GW501516
Also known as: Cardarine, GW-501516, Endurobol, GSK-516
Evidence: Clinical
Overview
Small-molecule PPAR-delta agonist (Cardarine), not a peptide. Raised HDL and lowered LDL and triglycerides in 2 to 12 week human trials; development stopped after rodent studies found tumours at all doses.
GW501516 is a selective PPAR-delta agonist from GlaxoSmithKline, described in 2003 (Sznaidman). In obese rhesus monkeys it raised HDL and lowered triglycerides and insulin (Oliver 2001). In healthy volunteers, 2.5 or 10 mg daily for 2 weeks raised HDL (Sprecher 2007); in moderately obese men, 10 mg daily for 2 weeks lowered triglycerides, LDL, insulin and liver fat and raised fat oxidation (Risérus 2008). A 12-week phase 2 trial in 268 people with low HDL found HDL up to 16.9% higher at 10 mg (Olson 2012). In mice it raised running endurance with exercise (Narkar 2008). Two-year GSK studies found treatment-related tumours in many tissues in rats and mice at every dose, and development was halted. WADA has prohibited it since 2009 and issued a health warning in 2013. No trial is active.
Benefits
Raised HDL cholesterol and lowered LDL, triglycerides and apoB (human RCTs, 2 to 12 weeks), increased fat oxidation and lowered liver fat (human, 2 weeks, n=6 per arm), running endurance (mouse)
Dosing reference
- Research dose
- 2.5 to 10 mg once daily by mouth (doses used in 2 to 12 week human trials; development halted for rodent carcinogenicity)
- Range
- 2500 to 10000 mcg, 1x daily
Oral. Human trials used 2.5, 5 or 10 mg once daily for 2 weeks (Sprecher 2007; Risérus 2008) or 12 weeks (Olson 2012). Rodent carcinogenicity studies dosed 3 to 80 mg/kg/day for 104 weeks and found tumours at every dose. No long-term human dosing has been studied.
Mechanism
GW501516 binds and activates PPAR-delta (PPARβ/δ), a nuclear receptor, with high selectivity over PPAR-alpha and PPAR-gamma (Sznaidman 2003). In human skeletal muscle cells it raised fatty acid oxidation and expression of CPT1, CD36 and the cholesterol efflux transporter ABCA1 (Sprecher 2007). In obese men it raised the share of dietary fat oxidised and muscle CPT1b expression (Risérus 2008). In primates, ABCA1 induction is the proposed basis of the HDL rise (Oliver 2001). In mice, combined with exercise, it induced oxidative muscle gene programmes (Narkar 2008). PPAR-delta activation also accelerated intestinal adenoma growth in Apc(min) mice, which is the proposed link to the rodent tumour findings (Gupta 2004).
Evidence
Clinical: at least one published human trial or an approved drug
- 12 weeks of 2.5 to 10 mg daily in 268 people with low HDL raised HDL up to 16.9% and lowered LDL 7.3% and triglycerides 16.9% (Olson et al., 2012)
- 10 mg daily for 2 weeks in moderately obese men lowered triglycerides 30%, LDL 23%, insulin 11% and liver fat 20%, and raised fat oxidation (Risérus et al., 2008)
- First human report: 2.5 or 10 mg daily for 2 weeks raised HDL in healthy volunteers (Sprecher et al., 2007)
- Raised running endurance in exercised mice; with AICAR it was the original 'exercise mimetic' paper (Narkar et al., 2008)
- Increased the number and size of intestinal polyps in Apc(min) mice (Gupta et al., 2004); 104-week GSK studies found tumours in many tissues in rats and mice at all doses (Geiger and Newsholme, Toxicologist 2009)
- Human-trial status: development halted after the rodent carcinogenicity findings; no active trials; WADA-prohibited since 2009
References
- Novel selective small molecule agonists for peroxisome proliferator-activated receptor delta (PPARdelta)--synthesis and biological activity. Sznaidman ML, Haffner CD, Maloney PR, et al., Bioorganic & Medicinal Chemistry Letters, 2003
- A selective peroxisome proliferator-activated receptor delta agonist promotes reverse cholesterol transport. Oliver WR Jr, Shenk JL, Snaith MR, et al., Proceedings of the National Academy of Sciences of the United States of America, 2001
- Triglyceride:high-density lipoprotein cholesterol effects in healthy subjects administered a peroxisome proliferator activated receptor delta agonist. Sprecher DL, Massien C, Pearce G, et al., Arteriosclerosis, Thrombosis, and Vascular Biology, 2007
- Activation of peroxisome proliferator-activated receptor (PPAR)delta promotes reversal of multiple metabolic abnormalities, reduces oxidative stress, and increases fatty acid oxidation in moderately obese men. Risérus U, Sprecher D, Johnson T, et al., Diabetes, 2008
- Lipid effects of peroxisome proliferator-activated receptor-δ agonist GW501516 in subjects with low high-density lipoprotein cholesterol: characteristics of metabolic syndrome. Olson EJ, Pearce GL, Jones NP, Sprecher DL, Arteriosclerosis, Thrombosis, and Vascular Biology, 2012
- AMPK and PPARdelta agonists are exercise mimetics. Narkar VA, Downes M, Yu RT, et al., Cell, 2008
- Activation of nuclear hormone receptor peroxisome proliferator-activated receptor-delta accelerates intestinal adenoma growth. Gupta RA, Wang D, Katkuri S, et al., Nature Medicine, 2004
- Metabolic modulators of the exercise response: doping control analysis of an agonist of the peroxisome proliferator-activated receptor δ (GW501516) and 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR). Pokrywka A, Cholbinski P, Kaliszewski P, et al., Journal of Physiology and Pharmacology, 2014
Side effects
Published human trials (2 to 12 weeks, up to 10 mg daily) report lipid outcomes and no serious drug-related findings, but none ran long enough to address cancer risk. In 104-week GSK studies, rats given 3 to 40 mg/kg/day developed treatment-related tumours in liver, bladder, thyroid, stomach, tongue, skin, uterus and other tissues, with higher mortality in females at all doses; mice given 10 to 80 mg/kg/day developed liver and squamous stomach tumours. It enlarged intestinal polyps in Apc(min) mice. WADA issued a public health warning in 2013. No long-term human safety data exist.
Storage
- Storage
- Room temperature, dry, protected from light (general small-molecule guidance; no compound-specific CoA located)
- Lyophilized
- 24+ months
Pharmacology
- Half-life
- Not reported in peer-reviewed literature; human trials dosed once daily by mouth (Sprecher 2007; Olson 2012)
- Bioavailability
- Orally active in rodents, primates and humans (Oliver 2001; Sprecher 2007); no absolute bioavailability figure published
- Molecular weight
- 453.5 Da