TL;DR: SGLTi, originally developed for type 2 diabetes, shows promise as a geroprotective agent that may slow aging, prevent age-related diseases, and improve life expectancy. Its mechanisms of action include promoting autophagy, restoring mitochondrial health, reducing oxidative stress, and decreasing inflammation. Large clinical studies demonstrate reduced risks for many common age-related conditions and improved overall survival with SGLTi use.
Key Takeaways:
- Disease Prevention:
- SGLTi is associated with decreased risks for heart failure, chronic kidney disease, atrial fibrillation, cancer, gout, neurodegenerative diseases, emphysema, non-alcoholic fatty liver disease, atherosclerotic disease, and infections.
- Meta-analyses show SGLTi reduces all-cause mortality by 14-45% in various studies.
- Cardiovascular Benefits:
- Reduces risk of heart failure hospitalization by 29% and cardiovascular death by 13%.
- Decreases risk of atrial fibrillation by ~25%.
- Shows benefits within 12 days of initiation in clinical trials.
- Renal Protection:
- Most effective drug class for preserving renal function and slowing CKD progression.
- Reduces risk of kidney disease progression and acute kidney injury by 25-40%.
- Estimated to delay end-stage renal disease by 15 years.
- Cancer Effects:
- May have anticancer activity against pancreatic, breast, prostate, liver, thyroid, and lung cancers.
- Associated with improved survival in cancer patients in observational studies.
- Neuroprotection:
- Crosses blood-brain barrier and shows potential protective effects against neurodegenerative diseases.
- Associated with 38% lower risk of all-cause dementia in T2D patients.
- Mechanisms of Action:
- Enhances autophagy, promoting cellular “housekeeping” and rejuvenation.
- Upregulates nutrient deprivation signaling (AMPK, sirtuins, PGC-1α) and downregulates nutrient surplus signaling (mTOR).
- Reduces oxidative stress, inflammation, and fibrosis.
- Improves mitochondrial function and stimulates mitochondrial biogenesis.
- Safety Profile:
- Generally well-tolerated with discontinuation rates similar to placebo in RCTs.
- Main side effect is increased risk of genital yeast infections (6.3% vs 1.7% in controls).
- Rare risks of ketoacidosis in diabetics; virtually no risk in non-diabetics.
- Comparison to Other Geroprotective Agents:
- Has the most robust RCT data for safety and efficacy in humans compared to metformin and rapamycin.
- Future Directions:
- Further randomized trials needed to test SGLTi as a geroprotective agent in non-diabetic populations.
- Empagliflozin, dapagliflozin, and sotagliflozin show strongest evidence for improving healthspan and lifespan.
Source:
Paper — SGLT inhibitors for improving Healthspan and lifespan