Chicago, IL - Results of the RIO-North America study, appearing in the February 15, 2006 issue of the Journal of the American Medical Association, reinforce both the undeniable weight-loss effects of rimonabant but also the high dropout rates seeming endemic in weight-loss studies [1]. In this study, 20 mg bid of the endocannabinoid-receptor antagonist rimonabant compared with placebo was associated with significantly greater reductions in weight, waist circumference, and improvements in cardiometabolic risk factors in the RIO-North America study.
But as Dr F Xavier Pi-Sunyer and colleagues note in their paper, the dropout rate for both the active treatment and the placebo arm of the study was 50%. While this rate is consistent with other weight-loss drug trials, the problem complicates analysis of the true effects of the study drug. "It must be acknowledged that the trial was limited by a high dropout rate and that long-term effects of the drug require further study," they write. "Still, our observations collectively suggest that rimonabant may well represent an innovative approach to the management of multiple cardiometabolic risk factors, facilitating and maintaining improvements through weight-loss-dependent and -independent pathways."
In an accompanying editorial, Dr Denise G Simons-Morton and colleagues (NHLBI, Bethesda, MD) grapple with the problems of interpreting RIO-North America's findings, given the high dropout rate [2]. They note that 220 patients out of 3035 patients in the study were lost to follow-up over one year, yet the investigators analyzed data only for the 1602 subjects who completed the treatment to which they were assigned, rather than all the subjects not lost to follow-up. Instead, analyses were done to estimate data for dropouts, based on predicted weight at one year, but as the editorialists point out, such analyses can end up skewing the data in an "unknown direction."
"To their credit, the authors also imputed values for missing data using two other methods, but when so much data are missing, no method for imputing missing data can ensure a valid answer to the research question," they write.
Elaborating to renalwire, Simons-Morton emphasized that the main message from the high dropout rate is that the trial results must be interpreted cautiously. "It may be, for example, that the amount of weight loss in the drug groups compared with the placebo group was actually less than reported," she explained. Moreover, "The dropout rates for this weight-loss drug study are similar, and even a bit higher, than other weight-loss drug studies."
Other drugs, other strategies
Indeed, the issue of how rimonabant stacks up against other drugs will be a key question if and when the drug is approved. As Simons-Morton points out, rimonabant relies on a different mechanism of action than approved weight-loss agents sibutramine and orlistat, but, she says, "effects on weight loss reported so far do not indicate that rimonabant is better than the other weight-loss medications in terms of amount of weight loss achieved."
To think that a pill can be effective against [societal] pressures is simplistic.
In fact, no weight-loss drugs have demonstrated weight loss as successfully as lifestyle studies focusing on diet and exercise, the editorialists note. Simons-Morton acknowledged to renalwire that the public often seems to want a "magic pill" to solve weight/obesity problems, but "that does not mean such a pill is, or ever will be, available," she said.
"Health behaviors, like diet and physical activity, are influenced by a myriad of societal factors, including the types of occupations we have (mostly sedentary), the types of leisure pursuits that are common (mostly sedentary), and the type of foods that are available (large amounts of high-calorie/large-portion foods). These factors create societal pressures that lead to poor energy balance, which ultimately leads to obesity. To think that a pill can be effective against such pressures is simplistic."¿
She also points to the fact that 65% of Americans are overweight or obese: "Do we want to place all of these millions of people on medication for their weight?" she asked. "We have no idea what the consequences of that action will be, for example, or what the magnitude of side effects might be, especially long term. I don't think such an approach would be good for the patients, the healthcare system, or the nation's public health status."
Instead, she said, what is needed is a concerted emphasis on healthful food and more opportunities for being physically active. "That will take political will and efforts at all societal levels," she added.
Caution urged, but potential advantages
Also commenting for renalwire, Dr Richard J Glassock (University of California, Los Angeles David Geffen School of Medicine) urged caution in interpreting rimonabant as a "breakthrough" drug in the management of obesity and metabolic syndrome.
"The high recidivism rate and the lack of comparison with other weight-reduction medications (this was a placebo-controlled trial) make the study difficult to evaluate," Glassock said. "Of course, we do not know whether rimonabant-induced weight loss would reduce the rate of development of albuminuria, hypertension, or [chronic kidney disease] CKD, as this would take a longer-term study to define."
He noted that the recent rejection of the term metabolic syndrome by several medical societies stems from the fact that each of the components that define metabolic syndrome contribute to the risk of cardiovascular disease (CVD) and CKD, and each of these may require intervention. The concern is that requiring that patients have three or more of the risk factors to define the syndrome could mean that those who don't reach the requirement for the definition might not be offered management of one of these individual risk factors.
"Personally, I find 'metabolic syndrome' a convenient and useful term to define a group of patients at particularly high risk for the development of CVD and CKD," Glassock said. "Whether rimonabant is a new and powerful drug to treat metabolic syndrome remains to be seen." However, he adds, "The effect to reduce smoking is an added benefit not seen with the other agents currently marketed for weight reduction, and in a smoking, obese person with diabetes, this could be a real advantage to the drug."
