There's probably no other thought that pops into our heads more often than "what should I eat?" The answer should be simple, but the question has become frustratingly complex. Should we eat for taste, or for health? What about convenience? And what about the more nebulous, but vitally important, question of the ecological impact of the food we are eating?
A corollary of the mealtime question, of course, is "what should I drink?" We can again ask many questions about our liquid refreshments, and fortunately, a couple studies from the recent issue of The American Journal of Clinical Nutrition provide us with some answers.
One of these is not like the others...
The first study, by a group in Denmark, indicates what not to drink. Designed as an experiment with their subjects freely roaming the world, the researchers gave groups of participants a different liter of fluid to drink each day for six months. The experimental drink was good ole' Coca-Cola (made with sucrose rather than high fructose corn syrup in Europe), and the control drinks were reduced fat milk, diet-Coke, and water. Drinks were delivered to the subjects homes at the start of the study, and empty bottles were collected afterwords; as such, it's likely that at least some of the daily allotments made it down the drain instead of the gullet. But regardless of the precise amount consumed, the results are telling.
The regular cola, or as the Danish-scientists fondly called them, sucrose-sweetend soft drinks (SSSDs), but none of the other drinks, drove fat to accumulate in all of the wrong places. The regular soda caused a 135% increase in liver fat, a 120% increase in intramuscular fat (think marbling in a corn-fed steak), and a 25% increase in visceral fat, which is the particularly deleterious fat that surrounds the organs within the abdomen. Together, the liver and muscles comprise the greatest amount of insulin-sensitive tissue in the body. When fat infiltrates these organs, they have trouble following insulin's orders, so the pancreas has to squeeze out more insulin to compensate. This is insulin resistance. But while none of the subjects showed compromised insulin function in the first 6 months, ectopic, or out of place, fat deposits are paramount to insulin resistance and the associated metabolic syndrome.
And the relative non-effects of the other drinks are equally interesting.
Despite a similar caloric content to the SSSBs, daily milk intake decreased the ratio of visceral fat to subcutaneous fat, meaning that milk helped carve people into a "pear" rather than an "apple" shape. A calorie is a calorie, indeed.
Surprisingly, both diet soda and milk lead to a decrease in blood pressure. What's more, the diet soda didn't cause any fat gain. Diet soda is thought, at least by some, to contribute to weight gain because the sweet taste of diet soda is sufficient for the pancreas to secrete some insulin. This study clearly argues against an "obesogenic" effect of artificial sweeteners, both directly, or indirectly by encouraging a sweet tooth.
But what shall we order at Happy Hour?
Red wine has become famous for being "heart healthy." After all, the Mediterraneans are famous for drinking wine and having a relative absence of heart disease. Additionally, the grape-derived compound resveratrol has been shown to extend life... in metabolically compromised mice, anyway. But really pinning down the benefit of red wine as been a challenge.
There isn't actually a whole lot of resveratrol in wine, and most animal studies employ pharmacological doses extracted from grapes. So is it some other compound in wine? Is it a combination of some?
And epidemiological evidence on red wine must be taken with a grain of salt. Prospective cohort studies - like the Nurse's Health Study - are the best form of observational epidemiology, but they cannot exclude selection bias, that is, people who tend to drink red wine also tend to be wealthier, healthier, or live more moderate lives. Selection bias prohibits researchers from truly knowing if it's the red wine or if it's simply the people who choose to drink red wine, that's the determinant of health. Fortunately, researchers conducted an experiment.
This study examined the impact of red wine on heart disease risk factors, specifically the abundance of inflammatory proteins and immune cells in the blood. Heart disease is characterized by systemic inflammation and the accumulation of immune cells, like macrophages and lymphocytes, within the blood vessel walls. There's good reason to think that it's this inflammation, rather than cholesterol per se, that contributes to cardiovascular disease. Any modality that can reduce inflammation likely protects the heart.
Each subject in the experiment participated in each of three four-week trials where they got to enjoy a couple of daily servings of red wine, gin, or de-alcoholized red wine. The gin allowed the researchers to examine the impact of the alcohol, while the de-alcoholized wine isolated the multitude of polyphenols unique to fermented grape juice. The results are intriguing, if not a bit complex.
Does this mean that my birthday celebration was good for my heart?
I'd like to think so.
Red wine, and not the individual components, lowered several pro inflammatory molecules in the blood. Collectively called "chemokines," CD40a, IL-16, MCP-1, and VCAM-1 were all reduced. These molecules help immune cells cling and penetrate into blood vessel walls, where they form fatty plaques. Other effects were specifically attributed to the components of the wine.
Two daily shots of gin made immune cells less sticky, while also increasing IL-10, a potent anti-inflammatory molecule that mellows-out aggressive immune cells.
And the polyphenols themselves lowered IL-6, an acute-phase protein that stimulates the liver to secrete C-reactive protein, which is routinely measured by doctors to assess heart disease risk. Grape juice also contains polyphenols, but all of the sugar without the fiber likely makes the teetotaling drink more harmful than helpful.
Of course, the participants probably didn't drink every last drop; some of the soda, although perhaps not the wine, surely went right down the sink. And we don't know exactly how important it is to decrease esoteric molecules like IL-16 from 478pg/ml to 450pg/ml. But we do have a certain degree of confidence in deciding what we should drink.
We can say that soda consumption does indeed cause fat to be deposited throughout the body. And the benefits of drinking wine could very well be attributable to the wine itself; and at the very least, some merlot doesn't appear harmful to the heart.
It looks like the cherry-brandy diet Coke highball I made the other weekend was an even better idea that I originally thought!
I've recently developed an obsession with 88% dark chocolate that I can find on sale at Sprouts. It has about as much fiber as it does sugar, and it's bitterness verges on espresso. I've prescribed myself to a near-nightly dose of it after dinner. And one night, while I was medicating, I came across a new study and some responses to the study that got me thinking about how easy it is to be critical about data that do not conform to our preconceived notions.
A meta-analysis was recently published on the effects of chocolate consumption and cardiovascular disease (the full text article can be found here). The analysis only included 7 studies: 6 cohort studies, one cross-sectional study, and no randomized controlled trials. Needless to say, I was surprised by the relative strength and consistency of the findings.
Source: Buitrago-Lopez et. al British Medical Journal 2011.
The various levels of chocolate intake were associated with a 37% decrease in the risk of any cardiovascular disease, and a 29% decrease in the risk of stroke. This is indicated in the figure by the diamond-shaped confidence intervals, which represent the risk of the combined studies, stratified by cardiovascular outcome, hovering around estimated relative risks. There was no association between chocolate intake and heart failure, as you can see by the respective diamond crossing the relative risk axis of 1. Unfortunately, none of these studies measured CVD mortality or total mortality, so we don't know if this reduced CVD risk was associated with a longer lifespan.
If you've been following my previous posts, then hopefully you've taken note that all of these studies are observational rather than randomized and interventional. This makes this type of data prone to confounding variables (although many of these studies corrected for numerous confounders) and bias. The bias is especially worrisome given that chocolate is somewhat of a luxury that probably associates with discerning palates, and because of all the marketing buzz regarding cocoa's abundance of antioxidants.
Even the authors are dubious of their findings since chocolate has more than just antioxidant-rich cocoa. "The high energy density of commercially available chocolate (about 500 kcal/100 g) means excessive consumption will probably induce weight gain, a risk factor for hypertension, dyslipidaemia, diabetes, and cardiometabolic disorders in general." And they didn't even mention sugar, which I'm more concerned about than calories. And others are quick to point out that the association may very well not be due to the chocolate, as I mentioned above. Marion Nestle, at FoodPolitics, concurs: "wisely, the authors point out that much more research is needed to confirm these benefits, not least because the studies were observational, not clinical trials."
I agree with all of these issues. And personally, I need substantial evidence to convince me that a food is not just food, but is actually therapeutic. But if we are going to be skeptical about chocolate because of insufficient evidence, shouldn't we be just as skeptical of other foods or nutrients with similar insufficient evidence?
My last post on meta-analyses featured a study by Siri-Tarino et al. that concluded that prospective cohort studies show no association between saturated fat intake and CVD*. Chocolate, on the other hand, does show a benefit, even in studies with similar design. Furthermore, the reduction in the risk of stroke appears greater than might be expected from abstaining from processed meat. Despite these difference, recommendations to reduce saturated fat abound, while poor chocolate only gets criticism.
Again, we have to be skeptical about all of these studies until there is either sufficint clinical trial data, overwhelming epidemiological data, or preferrably, a combination of clinical trials, epidemiology, and laboratory experiments. It's imprudent to disparage a study because chocolate "just can't be healthy" or quickly agree with an association becuase processed meats "must be bad for you." We have to be equally critical of all studies of the same methodology, regardless of the outcome.
As with coffee, I'm not convinced that chocolate is a health food or will prevent heart disease; although if you can restrain yourself, it certainly doesn't appear harmful. And with more investigation, perhaps chocolate will be definitively healthy. So until we have more conclusive evidence, eat chocolate because it is divine, because we can mull over the richness of it will friends at the dinner table, and because it is the perfect end to a meal. And be equally skeptical of claims for all foods, regardless of how sweet, sweet, delicious they may be.
*As I described in the previous post, and to be accurate, there have been clinical trials to investigate the benefit of saturated fat reduction. Replacing saturated fat with polyunsaturated fat does indeed lower the risk of cardiovascular disease. Although it does not appear to reduce CVD mortality or total mortality.
"The great tragedy of Science (is) the slaying of a beautiful hypothesis by an ugly fact"
- Thomas Henry Huxley
I eat butter. Plenty of it. And I also started rendering lard and beef tallow for cooking. Not many people my age (26) have ever seen someone render lard, let alone use it readily. The reason I use these fats is because they are delicious, and because I can buy them at the farmers market. The conventional wisdom is that I should be scared - or nearly terrified - of saturated fat. Just take a look at this YouTube video from the U.K (see below).* The eerie lighting and tone of the television announcer is enough to make me worry, but let's take a look at some recent evidence regarding saturated fat and heart disease to see if the sink analogy is apropos.
The reason that saturated fat has been demonized by the nutrition community is because it is the cornerstone of the Lipid Hypothesis. The Lipid Hypothesis, which is more of a concept than a working hypothesis, proposes that dietary saturated fat elevates cholesterol in the blood, specifically LDL cholesterol, which in turn causes atherosclerosis. Cardiovascular disease (CVD) is characterized by atherosclerosis (plaque in the arteries) and includes coronary heart disease (CHD; atherosclerosis of blood vessels in the heart) and cerebrovascular disease (atherosclerosis of blood vessels in the brain leading to stroke).
Source: Wikipedia. Myristic acid, a saturated fat
The Lipid Hypothesis has always had its critics, but it has generally been accepted as fact. However, the totality of evidence is a bit fuzzy, as many studies are contradictory or only show a small benefit from restricting saturated fat. But since CVD is the leading cause of death in the U.S., public health authorities argue that any intervention, even if it's small or somewhat uncertain, will be beneficial to the health of the population. These circumstances are ideal for what medical researchers call a "meta-analysis."
Simply put, a meta-analysis is a single study that combines the results from numerous smaller studies to form an artifical mega-study that will have enough statistical power (ability to detect a difference between the control and experimental group) to determine what the true impact of an intervention is. The goal is to walk away with an actual number, such as a relative risk or mortality statistic. For a meta-analysis to be valid, the included studies must be sufficiently similar and test the same exposure-outcome hypothesis, e.g. dietary saturated fat causes heart disease. And researchers will further restrict their inclusion criteria to well designed studies. But even with these criteria, you might ask: if I lump all these studies together, doesn't that falsely give equal credibility to both good and not-so-good studies?
Researchers address the issue of good, better, and best studies by "weighting" the different study results. This means that each study will have more or less impact on the final outcome measurement - again, such as the relative risk for heart disease - depending on the quality of the study. What makes one study better than another? Usually the size of the study (10,000 subjects is likely more accurate than 1,000), the number of confounders adjusted for (older studies might only correct for age and smoking status, whereas a newer study might have adjusted for age, smoking, socioeconomic status, cholesterol, fasting glucose, etc.), and the quality of the methods used (in a diet study, a trial that provided all of the food for the subjects is much more reliable than giving subjects a questionnaire to determine what they ate). Once you have all the studies tabulated and weighted, then you can get a summary outcome measurement and a neat graph that looks something like this:
Fig 1. Anatomy of a meta-analysis
Every meta-analysis has a graphic like this (Fig. 1), and usually they have several more depending on how many hypotheses are being investigated. The x-axis represents the relative risk. If you remember from my last post, a relative risk of 1 means no difference in risk between groups, whereas a relative risk greater than 1 indicates that the "experimental" group has more risk than the control group. Each study included in the graph is represented by a hash; the length of the hash represents the 95% confidence interval for the relative risk of that study. If you are unfamiliar with statistics, the 95% confidence interval shows the range of numbers that we are reasonably confident includes the true effect of the experiment. A smaller interval means you are more confident of the real number. All you need to know is that if the confidence interval intersects the vertical line, then our safest bet is to conclude that there is no difference between the groups, since the relative risk is likely to be 1. If the confidence interval does not intersect the vertical line, then we can conclude with reasonable certainty that there is a difference in risk between the groups. At the bottom of the graph there is a diamond that represents the confidence interval derived from all the (weighted) studies included in the meta-analysis. As you can see in the example, the diamond does not intersect the vertical line, and so the relative risk of all the studies combined is 0.85. This would mean that the totallity of the evidence, based on this meta-analysis, indicates that the treatment reduces the risk of whatever outcome by 15%.
This is virtually all that you need to know in order to interpret a meta-analysis. And if you are still reading this post, now it's time to talk about saturated fat. Several large meta-analyses have been published in the past couple of years, and they all seem to give roughly the same answer.
In 2010, Siri-Tarino et al., published a meta-analysis on prospective cohort studies that evaluated the assocation of saturated fat with cardiovascular disease. Based on 21 studies, they find no difference in the risk of CVD (the confidence interval contained 1), and conclude that "there is insufficient evidence from prospective epidemiologic studies to conclude that dietary saturated fat is associated with an increased risk of CHD, stroke, or CVD." Interestingly, they assert that there is evidence of publication bias.** But as the authors correctly point-out, this meta-analysis was limited to cohort studies and not powered enough (not large enough) to analyze the effect of replacing saturated fat with specific nutrients, such as carbohydrates or polyunsaturated fats (PUFA; think walnuts and seed oils). Fortunately, other meta-analyses have.
Mozaffarian et. al performed a meta-analysis on randomized controlled trials that replaced dietary saturated fat with PUFA. They only looked at myocardial infarction (heart attack) and CHD death; these are known as "hard endpoints," as heart attacks and death are not usually mis-diagnosed. They show that increased PUFA intake (from 5% of daily calories to 15%) in place of saturated fat reduces the combined risk of heart attack and CHD death by 19% (Fig 2). However, when the analysis isolated people who did not have pre-existing CHD, the aforementioned benefit disappeared (became statistically insignificant). And there was no benefit seen in total mortality. That is, replacing saturated fat with PUFA did reduce CHD and CHD death, but the risk of dying from all causes remained the same.
What saturated fat is replaced with is not trivial. Mozaffarian et al. also analyzed studies that replaced saturated fat with carbohydrates and monounsaturated fat (think olive oil). The single randomized controlled trial showed that replacing saturated fat with carbohydrate had no benefit, and in cohort studies, carbohydrates appear to increase the risk of CHD. Monounsaturated fat is expected to lower the risk of CHD because of its beneficial effects on the cholesterol profile, but this has not been tested in a randomized controlled trial, and pooled analysis of available cohort data show a borderline increased risk of CHD (Fig. 3). Weird, huh?
And lastly, The Cochrane Collaboration has recently published an updated meta-analysis on the effect of dietary fat reduction and/or modification (PUFA instead of saturated fat) interventions, in randomized controlled trials, on cardiovascular outcomes. Similar to their previous study and the aforementioned meta-analyses, they find that reducing and/or modifying dietary fat intake, for greater than six months, reduces the risk of CVD (events, not deaths) by 14%. This decrease is attributable to:
"studies of fat modification and reduction (not studies of fat reduction alone), seen in studies of at least two years duration, in studies of men (and not those of women), and in those with moderate or high cardiovascular risk at baseline (not general population groups)."
This means that there is a small benefit from replacing some dietary saturated fat with unsaturated fats, but this may only apply to men and those who are at risk of or already have CVD. And again, with a "high quality of evidence" given the shear number and size of the studies included, reduction of fat intake or modification of fat intake did not decrease the risk of CVD mortality or total mortality.
To be a bit critical, meta-analyses are far from perfect. Remember, they are simply a pooling of results that improves statistical power in order to weed-out a result. They do not improve the quality of the data or the individual studies themselves. An accurate colloquialism is that a meta-analysis of garbage is still garbage. Given their difficulties, I wouldn't go out and replace all of my butter with vegetable oil and expect a precisely 14% decrease in my risk of CVD. But they give a nice summary of the evidence.
In the case of saturated fat, there is consistency between these analyses. Total dietary fat is irrelevant to heart disease. Replacing saturated fat with polyunsaturated fat modestly reduces the risk of cardiovascular disease, whereas replacing saturated fat with carbohydrate has no effect and may be harmful (if it's refined carbohydrates or sugar). But at the end of the day, modifying or decreasing saturated fat likely does not decrease the risk of dying from heart disease and certainly has no effect on total mortality. So after looking over these meta-analyses and bouncing it off of my current understanding of diet and diease, here is my conclusion: there is clearly no over-whelming evidence that saturated fat is bad, and in fact, there doesn't really seem to be any evidence. And if it replaces sugar (butter instead of jam on toast), then it might actually be "healthy." And yes, I'm aware of how crazy that notion sounds. So what is one to do?
There are plenty of people who have given up butter and whole fat milk because of trepidation about saturated fat bringing them to an early grave. Or in the words of Michael Pollan from In Defense of Food, "over the last several decades, mom lost much of her authority over the dinner menu, ceding it to scientists and food marketers (p. 3)." Since the message to restrict saturated fat was loud enough to disrupt dinner, it is shocking that the evidence seems to have vanished. And this is why the conventional wisdom will not change overnight. Marion Nestle, a nutrition professor whose schtick I otherwise like, wrote a post on her blog to acknowledge these recent publications, but she inexplicably fell short of saying that saturated fat is probably harmless. So in my opinion, it seems that the facts have ruined yet another hypothesis, because clearly, butter isn't out to get you.
* Ignore the impossibility that the "saturated fat" in the video is liquid in the refrigerator but solid at room temperature in the drain. Saturated fats (coconut oil, beef tallow, butter) are solid in the refrigerator AND at room temperature.
** Smaller studies showed an increased risk of CVD from dietary saturated fat, but larger studies, which will always be published since they are well-known and anticipated, showed an equal distribution of increased, decreased, and neutral risk. The implication is that smaller studies that showed a detrimental effect of saturated fat were published, whereas smaller studies that showed no effect or a beneficial effect of saturated fat were either not submitted for publication or not accepted for publication.
The latest issue of the American Journal of Clinical Nutrition has a perspective article highlighting topics discussed at an international nutritional symposium (Nutrition Symposium). The goal of the symposium was to reach an expert consensus on the current state of research regarding the evidence for the reduction of dietary saturated fat for the prevention of cardiovascular disease (CVD). There were several notable researchers. This included Walter Willett, the nutrition research juggernaut who leads the ongoing Nurse's Health Study, and Ronald Krauss, whose research describes the deleterious effects of high carbohydrate diets on LDL particle and subsequent atherogenicity.
The article seemed oddly cold and ambiguous. While this may seem like an odd criticism of a scientific article, I usually characterize scientific writing as calculated and skeptical. Perhaps it was just strange to see how little confidence the experts had on the available data which have been used to establish a very specific and rigorous public health message; that is, "reduce your saturated fat intake. I don't care how you do it. Good God! Why aren't you reducing your saturated fat intake?!"
Regardless, there were some interesting and important topics discussed:
1. Given that some evidence, but certainly not all (my words), indicates that it is beneficial to reduce saturated fat intake, there is insufficient research examining what nutrients should replace it. Thus, replacing saturated fat with transfats or carbohydrates, especially refined carbohydrates, likely offers no benefit and may increase the risk of CVD.
2. There is actually little to no direct human evidence that monounsaturated fats (think olive oil) offer a beneficial replacement for saturated fats to reduce the risk of CVD. The recommendations given are based on animal studies, epidemiological studies, and risk factors (cholesterol) and not intervention studies with hard CVD outcomes.
3. There is no consistent epidemiological evidence that dairy products adversely effect CVD risk and no intervention research indicating that it actually does. Although I would not have this perception given the nutritional Zeitgeist.
4. Research needs to address the role of individual saturated fats in the diet (although whole foods never contain them in isolation). Single biomarkers for CVD risk, such as LDL, HDL, triglycerides, LDL particle size, and many more, may be insufficient to judge the effects of diet on actual CVD risk (although by my count, most of these markers are adversely affected by refined carbohydrates and unaffected or improved by fat). Also, genetics appear to play an important role, but there isn't enough data to clarify this role.
I'm not sure what the impetus was to have all of these researchers convene and address this issue. I can only imagine (hope?) that it has been the mounting skepticism for the current dietary recommendations given by numerous organizations; and thus, an opportunity to reevaluate the evidence. I'm happy to see that refined carbohydrates are being put under the microscope not only for obesity, but now also for heart disease.
(Side note: I'm doing my best to avoid becoming a sarcastic or overtly critical blogger who constantly points out perceived flaws in what I share. But I have to say that I'm concerned that eight of the eleven organizations that provided (unrestricted) grants were industrial food groups, most of which were dairy groups.)
