Cardarine and PPAR-delta: what was measured

Cardarine is a PPAR-delta agonist with a real mechanism, a real preclinical literature and a real history — which is not the same as a drug with a body of human evidence behind it. The most useful thing this page can do is hold those two facts apart and let the sources do it.

What the receptor is

PPAR-delta is a nuclear hormone receptor, one of a family that includes the two targets this market already knows: PPAR-alpha and PPAR-gamma. What the receptor does was worked out in pieces. A 2013 Life Sciences review describes it as a key transcriptional factor that moderates proliferation and inflammatory effects. A 2008 review in Expert Opinion on Investigational Drugs records the order things happened in: small-molecule agonists were identified first, which is what made it possible to characterise the receptor’s functions in preclinical models at all.

The fuel-switch paper below is the cleanest of those experiments. What it shows in isolated rat muscle is a switch in mitochondrial substrate preference, from carbohydrate to lipid, plus uncoupling of oxidative phosphorylation at high concentrations. That is the mechanism the marketing language borrows. It is a statement about oxidative metabolism in a muscle chamber. It is not a statement about a person running further.

The fuel-switch experiment, in isolated rat muscle

The cleanest mechanistic paper is from Diabetologia in 2006, and it is ex vivo rat skeletal muscle, not people. Rat muscle was pretreated with GW501516 between 0.01 and 30 µmol/l for 0.5, 4 or 24 hours and rates of fuel metabolism were measured. Between 0.01 and 1 µmol/l the compound dose-dependently increased fatty-acid oxidation and reduced glucose utilisation.

After 24 hours of preincubation at 1 µmol/l, the numbers were: palmitate oxidation +46±10%, glucose oxidation -46±8%, glycogen synthesis -42±6%, lactate release -20±2%, glucose transport -15±6%, all p<0.05. One detail in that abstract is worth more than the rest, because it is the paper contradicting the marketing in miniature: the reduction in glucose utilisation persisted independently of insulin stimulation and of muscle fibre type, but depended on fatty-acid availability — in the absence of fatty acids, the effect on glucose transport was an increase of 30±9% (p<0.01). The authors attribute this to the glucose-fatty acid cycle.

And at higher concentrations, the same paper reports, GW501516 uncoupled oxidative phosphorylation by direct action on isolated mitochondria — independently of PPAR-delta. That is a mitochondrial side effect, not a receptor mechanism, and it belongs in any honest account of the compound.

The endothelial papers

In human umbilical vein endothelial cells, the 2008 Arteriosclerosis, Thrombosis and Vascular Biology paper reports that the synthetic PPAR-delta ligands GW0742 and GW501516 significantly inhibited TNF-alpha-induced expression of vascular cell adhesion molecule-1 and E-selectin, and the adhesion that follows. Activating the receptor raised antioxidant genes — superoxide dismutase 1, catalase and thioredoxin — and cut reactive oxygen species production. The mechanism is described as binary: induction of antioxidative genes plus the release of a transcriptional repressor, BCL-6, from the adhesion-molecule promoter.

There is a line in that abstract that most summaries of this compound leave out. Small interfering RNA that reduced endogenous PPAR-delta expression potentiated the suppressive effect of GW0742, which the authors read as the non-liganded receptor possibly having the opposite effect. The receptor is not a simple accelerator.

A 2013 European Heart Journal paper runs the muscle-and-vascular story in mice. GW501516 induced matrix metalloproteinase 9 in endothelial progenitor cells, which broke down insulin-like growth factor binding protein 3 and activated the IGF-1 receptor on nearby cells. Systemic GW501516 in mice raised MMP-9 in those progenitor cells and increased IGFBP-3 degradation in serum; in a mouse hindlimb ischaemia model it induced IGF-1R phosphorylation in endothelial cells and skeletal muscle in the ischaemic limbs, with more angiogenesis and more skeletal muscle regeneration, and it improved healing in a mouse skin punch wound. Those effects were abolished in MMP-9 knock-out mice.

The human programme, and the paper that ended it

Here is the part that is usually told wrong. It is not that GW501516 was never given to people. A 2006 profile in Current Opinion in Investigational Drugs describes it as a GlaxoSmithKline and Ligand compound for dyslipidaemia with phase II trials ongoing. A 2008 review, written from inside GSK, called the class “an adopted orphan still looking for a home” and said the activities seen in the clinic were “broadly similar” to those seen in the preclinical models — while noting it was still not known whether the agonists would be differentiated enough from current treatments to justify their use, and that the path forward was “as yet undefined”.

Then the rodent data landed. A 2013 Life Sciences review states it plainly: following “highly successful clinical trials using the PPARβ/δ agonists GW501516 for treatment of diabetes”, GSK announced that any further research would be discontinued because preclinical trials in rodents linked the drug to widespread tumour development.

The mechanism behind that finding was published in the Proceedings of the National Academy of Sciences in 2006, and it is a strong paper. Deleting PPAR-delta decreased intestinal adenoma growth in Apc(Min/+) mice and inhibited the tumour-promoting effects of GW501516. Activating PPAR-delta up-regulated VEGF in colon carcinoma cells, and VEGF promotes colon tumour epithelial cell survival through PI3K-Akt signalling. The authors’ own conclusion was that these data “highlight concerns about the use of PPARdelta agonists for treatment of metabolic disorders in patients who are at high risk for colorectal cancer”.

What the data do not show

They do not show that anyone got more endurance. Every performance result in this literature is rat muscle in a chamber, or mice in an ischaemia model. The “more oxidative fibres” claim is a mechanistic explanation of why a drug might help an endurance athlete, not a measured outcome in an endurance athlete.

They do not show a lipid or glucose result in a person on this page. The human work existed and was described as successful by a 2013 review, and the only PubMed-indexed human information cited here is a 2006 trial-status profile and a 2008 review stating that the clinic and the preclinical models looked similar and that differentiation from existing treatment was unproven. No efficacy number is quoted from a human GW501516 trial on this page, because the abstracts indexed here do not print one.

They do not show a clean safety profile. Rodent tumour development across tissues is the reason the development programme stopped. Uncoupling of oxidative phosphorylation at higher concentrations is a separate finding, and it happened independently of the receptor.

They do not show that the material on this shelf is what any of these papers used. The published work uses a research compound in cell medium, in isolated rat muscle and in mice. That is a fact about the evidence base, not a comment on the product — but a page that implied the two were the same thing would be misreading the literature it cites.

SARMs part 2 counts which of the non-approved agents on this shelf have any controlled human study behind them at all, and this page is the long version of one entry in that count. Where the two tell the same story at different lengths, the abstracts quoted here are the ones to read.

Where this sits on the shelf

The compound as supplied by the manufacturer: Cardarine

What we supply

The Cardarine preparation above, as supplied by the manufacturer, tracked, from inside the EU.

Research use only. This page summarises published studies for research reference. It is not medical advice, not a protocol, and not a suggestion for human use. Nothing we supply is for human or veterinary use.