Diabetes Drug Canagliflozin Doubles Risk of Amputations, FDA Warns

A year after announcing that it was investigating a possible association between the recently approved diabetes drug canagliflozin (INVOKAMET, INVOKANA) and an increased risk of foot and leg amputations,[1] the Food and Drug Administration (FDA) confirmed this relationship in a drug safety communication issued on May 16, 2017.[2] The communication warned health care professionals and patients about the evidence for this drug-induced risk and indicated that the agency is requiring the addition of a black-box warning — the strongest warning the FDA can require — to the drug’s label to highlight this risk.

About canagliflozin

Canagliflozin is one of three medications in the newest diabetes drug class known as sodium-glucose cotransporter-2 inhibitors,[3] frequently referred to as “flozins.” These medications have been approved, along with diet and exercise, to treat type 2 diabetes in adults.[4] They lower blood sugar levels by removing sugar from the body through the urine.

Public Citizen’s Health Research Group has previously recommended against the use of canagliflozin and all other flozins because their risks outweigh their benefits.[5]

Although flozins have a modest sugar-lowering action, there is no strong evidence that they can reduce the long-term complications associated with type 2 diabetes, including cardiovascular disease (heart attack and stroke) and kidney failure, which is the main goal of drug therapy for this condition. Notably, flozins can increase low-density lipoprotein — “bad” cholesterol — and red blood cell levels, two factors that can raise the risk of cardiovascular disease.[6]

The diuretic effect of flozins — water loss due to an increase in the amount of sugar in the urine — causes body fluid depletion. This effect is responsible for a series of additional, potentially serious, adverse effects associated with dehydration, particularly hypotension (low blood pressure).[7] Low blood pressure can predispose patients to falls, the leading cause of fatal and nonfatal injuries in older adults.[8]

Similar to other flozins, canagliflozin also is associated with kidney damage and kidney failure.[9] Other serious adverse events associated with canagliflozin include ketoacidosis (too much acid in the blood), high potassium levels in the blood (which can lead to life-threatening abnormal heart rhythms), serious urinary tract infections, low blood sugar when the drug is combined with other diabetes medications, genital fungal infections and bone fractures.[10],[11] Evidence also points to a possible risk of cancer, particularly bladder cancer, associated with these drugs.[12],[13]

Risk of amputations

People with diabetes already have a higher risk of foot and leg amputations than those without diabetes. Diabetes patients often develop peripheral vascular disease (blood vessel disease outside the brain or heart), which reduces blood flow to the legs and feet. Many also have damaged nerves (diabetic neuropathy), which reduces sensation. These factors together make it easier for diabetes patients to develop foot ulcers and infections that may lead to amputations.[14]

The FDA’s decision to issue its latest safety warning regarding canagliflozin is based on the final results of two large, long-term clinical trials (the Canagliflozin Cardiovascular Assessment [CANVAS] and CANVAS-Renal trials), which examined the effects of canagliflozin on cardiovascular and kidney outcomes in adult patients with type 2 diabetes.[15]

In these trials, leg and foot amputations occurred about twice as often in patients treated with canagliflozin, compared with those treated with a placebo.[16] Seventy-one percent of the amputations involved the toes or midfoot and the remaining amputations were at the ankle, below the knee level or above the knee level. Some patients had multiple amputations in the same or both limbs.[17]

Lower limb infections, gangrene, diabetic foot ulcers and decreased blood flow to the limbs were the most common triggering medical events leading to an amputation. The highest risk of amputation was among patients who had a history of prior amputation or peripheral vascular disease.

What You Can Do

Do not use canagliflozin for type 2 diabetes. You are especially at risk from using this medicine if you have a history of prior amputation, peripheral vascular disease, neuropathy or diabetic foot ulcers. Regardless of whether you are taking canagliflozin, if you have diabetes, you should notify your doctor immediately if you develop new pain, tenderness, sores or ulcers, or infections in your legs or feet.

Do not use other flozins (dapagliflozin [FARXIGA, XIGDUO XR] or empagliflozin [GLYXAMBI, JARDIANCE, SYNJARDY]) because their risks also outweigh their benefits.

If you are currently taking a flozin, talk with your doctor about switching to an older and safer diabetes drug, such as metformin (FORTAMET, GLUCOPHAGE, GLUMETZA, RIOMET) or a second- or third-generation sulfonylurea drug like glyburide (DIABETA, GLYNASE) or glimepiride (AMARYL).[18] Do not stop or change your diabetes medicines without first talking to your doctor. See the May 2014 issue of Worst Pills, Best Pills News for more information about our recommendations for managing type 2 diabetes.

References

[1] 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. May 18, 2016. http://www.fda.gov/Drugs/DrugSafety/ucm500965.htm. Accessed August 10, 2017.

[2] 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). May 16, 2017. https://www.fda.gov/Drugs/DrugSafety/ucm557507.htm. Accessed August 10, 2017.

[3] Shyangdan DS, Uthman OA, Waugh N. SGLT-2 receptor inhibitors for treating patients with type 2 diabetes mellitus: A systematic review and network meta-analysis. BMJ Open. 2016;6(2):e009417.

[4] Janssen Pharmaceuticals, Inc. Label: Canagliflozin (INVOKAMET). July 6, https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6868666b-c25e-40d1-9d1f-306bbe9390c1&audience=consumer. Accessed August 10, 2017.

[5] Risks but no benefits to taking newest drugs for type 2 diabetes. Worst Pills, Best Pills News. August 2015. /newsletters/view/981. Accessed August 10, 2017.

[6] Ibid.

[7] Ibid.

[8] Centers for Disease Control and Prevention. Preventing falls: A guide to implementing effective community-based fall prevention programs. 2015. https://www.cdc.gov/homeandrecreationalsafety/pdf/falls/fallpreventionguide-2015-a.pdf. Accessed August 14, 2017.

[9] Janssen Pharmaceuticals, Inc. Label: canagliflozin (INVOKAMET). July 6, 2017. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6868666b-c25e-40d1-9d1f-306bbe9390c1&audience=consumer. Accessed August 10, 2017.

[10] Food and Drug Administration (FDA). FDA drug safety communication: FDA confirms increased risk of leg and foot amputations with the diabetes medicine canagliflozin (Invokana, Invokamet, Invokamet XR). May 16, 2017. https://www.fda.gov/Drugs/DrugSafety/ucm557507.htm. Accessed August 10, 2017.

[11] Janssen Pharmaceuticals, Inc. Label: Canagliflozin (INVOKAMET). July 6, 2017. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6868666b-c25e-40d1-9d1f-306bbe9390c1&audience=consumer. Accessed August 10, 2017.

[12] Empagliflozin (Jardiance). Type 2 diabetes: No rush to use this drug. Prescrire Int. 2016;36(389):168-173.

[13] Canagliflozin (INVOKANA). A “me-too” of the dangerous dapagliflozin. Prescrire Int. 2014;34(372):733-736.

[14] American Diabetes Association. Foot complications. http://www.diabetes.org/living-with-diabetes/complications/foot-complications/?referrer=https://www.google.com/. Accessed August 10, 2017.

[15] Food and Drug Administration (FDA). FDA drug safety communication: FDA confirms increased risk of leg and foot amputations with the diabetes medicine canagliflozin (Invokana, Invokamet, Invokamet XR). May 16, 2017. https://www.fda.gov/Drugs/DrugSafety/ucm557507.htm. Accessed August 10, 2017.

[16] Neal B, Perkovic V, Mahaffey K, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017; June 12. doi:10.1056/NEJMoa1611925.

[17] Food and Drug Administration (FDA). FDA drug safety communication: FDA confirms increased risk of leg and foot amputations with the diabetes medicine canagliflozin (Invokana, Invokamet, Invokamet XR). May 16, 2017. https://www.fda.gov/Drugs/DrugSafety/ucm557507.htm. Accessed August 10, 2017.

[18] Type 2 diabetes: A guide to prevention and treatment. Worst Pills, Best Pills News. May 2014. /newsletters/view/916. Accessed August 10, 2017.