobial bacterial growth. Clinicians should educate patients to report any perineal pain, swelling, or erythema immediately; SGLT-2 inhibitors should be discontinued in any patient presenting with suspected Fournier gangrene and immediate surgical consultation obtained, as mortality without early surgical debridement is high.14
Genital mycotic infections are the most common adverse effect of SGLT-2 inhibitors, occurring in approximately 6 to 14% of women and 3 to 5% of men in clinical trials, compared with 1 to 3% with placebo. The mechanism is glucosuria creating a favorable environment for Candida species growth in the genital area. Most infections are vulvovaginal candidiasis in women or balanitis in uncircumcised men, are mild to moderate in severity, respond to standard topical or oral antifungal treatment, and do not require drug discontinuation unless recurrent or severe. Urinary tract infections occur with a modest increase in frequency with SGLT-2 inhibitors, though the cardiovascular outcome trial (CVOT) data show that the absolute increase in urinary tract infections is small and that the reduction in pyelonephritis observed in some trials may partially offset this risk. Volume depletion from osmotic diuresis is most clinically significant in elderly patients, those on loop diuretics or renin-angiotensin-aldosterone system (RAAS) blockers, and those with baseline low blood pressure; initiation in these patients should be at lower doses with blood pressure monitoring and dose adjustment of concurrent diuretics.1
The canagliflozin-specific amputation risk identified in the Canagliflozin Cardiovascular Assessment Study (CANVAS) program (hazard ratio 1.97 for lower extremity amputation) has generated significant clinical concern, though subsequent analyses have not consistently replicated this signal across all canagliflozin trials or across the broader SGLT-2 inhibitor class. The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial in diabetic kidney disease (DKD) patients showed no significant amputation excess with canagliflozin. A 2019 meta-analysis of all SGLT-2 inhibitor trials found no class-wide amputation signal. Current clinical guidance recommends that canagliflozin be used with caution in patients with peripheral arterial disease, prior amputation, active foot ulcers, or neuropathy, and that lower extremity circulation be monitored periodically in patients on canagliflozin. Canagliflozin’s bone fracture signal from CANVAS, attributed to possible effects on bone metabolism through sodium-glucose cotransporter 1 (SGLT-1) inhibition in osteoclasts and possible effects on calcium and phosphate handling, has also not been consistently replicated. The fracture risk should be considered when selecting among agents in patients with established osteoporosis or fracture history.3
The American Diabetes Association (ADA) comorbidity-driven prescribing framework positions SGLT-2 inhibitors as the preferred second agent (after metformin in most patients without contraindications) in T2DM patients with established heart failure, chronic kidney disease (CKD) with albuminuria, or atherosclerotic cardiovascular disease (ASCVD) where weight reduction and blood pressure reduction are priorities. When both ASCVD and heart failure are present, combining a glucagon-like peptide-1 (GLP-1) receptor agonist (for atherosclerotic protection) with an SGLT-2 inhibitor (for heart failure protection) is appropriate and the two classes are pharmacodynamically complementary. SGLT-2 inhibitors should not be combined with each other. They can be combined with metformin, sulfonylureas (with attention to hypoglycemia risk from the sulfonylurea), dipeptidyl peptidase-4 (DPP-4) inhibitors (noting no additional HbA1c benefit when combined with GLP-1R agonists), insulin (with ~20% insulin dose reduction at initiation to reduce hypoglycemia risk), and GLP-1R agonists. Subgroup analyses from the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure trial (DAPA-HF) and the Empagliflozin Outcome in Patients with Chronic Heart Failure (EMPEROR) trials confirm that SGLT-2 inhibitors maintain their heart failure benefits in patients already receiving guideline-directed medical therapy including sacubitril/valsartan, beta-blockers, and RAAS blockade.15
Stop all SGLT-2 inhibitors 3 to 4 days before any major elective surgery. Do not rely on normal preoperative glucose to exclude euglycemic DKA risk. Before resuming post-operatively, confirm: patient is eating and drinking normally, no nausea or vomiting, ketones negative, no ongoing infection. Resume only after all criteria met. For emergency surgery, check ketones in any patient on an SGLT-2 inhibitor regardless of plasma glucose level.
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