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More diabetic foot amputations in those on Canagliflozin

Discussion in 'Diabetic Foot & Wound Management' started by NewsBot, May 19, 2016.

  1. NewsBot

    NewsBot The Admin that posts the news.

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    Members do not see these Ads. Sign Up.
    Press reelase:
    Canagliflozin (Invokana, Invokamet): Drug Safety Communication - Clinical Trial Results Find Increased Risk of Leg and Foot Amputations
     
  2. NewsBot

    NewsBot The Admin that posts the news.

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    The Brits have now issued their warning:
    https://www.gov.uk/drug-safety-upda...in-trial-in-high-cardiovascular-risk-patients
     
  3. Admin2

    Admin2 Administrator Staff Member

    Canagliflozin

    Canagliflozin (trade name Invokana or Sulisent) is a medication used for the treatment of type 2 diabetes.[1][2] It is of the gliflozin class or subtype 2 sodium-glucose transport (SGLT-2) inhibitors class.

    This mechanism is associated with a low risk of hypoglycaemia (too low blood glucose) compared to sulfonylurea derivatives and insulin.[3] In 2017, the FDA concluded that canagliflozin causes an increased risk of leg and foot amputations.[4] The FDA began requiring a Boxed Warning to be added to the canagliflozin drug labels to describe this risk.[5]

    Canagliflozin is an inhibitor of subtype 2 sodium-glucose transport proteins (SGLT2), which is responsible for at least 90% of renal glucose reabsorption (SGLT1 being responsible for the remaining 10%). Blocking this transporter causes up to 119 grams of blood glucose per day to be eliminated through the urine.[6] It was developed by Mitsubishi Tanabe Pharma and is marketed under license by Janssen, a division of Johnson & Johnson.[7]

    1. ^ New J&J diabetes drug effective in mid-stage study, Jun 26, 2010
    2. ^ Edward C. Chao (2011). "Canagliflozin". Drugs of the Future. 36 (5): 351–357. doi:10.1358/dof.2011.036.05.1590789.
    3. ^ A. Klement (20 January 2014). "Tubuläre Senkung des Blutzuckers bei Diabetes mellitus: Invokana". Österreichische Apothekerzeitung (in German) (2/2014): 20f.
    4. ^ "Press Release: FDA Confirms Increased Risk of Leg and Foot Amputations With Diabetes Medicine Canagliflozin". Fox Business. 2017-05-16. Retrieved 2017-05-16.
    5. ^ "FDA Drug Safety Communication: FDA confirms increased risk of leg and foot amputations with the diabetes medicine canagliflozin (Invokana, Invokamet, Invokamet XR)". FDA.gov. 2017-05-16. Retrieved 2017-05-16.
    6. ^ Prous Science: Molecule of the Month November 2007
    7. ^ http://www.investor.jnj.com/releasedetail.cfm?releaseid=710584
     
  4. NewsBot

    NewsBot The Admin that posts the news.

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    Medscape are reporting:
    EMA: Amputation Warning With SGLT2 Inhibitors Must Be on Label
     
  5. NewsBot

    NewsBot The Admin that posts the news.

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    New Update from gov.uk:
    SGLT2 inhibitors: updated advice on increased risk of lower-limb amputation (mainly toes)

     
  6. NewsBot

    NewsBot The Admin that posts the news.

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    FDA Warning:
    Canagliflozin (Invokana, Invokamet): Drug Safety Communication - Increased Risk of Leg and Foot Amputations
    [Posted 05/16/2017]
    ISSUE: Based on new data from two large clinical trials, the FDA has concluded that the type 2 diabetes medicine canagliflozin (Invokana, Invokamet, Invokamet XR) causes an increased risk of leg and foot amputations. FDA is requiring new warnings, including the most prominent Boxed Warning, to be added to the canagliflozin drug labels to describe this risk.

    Final results from two clinical trials – the CANVAS (Canagliflozin Cardiovascular Assessment Study) and CANVAS-R (A Study of the Effects of Canagliflozin on Renal Endpoints in Adult Participants With Type 2 Diabetes Mellitus) – showed that leg and foot amputations occurred about twice as often in patients treated with canagliflozin compared to patients treated with placebo, which is an inactive treatment. Amputations of the toe and middle of the foot were the most common; however, amputations involving the leg, below and above the knee, also occurred. Some patients had more than one amputation, some involving both limbs. See the FDA Drug Safety Communication for additional information, including a data summary.

    BACKGROUND: This information is an update to the May 18, 2016 MedWatch safety alert. Canagliflozin is a prescription medicine used with diet and exercise to lower blood sugar in adults with type 2 diabetes. It belongs to a class of drugs called sodium-glucose cotransporter-2 (SGLT2) inhibitors. Canagliflozin lowers blood sugar by causing the kidneys to remove sugar from the body through the urine. It is available as a single-ingredient product under the brand name Invokana and also in combination with the diabetes medicine metformin under the brand name Invokamet.

    RECOMMENDATION: Patients taking canagliflozin should notify your health care professionals right away if you develop new pain or tenderness, sores or ulcers, or infections in your legs or feet. Talk to your health care professional if you have questions or concerns. Do not stop taking your diabetes medicine without first talking to your health care professional.

    Health care professionals should, before starting canagliflozin, consider factors that may predispose patients to the need for amputations. These factors include a history of prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers. Monitor patients receiving canagliflozin for the signs and symptoms described above and discontinue canagliflozin if these complications occur.

    Healthcare professionals and patients are encouraged to report adverse events or side effects related to the use of these products to the FDA's MedWatch Safety Information and Adverse Event Reporting Program:

    Complete and submit the report Online: www.fda.gov/MedWatch/report
    Download form or call 1-800-332-1088 to request a reporting form, then complete and return to the address on the pre-addressed form, or submit by fax to 1-800-FDA-0178
     
  7. NewsBot

    NewsBot The Admin that posts the news.

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    Still an effective drug:

    INVOKANA® (canagliflozin) Significantly Reduces the Combined Risk of Cardiovascular Death, Myocardial Infarction, and Stroke in the CANVAS Programme
    Study results published in the New England Journal of Medicine and discussed in special symposium at the American Diabetes Association 77th Scientific Sessions

    June 13, 2017 05:19 AM Eastern Daylight Time
    BEERSE, Belgium--(BUSINESS WIRE)--Janssen-Cilag International NV today announced results from the CANVAS Programme which showed INVOKANA® (canagliflozin) when added to standard of care significantly reduced the combined risk of cardiovascular (CV) death, nonfatal myocardial infarction (MI), and nonfatal stroke by 14%, versus placebo in patients with type 2 diabetes mellitus (T2DM) at risk for or with a history of CV disease. The results also showed canagliflozin treatment was associated with a reduced risk of hospitalisation for heart failure and demonstrated potential renal protective effects. These data from the integrated analysis of the CANVAS and CANVAS-R trials were published in the New England Journal of Medicine, and presented in a special symposium at the American Diabetes Association 77th Scientific Sessions on Monday, June 12th, in San Diego, CA.

    Canagliflozin was studied in one of the largest completed CV outcomes programme of any sodium glucose cotransporter-2 (SGLT2) inhibitor. The CANVAS Programme is the first to assess the long-term efficacy and safety of canagliflozin in more than 10,000 patients with T2DM, who had either a prior history of CV disease, or at least two CV risk factors.

    The International Diabetes Federation estimates that, in 2015, over 59 million people were living with diabetes in Europe.1 If left uncontrolled, T2DM can lead to serious long-term microvascular and macrovascular complications.

    Canagliflozin achieved a 14% reduction in the risk of the composite primary endpoint of CV death, nonfatal MI, or nonfatal stroke (Hazard Ratio - HR: 0.86; 95% Confidence Interval - CI: 0.75 to 0.97), and demonstrated an improved cardiovascular safety profile compared to placebo (p<0.0001 for non-inferiority) and superiority compared to placebo (p=0.0158). Each component evenly contributed to this risk reduction, including nonfatal MI by 15% (HR: 0.85; 95% CI: 0.69 to 1.05), CV death by 13% (HR: 0.87; 95% CI: 0.72 to 1.06), and nonfatal stroke by 10% (HR: 0.90; 95% CI: 0.71 to 1.15). These outcomes were broadly consistent across various patient subgroups, and across the individual components of the primary endpoint.2

    Additional analysis further revealed canagliflozin lowered the risk of hospitalization for heart failure by 33% (HR: 0.67; 95% CI: 0.52 to 0.87) and provided sustained positive effects on glycemic and blood pressure control, as well as weight reduction, demonstrating wide-ranging durability.2

    In addition, canagliflozin showed potential renal protective effects, delaying progression of albuminuria and reducing the risk of clinically important renal composite outcomes (such as 40% reduction of estimated glomerular filtration rate (eGFR), renal death, or renal replacement therapy) by 40% (HR: 0.60; 95% CI: 0.47 to 0.77). The ongoing, fully enrolled CREDENCE study, the first dedicated SGLT2 inhibitor renal outcome trial in patients with T2DM and kidney disease, is further evaluating the effects of canagliflozin on renal and CV outcomes.

    “Patients with diabetes are two to four times more likely to suffer from associated comorbidities such as heart failure and kidney disease, and the CANVAS results demonstrate the potential of canagliflozin in reducing the risk for such conditions in high-risk type 2 diabetes patients,” said David Matthews, CANVAS Steering Committee co-chair, and Professor of Diabetic Medicine and Honorary Consultant Physician, University of Oxford. “These data are promising as they suggest canagliflozin may offer potential benefits for patients with type 2 diabetes, who are also facing complications from, or are at risk for, hospitalization for heart failure or kidney disease.”

    Overall adverse events seen in the CANVAS Programme were consistent with previous findings. An increased risk of amputation with canagliflozin was seen in both the completed CANVAS study and in the CANVAS-R study. This is consistent with the observation made by the study’s Independent Data Monitoring Committee (IDMC) in 2016, and the data shared with Health Authorities and Health Care Professionals. There was an increased risk of amputation (6.3 vs. 3.4/1000 patient-years) corresponding to a hazard ratio (HR) of 1.97. The highest absolute risk of amputation occurred in patients with a prior history of amputation or peripheral vascular disease, but the relative risk for amputation with canagliflozin was comparable across these subgroups. A warning of the potential increased risk of toe amputation is being included in the prescribing information for SGLT2 inhibitors in the European Union and the risk has been included in the canagliflozin EU Summary of Product Characteristics (SmPC).

    Separately, while an increased risk of adjudicated low trauma fracture was identified in the CANVAS study, no increase was observed in the CANVAS-R study. A full assessment is ongoing to provide a complete safety review of the CANVAS and CANVAS-R results.

    “The results of the CANVAS Programme are extremely exciting for us at Janssen and the wider diabetes community,” said Jose Antonio Buron Vidal, Vice-President Medical Affairs, Janssen Europe, Middle-East and Africa. “Janssen has an ongoing commitment to address unmet needs in the treatment of type 2 diabetes and the positive and broad benefit-risk profile demonstrated here with canagliflozin reinforces our commitment to exploring the potential of canagliflozin in additional patient populations.”
     
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    NewsBot The Admin that posts the news.

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    What's all the fuss about canagliflozin?
     
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    Risks of Diabetic Foot Syndrome and Amputation associated with Sodium Glucose Co-transporter 2 Inhibitors: A Meta-analysis of Randomized Controlled Trials
    Li. Dandan et al
    Diabetes & Metabolism; 3 February 2018
     
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    Risk of Amputations Associated with SGLT2 Inhibitors Compared to DPP-4 Inhibitors: A Propensity-Matched Cohort Study.
    Adimadhyam S et al
    Diabetes Obes Metab. 2018 Jul 3.
     
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    SGLT2 inhibitors in Type 1 diabetes: is this the future?
    Herring R et al
    Diabet Med. 2018 Aug 8. doi: 10.1111/dme.13791.
     
  13. NewsBot

    NewsBot The Admin that posts the news.

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    Association Between Sodium-Glucose Cotransporter 2 Inhibitors and Lower Extremity Amputation Among Patients With Type 2 Diabetes.
    Chang HY et al
    JAMA Intern Med. 2018 Aug 13. doi: 10.1001/jamainternmed.2018.3034.
     
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