Empagliflozin vs Canagliflozin

## Overview

Canagliflozin was the first SGLT2 inhibitor approved by the FDA. Empagliflozin followed and showed the most striking CV mortality benefit in EMPA-REG OUTCOME. Both reduce glucose, weight, and BP, but canagliflozin has a distinctive amputation risk signal (particularly foot/toe) that led to an FDA boxed warning.

## Mechanism of Action

Both inhibit SGLT2. Canagliflozin also partially inhibits SGLT1 (the intestinal glucose transporter) at higher doses (300 mg), potentially providing additional glucose lowering via reduced intestinal absorption.

## Pharmacokinetics

Canagliflozin: bioavailability ~65%, UGT1A9/2B4 metabolism, half-life 10–13 h, once daily with first meal of the day. Empagliflozin: bioavailability ~78%, once daily without food requirement.

## Cardiovascular and Renal Evidence

EMPA-REG OUTCOME: empagliflozin demonstrated landmark CV mortality reduction (38% relative risk reduction). CANVAS/CREDENCE (canagliflozin): CV benefit confirmed plus CREDENCE showed renal protection in diabetic nephropathy. However, canagliflozin is associated with ~2× increased lower-limb amputation risk (FDA 2017 boxed warning).

## Amputation Risk

Canagliflozin's amputation risk (primarily foot/toe) appears class-specific to canagliflozin or at least more pronounced than other SGLT2 inhibitors. Empagliflozin and dapagliflozin have not shown this signal in large trials. The mechanism is thought to involve volume contraction and reduced limb perfusion in at-risk patients.

## Key Takeaways

- Empagliflozin: stronger CV mortality data, no amputation signal
- Canagliflozin: first-in-class, SGLT1 partial inhibition (300 mg), FDA amputation boxed warning
- Prefer empagliflozin or dapagliflozin in patients with peripheral artery disease or amputation risk