Empagliflozin

An increased incidence of bone fractures has been observed with other SGLT2 inhibitors in some clinical trials. However, meta-analyses of trial data for canagliflozin, dapagliflozin, and empagliflozin have not demonstrated increased risk of fracture overall (Ruanpeng 2017; Tang 2016).

May increase the risk of genital mycotic infections (eg, vulvovaginal mycotic infection, vulvovaginal candidiasis, vulvovaginitis, candida balanitis, balanoposthitis). Patients with a history of these infections or uncircumcised males are at greater risk.

Hypersensitivity reactions (eg, angioedema, skin, urticaria) have been observed; discontinue promptly if hypersensitivity occurs and treat as indicated. Use is contraindicated in patients with a previous serious hypersensitivity reaction to empagliflozin.

May cause symptomatic hypotension due to intravascular volume depletion especially in patients with renal impairment (ie, eGFR 2), elderly, patients on other antihypertensives (eg, diuretics, ACE inhibitors, angiotensin receptor blockers [ARBs]), or those with low systolic blood pressure. Assess volume status prior to initiation in patients at risk of hypotension and correct if depleted; monitor for signs and symptoms of hypotension after initiation.

Cases of ketoacidosis (some fatal) have been reported in patients with type 1 and type 2 diabetes mellitus receiving sodium-glucose cotransporter 2 (SGLT2) inhibitors; in some cases, patients have presented with normal or only modestly elevated blood glucose (• Lipid abnormality: May cause low-density lipoprotein cholesterol (LDL-C) elevation; monitor LDL-C and treat as needed.

Acute kidney injury has been reported. Prior to initiation, consider risk factors for acute kidney injury (eg, hypovolemia, chronic renal insufficiency, heart failure, use of concomitant medications [eg, diuretics, ACE inhibitors, angiotensin receptor blockers, or NSAIDs]). Temporarily discontinue use with reduced oral intake or fluid losses; discontinue use if acute kidney injury occurs. Additional abnormalities in renal function (decreased eGFR, increased serum creatinine) and adverse effects related to renal function may occur. In the EMPA-REG OUTCOME study, administration of empagliflozin caused early decline in eGFR which tended to stabilize after ~4 weeks (Wanner 2016). Assess renal function prior to initiation and periodically during treatment.

Serious urinary infections including urosepsis and pyelonephritis requiring hospitalization have been reported; treatment with SGLT2 inhibitors increases the risk for urinary tract infection (UTI); monitor for signs and symptoms of UTI and treat as needed. Disease-related concerns:

Glycemic efficacy may be decreased in renal impairment. Assess renal function prior to initiation and periodically during treatment. Use is contraindicated in severe renal impairment (eGFR 2), ESRD, and in dialysis patients. According to the manufacturer, empagliflozin should not be initiated in patients with eGFR 2 and should be discontinued when eGFR is persistently 2. In the EMPA-REG OUTCOME trial, empagliflozin reduced the occurrence of incident or worsening nephropathy (a secondary end-point) in diabetic patients with an eGFR ≥30 mL/minute/1.73 m2 and high cardiovascular risk receiving standard care. Post-hoc analysis suggested that the renal benefits may persist in the subset of patients with baseline renal impairment (eGFR 30 to 2) (Wanner 2016). An additional post-hoc analysis showed consistent cardiovascular mortality benefits across subgroups with eGFR 30 to 2 (Wanner 2018). However, additional trials may be necessary to definitively establish whether empagliflozin improves these outcomes in patients with renal impairment. Concurrent drug therapy issues:

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Special populations:

Risk of intravascular volume depletion, renal impairment, and UTI may be increased in elderly patients. Other warnings/precautions:

Not for use in patients with diabetic ketoacidosis (DKA) or patients with type 1 diabetes mellitus.