Canagliflozin and Amputation Risk: What You Need to Know Now

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 sparked intense debate is canagliflozin - sold as INVOKANA®. It helps control glucose, reduces heart failure risk, and protects the kidneys. But it’s also linked to a higher chance of foot and leg amputations. If you’re on this drug, or your doctor is considering it, you need to know the facts - not the hype, not the fear, but what the data actually says.

What the Studies Actually Found

The big red flag came from the CANVAS Program in 2017. This wasn’t a small study. It combined two major clinical trials with over 10,000 people with type 2 diabetes and high heart disease risk. The results showed something alarming: people taking canagliflozin had nearly twice the rate of lower-limb amputations compared to those on placebo.

The numbers were clear: 5.5 amputations per 1,000 patient-years for the 300 mg dose. That’s compared to 2.8 per 1,000 with placebo. The risk wasn’t random. Most amputations were minor - toes or parts of the foot. But about 20% were major, above the ankle. That’s life-changing.

The FDA reacted fast. In June 2017, they added a boxed warning - the strongest safety alert they have - for amputation risk. For years, doctors and patients were on edge. But then came more data.

The CREDENCE trial, focused on people with diabetic kidney disease, showed that canagliflozin cut kidney failure and heart attacks. The benefits were too strong to ignore. In January 2020, the FDA removed the boxed warning. But they didn’t say the risk disappeared. They moved it to the Warnings and Precautions section, where it still sits today.

Is This a Class-Wide Problem?

This is the million-dollar question. Are all SGLT2 inhibitors dangerous? Or is this just canagliflozin?

The answer is: it’s not the whole class. Empagliflozin (Jardiance) and dapagliflozin (Farxiga) didn’t show the same signal in their own large trials. EMPA-REG OUTCOME found no increase in amputations with empagliflozin. DECLARE-TIMI 58 even showed a slight drop in amputation risk with dapagliflozin - not enough to be called protective, but certainly not harmful.

A 2023 meta-analysis of 74,000 patients confirmed it: only canagliflozin had a statistically significant link to amputation. The odds ratio was 1.6 - meaning a 60% higher chance compared to other drugs or placebo. For other SGLT2 inhibitors, the risk was flat.

Why? No one’s 100% sure. But experts suspect it’s tied to how strongly canagliflozin lowers blood pressure and body weight. It drops systolic pressure by about 3.7 mmHg more than other drugs in the class. That might reduce blood flow to already compromised feet. It also causes more fluid loss, which could worsen dehydration in people with poor circulation.

Who’s at Real Risk?

Not everyone on canagliflozin will lose a toe. The risk is concentrated in a specific group.

If you have any of these, your risk goes up:

• History of foot ulcers or prior amputation
• Diabetic neuropathy (nerve damage causing numbness)
• Peripheral artery disease (PAD) - blocked arteries in the legs
• Current smoking
• Absent or weak foot pulses

Studies show that 20-30% of people with type 2 diabetes have PAD. Half have neuropathy. If you have even one of these, you’re in the high-risk group. The American Diabetes Association and American Podiatric Medical Association recommend avoiding canagliflozin in people with two or more of these risk factors.

The ankle-brachial index (ABI) test - a simple, non-invasive scan that measures blood pressure in your ankles compared to your arms - is now recommended before starting canagliflozin if you have any heart disease risk. An ABI under 0.9 means you have significant artery blockage. In that case, doctors should pick another drug.

Real People, Real Stories

Behind the statistics are real lives.

On Reddit, one user wrote: “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 said: “Three years on Invokana. No foot issues. My A1c dropped from 8.5% to 6.2%. I feel great.”

These aren’t outliers. They’re the spectrum. The FDA’s adverse event database shows about 1,892 amputation reports among 4.2 million canagliflozin prescriptions - a rate of 0.045%. That sounds small. But when you’re the one losing a toe, it’s not small at all.

The number needed to harm - how many people need to be treated before one extra amputation happens - is about 556 per year. That’s low compared to many side effects. But for someone with poor circulation, the risk isn’t theoretical. It’s immediate.

How to Stay Safe If You’re on Canagliflozin

You don’t have to stop the drug. But you must be vigilant.

Here’s what you should do:

1. Check your feet every day. Look for redness, swelling, cuts, blisters, or sores. Use a mirror if you can’t see the bottom of your feet.
2. Never go barefoot. Even indoors. A small step on a sharp object can turn into an ulcer if you have neuropathy.
3. Report any pain or sores immediately. Don’t wait. Don’t assume it’s just a callus. Early treatment stops amputations.
4. Get foot exams at every doctor visit. Your provider should check pulses, sensation, and skin condition.
5. Stop smoking. Smoking narrows arteries. It makes everything worse.
6. Ask about your ABI. If you’ve never had it done, ask your doctor. It takes 5 minutes and can change your treatment plan.

The National Institute for Health and Care Excellence (NICE) tells patients: “If you have numbness in your feet and notice a new sore, call your doctor the same day.” That’s not alarmist. That’s life-saving advice.

What About Other SGLT2 Inhibitors?

If you’re worried, you have options.

Empagliflozin (Jardiance) has the strongest evidence for heart and kidney protection without the amputation signal. Dapagliflozin (Farxiga) is similar. Both are now preferred in guidelines for patients with heart failure or kidney disease - and they’re safer for feet.

In 2024, a survey of U.S. endocrinologists found that canagliflozin prescriptions had dropped from 35% to 22% of all SGLT2 inhibitor use since 2017. That’s not because the drug was pulled. It’s because doctors learned to choose better.

If you’re on canagliflozin and have risk factors, talk to your doctor about switching. The benefits of empagliflozin or dapagliflozin are just as strong - without the foot risk.

What’s Next?

The science isn’t done. The FOOT-STEP trial, running until 2026, is testing whether structured foot care - daily checks, specialist visits, education - can cut amputation rates in high-risk patients on canagliflozin. Early results are promising.

Janssen is also testing a new extended-release version of canagliflozin (INVOKANA XR), designed to release the drug more slowly. The theory? Lower peak levels might mean less impact on blood pressure and circulation. If it works, it could bring this drug back into wider use - safely.

Meanwhile, the World Health Organization still lists canagliflozin as an essential medicine - but with a footnote: “Requires foot monitoring.” That’s the key. It’s not banned. It’s not unsafe. It’s a tool that needs careful handling.

Final Takeaway

Canagliflozin is not a dangerous drug for everyone. But it’s not risk-free. For people with healthy feet and good circulation, it can be a powerful ally against heart disease and kidney damage. For those with nerve damage, poor blood flow, or past foot problems - it’s a gamble that doesn’t pay off.

The goal isn’t to scare you off a medication. It’s to make sure you’re using it wisely. Ask your doctor: “Do I have any risk factors for foot problems?” Get your ABI checked. Check your feet daily. If you see anything unusual, don’t wait.

Your feet matter. They carry you through life. Don’t let a diabetes drug take them away - if you can prevent it.