Canagliflozin and Amputation Risk: What You Need to Know Now

When you're managing type 2 diabetes, finding a medication that lowers blood sugar without causing serious harm is critical. Canagliflozin, sold under the brand name INVOKANA®, was once a popular choice - effective, weight-loss friendly, and proven to protect the heart and kidneys. But since 2017, a quiet alarm has been ringing: this drug may increase the risk of losing a toe, foot, or even part of your leg. It’s not a rumor. It’s not a scare tactic. It’s data - from large clinical trials, real-world reports, and years of follow-up. And while the FDA removed its strongest warning in 2020, the risk hasn’t disappeared. It’s just better understood now.

What the Studies Actually Showed

The CANVAS Program, a pair of major trials involving over 10,000 people with type 2 diabetes and heart disease, found something unexpected. People taking canagliflozin had nearly twice the rate of lower-limb amputations compared to those on placebo. For the 300 mg dose, it was 5.5 amputations per 1,000 people each year. On placebo? Just 2.8. That’s a 79% increase. Most of these were minor - toes or the ball of the foot. But about 1 in 5 were major, above the ankle. That’s life-changing.

The numbers might sound small, but when you’re talking about limbs, even one extra case matters. Experts calculated that for every 556 people treated with canagliflozin for a year, one extra amputation would happen. That’s not common. But it’s not rare either - especially if you already have foot problems.

What made this worse was that the risk wasn’t evenly spread. People with existing nerve damage (neuropathy), poor circulation (peripheral artery disease), or past foot ulcers were at highest risk. In fact, nearly 40% of those who had amputations in the trials had a history of foot ulcers. The drug didn’t cause amputations out of nowhere. It made existing vulnerabilities worse.

Why Only Canagliflozin? Not All SGLT2 Inhibitors Are the Same

Here’s where things get important: this risk doesn’t apply to all drugs in the same class. SGLT2 inhibitors - including empagliflozin (Jardiance), dapagliflozin (Farxiga), and others - work similarly. They help the kidneys flush out extra sugar. But only canagliflozin has shown this consistent link to amputations.

The EMPA-REG OUTCOME trial with empagliflozin found no increase in amputation risk. The DECLARE-TIMI 58 trial with dapagliflozin even showed a slight reduction. A 2023 meta-analysis of 74,000 patients confirmed it: only canagliflozin had a statistically significant rise in amputation risk. Other SGLT2 drugs? No signal. That’s not a coincidence. It suggests the problem isn’t the class - it’s canagliflozin itself.

Why? Scientists aren’t sure. But clues point to how much it lowers blood pressure and body weight. Canagliflozin drops systolic pressure by about 3.7 mmHg more than other drugs in its class. It also causes more weight loss - nearly 3 kg on average. For someone with already narrowed leg arteries, that drop in blood pressure might reduce blood flow enough to turn a small sore into a non-healing wound. Add in the fact that canagliflozin increases urine output, which can lead to mild dehydration, and you’ve got a perfect storm for foot tissue breakdown in vulnerable people.

Who Should Avoid Canagliflozin?

You don’t need to stop taking canagliflozin if you’re doing fine. But you do need to know if you’re at risk. If you have any of these, your doctor should strongly consider another option:

• History of foot ulcers or amputations
• Diagnosed peripheral artery disease (PAD)
• Diabetic neuropathy with loss of feeling in feet
• Current smoking
• Absent or weak pulses in your feet
• Chronic kidney disease with dialysis or severe impairment

The American Diabetes Association and podiatry groups now recommend checking your ankle-brachial index (ABI) before starting canagliflozin. This simple test measures blood pressure in your ankles compared to your arms. An ABI below 0.9 means your leg arteries are significantly blocked - and that’s a red flag. In this group, the risk of amputation jumps dramatically.

If you have two or more of these risk factors, guidelines from the University of Michigan and others advise avoiding canagliflozin entirely. Switch to empagliflozin or dapagliflozin. Both have the same heart and kidney benefits - without the foot risk.

What You Should Do If You’re Already on Canagliflozin

If you’re on canagliflozin and have no foot problems, don’t panic. But don’t ignore your feet, either. Check them every day. Look for:

• Redness, swelling, or warmth
• Sores that won’t heal
• Changes in skin color (pale, blue, or black)
• New pain, especially if you have nerve damage and can’t feel it
• Odor or drainage from any wound

If you see any of these, call your doctor immediately. Don’t wait. Don’t try to treat it yourself. A small ulcer can turn into an amputation in weeks if not caught early.

Your doctor should be checking your feet at every visit - not just once a year. The American Podiatric Medical Association says foot exams should be part of every diabetes appointment for people on canagliflozin. If they’re not doing it, ask why. You have the right to this basic care.

Real Stories, Real Consequences

Online forums like PatientsLikeMe and Reddit are full of personal accounts. One user, u/DiabetesWarrior2020, shared that after 18 months on INVOKANA, he developed a non-healing ulcer that led to a toe amputation. His endocrinologist switched him to Jardiance right away. Another user, u/SugarFreeLife, said she’s been on it for three years with no issues - and her A1c dropped from 8.5% to 6.2%.

These aren’t outliers. They’re the spectrum. The drug works wonders for some. For others, it’s a danger. The difference? Risk factors. Awareness. Early action.

The FDA’s own adverse event database shows 1,892 amputation reports tied to canagliflozin out of 4.2 million prescriptions - a rate of 0.045%. That’s low. But compared to empagliflozin, the risk is nearly 18 times higher. That’s not noise. That’s a signal.

How Doctors Are Changing How They Prescribe

In 2017, canagliflozin was one of the most prescribed SGLT2 inhibitors. By 2024, its share of prescriptions dropped from 35% to 22%. That’s not because it stopped working. It’s because doctors learned to be smarter.

Now, most prescriptions come with a mandatory medication guide explaining the foot risk. In 2023, 68% of new canagliflozin prescriptions included this guide - up from 42% in 2017. That means more patients know what to watch for.

The American Diabetes Association’s 2025 guidelines now require an ABI test before prescribing canagliflozin to anyone with cardiovascular risk. That’s a game-changer. It turns a vague warning into a concrete screening step.

Even Janssen, the maker of INVOKANA, is trying to fix the problem. They’re testing a new extended-release version (INVOKANA XR) that lowers peak drug levels in the blood. Early data suggests it might reduce the amputation risk - but results won’t be ready until 2027.

What’s Next? The Foot-Step Trial and What It Could Mean

The biggest hope for the future is the FOOT-STEP trial. It’s currently recruiting people with diabetes and high foot risk who are on canagliflozin. Half get standard care. The other half get intensive foot care: weekly check-ups, custom shoes, nerve tests, and urgent wound treatment. The goal? Prove that with better monitoring, you can prevent amputations even while using the drug.

If it works, it could change everything. Maybe you won’t have to stop canagliflozin - you’ll just need more support.

Until then, the message is clear: don’t ignore your feet. Don’t assume you’re fine because you feel okay. Diabetic foot problems don’t always hurt. They just get worse - quietly.

Final Takeaway: It’s Not About Avoiding the Drug - It’s About Using It Wisely

Canagliflozin still has real benefits. It lowers heart failure risk. It protects kidneys. It helps with weight. For many people, especially those without foot problems, it’s a great tool.

But it’s not a one-size-fits-all drug. It’s a tool with a warning label. And like any tool, it’s safe only if you know how to use it.

If you’re on canagliflozin:

• Check your feet daily
• Ask your doctor for an ABI test if you haven’t had one
• Report any skin changes, sores, or pain - no matter how small
• Ask if switching to empagliflozin or dapagliflozin makes sense for you

If you’re thinking about starting it:

• Get a full foot exam first
• Ask about your ABI
• Discuss alternatives - they exist and they’re safer for high-risk patients

The goal isn’t to scare you off a good medication. It’s to make sure you don’t lose a foot because no one told you to look.