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Invokana

Generic Name: Canagliflozin
Class: Sodium-glucose Cotransporter 2 (SGLT2) Inhibitors
Chemical Name: (1S)-Hydrate (2:1), 1,5-anhydro-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-d-glucitol
Molecular Formula: C24H25FO5S•½H2O
CAS Number: 928672-86-0

Medically reviewed by Drugs.com. Last updated on Nov 18, 2019.

Warning

  • Canagliflozin therapy is associated with an increased risk of requiring lower limb amputation.1 55 56 Amputations of the toe or midfoot are most common; however, amputations involving the leg and multiple amputations, some involving both limbs, also reported.1 55 (See Lower Limb Amputations under Cautions.)

  • Consider patient factors that may increase the risk of the need for amputation (e.g., history of amputation, peripheral vascular disease, neuropathy, diabetic foot ulcers) prior to initiating canagliflozin therapy.1 55

  • Monitor patients during therapy for infections (including osteomyelitis), new pain or tenderness, or sores or ulcers involving lower limbs; discontinue canagliflozin if such complications occur.1 55

Introduction

Antidiabetic agents; sodium-glucose cotransporter 2 (SGLT2) inhibitor.1 15

Uses for Invokana

Type 2 Diabetes Mellitus

Used as monotherapy as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus.1 2 11

Used to reduce the risk of major cardiovascular events (e.g., cardiovascular death, nonfatal MI, nonfatal stroke) in patients with type 2 diabetes mellitus and established cardiovascular disease.1 82 83

May have beneficial effects on renal function; reduction of the risk of CKD progression demonstrated in clinical studies.82 86 87

Commercially available in fixed combination with immediate- or extended-release metformin hydrochloride (Invokamet or Invokamet XR); the fixed combination is used when treatment with both drugs is appropriate.63 Manufacturer states that effectiveness of the fixed combination of canagliflozin and immediate- or extended-release metformin hydrochloride in reducing the risk of major cardiovascular events in patients with type 2 diabetes mellitus and cardiovascular disease not established.63

Used in combination with other antidiabetic agents (e.g., metformin, a sulfonylurea, a peroxisome proliferator-activated receptorγ [PPARγ] agonist [thiazolidinedione]) or insulin 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 10

Current guidelines for the treatment of type 2 diabetes mellitus generally recommend metformin as first-line therapy in addition to lifestyle modifications due to its well-established safety and efficacy (e.g., beneficial effects on glycosylated hemoglobin [hemoglobin A1c; HbA1c], weight, and cardiovascular mortality).598 604 Consider patient's comorbidities when selecting additional antidiabetic agents.598 604

In patients with type 2 diabetes mellitus and CKD, an SGLT2 inhibitor or glucagon-like peptide-1 (GLP-1) receptor agonist with demonstrated ability to reduce the risk of CKD progression, cardiovascular events, or both (e.g., canagliflozin, empagliflozin, liraglutide) should be considered.604

Patients with type 2 diabetes mellitus who have established atherosclerotic cardiovascular disease (ASCVD) should receive a drug with demonstrated cardiovascular disease benefit (e.g., GLP-1 receptor agonist [e.g., liraglutide], SGLT2 inhibitor [e.g., canagliflozin, empagliflozin]).82 83 604 In patients with ASCVD and heart failure or with an increased risk of heart failure, an SGLT2 inhibitor with demonstrated cardiovascular benefit may be preferred.604

In patients without ASCVD, heart failure, or CKD, the decision regarding the addition of other antidiabetic agents (e.g., sulfonylurea, thiazolidinedione, dipeptidyl peptidase-4 [DPP-4] inhibitor, SGLT2 inhibitor, GLP-1 receptor agonist, basal insulin) should be based on drug-specific effects and individual patient factors.604

Not indicated for type 1 diabetes mellitus or diabetic ketoacidosis.1 63

Invokana Dosage and Administration

Administration

Oral Administration

Administer canagliflozin once daily, before the first meal of the day.1

Administer the fixed combination of canagliflozin and immediate-release metformin hydrochloride twice daily with meals.63

Administer the fixed combination of canagliflozin and extended-release metformin hydrochloride once daily with the morning meal; swallow the tablet whole and do not crush, chew, or cut.63

If a dose is missed, take missed dose as soon as it is remembered followed by resumption of regular schedule.1 If missed dose is not remembered until the time of the next dose, skip missed dose and resume regular schedule; do not double dose to replace a missed dose.1

Dosage

Dosage of canagliflozin expressed in terms of anhydrous canagliflozin.1

Adults

Type 2 Diabetes Mellitus
Canagliflozin Monotherapy
Oral

Initially, 100 mg once daily, taken before first meal of day.1

If well tolerated, increase dosage to 300 mg once daily in patients with an eGFR ≥60 mL/minute per 1.73 m2 who require additional glycemic control.1

In patients with an eGFR ≥60 mL/minute per 1.73 m2 who are receiving concurrent therapy with a uridine diphosphate-glucuronosyltransferase (UGT) enzyme inducer (e.g., phenobarbital, phenytoin, rifampin, ritonavir), consider increasing canagliflozin dosage to 300 mg once daily in patients who are tolerating a dosage of 100 mg once daily and require additional glycemic control.1 (See UGT Enzyme Inducers and see Specific Drugs and Laboratory Tests under Interactions.)

If necessary, correct volume depletion before initiation of canagliflozin therapy.1

Canagliflozin/Immediate-release Metformin Hydrochloride Fixed-combination Therapy
Oral

Individualize dosage based on the patient's current antidiabetic regimen.63 May increase dosage gradually based on effectiveness and tolerability.63

Patients not currently receiving treatment with either canagliflozin or metformin hydrochloride: Initially, 50 mg of canagliflozin and 500 mg of immediate-release metformin hydrochloride (Invokamet) twice daily.63

Patients currently receiving metformin hydrochloride: Initially, 100 mg of canagliflozin and a total daily metformin hydrochloride dosage similar to the patient's existing dosage, administered in 2 divided doses.63 In patients currently receiving an evening dose of extended-release metformin hydrochloride, skip last dose prior to initiating therapy with the fixed combination of canagliflozin and metformin hydrochloride the following morning.63

Patients currently receiving canagliflozin: Initially, same daily dosage of canagliflozin and metformin hydrochloride 1 g, administered in 2 divided doses.63

Patients currently receiving canagliflozin and metformin hydrochloride: Initially, same daily dosage of canagliflozin and a total daily metformin hydrochloride dosage similar to patient's existing dosage, administered in 2 divided doses.63

In patients with an eGFR ≥60 mL/minute per 1.73 m2 who are receiving concurrent therapy with a UGT enzyme inducer, consider increasing canagliflozin dosage to 300 mg once daily in patients who are tolerating a dosage of 100 mg once daily and require additional glycemic control.63 (See UGT Enzyme Inducers and see Specific Drugs and Laboratory Tests under Interactions.)

Canagliflozin/Extended-release Metformin Hydrochloride Fixed-combination Therapy
Oral

Individualize dosage based on the patient's current antidiabetic regimen.63 May increase dosage gradually based on effectiveness and tolerability.63

Patients not currently receiving treatment with either canagliflozin or metformin hydrochloride: Initially, 100 mg of canagliflozin and 1 g of extended-release metformin hydrochloride (Invokamet XR) once daily.63

Patients currently receiving metformin hydrochloride: Initially, 100 mg of canagliflozin and a total daily metformin hydrochloride dosage similar to the patient's existing dosage once daily.63 In patients currently receiving an evening dose of extended-release metformin hydrochloride, skip last dose prior to initiating therapy with the fixed combination of canagliflozin and metformin hydrochloride the following morning.63

Patients currently receiving canagliflozin: Initially, same daily dosage of canagliflozin and 1 g metformin hydrochloride once daily.63

Patients currently receiving canagliflozin and metformin hydrochloride: Initially, same daily dosage of canagliflozin and a total daily metformin hydrochloride dosage similar to patient's existing dosage once daily.63

In patients with an eGFR ≥60 mL/minute per 1.73 m2 who are receiving concurrent therapy with a UGT enzyme inducer, consider increasing canagliflozin dosage to 300 mg once daily in patients who are tolerating a dosage of 100 mg once daily and require additional glycemic control.63 (See UGT Enzyme Inducers and see Specific Drugs and Laboratory Tests under Interactions.)

Special Populations

Hepatic Impairment

Canagliflozin Monotherapy

Mild or moderate hepatic impairment: No dosage adjustment necessary.1

Severe hepatic impairment: Data lacking; not recommended.1

Canagliflozin/Metformin Hydrochloride Fixed-combination Therapy

Use of the fixed-combination preparation of canagliflozin and metformin hydrochloride not recommended.63

Renal Impairment

Canagliflozin Monotherapy

Mild renal impairment (eGFR ≥60 mL/minute per 1.73 m2): No dosage adjustment necessary.1

Moderate renal impairment (eGFR 45 to <60 mL/minute per 1.73 m2): 100 mg once daily.1 Initiation not recommended if eGFR <45 mL/minute per 1.73 m2.1 Continued use not recommended in patients with eGFR persistently <45 mL/minute per 1.73 m2.1

Consider another antidiabetic agent in patients with an eGFR of 45 to <60 mL/minute per 1.73 m2 receiving concurrent therapy with a UGT enzyme inducer.1 (See UGT Enzyme Inducers and see Specific Drugs and Laboratory Tests under Interactions.)

Severe renal impairment (eGFR <30 mL/minute per 1.73 m2): Contraindicated.1

Canagliflozin/Metformin Hydrochloride Fixed-combination Therapy

Moderate renal impairment (eGFR 45 to <60 mL/minute per 1.73 m2): Do not exceed 100 mg of canagliflozin component daily.63

Consider another antidiabetic agent in patients with an eGFR of 45 to <60 mL/minute per 1.73 m2 receiving concurrent therapy with a UGT enzyme inducer.63 (See UGT Enzyme Inducers and see Specific Drugs and Laboratory Tests under Interactions.)

eGFR <45 mL/minute per 1.73 m2: Use of the fixed combination of canagliflozin and metformin hydrochloride contraindicated.63

Geriatric Patients

Canagliflozin Monotherapy

No specific dosage recommendations.1

Canagliflozin/Metformin Hydrochloride Fixed-combination Therapy

Monitor renal function frequently after initiating the fixed-combination preparation; adjust dosage according to the patient's renal function.63 (See Renal Impairment under Dosage and Administration.)

Cautions for Invokana

Contraindications

  • History of serious hypersensitivity reaction (e.g., anaphylaxis, angioedema) to canagliflozin.1

  • Severe renal impairment (eGFR <30 mL/minute per 1.73 m2), end-stage renal disease, or on hemodialysis.1

Warnings/Precautions

Warnings

Lower Limb Amputation

Analysis of data from clinical studies evaluating canagliflozin (Canagliflozin Cardiovascular Assessment Study [CANVAS] and CANVAS-R) revealed a twofold increase in leg and foot amputations, mostly affecting the toes and midfoot, in patients receiving the drug.1 52 53 55 56 (See Boxed Warning.)

Prior to initiating canagliflozin therapy, consider factors that may predispose patients to the need for amputation (e.g., history of amputation, peripheral vascular disease, neuropathy, diabetic foot ulcers).1 55

Monitor patients for the presence of infection (including osteomyelitis), new pain or tenderness, or sores or ulcers involving the lower limbs; discontinue canagliflozin if such complications occur.1 55

Other Warnings/Precautions

Use of Fixed Combinations

When used in fixed combination with other drugs (e.g., metformin), consider the cautions, precautions, contraindications, and interactions associated with the concomitant agent(s) in addition to those associated with canagliflozin.1 63

Ketoacidosis

Ketoacidosis (e.g., diabetic ketoacidosis, ketoacidosis, ketosis) requiring hospitalization reported with SGLT2 inhibitors; may occur without markedly elevated blood glucose concentrations (e.g., <250 mg/dL).1 39 40 41 42 50

Evaluate for the presence of acidosis, including ketoacidosis, in patients experiencing signs or symptoms of acidosis regardless of the patient's blood glucose concentration; discontinue SGLT2 inhibitor and initiate appropriate treatment to correct acidosis if confirmed.1 39 40 50 (See Advice to Patients.)

Prior to initiating canagliflozin therapy, consider factors that may predispose patients to ketoacidosis (e.g., pancreatic insulin deficiency, reduced caloric intake, alcohol abuse).1 50

Consider temporarily discontinuing SGLT2 inhibitor in patients with clinical situations known to predispose patients to ketoacidosis (e.g., prolonged fasting due to acute illness or surgery).1 50

Advise patients to monitor urine and/or plasma ketone levels if patients feel unwell (see Advice to Patients).1 40 42 50

Hypotension

May cause intravascular volume contraction.1 Symptomatic hypotension can occur, particularly in patients with impaired renal function (eGFR <60 mL/minute per 1.73 m2), geriatric patients, patients receiving diuretics or drugs that interfere with the renin-angiotensin-aldosterone system (e.g., angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists), or patients with low systolic BP.1 Assess and correct intravascular volume prior to initiating canagliflozin in such patients.1

Monitor patients for sign and symptoms of hypotension after initiating therapy.1

Renal Effects

Causes intravascular volume contraction and can cause renal impairment.1 51

May increase Scr concentration and decrease eGFR; hypovolemic patients may be more susceptible.1 Renal function abnormalities can occur following initiation of therapy.1

Consider factors that may predispose patients to acute kidney injury, such as hypovolemia, chronic renal insufficiency, heart failure, concomitant medications (e.g., diuretics, ACE inhibitors, angiotensin II receptor antagonists, NSAIAs), prior to initiating canagliflozin therapy.1 51

Consider temporarily discontinuing canagliflozin in any setting of reduced oral intake (e.g., acute illness, fasting) or fluid losses (e.g., GI illness, excessive heat exposure).1 51

Monitor patients for acute kidney injury; monitor patients with an eGFR <60 mL/minute per 1.73 m2 more frequently.1 Discontinue canagliflozin and initiate appropriate treatment if such injury occurs.1 51

Concomitant Therapy with Hypoglycemic Agents

When adding canagliflozin to therapy with an insulin secretagogue (e.g., a sulfonylurea) or insulin, consider reducing dosage of the concomitant insulin secretagogue or insulin to reduce the risk of hypoglycemia.1 (See Specific Drugs and Laboratory Tests under Interactions.)

Fournier Gangrene

Fournier gangrene (necrotizing fasciitis of the perineum), a rare but serious or life-threatening bacterial infection requiring urgent surgical intervention, reported during postmarketing surveillance in men and women with type 2 diabetes mellitus receiving an SGLT2 inhibitor.1 59 60 61 62

Assess for necrotizing fasciitis in patients receiving canagliflozin who develop pain or tenderness, erythema, or swelling in the genital or perineal area, in addition to fever or malaise.1 60 Discontinue canagliflozin if Fournier gangrene suspected; initiate treatment with broad-spectrum antibiotics and perform surgical debridement if necessary.1 60 Monitor blood glucose concentrations closely; initiate alternative antidiabetic agents to maintain glycemic control.1 60

Genital Mycotic Infections

Possible increased risk of genital mycotic infections in males (e.g., balanoposthitis, candidal balanitis) and females (e.g., vulvovaginal candidiasis, vulvovaginal mycotic infection, vulvovaginitis).1 Patients with a history of genital mycotic infections and uncircumcised males more likely to develop such infections.1

Monitor patients for genital mycotic infections and institute appropriate treatment if these infections occur.1

Urosepsis and Pyelonephritis

May increase the risk of serious urinary tract infections (e.g., urosepsis, pyelonephritis requiring hospitalization).1 50

Prior to initiating canagliflozin therapy, consider patient factors that may predispose to serious urinary tract infections (e.g., history of difficulty urinating; infection of the bladder, kidneys, or urinary tract).50

Monitor patients for urinary tract infections and initiate treatment if indicated.1 50

Risk of Bone Fracture

Increased risk of bone fracture.1 43 Fractures observed as early as 12 weeks after initiation of canagliflozin treatment; more likely to affect the distal portion of upper and lower extremities and be associated with minor trauma (e.g., falls from no greater than standing height).1

Dose-related decreases in bone mineral density also observed in older adults (mean age: 64 years) receiving canagliflozin.1 43

Consider factors that contribute to fracture risk and counsel patients about such factors prior to initiating canagliflozin therapy.1 43

Effects on Lipoproteins

Dose-related increases in LDL-cholesterol can occur.1 Monitor serum lipid concentrations and treat if appropriate.1

Sensitivity Reactions

Hypersensitivity reactions (e.g., generalized urticaria), some serious, reported.1 Discontinue the drug if hypersensitivity reaction occurs, institute appropriate treatment, and monitor patients until signs and symptoms resolve.1

Specific Populations

Pregnancy

Studies in animals indicate that canagliflozin use during pregnancy may affect renal development and maturation.1

Not recommended for use in the second or third trimesters of pregnancy.1

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established in pediatric patients <18 years of age.1

Geriatric Use

Reduced efficacy compared with younger patients, which may be related to decreased renal function in geriatric patients.1 8 Such patients more likely to experience certain adverse effects related to reduced intravascular volume (e.g., hypotension, postural dizziness, orthostatic hypotension, syncope, dehydration), particularly with canagliflozin 300 mg daily.1 8

Hepatic Impairment

Canagliflozin: Not studied in severe hepatic impairment (Child-Pugh class C); use not recommended.1 (See Hepatic Impairment under Dosage and Administration.)

Fixed combination of canagliflozin and metformin hydrochloride: Use not recommended.63

Renal Impairment

Canagliflozin: Poorer overall glycemic control and higher rates of adverse effects reported in patients with moderate renal impairment and type 2 diabetes mellitus; may require dosage adjustment.1 (See Renal Impairment under Dosage and Administration.) Contraindicated in patients with severe renal impairment, end-stage renal disease, or on hemodialysis.1 Assess renal function prior to initiation of therapy and periodically thereafter.1

Fixed combination of canagliflozin and metformin hydrochloride: Use contraindicated in patients with eGFR <45 mL/minute per 1.73 m2. (See Renal Impairment under Dosage and Administration.)63

Common Adverse Effects

Female genital mycotic infections,1 urinary tract infection,1 increased urination,1 male genital mycotic infections,1 vulvovaginal pruritus,1 thirst,1 constipation,1 nausea.1

Interactions for Invokana

Major metabolic elimination pathway is O-glucuronidation; mainly glucuronidated by uridine disphosphoglucuronosyltransferase (UGT) isoenzymes UGT1A9 and UGT2B4.1

P-glycoprotein substrate and weak P-glycoprotein inhibitor.1 Also a substrate of MRP2.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Did not induce CYP-450 isoenzymes 3A4, 2C9, 2C19, 2B6, or 1A2 in cultured human hepatocytes; did not inhibit CYP1A2, 2A6, 2C19, 2D6, or 2E1 but weakly inhibits CYP2B6, 2C8, 2C9, and 3A4 in human hepatic microsomes.1

UGT Enzyme Inducers

Concomitant use of canagliflozin with an inducer of UGT enzymes may decrease the efficacy of canagliflozin.1 If concomitant use with an inducer of these UGT isoenzymes cannot be avoided, consider increasing the daily dosage of canagliflozin to 300 mg once daily in patients currently tolerating 100 mg once daily with an eGFR >60 mL/minute per 1.73 m2 who require additional glycemic control.1 Consider alternative antidiabetic agent in patients with an eGFR of 45 to <60 mL/minute per 1.73 m2 receiving concomitant therapy with a UGT inducer who require additional glycemic control.1

Specific Drugs and Laboratory Tests

Drug or Test

Interaction

Comments

ACE inhibitors

May increase the incidence of symptomatic hypotension1

May cause hyperkalemia in patients with moderate renal impairment1

Assess and correct intravascular volume prior to canagliflozin initiation; monitor for signs and symptoms of hypotension after initiating therapy1

Monitor serum potassium concentrations periodically in patients predisposed to hyperkalemia due to drug therapy1

Acetaminophen

Increased acetaminophen AUC1

No adjustment of acetaminophen dosage necessary1

Angiotensin II receptor antagonists

May increase the incidence of symptomatic hypotension1

May cause hyperkalemia in patients with moderate renal impairment1

Assess and correct intravascular volume prior to canagliflozin initiation; monitor for signs and symptoms of hypotension after initiating therapy1

Monitor serum potassium concentrations periodically in patients predisposed to hyperkalemia due to drug therapy1

Antidiabetic agents

Risk of hypoglycemia increased when canagliflozin is used concomitantly with a sulfonylurea or insulin1

Glyburide (single dose) with concomitant canagliflozin increased glyburide AUC and decreased peak plasma glyburide concentration1

Reduced dosage of insulin or sulfonylurea may be required to reduce risk of hypoglycemia1

No adjustment of glyburide dosage necessary1

Cyclosporine

Increased cyclosporine AUC and peak plasma concentration1

No adjustment of canagliflozin dosage necessary1

Digoxin

Increased AUC and peak plasma concentration of digoxin1

Monitor appropriately when canagliflozin and digoxin used concomitantly1

Diuretics

Risk of hypotension may be increased when canagliflozin is used concomitantly with diuretics1

Potassium-sparing diuretics: Patients with moderate renal impairment receiving concomitant canagliflozin and potassium-sparing diuretics more likely to develop hyperkalemia1

Assess and correct intravascular volume prior to canagliflozin initiation; monitor for signs and symptoms of hypotension after initiating therapy1

Monitor serum potassium concentrations periodically in patients predisposed to hyperkalemia due to drug therapy1

Hormonal contraceptives

Increased AUCs and peak plasma concentrations of ethinyl estradiol and levonorgestrel; decreased canagliflozin AUC and peak plasma concentration1

No dosage adjustment necessary1

Hydrochlorothiazide

Increased canagliflozin AUC and peak plasma concentration; decreased hydrochlorothiazide AUC and peak plasma concentration1 (see also Diuretics entry in this table.)

No dosage adjustment necessary1

Metformin

Increased canagliflozin and metformin AUCs and peak plasma concentrations1

No dosage adjustment necessary1

Phenobarbital

Possible decreased efficacy of canagliflozin due to reduced exposure with concurrent UGT inducers1

For eGFR >60 mL/minute per 1.73 m2: if concomitant use cannot be avoided, increase canagliflozin to 300 mg once daily1

For eGFR 45 to <60 mL/minute per 1.73 m2: consider alternative antidiabetic agent1

Phenytoin

Possible decreased efficacy of canagliflozin due to reduced exposure with concurrent UGT inducers1

For eGFR >60 mL/minute per 1.73 m2: if concomitant use cannot be avoided, increase canagliflozin to 300 mg once daily1

For eGFR 45 to <60 mL/minute per 1.73 m2: consider alternative antidiabetic agent1

Probenecid

Increased canagliflozin AUC and peak plasma concentration

No adjustment of canagliflozin dosage necessary1

Rifampin

Concomitant administration decreased canagliflozin AUC and peak plasma concentration1

Possible decreased efficacy of canagliflozin due to reduced exposure with concurrent UGT inducers1

For eGFR >60 mL/minute per 1.73 m2: if concomitant use cannot be avoided, increase canagliflozin to 300 mg once daily1

For eGFR 45 to <60 mL/minute per 1.73 m2: consider alternative antidiabetic agent1

Ritonavir

Possible decreased efficacy of canagliflozin due to reduced exposure with concurrent UGT inducers1

For eGFR >60 mL/minute per 1.73 m2: if concomitant use cannot be avoided, increase canagliflozin to 300 mg once daily1

For eGFR 45 to <60 mL/minute per 1.73 m2: consider alternative antidiabetic agent1

Simvastatin

Increased simvastatin AUC and peak plasma concentration1

No adjustment of simvastatin dosage necessary1

Urine glucose tests (e.g., 1,5-anhydroglucitol assay)

SGLT2 inhibitors increase urinary glucose excretion and will result in false-positive urine glucose tests1

Use alternative methods to monitor glycemic control1

Warfarin

Slightly increased R- and S-warfarin AUC and peak plasma concentrations1

No adjustment of warfarin dosage necessary1

Invokana Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations usually attained within 1–2 hours after oral dosing.1 12 Mean absolute oral bioavailability approximately 65%.1

Bioequivalence study: Fixed-combination tablets of canagliflozin and immediate-release metformin hydrochloride (Invokamet) are bioequivalent to individual tablets of canagliflozin and metformin hydrochloride administered concomitantly in equivalent doses under fed conditions.63

Fixed combination of canagliflozin and extended-release metformin hydrochloride (Invokamet XR) contains immediate-release canagliflozin and extended-release metformin hydrochloride.63

Food

Administration with a high-fat meal had no effect on canagliflozin pharmacokinetics.1 However, based on the drug's potential to reduce postprandial plasma glucose excursions due to delayed intestinal glucose absorption, take canagliflozin with the first meal of the day.1

Specific Populations

Mild hepatic impairment (Child-Pugh class A): AUC and peak plasma concentration increased by 10 and 7%, respectively, compared with individuals with normal hepatic function.1

Moderate hepatic impairment (Child-Pugh class B): AUC increased by 11% and peak plasma concentration decreased by 4% compared with individuals with normal hepatic function.1

Mild renal impairment (eGFR 60 to <90 mL/minute per 1.73 m2): AUC increased by 15%, compared with healthy individuals following a single 200-mg dose of the drug.1

Moderate renal impairment (eGFR 30 to <60 mL/minute per 1.73 m2): AUC increased by 29% compared with healthy individuals following a single 200-mg dose of the drug.1

Severe renal impairment (eGFR <30 mL/minute per 1.73 m2): AUC was increased by 53% compared with healthy individuals following a single 200-mg dose of the drug.1

Distribution

Extent

Extensively distributes into tissues.1

Plasma Protein Binding

99% (mainly to albumin).1

Specific Populations

Renal or hepatic impairment does not meaningfully alter plasma protein binding.1

Elimination

Metabolism

Metabolized principally via O-glucuronidation by UGT1A9 and UGT2B4 to inactive metabolites.1

Elimination Route

41.5, 7, and 3% recovered in feces as canagliflozin, a hydroxylated metabolite, and an O-glucuronide metabolite, respectively.1

33% excreted in urine; 30.5% as O-glucuronide metabolite and <1% as unchanged drug.1

Half-life

Terminal elimination half-life was 10.6 and 13.1 hours for single doses of 100 and 300 mg, respectively.1

Stability

Storage

Oral

Tablets

Canagliflozin: 25°C (may be exposed to 15–30°C).1

Fixed combination of canagliflozin and metformin hydrochloride: 20–25°C (may be exposed to 15–30°C).63 Store and dispense in original container. May store in pill box for ≤30 days.

Actions

  • Inhibits SGLT2, a transporter expressed in proximal renal tubules and responsible for majority of reabsorption of filtered glucose from tubular lumen.1 14

  • Reduces reabsorption of filtered glucose and lowers the renal threshold for glucose in a dose-dependent manner, leading to increased urinary glucose excretion.1 12 13

  • Increases glucose excretion independent of insulin secretion.14

  • May delay oral glucose absorption through transient inhibition of SGLT1 in the intestinal lumen.13 14

Advice to Patients

  • When canagliflozin is used in fixed combination with other drugs, importance of informing patients of important cautionary information about the concomitant agent(s).1 63

  • Importance of patient reading medication guide before initiating therapy and each time the drug is dispensed.1 17

  • Importance of informing patients of the potential risks and benefits of canagliflozin and of alternative therapies.1 Importance of not using canagliflozin in patients with type 1 diabetes mellitus or diabetic ketoacidosis.1 17

  • Importance of informing patients that if a dose of canagliflozin or the fixed combination of canagliflozin and metformin hydrochloride is missed, it should be taken as soon as it is remembered; if it is almost time for the next dose, the patient should skip the missed dose and take the drug at the next regularly scheduled time.1 63 Advise patients not to take 2 doses of the drug at the same time.1 63

  • Importance of informing patients that ketoacidosis, which can be a life-threatening condition, has been reported with canagliflozin therapy.1 17 Importance of informing patients and their caregivers of the signs and symptoms of ketoacidosis (e.g., tachypnea or hyperventilation, anorexia, abdominal pain, nausea, vomiting, lethargy, mental status change) and of instructing patients to discontinue canagliflozin and seek medical attention immediately should they experience any such signs or symptoms.1 17 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 (i.e., <250 mg/dL).1 17 50

  • Importance of informing patients that canagliflozin therapy is associated with an increased risk of the need for lower limb amputation, which may be higher in some patients, including those with peripheral vascular disease, neuropathy, diabetic foot ulcers, or a history of amputation.1 55 Importance of counseling patients on the importance of routine preventative foot care.1 Advise patients to monitor for new pain or tenderness, sores or ulcers, or infections involving the leg or foot and to seek medical attention immediately should they experience such signs or symptoms.1 52 55

  • Importance of informing patients that symptomatic hypotension may occur with canagliflozin and to report such symptoms to their clinicians.1 Inform patients that canagliflozin-induced dehydration may increase the risk of hypotension and that patients should maintain adequate fluid intake.1 17

  • Importance of informing patients that acute kidney injury has been reported with canagliflozin therapy.1 17 51 Advise patients to seek medical attention immediately if they experience decreased urine output, or swelling of the legs or feet.51 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 canagliflozin in those settings.1 51

  • Importance of informing patients that yeast infection may occur (e.g., vulvovaginitis, balanitis, balanoposthitis).1 17 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 17 Advise patients of treatment options and when to seek medical advice.1 17

  • Importance of informing patients of the potential for urinary tract infections, which may be serious.1 17 50 Advise patients of the signs and symptoms of urinary tract infection and the need to contact a clinician promptly if such signs and symptoms occur.1 50

  • Importance of informing patients that necrotizing infections of the perineum (Fournier gangrene) have occurred with canagliflozin therapy.1 60 Advise patients to seek prompt medical attention if they experience any symptoms of tenderness, redness, or swelling of the genitals or the area from the genitals back to the rectum, occurring with a fever above 38°C or malaise.1 60

  • Importance of informing patients that due to the mechanism of action of canagliflozin, patients taking the drug will test positive for glucose in their urine.1 Importance of not using urine glucose tests to monitor glycemic status.1

  • Risk of serious hypersensitivity reactions, such as rash, urticaria, and swelling of the face, lips, tongue, and throat that may result in difficulty breathing or swallowing.1 17 If signs or symptoms of such a reaction or anaphylaxis or angioedema occur , importance of discontinuing canagliflozin and informing clinician promptly.1 17

  • Importance of informing patients about the potential for bone fractures (e.g., hip, lumbar spine) and providing them with information about factors contributing to fracture risk.1 17 43

  • Importance of informing patients about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and glycosylated hemoglobin (hemoglobin A1c; HbA1c) testing, recognition and management of hypoglycemia and hyperglycemia, and assessment of diabetes complications.1 17

  • Importance of seeking medical advice promptly during periods of stress such as fever, trauma, infection, or surgery as drug requirements may change.1 17

  • Importance of taking canagliflozin exactly as directed by clinician.1 17 Importance of patients not discontinuing canagliflozin without discussion with prescribing clinician.1 17 43

  • Importance of women informing their clinicians if they are or plan to become pregnant or plan to breast-feed.1 17 Advise pregnant women and women of childbearing potential of the possible risk to a fetus with canagliflozin therapy.1 Advise women that breastfeeding is not recommended during canagliflozin therapy.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription (e.g., diuretics, rifampin, phenytoin, phenobarbital, ritonavir, digoxin) and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1 17

  • Importance of informing patients of other important precautionary information.1 17 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Canagliflozin

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablet, film-coated

100 mg (of anhydrous canagliflozin)

Invokana

Janssen

300 mg (of anhydrous canagliflozin)

Invokana

Janssen

Canagliflozin Combinations

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, extended-release

50 mg (of anhydrous canagliflozin) with Extended-release Metformin Hydrochloride 500 mg

Invokamet XR

Janssen

50 mg (of anhydrous canagliflozin) with Extended-release Metformin Hydrochloride 1 g

Invokamet XR

Janssen

150 mg (of anhydrous canagliflozin) with Extended-release Metformin Hydrochloride 500 mg

Invokamet XR

Janssen

150 mg (of anhydrous canagliflozin) with Extended-release Metformin Hydrochloride 1 g

Invokamet XR

Janssen

Tablets, film-coated

50 mg (of anhydrous canagliflozin) with Metformin Hydrochloride 500 mg

Invokamet

Janssen

50 mg (of anhydrous canagliflozin) with Metformin Hydrochloride 1 g

Invokamet

Janssen

150 mg (of anhydrous canagliflozin) with Metformin Hydrochloride 500 mg

Invokamet

Janssen

150 mg (of anhydrous canagliflozin) with Metformin Hydrochloride 1 g

Invokamet

Janssen

AHFS DI Essentials™. © Copyright 2020, Selected Revisions November 18, 2019. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Janssen Pharmaceuticals, Inc. Invokana (canagliflozin) tablets prescribing information. Titusville, NJ; 2018 Oct.

2. Stenlöf K, Cefalu WT, Kim KA et al. Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes Obes Metab. 2013; 15:372-82. http://www.ncbi.nlm.nih.gov/pubmed/23279307?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3593184&blobtype=pdf

3. Cefalu WT, Leiter LA, Yoon KH et al. Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial. Lancet. 2013; :. http://www.ncbi.nlm.nih.gov/pubmed/23850055?dopt=AbstractPlus

4. Fulcher G, Matthews DR, Perkovic V et al. Canagliflozin (CANA) in subjects with type 2 diabetes mellitus (T2DM) inadequately controlled on sulfonylurea (SU) monotherapy: a CANVAS study. Abstract presented at 73rd annual American Diabetes Association scientific sessions. Chicago, IL, 2013 June 21-5. Abstract No. 1124-P.

5. Wilding JP, Mathieu C, Vercruysse F et al. Canagliflozin (CANA), a sodium glucose co-transporter 2 inhibitor, improves glycemic control and reduced body weight in subjects with type 2 diabetes (T2D) inadequately controlled with metformin (MET) and sulfonylurea (SU). Abstract presented at 72rd annual American Diabetes Association scientific sessions. Philadelphia, PA, 2012 June 8-12. Abstract No. 1022-P.

6. Schernthaner G, Gross JL, Rosenstock J et al. Canagliflozin Compared With Sitagliptin for Patients With Type 2 Diabetes Who Do Not Have Adequate Glycemic Control With Metformin Plus Sulfonylurea: A 52-week randomized trial. Diabetes Care. 2013; :.

7. Forst T, Guthrie R, Goldenberg R, et al. Efficacy and safety of canagliflozin in subjects with type 2 diabetes on metformin and pioglitazone. Abstract presented at 4th World Congress on controversies to consensus in diabetes, obesity, and hypertension (CODHy). Barcelona, Spain, 2012 Nov 8-11.

8. Bode B, Stenlöf K, Sullivan D et al. Efficacy and safety of canagliflozin treatment in older subjects with type 2 diabetes mellitus: a randomized trial. Hosp Pract (1995). 2013; 41:72-84. http://www.ncbi.nlm.nih.gov/pubmed/23680739?dopt=AbstractPlus

9. Yale JF, Bakris G, Cariou B et al. Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease. Diabetes Obes Metab. 2013; 15:463-73. http://www.ncbi.nlm.nih.gov/pubmed/23464594?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3654568&blobtype=pdf

10. Devineni D, Morrow L, Hompesch M et al. Canagliflozin improves glycaemic control over 28 days in subjects with type 2 diabetes not optimally controlled on insulin. Diabetes Obes Metab. 2012; 14:539-45. http://www.ncbi.nlm.nih.gov/pubmed/22226086?dopt=AbstractPlus

11. Inagaki N, Kondo K, Yoshinari T et al. Efficacy and safety of canagliflozin in Japanese patients with type 2 diabetes: a randomized, double-blind, placebo-controlled, 12-week study. Diabetes Obes Metab. 2013; :. http://www.ncbi.nlm.nih.gov/pubmed/23782594?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3906835&blobtype=pdf

12. Devineni D, Curtin CR, Polidori D et al. Pharmacokinetics and pharmacodynamics of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in subjects with type 2 diabetes mellitus. J Clin Pharmacol. 2013; 53:601-10. http://www.ncbi.nlm.nih.gov/pubmed/23670707?dopt=AbstractPlus

13. Polidori D, Sha S, Mudaliar S et al. Canagliflozin Lowers Postprandial Glucose and Insulin by Delaying Intestinal Glucose Absorption in Addition to Increasing Urinary Glucose Excretion: Results of a randomized, placebo-controlled study. Diabetes Care. 2013; 36:2154-61. http://www.ncbi.nlm.nih.gov/pubmed/23412078?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3714520&blobtype=pdf

14. 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; :. http://www.ncbi.nlm.nih.gov/pubmed/23744749?dopt=AbstractPlus

15. Nomura S, Sakamaki S, Hongu M et al. Discovery of canagliflozin, a novel C-glucoside with thiophene ring, as sodium-dependent glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes mellitus. J Med Chem. 2010; 53:6355-60. http://www.ncbi.nlm.nih.gov/pubmed/20690635?dopt=AbstractPlus

16. Rosenstock J, Aggarwal N, Polidori D et al. Dose-ranging effects of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, as add-on to metformin in subjects with type 2 diabetes. Diabetes Care. 2012; 35:1232-8. http://www.ncbi.nlm.nih.gov/pubmed/22492586?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3357223&blobtype=pdf

17. Janssen Pharmaceuticals, Inc. Invokana (canagliflozin) tablets medication guide. Titusville, NJ; 2018 Oct.

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. http://www.fda.gov/downloads/Drugs/DrugSafety/UCM446954.pdf

40. Rosenstock J, Ferrannini E. Euglycemic diabetic ketoacidosis: a predictable, detectable, and preventable safety concern with SGLT2 inhibitors. Diabetes Care. 2015; 38:1638-42. http://www.ncbi.nlm.nih.gov/pubmed/26294774?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/26203064?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=4542268&blobtype=pdf

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. http://www.ncbi.nlm.nih.gov/pubmed/26078479?dopt=AbstractPlus

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. http://www.fda.gov/Drugs/DrugSafety/ucm461449.htm

44. Rosenstock J, Chuck L, González-Ortiz M et al. Initial Combination Therapy With Canagliflozin Plus Metformin Versus Each Component as Monotherapy for Drug-Naïve Type 2 Diabetes. Diabetes Care. 2016; 39:353-62. http://www.ncbi.nlm.nih.gov/pubmed/26786577?dopt=AbstractPlus

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. http://www.fda.gov/downloads/Drugs/DrugSafety/UCM475487.pdf

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. http://www.fda.gov/downloads/Drugs/DrugSafety/UCM506772.pdf

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. http://www.fda.gov/downloads/Drugs/DrugSafety/UCM501749.pdf

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. http://www.ncbi.nlm.nih.gov/pubmed/23895803?dopt=AbstractPlus

54. Rodbard HW, Seufert J, Aggarwal N et al. Efficacy and safety of titrated canagliflozin in patients with type 2 diabetes mellitus inadequately controlled on metformin and sitagliptin. Diabetes Obes Metab. 2016; 18:812-9. http://www.ncbi.nlm.nih.gov/pubmed/27160639?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=5089595&blobtype=pdf

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. https://www.fda.gov/downloads/Drugs/DrugSafety/UCM558427.pdf

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; http://www.ncbi.nlm.nih.gov/pubmed/31060053?dopt=AbstractPlus

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. https://www.fda.gov/downloads/Drugs/DrugSafety/UCM618466.pdf

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. http://www.ncbi.nlm.nih.gov/pubmed/28887847?dopt=AbstractPlus

63. Janssen Pharmaceuticals, Inc. Invokamet/Invokamet XR (canagliflozin and immediate- or extended-release metformin hydrochloride) tablets prescribing information. Titusville, NJ; 2018 Oct.

82. Neal B, Perkovic V, Mahaffey KW et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017; 377:644-657. http://www.ncbi.nlm.nih.gov/pubmed/28605608?dopt=AbstractPlus

83. Mahaffey KW, Neal B, Perkovic V et al. Canagliflozin for primary and secondary prevention of cardiovascular events: results from the CANVAS program (canagliflozin cardiovascular assessment study). Circulation. 2018; 137:323-334. http://www.ncbi.nlm.nih.gov/pubmed/29133604?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/28102030?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/25589482?dopt=AbstractPlus

86. 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. http://www.ncbi.nlm.nih.gov/pubmed/30990260?dopt=AbstractPlus

87. Jardine MJ, Mahaffey KW, Neal B et al. The Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) Study Rationale, Design, and Baseline Characteristics. Am J Nephrol. 2017; 46:462-472. http://www.ncbi.nlm.nih.gov/pubmed/29253846?dopt=AbstractPlus

88. Ingelfinger JR, Rosen CJ. Clinical Credence - SGLT2 Inhibitors, Diabetes, and Chronic Kidney Disease. N Engl J Med. 2019; 380:2371-2373. http://www.ncbi.nlm.nih.gov/pubmed/30990261?dopt=AbstractPlus

598. Garber AJ, Abrahamson MJ, Barzilay JI et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endorinology on the comprehensive type 2 diabetes management algorithm - 2019 executive summary. Endocr Pract. 2019; 25:69-100. http://www.ncbi.nlm.nih.gov/pubmed/30742570?dopt=AbstractPlus

604. American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes-2019. Diabetes Care. 2019; 42:S90-S102. http://www.ncbi.nlm.nih.gov/pubmed/30559235?dopt=AbstractPlus

606. American Diabetes Association. 11. Microvascular complications and foot care: standards of medical care in diabetes-2019. Diabetes Care. 2019; 42:S124-S138. http://www.ncbi.nlm.nih.gov/pubmed/30559237?dopt=AbstractPlus

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