This first slide is a compilation of data from a systematic review that clearly illustrates the point that the prevalence of gastroesophageal reflux-related symptomatology is rising worldwide. Certainly there can be no argument that within the United States, there is growing evidence to suggest an increasing prevalence of GERD-related symptoms. Similarly, the same argument can be made for data coming from Europe. Emerging data from South America as well as Asia show similar trends — maybe to lesser degrees, but still very similar trends.

Now this rising prevalence of GERD-related symptoms has very tangible consequences with regard to health resource utilization. These are data from the US National Ambulatory Medical Care Survey that very clearly show an increasing proportion of primary care physician visits attributable to GERD. Actually, according to this data set, 22% of primary care visits were related in some way to GERD in data collected from 2000 to 2001.

In addition, there's been a 46% increase in the number of GERD-related visits to primary care physicians; by comparison, the rise in visits for other, non-GERD-related indications was around 5% to 6%. So there seems to be a growing increase in patient complaints related to GERD.

In addition, another important observation that's been made over the past few years is that not only symptoms, but also the downstream consequences of GERD appear to be rising. So whether you look at curves relating to Barrett's esophagus or, in this particular case, esophageal adenocarcinoma, the incidence of these problems appears to be increasing over time.

Now, of course, the question is, what are the potential explanations for the increasing prevalence of GERD and the incidence of esophageal carcinoma? There are a number of potential explanations. First, the effect of advancing age on symptoms, and also the growing problem with obesity. If you're going to talk about an epidemic, certainly in the Western world, I think you'd have to focus a lot of attention on obesity-related complications — not only gastroesophageal disease, but things like non-alcoholic fatty liver disease.

We'll also briefly discuss data on dietary and lifestyle issues. We won't talk here about the decreasing prevalence of H. pylori, but that will be discussed later.

First, with regard to the data we have on the potential relationship between advancing age and reflux-related symptomatology, we really don't have very much data on this particular issue. And the data that we do have are somewhat conflicting.

But data from a study conducted at the Houston VA Hospital suggest a trend toward increasing prevalence of GERD-related symptoms with advancing age. They also found that the likelihood of GERD-related symptoms was not influenced by ethnicity. However, there are some data suggesting that a lot of the increased visits we're seeing for GERD-related symptoms are attributable to females as opposed to males.

Now let's turn our attention to obesity, because here the data appear to be fairly clear. This is a compilation of data from the Centers for Disease Control and Prevention (CDC), basically a series of maps illustrating the prevalence of obesity — in other words, the percentage of patients defined as obese — in the United States over the past 15 years.

What you can see is that in 1990, there were no states reporting more than 20% prevalence of obesity in the United States. Now compare that to 1995, where there's an increasing prevalence, and certainly in 2005, where 16 states reported a prevalence of obesity of greater than 20% and 2 states reported a prevalence of greater than 30% — so truly there has been a remarkable explosion of obesity within the United States.

This isn't only a United States phenomenon. We certainly talk about it a lot in the United States, but similar trends have been observed in Europe — and I'm using this McDonald's paradigm to emphasize the point. In addition, in South America, the same trends are being observed.

Finally, the only country in the world that has the Mega Mac — an ingenious invention by some employee of McDonald's — is Japan. This thing is 4 all-beef patties, special sauce, lettuce, cheese, pickles, and onions on a sesame seed bun. When they released this thing, they sold 3.2 million Mega Macs in 4 months in Japan. So it's been a big hit.

What are the data on the relationship between obesity and reflux-related symptomatology? Well, this slide shows data from a meta-analysis performed recently and published by Doug Corley's group, data that very nicely illustrate the fact that obesity is associated with an increased risk of GERD-related symptomatology.

In fact, there may be a stepwise increase in the likelihood of GERD-related symptomatology based on how overweight you are, at least in terms of your body mass index (BMI). These investigators also broke the data down by US vs European studies and made the exact same observation in terms of the association between obesity, or BMI, and GERD-related symptoms.

A very nice study, and a very important study, published by Jacobson and colleagues in The New England Journal of Medicine showed a nearly linear relationship between body mass index and the likelihood of experiencing GERD-related symptoms. I think this is a truly remarkable observation.

The next question that you might ask is, why is obesity associated with an increased likelihood of reflux-related symptoms? We're starting to accrue a body of literature on this particular topic. This slide shows data from a couple of recently published studies that addresses this issue.

One study found that the mean number of reflux episodes, as well as the total number of acid reflux episodes, were increased in obese patients who experienced GERD-related symptoms. In addition, the total percentage of time with pH <4 was also dramatically increased in obese patients experiencing reflux-related symptoms, compared with nonobese controls.

A second study was published earlier this year in Gastroenterology and drew some very nice associations between waist circumference and the frequency of transient lower esophageal sphincter relaxation. So this is another potential etiology for why this association exists.

The association with obesity is not only about reflux-related symptoms. Data from a meta-analysis by Kubo and colleagues show a significant association between obesity or BMI and esophageal adenocarcinoma. So again, there is an association not only between obesity and GERD-related symptoms, but also between obesity and the downstream effects of GERD, or esophageal adenocarcinoma.

What about other potential risk factors for GERD-related symptoms? We've recognized for a long time that high-fat meals can be associated with a greater likelihood of experiencing GERD-related symptoms. In addition, in a couple of recent analyses, smoking has been associated with a greater likelihood of experiencing reflux-related symptomatology.

Although we talk about alcohol and caffeine quite a bit, specifically coffee, it turns out that when you critically analyze the data, the literature is quite mixed on both of these particular topics with data for and data against an association between alcohol and coffee consumption and reflux-related symptomatology.

Now with this clear increase in the prevalence of GERD-related symptoms, we've seen, not surprisingly, a clear increase in the use of antisecretory therapies to address these symptoms. This is related to a variety of different issues, including the increased level of comfort with the use of acid-suppressive therapies, specifically proton pump inhibitors (PPIs) — particularly among primary care physicians — and now the availability of acid-suppressive medications over the counter.

When you look at the available data addressing symptom response with the use of potent antisecretories like PPIs, it's important to remember that these drugs are clearly more effective than H₂ receptor antagonists or placebo.

This recent systematic review stratified data on the basis of erosive esophagitis (EE) versus endoscopy-negative reflux disease (ENRD), and you can see that these numbers are clearly better than H₂ blockers or placebo.

What strategies can we think about to address patients with persistent reflux symptomatology? Well, for nocturnal heartburn, you can certainly think about giving the PPI before the evening meal instead of in the morning. You can also consider the addition of an H₂ receptor antagonist, particularly if the evening symptoms are intermittent and not all the time. You can consider increasing PPI dosing to twice-daily therapy, an issue that becomes particularly relevant when you're using over-the-counter omeprazole.

What is the potential role for new antisecretory therapies? There are a number in development at the current time. There are isomers of existing proton pump inhibitors. One example would be dexlansoprazole. There are long plasma half-life PPIs, like ilaprazole. There are also P-CABs as listed here, as well as other agents that don't necessarily target acid secretion, but instead address other potential etiologic, pathophysiologic targets for GERD.

So the conclusions and take-home messages are: The prevalence of GERD has increased globally and continues to increase. Age may be a risk factor for reflux-related symptomatology, but at this point it's difficult to conclude that that's a clear association. We need more data on that particular issue, and we need to control the data for potential confounders like, for example, medications or obesity.

I think that there is very good evidence now to clearly draw an association between reflux symptoms and esophageal adenocarcinoma and body mass index. Diet and tobacco appear to play a role in reflux-related symptomatology, while other things like alcohol and coffee are more controversial.

There appears to be an inverse relationship between H. pylori and gastroesophageal reflux disease, and we'll touch on that in a just a few moments.

And PPI consumption is increasing in westernized countries. And it's important to remember that, while these agents are very good, they're not perfect. There certainly are other agents in development that will hopefully create opportunities for patients who don't respond to traditional PPI therapy.

DR. LAINE: I don't know about you, but I never get tired of hearing about Barrett's esophagus — and I know our next speaker never gets tired of talking about it. Stuart Spechler has tremendous expertise in this area and certainly is one of the world's experts.