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Dr. Corbette is a Clinical Teaching Fellow in the Clinical Foundations Department at Ross University School of Medicine, Commonwealth of Dominica, West Indies. Dr. Selfridge is Professor and Chair, Clinical Foundations Department at Ross University School of Medicine, Commonwealth of Dominica, West Indies.
Dr. Corbette and Dr. Selfridge report no financial relationships relevant to this field of study.
SYNOPSIS: A prospective, cohort study of health professionals conducted over 24 years revealed no significant association between long-term consumption of gluten and the risk of coronary artery disease in both adult men and women with no history of coronary artery disease.
SOURCE: Lebwohl B, Cao Y, Zong G, et al. Long term gluten consumption in adults without celiac disease and risk of coronary heart disease: Prospective cohort study. BMJ 2017;357:j1892.
Gluten describes a family of storage proteins found largely in wheat, rye, and barley, consisting primarily of gliadin and glutenin. Gliadin is the main protein responsible for the pathology of celiac disease, an autoimmune disorder of the small bowel characterized by inflammation of the intestinal mucosa, villous atrophy, and hyperplasia of intestinal crypts triggered by exposure to dietary gluten.1,2 The prevalence of celiac disease in the United States and Europe is about 1% and has risen over the last four decades.1 Celiac patients may experience symptoms of malabsorption, including diarrhea, weight loss, and nutrient deficiencies, but many only have minor gastrointestinal (GI) symptoms or none at all. In addition, persons who do not have celiac disease may experience GI and other symptoms associated with consumption of gluten, as well as symptom improvement with removal of gluten from their diets. Such individuals have non-celiac gluten sensitivity, a clinical diagnosis with an undetermined pathophysiology, no known biomarker, and a worldwide prevalence reported to range from 0.6% to 6.0%.1,3
Coronary artery disease, also known as coronary heart disease (CHD) and ischemic heart disease, is one of the leading causes of morbidity and mortality in the United States. Celiac disease has been associated with an increased risk of CHD, a risk that is mitigated by a gluten-free diet in these patients.1 To determine the potential effects of gluten on cardiovascular health in individuals without celiac disease, Lebwohl et al examined the association between estimated long-term gluten intake and the development of incident coronary artery disease.
Data were analyzed from 110,017 participants, including 64,714 women from the Nurses’ Health Study (NHS) and 45,303 men from the Health Professionals Follow-up Study (HPFS). The NHS was initiated in 1976 with 121,700 female nurses, ages 30-55 years. The HPFS was implemented in 1986 to complement the NHS and included 51,529 male health professionals. Both studies were prospective and longitudinal in design, with an objective of investigating major risk factors for chronic disease development using data from questionnaires on various health practices and lifestyle habits.
Exclusion criteria for analysis in this study included: implausible reported daily energy intake (< 600 or > 3,500 kcal/day for women and < 800 or > 4,200 kcal/day for men); questionnaires missing gluten data; or a previous diagnosis of myocardial infarction (MI), angina, stroke, coronary artery bypass graft surgery, and cancer. In 2014, a history of celiac disease was solicited from participants; any individuals with a diagnosis of celiac disease were excluded from data analysis. If a participant developed a significant illness during the study period, such as diabetes, cardiovascular disease, or cancer, data for that individual were suspended assuming that significant illness might dramatically affect dietary composition. In these instances, the cumulative dietary gluten before onset of illness was used for analysis until the end of follow-up.
The two cohorts were evaluated using a 136-item, validated, semiquantitative food-frequency questionnaire, initially administered in 1986 and readministered every four years (1990, 1994, 1998, 2002, 2006, and 2010). Investigators used the Harvard T.H. Chan School of Public Health nutrient database, which is updated every two to four years, to calculate major nutrients consumed in the participants’ diets. The quantity of gluten consumed was calculated from the protein content in the wheat, rye, and barley products reported in the participants’ food questionnaires, based on recipe ingredient lists and using a conservative estimate of the gluten proportion of the protein at 75%. Coronary artery disease, the primary outcome of the study, consisted of fatal or nonfatal MIs. Fatal outcomes were confirmed by medical or autopsy records or as stated on the death certificate. Nonfatal events were self-reported by patients. If there was no history of CHD, but it was listed as the underlying cause of death, the outcome was termed probable myocardial infarction and was considered together with the primary outcome as fatal MI.
Testing the hypothesis that greater amounts of dietary gluten are associated with an increased risk of CHD as indicated by acute nonfatal and fatal MI, participants were followed from 1986 until development of acute MI, death, or end of follow-up (June 2012 for NHS and January 2012 for HPFS). Participants were divided into quintiles of estimated gluten consumption based on the energy-adjusted grams of gluten per day. Cumulative average estimated gluten consumption was calculated and treated as a time variable. The authors conducted several secondary and post hoc analyses, taking into consideration the variables indicated in Table 1. The mean estimated daily gluten intake at baseline was 7.5 g (standard deviation [SD], 1.4) for women and 10.0 g (SD, 2.0) for men in the highest quintile, and 2.6 g (SD, 0.6) for women and 3.3 g (SD, 0.8) for men in the lowest quintile.
During the study period, 6,529 participants (2,431 women and 4,098 men) were reported to develop coronary artery disease, as indicated by acute MI. Of these, fatal MI was reported in 2,286 participants (540 women and 1,746 men).
Participants in the lowest quintile of gluten intake had a CHD incidence rate of 352 per 100,000-person years, while participants in the highest quintile of gluten intake had a CHD incidence rate of 277 per 100,000-person years, yielding an unadjusted rate difference of 75 (95% confidence interval [CI], 51-98) fewer cases per 100,000-person years between the upper and lower quintiles. However, after adjustments for non-dietary and dietary covariates, there was no association when comparing upper and lower quintiles of gluten intake (HR, 0.95; 95% CI, 0.88-1.02; P for trend = 0.29).
The authors performed a secondary analysis specifically to adjust for gluten consumption from whole grains and refined grains. Adjusting for refined grains, so that all the variance in gluten intake was attributable to dietary whole grains, resulted in an inverse relationship between estimated gluten intake and the development of CHD (HR, 0.85; 95% CI, 0.77-0.93; P for trend = 0.002). However, adjusting for whole grains, so that all the variance in gluten intake was attributable to dietary refined grains, resulted in no association between estimated gluten intake and incident CHD (HR, 1.00; 95% CI, 0.92-1.09; P for trend = 0.77). Thus, higher levels of gluten consumption were associated with increased incident CHD only if the source of dietary gluten was from refined grain products.
According to the Centers for Disease Control and Prevention (CDC), heart disease is the leading cause of mortality in both men and women, with CHD being the most common pathology.4 Approximately 370,000 deaths per year have been reported, along with more than 700,000 cases of MI.5 There are many known risk factors for CHD, including hypertension, diabetes, smoking, and obesity. In recent years, the popularity of gluten-free diets among individuals without celiac disease has increased, possibly because the known high glycemic index of many gluten-containing foods contributes to insulin resistance or recent recognition of gliadin’s proinflammatory properties, even in patients without celiac disease.6 Certainly, social media and consumer product marketing have promoted these diets from a variety of angles, for better or worse.
There is limited evidence about the effect of gluten-free diets on overall cardiovascular health, although there is sufficient evidence that inclusion of whole grains in the diet has beneficial effects on health, including reduction in risk for CHD and type 2 diabetes.7 These authors concluded there is no significant association with long-term gluten intake and the risk of developing incident CHD in patients without a prior history of CHD. The authors supported the current literature by showing a decrease in CHD risk with higher levels of gluten intake when the gluten intake was attributable to dietary whole grains, a positive effect likely due to soluble and insoluble fiber.
Although this study benefitted from a large sample size and long-term follow-up using repeated assessments, methodologic limitations should be considered. The study population was comprised of health professionals only, a potential selection bias prohibiting generalization of results to a more representative population, since health professionals may be more cognizant of evolving risk factors related to heart disease and may adjust health and lifestyle habits accordingly. In addition, participants with chronic disease diagnoses such as diabetes were not included in the analyses, again limiting generalization of the results to a more representative population. The investigators attempted to control for many covariates associated with heart disease risk in their analyses, but could not possibly control for all known and unknown health habits conferring possible benefit. Recall bias is another potential confounder in this study, since dietary questionnaires asking for detail on estimated frequency and type of food intake and characteristic portion sizes consumed over the previous year were distributed only every four years. Although patients with celiac disease were excluded from the analysis, patients with non-celiac gluten sensitivity were neither identified nor excluded. Since the latter condition is at least as common as celiac disease, and implies a robust immunologically based inflammatory reaction to gluten, it would make sense to treat. Also, it is unknown who might have gluten reactions beyond celiac disease; this was not assessed, with no screening for non-celiac gluten sensitivity.
Physicians may find themselves fielding questions about gluten-free diets from patients without celiac disease or documented gluten sensitivity. This study fails to support any notion that gluten consumption is associated with an increased risk of CHD. Further, this study supports what other research has concluded: Consumption of whole grains is a “good thing” in that it is independently associated with a decreased risk of coronary disease.
Additional research would be beneficial, assessing a more diverse study population and potentially employing digital technology and devices to assist with real-time dietary data monitoring in longitudinal studies. In the meantime, physicians can inform patients who do not have celiac disease or symptomatic gluten sensitivity that limiting dietary gluten intake does not provide any reduced risk of coronary disease and may interfere with a desirable and health-promoting intake of whole grains.
Financial Disclosure: Integrative Medicine Alert’s Executive Editor David Kiefer, MD; Peer Reviewer Suhani Bora, MD; Relias Media Executive Editor Leslie Coplin; Editor Jonathan Springston; and Editorial Group Manager Terrey L. Hatcher report no financial relationships relevant to this field of study.