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 weighing every possible risk-especially when one of them could mean losing a toe, or worse. Canagliflozin, sold under the brand name Invokana, is one of those drugs that came with a warning that shook the diabetes world. In 2017, the FDA slapped a boxed warning on it: higher risk of leg and foot amputations. That warning was pulled two years later. But the risk? It didn’t disappear. It just got quieter.

What the Data Actually Shows

The biggest study that raised the alarm was the CANVAS Program, which tracked over 10,000 people with type 2 diabetes and heart disease over several years. Those taking canagliflozin had about twice the rate of amputations compared to those on placebo. For the 300 mg dose, it was 5.5 amputations per 1,000 people each year-up from 2.8 in the placebo group. That’s not a small jump. And while most of these were minor-like toe or metatarsal amputations-20% were major, above the ankle.

Here’s the twist: this risk doesn’t seem to apply to all drugs in the same class. Empagliflozin (Jardiance) and dapagliflozin (Farxiga) didn’t show the same pattern in their own large trials. In fact, dapagliflozin’s trial suggested a possible reduction in amputation risk. A 2023 meta-analysis confirmed it: among SGLT2 inhibitors, only canagliflozin had a statistically significant link to amputation. That’s not a coincidence. It’s a signal.

Why Only Canagliflozin?

Scientists aren’t 100% sure why, but they have strong theories. Canagliflozin lowers blood pressure and body weight more than other drugs in its class. That might sound good-until you’re someone with poor circulation in your legs. If your arteries are already narrowed from diabetes, a sudden drop in blood pressure might reduce blood flow even further. Add in nerve damage (common in diabetes), and you’ve got a perfect storm: you can’t feel a sore developing, and your body can’t heal it fast enough.

The numbers tell the story. One analysis found that for every 556 people treated with canagliflozin for a year, one extra amputation happened. That’s rare-but not rare enough to ignore, especially if you’re already at risk.

Who’s Most at Risk?

This isn’t a risk for everyone on canagliflozin. It’s focused. 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)-poor blood flow to the legs
• Smoking
• Absent foot pulses (a sign of blocked arteries)

About 30% of people with type 2 diabetes have PAD. Half have nerve damage. If you have two or more of these factors, guidelines from the University of Michigan and others say you shouldn’t start canagliflozin at all. Alternative SGLT2 inhibitors like Jardiance or Farxiga are safer choices.

What Doctors Are Doing Now

The FDA removed the boxed warning in 2020-not because the risk vanished, but because the benefits in kidney and heart protection outweighed the risk for many. Still, the prescribing label still says: monitor for pain, sores, or infections in the feet and legs.

In 2024, the American Diabetes Association updated its guidelines to recommend an ankle-brachial index (ABI) test before starting canagliflozin. This simple, non-invasive test measures blood pressure in your ankles compared to your arms. If the ratio is below 0.9, it means your leg arteries are narrowed. That’s a red flag. Don’t start canagliflozin without addressing it first.

Clinics are also stepping up foot checks. Instead of a quick glance at your toes once a year, doctors are now expected to examine your feet at every visit. They’re checking for cracks, calluses, swelling, and loss of sensation. And they’re handing out printed guides-68% of new prescriptions in 2023 came with a warning sheet about foot care, up from 42% in 2017.

Real Stories, Real Consequences

On PatientsLikeMe, nearly 7% of canagliflozin users reported foot problems. A Reddit user shared that after 18 months on Invokana, a non-healing ulcer led to a toe amputation. His endocrinologist switched him to Jardiance immediately. Another user, on the same platform, said she’s been on it for three years with no issues and her A1c dropped from 8.5% to 6.2%.

The FDA’s own database shows a stark difference: 1,892 amputation reports for canagliflozin versus just 327 for empagliflozin-despite far more people taking the latter. The reporting odds ratio? Nearly 18 times higher. That’s not noise. That’s a pattern.

What You Can Do

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

1. Check your feet every single day. Look between your toes. Feel for warmth, swelling, redness.
2. Report any sore, cut, blister, or pain-even if it doesn’t hurt. Nerve damage hides pain.
3. Wear properly fitted shoes. No barefoot walking, even indoors.
4. Don’t ignore dry, cracked skin. Use moisturizer daily.
5. Ask your doctor for an ABI test if you’ve never had one.
6. If you smoke, quit. Smoking kills circulation faster than almost anything.

If you’re considering starting canagliflozin, ask your doctor: Do I have any risk factors for poor circulation or foot ulcers? If the answer is yes, push for an alternative. Jardiance and Farxiga have the same heart and kidney benefits-with no amputation signal.

The Bigger Picture

Despite the concerns, canagliflozin still made $1.87 billion in sales in 2023. It’s still prescribed. It still works. For someone without foot problems, with strong circulation, and who needs to protect their kidneys and heart, it can be life-changing.

But it’s not for everyone. And it’s not a drug you should take without knowing the risks-and how to prevent them. The goal isn’t to scare you off. It’s to make sure you’re not blindsided.

The FOOT-STEP trial, set to finish in 2026, is testing whether structured foot care programs can cut the amputation risk in half. Janssen is even testing a new extended-release version of the drug, hoping to reduce peak blood levels that might be contributing to the problem.

For now, the message is clear: canagliflozin is a tool. Like any tool, it’s powerful when used right-and dangerous when used carelessly. Know your risks. Monitor your feet. Ask questions. And if your doctor doesn’t bring up foot health, bring it up yourself.