(canagliflozin)
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Last Updated: 07/25/2023
After a median follow-up of 2.62 years, the CREDENCE trial was stopped early for achieving the pre-specified criteria for the primary outcome (P<0.01) and the composite of ESKD or death from renal and CV causes (P<0.025).23, 47
Janssen designated all lower-extremity amputation procedures as an AE of special interest and required reporting of any amputation procedure within 24 hours of becoming aware of the procedure. Janssen created a designated Lower-Extremity Amputation electronic case report form (eCRF) where all details relating to the amputation procedure(s) must be recorded.
From: Perkovic V, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy (CREDENCE). Data presented at the International Society of Nephrology: World Congress of Nephrology, 15 April 2019; Melbourne, Australia. Reprinted with permission from The George Institute for Global Health. ©The George Institute for Global Health.
The CANVAS Program25 (N=10,142) comprises 2 large CANA CV outcome studies, CANVAS52, 53 and CANVAS-R54, 55, designed to meet FDA post-marketing requirement (PMR) to evaluate CV safety and efficacy of CANA in patients with T2DM who had either a prior history of CV disease or at least two CV risk factors.54-57 The mean duration of diabetes at baseline was 13.5 years 25
Baseline characteristics were similar in the CANA and placebo treatment groups and were comparable across CANVAS and CANVAS-R.
During interim analysis of safety data from CANVAS, the IDMC identified amputation as a potential signal that should be further investigated.58Prior clinical or preclinical studies did not find any risk or concern for amputation with CANA.26 Before the interim analysis, amputation events and other AEs were recorded by investigators using electronic case record forms. Following the notification of the potential signal, in July 2016, a dedicated case report form (CRF) was created to prospectively and retroactively collect information on all cases of amputation. Additionally, all participant care records and the pharmacovigilance database were searched to identify additional possible events.
The proximate etiologies (infection, chronic, or acute ischemia) underlying each amputation event was evaluated in a secondary post hoc assessment by a specialist in peripheral vascular disease.26
Patients with amputation n (%) | Total amputationsa | Amputation incidence (per 1000 PYs) | HR (95% CI) | ||
---|---|---|---|---|---|
CANVAS Program25 | PBO (N=4344) | 47 (1.1) | 69 | 3.4 | 1.97 (1.41-2.75) |
CANA (N=5790) | 140 (2.4) | 221 | 6.3b | ||
CANVAS24 | PBO (N=1441) | 22 (1.5) | 33 | 2.8 | - |
CANA 100 mg (N=1445) | 50 (3.5) | 83 | 6.2 | 2.24 (1.36-3.69) | |
CANA 300 mg (N=1441) | 45 (3.1) | 79 | 5.5 | 2.01 (1.20-3.34) | |
CANA-Pooled (N=2886) | 95 (3.3) | 162 | 5.9 | 2.12 (1.34-3.38) | |
CANVAS-R24 | PBO (N=2903) | 25 (0.9) | 36 | 4.2 | 1.80 (1.10-2.93) |
CANAc (N=2904) | 45 (1.5) | 59 | 7.5 | ||
Abbreviations: CANA, INVOKANA; CI, confidence interval; HR, hazard ratio; PBO, placebo; PYs, patient-years. aSome patients had more than one surgical amputation; bP<0.001 vs placebo. cInitial dose of CANA 100 mg with optional up-titration to 300 mg at 13 weeks. |
Matthews et al (2019)26 conducted secondary analyses of amputation events from the integrated dataset of the CANVAS Program, apart from dose effects, which was done on the CANVAS study dataset alone.
Univariate associations were determined for risk factors for amputation independent of study drug, then those risk factors were included in a multivariate model that included the randomized treatment. The absolute effects of amputation (all events and major events) were modelled to estimate events for 1000 patients treated for 5 years, excluding patients with >1 amputation risk that was found to be significant in the multivariate model.
At baseline, 238 patients had a history of amputation.
CANA | PBO | HR (95% CI) | |||
---|---|---|---|---|---|
N/140 (%) | EVRT/1000 PY | N/47 (%) | EVRT/1000 PY | ||
Infection | 136 (97) | 2.43 | 47 (100) | 1.15 | 2.18 (1.24-3.83) |
Chronic ischemia | 82 (59) | 3.68 | 31 (66) | 2.22 | 1.77 (1.17-2.69) |
Acute ischemia | 2 (1.4) | 0.09 | 0 | 0.00 | - |
Undetermined | - | 0.14 | 0 | 0.00 |
|
Abbreviations: CI, confidence interval; HR, hazard ration; PBO, placebo; PY, patient-year. |
At the time of the amputation event: 75% of total patients were on randomized treatment (n=140); 10% were within 30 days after discontinuation of treatment (n=19), and 15% were >30 days after treatment discontinuation (n=28).26
Major Amputation Events in the INVOKANA vs Placebo Groups During the CANVAS Program26
From: Matthews, et al. Effects of canagliflozin on amputation risk in type 2 diabetes: the CANVAS Program. Diabetologia. 2019;62(6):926-938. Reprinted with permission from Creative Commons Attribution 4.0.
Minor Amputation Events in the INVOKANA vs Placebo Groups During the CANVAS Program26
From: Matthews, et al. Effects of canagliflozin on amputation risk in type 2 diabetes: the CANVAS Program. Diabetologia. 2019;62(6):926-938. Reprinted with permission from Creative Commons Attribution 4.0.
Barraclough et al (2021)27 conducted a pooled analysis of individual patient data from the CANVAS Program and CREDENCE study to evaluate the cardiovascular and renal outcomes of INVOKANA in patients with T2DM with and without PAD. Safety data in terms of amputation events in patients treated with INVOKANA vs placebo has been described.
A literature search of MEDLINE®, Embase®, BIOSIS Previews®, Derwent Drug File (and/or other resources, including internal/external databases) was conducted on 09 March 2023.
1 | Pharmacovigilance Risk Assessment Committee (PRAC) Assessment Report: SGLT2 inhibitors and lower limb amputation (canagliflozin, dapagliflozin, empagliflozin-containing medicines). EMA/PRAC/637349/2016. 9 February 2017. http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/SGLT2_inhibitors_Canagliflozin_20/European_Commission_final_decision/WC500227102.pdf. Published 8 May 2017. |
2 | (EMA) European Medicines Agency. SGLT2 inhibitors: information on potential risk of toe amputation to be included in prescribing information. EMA/118223/2017. http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/SGLT2_inhibitors_Canagliflozin_20/Opinion_provided_by_Committee_for_Medicinal_Products_for_Human_Use/WC500222187.pdf. Published 24 February 2017. |
3 | Health Canada. Health Product InfoWatch - December 2016: New Health Product Safety Information. Ottawa (ON): Health Canada. 2016. http://www.hc-sc.gc.ca/dhp-mps/medeff/bulletin/hpiw-ivps_2016-12-page2-eng.php. Accessed 2017 February 9. |
4 | Canagliflozin: Safety advisory - potential increased risk of lower limb amputation. Available at: https://www.tga.gov.au/alert/canagliflozin. Accessed. |
5 | 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. Published June 12. doi:10.1056/NEJMoa1611925. |
6 | Yuan Z, DeFalco FJ, Ryan PB, et al. Risk of Lower Extremity Amputations in Patients With Type 2 Diabetes Mellitus Treated with SGLT2 Inhbitors in the United States: A Retrospective Cohort Study. Diabetes Obes Metab. 2018 March;20(3):582-589. doi:10.1111/dom.13115. |
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21 | Lin C, Zhu X , Cai X , et al. SGTL2 inhibitors and lower limb complications: an updated meta-analysis. Cardiovasc Diabetol. 2021;20:91. |
22 | FDA Drug Safety Communication: FDA removes boxed warning about risk of leg and foot amputations for the diabetes medicine canagliflozin (Invokana, Invokamet, Invokamet XR). Food and Drug Administration (FDA); 2020. https://www.fda.gov/drugs/drug-safety-and-availability/fda-removes-boxed-warning-about-risk-leg-and-foot-amputations-diabetes-medicine-canagliflozin. Accessed August 26, 2020. |
23 | Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy [published online ahead of print April 14 2019]. NEJM. 2019. doi:10.1056/NEJMoa1811744. |
24 | FDA Drug Safety Communication: FDA confirms increased risk of leg and foot amputations with the diabetes medicine canagliflozin (Invokana, Invokamet, Invokamet XR). FDA Safety Announcement. May 16, 2017. https://www.fda.gov/Drugs/DrugSafety/ucm557507.htm. |
25 | Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644-657. |
26 | Matthews DR, Li Q, Perkovic V, et al. Effects of canagliflozin on amputation risk in type 2 diabetes: the CANVAS Program. Diabetologia. 2019;62(6):926-938. |
27 | Barraclough JY, Yu J, Figtree GA, et al. Cardiovascular and renal outcomes with canagliflozin in patients with peripheral arterial disease: Data from the CANVAS Program and CREDENCE trial. Diabetes Obes Metab. 2022;24(6):1072-1083. |
28 | Arnott C, Huang Y, Neuen BL, et al. The effect of canagliflozin on amputation risk in the CANVAS program and the CREDENCE trial. Diabetes Obes Metab. 2020;22:1753-1766. |
29 | Janssen Pharmaceuticals, Inc. INVOKANA® and INVOKAMET® Dear Healthcare Professional Letter. Interim Safety Analysis from an Ongoing Trial Observed a Higher Incidence of Lower Limb Amputations (Primarily of the Toe) in Patients Treated with INVOKANA® (canagliflozin). Reminder Regarding the Importance of Foot Care in Patients with Diabetes. 20-May-16. |
30 | Matthews DR. The CANVAS Program (CANagliflozin cardioVascular Assessment Study). Symposium presented at the 53rd Annual Meeting of the European Association for the Study of Diabetes (EASD); 15 September 2017; Lisbon, Portugal. Available at: http://www.georgeinstitute.org/sites/default/files/easd_2017_canvas_program_symposium_deck_0.pdf. Webcast available at: https://www.easd.org/virtualmeeting/home.html#!resources/canagliflozin-cardiovascular-assessment-study-canvas . |
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38 | Yale JF, Bakris G, Xi L, et al. Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease. Diabetes, Obesity and Metabolism. 2013;15:463-473. |
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40 | 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;382:941-950. |
41 | Leiter LA, Yoon KH, Arias P, et al. Canagliflozin provides durable glycemic improvements and body weight reduction over 104 weeks versus glimepiride in patients with type 2 diabetes on metformin: a randomized, double-blind, phase 3 study. Diabetes Care. 2015;38(3):355-364. |
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44 | Rosenstock J, Chuck L, Gonzalez-Ortiz M, et al. Initial combination therapy with canagliflozin plus metformin versus each component as monotherapy for drug-naive type 2 diabetes mellitus. Diabetes Care. 2016;19(39):353-362. |
45 | Townsend RR, Machin I, Ren J, et al. Reductions in mean 24-hour ambulatory blood pressure after 6-week treatment with canagliflozin in patients with type 2 diabetes mellitus and hypertension. The Journal of Clinical Hypertension. 2016;18(1):43-52. |
46 | 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, Obesity and Metabolism. 2016;18(8):812-819. |
47 | 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(6):462-472. |
48 | Perkovic V, Jardine MJ, Neal B, et al. Supplementary Appendix for: Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019;380(24):2295-2306. |
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50 | Jardine MJ, Mahaffey KW, Neal B, et al. Supplementary Material for: The Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) Study Rationale, Design, and Baseline Characteristics. Am J Nephrol. 2017;46(6). |
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54 | Janssen Research & Development. (Posted 2013). A Randomized, Multicenter, Double-Blind, Parallel, Placebo-Controlled Study of the Effects of Canagliflozin on Renal Endpoints in Adult Subjects With Type 2 Diabetes Mellitus (NCT01989754). https://clinicaltrials.gov/show/NCT01989754. |
55 | Neal B, Perkovic V, Matthews D, et al. Rationale, design and baseline characteristics of the CANagliflozin cardioVascular Assessment Study-Renal (CANVAS-R): a randomized, placebo-controlled trial. Diabetes Obes Metab. 2017;19(3):387-393. |
56 | Neal B, Perkovic V, Mahaffey K, et al. Optimizing the analysis strategy for the CANVAS program: a prespecified plan for the integrated analyses of the CANVAS and CANVAS-R trials. Diabetes Obes Metab. 2017;19(7):926-935. |
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58 | 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. FDA Safety Announcement. May 18, 2016. http://www.fda.gov/Drugs/DrugSafety/ucm500965.htm. |
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