Cardarine (GW501516, GW516)

Description:

Cardarine is a PPARD (Peroxisome Proliferator-Activated Receptor Delta) receptor agonist. This receptor plays an important role in human metabolism, as it is involved in the regulation of genes that help manage the transport and oxidation of fatty acids. PPARD agonists are of great interest in medical research at present, as they hold the potential to influence areas such as insulin sensitivity, glucose tolerance, and lipid balance. Further, they may offer therapeutic benefit with conditions such as obesity, type 2 diabetes, and high cholesterol. Cardarine is a research drug, once under development for improving HDL cholesterol in patients with dyslipidemia.

As a PPARD agonist, cardarine has several effects that are of interest in the sports and fitness community. First, its use may cause a shift in energy metabolism, reducing glucose utilization and increasing the capacity for fatty acid oxidation.1 It can also favor glycogen storage in muscle tissue, improve ATP energy efficiency, and enhance exercise endurance.2 3 In early animal studies, it dramatically increased the running capacity of mice.4 This drastic shift in the utilization of fat for energy may further improve body composition. To that effect, cardarine has been associated with a significant reduction in body fat in both animal studies and human anecdotal reports.

Perhaps most interesting, PPARD activation increases mitochondrial biogenesis in the muscles. This can actually remodel the muscle tissue. In studies using both trained and untrained mice, cardarine caused fast twitch muscle fibers to convert to slow twitch fibers. The latter use oxygen for ATP energy, and are less susceptible to fatigue. Slow twitch fibers are also expressed more abundantly in endurance vs. strength athletes. Again, this effect can substantially improve exercise endurance. Cardarine is often called an exercise mimetic, because it can produce these changes in metabolism and fiber composition, which we normally associate with endurance training.

Cardarine successfully completed preliminary Phase 1 human safety studies,5 and then Phase Il clinical trials.6 The Phase II study examined the effects of 2.5, 5, and 10 mg daily for 12 weeks in 268 patients with low HDL levels. During this investigation, the drug was shown to significantly improve serum lipids, with the 10 mg dose most impactful. This increased HDL (good) cholesterol by approximately 17%, and reduced LDL and triglycerides by 7% and 17%, respectively. A further analysis of particle size suggests changes that were cardioprotective.

Bodyweight also increased by 1.3 kg. Lean vs. fat mass analysis was not done, however an increase in LBM compartment would be consistent with metabolic changes expected of a PPARD agonist.

In 2009, GSK withdrew its New Drug Application. Cardarine was officially pulled from development. During long-term preclinical safety studies, the drug had produced cancer in animals at all doses tested.7 8 Neoplasms appeared in the liver, bladder, thyroid, tongue, stomach, skin, testes, eyes, and uterus. With these findings, the drug will likely progress no further. These studies are often criticized in the athletic community for using high doses and a prolonged duration. While this may be true, this type of testing is also standard for preclinical safety evaluations. Incidentally, the lowest dose used and also determined to be carcinogenic was 5 mg/kg per day. When calculated across species, the rough equivalent is 65 mg for an 80 kg human.

Key Points:

• Enhances Fat Oxidation

• Remodels Muscle Fiber Type

• Improves Endurance

• Improves Lipids

• Failed Safety Study. Possible Carcinogen.

History:

Cardarine was developed by the U.S. biotechnologies firm Ligand Pharmaceuticals. This drug came about as part of an agreement the company signed with GlaxoSmithKline (GSK) in 1992, which focused on developing drugs jointly for the treatment of cardiovascular diseases.9 As subject to this agreement, GSK would obtain worldwide exclusive rights to cardarine. GSK would fund further development, and Ligand would receive substantial royalties and milestone payments as the drug progressed through investigatory stages.

The first appearance of cardarine in the medical literature came in 2001, when its effect on reverse cholesterol transport was investigated.10 For several years, there appeared to be a flurry of research activity around this agent. The drug appeared in numerous animal studies, and then entered Phase l human trials. Ligand announced the receipt of a $1 million milestone payment in 2004, when GSK then announced the decision to progress to Phase II trials. The drug seemed to be on a strong development track. However, it was discontinued in 2009, when long-term animal studies revealed a carcinogenic effect (see: Description).

In 2013, the World Anti Doping Agency (WADA) issued a press release warning the public about the ‘serious toxicities” that were discovered during pre-clinical testing of cardarine.11 This statement came as a result of an emerging cooperation between GSK and WADA, which involved the sharing of information. GSK had apparently learned of the black market availability of cardarine. WADA learned of the drug’s potential carcinogenicity. As expected, cardarine appears on the WADA banned substances list.12 Its use can now be detected during a doping test.13

How Supplied:

Cardarine is not available as a pharmaceutical product. Standard dosage information is unavailable. When used in clinical studies, cardarine was prepared in 2.5, 5, and 10 mg tablets.

As a research compound, it is found in both encapsulated powder form, and as a liquid suspension. It is typically supplied at a dosage of 10 mg when in capsules, and 20 mg/mL for liquid oral suspensions.

Structural Characteristics:

Cardarine is a thiazolyl derived compound. It has the chemical name 2-[2-Methyl-4-[[[4-methyl-2-[4( t r I f l u o r o m e t h y l ) p h e n y I ] – 5 – thiazolyl]methyl]thio]phenoxy]-acetic acid.

Warnings:

Cardarine is an unapproved new drug. A thorough understanding of its safety and propensity for side effects in humans is lacking at this time. Further, the discontinuation of human studies, combined with striking animal carcinogenicity data, leaves us with serious concerns about its safety. More research would be needed before this could be considered safe for human use, and that does not appear likely at this time.

Side Effects:

During Phase I and II human studies, cardarine was well tolerated. There were no significant side effects reported. Further, an examination of liver enzymes (AST and ALT), hematology (blood cell counts), and renal function (creatinine) tests found no changes with the daily administration of 10 mg. Again, the potential side effects of this drug have not been fully characterized.

Administration:

Cardarine is taken orally.This drug has not been approved for use in humans. Prescribing guidelines are unavailable. During clinical studies, the maximum daily human therapeutic dosage tested was 10 mg.

When used for physique- or performance-enhancing purposes, cardarine is most commonly taken at a dosage of 10-20 mg per day. This is administered in one episode, often before exercise on training days. Cycles of cardarine usually last 6 to 12 weeks.

There are no commercial preparations containing cardarine known to exist. This drug is currently available as a research compound only.

1 Lipids, Lipoproteins, and Peroxisome Proliferator Activated ReceptorDelta Sprecher DL 2007

2 Regulation of Muscle Fiber Type and Running Endurance by PPARd. YongXu Wang et al. PLoS Biol 2(10): e294

3 Exercise-Induced AMPK Activation Does Not Interfere with Muscle Hypertrophy in Response to Resistance Training in Men Lundberg TR, Fernandez-Gonzalo R, Tesch PA. 2014

4 A metabolomic study of the PPAR%o agonist GW501516 for enhancing running endurance in Kunming mice. Wei Chen et al. Scientific Reports 5:09884. DOI: 10.1038/srep09884

5 Activation of Peroxisome Proliferator-Activated Receptor (PPAR)%o Promotes Reversal of Multiple Metabolic Abnormalities, Reduces Oxidative Stress, and increases Fatty Acid Oxidation in Moderately Obese Men. Ulf Risérus et al. Diabetes 2008 Feb;57(2): 332-339

6 Lipid Effects of Peroxisome Proliferator-Activated Receptor-%o Agonist GW501516 in Subjects With Low High-Density Lipoprotein Cholesterol. Characteristics of Metabolic Syndrome. Eric J. Olson, Gregory L. Pearce, Nigel P.Jones, Dennis L. Sprecher. Arterioscler Thromb Vasc Biol. 2012;32:22892294.

7 MOUSE CARCINOGENICITY STUDY WITH GW501516, A PPAR DELTA AGONIST. S.J. Newsholme, W. S. Dunsford, T. Brodie, C. Brennan, M. Brown and L. E. Geiger. The Toxicologist. Volume 108, Number 1, March 2009

8 Rat Carcinogenicity Study With GW501516, a PPAR Delta Agonist L.E. Geiger, W.S.Dunsford, D.J. Lewis, C. Brennan, K.C.Liu and S.J. Newsholme. The Toxicologist. Volume 108, Number 1, March 2009

9 Form 10-K filing for Ligand Pharmaceuticals, Fiscal Year ending December 31, 2001.

10 A selective peroxisome proliferator-activated receptor delta agonist promotes reverse cholesterol transport. Oliver WR Jr. et al. Proc Natl Acad

Sci US A. 2001 Apr 24;98(9):5306-11. Epub 2001 Apr 17

11 WADA issues alert on GW501516. March 21, 2013 www.wadaama.org

12 Telmisartan as Metabolic Modulator: A New Perspective in Sports Doping? Sanchis-Gomar F, Lippi G. 2012

13 Synthesis, mass spectrometric characterization, and analysis of the PPAR%o agonist GW1516 and its major human metabolites: targets in sports drug testing. Thevis M, Möller I, Beuck S, Schänzer W. et al. Methods Mol Biol. 2013;952:301-12. doi: 10.1007/978-1-62703-1554_22.