Canagliflozin and Amputation Risk: What You Need to Know Today

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 under the brand name INVOKANA®. Since its approval in 2013, it’s helped millions lower A1c levels, lose weight, and protect their kidneys. But it’s also been linked to a troubling side effect: lower-limb amputations.

What the Data Actually Shows

The biggest red flag came from the CANVAS Program, a pair of large clinical trials published in 2017. Researchers found that people taking canagliflozin had about twice the risk of needing an amputation compared to those on placebo. The numbers weren’t small: 5.5 amputations per 1,000 patient-years for the 300 mg dose, versus 2.8 for placebo. That’s not a rare event-it’s a clear signal.

But here’s what most people don’t realize: the vast majority of these amputations were minor. About 80% involved toes or parts of the foot, not above-the-ankle surgeries. Still, losing even one toe can change your life-your balance, your mobility, your independence. And for someone already dealing with diabetes complications, that’s a heavy burden.

The FDA responded quickly. In 2017, they added a boxed warning-the strongest possible alert-to the drug label. But by 2020, after reviewing more data, including results from the CREDENCE trial, they removed it. Why? Because the benefits, especially for patients with kidney disease, outweighed the risk. That doesn’t mean the risk disappeared. It just means the FDA now sees it as manageable, not unavoidable.

Is This a Class-Wide Problem?

This is critical: the amputation risk isn’t the same for all SGLT2 inhibitors. Canagliflozin stands out. Studies on empagliflozin (Jardiance) and dapagliflozin (Farxiga) show no similar increase in amputation rates. In fact, dapagliflozin’s trial data suggested a possible reduction in amputation risk.

A 2023 meta-analysis of over 74,000 patients confirmed this. Only canagliflozin had a statistically significant link to amputation (odds ratio of 1.6). Other drugs in the class? No signal. That’s not just a coincidence-it points to something unique about canagliflozin’s effects.

Why might that be? Researchers suspect it’s tied to how strongly canagliflozin lowers blood pressure and body weight. These changes can reduce blood flow to the feet, especially in people who already have narrowed arteries or nerve damage. Other SGLT2 inhibitors don’t hit as hard in those areas, which may explain the difference.

Who’s at Highest Risk?

Not everyone on canagliflozin will face this risk. But certain people are far more vulnerable:

• Those with pre-existing peripheral artery disease (PAD)-affecting 20-30% of people with type 2 diabetes
• People with diabetic neuropathy-about half of all patients
• Anyone who’s had a prior foot ulcer or amputation (recurrence rates hit 40% within a year)
• Current smokers
• Those with absent or weak pulses in the feet

If you have two or more of these risk factors, most experts now recommend avoiding canagliflozin entirely. The American Diabetes Association and the American Podiatric Medical Association both say: if you’re high-risk, choose a different SGLT2 inhibitor-or another class of drug altogether.

What Doctors Are Doing Differently Now

Since the warning came out, prescribing habits shifted. In 2017, canagliflozin made up 35% of SGLT2 prescriptions. By 2023, that dropped to 22%. But it didn’t vanish. Clinicians didn’t abandon it-they got smarter.

Now, before prescribing canagliflozin, many doctors check the ankle-brachial index (ABI). This simple test measures blood pressure in the ankle compared to the arm. An ABI under 0.9 means poor circulation-a red flag. The American Diabetes Association’s 2025 guidelines now explicitly recommend this test before starting canagliflozin in anyone with cardiovascular risk factors.

Also, medication guides are no longer an afterthought. In 2023, 68% of new canagliflozin prescriptions came with a detailed patient guide explaining foot risks-up from just 42% in 2017. That’s a big change in how the industry communicates risk.

What You Should Do If You’re Taking Canagliflozin

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

• Check your feet every day-look for redness, swelling, sores, blisters, or cuts, even if you don’t feel pain
• Report any new foot pain, warmth, or discharge to your doctor immediately
• Never ignore a minor wound. Diabetic foot ulcers can turn serious in days
• Ask your doctor for a foot exam at every visit. Don’t assume they’ll do it unless you remind them
• If you have any risk factors listed above, ask if switching to Jardiance or Farxiga makes sense

Real stories back this up. 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 right away. Another user, u/SugarFreeLife, said she’s been on it for three years with no foot issues and her A1c dropped from 8.5% to 6.2%. Both are true. That’s the reality: for some, it’s life-changing. For others, it’s dangerous.

The Bigger Picture: Benefits Still Matter

Canagliflozin isn’t a bad drug. It reduces heart failure hospitalizations. It slows kidney disease progression. In the CREDENCE trial, it cut the risk of kidney failure by 30% in patients with diabetic kidney disease. That’s huge. For someone with advanced kidney damage, that benefit might mean the difference between dialysis and staying off it for years.

The key is matching the drug to the right patient. It’s not about avoiding all risk-it’s about minimizing it through smart selection and careful monitoring.

What’s Next?

Research is still evolving. The FOOT-STEP trial, set to finish in late 2026, is testing whether structured foot care-daily checks, proper footwear, regular podiatrist visits-can cut amputation rates in high-risk patients on canagliflozin. Early results are promising.

Janssen, the maker of INVOKANA, is also testing a new extended-release version (INVOKANA XR). The theory? Lower peak blood levels might reduce the drop in blood pressure that could trigger circulation problems in the feet. It’s still in Phase 2, but if it works, it could change how we use this drug entirely.

Bottom Line

Canagliflozin carries a real, documented risk of amputation-but only in specific patients. For most people without foot or circulation problems, the risk is low. For those with neuropathy, PAD, or prior ulcers, it’s too high to ignore.

Don’t stop your medication without talking to your doctor. But do ask: Do I have any of the risk factors? Has my circulation been checked? Is there a safer alternative for me?

This isn’t about fear. It’s about awareness. The goal isn’t to avoid all risk-it’s to make sure you’re not taking a risk you don’t need to.