Note: Hypovolemia, if present, should be corrected prior to initiating treatment. May require a gradual dose reduction of insulin and/or insulin secretagogues (sulfonylureas, meglitinides) to avoid hypoglycemia (Ref).
Chronic kidney disease (adjunctive agent) (off-label use):
Note: May be used as a secondary agent in patients with persistently elevated urinary albumin excretion (urine albumin-to-creatinine ratio >300 mg/g) who are receiving other first-line therapies. Benefits were consistently demonstrated in patients with or without diabetes mellitus (Ref).
Oral: 10 mg once daily (Ref).
Diabetes mellitus, type 2, treatment:
Note: May be used as an adjunctive agent or alternative monotherapy for patients in whom initial therapy with lifestyle intervention and metformin failed or those who cannot take metformin. May be preferred in patients with atherosclerotic cardiovascular disease (ASCVD), heart failure, or diabetic kidney disease given demonstrated cardiovascular and renal benefits (Ref).
Hyperglycemia: Oral: Initial: 10 mg once daily; may increase to 25 mg once daily after 4 to 12 weeks if needed to achieve glycemic goals (Ref).
Atherosclerotic cardiovascular disease: Note: In patients with type 2 diabetes mellitus and established ASCVD, empagliflozin is approved to reduce the risk of major adverse cardiovascular events and cardiovascular death and has been shown (off label) to reduce the risk of heart failure hospitalization in these patients (Ref).
Oral: 10 or 25 mg once daily (Ref).
Diabetic kidney disease (off-label use): Oral: 10 mg once daily in patients with urinary albumin excretion >300 mg/day; it is unknown if higher doses result in better kidney protection.
Note: Some experts also use this regimen in patients without severely increased albuminuria (eg, urinary albumin excretion ≤300 mg/day); benefits and harms may be more closely balanced due to smaller absolute benefit (Ref). Because SGLT2 inhibitors have less glycemic benefit as eGFR declines, another agent may be needed to achieve glycemic goals (Ref).
Heart failure: Oral: 10 mg once daily (Ref).
Note: In patients with type 2 diabetes mellitus and heart failure, empagliflozin has been shown to reduce the risk of hospitalization for heart failure (Ref).
Heart failure:
Note: Should be considered for use in combination with other evidence-based medical therapies as part of an optimal medical regimen for heart failure (Ref). Benefits were consistently demonstrated in patients with or without type 2 diabetes, regardless of ejection fraction (Ref).
Oral: 10 mg once daily.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Altered kidney function:
eGFR ≥30 mL/minute/1.73 m2: No dosage adjustment necessary (Ref).
eGFR <30 mL/minute/1.73 m2:
Chronic kidney disease (off-label use): No dosage adjustment necessary for eGFR ≥20 mL/minute/1.73 m2; therapy was not initiated in patients with an eGFR <20 mL/minute/1.73 m2 (Ref).
Diabetes mellitus, type 2, treatment:
The US manufacturer does not recommend use for glycemic control; however, in patients previously established on empagliflozin, some experts continue use off label at a dose of 10 mg once daily as a treatment for diabetic kidney disease; renal and heart failure benefits have been shown in patients with an eGFR ≥20 mL/minute/1.73 m2 (Ref).
Heart failure: Benefits of 10 mg once daily have been shown in patients with an eGFR ≥20 mL/minute/1.73 m2 (Ref).
Hemodialysis, intermittent (thrice weekly): Use is contraindicated (Ref).
Peritoneal dialysis: Use is contraindicated (Ref).
CRRT: Avoid use (Ref).
PIRRT (eg, sustained, low-efficiency diafiltration): Avoid use (Ref).
No dosage adjustment necessary. Systemic exposure is increased in hepatic impairment, but changes are not considered clinically significant (Ref).
Refer to adult dosing.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Jardiance: 10 mg, 25 mg
No
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Jardiance: 10 mg, 25 mg
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Jardiance: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/204629s033lbl.pdf#page=40
Oral: Administer once daily in the morning, with or without food.
Surgical procedures: Consider temporary discontinuation of therapy at least 3 days prior to surgery; ensure risk factors for ketoacidosis are resolved prior to reinitiating therapy.
Diabetes mellitus, type 2, treatment: As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus; risk reduction of cardiovascular mortality in adults with type 2 diabetes mellitus and established cardiovascular disease.
Heart failure: Risk reduction of cardiovascular mortality and hospitalization for heart failure in adults with heart failure.
Chronic kidney disease
Cases of acute kidney injury (AKI) have been reported in patients receiving sodium-glucose cotransporter 2 (SGLT2) inhibitors (specifically canagliflozin and dapagliflozin), including cases that have required hospitalization and dialysis (Ref). In addition, cases of AKI (including acute interstitial nephritis [Ryan 2020]), acute renal failure, and increased serum creatinine have been noted with some patients receiving empagliflozin, although less often than what was seen with placebo (Ref); further analysis of this showed an early decreased estimated GFR (eGFR) (empagliflozin 10 mg: -0.62 mL/minute/1.73 m2 per week; empagliflozin 25 mg: -0.82 mL/minute/1.73 m2 per week; placebo: +0.01 mL/minute/1.73 m2 per week [p<0.001 for both comparisons with placebo]) which tended to stabilize after ~4 weeks and an overall reduction in adverse kidney outcomes (eg, initiation of renal replacement therapy, doubling of serum creatinine with eGFR ≤45 mL/minute/1.73 m2, progression to macroalbuminuria, death from kidney disease) (Ref). As evidence mounts for the positive effects of these agents on long-term kidney outcomes and a possible reduction in the incidence of AKI with empagliflozin specifically, clinicians will need to weigh the potential risk of AKI with the overall benefit of these agents (Ref).
Mechanism: Dose-related; related to the pharmacologic action. SGLT2 inhibition causes increased excretion of glucose and sodium, thereby resulting in an osmotic diuresis; the subsequent hyperosmolarity and volume contraction may increase the risk of AKI. Glucose in the urine may be reabsorbed by glucose transporters in exchange for uric acid, resulting in uricosuria and associated crystal-dependent and -independent damage. Lastly, SGLT2 inhibition results in increased fructose generation; the metabolism of fructose may lead to increased uric acid, oxidative stress, and the release of chemokines, thus causing local tubular injury and inflammation (Ref).
On the other hand, empagliflozin may confer some protection against AKI. Proposed mechanisms based on animal studies regarding the beneficial effects of SGLT2 inhibition on AKI include improved kidney cortical oxygen tension, tubular cell integrity, and tubular albumin reabsorption (Ref); in addition, improved cardiac function may be related to improved kidney function (Ref).
Onset: Varied. With regard to decreases in eGFR, in the EMPA-REG OUTCOME study, administration of empagliflozin caused early decline in eGFR which tended to stabilize after ~4 weeks (Ref).
Risk factors:
• Preexisting risk factors for AKI (eg, hypovolemia, chronic kidney insufficiency, heart failure, use of concomitant medications [eg, diuretics, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs]).
An increased incidence of bone fractures has been observed with other sodium-glucose cotransporter 2 (SGLT2) inhibitors in some clinical trials. However, meta-analyses of trial data for empagliflozin have not demonstrated increased risk of fracture (Ref).
Hypersensitivity reactions, including angioedema, asthma, urticaria, and skin rash, have been reported in patients receiving sodium-glucose cotransporter 2 (SGLT2) inhibitors (Ref).
Mechanism: Multiple potential mechanisms
Non–dose-related; immunologic: IgE-mediated or direct mast cell stimulation (Ref)
Dose-related; related to the pharmacologic action: Elevated levels of bradykinin (Ref)
Onset: Varied; generally occurs hours to days after treatment initiation. In a review of postmarketing data, time to onset was within 1 month (Ref).
Risk factors:
• Prior serious hypersensitivity reaction to empagliflozin
• Cross-reactivity:Although other SGLT2 have also been associated with hypersensitivity reactions, there are no reports of cross-reactions between these agents
Sodium-glucose cotransporter 2 (SGLT2) inhibitors may cause events consistent with hypovolemia, including symptomatic hypotension, syncope, and dehydration (Ref). Overall, a reduction in both systolic and diastolic blood pressure (-4 to -6/-1 to -2 mm Hg) has been documented for SGLT2 inhibitors (Ref).
Mechanism: Dose-related; related to the pharmacologic action. Inhibition of SGLT2 causes an increase in the excretion of glucose and sodium, thereby resulting in an osmotic diuresis and intravascular volume contraction (Ref).
Onset: Varied; timing is impacted by volume status (eg, reduced oral intake, fluid losses) and concomitant use of medications known to impact volume status or blood pressure (eg, diuretics, angiotensin-converting enzyme [ACE] inhibitors, angiotensin receptor blockers [ARBs]) (Ref).
Risk factors:
• Kidney impairment (ie, eGFR <60 mL/minute/1.73 m2)
• Older adults
• Concomitant use of antihypertensives (eg, diuretics, ACE inhibitors, ARBs)
• Preexisting low systolic blood pressure
• Reduced oral intake or increased fluid losses
Sodium-glucose cotransporter 2 (SGLT2) inhibitors, including empagliflozin, have been associated with an increased risk of genitourinary fungal infection (eg, vulvovaginal mycotic infection, vulvovaginal candidiasis, vulvovaginitis, candida balanitis, balanoposthitis) and, to a lesser extent, urinary tract infections, including severe cases of urinary tract infection with sepsis and pyelonephritis requiring hospitalization (Ref). These events are generally mild in intensity, respond to treatment, and do not lead to discontinuation (Ref). Additionally, rare but serious and potentially fatal cases of necrotizing fasciitis (perineum) (ie, Fournier gangrene) have been reported (Ref).
Mechanism: Dose-related; related to the pharmacologic action. Patients with diabetes are more prone to urinary tract and genital infections, potentially due to glucosuria-induced bacterial growth, increased adherence of bacteria to the uroepithelium, and altered immune function (Ref). Because SGLT2 inhibitors increase urinary excretion of glucose, it has been hypothesized that these agents further increase the risk of these infections (Ref).
Onset: Varied; available literature suggests that the increased risk of genital infection may be apparent within the first month of SGLT2 inhibitor therapy and remain elevated throughout the course of therapy (Ref); Fournier gangrene may have an average onset of 9 months (range: 5 days to 49 months) (Ref).
Risk factors:
• Diabetes and/or uncontrolled hyperglycemia (Ref)
• Older adults
• Prior history of these types of infections
• Uncircumcised males (increased risk for genital infections) (Ref)
Cases of ketoacidosis have been reported in patients with type 1 and type 2 diabetes mellitus receiving sodium-glucose cotransporter 2 (SGLT2) inhibitors, including empagliflozin (Ref).
In some cases, patients have presented with normal or only modestly elevated blood glucose (<250 mg/dL), which can lead to misdiagnosis, prevent timely initiation of treatment, and negatively influence duration of illness (Ref). In addition, SGLT2 inhibitor-mediated increases in urinary glucose loss may persist for several days after discontinuation which may impact duration of illness in patients who develop ketoacidosis (Ref).
Mechanism: Dose-related; related to the pharmacologic action. Several mechanisms have been proposed centered on increased ketone body production and reabsorption. Because SGLT2 inhibitors decrease urinary excretion of ketone bodies and decrease blood glucose in an insulin-independent manner, plasma glucose and urine ketone concentrations may be lower than what is typically expected in classic presentations of diabetic ketoacidosis (Ref).
Onset: Varied; timing is often impacted by the onset of metabolically stressful events (eg, surgery, extensive exercise, myocardial infarction, stroke, severe infections, prolonged fasting) (Ref).
Risk factors:
• Patients with diabetes who are insulin deficient (eg, latent autoimmune diabetes in adults, type 1 diabetes, or some patients with long-standing type 2 diabetes) (Ref)
• Metabolically stressful events (eg, surgery, extensive exercise, myocardial infarction, stroke, severe infections, prolonged fasting) (Ref)
• Presence of other risk factors that may predispose a patient to ketoacidosis (eg, pancreatic insulin deficiency, dose decreases of insulin, caloric restriction, alcohol abuse, acute febrile illness, surgery, or any other extreme stress event)
There are conflicting data involving the risk of lower limb amputations with sodium-glucose cotransporter 2 (SGLT2) inhibitor therapy; canagliflozin, specifically, has been of concern (Ref). Canagliflozin was associated with almost a twofold increased risk of lower limb amputations compared to placebo in the CANVAS and CANVAS-R trials, which included patients with type 2 diabetes at high cardiovascular risk (Ref). Trials involving empagliflozin have not consistently shown an increased risk of lower limb amputation associated with its use (Ref).
Mechanism: Not clearly established (Ref).
Onset: Varied; timing is often impacted by the onset of metabolically stressful events (eg, surgery, extensive exercise, myocardial infarction, stroke, severe infections, prolonged fasting) (Ref).
Risk factors:
• Preexisting risk factors for amputation (eg, prior amputation, peripheral vascular disease, neuropathy, diabetic foot ulcers, cardiovascular disease) (Ref)
• Age ≥65 years (Ref)
• Lack of preventative foot care
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adults.
1% to 10%:
Endocrine & metabolic: Dyslipidemia (4%), increased thirst (2%)
Gastrointestinal: Nausea (2%)
Genitourinary: Genitourinary fungal infection (2% to 6%) (table 1), increased urine output (3%), urinary tract infection (8% to 9%; incidence higher in females) (table 2)
|
Drug (Empagliflozin) |
Placebo |
Population |
Dose |
Number of Patients (Empagliflozin) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|
|
6% |
2% |
Females |
25 mg once daily |
420 |
481 |
|
5% |
2% |
Females |
10 mg once daily |
443 |
481 |
|
3% |
0.4% |
Males |
10 mg once daily |
556 |
514 |
|
2% |
0.4% |
Males |
25 mg once daily |
557 |
514 |
|
Drug (Empagliflozin) |
Placebo |
Dose |
Number of Patients (Empagliflozin) |
Number of Patients (Placebo) |
|---|---|---|---|---|
|
9% |
8% |
10 mg once daily |
999 |
995 |
|
8% |
8% |
25 mg once daily |
977 |
995 |
Hematologic & oncologic: Increased hematocrit (3% to 4%)
<1%: Genitourinary: Phimosis
Postmarketing:
Dermatologic: Skin rash (EMA 2017), urticaria (EMA 2017)
Endocrine & metabolic: Hypovolemia (higher incidence in older patients) (Kohler 2017), ketoacidosis (patients may be euglycemic; without concomitant insulin) (FDA 2015; Handelsman [AACE/ADA 2016]; Rosenstock 2018; Zinman 2015)
Gastrointestinal: Acute pancreatitis (Dziadokwiec 2021, Zeidan 2020), constipation
Genitourinary: Urinary tract infection with sepsis (Fisher 2020)
Hypersensitivity: Angioedema (EMA 2017), hypersensitivity angiitis (To 2018)
Infection: Necrotizing fasciitis (perineum) (Bersoff-Match 2019; FDA 2018)
Renal: Acute interstitial nephritis (Ryan 2020), acute kidney injury (Wanner 2016; Zinman 2015), decreased estimated GFR (eGFR) (occurring early after initiation) (Wanner 2016), increased serum creatinine (Wanner 2016), pyelonephritis (Kohler 2016; Kufel 2017)
Respiratory: Asthma (DeFronzo 2018)
History of serious hypersensitivity to empagliflozin or any component of the formulation; patients on dialysis.
Canadian labeling: Additional contraindications (not in US labeling): Severe renal impairment (eGFR <20 mL/minute/1.73 m2); end-stage renal disease.
Concerns related to adverse effects:
• Bone fractures: An increased incidence of bone fractures has been observed with other SGLT2 inhibitors in some clinical trials. However, meta-analyses of trial data for empagliflozin have not demonstrated increased risk of fracture (Ruanpeng 2017; Tang 2016).
• Lower limb amputation: There is conflicting data involving the risk of lower limb amputations with SGLT2 inhibitor therapy. Canagliflozin was associated with almost a 2-fold increased risk of lower limb amputations compared to placebo in the CANVAS and CANVAS-R trials, which included patients with type 2 diabetes at high cardiovascular risk (Neal 2017). Trials involving empagliflozin have not consistently shown an increased risk of lower limb amputation associated with its use (Inzucchi 2018; Khouri 2018). The following FDA guidance (developed specifically for canagliflozin) may reasonably apply to use of other SGLT2 inhibitors: Prior to initiation consider risk factors for amputation including prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers. Counsel patients about the importance of preventative foot care. Discontinue therapy if any of the following occur: signs and symptoms of new infection (including osteomyelitis), new pain or tenderness, or sores/ulcers involving the lower limbs (FDA 2017).
Disease-related concerns:
• Bariatric surgery:
– Altered absorption: Absorption may be altered given the anatomic and transit changes created by gastric bypass and sleeve gastrectomy surgery (Mechanick 2020; Melissas 2013).
– Dehydration: Evaluate, correct, and maintain postsurgical fluid requirements and volume status prior to initiating therapy, and closely monitor the patient for the duration of therapy; acute and chronic kidney failure exacerbation may occur. A majority of cases occurred in patients with nausea, vomiting, diarrhea, and/or dehydration. Nausea is common and fluid intake may be more difficult after gastric bypass, sleeve gastrectomy, and gastric band (Mechanick 2020).
– Euglycemic diabetic ketoacidosis: Discontinue therapy 3 to 5 days prior to surgery (Bobart 2016). Postoperatively, assess volume status, caloric intake, and need for diabetes treatment and withhold antidiabetic medication if type 2 diabetes is in remission. Ketoacidosis has been reported in patients with type 1 and type 2 diabetes on SGLT2 inhibitors. In some cases, normal or only modestly elevated blood glucose was present (<250 mg/dL) (van Niekerk 2018). Risk factors include significant reduction in insulin, caloric restriction, stress of surgery, and infection.
Special populations:
• Older adults: Risk of intravascular volume depletion may be increased in patients ≥75 years of age.
Other warnings/precautions:
• Appropriate use: Not for use in patients with diabetic ketoacidosis or patients with type 1 diabetes mellitus.
• Hospitalized patients: Use of SGLT2 inhibitors is not routinely recommended for hospitalized patients (ADA 2021).
• Surgical procedures: Consider temporary discontinuation of therapy at least 3 days prior to surgery; ensure risk factors for ketoacidosis are resolved prior to reinitiating therapy.
Substrate of BCRP/ABCG2, OAT1/3, OATP1B1/1B3 (SLCO1B1/1B3), P-glycoprotein/ABCB1 (minor), UGT1A3, UGT1A8, UGT1A9, UGT2B7; Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Alpha-Lipoic Acid: May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Androgens: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Beta-Blockers (Beta1 Selective): May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Beta-Blockers (Nonselective): May enhance the hypoglycemic effect of Antidiabetic Agents. Beta-Blockers (Nonselective) may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Bortezomib: May enhance the therapeutic effect of Antidiabetic Agents. Bortezomib may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Direct Acting Antiviral Agents (HCV): May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Etilefrine: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Guanethidine: May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Hyperglycemia-Associated Agents: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Hypoglycemia-Associated Agents: Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Risk C: Monitor therapy
Insulins: Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors may enhance the hypoglycemic effect of Insulins. Management: Consider a decrease in insulin dose when initiating therapy with a sodium-glucose cotransporter 2 inhibitor and monitor patients for hypoglycemia. Risk D: Consider therapy modification
Lithium: Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors may decrease the serum concentration of Lithium. Risk C: Monitor therapy
Loop Diuretics: Empagliflozin may enhance the hypotensive effect of Loop Diuretics. Risk C: Monitor therapy
Maitake: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Monoamine Oxidase Inhibitors: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Pegvisomant: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Prothionamide: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Quinolones: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Quinolones may diminish the therapeutic effect of Agents with Blood Glucose Lowering Effects. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use. Risk C: Monitor therapy
Ritodrine: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Salicylates: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Selective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Sulfonylureas: Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors may enhance the hypoglycemic effect of Sulfonylureas. Management: Consider a decrease in sulfonylurea dose when initiating therapy with a sodium-glucose cotransporter 2 inhibitor and monitor patients for hypoglycemia. Risk D: Consider therapy modification
Thiazide and Thiazide-Like Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Sodium-glucose cotransporter 2 (SGLT2) inhibitors are not recommended for patients with type 2 diabetes mellitus planning to become pregnant. Patients who could become pregnant should use effective contraception during therapy. Transition to a preferred therapy should be initiated prior to conception and contraception should be continued until glycemic control is achieved (ADA 2021; Alexopoulos 2019; Egan 2020)
Information related to the use of empagliflozin in pregnancy is limited (Formoso 2018). Due to adverse effects on renal development observed in animal studies, the manufacturer does not recommend use of empagliflozin during the second and third trimesters of pregnancy.
Poorly controlled diabetes during pregnancy can be associated with an increased risk of adverse maternal and fetal outcomes, including diabetic ketoacidosis, preeclampsia, spontaneous abortion, preterm delivery, delivery complications, major malformations, stillbirth, and macrosomia. To prevent adverse outcomes, prior to conception and throughout pregnancy, maternal blood glucose and HbA1c should be kept as close to target goals as possible but without causing significant hypoglycemia (ADA 2021; Blumer 2013).
Agents other than empagliflozin are currently recommended to treat diabetes mellitus in pregnancy (ADA 2021).
It is not known if empagliflozin is present in breast milk.
Due to the potential for serious adverse reactions in the breastfeeding infant, breastfeeding is not recommended by the manufacturer.
Individualized medical nutrition therapy (MNT) based on ADA recommendations is an integral part of therapy
Blood glucose; renal function (baseline and periodically during treatment); volume status (eg, BP, hematocrit, electrolytes); monitor for genital mycotic infections and UTI; assess patients presenting with fever or malaise along with genital or perianal pain, tenderness, erythema, or swelling for necrotizing fasciitis; BP; if signs/symptoms of ketoacidosis (eg, nausea/vomiting, abdominal pain, malaise, shortness of breath), confirm diagnosis by direct measurement of blood ketones and arterial pH (measurement of serum bicarbonate or urinary ketones may not be adequate) (AACE [Handelsman 2016]).
In patients with diabetes mellitus: HbA1c: Monitor at least twice yearly in patients who have stable glycemic control and are meeting treatment goals; monitor quarterly in patients in whom treatment goals have not been met, or with therapy change. Note: In patients prone to glycemic variability (eg, patients with insulin deficiency), or in patients whose HbA1c is discordant with serum glucose levels or symptoms, consider evaluating HbA1c in combination with blood glucose levels and/or a glucose management indicator (ADA 2021; KDIGO 2020).
Recommendations for glycemic control in patients with diabetes:
Nonpregnant adults (ADA 2021):
HbA1c: <7% (a more aggressive [<6.5%] or less aggressive [<8%] HbA1c goal may be targeted based on patient-specific characteristics). Note: In patients using a continuous glucose monitoring system, a goal of time in range >70% with time below range <4% is recommended and is similar to a goal HbA1c <7%.
Preprandial capillary blood glucose: 80 to 130 mg/dL (more or less stringent goals may be appropriate based on patient-specific characteristics).
Peak postprandial capillary blood glucose (~1 to 2 hours after a meal): <180 mg/dL (more or less stringent goals may be appropriate based on patient-specific characteristics).
Older adults (≥65 years of age) (ADA 2021):
Note: Consider less strict targets in patients who are using insulin and/or insulin secretagogues (sulfonylureas, meglitinides) (ES [LeRoith 2019]).
HbA1c: <7% to 7.5% (healthy); <8% to 8.5% (complex/intermediate health). Note: Individualization may be appropriate based on patient and caregiver preferences and/or presence of cognitive impairment. In patients with very complex or poor health (ie, limited remaining life expectancy), consider making therapy decisions based on avoidance of hypoglycemia and symptomatic hyperglycemia rather than HbA1c level.
Preprandial capillary blood glucose: 80 to 130 mg/dL (healthy); 90 to 150 mg/dL (complex/intermediate health); 100 to 180 mg/dL (very complex/poor health).
Bedtime capillary blood glucose: 80 to 180 mg/dL (healthy); 100 to 180 mg/dL (complex/intermediate health); 110 to 200 mg/dL (very complex/poor health).
Classification of hypoglycemia (ADA 2021):
Level 1: 54 to 70 mg/dL; hypoglycemia alert value; initiate fast-acting carbohydrate (eg, glucose) treatment.
Level 2: <54 mg/dL; threshold for neuroglycopenic symptoms; requires immediate action.
Level 3: Hypoglycemia associated with a severe event characterized by altered mental and/or physical status requiring assistance.
By inhibiting sodium-glucose cotransporter 2 (SGLT2) in the proximal renal tubules, empagliflozin reduces reabsorption of filtered glucose from the tubular lumen and lowers the renal threshold for glucose (RTG). SGLT2 is the main site of filtered glucose reabsorption; reduction of filtered glucose reabsorption and lowering of RTG result in increased urinary excretion of glucose, thereby reducing plasma glucose concentrations. Empagliflozin also reduces sodium reabsorption and increases the delivery of sodium to the distal tubule, which may lower both pre- and afterload of the heart and downregulate sympathetic activity.
Duration: Following discontinuation, urinary glucose excretion returns to baseline within ~3 days for the 10 mg and 25 mg doses.
Distribution: Vd: 73.8 L.
Protein binding: 86.2%.
Metabolism: Primarily through glucuronidation by UGT2B7, UGT1A3, UGT1A8, and UGT1A9 to minor metabolites.
Half-life Elimination: 12.4 hours.
Time to Peak: 1.5 hours.
Excretion: Urine (54.4%; 50% as unchanged drug); feces (41.2%; majority as unchanged drug).
Altered kidney function: Clearance is decreased and AUC is increased in patients with impaired renal function. In mild, moderate, and severe renal impairment and in end-stage renal disease (ESRD), AUC increased approximately 18%, 20%, 66%, and 48% respectively.
Hepatic function impairment: In patients with mild, moderate, and severe hepatic impairment, AUC increased by approximately 23%, 47%, and 75%, and Cmax increased by approximately 4%, 23%, and 48%, respectively.
Tablets (Jardiance Oral)
10 mg (per each): $22.82
25 mg (per each): $22.82
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