Muscular Development
Fat Attack
By Dan Gwartney, MD
Rimonabant: The Revolutionary New Fat-Loss Drug
The most successful marketing campaigns generate a buzz. The weight-loss and investment communities have both been buzzing for a couple of years about a flagship product being developed by French pharmaceutical giant Sanofi-Aventis. Ironically, this wonder product is based on a plant that’s been providing a buzz to millions for decades, if not centuries— marijuana.
Natural Hormone-like Chemicals
Sanofi announced in February 2006 that they expected a midyear launch of their widely anticipated drug, rimonabant. Originally designated as SR141716A, rimonabant represents an example of broad-minded thinking resulting in a novel solution to an age-old problem.1 Marijuana is a popular drug in America, with its use being ubiquitous in populations ranging from high school stoners to geriatric glaucoma patients.2 Pot, as it’s more familiarly known, creates psychotropic effects through the actions of THC (tetrahydrocannabinol). In addition to a relaxing effect many find to be pleasant, pot also induces an impulsive hunger referred to as the “munchies.”3
During the early 1990s, researchers discovered specific receptors that responded to THC, called cannabinoid receptors (CB-1 and CB-2). Natural hormone-like chemicals were later discovered that reacted with the cannabinoid receptors, called endocannabinoids. These endocannabinoids produced similar effects to THC in animal studies (decreased activity, reduced pain and increased appetite).4
Wisely, researchers searched for chemicals that might suppress the actions of cannabinoids, realizing the promise of utilizing this pathway in the treatment of obesity. Several candidate drugs were discovered, including rimonabant. Acting as an inverse agonist (a drug that produces the opposite effect in a system), rimonabant has proven to be a successful tool in reducing weight in animal and human studies.
Originally, it was believed that the effects of rimonabant were entirely due to its interaction with receptors in the brain, which decreased appetite and reduced the rewarding sensations users experienced during meals.5 It’s understandable why the scientists focused so rapidly on this set of effects, as marijuana is regarded almost exclusively for its effects on behavior and coordination. Elaborate studies established rimonabant’s role in altering neurotransmitter levels in key areas of the brain that control feeding behaviors (the hypothalamus), as well as the positive emotional response generated by eating (the mesolimbic system).6,7 An interesting set of studies demonstrated the ability of rimonabant to reduce sucrose (sugar) intake and ethanol (alcohol) ingestion at doses that didn’t reduce food intake, presumably by blunting the emotional and mental reward associated with sugar and alcohol.8 Rimonabant also lessened the orexigenic effects of ghrelin, a hormone released by the stomach when it’s empty to stimulate feeding.9 Clearly, rimonabant’s effectiveness is promoted by its diverse roles in appetite control.
The early studies with rimonabant demonstrated its potency as an appetite-suppressant, as rodents lost weight or avoided weight gain, initially through a reduction in food consumption, with a sustained reduction in body fat mass over time. These promising findings encouraged clinical trials in humans, hoping the same behavioral and metabolic changes and weight loss would be observed.
When applied to human subjects, rimonabant continued to be effective, as it reduced appetite and increased weight loss in obese and overweight subjects.10 Not only was rimonabant effective in producing short-term weight loss, it maintained the weight loss over a period of two years, with no serious side effects. Approximately 12 percent of the subjects taking the higher dose (20 milligrams per day) complained of nausea; about half that number experienced nausea with the lower dose (5 milligrams per day).
Hidden Benefits
At first glance, rimonabant appears to be an extremely effective appetite suppressant that offers hope for the millions of obese and overweight people in Europe and the U.S. However, a closer examination of the studies discloses some interesting facts, findings that make rimonabant even more attractive and suggest that even more promising drugs may be developed over time.
The appetite suppressing effect of rimonabant isn’t persistent. In fact, though subjects receiving rimonabant initially decrease calorie intake, they were soon eating the same number of calories as their counterparts in the placebo group. Yet, they continued to lose weight.11 Clearly, rimonabant must be doing more than just suppressing appetite as part of its fat-reducing properties. This might have been anticipated, since mice bred to not have the cannabinoid receptors are also leaner than normal mice, despite eating the same amount of food.12
Scientists then endeavored to account for these findings. They discovered that rimonabant interacts with cannabinoid receptors outside the brain as well, particularly in adipose (fat) tissue and the liver. Under the influence of rimonabant, liver enzymes are down-regulated, resulting in a lower rate of de novo lipogenesis, which is a term that describes the production of new fatty acids in an overfed state.4 Thus, the liver makes fewer fatty acids, which are the building blocks of triglycerides (the storage form of fat). The fat cell, in addition to receiving a reduced supply of new fatty acids from the liver, also becomes less efficient at turning these free fatty acids into triglycerides.1
Rimonabant also affects the fat cells through another mechanism. It was always assumed that fat cells were passive storage depots, existing merely to provide a place for excess calories to reside. This assumption has been proven false, as it’s clear that fat cells communicate with the brain and other tissues, alerting the system as to how much stored energy is available. Leptin is one fat cell-derived hormone, another is adiponectin. Adiponectin is the most abundant, though less well known, gene product of fat cells. Adiponectin induces changes that improve insulin sensitivity, reduce bad cholesterol and triglyceride levels and also lower the risk of diabetes. Rimonabant’s ability to increase adiponectin output from the fat cell is felt to be one of the major components of its peripheral actions.1 It’s also possible, based on animal observations, that total energy expenditure goes up (calories burning) by increasing uncoupling protein activity, offering yet another avenue of fat loss.1
The discovery that rimonabant has a peripheral set of actions (effects taking place outside of the brain) is very exciting, as there have been reports of depression and anxiety among some subjects.10 As the central actions (appetite suppression) of rimonabant only seem to play a role in the early phase of weight loss, the possibility that a new drug could be developed that only acts peripherally is wonderful, as it would allow people to stay on the drug long term, with a much lower risk of psychological side effects. It’s also possible that a rimonabant-based drug that’s specific about acting in the brain might be beneficial for another suggested use— smoking cessation.
Even more exciting, for investors and scientists, is the hope that the peripheral-acting component would provide a treatment for other conditions that rimonabant may be used in the treatment of— including dyslipidemia (elevated cholesterol and triglycerides), insulin resistance and the Metabolic Syndrome. Studies have established that rimonabant raises HDL (good) cholesterol, improves insulin sensitivity and reduces visceral fat.10 Visceral fat is a specific region of fat that surrounds the organs in the abdomen. It’s related to insulin resistance and raises the risk of cardiovascular disease. The reduction in visceral fat may account for the observation that rimonabant-treated subjects reduced their waist size more than the control group.
Currently, rimonabant has received positive response from the FDA. Sanofi was granted an “approvable” letter from the FDA, which means that they must answer a few questions, typically relating to safety, before it can be marketed.14 Rimonabant is already approved for sale in Europe, possibly under the brand name Acomplia®, though it hasn’t yet been released. Sadly, counterfeit products are already being sold on the Internet to gullible consumers, who may be wasting their money or risking their health.15
Rimonabant offers great promise to the obese and overweight. It’s also an interesting drug for bodybuilders, as it appears to reduce fat by making it less available to the fat cell and harder to store, as well as raising HDL cholesterol. Certain anabolic steroids lower HDL cholesterol, a state associated with greater risk of cardiovascular disease if it persists long-term.16 Additionally, the improved insulin sensitivity suggests it may aid in shuttling nutrients into muscle and lean tissue.1
Surprisingly, one area that hasn’t been reported on for a possible use of rimonabant is in the field of addiction. Marijuana use is currently illegal in the United States, though it remains one of the most commonly used illicit drugs, especially among youth.2 If rimonabant aids in preventing use for habitual marijuana users, that would be very intriguing. This may be thought controversial though, as many Americans believe marijuana should be legalized. However, in the current environment, rimonabant may play a role in curbing the demand for one illicit drug.
Rimonabant will soon be available in the United States, though the demand will likely outstrip supply. Happily, Sanofi’s announcement suggests that Acomplia is nearly fait accompli. It appears that indications for use will include the obese (BMI over 30) and the overweight (BMI between 25.0 and 29.9) with associated cholesterol/triglyceride problems or type 2 diabetes.17 It’s to be expected that some of the earliest prescriptions will go to athletes or lifters with high cholesterol. Hopefully, they’ll provide feedback to the community as the story of this exciting drug unfolds.
References:
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2. Johnston LD, O'Malley PM, et al. (2006). Monitoring the Future national results on adolescent drug use: Overview of key findings, 2005 (NIH Publication No. 06-5882). Bethesda, MD: National Institute on Drug Abuse, 67 pp.
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13. Gelfand EV, Cannon CP. Rimonabant: a selective blocker of the cannabinoid CB1 receptors for the management of obesity, smoking cessation and cardiometabolic risk factors. Expert Opin Invest Drugs, 2006;15:307-15.
14. Whalen J. Sanofi aims to sell obesity drug this year, despite FDA setback. Wall Street Journal, 2006 Feb 25-26;A5.
15. Reuters News Service. EU warns consumers over fake anti-obesity drug. 2006 Mar 27.
16. Hislop MS, St Clair Gibson A, et al. Effects of androgen manipulation on postprandial triglyceridaemia, low-density lipoprotein particle size and lipoprotein (a) in men. Atherosclerosis, 2001;159:425-32.
17. Whalen J. Sanofi weight-loss drug gains support in Europe. Wall Street Journal, 2006 Apr 29-30.
