Canagliflozin

WHAT IT DOES

Canagliflozin inhibits sodium-glucose cotransporter 2 in the proximal renal tubule, blocking reabsorption of filtered glucose so that glucose is excreted in the urine, and it also has weaker activity against intestinal SGLT1, which slows and redistributes glucose absorption. The result is lower fasting glucose and, importantly for the aging hypothesis, blunted post-meal glucose peaks, achieved without stimulating insulin secretion. The Interventions Testing Program investigators framed the lifespan result explicitly around this: the male lifespan benefit is likely to reflect blunting of peak glucose, because a similar male-specific effect is seen with acarbose, a structurally unrelated drug that lowers glucose surges by slowing intestinal carbohydrate breakdown (Miller 2020, PMID: 32990681).

There is a second, glucose-independent mechanism, and it was shown in cultured cells rather than in animals or people. At clinically achievable concentrations canagliflozin reduced glucose uptake, mitochondrial complex-I supported respiration, cellular ATP, and lipogenesis in prostate and lung cancer cell lines while increasing the activating phosphorylation of AMP-activated protein kinase, in a pattern the authors compare directly to the biguanide metformin; overexpressing NDI1, a protein that maintains complex-I supported respiration, blocked the antiproliferative effect, which places the mitochondrial action upstream (Villani 2016, PMID: 27689018). Canagliflozin also sits alongside rapamycin, acarbose, 17-alpha-estradiol, and calorie restriction in producing a shared set of tissue changes in young mice, including increased UCP1 in brown and white fat, a shift from proinflammatory M1 toward anti-inflammatory M2 macrophages, and higher muscle FNDC5 and irisin and brain doublecortin and BDNF (Li 2023, PMID: 36920743). In a proteomic survey of seven longevity-promoting interventions in mice, canagliflozin produced a largely distinct set of protein changes, with the strongest responses across all interventions seen in liver and limited concordance between tissues (Burns 2023, PMID: 37653270). Mechanistic coherence is where the honest limit sits: a shared molecular fingerprint in mice is not a human outcome.

The sex dimorphism remains unexplained, and it matters. End-of-life histopathology across all three Interventions Testing Program sites found no significant drug-induced change in inferred cause of death, though the authors note that statistical power for that comparison was low, and no clear lesion pattern that would account for why the same drug extends male and shortens female lifespan, leading the investigators to suggest the female-specific harm may be a toxic effect not easily detectable by histopathology (Snyder 2025, PMID: 40601216). The leading candidate explanation is pharmacokinetic rather than pathological: blood levels of canagliflozin were roughly 20-fold higher in aged female mice than in young males (Miller 2024, PMID: 38753230). Until that is resolved in a species other than mice, the longevity hypothesis cannot be treated as sex-neutral.

Pharmacokinetically, canagliflozin is metabolized by UGT1A9 and UGT2B4 and is a substrate of P-glycoprotein, which is the basis of its clinically relevant interactions (Devineni 2015, PMID: 25407255). A review of interactions across the SGLT2 inhibitor class found that exposure to these drugs was not significantly changed by most co-administered glucose-lowering or cardiovascular agents, but that drugs interfering with their metabolic pathways, such as rifampicin and UGT inducers or inhibitors, can produce significant changes (Scheen 2014, PMID: 24420910).

SAFETY PROFILE

Critical Interactions (Do Not Combine Without Medical Supervision)

Moderate Interactions (Monitor Closely)

Theoretical/Low-Risk Interactions