canagliflozin (Invokana)
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Indications
- diabetes mellitus type 2
- slows progression of diabetic nephropathy
- reduces risk of hospitalization for heart failure[18]
Contraindications
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]
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
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 adverse effects of hypoglycemic agents
- drug adverse effects of oral glucosuric agent; SGLT-2 inhibitor; flozin
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]
- drug interaction(s) SGLT2 inhibitors (flozins) with diuretics
- drug interaction(s) of aldosterone antagonists with SGLT2-inhibitor
- drug interaction(s) of fluoroquinolones with hypoglycemic agents
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]
More general terms
Component of
References
- ↑ 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 - ↑ 2.0 2.1 2.2 FDA News Release: March 29, 2013 FDA approves Invokana to treat type 2 diabetes http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm345848.htm
- ↑ Prescriber's Letter 20(5): 2013 New Drug: Invokana (Canagliflozin) Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=290508&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ 4.0 4.1 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 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/23850055 <Internet> http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(13)60683-2/fulltext
- ↑ 5.0 5.1 5.2 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
- ↑ 6.0 6.1 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
- ↑ 7.0 7.1 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 - ↑ 8.0 8.1 8.2 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 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/26078479 <Internet> http://care.diabetesjournals.org/content/38/9/1687
- ↑ 9.0 9.1 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. <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/26989182 <Internet> http://care.diabetesjournals.org/content/39/4/532
- ↑ 10.0 10.1 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 - ↑ 11.0 11.1 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
- ↑ 12.0 12.1 12.2 12.3 12.4 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 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/28605608 Free Article <Internet> http://www.nejm.org/doi/10.1056/NEJMoa1611925
- ↑ 13.0 13.1 13.2 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 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/29437648 Free full text <Internet> http://www.bmj.com/content/360/bmj.k119
- ↑ 14.0 14.1 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: https://www.ncbi.nlm.nih.gov/pubmed/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: https://www.ncbi.nlm.nih.gov/pubmed/30105365 - ↑ Brooks M Canagliflozin (Invokana) Gets FDA Nod for CV Protection. Medscape - Oct 31, 2018 https://www.medscape.com/viewarticle/904201
- ↑ 16.0 16.1 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: https://www.ncbi.nlm.nih.gov/pubmed/30597484
- ↑ 17.0 17.1 17.2 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: https://www.ncbi.nlm.nih.gov/pubmed/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: https://www.ncbi.nlm.nih.gov/pubmed/30990261 https://www.nejm.org/doi/full/10.1056/NEJMe1904740 - ↑ 18.0 18.1 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
- ↑ 19.0 19.1 Brailovski E et al Rosuvastatin Myotoxicity After Starting Canagliflozin Treatment: A Case Report. Ann Intern Med. Aug 4, 2020 PMID: https://www.ncbi.nlm.nih.gov/pubmed/32744865 https://www.acpjournals.org/doi/10.7326/L20-0549
- ↑ 20.0 20.1 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=
- ↑ 21.0 21.1 Canagliflozin (Invokana) Prescribing Information http://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/INVOKANA-pi.pdf