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canagliflozin (Invokana)

Indications: - diabetes mellitus type 2 - slows progression of diabetic nephropathy - reduces risk of hospitalization for heart failure [18] Contraindications: - diabetes mellitus type 1 - diabetic ketoacidosis - renal impairment: GFR < 30 ml/min/1.73 m2 [21] Dosage: - start 100 mg PO QD before 1st meal of day - may increase to 300 mg QD if GFR > 60 ml/min/1.73 m2 - stop 3 days prior to surgery Tabs: 100 mg, 300 mg Benefit/risk: - small, but statistically significant decrease in cardiovascular risk & in risk of chronic renal failure: (studies sponsored by manufacturer) NNT = 250 - composite of end-stage kidney disease, creatinine doubling, or death due to renal complications significantly lower with canagliflozin vs placebo (27 vs 40 per 1000 patient years) [17] - rate of myocardial infarction, stroke, or CV death significantly lower with canagliflozin vs placebo (39 vs 49 per 1000 patient years) [17] - lower risk of hospitalization for heart failure than with other hypoglycemic agents: events/1000 patient years = 7-9 vs 13 for DPP-4 inhibitors, 14 for sulfonylureas, & 12 for GLP-1-receptor agonists [13] - no difference in composite risk of myocardial infarction or stroke [13] Adverse effects: - orthostatic hypotension common during 1st 3 months of therapy - vaginal yeast infection (vulvovaginal candidiasis) [12] - urinary tract infection [2] - male genital infections [12] - ketoacidosis [6,8] - bone fractures can occur as early as 12 weeks after starting canagliflozin [7,8] - decreases in bone mineral density at the hip & lumbar spine - fractures not more common in patients taking canagliflozin [16] - diabetic ketoacidosis (5%) when prescribed off-label for type 1 diabetes [9] - increased risk of leg, foot & toe amputations [10,12,14] - FDA removes boxed warning about amputation risk [20] - risk of acute kidney injury [11] Drug interactions: - case report of myopathy, rhabdomyolysis & hepatotoxicity 15 days after statring canagliflozin (100 mg) in a patient who has been taking rosuvastatin (40 mg) for 5 years [19] Laboratory: - increases HDL cholesterol & LDL cholesterol - decreases serum triglycerides [4] - lowers hemoglobin A1c by ~ 1% [5] Mechanism of action: - selective sodium glucose co-transporter 2 inhibitor - prevents reabsorption of glucose by the kidney, thus increasing glucose excretion in the urine - associated weight reduction (~ 3 kg) [5] & decrease in blood pressure - has diuretic effect [2] Notes: - 2017 cost $6000/year [12]

Interactions

drug adverse effects of hypoglycemic agents

General

SGLT-2 inhibitor; oral glucosuric agent; flozin

References

  1. Thomas K F.D.A. Advisory Panel Votes to Approve Diabetes Drug New York Times. Jan 10, 2013 http://www.nytimes.com/2013/01/11/business/fda-advisory-panel-votes-to-approve-diabetes-drug.html?_r=0 - Johnson & Johnson. News Release. Jan 10, 2013 FDA Advisory Committee Recommends Approval of Canagliflozin for Treatment of Adults with Type 2 Diabetes http://www.jnj.com/connect/news/all/fda-advisory-committee-recommends-approval-of-canagliflozin-for-treatment-of-adults-with-type-2-diabetes
  2. FDA News Release: March 29, 2013 FDA approves Invokana to treat type 2 diabetes http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm345848.htm
  3. Prescriber's Letter 20(5): 2013 New Drug: Invokana (Canagliflozin) Detail-Document#: 290508 (subscription needed) http://www.prescribersletter.com
  4. Cefalu WT 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 Jul 12 PMID: 23850055 http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(13)60683-2/fulltext
  5. Schernthaner G 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 Sep; 36:2508
  6. FDA MedWatch. May 15, 2015 SGLT2 inhibitors: Drug Safety Communication - FDA Warns Medicines May Result in a Serious Condition of Too Much Acid in the Blood. https://mail.google.com/mail/u/0/?tab=wm#inbox/14d587f1089e0791
  7. FDA Safety Alert. 09/10/2015 Invokana and Invokamet (canagliflozin): Drug Safety Communication - New Information on Bone Fracture Risk and Decreased Bone Mineral Density. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm461876.htm
  8. 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 Sep; 38:1687 PMID: 26078479 http://care.diabetesjournals.org/content/38/9/1687
  9. Peters AL, Henry RR, Thakkar P, Tong C, Alba M. Diabetic ketoacidosis with canagliflozin, a sodium-glucose cotransporter 2 inhibitor, in patients with type 1 diabetes. Diabetes Care 2016 Apr; 39:532. PMID: 26989182 http://care.diabetesjournals.org/content/39/4/532
  10. FDA Safety Alert. May 18, 2016 Canagliflozin (Invokana, Invokamet): Drug Safety Communication - Clinical Trial Results Find Increased Risk of Leg and Foot Amputations. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm501565.htm - FDA Drug Safety Communication May 16, 2017: FDA confirms increased risk of leg and foot amputations with the diabetes medicine canagliflozin (Invokana, Invokamet, Invokamet XR). https://www.fda.gov/Drugs/DrugSafety/ucm557507.htm
  11. FDA Safety Alert. June 14, 2016 Canagliflozin (Invokana, Invokamet) and Dapagliflozin (Farxiga, Xigduo XR): Drug Safety Communication - Strengthened Kidney Warnings. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm506554.htm
  12. Neal B, Perkovic V, Mahaffey KW et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017 Jun 12 PMID: 28605608 Free Article http://www.nejm.org/doi/10.1056/NEJMoa1611925
  13. Patorno E, Goldfine AB, Schneeweiss S. Cardiovascular outcomes associated with canagliflozin versus other non-gliflozin antidiabetic drugs: population based cohort study. BMJ 2018;360:k119 PMID: 29437648 Free full text http://www.bmj.com/content/360/bmj.k119
  14. Chang HY, Singh S, Mansour O, Baksh S, Alexander GC Association between sodium-glucose cotransporter 2 inhibitors and lower extremity amputation among patients with type 2 diabetes. JAMA Intern Med 2018 Aug 13; PMID: 30105373 - Fralick M, Patorno E, Fischer MA Sodium-glucose cotransporter 2 inhibitors and the risk of amputation: Results and challenges from the real world. JAMA Intern Med 2018 Aug 13; PMID: 30105365
  15. Brooks M Canagliflozin (Invokana) Gets FDA Nod for CV Protection. Medscape - Oct 31, 2018 https://www.medscape.com/viewarticle/904201
  16. Fralick M, Kim SC, Schneeweiss S et al. Fracture risk after initiation of use of canagliflozin: A cohort study. Ann Intern Med 2019 Jan 1 PMID: 30597484
  17. Perkovic V, Jardine MJ, Neal B et al Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med 2019. April 14. PMID: 30995972 https://www.nejm.org/doi/full/10.1056/NEJMoa1811744 - Ingelfinger JR, Rosen CJ Clinical Credence - SGLT2 Inhibitors, Diabetes, and Chronic Kidney Disease N Engl J Med 2019. April 14, PMID: 30990261 https://www.nejm.org/doi/full/10.1056/NEJMe1904740
  18. Janssen, Johnston & Johnson News Release. Sep 30, 2019 U.S. FDA Approves INVOKANA (canagliflozin) to Treat Diabetic Kidney Disease (DKD) and Reduce the Risk of Hospitalization for Heart Failure in Patients with Type 2 Diabetes (T2D) and DKD. https://www.janssen.com/us-fda-approves-invokana-canagliflozin-treat-diabetic-kidney-disease-dkd-and-reduce-risk
  19. Brailovski E et al Rosuvastatin Myotoxicity After Starting Canagliflozin Treatment: A Case Report. Ann Intern Med. Aug 4, 2020 PMID: 32744865 https://www.acpjournals.org/doi/10.7326/L20-0549
  20. FDA Safety INformation. Aug 26, 2020 Invokana, Invokamet, Invokamet XR (canagliflozin): MedWatch Safety Alert - Boxed Warning about Risk of Leg and Foot Amputations Removed. https://www.fda.gov/safety/medical-product-safety-information/invokana-invokamet-invokamet-xr-canagliflozin-medwatch-safety-alert-boxed-warning-about-risk-leg-and?utm_campaign=
  21. Canagliflozin (Invokana) Prescribing Information http://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/INVOKANA-pi.pdf

Component-of

canagliflozin/metformin (Invokamet)