Weight Loss: What We Know

by Hugh Nymeyer, MD, PhD

What we know about healthy dietary practices and weight loss is little to none. Although there is a lot of anecdotal and "common-sense" advice, most of this is apocryphal at best. Observational studies have largely failed at disentangling the lifestyle factors that affect longevity and health. Fortunately, a number of careful, controlled studies are beginning to reveal reliable information that we can depend upon.

This white paper is intended to be a brief summary of some of the latest and most reliable information about weight loss. This is a large area, so the focus will be on the following question: what are the most effective dietary and pharmacologic practices for rapid, safe and sustainable weight loss?

Dietary Practice

What should one eat to lose and maintain weight? Conservation of energy would seem to provide the answer to this question. As fat is stored energy, the change in the amount of fat is proportional to difference between caloric intake and caloric expenditure. Because one pound of fat has an energy content of 4100 food calories2, then decreasing caloric intake by 500 calories a day will cause you to lose almost a pound of weight in eight days. Unfortunately, life is not so simple. After a short amount of time, homeostatic mechanisms will adjust your metabolic rate to compensate for the decreased caloric intake. Likewise, dietary changes will affect how incoming energy is stored as well as overall satiety. These other changes are often more important than the decrease in caloric intake in determining the long-term success of a weight-loss regime. These complexities prevent us from using simple reductionist arguments to deduce what is or is not an effective weight-loss diet.

Although observational studies might seem ideal to study dietary influence, we know that these studies are not especially reliable because they cannot control for the numerous factors that differentiate healthy from unhealthy individuals. Discrepancies between the predictions of observational studies and randomized controlled studies (RCTs) are too numerous to mention. One need only google hormone replacement therapy to observe the limitations of observational studies.

Fortunately, high-quality RCTs comparing various diets now exist, and their results are clear and consistent. No diet has been found to be more effective for weight-loss than a low carbohydrate diet. For rapid weight-loss (<6 months), low carbohydrate diets are superior to all other studied diets. Common disease markers are all as good or better on a low carbohydrate diet than other diets with the possible exception of LDL cholesterol and total cholesterol levels. Fig. 1 (reproduced from Shai et al.1) compares the observed weight loss among the three dietary cohorts. This response is consistent across all of the large, long-term dietary RCTs1, 3-12 and in recent meta-analyses of these same RCTs13.

As to the long-term safety of any diet, the most anyone can say reliably is that we just don't know. No RCTs have been (nor probably will be) carried on long enough to answer that question definitively. Although longitudinal observational studies are not as reliable as RCTs, they do support the premise that low carbohydrate diets are not associated with long-term cardiovascular risk. For example, an analysis of data from 82,802 women in the Nurses' Health Study shows that "diets lower in carbohydrate and higher in protein and fat are not associated with increased risk of coronary heart disease in women"14; although, the type of dietary fat may have some influence in cardiovascular risk. In the absence of additional evidence, perhaps the best we can say is this: it is clear that obesity is detrimental to both longevity and health, and any dietary practice that maintains a healthy weight while delivering appropriate nutrition is probably preferable to obesity.

Pharmacologic Practice

Although diet alone or diet and exercise are effective means for weight loss, dietary attrition rates are high. Most diets fail because the dieters don't follow the diet, not because the diet doesn't work. Similarly, the most effective diet is usually the one that is easiest to follow. The types of food common to a diet, its overall variety and ease of preparation, psychological factors including motivation, general level of satiety, and the amount of diet supervision all affect the success rate for short and long term weight loss.

Anti-obesity medications can serve as an important component of a weight loss program, particularly as an aid to staying on a diet. Although anti-obesity drugs can have varied modes of action — for example, some drugs such as orlistat can work by inhibiting nutrient absorption or as thermogenic agents — most anti-obesity drugs work primarily as appetite suppressants. This is true for most of the most popular anti-obesity drugs including sibutramine, phentermine, and phendimetrazine. The large number of drugs and their varied modes of action preclude a detailed discussion here; however, it is worthwhile to take a birds-eye view of the effectiveness of these drugs for weight loss.

There are a number of recent reviews of anti-obesity medications15-20. These reviews tend to focus on recently approved, pending, and novel therapeutic agents — especially sibutramine and orlistat, the two drugs specifically FDA approved for long-term weight management; however, the most widely used pharmacologic agents in the practices of physician obesity specialists21 continue to be the norandrenergic drugs phentermine, diethylpropion and phendimetrazine which have been approved for short-term use in weight management. Off-label prescriptions of the anti-convulsant topiramate and prescriptions for sibutramine and orlistat follow in usage.

The important question that concerns us here is: are these medications more effective than diet and exercise in combination with a placebo? There have been a number of studies, and essentially all of them support this conclusion for the studied medications. For example, Haddock et al.22 performed a meta-analysis of all the RCTs completed by December 1999 that involve FDA-approved drugs used for weight loss. They concluded that, compared with diet and lifestyle management and placebo, there is a modest but significant amount of additional short-term weight loss — usually between 4 and 8 lbs — with most of the approved medications. Similar effects were found by Padwal and coworkers18, 23 in a review of long-term usage of Orlistat and Sibutramine and by Arterburn et al24. Although this additional weight loss may seem small, it is large enough to have measurable affects on blood pressure and lipid profiles.

Reliable information about weight loss medications and diets are important, because erroneous information is widespread. For example, Human chorionic gonadotrophin (HCG) injections continue to be widely used as a weight loss therapy, despite strong evidence that HCG is completely ineffective25. A large number of new and combination drug therapies are being studied, so the pharmacological options for weight loss are likely to expand greatly in the near future. Clearly, more information is needed about the long-term maintainability and safety of various diets; however, in the interim, the studies reviewed in this manuscript are revealing to us reliable approaches for counteracting the epidemic of obesity and its detrimental health effects.


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