Canagliflozin and Amputation Risk: What You Need to Know Today

When you're managing type 2 diabetes, choosing the right medication isn't just about lowering blood sugar. It's about balancing benefits with real, sometimes serious, risks. One drug that’s stirred up serious concern is canagliflozin - sold under the brand name INVOKANA®. Since 2017, doctors and patients have been asking: does this drug increase the chance of losing a toe, foot, or even a leg? The answer isn’t simple, but the evidence is clear enough to change how we use it.

What Happened? The CANVAS Study That Changed Everything

In 2017, the results of the CANVAS Program shook the diabetes world. This large study tracked over 10,000 people with type 2 diabetes who were taking either canagliflozin or a placebo. The findings were alarming: those on canagliflozin had nearly twice the risk of needing a lower-limb amputation compared to those on placebo. For the 300 mg dose, the rate jumped to 5.5 amputations per 1,000 patient-years - up from 2.8 in the placebo group.

These weren’t random numbers. They came from real people. Many of these amputations were minor - toes or parts of the foot. But about 20% were major, above the ankle. The FDA responded quickly, adding a boxed warning - the strongest kind - to the drug label. For a while, many doctors stopped prescribing it altogether.

Why Did This Happen? The Science Behind the Risk

The big question: is this a problem with all drugs in its class, or just canagliflozin? The answer matters because SGLT2 inhibitors are a whole group of diabetes drugs that work the same way - by making the kidneys flush out extra sugar. But here’s the key: canagliflozin is the only one linked to this risk.

Studies on other drugs in the class - like empagliflozin (Jardiance) and dapagliflozin (Farxiga) - showed no similar spike in amputations. In fact, some showed no change at all, or even a slight drop. A 2023 meta-analysis of over 74,000 patients confirmed this: only canagliflozin carried a statistically significant increase in amputation risk.

So why just this one? Researchers think it might be tied to how strongly it lowers blood pressure and body weight. Canagliflozin tends to drop systolic blood pressure by about 3.7 mmHg more than other SGLT2 inhibitors. That might reduce blood flow to already vulnerable feet in people with poor circulation - especially those with peripheral artery disease or nerve damage from diabetes.

Who’s at Real Risk? It’s Not Everyone

This isn’t a risk for every person with diabetes. The data shows it’s concentrated in a smaller group:

• People with existing peripheral artery disease (PAD) - about 1 in 5 with type 2 diabetes have this
• Those with diabetic neuropathy - up to half of patients lose sensation in their feet
• Anyone who’s had a foot ulcer before - 40% of them get another within a year
• Smokers - tobacco narrows blood vessels, making feet more vulnerable
• People with a history of prior amputation

If you have two or more of these risk factors, most experts now say: avoid canagliflozin. The American Diabetes Association and podiatry groups recommend screening for these conditions before even starting the drug.

The FDA Changed Its Mind - But the Warning Didn’t Disappear

In January 2020, the FDA removed the boxed warning. That made headlines. But don’t be fooled - the risk didn’t vanish. The agency just decided that the benefits - especially for patients with heart or kidney disease - outweighed the risk for many.

The CREDENCE trial was key here. It showed canagliflozin cut the risk of kidney failure and heart-related death in people with diabetic kidney disease. That’s huge. So the FDA didn’t say, “It’s safe.” They said, “It’s safe for some - but you need to know the signs.”

The current prescribing label still says: “Monitor for new pain, tenderness, sores, ulcers, or infections in the legs or feet.” That’s not a suggestion. It’s a requirement.

Real Stories: What Patients Are Saying

Behind every statistic is a person. On patient forums like PatientsLikeMe, about 7% of canagliflozin users reported foot problems. A small number - less than 1% - said they or someone they knew had an amputation.

One Reddit user, u/DiabetesWarrior2020, shared: “After 18 months on Invokana, my podiatrist found a non-healing ulcer. I lost my toe. My endocrinologist switched me to Jardiance right away.”

Another, u/SugarFreeLife, said: “I’ve been on it for three years. No foot issues. My A1c dropped from 8.5% to 6.2%.”

The FDA’s own database shows a 17.8 times higher reporting rate of amputations with canagliflozin compared to empagliflozin. That’s not proof of causation, but it’s a loud signal.

What Doctors Do Now: Prevention Is the Rule

Today, responsible prescribing means more than just writing a script. It means a plan:

• Check your feet at every doctor visit - no exceptions
• Get an ankle-brachial index (ABI) test before starting canagliflozin if you have any heart disease or risk factors. An ABI under 0.9 means poor leg circulation - don’t start the drug
• Ask for a referral to a podiatrist if you have numbness, calluses, or sores
• Never ignore a blister, cut, or red spot on your foot - even if you can’t feel it
• Stop smoking. Period. It’s the single biggest thing you can do to protect your feet

The University of Michigan’s protocol is simple: if you have two or more risk factors, pick another SGLT2 inhibitor. Jardiance or Farxiga are safer choices for high-risk patients.

What’s Next? New Research and Better Tools

The story isn’t over. The FOOT-STEP trial, running until 2026, is testing whether structured foot care - weekly checks, proper shoes, education - can cut amputation rates in half for people on canagliflozin.

Janssen, the maker of INVOKANA, is also testing a new extended-release version. Early data suggests it might cause lower spikes in blood concentration, which could mean less impact on blood pressure and circulation. It’s still in trials, but it’s a sign the company is listening.

And in 2024, the FDA required all SGLT2 inhibitors to include standardized foot care instructions in their patient medication guides. That’s progress.

Should You Still Take It?

If you’re on canagliflozin and you’re healthy - no foot problems, no smoking, no circulation issues - you’re likely fine. Many people benefit from it. It helps with weight loss, lowers blood pressure, and protects the heart and kidneys.

But if you’ve had a foot sore, a numb foot, or poor circulation, you need to talk to your doctor now. Don’t wait for a wound to appear. Don’t assume it won’t happen to you. The risk is low for most, but it’s real for some - and the consequences are permanent.

The best approach? Know your risk. Check your feet daily. Ask your doctor for an ABI test if you’re unsure. And if you’re starting a new diabetes drug, ask: “Is this the safest choice for my feet?”

What About Other SGLT2 Inhibitors?

You don’t have to give up the benefits of this drug class. If canagliflozin isn’t right for you, here are your alternatives:

• Empagliflozin (Jardiance): Proven heart and kidney protection. No increased amputation risk in large trials.
• Dapagliflozin (Farxiga): Also safe for the feet. Shown to reduce heart failure hospitalizations.
• Ertugliflozin (Steglatro): Less data, but no amputation signal so far.

None of these drugs are perfect. All can cause yeast infections or dehydration. But when it comes to foot safety, they’re the safer bets.

Bottom Line: Awareness Saves Limbs

Canagliflozin isn’t banned. It’s not evil. It’s a tool - powerful, useful, but with a known danger zone. For the right patient, it can be life-saving. For others, it could be devastating.

The difference? Awareness. Screening. Communication. Daily foot checks. No sugar-coating.

If you’re on this medication, don’t panic. But don’t ignore your feet either. Your toes matter. Your mobility matters. And with the right precautions, you can keep both.