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 (AACE/ACE [Garber 2020]).
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 who cannot take metformin. In patients with established atherosclerotic cardiovascular disease, use has been associated with a reduced risk of hospitalization for heart failure (ADA 2021; Cannon 2020).
Oral: Initial: 5 mg once daily; may increase to 15 mg once daily after 4 to 12 weeks if needed to achieve glycemic goals (maximum: 15 mg/day) (DeSantis 2021; manufacturer’s labeling).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
eGFR ≥45 mL/minute/1.73 m2: No dosage adjustment necessary.
eGFR <45 mL/minute/1.73 m2: Use is not recommended.
Patients on dialysis: Use is contraindicated.
Mild or moderate impairment (Child-Pugh class A or B): No dosage adjustment necessary.
Severe impairment (Child-Pugh class C): Use is not recommended (has not been studied).
Refer to adult dosing.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Steglatro: 5 mg, 15 mg
No
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Tablet, Oral:
Steglatro: 5 mg [DSC], 15 mg [DSC]
An FDA-approved medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Steglatro: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/209803s006lbl.pdf#page=25
Oral: Administer in the morning without regard to meals.
Diabetes mellitus, type 2, treatment: As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
Steglatro may be confused with Spravato
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Reported incidences are for adults and may include ertugliflozin used as add on therapy.
>10%:
Genitourinary: Urinary tract infections (12%)
Infection: Genitourinary fungal infection (females: 9% to 12%; males: 4%)
1% to 10%:
Endocrine & metabolic: Hypoglycemia (3%; severe hypoglycemia: 1%), hypovolemia (2% to 4%), increased thirst (1% to 3%), weight loss (2%)
Genitourinary: Increased urine output (2% to 3%), vulvovaginal pruritus (2% to 3%)
Nervous system: Headache (3% to 4%)
Neuromuscular & skeletal: Back pain (3%)
Respiratory: Nasopharyngitis (3%)
<1%:
Endocrine & metabolic: Ketoacidosis
Genitourinary: Phimosis
Hematologic & oncologic: Increased hemoglobin
Frequency not defined:
Endocrine & metabolic: Increased LDL cholesterol, increased serum phosphate
Genitourinary: Decreased estimated GFR (eGFR)
Renal: Increased serum creatinine
Postmarketing:
Genitourinary: Urinary tract infection with sepsis
Hypersensitivity: Angioedema
Infection: Necrotizing fasciitis (Fournier’s gangrene)
Renal: Acute kidney injury, pyelonephritis
History of serious hypersensitivity reaction to ertugliflozin or any component of the formulation; patients on dialysis.
Concerns related to adverse effects:
• Bone fractures: An increased incidence of bone fractures has been observed with other sodium-glucose cotransporter 2 (SGLT2) inhibitors in some clinical trials. A placebo-controlled trial with ertugliflozin conducted over 2 years did not demonstrate an increased fracture risk; similar changes in bone mineral density (BMD) were observed between groups, except at the hip where a greater decrease in BMD was observed with ertugliflozin (Gallo 2019).
• Genital mycotic infections: 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.
• Hypotension: May cause symptomatic hypotension due to intravascular volume depletion especially in patients with renal impairment (ie, eGFR <60 mL/minute/1.73 m2), elderly, patients on other antihypertensives (eg, diuretics, ACE inhibitors, or 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.
• Ketoacidosis: Cases of ketoacidosis (some fatal) have been reported in patients with type 1 and type 2 diabetes mellitus receiving SGLT2 inhibitors; in some cases, patients have presented with normal or only modestly elevated blood glucose (<250 mg/dL). Before initiating treatment, consider risk factors that may predispose to ketoacidosis (eg, pancreatic insulin deficiency, dose decreases of insulin, caloric restriction, alcohol abuse, acute febrile illness, surgery, any other extreme stress event). Consider temporary discontinuation of therapy ≥4 days prior to surgery or any event that may precipitate ketoacidosis; ensure risk factors are resolved prior to reinitiating therapy. Patients presenting with nausea/vomiting, abdominal pain, generalized malaise, and/or shortness of breath should be assessed immediately for ketoacidosis; discontinue therapy and treat promptly if ketoacidosis is suspected.
• 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). Similar long-term analyses with ertugliflozin have not yet been published; the observed incidence in the initial clinical trials was ≤0.5% over 26 weeks. 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.
• Necrotizing fasciitis: Cases of necrotizing fasciitis of the perineum (Fournier gangrene), a rare but serious and potentially fatal infection, have been reported in patients receiving SGLT2 inhibitors. Assess patients presenting with fever or malaise along with genital or perianal pain, tenderness, erythema, or swelling for necrotizing fasciitis. Discontinue in patients who develop necrotizing fasciitis and initiate treatment immediately.
• Renal effects: 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, 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. Assess renal function prior to initiation and periodically during treatment.
• Urinary tract infection: Serious urinary infections, including urosepsis and pyelonephritis, requiring hospitalization have been reported; treatment with SGLT2 inhibitors increases the risk for urinary tract infections (UTI); monitor for signs and symptoms of UTI and treat as needed.
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; volume depletion and related adverse events (eg, hypotension, orthostatic hypotension, syncope) have occurred. 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.
• Hepatic impairment: Not recommended for use in severe hepatic impairment (has not been studied).
• Renal impairment: Glycemic efficacy may be decreased in renal impairment. Assess renal function prior to initiation and periodically during treatment. Use is not recommended when eGFR is persistently <45 mL/minute/1.73 m2 due to lack of efficacy, and use is contraindicated in patients on dialysis.
Special populations:
• Older adult: Elderly patients may be predisposed to symptoms related to intravascular volume depletion (eg, hypotension, orthostatic hypotension, dizziness, syncope, dehydration) and renal impairment or failure.
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 ≥4 days prior to surgery; ensure risk factors for ketoacidosis are resolved prior to reinitiating therapy.
Substrate of BCRP/ABCG2, P-glycoprotein/ABCB1 (minor), 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
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)
Due to adverse effects on renal development observed in animal studies, the manufacturer does not recommend use of ertugliflozin 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 ertugliflozin are currently recommended to treat diabetes mellitus in pregnancy (ADA 2021).
It is not known if ertugliflozin is present in breast milk.
Due to the potential for adverse events in the breastfeeding infant, breastfeeding is not recommended by the manufacturer.
Individualized medical nutrition therapy (MNT) based on American Diabetes Association (ADA) recommendations is an integral part of therapy.
Blood glucose; renal function (baseline and periodically during treatment); volume status (eg, BP, hematocrit, electrolytes); genital mycotic infections and urinary tract infection; hypersensitivity reactions; blood pressure; lower limb and feet (sores, ulcers, infection); 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]).
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, ertugliflozin 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.
Distribution: Vdss: 85.5 L
Protein binding: 93.6%
Metabolism: Primarily by UGT1A9 and UGT2B7-mediated O-glucuronidation to metabolites that are inactive at clinically relevant concentrations; CYP-mediated metabolism is minimal
Bioavailability: ~100%
Half-life elimination: 16.6 hours
Time to peak (plasma): 1 hour (fasting); 2 hours (administered with high-fat, high-calorie meal)
Excretion: Urine (50.2%; 1.5% as unchanged drug); feces (40.9%; 33.8% as unchanged drug)
Tablets (Steglatro Oral)
5 mg (per each): $12.98
15 mg (per each): $12.98
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