Canagliflozin and Amputation Risk: What You Need to Know Now

When you’re managing type 2 diabetes, finding the right medication isn’t just about lowering blood sugar. It’s about balancing benefits with real, sometimes serious, risks. Canagliflozin - sold as INVOKANA® - is one of those drugs that sparked major debate. In 2017, data from the CANVAS trials showed a clear rise in leg and foot amputations among people taking it. The FDA slapped on a boxed warning. Many doctors stopped prescribing it. But by 2020, that warning was pulled. So what’s the truth today? Is canagliflozin safe? And if you’re on it, should you be worried?

What the Data Actually Shows

The numbers don’t lie, but they need context. In the CANVAS Program, which tracked over 10,000 people with type 2 diabetes and heart disease, those taking canagliflozin had about twice the risk of amputation compared to those on placebo. For the 300 mg dose, that meant 5.5 amputations per 1,000 people each year - up from 2.8 in the placebo group. That’s a real increase. But here’s what most people miss: most of these were minor amputations. About 80% were toe or metatarsal removals - not above-the-knee or above-the-ankle surgeries. These are often the result of slow-healing ulcers, especially in people who already have nerve damage or poor circulation.

The absolute risk? Roughly 1.8 extra amputations per 1,000 people per year. That means you’d need to treat 556 people with canagliflozin for one full year to cause one additional amputation. That’s not common. But it’s not rare either - especially if you’re already at risk.

Not All SGLT2 Inhibitors Are the Same

This is critical: the amputation risk doesn’t apply to all drugs in this class. Canagliflozin is the outlier. Empagliflozin (Jardiance) and dapagliflozin (Farxiga) showed no increased amputation risk in their large outcome trials. In fact, dapagliflozin had a trend toward fewer amputations. A 2023 meta-analysis of over 74,000 patients confirmed that only canagliflozin had a statistically significant link to amputation among SGLT2 inhibitors.

Why? It’s not fully understood. Some researchers think it’s tied to how strongly canagliflozin lowers blood pressure and body weight - more than the others. That can reduce blood flow to the feet, especially if you already have narrowed arteries from diabetes. It’s not a class effect. It’s a drug-specific signal.

Who’s at Highest Risk?

You’re not equally at risk. If you’ve got:

• Peripheral artery disease (PAD) - blocked arteries in your legs
• Diabetic neuropathy - numbness or tingling in your feet
• A past foot ulcer or amputation
• Current smoking
• Absent foot pulses

…then canagliflozin may not be the right choice for you. The University of Michigan’s 2023 guidelines say: if you have two or more of these, avoid canagliflozin entirely. Other SGLT2 inhibitors like empagliflozin or dapagliflozin are safer options.

Even if you don’t have these risk factors, your doctor should check your feet before starting canagliflozin. The American Diabetes Association’s 2025 guidelines now recommend an ankle-brachial index (ABI) test - a simple, non-invasive scan that measures blood flow to your legs - if you have any heart disease or vascular risk. An ABI below 0.9 means poor circulation. That’s a red flag.

What the FDA and Experts Really Say

The FDA removed the boxed warning in 2020 - not because the risk disappeared, but because the benefits outweighed the risk for many patients. The CREDENCE trial showed canagliflozin dramatically slowed kidney disease progression in people with diabetic kidney disease. That’s huge. For someone with failing kidneys, preventing dialysis might be worth the small chance of a toe amputation.

Dr. Darren McGuire, who led the CANVAS trial, put it plainly: “The risk is real, but it’s mostly in patients who already have foot problems.” Dr. David Nathan, a top diabetes expert, agrees: “Be vigilant. Check your feet every day.”

The FDA’s own database shows 1,892 amputation reports for canagliflozin out of 4.2 million prescriptions - that’s 0.045%. For empagliflozin, it was 0.0026%. That’s a 17.8 times higher reporting rate. Real-world data matches the clinical trials.

What Patients Are Saying

On patient forums, stories are mixed. One Reddit 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 immediately. Another user, u/SugarFreeLife, has been on it for three years with no foot issues and an A1c drop from 8.5% to 6.2%.

The difference? One had undiagnosed poor circulation. The other didn’t. That’s why screening matters.

How to Stay Safe - Step by Step

If you’re prescribed canagliflozin, here’s what to do:

1. Get a foot exam before starting. Your doctor should check for pulses, sensation, skin changes, and deformities.
2. Ask for an ABI test. If you have heart disease, high blood pressure, or are over 50, this simple test can reveal hidden artery blockage.
3. Check your feet daily. Look for redness, swelling, cuts, blisters, or sores. Use a mirror if you can’t see the bottom of your feet.
4. Report any new pain or sores immediately. Don’t wait. Even a small blister can turn into an ulcer fast if you have neuropathy.
5. Wear proper shoes. No barefoot walking. Avoid tight or ill-fitting footwear.
6. Don’t smoke. Smoking worsens blood flow. Quitting is one of the best things you can do for your feet.
7. Ask about alternatives. If you have any risk factors, ask your doctor if empagliflozin or dapagliflozin would work just as well - and safer.

The Bigger Picture: Why Canagliflozin Is Still Prescribed

Despite the risks, canagliflozin made $1.87 billion in sales in 2023. Why? Because it works - and for many, it’s life-changing. It lowers A1c, helps with weight loss, reduces heart failure hospitalizations, and protects the kidneys. For someone with advanced kidney disease, it’s often the best option.

Doctors aren’t ignoring the risk. Medicare data shows 68% of new canagliflozin prescriptions in 2023 came with a mandatory medication guide explaining amputation risk - up from 42% in 2017. That’s better communication.

And now, Janssen is testing a new extended-release version (INVOKANA XR) designed to reduce peak drug levels - potentially lowering the risk. A major clinical trial called FOOT-STEP, ending in 2026, is testing whether structured foot care programs can prevent amputations in high-risk patients on canagliflozin.

Bottom Line: Don’t Panic - But Don’t Ignore It

Canagliflozin isn’t dangerous for everyone. But it’s not risk-free. If you’re on it and you’re healthy - no nerve damage, no circulation problems, no past foot issues - the chance of amputation is very low. The benefits likely outweigh the risks.

But if you’ve got any foot or circulation problems, you need to talk to your doctor. There are safer SGLT2 inhibitors. There are other diabetes medications. You don’t have to settle for a drug that might put you at risk.

Your feet matter. Don’t wait for a sore to become a crisis. Check them. Talk to your care team. Ask questions. You’re not just managing blood sugar - you’re protecting your mobility, your independence, and your future.