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 under the brand name INVOKANA®. Since its approval in 2013, it’s helped millions of people control their glucose levels and reduce heart failure risk. But it’s also been linked to a higher chance of foot and leg amputations. The question isn’t whether the risk exists-it’s who’s most at risk, and what you can do about it.

What the Data Shows: A Real, But Specific Risk

The alarm bells rang in 2017 after the CANVAS Program, a major study combining two clinical trials, found that people taking canagliflozin had nearly twice the risk of lower-limb 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 difference. It led the FDA to issue a boxed warning-the strongest safety alert they can give. But here’s what’s often missed: that warning was removed in January 2020. Not because the risk disappeared, but because regulators looked deeper. The CREDENCE trial, which focused on patients with diabetic kidney disease, showed that the heart and kidney benefits of canagliflozin outweighed the amputation risk in that group. So the FDA updated the label instead of pulling the drug. Today, the prescribing information still warns about amputation risk-but it’s now in the Warnings and Precautions section, not the boxed warning. The risk is real, but it’s not universal. And it’s not the same across all drugs in the SGLT2 inhibitor class.

Why Only Canagliflozin? The Class Difference

It’s easy to assume all SGLT2 inhibitors are the same. They’re not. Empagliflozin (Jardiance) and dapagliflozin (Farxiga) have not shown the same amputation signal in large trials. In fact, dapagliflozin’s DECLARE-TIMI 58 trial showed a trend toward fewer amputations, not more. A 2023 meta-analysis of over 74,000 patients confirmed it: only canagliflozin had a statistically significant increase in amputation risk (odds ratio 1.6). Other SGLT2 inhibitors? No clear link. This isn’t a class effect. It’s specific to canagliflozin. Why? Researchers aren’t 100% sure, but clues point to its stronger effects on blood pressure and weight loss. Canagliflozin lowers systolic blood pressure by about 3.7 mmHg more than other drugs in its class and causes an average weight loss of 2.8 kg. For someone with poor circulation in their legs-common in long-term diabetes-this drop in pressure might reduce blood flow just enough to turn a small sore into a life-altering problem.

Who’s Most at Risk?

Not everyone on canagliflozin will face amputation. But some people are far more vulnerable. The highest risk group includes those with:

• Pre-existing peripheral artery disease (PAD)-affects 20-30% of people with type 2 diabetes
• Diabetic neuropathy-loss of sensation in the feet, present in about half of long-term patients
• History of foot ulcers or prior amputation
• Current tobacco use
• Absent or weak pedal pulses (a sign of poor circulation)

If you have two or more of these risk factors, most experts now recommend avoiding canagliflozin altogether. The American Diabetes Association and American Podiatric Medical Association both say: if you’ve had a foot ulcer before, or your pulses are gone, don’t start this drug. And here’s something many patients don’t realize: most amputations linked to canagliflozin are minor. About 80% involve just the toes or metatarsals-not the whole leg. But even a toe amputation can change your mobility, increase your fall risk, and lead to more serious problems down the line.

Real Stories: Patients Speak Up

Behind the statistics are real people. On PatientsLikeMe, nearly 7% of canagliflozin users reported foot problems. Seventeen users specifically mentioned amputation concerns. One Reddit user, u/DiabetesWarrior2020, shared: “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, u/SugarFreeLife, said: “Three years on Invokana. No foot issues. My A1c dropped from 8.5% to 6.2%.” Both stories are true. And both matter. The drug works wonders for some. It’s dangerous for others. The difference? Awareness, screening, and early action.

What Doctors Should Do-and What You Should Too

The best way to prevent amputation isn’t to avoid the drug entirely. It’s to use it wisely. Before starting canagliflozin:

• Get a full foot exam-check for ulcers, calluses, pulses, and sensation
• Ask for an ankle-brachial index (ABI) test. An ABI under 0.9 means poor leg circulation and is now considered a relative contraindication by the 2025 ADA guidelines
• Review your history: any past foot problems? Smoking? Nerve damage?

While taking it:

• Check your feet daily. Look for redness, swelling, cracks, or sores-even if you don’t feel pain
• Report any new foot pain, warmth, or sores immediately. Don’t wait
• See your podiatrist every 3-6 months if you have any risk factors
• Wear properly fitted shoes. No barefoot walking

The National Institute for Health and Care Excellence (NICE) tells patients: “If you have numb feet, you can’t feel damage. So you must look.”

The Bigger Picture: Why This Drug Still Matters

Despite the risks, canagliflozin is still prescribed. In 2023, it generated $1.87 billion in global sales. It’s still on the WHO’s Model List of Essential Medicines-with a footnote about foot monitoring. Why? Because for the right patient, it’s life-changing. It reduces heart failure hospitalizations. It slows kidney disease progression. It lowers A1c without causing hypoglycemia. And for many, it’s the only drug that works when others fail. The key isn’t fear. It’s selection. If you’re a 65-year-old with diabetes, heart disease, and no foot problems? Canagliflozin might be a great choice. If you’re a 55-year-old smoker with neuropathy and a history of ulcers? You’re better off with empagliflozin or another alternative.

What’s Next? New Research and Better Safety

The story isn’t over. The FDA now requires all SGLT2 inhibitors to include standardized foot care instructions in their medication guides-starting in January 2024. That’s a direct response to the lessons learned from canagliflozin. A new trial called FOOT-STEP (NCT05123705) is testing whether structured foot care programs can prevent amputations in high-risk patients on canagliflozin. Results are expected in 2026. Janssen is also testing a new extended-release version, INVOKANA XR, designed to lower peak drug levels in the blood. Early data suggests this might reduce the amputation signal-though it’s still in Phase 2.

Final Takeaway: Knowledge Is Protection

Canagliflozin isn’t dangerous for everyone. But it’s dangerous for some-and that’s the problem. The risk is real, measurable, and preventable. The best way to protect yourself isn’t to avoid the drug blindly. It’s to know your risk, get screened, and stay vigilant. If you’re on canagliflozin and have diabetes, ask yourself: Have I had a foot exam this year? Do I know my ABI? Do I check my feet every day? If the answer is no, it’s time to talk to your doctor-not to stop the drug, but to make sure you’re safe while taking it.