AHFS Class:

• Sodium-glucose Cotransporter 2 (SGLT2) Inhibitors 68:20.18

Generic Name(s):

• Ertugliflozin L-pyroglutamic Acid

• Ertugliflozin and Metformin Hydrochloride

• Ertugliflozin and Sitagliptin

Chemical Name:

• (1S,2S,3S,4R,5S)-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol with (2S)-5-oxopyrrolidine-2-carboxylic acid

Molecular Formula:

• C₂₇H₃₂ClNO₁₀

Ertugliflozin L-pyroglutamic acid, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, is an antidiabetic agent.1,11,19

Type 2 Diabetes Mellitus

Ertugliflozin is used as monotherapy as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus.1,2 Ertugliflozin also is used in combination with other antidiabetic agents (e.g., metformin, sitagliptin) as an adjunct to diet and exercise in patients with type 2 diabetes mellitus who have not achieved adequate glycemic control.1,3,4,5,6,7 Ertugliflozin is commercially available in fixed combination with metformin hydrochloride (Segluromet^®) or sitagliptin (Steglujan^®).9,10 The fixed combination of ertugliflozin and metformin hydrochloride is used as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus who are not adequately controlled with ertugliflozin or metformin monotherapy, or in patients who are already receiving therapy with both drugs.9 The fixed combination of ertugliflozin and sitagliptin is used as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus when treatment with both drugs is appropriate.10

Glycemic Control

Current guidelines for the treatment of type 2 diabetes mellitus generally recommend metformin as first-line therapy in addition to lifestyle modifications in patients with recent-onset type 2 diabetes mellitus or mild hyperglycemia because of its well-established safety and efficacy (i.e., beneficial effects on glycosylated hemoglobin [hemoglobin A_1c; HbA_1c], weight, and cardiovascular mortality).698,704,705 (See Uses: Type 2 Diabetes Mellitus, in Metformin 68:20.04.) In patients with contraindications or intolerance to metformin (e.g., risk of lactic acidosis, GI intolerance) or in selected other patients,698 some experts suggest that initial therapy with a drug from another class of antidiabetic agents (e.g., a glucagon-like peptide-1 [GLP-1] receptor agonist, SGLT2 inhibitor, dipeptidyl peptidase-4 [DPP-4] inhibitor, sulfonylurea, thiazolidinedione, basal insulin) may be acceptable based on patient factors.698,704 Initiating antidiabetic therapy with 2 agents (e.g., metformin plus another drug) may be appropriate in patients with an initial HbA_1c exceeding 7.5% or at least 1.5% above the target level.698,704 In metformin-intolerant patients with high initial HbA_1c levels, some experts suggest initiation of therapy with 2 agents from other antidiabetic classes with complementary mechanisms of action.698

Because of the progressive nature of type 2 diabetes mellitus, patients initially receiving an oral antidiabetic agent will eventually require multiple oral and/or injectable noninsulin antidiabetic agents of different therapeutic classes and/or insulin for adequate glycemic control.698,704 Patients who have inadequate glycemic control with initial (e.g., metformin) monotherapy should receive treatment with additional antidiabetic agents; data suggest that the addition of each noninsulin agent to initial therapy lowers HbA_1c by approximately 0.7-1%.704 In addition, early initiation of combination therapy may help to more rapidly attain glycemic goals and extend the time to treatment failure.704

Factors to consider when selecting additional antidiabetic agents for combination therapy in patients with inadequate glycemic control on metformin monotherapy include patient comorbidities (e.g., atherosclerotic cardiovascular disease [ASCVD], established kidney disease, heart failure), hypoglycemia risk, impact on weight, cost, risk of adverse effects, and patient preference.698,699,704,705,706 When the greater glucose-lowering effect of an injectable drug is needed in patients with type 2 diabetes mellitus, some experts currently state that an injectable GLP-1 receptor agonist is preferred over insulin in most patients because of beneficial effects on body weight and a lower risk of hypoglycemia, although adverse GI effects may diminish tolerability.704 While addition of a GLP-1 receptor agonist may successfully control hyperglycemia, many patients will eventually require insulin therapy.698 Early introduction of insulin therapy should be considered when hyperglycemia is severe (e.g., blood glucose of at least 300 mg/dL or HbA_1c exceeding 9-10%), especially in the presence of catabolic manifestations (e.g., weight loss, hypertriglyceridemia, ketosis) or symptoms of hyperglycemia.698,704 For additional information regarding the initiation of insulin therapy in patients with diabetes mellitus, see Uses: Diabetes Mellitus, in the Insulins General Statement 68:20.08.

Patients with type 2 diabetes mellitus who have established (or are at a high risk for) ASCVD, established kidney disease, or heart failure should receive a GLP-1 receptor agonist or SGLT2 inhibitor with demonstrated cardiovascular disease benefit.704,705 (See Reduction in Risk of Major Adverse Cardiovascular Events under Uses: Type 2 Diabetes Mellitus, in Liraglutide 68:20.06 and also see Reduction in Risk of Heart Failure-Related Hospitalization under Uses: Type 2 Diabetes Mellitus, in Dapagliflozin 68:20.18.) Experts state that therapy with a GLP-1 receptor agonist or SGLT2 inhibitor should be considered for patients with the aforementioned comorbidities independently of the patients' HbA_1c.704 GLP-1 receptor agonists and SGLT2 inhibitors appear to have effects on the kidneys independent of their glycemic effects, and some experts suggest that an agent from one of these classes of drugs be considered in patients with type 2 diabetes mellitus and chronic kidney disease (CKD). 698,704,706 (See Beneficial Effects on Renal Function and Cardiovascular Morbidity and Mortality in Diabetic Nephropathy under Uses: Type 2 Diabetes Mellitus, in Canagliflozin 68:20.18.) In patients without established ASCVD or indicators of high ASCVD risk, heart failure, or CKD, the decision regarding the addition of other antidiabetic agents (e.g., GLP-1 receptor agonist, SGLT2 inhibitor, DPP-4 inhibitor, thiazolidinedione, sulfonylurea, basal insulin) to metformin therapy should be based on avoidance of adverse effects, cost, and individual patient factors.704

The manufacturer states that ertugliflozin is not indicated for treatment of type 1 diabetes mellitus or diabetic ketoacidosis.1,9,10

Ertugliflozin Monotherapy

When given as monotherapy for the management of type 2 diabetes mellitus, ertugliflozin improves glycemic control compared with placebo as evidenced by reductions in HbA_1c and in fasting and 2-hour postprandial plasma glucose concentrations.1,2 Efficacy of ertugliflozin as monotherapy has been established in a double-blind, placebo-controlled trial of 26-weeks' duration in approximately 460 patients with type 2 diabetes mellitus and a mean baseline HbA_1c of 8.21%.1,2 Patients were either treatment naive or were not receiving any antidiabetic agents for at least 8 weeks prior to trial screening.1,2 Ertugliflozin (5 or 15 mg once daily) improved glycemic control as evidenced by reductions in HbA_1c and fasting and 2-hour postprandial plasma glucose concentrations.1,2 HbA_1c was reduced by 0.7 or 0.8% in patients receiving ertugliflozin 5 or 15 mg once daily, respectively, compared with a reduction of 0.2% in those receiving placebo.1 In patients who received ertugliflozin 5 or 15 mg, approximately 30 or 39%, respectively, had HbA_1c reductions to less than 7% compared with approximately 17% of patients receiving placebo.1 Patients receiving ertugliflozin 5 or 15 mg once daily also lost substantially more body weight (reduction of 3 or 3.1 kg, respectively) than those receiving placebo (reduction of 1 kg).1

Combination Therapy

When given in combination with one or more oral antidiabetic agents, ertugliflozin improves glycemic control compared with monotherapy with these drugs and generally is associated with reductions in body weight and systolic blood pressure.1,3,4,5,6,9,10 Ertugliflozin generally is well tolerated, although genital mycotic infections appear to be more common with SGLT2 inhibitors such as ertugliflozin than with other classes of antidiabetic drugs.1,3,4,5,6

Efficacy of ertugliflozin in combination with other antidiabetic agents for the management of type 2 diabetes mellitus is supported by results from several randomized, active- or placebo-controlled trials in patients receiving ertugliflozin with metformin, sitagliptin, or metformin and sitagliptin.1 In these trials, initial combined therapy with ertugliflozin (5 or 15 mg once daily) and one or more antidiabetic drugs or addition of ertugliflozin to existing therapy improved glycemic control as evidenced by reductions in HbA_1c, fasting plasma glucose, and 2-hour postprandial plasma glucose concentrations; combined therapy also had beneficial effects on weight reduction and blood pressure compared with placebo and/or monotherapy.1,3,4,5,6,7,9,10

In a 26-week, randomized, double-blind trial in patients with type 2 diabetes mellitus inadequately controlled with metformin monotherapy, concomitant therapy with ertugliflozin (5 or 15 mg once daily) and existing metformin hydrochloride therapy (dosage of at least 1.5 g daily) substantially improved glycemic control (as evidenced by reductions in HbA_1c) compared with metformin monotherapy.1,3 Reductions in HbA_1c were 0.7 or 0.9% with ertugliflozin 5 or 15 mg once daily, respectively, plus metformin and 0.2% with existing metformin hydrochloride monotherapy.1 In patients who received metformin in conjunction with ertugliflozin 5 or 15 mg, approximately 36 or 43%, respectively, had HbA_1c reductions to less than 7%, compared with approximately 18% of patients receiving metformin monotherapy.1 The addition of ertugliflozin to existing metformin therapy also was associated with greater reductions in fasting plasma glucose, body weight, and blood pressure.1,3

In a noninferiority trial of 52 weeks' duration in patients with type 2 diabetes mellitus who were inadequately controlled with metformin hydrochloride monotherapy (dosage of at least 1.5 g daily), once-daily therapy with ertugliflozin (5 or 15 mg) or glimepiride (mean daily dose 3 mg) was added to existing therapy with metformin.1,4 Ertugliflozin and glimepiride provided similar improvements in glycemic control (as measured by HbA_1c) and ertugliflozin 15 mg once daily was noninferior to glimepiride therapy.1,4 At week 52, approximately 48, 40, and 42% of patients in the glimepiride, ertugliflozin 5 mg, and ertugliflozin 15 mg treatment groups, respectively, had an HbA_1c of less than 7%.1 Greater reductions in body weight and systolic blood pressure from baseline also were observed in those patients who received ertugliflozin.4

In a trial evaluating the safety and efficacy of ertugliflozin in combination with sitagliptin in adults with type 2 diabetes mellitus inadequately controlled with metformin hydrochloride monotherapy (dosage of at least 1.5 g daily), the addition of ertugliflozin and sitagliptin combination therapy to existing metformin therapy substantially improved glycemic control compared with the addition of either ertugliflozin or sitagliptin alone.1,5 In this trial, patients received ertugliflozin 5 mg, ertugliflozin 15 mg, sitagliptin 100 mg, ertugliflozin 5 mg and sitagliptin 100 mg, or ertugliflozin 15 mg and sitagliptin 100 mg once daily.1,5 At week 26, patients who received concomitant therapy with ertugliflozin 5 or 15 mg and sitagliptin 100 mg had greater reductions in HbA_1c (reduction of 1.4%) compared with those receiving ertugliflozin or sitagliptin alone (reduction of 1%).1,5 Additionally, a higher proportion of patients who received ertugliflozin 5 or 15 mg and sitagliptin 100 mg as an add-on to existing metformin therapy achieved an HbA_1c of less than 7% (53 or 51%, respectively) compared with those who received ertugliflozin 5 or 15 mg or sitagliptin 100 mg alone (29, 34, or 39%, respectively).1

In a 26-week trial in patients receiving metformin hydrochloride (dosage of at least 1.5 g daily) and sitagliptin (100 mg once daily), the addition of ertugliflozin 5 or 15 mg once daily resulted in a reduction in HbA_1c of 0.7 or 0.8%, respectively, compared with a 0.2% reduction in HbA_1c with placebo.1,6 Approximately 35 or 42% of patients who received ertugliflozin 5 or 15 mg, respectively, had HbA_1c reductions to less than 7%, compared with approximately 20% of patients receiving placebo.1 Patients receiving ertugliflozin 5 or 15 mg once daily also had greater reductions in fasting plasma glucose, body weight, and systolic blood pressure than those receiving placebo.1,6

Efficacy and safety of the combination of ertugliflozin and sitagliptin as initial therapy in patients with type 2 diabetes mellitus inadequately controlled with diet and exercise are supported by results of a 26-week, randomized, double-blind, placebo-controlled trial.1,7 In this trial, concomitant therapy with ertugliflozin (5 or 15 mg once daily) and sitagliptin (100 mg daily) substantially improved glycemic control (as evidenced by reductions in HbA_1c) compared with placebo.1,7 Reductions in HbA_1c were 1.6 or 1.7% with ertugliflozin 5 or 15 mg once daily, respectively, plus sitagliptin and 0.4% with placebo.7 Additionally, a greater proportion of patients receiving ertugliflozin and sitagliptin combination therapy achieved an HbA_1c of less than 7%, and greater reductions in fasting plasma glucose were observed with ertugliflozin and sitagliptin combination therapy compared with placebo.1

Reduction in Risk of Cardiovascular Events

Some SGLT2 inhibitors (e.g., canagliflozin, empagliflozin) have demonstrated the ability to reduce the risk of cardiovascular events† in patients with type 2 diabetes mellitus and established cardiovascular disease.704 In addition to lowering blood glucose, SGLT2 inhibitors appear to modify several nonglycemic cardiovascular risk factors such as blood pressure, body weight, adiposity, and arterial stiffness.84,85

The manufacturer states that data on the use of ertugliflozin for macrovascular risk reduction are lacking.1 For further discussion on the use of SGLT2 inhibitors for cardiovascular risk reduction, see Reduction in Risk of Major Adverse Cardiovascular Events under Uses: Type 2 Diabetes Mellitus, in Canagliflozin 68:20.18.

Beneficial Effects on Renal Function

SGLT2 inhibitors reduce renal tubular glucose reabsorption, body weight, systemic blood pressure, intraglomerular pressure, and albuminuria and slow glomerular filtration rate (GFR) loss through mechanisms that appear to be independent of glucose-lowering effects.706 In several cardiovascular outcomes trials involving the use of SGLT2 inhibitors (e.g., canagliflozin, dapagliflozin, empagliflozin) in patients with type 2 diabetes mellitus at high risk for cardiovascular disease or with existing cardiovascular disease, beneficial effects on renal function were observed as a secondary outcome.84,704,706 Some experts state that the use of an SGLT2 inhibitor should be considered to reduce the risk of CKD progression, cardiovascular events, or both in patients with type 2 diabetes mellitus and diabetic kidney disease with albuminuria† (an eGFR of at least 30 mL/minute per 1.73 m² and urinary albumin exceeding 30 mg/g creatinine, particularly urinary albumin exceeding 300 mg/g creatinine).706

A clinical study evaluating the use of canagliflozin in patients with type 2 diabetes mellitus, CKD (eGFR 30-89 mL/minute per 1.73 m²; mean: 56.2 mL/minute per 1.73 m²), and albuminuria (urine albumin:creatinine ratio exceeding 300 but less than 5000 mg/g) found that canagliflozin therapy reduced the risk of end-stage kidney disease, doubling of serum creatinine, cardiovascular death, and hospitalization for heart failure.100 For further discussion of the beneficial effects on renal function of SGLT2 inhibitors, see Beneficial Effects on Renal Function and Cardiovascular Morbidity and Mortality in Diabetic Nephropathy under Uses: Type 2 Diabetes Mellitus, in Canagliflozin 68:20.18 and in Empagliflozin 68:20.18.

General

Volume depletion should be corrected before initiating ertugliflozin.1 In addition, renal function should be assessed prior to treatment and periodically thereafter.1 (See Renal Impairment under Dosage and Administration: Special Populations.)

Administration

Ertugliflozin or the fixed combination of ertugliflozin and sitagliptin is administered orally once daily in the morning, with or without food.1,10

The fixed combination of ertugliflozin and metformin hydrochloride is administered orally twice daily with meals to reduce the adverse GI effects of the metformin hydrochloride component.9

If a dose of ertugliflozin, the fixed combination of ertugliflozin and metformin hydrochloride, or the fixed combination of ertugliflozin and sitagliptin is missed, the missed dose should be taken as soon as it is remembered followed by resumption of the regular schedule.1,9,10 If the missed dose is not remembered until it is almost time for the next dose, the missed dose should be skipped and the regular schedule resumed; the dose should not be doubled to replace a missed dose.1,9,10

Dosage

Type 2 Diabetes Mellitus

Dosage of ertugliflozin L-pyroglutamic acid is expressed in terms of ertugliflozin.1,9,10

Ertugliflozin Monotherapy

The recommended initial dosage of ertugliflozin for the management of type 2 diabetes mellitus in adults is 5 mg once daily.1 If well tolerated, the dosage may be increased to 15 mg once daily in patients who require additional glycemic control.1

Ertugliflozin/Metformin Hydrochloride Fixed-combination Therapy

When the commercially available fixed-combination preparation containing ertugliflozin and immediate-release metformin hydrochloride (Segluromet^®) is used in patients with type 2 diabetes mellitus, the recommended initial dosage is based on the patient's current regimen of ertugliflozin and/or metformin hydrochloride.9 The dosage of the fixed combination may be increased gradually based on effectiveness and tolerability.9 The total dosage of the drugs in the fixed combination should not exceed 15 mg of ertugliflozin and 2 g of metformin hydrochloride daily.9

For patients currently receiving metformin hydrochloride, the recommended initial total daily dosage of the fixed combination is 5 mg of ertugliflozin (using the fixed-combination tablets containing 2.5 mg of ertugliflozin) and a metformin hydrochloride dosage similar to the patient's existing total daily dosage, administered in 2 divided doses.9

For patients currently receiving ertugliflozin, the recommended initial total daily dosage of the fixed combination is 1 g of metformin hydrochloride and an ertugliflozin dosage similar to the patient's existing total daily dosage, administered in 2 divided doses.9

For patients currently receiving both ertugliflozin and metformin hydrochloride as separate components, the initial total daily dosage of the fixed combination is the same daily dosage of ertugliflozin and a metformin hydrochloride dosage similar to the patient's existing total daily dosage, administered in 2 divided doses.9

Ertugliflozin/Sitagliptin Fixed-combination Therapy

The recommended initial dosage of the fixed combination of ertugliflozin and sitagliptin is 5 mg of ertugliflozin and 100 mg of sitagliptin once daily in the morning without regard to meals.10 If tolerated, the dosage may be increased to a dosage of 15 mg of ertugliflozin and 100 mg of sitagliptin in patients who require additional glycemic control.10 In patients currently receiving ertugliflozin and switching to the fixed combination of ertugliflozin and sitagliptin therapy, the current dosage of ertugliflozin can be maintained.10

Special Populations

Hepatic Impairment

Dosage adjustments of ertugliflozin or the fixed combination of ertugliflozin and sitagliptin are not necessary in patients with mild or moderate hepatic impairment.1,10 Data are lacking on use of ertugliflozin or the fixed combination of ertugliflozin and sitagliptin in patients with severe hepatic impairment, and the manufacturer states that such use is not recommended.1,10 The manufacturer states that the use of the fixed combination of ertugliflozin and metformin hydrochloride is not recommended in patients with hepatic impairment.9

Renal Impairment

Dosage adjustments of ertugliflozin or the fixed combinations of ertugliflozin and metformin hydrochloride or ertugliflozin and sitagliptin are not necessary in patients with mild renal impairment (estimated glomerular filtration rate [eGFR] 60-89 mL/minute per 1.73 m²).1,9,10 Initiation of ertugliflozin or the fixed combinations of ertugliflozin and metformin hydrochloride or ertugliflozin and sitagliptin is not recommended in patients with an eGFR of 30 to less than 60 mL/minute per 1.73 m².1,9,10 Continued use of ertugliflozin or the fixed combinations of ertugliflozin and metformin hydrochloride or ertugliflozin and sitagliptin is not recommended in patients with an eGFR persistently between 30 and less than 60 mL/minute per 1.73 m².1,9,10 The use of ertugliflozin or the fixed combinations of ertugliflozin and metformin hydrochloride or ertugliflozin and sitagliptin is contraindicated in patients with an eGFR less than 30 mL/minute per 1.73 m².1,9,10 (See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Contraindications

History of serious hypersensitivity reaction to ertugliflozin or any ingredient in the formulation.1,9,10

Severe renal impairment (estimated glomerular filtration rate [eGFR] less than 30 mL/minute per 1.73 m²), end-stage renal disease (ESRD), or on dialysis.9,10

Warnings/Precautions

Hypotension

Ertugliflozin may cause intravascular volume contraction.1 Following initiation of ertugliflozin, symptomatic hypotension can occur, particularly in patients with impaired renal function (eGFR less than 60 mL/minute per 1.73 m²), geriatric patients, patients with low systolic blood pressure, or patients receiving diuretics.1 (See Drug Interactions: Diuretics.) Prior to initiating ertugliflozin in such patients, intravascular volume status should be assessed and corrected.1 Patients should be monitored for signs and symptoms of hypotension after initiating ertugliflozin therapy.1

Ketoacidosis

Use of sodium glucose cotransporter 2 (SGLT2) inhibitors in patients with type 1 or 2 diabetes mellitus may lead to ketoacidosis requiring hospitalization.1 In clinical studies, ketoacidosis was reported in 0.1% of patients who received ertugliflozin; ketoacidosis was not reported in any of the comparator-treated patients.1 Ketoacidosis associated with use of SGLT2 inhibitors may be present without markedly elevated blood glucose concentrations (e.g., less than 250 mg/dL).1

FDA identified 73 cases of acidosis (reported as diabetic ketoacidosis [DKA], ketoacidosis, or ketosis) associated with SGLT2 inhibitor use in the FDA Adverse Event Reporting System (FAERS) between March 2013 and May 2015.41,50 DKA had an atypical presentation in most of the reported cases in that type 2 diabetes mellitus was noted as the indication for the drug, and glucose concentrations were only slightly elevated (median: 211 mg/dL); type 1 diabetes mellitus was named as the indication in a few cases, and in some reports the indication was not specified.39,40,50 The median time to onset of symptoms of acidosis following initiation or increase in dosage of the SGLT2 inhibitor was 43 days (range: 1-365 days).50 No trend demonstrating a relationship between the dosage of an SGLT2 inhibitor and the risk of ketoacidosis was identified.50 In all reported episodes, a diagnosis of DKA or ketoacidosis was made by the clinician and hospitalization or treatment in an emergency department was warranted.39,50 In most cases, at least 1 diagnostic laboratory criterion suggestive of ketoacidosis (e.g., high anion gap metabolic acidosis, ketonemia, reduced serum bicarbonate) was reported.50 Potential factors for the development of ketoacidosis with SGLT2 inhibitor therapy identified in the 73 cases included infection, low carbohydrate diet or reduced caloric intake (due to illness or surgery), pancreatic disorders suggesting insulin deficiency (e.g., type 1 diabetes mellitus, history of pancreatitis, pancreatic surgery), reduced dosage or discontinuance of insulin, discontinuance of an oral insulin secretagogue, and alcohol use.1,50

Prior to initiating therapy with an SGLT2 inhibitor, clinicians should consider patient factors that may predispose the patient to ketoacidosis such as pancreatic insulin deficiency from any cause, reduced caloric intake, and alcohol abuse.1,50

Clinicians should evaluate for the presence of acidosis, including ketoacidosis, in patients experiencing signs or symptoms of acidosis while receiving SGLT2 inhibitors, regardless of the patient's blood glucose concentration.39,40,50 For patients who undergo scheduled surgery, temporary discontinuation of ertugliflozin for at least 4 days prior to surgery should be considered.1 Clinicians should consider monitoring for ketoacidosis and temporarily discontinuing therapy with an SGLT2 inhibitor in other clinical situations known to predispose individuals to ketoacidosis (e.g., prolonged fasting due to acute illness or post-surgery).1,50 If acidosis is confirmed, the SGLT2 inhibitor should be discontinued and appropriate treatment initiated to correct the acidosis; glucose concentrations should be monitored appropriately.39,40 In addition, supportive medical treatment should be instituted to treat and correct factors that may have precipitated or contributed to the metabolic acidosis.39 Risk factors for the development of ketoacidosis should be resolved prior to restarting ertugliflozin therapy.1

Euglycemic DKA associated with SGLT2 inhibitors may be detected and potentially prevented by having patients monitor urine and/or plasma ketone levels if they feel unwell, regardless of ambient glucose concentrations.1,40,42,50 Clinicians should inform patients and caregivers of the signs and symptoms of ketoacidosis (e.g., tachypnea or hyperventilation, anorexia, abdominal pain, nausea, vomiting, lethargy, mental status changes) and instruct patients to discontinue the SGLT2 inhibitor and immediately seek medical attention should they experience such signs or symptoms.1,39,42,50

Renal Effects

Ertugliflozin causes intravascular volume contraction and can cause renal impairment.1 Ertugliflozin increases serum creatinine concentrations and decreases eGFR; patients with impaired renal function may be more susceptible to these changes.1 Adverse effects related to renal function can occur following initiation of the drug.1 Renal function should be evaluated prior to initiation of ertugliflozin and periodically thereafter.1

FDA identified 101 cases of acute kidney injury associated with canagliflozin or dapagliflozin therapy in FAERS between March 2013 and October 2015.51 Hospitalization for evaluation and management of kidney injury was warranted in most cases, and some cases required admission to an intensive care unit and dialysis.1,51 In approximately half of the cases, onset of acute kidney injury occurred within 1 month or less of initiating canagliflozin or dapagliflozin therapy, and most patients' kidney function improved after stopping the drug.51 However, kidney injury may not be fully reversible in some situations and has led to death in some patients.51

Prior to initiating ertugliflozin therapy, clinicians should consider patient factors that may predispose the patient to acute kidney injury, including hypovolemia, chronic renal insufficiency, heart failure, and concomitant medications (e.g., diuretics, angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, nonsteroidal anti-inflammatory agents [NSAIAs]).1 Clinicians should consider temporarily discontinuing ertugliflozin in any setting of reduced oral intake (e.g., acute illness, fasting) or fluid losses (e.g., GI illness, excessive heat exposure).1 Patients should be monitored for acute kidney injury and the drug should be discontinued and appropriate treatment should be initiated if such injury occurs.1,51

Urosepsis and Pyelonephritis

Treatment with an SGLT2 inhibitor increases the risk for urinary tract infections.1

Cases of serious urinary tract infections, including urosepsis and pyelonephritis, have been reported in patients receiving an SGLT2 inhibitor.1,50 FDA identified 19 cases of urosepsis and pyelonephritis, which began as urinary tract infections associated with SGLT2 inhibitor use, in FAERS between March 2013 and October 2014.50 In all cases reported, hospitalization was warranted and some patients required admission to an intensive care unit or dialysis for treatment.50 The median time to onset of infection following initiation of the SGLT2 inhibitor was 45 days (range: 2-270 days).50

Prior to initiating therapy with an SGLT2 inhibitor, clinicians should consider patient factors that may predispose the patient to serious urinary tract infections such as a history of difficulty urinating or infections of the bladder, kidneys, or urinary tract.50 Patients should be monitored for urinary tract infections and treatment instituted if indicated.1,50

Lower Limb Amputation

In 2 randomized, placebo-controlled studies evaluating the effects of another drug in the SGLT2 inhibitor class (canagliflozin) on the risk of cardiovascular disease and the overall safety and tolerability of the drug, canagliflozin-treated patients had a twofold increased risk of lower limb (leg and foot) amputations (mostly affecting the toes and midfoot) compared with placebo recipients.1,52,53,55,56 (See Lower Limb Amputation under Warnings/Precautions: Warnings, in Cautions, in Canagliflozin 68:20.18.) In clinical trials conducted with ertugliflozin, nontraumatic lower limb amputations were reported in 0.2 or 0.5% of patients receiving ertugliflozin 5 or 15 mg daily, respectively, compared with 0.1% of patients receiving a comparator drug.1 A causal association between ertugliflozin and lower limb amputation has not been established.1 Prior to initiating therapy with ertugliflozin, clinicians should consider patient factors that may predispose them to the need for amputation, such as a history of amputation, peripheral vascular disease, neuropathy, or diabetic foot ulcers.1 Clinicians should monitor patients receiving ertugliflozin for the presence of infection (including osteomyelitis), new pain or tenderness, and sores or ulcers involving the lower limbs; ertugliflozin should be discontinued if such complications occur.1 Patients should also be counseled on the importance of routine preventative foot care.1

Concomitant Therapy with Hypoglycemic Agents

When ertugliflozin is added to therapy with an insulin secretagogue (e.g., a sulfonylurea) or insulin, the incidence of hypoglycemia is increased compared with sulfonylurea or insulin monotherapy.1 Therefore, patients receiving ertugliflozin may require a reduced dosage of the concomitant insulin secretagogue or insulin to reduce the risk of hypoglycemia.1

Fournier Gangrene

Fournier gangrene (necrotizing fasciitis of the perineum), a rare but serious or life-threatening bacterial infection requiring urgent surgical intervention, has been reported during postmarketing surveillance in men and women with type 2 diabetes mellitus receiving an SGLT2 inhibitor.1,60 Permanent disfigurement, prolonged hospitalization, disability, and complications from sepsis all may be caused by Fournier gangrene.59 Although diabetes mellitus is a risk factor for developing Fournier gangrene, this condition is still rare among patients with diabetes mellitus.60

FDA identified 12 cases of Fournier gangrene in patients taking an SGLT2 inhibitor reported in FAERS and medical literature between March 2013 and May 2018.60,61,62 Since FDA's review, additional cases of Fournier gangrene have been reported.59 In the initial cases reviewed by FDA, the average time to onset of infection was 9.2 months (range 7 days to 25 months) after initiating therapy with an SGLT2 inhibitor.60 Some experts speculate that the variation in time to diagnosis of Fournier gangrene might be due to fluctuating glycemic control, microvascular complications, or an inciting event associated with SGLT2 inhibitors (e.g., urinary tract infection, mycotic infection, skin or mucosal breakdown due to pruritus).59 In all cases reported, hospitalization and surgery were required.60 Among these cases, some patients required multiple disfiguring surgeries, some developed complications (e.g., diabetic ketoacidosis, acute kidney injury, septic shock), and 1 patient died.60 In a review of other antidiabetic drugs (e.g., insulin, biguanides, sulfonylureas, dipeptidyl peptidase-4 inhibitors) over a period of more than 30 years, only 6 cases of Fournier gangrene were identified; all of theses cases occurred in men.60

Patients receiving ertugliflozin who develop pain or tenderness, erythema, or swelling in the genital or perineal area, in addition to fever or malaise, should be assessed for necrotizing fasciitis.1,60 If Fournier gangrene is suspected, ertugliflozin should be discontinued and treatment should be initiated with broad-spectrum antibiotics; surgical debridement should be performed if necessary.1,60 Blood glucose concentrations should be closely monitored; alternative antidiabetic agents should be initiated to maintain glycemic control.1,60

Genital Mycotic Infections

Ertugliflozin increases the risk of genital mycotic infections in males (e.g., balanitis) and females (e.g., vulvovaginal mycotic infection).1 Patients with a history of genital mycotic infections and uncircumcised males are at an increased risk for developing genital mycotic infections.1 Patients should be monitored for genital mycotic infections and appropriate treatment should be instituted if these infections occur.1

Risk of Bone Fracture

An increased risk of bone fracture, along with dose-related decreases in bone mineral density in older adults, has been observed in patients receiving another drug in the SGLT2 inhibitor class (canagliflozin).43 (See Risk of Bone Fracture under Warnings/Precautions: Other Warnings/Precautions, in Cautions, in Canagliflozin 68:20.18.) FDA is continuing to evaluate the risk of bone fracture with SGLT2 inhibitors.43

Effects on Lipoproteins

Increases in low-density lipoprotein (LDL)-cholesterol can occur during ertugliflozin therapy.1 Serum LDL-cholesterol concentrations should be monitored during treatment with ertugliflozin and such lipid elevations treated according to the standard of care.1

Laboratory Test Interferences

SGLT2 inhibitors such as ertugliflozin increase urinary glucose excretion and will result in false-positive urine glucose tests.1 In addition, the manufacturer states that the 1,5-anhydroglucitol assay is unreliable for monitoring glycemic control in patients taking SGLT2 inhibitors.1 Alternative methods of monitoring glycemic control should be used in patients receiving SGLT2 inhibitors.1

Use of Fixed Combinations

When ertugliflozin is used in fixed combination with metformin, sitagliptin, or other drugs, the cautions, precautions, contraindications, and interactions associated with the concomitant agent(s) should be considered in addition to those associated with ertugliflozin.1,9,10

Specific Populations

Pregnancy

Based on the results of reproductive and developmental toxicity studies in animals, ertugliflozin use during pregnancy may affect renal development and maturation, especially during the second and third trimesters of pregnancy.1 Limited data with ertugliflozin in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage, and poorly controlled diabetes mellitus during pregnancy carries risks to the mother and fetus; however, ertugliflozin therapy is not recommended in pregnant women during the second and third trimesters of pregnancy.1

Lactation

Ertugliflozin is distributed into milk in rats; it is not known whether the drug is distributed into human milk.1 Because many drugs are distributed into human milk and because of the potential for serious adverse reactions in nursing infants from ertugliflozin, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.1

Pediatric Use

Safety and efficacy of ertugliflozin have not been established in pediatric patients younger than 18 years of age.1,9,10

Geriatric Use

In clinical trials, 25.7% of patients were 65 years of age or older and 4.5% were 75 years of age or older.1 Geriatric patients receiving ertugliflozin were more likely to experience certain adverse reactions related to volume depletion compared with younger patients.1 Ertugliflozin is expected to have diminished efficacy in geriatric patients with renal impairment.1

Hepatic Impairment

Compared with values in individuals with normal hepatic function, ertugliflozin area under the concentration-time curve (AUC) and peak plasma concentrations were decreased by 13 and 21%, respectively, in patients with moderate hepatic impairment (Child-Pugh class B); however, these decreases are not considered clinically meaningful.1 The plasma protein binding of ertugliflozin is unaffected in patients with moderate hepatic impairment.1 Data are lacking on the use of ertugliflozin in patients with severe hepatic impairment (Child-Pugh class C), and such use is not recommended.1

Renal Impairment

Renal function should be assessed prior to initiation of ertugliflozin therapy and periodically thereafter.1

Safety and efficacy of ertugliflozin have not been established in patients with moderate renal impairment (estimated glomerular filtration rate [eGFR] 30-59 mL/minute per 1.73 m²).1 The safety and efficacy of ertugliflozin were evaluated in adults with moderate renal impairment (mean eGFR: 47 mL/minute per 1.73 m²) and type 2 diabetes mellitus inadequately controlled on diet and exercise with or without other antidiabetic agents (a biguanide [24.6%], a dipeptidyl peptidase-4 [DPP-4] inhibitor [13.5%], a glucagon-like peptide-1 [GLP-1] receptor agonist [2.8%], insulin [55.9%], a sulfonylurea [40.3%], other [5.4%]).1,8 The addition of ertugliflozin 5 or 15 mg administered once daily to background antidiabetic agents did not improve glycemic control compared with placebo.1,8 Additionally, patients who received ertugliflozin had an increased risk of renal impairment, renal-related adverse effects, and adverse effects related to volume depletion compared with placebo-treated patients.1,8

Ertugliflozin is not expected to be effective in patients with severe renal impairment (including those with end-stage renal disease [ESRD]) or those undergoing dialysis; the drug is contraindicated in such patients.1 (See Contraindications.)

In patients with mild (eGFR 60-89 mL/minute per 1.73 m²), moderate (eGFR 30-59 mL/minute per 1.73 m²), or severe (eGFR less than 30 mL/minute per 1.73 m²) renal impairment, AUC of ertugliflozin was increased by 1.6-, 1.7-, or 1.6-fold, respectively, compared with those with normal renal function.1,18 However, these increases are not considered clinically important.1,18 In patients receiving ertugliflozin, 24-hour urinary glucose excretion declined with increasing severity of renal impairment.1,18 Plasma protein binding of ertugliflozin was unaffected in patients with renal impairment.1

Common Adverse Effects

Adverse effects reported in at least 2% of patients receiving ertugliflozin in clinical trials and more commonly than with placebo include female genital mycotic infection,1,2,3,6,7 male genital mycotic infection,1,2,3,6,7 urinary tract infection,1,3,6,7 headache,1 vaginal pruritus,1 increased urination,1 nasopharyngitis,1,6 back pain,1 decreased weight,1 and thirst.1

The major metabolic pathway for ertugliflozin is glucuronidation; the drug is principally glucuronidated by uridine diphosphate-glucuronosyltransferase (UGT) isoenzymes 1A9 and 2B7.1,17

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Ertugliflozin in minimally metabolized by cytochrome P-450 (CYP) isoenzymes.1 Ertugliflozin and ertugliflozin glucuronides (clinically inactive metabolites) did not inhibit CYP isoenzymes 1A2, 2B6, 2C9, 2C19, 2C8, 2D6, or 3A4 and did not induce CYP isoenzymes 1A2, or 3A4 in vitro.1 Additionally, the drug is not a time-dependent inhibitor of CYP3A in vitro.1 Pharmacokinetic interactions are unlikely with drugs that are metabolized by these CYP isoenzymes.1

Drugs Affecting or Affected by Organic Anion Transporters

Ertugliflozin is not a substrate of organic anion transporter (OAT) 1 or OAT3.1 Ertugliflozin and ertugliflozin glucuronides did not meaningfully inhibit OAT1 or OAT3; pharmacokinetic interactions are unlikely with substrates of OAT1 or OAT3.1

Drugs Affecting or Affected by Organic Cation Transporters

Ertugliflozin is not a substrate of organic cation transporter (OCT) 1 or OCT2.1 Ertugliflozin and ertugliflozin glucuronides did not meaningfully inhibit OCT2; pharmacokinetic interactions are unlikely with substrates of OCT2.1

Drugs Affecting or Affected by P-glycoprotein Transport

Ertugliflozin is a P-glycoprotein (P-gp) substrate.1 Ertugliflozin and ertugliflozin glucuronides did not meaningfully inhibit P-gp.1 Ertugliflozin is unlikely to affect the pharmacokinetics of concomitantly administered P-gp substrates.1

Drugs Affected by Uridine Diphosphate-glucuronosyltransferase

Ertugliflozin did not inhibit UGT isoenzymes 1A6, 1A9, or 2B7 in vitro and was a weak inhibitor of UGT1A1 and 1A4.1 Ertugliflozin glucuronides did not inhibit UGT1A1, 1A4, 1A6, 1A9, or 2B7 in vitro.1 Pharmacokinetic interactions are unlikely with drugs that are metabolized by these enzymes.1

Drugs Affecting Breast Cancer Resistance Protein

Ertugliflozin is a substrate of breast cancer resistance protein (BCRP).1

Drugs Affecting or Affected by Organic Anion Transport Polypeptides

Ertugliflozin is not a substrate of organic anion transport polypeptides (OATP) 1B1 or 1B3.1 Ertugliflozin and ertugliflozin glucuronides did not meaningfully inhibit OATP1B1 or OATP1B3; pharmacokinetic interactions are unlikely with substrates of OATP1B1 or OATP1B3.1

Diuretics

Concomitant use of ertugliflozin with diuretics may increase the incidence of symptomatic hypotension.1 Prior to initiation of ertugliflozin, volume status should be assessed and corrected in patients receiving diuretics.1 Patients should be monitored for signs and symptoms of symptomatic hypotension following initiation of ertugliflozin therapy.1

Mefenamic Acid

Concomitant use of mefenamic acid, a UGT inhibitor, and ertugliflozin increased ertugliflozin peak plasma concentration and area under the concentration-time curve (AUC) by 1.51- and 1.19-fold, respectively.1 These increases are not considered to be clinically relevant.1

Metformin

Administration of a single dose of metformin hydrochloride (1 g) with a single dose of ertugliflozin (15 mg) did not have a clinically meaningful effect on the pharmacokinetics of ertugliflozin or metformin. 1 No adjustment of ertugliflozin dosage is necessary when used concomitantly with metformin.1

Rifampin

Administration of rifampin (600 mg once daily) with a single dose of ertugliflozin (15 mg) decreased ertugliflozin peak plasma concentration and AUC by 15 and 39%, respectively.1 No adjustment of ertugliflozin dosage is necessary when used concomitantly with rifampin.1

Simvastatin

Administration of a single dose of simvastatin (40 mg) with a single dose of ertugliflozin (15 mg) did not have a clinically meaningful effect on the pharmacokinetics of ertugliflozin or simvastatin.1 No adjustment of ertugliflozin dosage is necessary when used concomitantly with simvastatin.1

Sitagliptin

Administration of a single dose of sitagliptin (100 mg) with a single dose of ertugliflozin (15 mg) did not have a clinically meaningful effect on the pharmacokinetics of ertugliflozin or sitagliptin. 1 No adjustment of ertugliflozin dosage is necessary when used concomitantly with sitagliptin.1

Sulfonylureas or Insulin

When ertugliflozin is added to therapy with an insulin secretagogue (e.g., a sulfonylurea) or insulin, the incidence of hypoglycemia is increased compared with sulfonylurea or insulin monotherapy.1 Patients receiving ertugliflozin may require a reduced dosage of the concomitant insulin secretagogue or insulin to reduce the risk of hypoglycemia.1

Glimepiride

Administration of a single dose of glimepiride (1 mg) with a single dose of ertugliflozin (15 mg) did not have a clinically important effect on the pharmacokinetics of glimepiride or ertugliflozin.1

Description

Ertugliflozin is a reversible and highly selective inhibitor of sodium-glucose cotransporter 2 (SGLT2), a transporter that is expressed in the proximal renal tubules and is responsible for most of the reabsorption of filtered glucose from the tubular lumen.1,11,12,13,17 Through inhibition of SGLT2, ertugliflozin reduces reabsorption of filtered glucose and lowers the renal threshold for glucose in a dose-dependent manner, leading to increased urinary glucose excretion;1,11,12,13 increased glucose excretion is independent of insulin secretion.12

Following oral administration of ertugliflozin in the fasting state, peak plasma concentration is attained in 1 hour.1,17 Following oral administration of a 15-mg dose of ertugliflozin, the absolute oral bioavailability of the drug is 100%.1 Administration of ertugliflozin with a high-fat, high-calorie meal decreased peak plasma ertugliflozin concentration by 29% and prolonged time to peak plasma concentration by 1 hour, but did not alter the area under the concentration-time curve (AUC).1 These changes are not considered clinically meaningful and ertugliflozin can be administered with or without food.1 Ertugliflozin is 93.6% protein bound.1 Renal or hepatic impairment does not meaningfully alter plasma protein binding.1 Ertugliflozin is principally metabolized by uridine diphosphate-glucuronosyltransferase (UGT) 1A9 and UGT2B7 to inactive metabolites.1 Following oral administration of a radiolabeled 25-mg dose of ertugliflozin, 41% of the total radioactivity was excreted in urine and 50% was excreted in feces, with 1.5 or approximately 33.8% of the administered dose recovered as parent drug in urine or feces, respectively.1,17 The mean elimination half-life of ertugliflozin is approximately 16.6 hours.1

Advice to Patients

When ertugliflozin is used in fixed combination with other drugs, importance of informing patients of important cautionary information about the concomitant agent(s).1,9,10

Importance of patient reading medication guide before initiating therapy and each time the drug is dispensed.1,9,10,14,15,16

Importance of informing patients of the potential risks and benefits of ertugliflozin-containing therapy and of alternative therapies.1,9,10

Importance of informing patients about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and glycosylated hemoglobin (hemoglobin A_1c; HbA_1c) testing, recognition and management of hypoglycemia and hyperglycemia, and assessment of diabetes mellitus complications.1

Importance of promptly seeking medical advice during periods of stress such as fever, trauma, infection, or surgery as medication requirements may change.1

Importance of taking ertugliflozin exactly as directed by the clinician.1 Importance of advising patients about what to do if a dose of ertugliflozin is missed.1 (See Dosage and Administration: Administration.)

Importance of informing patients that the incidence of hypoglycemia may be increased if ertugliflozin is used concomitantly with insulin and/or an insulin secretagogue.1 Importance of informing patients that a lower dosage of insulin or insulin secretagogue may be required to reduce the risk of hypoglycemia if used concomitantly with ertugliflozin.1

Importance of informing patients that symptomatic hypotension may occur with ertugliflozin and advising patients to report such symptoms to their clinician.1 Inform patients that ertugliflozin-induced dehydration may increase the risk of hypotension and that patients should maintain adequate fluid intake.1

Importance of informing patients that ketoacidosis, which can be a life-threatening condition, has been reported with ertugliflozin therapy (sometimes associated with illness or surgery, among other risk factors).1 Importance of informing patients receiving ertugliflozin and their caregivers of the signs and symptoms of ketoacidosis (e.g., tachypnea or hyperventilation, anorexia, abdominal pain, nausea, vomiting, lethargy, mental status changes) and importance of instructing patients to discontinue ertugliflozin and seek medical attention immediately should they experience any such signs or symptoms.1,39,42,50 Advise patients to use a ketone dipstick to check for ketones in their urine (when possible) if symptoms of ketoacidosis occur, even if blood glucose is not elevated (e.g., less than 250 mg/dL).1,50

Importance of informing patients that acute kidney injury has been reported with ertugliflozin therapy.1 Advise patients to seek medical advice immediately if they have reduced oral intake (such as due to acute illness or fasting) or increased fluid losses (such as due to vomiting, diarrhea, or excessive heat exposure), as it may be appropriate to temporarily discontinue ertugliflozin in those settings.1 Importance of regular renal function testing during ertugliflozin therapy.1

Importance of informing patients receiving ertugliflozin of the potential for urinary tract infections, which may be serious.1,50 Advise patients of the signs and symptoms of urinary tract infection and the need to contact a clinician if such signs and symptoms occur.1,50

Importance of informing patients of the potentially increased risk of amputation with ertugliflozin therapy.1 Advise patients of the importance of routine preventative foot care.1 Advise patients to monitor for new pain, tenderness, sores or ulcers, or infections involving the leg or foot, and to seek prompt medical advice if such signs or symptoms develop.1

Importance of informing patients that necrotizing infections of the perineum (Fournier gangrene) have occurred with sodium-glucose cotransporter 2 (SGLT2) inhibitor therapy.1,60 Advise patients to promptly seek medical attention if they develop pain or tenderness, redness, or swelling of the genitals or the area from the genitals back to the rectum, in addition to fever (above 38°C) or malaise.1,60

Importance of informing patients that yeast infection may occur (e.g., vulvovaginitis, balanitis, balanoposthitis).1 Importance of informing female patients of the signs and symptoms of vaginal yeast infections (e.g., vaginal discharge, odor, itching) and male patients of the signs and symptoms of balanitis or balanoposthitis (e.g., rash or redness of the glans or foreskin of the penis).1 Advise patients of treatment options and when to seek medical advice.1

Importance of informing patients that due to the mechanism of action of ertugliflozin, patients taking the drug will test positive for glucose in their urine.1 Importance of not using urine glucose tests to monitor glycemic status while taking ertugliflozin.1 (See Laboratory Test Interferences under Cautions: Warnings/Precautions.)

Importance of women informing their clinicians immediately if they are or plan to become pregnant or plan to breast-feed.1 Advise patients that ertugliflozin use is not recommended while breast-feeding.1 Importance of advising pregnant women about the potential risks to the fetus if ertugliflozin is used during pregnancy.1 All women of childbearing potential should be advised to report pregnancy to their clinician as soon as possible.1 (See Specific Populations under Cautions: Warnings/Precautions.)

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1

Importance of informing patients of other important precautionary information.1 (See Cautions.)

Additional Information

Overview^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. Merck. Steglatro^® (ertugliflozin) tablets prescribing information. Whitehouse Station, NJ; 2020 Jan.

2. Terra SG, Focht K, Davies M et al. Phase III, efficacy and safety study of ertugliflozin monotherapy in people with type 2 diabetes mellitus inadequately controlled with diet and exercise alone. Diabetes Obes Metab . 2017; 19:721-728. [PubMed 28116776]

3. Rosenstock J, Frias J, Páll D et al. Effect of ertugliflozin on glucose control, body weight, blood pressure and bone density in type 2 diabetes mellitus inadequately controlled on metformin monotherapy (VERTIS MET). Diabetes Obes Metab . 2018; 20:520-529. [PubMed 28857451]

4. Hollander P, Liu J, Hill J et al. Ertugliflozin Compared with Glimepiride in Patients with Type 2 Diabetes Mellitus Inadequately Controlled on Metformin: The VERTIS SU Randomized Study. Diabetes Ther . 2018; 9:193-207. [PubMed 29282633]

5. Pratley RE, Eldor R, Raji A et al. Ertugliflozin plus sitagliptin versus either individual agent over 52 weeks in patients with type 2 diabetes mellitus inadequately controlled with metformin: The VERTIS FACTORIAL randomized trial. Diabetes Obes Metab . 2018; 20:1111-1120. [PubMed 29266675]

6. Dagogo-Jack S, Liu J, Eldor R et al. Efficacy and safety of the addition of ertugliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sitagliptin: The VERTIS SITA2 placebo-controlled randomized study. Diabetes Obes Metab . 2018; 20:530-540. [PubMed 28921862]

7. Miller S, Krumins T, Zhou H et al. Ertugliflozin and Sitagliptin Co-initiation in Patients with Type 2 Diabetes: The VERTIS SITA Randomized Study. Diabetes Ther . 2018; 9:253-268. [PubMed 29313282]

8. Grunberger G, Camp S, Johnson J et al. Ertugliflozin in Patients with Stage 3 Chronic Kidney Disease and Type 2 Diabetes Mellitus: The VERTIS RENAL Randomized Study. Diabetes Ther . 2018; 9:49-66. [PubMed 29159457]

9. Merck. Segluromet^® (ertugliflozin and metformin hydrochloride) tablets prescribing information. Whitehouse Station, NJ; 2018 Oct.

10. Merck. Steglujan^® (ertugliflozin and sitagliptin) tablets prescribing information. Whitehouse Station, NJ; 2018 Oct.

11. Cinti F, Moffa S, Impronta F et al. Spotlight on ertugliflozin and its potential in the treatment of type 2 diabetes: evidence to date. Drug Des Devel Ther . 2017; 11:2905-2919. [PubMed 29042751]

12. Riser Taylor S, Harris KB. The clinical efficacy and safety of sodium glucose cotransporter-2 inhibitors in adults with type 2 diabetes mellitus. Pharmacotherapy . 2013; 33:984-99. [PubMed 23744749]

13. US Food and Drug Administration. Center for Drug Evaluation and Research: Application number 209803Orig1s000, 209805Orig1s000, 209806Orig1s000: Clinical pharmacology and biopharmaceutics review(s). From FDA website. [Web]

14. Merck. Segluromet^® (ertugliflozin and metformin hydrochloride) tablets medication guide. Whitehouse Station, NJ; 2018 Oct.

15. Merck. Steglujan^® (ertugliflozin and sitagliptin) tablets medication guide. Whitehouse Station, NJ; 2018 Oct.

16. Merck. Steglatro^® (ertugliflozin) tablets medication guide. Whitehouse Station, NJ; 2018 Oct.

17. Miao Z, Nucci G, Amin N et al. Pharmacokinetics, metabolism, and excretion of the antidiabetic agent ertugliflozin (PF-04971729) in healthy male subjects. Drug Metab Dispos . 2013; 41:445-56. [PubMed 23169609]

18. Sahasrabudhe V, Terra SG, Hickman A et al. The effect of renal impairment on the pharmacokinetics and pharmacodynamics of ertugliflozin in subjects with type 2 diabetes mellitus. J Clin Pharmacol . 2017; 57:1432-1443. [PubMed 28703316]

19. . Ertugliflozin for type 2 diabetes. Med Lett Drugs Ther . 2018; 60:70-72. [PubMed 29667948]

39. US Food and Drug Administration. FDA Drug Safety Communication: FDA warns that SGLT2 inhibitors for diabetes may result in a serious condition of too much acid in the blood. 2015 May 15. From FDA website. Accessed 2015 July 6. [Web]

40. Rosenstock J, Ferrannini E. Euglycemic diabetic ketoacidosis: a predictable, detectable, and preventable safety concern with SGLT2 inhibitors. Diabetes Care . 2015; 38:1638-42. [PubMed 26294774]

41. Erondu N, Desai M, Ways K et al. Diabetic ketoacidosis and related events in the canagliflozin type 2 diabetes clinical program. Diabetes Care . 2015; 38:1680-6. [PubMedCentral][PubMed 26203064]

42. Peters AL, Buschur EO, Buse JB et al. Euglycemic diabetic ketoacidosis: a potential complication of treatment with sodium-glucose cotransporter 2 inhibition. Diabetes Care . 2015; 38:1687-93. [PubMed 26078479]

43. US Food and Drug Administration. FDA Drug Safety Communication: FDA revises label of diabetes drug canagliflozin (Invokana, Invokamet) to include updates on bone fracture risk and new information on decreased bone mineral density. 2015 Sep 10. From FDA website. Accessed 2015 Sep 13. [Web]

50. US Food and Drug Administration. FDA Drug Safety Communication: FDA revises labels of SGLT2 inhibitors for diabetes to include warnings about too much acid in the blood and serious urinary tract infections. From FDA website. [Web]

51. US Food and Drug Administration. FDA Drug Safety Communication: FDA strengthens kidney warnings for diabetes medicine canagliflozin (Invokana, Invokamet) and dapagliflozin (Farxiga, Xigduo XR). From FDA website. [Web]

52. US Food and Drug Administration. FDA Drug Safety Communication: Interim clinical trial results find increased risk of leg and foot amputations, mostly affecting the toes, with the diabetes medicine canagliflozin (Invokana, Invokamet); FDA to investigate. From FDA website. [Web]

53. Neal B, Perkovic V, de Zeeuw D et al. Rationale, design, and baseline characteristics of the Canagliflozin Cardiovascular Assessment Study (CANVAS)--a randomized placebo-controlled trial. Am Heart J . 2013; 166:217-223.e11. [PubMed 23895803]

55. US Food and Drug Administration. FDA Drug Safety Communication: FDA confirms increased risk of leg and foot amputations with the diabetes medicine canagliflozin (Invokana, Invokamet, Invokamet XR). From FDA website. [Web]

56. Neal B, Perkovic V, Mahaffey KW et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med . 2017;

59. Bersoff-Matcha SJ, Chamberlain C, Cao C et al. Fournier gangrene associated with sodium-glucose cotransporter-2 inhibitors: a review of spontaneous postmarketing cases. Ann Intern Med . 2019; [PubMed 31060053]

60. US Food and Drug Administration. FDA Drug Safety Communication: FDA warns about rare occurrences of a serious infection of the genital area with SGLT2 inhibitors for diabetes. Silver Spring, MD; 2018 Aug 29. From FDA website. [Web]

61. Cecilia-Chi W, Lim-Tio S. Fournier's syndrome: a life-threatening complication of SGLT2 inhibition in poorly controlled diabetes mellitus. 2016 Joint Annual Scientific Meeting of the Australian Diabetes Educators Association (ADEA) and Australian Diabetes Society (ADS). Abstract number 265.

62. Kumar S, Costello AJ, Colman PG. Fournier's gangrene in a man on empagliflozin for treatment of Type 2 diabetes. Diabet Med . 2017; 34:1646-1648. [PubMed 28887847]

84. Trujillo JM, Nuffer WA. Impact of sodium-glucose cotransporter 2 inhibitors on nonglycemic outcomes in patients with type 2 diabetes. Pharmacotherapy . 2017; 37:481-491. [PubMed 28102030]

85. Inzucchi SE, Zinman B, Wanner C et al. SGLT-2 inhibitors and cardiovascular risk: proposed pathways and review of ongoing outcome trials. Diab Vasc Dis Res . 2015; 12:90-100. [PubMed 25589482]

100. Perkovic V, Jardine MJ, Neal B et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med . 2019; 380:2295-2306. [PubMed 30990260]

698. Garber AJ, Handelsman Y, Grunberger G et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm 2020 executive summary. Endocr Pract . 2020; 26:107-139. [PubMed 32022600]

699. Zelniker TA, Wiviott SD, Raz I et al. Comparison of the effects of glucagon-like peptide receptor agonists and sodium-glucose cotransporter 2 inhibitors for prevention of major adverse cardiovascular and renal outcomes in type 2 diabetes mellitus. Circulation . 2019; 139:2022-2031. [PubMed 30786725]

704. American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment: Standards of Medical Care in Diabetes-2020 . Diabetes Care . 2020; 43:S98-S110. [PubMed 31862752]

705. American Diabetes Association. 10. Cardiovascular disease and risk management: Standards of Medical Care in Diabetes-2020 . Diabetes Care . 2020; 43:S111-S134. [PubMed 31862753]

706. American Diabetes Association. 11. Microvascular complications and foot care: Standards of Medical Care in Diabetes-2020 . Diabetes Care . 2020; 43:S135-S151. [PubMed 31862754]