Precision medicine, big data, Alzheimer’s Disease, migraine, and RNA therapeutics.
Learnings from the April 2018 meeting.
Edited by Jill Condello, PhD, ICON Access, Commercialisation & Communications
If you're the kind of person who knows — and perhaps takes pride in having achieved — all the right numbers (e.g., blood pressure, LDL-cholesterol, HDL-cholesterol, triglycerides, C-reactive protein, body mass index), you probably should stop reading right now.
Because otherwise you might choke on your tofu. (Which is a very healthful food, and you probably should eat more of it, if you find it to your taste. But you probably don't eat any. So keep reading.)
Yes, we're going to present the views of people who indulge in what many regard as health care heresy. They challenge the conventional wisdom that millions of Americans need to lose tons of weight, fast, to stave off diabetes, heart disease, cancer. They suggest that at least one of these numbers, BMI, doesn't matter much at all, and that if you take care of business (i.e., your cardiorespiratory and metabolic fitness), the stayin'-alive significance of most of the other numbers will be taken care of, too. Specifically, the heretics claim that:
Most of these arguments have been collected and espoused most recently in a new book, The Obesity Myth ( 2004), by Paul Campos, a professor at the University of Colorado School of Law. Space doesn't permit a detailed examination of all the claims mentioned above (but please see the reading list for recent articles that support these ideas). Indeed, Linda Bacon, PhD, a nutrition researcher who asserts that people can improve their health regardless of their weight, says she has given up on using grand rounds as a vehicle for teaching physicians about this approach to obesity — a full day is needed to overcome physicians' initial skepticism. But given enough time, she says, physicians become receptive to new ideas, mainly because they all know, from long, hard experience, that traditional diet and exercise programs aimed at weight loss typically fail over the long run.
The view from ... where?
Campos's book has been widely and favorably reviewed in the lay media, but experts in mainstream medicine have been less enthusiastic. For example, Harvard University's Walter C. Willett, M.D., told the Los Angeles Times, "Every 10 years we get somebody like [Campos] who comes along and thinks they've discovered fatal problems in the relationship between body mass index and mortality. But it's always somebody who doesn't understand medicine and human disease processes and epidemiology."
Willett is, of course, a physician (i.e., someone who presumably understands medicine and human disease processes) and an internationally renowned epidemiologist.
Obviously, Campos doesn't belong to either camp. And he sees that as a distinct advantage when it comes to sifting through the voluminous claims about the dangers of overweight and obesity and the benefits of weight loss. The experts are so thoroughly convinced of the dangers of overweight and the benefits of weight loss, Campos says, that a rational debate of alternative views isn't possible.
But books like Campos's have been coming along more often than every 10 years. His offering extends arguments advanced in earlier books such as Glenn Gaesser's Big Fat Lies: The Truth About Your Weight and Health (2002 [update of 1996 edition]), Francie Berg's Women Afraid to Eat: Breaking Free in Today's Weight-Obsessed World (2000), Marilyn Wann's Fat!So? (1999), Laura Fraser's Losing It: False Hopes and Fat Profits in the Diet Industry (1998), and Roberta Seid's Never Too Thin (1989), among others.
Berg, Gaesser, and Wann are members of the editorial board of the peer-reviewed journal Health at Every Size, formerly known as the Healthy Weight Journal, which has been publishing articles about these topics since its founding by Berg in 1986.
And even if these nay-sayers emerge more often than "every 10 years," their voice has been virtually unheard amidst the lose-weight-or-die din. Campos calls attention to the following passage in Never Too Thin:
[An NIH official said], "Is excess fat really dangerous?... There is no question about that. It is. Obesity has replaced vitamin deficiency as the #1 nutrition problem in the United States." [A consultant to a presidential commission said] that even "normal Americans" are so heavy "that [their weight] is inducing excessive mortality."... The press informed the lay public about the unsettling news in a barrage of articles, like the New York Times piece titled "Overweight: America's #1 Health Problem." For the rest of the decade, these dire warnings continued unabated. Scientists were unequivocal. Overweight shortened life. Dieting and weight reduction lengthened it. "Pleasingly plump" was not just unfashionable; it was deadly.
Not unreasonably, had you not known that Seid's book appeared in 1989, you might have concluded that the decade in question was the 1990s. In fact, it was the 1950s. The litany exhorting people to lose weight for their health's sake continues today in these very terms.
We'll cite just one example, an article in the Washington Post of Sept. 17, 2004, in which a representative of a major pharmaceutical company echoes the government consultant from half a century ago: "We'd like people to start thinking about weight loss not as a cosmetic issue but as a medical benefit."
In the same article, other experts foretell the future of therapy for obesity: lifelong polypharmacy. The reason, of course — in the reporter's words — is that, because existing weight-loss drugs have been found wanting, "the two-thirds of Americans who are overweight, including the one-third who are obese, [are left with] scant options beyond often ineffective or marginally effective diet and exercise programs and expensive, possibly risky stomach surgery."
Ergo, we need more and better drugs. Members of FDA's Endocrinologic & Metabolic Advisory Committee were told on Sept. 8 that at least 350 obesity drugs are in the pipeline. This meeting was convened to consider revisions to the FDA's "Guidance for the Clinical Evaluation of Weight-Control Drugs."
Some companies have been urging the FDA to limit safety studies to just one year instead of the two years called for in the current guidance, which dates from 1996, in order to speed the approval of new drugs to combat the obesity crisis.
Sanofi-Aventis's Accomplia (rimonabant), a projected blockbuster (possible per-pill price, $3.50; possible 2010 sales, $6 billion), and Regeneron's Axokine should be available first, each being in phase 3 trials. To much fanfare, interim one-year results from a two-year phase 3 study of rimonabant were announced in late August at the European Society of Cardiology 2004 Congress (see "Interim 1-Year Results of Rimonabant in Obesity — Europe" below). The information comes from a news release prepared by the study's investigator and posted on the society's Web site, and from an independent report on Medscape. Both sources are ambiguous about certain details, and they contain conflicting information in some instances, but they suffice to give us a good sense of what's in store.
|Interim 1-year results of rimonabant in obesity — Europe (RIO–Europe)|
|Average weight loss among patients completing 1 year of treatment||7.9 lb||10.6 lb||19.2 lb|
|Patients losing >5% of initial body weight||30%||44%||67%|
|Patients losing >10% of initial body weight||12%||15%||39%|
|Change in metabolic factors|
|Reduction in subjects meeting diagnostic criteria for metabolic syndrome||21%||31%||54%|
|Average decrease in waist circumference||1.8 in||2.1 in||3.3 in|
|Change in HDL-cholesterol||+17%||+19%||+27%|
|Change in triglycerides||+6.6%||+4.9%||–10.6%|
|SOURCES: Brookes L. RIO-Europe: Rimonabant in Obesity – Europe. Available at: «www.medscape.com/viewarticle/489224». Accessed Nov. 19, 2004. |
Van Gaal L. New study confirms benefits of rimonabant in weight loss, waist circumference reduction and metabolic risk factor improvement [press release]. Available at: «www.escardio.org/vpo/ESC_congress_information/ConferenceReleases/Van_Gaal.htm». Accessed Nov. 19, 2004.
In mid November, similar results were reported for two years of a North American trial of rimonabant. Patients receiving rimonabant 20 mg lost 19 pounds, most of it during the first six or seven months of treatment. It was reported that patients who continued taking rimonabant 20 mg during the second year maintained their initial loss but did not experience further weight loss — and patients who were switched to placebo after the first year regained almost all the pounds they had shed. The pharmaceutical industry's stance is that the FDA essentially has a bad attitude when it comes to weight-loss drugs. In a letter responding to the FDA's request for comments on the guidance, the executive director of the American Obesity Association spelled out the position of the AOA and many members of the pharmaceutical industry, with whom the AOA had met:
It is felt that negative perception of drugs to treat obesity is widespread at the FDA and affects the approval process.
In short, the obesity pharmacology development field sees the FDA as historically being resistant to medications to treat obesity. This is, of course, a significant concern to any company that must decide whether to allocate millions of dollars to development of a drug for obesity or some other condition.
That seems clear enough. Diet and exercise don't work, and people who need pharmaceutical treatment for obesity will just have to go without because of the FDA's bias.
But consider this statement at the end of the letter, "Finally, the AOA-industry group would prefer that the relevant end-points [in clinical trials of weight-loss drugs] should reflect a medically significant loss of body fat. However, there is no consensus on what is a medically significant loss of body fat at this time."
That seems clear enough, too. Obese people need to shed body fat — but nobody knows how much.
Now, there is widespread agreement that diet and exercise programs are ineffective or marginally effective — if their goal is to achieve and maintain long-term weight loss. In fact, Campos and other authors such as Gaesser, PhD, who is professor of exercise physiology and director of the kinesiology program at the University of Virginia, argue that weight-loss programs are worse than merely ineffective. They're counterproductive, in two respects. First, many people who lose weight eventually gain all of it back, and then some. Second, people who fail to lose weight or to sustain any loss become so discouraged that they see no point in continuing to try to change their lifestyles.
But if the goal of diet and exercise programs is to make people healthier and happier, they can succeed quite well — provided the focus is squarely placed on improving health instead of losing weight.
One of the tenets of weight-loss proponents is that major benefits accrue from even a modest loss of weight. To support this claim, they often cite the results of the Finnish Diabetes Prevention Study and the Diabetes Prevention Program. For example, in a document submitted to the FDA for the Sept. 8 advisory committee meeting, a representative of Abbott Laboratories wrote that both of these studies "showed that overweight patients who lost approximately 5 percent of their body weight reduced their risk for developing type 2 diabetes by 58%." Likewise, a recent article in Obesity Research, "Addressing the Unmet Medical Need for Safe and Effective Weight Loss Therapies" invoked the Finnish study to claim that "a weight loss of 4 kg in overweight subjects with impaired glucose tolerance reduced the risk of developing diabetes by 58%."
And that's impressive, but it's at best a partial truth. In neither study do the authors attribute the results to weight loss and weight loss alone.
The conclusion of the Finnish researchers: "Type 2 diabetes can be prevented by changes in the lifestyles of high-risk subjects." The conclusion of the DPP researchers: "Lifestyle changes and treatment with metformin both reduced the incidence of diabetes in persons at high risk. The lifestyle intervention was more effective than metformin." (Emphasis added.)
Campos thinks people are so focused on weight loss that when they see studies like these, they attribute any benefit to the slight change in weight while ignoring everything else.
Let's look at these studies in more detail. DPP enrolled 3,234 mostly obese (mean BMI, 34.0), mostly middle-aged (mean age, 51 years) nondiabetic subjects (female, 68 percent) with impaired fasting glucose. Patients were assigned to 1 of 3 interventions: standard lifestyle recommendations plus metformin twice daily, standard lifestyle recommendations plus placebo twice daily, or intensive lifestyle modification. Patients randomized to intensive lifestyle modification were to lose at least 7 percent of their initial body weight through a low-calorie, low-fat diet and to engage in physical activity of moderate intensity (e.g., brisk walking) for at least 150 minutes per week.
After three years, the patients receiving the intensive lifestyle intervention had lost about eight pounds, compared to little or no weight loss in the placebo and metformin groups. Such a modest amount of weight loss is trivial, Campos says, serving only to reduce mean BMI from 34 to 33 — that is, they still are officially obese. But when people write about this study, because of their focus on weight loss, the slight weight loss gets all the credit, while the changes in diet and physical activity that led to the reduced risk of diabetes (and probably only coincidentally to the weight loss) are ignored.
The Finnish study enrolled 523 middle-aged (aged 40 to 65; mean, 55), overweight (mean BMI, 31) subjects with impaired fasting glucose. They were randomly assigned to a control group, members of which received generalized information about diet and exercise, or an intervention group. Members of the intervention group received individualized instruction intended to help them achieve five goals: reduce their weight by at least 5 percent, limit fat to less than 30 percent of energy intake, limit saturated fat to less than 10 percent of energy intake, increase fiber intake to at least 15 grams per 1,000 kcal, and exercise moderately for at least 30 minutes daily.
No subject in either group who achieved at least four of these goals developed diabetes. Importantly, among patients in the intervention group who failed to reach their weight-loss goal but who exercised more than four hours per week, their risk of developing diabetes was reduced by 80 percent compared with other members of the intervention group who remained sedentary, and by 40 percent compared with the control group.
The authors spelled it out: "Achieving a relatively conservative target of more than four hours of exercise per week was associated with a significant reduction in the risk of diabetes in the subjects who did not lose weight."
Most studies showing correlations between overweight/obesity and diabetes, hypertension, cardiovascular disease, and other conditions don't account for physical activity, either ignoring it or relying on subjects' self-reported levels of activity.
Go back and take a look at the bottom line, "discontinuation," of the table if it hasn't already caught your attention. It shows that the rate at which people dropped out of the RIO–Europe study was about the same whether the subjects received placebo or either dose of rimonabant. From the company's perspective, that's good — there's nothing nasty about the drug to make people stop taking it. It's no worse than placebo. But even so, after just one year, 40 percent of patients have dropped out of the study, a clinical trial. Likewise, in the North American trial, about 50 percent of participants discontinued during the first year. Discontinuation rates are unlikely to be lower under real-world conditions.
Linda Bacon, PhD, a nutrition researcher at the University of California–Davis, holds a master's degree in psychotherapy and a second in exercise science in addition to her doctorate in physiology. Bacon recently completed a study designed to test whether "Health At Every Size" (HAES) — a nondiet intervention intended to improve health even in the absence of weight change (see "HAES Basic Principles," above) — is a realistic alternative to weight loss achieved through diet. The subjects were 78 obese (mean weight, 218 lb; BMI, 35.7) white women (mean age, 39).
Members of each group attended 24 weekly sessions, each lasting 90 minutes. Those randomized to the diet group received traditional information about eating behaviors and attitudes, nutrition, social support, and exercise. Those in the HAES group began by focusing on body acceptance to help them separate feelings of self-worth from feelings about their weight. Then they were taught how to eat intuitively — something very few Americans know how to do, Bacon says. That entails responding to internal body cues (e.g., feelings of hunger or satiety) instead of eating according to external cues (e.g., the clock that says lunchtime) and practicing restraint. Members of the HAES group also received information about nutrition and physical activities that they might enjoy, and they participated in a support group. After conclusion of the weekly sessions, participants in either group could attend optional monthly group support sessions, during which no new information was presented.
Here's what happened: After 52 weeks, the mean weight loss in the diet group was 13 pounds, or 5.8 percent of their initial body weight, dropping their BMI from 36.6 to 34.5. In the HAES group, there was no change in weight or BMI. However, both groups reduced their LDL-c, by 10 and 7 percent in the diet and HAES groups, respectively, and their triglycerides, by 27 and 24 percent, respectively. HDL-c also was reduced in each group, for unexplained reasons.
Systolic blood pressure also was reduced in each group, while diastolic blood pressure was unchanged. However, after 24 weeks, 42 percent of subjects in the diet group had dropped out, compared with 8 percent in the HAES group. So, after one year, subjects in the HAES group achieved health benefits similar to those achieved by the dieters without suffering the attrition characteristic of diet programs. Fifty percent of each group were available for two-year follow-up.
By that point, the dieters had regained much of the weight that had been lost after one year, and few of the health benefits were sustained. Members of the HAES group, however, had maintained their weight, improved in all outcome variables, and sustained the improvements seen after one year.
Bacon sees the issue of overweight/obesity as a cultural problem, not a medical one. At the age of 4, her son counts broccoli and Brussels sprouts among his favorite foods, and when he's taken to a Chinese restaurant, he asks for (and receives) brown rice instead of white. But she harbors no illusions that he'll continue being a role model for healthy eating much longer as he gains exposure to a culture that fosters very different attitudes toward food preferences and eating behaviors.
Drawing on research findings, Gaesser has devised his own 20/20 Program to help people improve their health regardless of what they weigh. He advocates two chief strategies: engaging in at least 20 minutes of moderate physical activity daily, and limiting calories from fat to about 20 percent of total calories. No calorie counting is required, although he does ask people to read nutrition labels and count fat grams for a few days, just to get an idea of the fat content in a given food. At 9 calories per gram of fat, most people will be allotted about 50 to 60 fat grams per day. No foods are forbidden. If you want ice cream, you can have some, provided you make adjustments elsewhere. Gaesser also urges people to eat much more of certain foods — more complex carbohydrates, more fiber, more fruit, more vegetables.
As for exercise, it need not be done in one 20-minute stint. Two minutes here, two minutes there — walking, gardening, anything that boosts your heart rate a bit — counts toward the total. You're not "working out," so you don't need to join a gym or fitness center, and you need no special equipment aside from comfortable walking shoes.
If you can do more than 20 minutes a day, that's great. If you can increase the intensity, that's great, too. But note that Gaesser rejects the "no pain, no gain" adage. He says that ill-considered advice just leads to injury or discouragement, or both, resulting in the abandonment of exercise altogether.
Gaesser's program is not intended to reduce weight, although weight loss may occur from following its simple principles. Rather, it is intended to improve a person's metabolic fitness (i.e., insulin sensitivity). Improvements in metabolic fitness will follow from either improved diet or increased activity, he says, so if people for some reason can't pursue both goals they should at least try to meet one.
Even if weight isn't lost, the amount of abdominal fat probably will diminish. Gaesser notes that abdominal fat poses more of a health risk than fat stored in the thighs or buttocks because of proximity to the liver.
Gaesser puts more emphasis on metabolic fitness than on cardiorespiratory fitness because the latter sometimes reflects nothing more than good genes, as opposed to a healthy lifestyle.
Nonetheless, overweight and even obese people who display cardiorespiratory fitness (as measured by a treadmill test) consistently have better outcomes, in terms of morbidity and mortality, than lean people with low levels of cardiorespiratory fitness. Numerous studies emanating from the Aerobics Center Longitudinal Study at the Cooper Institute in Dallas have pointed to the importance of cardiorespiratory fitness.
So what'll it be for most overweight and obese members of MCOs? Lifelong pharmaceutical treatment for maybe a couple of hundred dollars a month, or a sensible diet and getting off their duff for, say, a whole half hour every day? Remember, even if some of the new weight-loss drugs in the pipeline happen to result in sustained weight loss and improve various markers associated with the metabolic syndrome, they won't do a thing for cardiorespiratory fitness.
"The new weight-loss drugs will turn out to be about the same as the old ones, because they work on just one site, such as a particular receptor," Gaesser says. "But obesity is not that simple. Multiple genes and multiple sites are involved. It won't take just one drug, or even several, to treat obesity. "
The greatest danger, Gaesser says, is that weight-loss drugs could foster the impression that people can rely on drugs for their health, creating only the illusion of improved health.
"The data are there to support improving health through eating better and being more physically active," Gaesser says.
If you can demonstrate health improvements in the absence of weight loss, he says, that should be sufficient to prompt exercise physiologists, nutritionists, and physicians to emphasize lifestyle changes instead of weight loss. But adopting the HAES approach would constitute a dramatic departure from the medical mainstream, he notes.
Finally, consider what Steven Blair and colleagues at the Cooper Institute recently wrote:
Whereas most health professionals assume that intentional weight loss in overweight and obese individuals is beneficial, it is interesting to note that the scientific evidence that weight loss decreases all-cause mortality is limited to one study. Virtually all other studies on weight loss and mortality failed to differentiate between intentional and unintentional weight loss, making the results largely noninterpretable. Until we know for certain that intentional weight loss significantly decreases all-cause mortality, it is worth considering that perhaps our time as health professionals would be better spent striving to help sedentary and unfit individuals increase levels of [cardiorespiratory] fitness, and encouraging healthy diets and smoking cessation in the population, rather than focusing specifically on weight loss.
Learnings from the April 2018 meeting.
Edited by Jill Condello, PhD, ICON Access, Commercialisation & Communications