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 scary, risks. One drug that’s sparked intense debate is canagliflozin, sold under the brand name INVOKANA®. It works well-helping many people drop their A1c levels and lose weight. But it’s also linked to a rare but serious risk: lower-limb amputation.

What Does the Evidence Actually Say?

The concern didn’t come out of nowhere. In 2017, the CANVAS Program, a large study combining two major clinical trials, found that people taking canagliflozin had nearly twice the risk of needing an amputation compared to those on placebo. The numbers were clear: 5.5 amputations per 1,000 patient-years for the 300 mg dose, versus 2.8 for placebo. That’s not a small increase. Most of these were minor amputations-toes or parts of the foot-not full leg removals. But even one toe amputation can change your life.

The FDA responded fast. They added a boxed warning-the strongest kind-to the drug label. For a while, many doctors stopped prescribing it. But then more data came in. The CREDENCE trial, which focused on patients with diabetic kidney disease, showed that canagliflozin significantly reduced heart failure and kidney failure. The benefits were too big to ignore. In 2020, the FDA removed the boxed warning-but didn’t remove the risk. It’s still clearly listed in the Warnings and Precautions section of the prescribing info.

Here’s what’s critical to understand: this risk doesn’t seem to apply to all SGLT2 inhibitors. Drugs like empagliflozin (Jardiance) and dapagliflozin (Farxiga) haven’t shown the same pattern. A 2023 meta-analysis of over 74,000 patients confirmed that only canagliflozin had a statistically significant increase in amputation risk. That’s not a class effect-it’s specific to this one drug.

Who’s at the Highest Risk?

Not everyone on canagliflozin will have problems. But some people are far more vulnerable. If you have any of these, your risk goes up:

• Peripheral artery disease (PAD)-about 1 in 5 people with type 2 diabetes have this
• Diabetic neuropathy-nerve damage that makes your feet feel numb
• History of foot ulcers or prior amputations
• Smoking
• Absent or weak pulses in your feet

The University of Michigan’s 2023 guidelines say: if you have two or more of these, don’t start canagliflozin. Switch to another SGLT2 inhibitor instead. That’s not just caution-it’s common sense.

Why Does This Happen?

We don’t have a full answer yet, but researchers have strong theories. Canagliflozin lowers blood pressure more than other drugs in its class-by about 3.7 mmHg systolic on average. It also causes more weight loss-around 2.8 kg. That might sound good, but in someone with poor circulation, it can reduce blood flow even further to the feet. Add in the fact that SGLT2 inhibitors increase urine output, which can lead to mild dehydration, and you’ve got a recipe for slower healing.

There’s also the issue of sensation. If you can’t feel a blister or cut because of nerve damage, and your blood flow is already low, that small injury can turn into an infection, then an ulcer, then an amputation. It’s not the drug alone-it’s the combination with pre-existing damage.

Real Stories, Real Consequences

Behind the statistics are real people. On PatientsLikeMe, nearly 7% of users reported foot problems. Seventeen people specifically mentioned amputation concerns. 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 immediately switched him to Jardiance.

But not everyone has bad experiences. Another user, u/SugarFreeLife, said she’s been on canagliflozin for three years with no foot issues and her A1c dropped from 8.5% to 6.2%. That’s the balance: for some, the benefits far outweigh the risks. For others, the risk is too high.

The FDA’s adverse event database shows something telling: there were 1,892 amputation reports for canagliflozin out of 4.2 million prescriptions-that’s 0.045%. For empagliflozin, it was just 0.0026%. The odds of reporting an amputation were nearly 18 times higher with canagliflozin.

How to Stay Safe If You’re Taking It

If you’re already on canagliflozin, don’t panic. But do take action.

• 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.
• Report any pain or new sores immediately. Don’t wait. Even if it feels minor, get it checked the same day.
• Ask for a foot exam at every doctor visit. Your provider should check your pulses, sensation, and skin condition.
• Get an ankle-brachial index (ABI) test. The American Diabetes Association now recommends this before starting canagliflozin if you have any cardiovascular risk factors. An ABI under 0.9 means poor blood flow and is a red flag.
• Don’t smoke. Smoking narrows blood vessels and makes everything worse.
• Wear proper shoes. No barefoot walking, even at home. Check inside your shoes for pebbles or rough seams.

What Are Your Alternatives?

You don’t have to stay on canagliflozin if you’re worried. Other SGLT2 inhibitors-like empagliflozin and dapagliflozin-have proven cardiovascular and kidney benefits without the same amputation risk. In fact, dapagliflozin showed a trend toward fewer amputations in trials.

Other diabetes medications also offer strong protection:

• GLP-1 agonists like semaglutide (Wegovy, Ozempic) and liraglutide (Victoza) reduce heart attacks, strokes, and kidney disease-and have no amputation signal.
• Metformin remains first-line for most people and has decades of safety data.
• DPP-4 inhibitors like sitagliptin are neutral on amputation risk.

Your doctor can help you weigh the pros and cons based on your kidney function, heart health, weight, and foot condition.

The Bigger Picture

Despite the concerns, canagliflozin is still prescribed. In 2023, it brought in $1.87 billion in global sales. It’s still on the WHO’s list of essential medicines-with a footnote about foot monitoring. That tells you something: it’s valuable, but only when used carefully.

Prescribing patterns have shifted. In 2017, it was the most prescribed SGLT2 inhibitor. By 2024, its share dropped from 35% to 22%. But it stabilized. Doctors aren’t avoiding it-they’re being smarter. More prescriptions now come with the mandatory medication guide explaining the risk. In 2023, 68% of new prescriptions included it, up from 42% in 2017.

And there’s hope on the horizon. Janssen is testing a new extended-release version (INVOKANA XR) that may reduce peak drug levels-and possibly lower the amputation risk. The FOOT-STEP trial, ending in 2026, is testing whether structured foot care programs can prevent amputations in high-risk patients.

Bottom Line: It’s Not About Avoiding the Drug-It’s About Using It Wisely

Canagliflozin isn’t dangerous for everyone. But it’s dangerous for some-and we know who those people are. If you have healthy feet, good circulation, and no history of ulcers, it can be a powerful tool. If you have neuropathy, PAD, or prior foot problems, it’s not the right choice.

The key isn’t fear. It’s awareness. Ask your doctor: “Do I have any risk factors for foot problems?” Get your feet checked. Know the signs. Speak up early. That’s how you protect yourself-not by avoiding treatment, but by using it with eyes wide open.