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Comorbidities of overweight and obesity: current evidence and research issues


Medicine & Science in Sports & Exercise: November 1999 - Volume 31 - Issue 11 - p S602
Roundtable Consensus Statement

PI-SUNYER, F. X. Comorbidities of overweight and obesity; current evidence and research issues. Med. Sci. Sports Exerc., Vol. 31, No. 11, Suppl., pp. S602–S608, 1999.

Purpose The evidence with regard to the relationship of obesity with medical comorbidities was assessed and priority research issues identified.

Methods The existing literature in English was surveyed.

Results The evidence is overwhelming on the association of obesity to a number of medical conditions. These include: insulin resistance, glucose intolerance, diabetes mellitus, hypertension, dyslipidemia, sleep apnea, arthritis, hyperuricemia, gall bladder disease, and certain types of cancer. The independent association of obesity seems also clearly established for coronary artery disease, heart failure, cardiac arrhythmia, stroke, and menstrual irregularities. The relationship between central (or upper body) obesity and the above conditions is positive for most of them but with a lesser number of studies. Most of the fat distribution studies have been done using anthropometric measurements rather than the more accurate magnetic resonance imaging or computer tomographic scans. Priority research issues include the following: more definitive data on the relation of central fat to comorbidities; the proportional importance of subcutaneous versus visceral fat in producing comorbidities; the relationship between obesity and psychiatric disease; the genetics of the relationship between obesity and each of the comorbidities; the independent contribution of diet and of sedentariness to the development of each of the comorbidities; the impact of gender, race, intensity, and duration on these associations.

Conclusions The evidence for the relationship of obesity to a number of comorbidities is strong, though the strength of the relationship varies with the condition. Much more research is necessary on causation and on what other factors may play an interactive role.

St. Luke’s-Roosevelt Hospital Center, Columbia University College of Physicians and Surgeons, New York, NY 10025

Address for correspondence: F. Xavier Pi-Sunyer, M.D., Obesity Research Center, St. Luke’s-Roosevelt Hospital Center, 1111 Amsterdam Ave., New York, NY 10025; E-mail:

Roundtable held February 4–7, 1999, Indianapolis, IN.

There is a very large bibliography on the association of overweight and obesity with other medical conditions. The data include evidence for overweight and obesity and also for the distribution of body fat. The evidence that is available in English with regard to the former will be reviewed first and with regard to the latter second.

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Overweight and Obesity

Type II diabetes mellitus.

Although the relationship of obesity to Type II diabetes mellitus is not wholly clear, two facts are incontrovertible. Excess body fat leads to increasing insulin resistance (82), and insulin resistance predisposes to diabetes (82,116). Why, however, some individuals may be obese for years without developing diabetes, whereas others develop it readily, must depend on their genetic make-up. Until more is known about the genes responsible for insulin resistance and for Type II diabetes, the exact mechanisms involved will not be clarified.

Insulin resistance, impaired glucose tolerance, and diabetes mellitus have been strongly associated with overweight and obesity in many cross-sectional (68,100,115,120,149,150) (52,64,88,113,142,151,159) and longitudinal (17,20,57,81,92) studies.

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The association between increased blood pressure and overweight and obesity has been shown repeatedly in both cross-sectional (2,3,7,14,34, 47,61,97,123,127,133,141,143,152,155) and longitudinal (66,69,103,140) studies. The independence of obesity as a risk factor for hypertension is underscored by observations of a much higher prevalence of hypertension in obese persons than in the general population. This has been reported both in populations with a high prevalence of hypertension, such as African-Americans (129), as well as in populations with a low prevalence of hypertension, such as Mexican-Americans (54). Weight gain leads to an increase in blood pressure, as has been reported in the Framingham study (72) among others. The mechanisms proposed for this relationship have been many (114) and until the genes responsible for this multi-etiological condition and the relationship of these genes to the genes that predispose to obesity have been identified, these mechanisms will not be clarified.

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Obesity has been associated with two particular abnormalities: increased levels of triglycerides and decreased high-density lipoprotein cholesterol (high density lipoprotein (HDL)-C). Both of these are now recognized as independent risk factors for cardiovascular disease (8,9,48). Cross-sectional (128,143) as well as longitudinal (8,9) studies have shown the relationship of obesity to higher levels of triglycerides. Also, low HDL-C levels have been found in both cross-sectional (45,143) and longitudinal (48) studies. An increase in triglycerides has also been described longitudinally with an increase in weight (4). Total and low-density lipoprotein cholesterol (low density lipoprotein (LDL)-C) have been found to be either normal or elevated (8,37,128,142). In more recent years, there have been descriptions of a qualitative change in the size of LDL particles, with an increase in the number of small, dense ones that are more atherogenic (10). The relationship has been clearly shown for insulin resistance (11,98,117) and has thereby been extrapolated to obesity, which is an insulin resistant state (98). More research on the presence of this LDL-C phenotype (phenotype B) in obese populations is required.

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Coronary heart disease.

Coronary heart disease (CHD) is usually described epidemiologically as angina pectoris, nonfatal myocardial infarction, and sudden death. There have been differing opinions on the relationship of obesity to CHD. This is because, since the obesity enhances the risk of hypertension, dyslipidemia, and diabetes mellitus, all of which are risk factors for CHD, the independent effect of the obesity itself has been difficult to verify. However, recent studies have left little doubt of the relationship in both men and women (18,21,38,49,70,78,79,99,121,131). There is also an association between obesity and left ventricular hypertrophy and congestive heart failure (66,70,71,73,74). Arrhythmia and sudden death are also associated with obesity (31,66,73,101). The causative mechanisms between obesity and sudden death is not clear. Whether it is related to alterations in sympathetic and/or parasympathetic nervous activity has been debated (42,63,158).

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Gall bladder disease.

Both cross-sectional (16,50,83,120) and longitudinal (41,75,96,109,130,138) studies have reported an association between gall bladder disease and overweight and obesity.

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Respiratory disease.

There is a gradually increasing impairment of respiratory function with increasing obesity. The sheer burden of the extra fat in the chest wall and the abdomen causes a decreased compliance of respiratory function and reduces lung volume (102,147). A ventilation-perfusion abnormality occurs (12) that initially causes hypoxia with normal pCO2 (30,65). Eventually, however, as the severity of obesity increases, hypercarbia also develops. Sleep apnea occurs as the severity and duration of the obesity exacerbates (119,146,157). This may be obstructive sleep apnea (118) or central (13) or a combination of the two. Eventually, the obesity-hypoventilation syndrome, with depression of hypercapnic and hypoxic respiratory drives, irregular breathing, frequent apneic periods with resultant hypoxia (84) and daytime sleepiness supervenes. Finally, cor pulmonale can occur (124).

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The relationship of obesity to cancer has been a very difficult question to sort out and is still deeply mired in controversy. Part of the problem is that even though, in longitudinal studies, it is clear that obesity is associated with some cancers, it has been very difficult to separate the role of overweight and obesity per se from the effect of the macronutrient composition of the diet or of total calories (114). The American Cancer Society study, which was a longitudinal study that followed 750,000 men and women for 12 yr, found that the mortality ratio for cancer for men who were 40% or more overweight was 1.33 and for women it was 1.55 (43). These obese men had higher rates of colorectal and prostate cancers, whereas the women had higher rates of endometrial, gallbladder, cervical, ovarian, and breast cancers (43). With regard to breast cancer, other longitudinal studies have described a greater risk for obese postmenopausal women but not for obese premenopausal women (23,93,94,108,132,136,145,154). There have been a number of studies that have shown positive associations between weight and endometrial cancer (40,85,89,90,125,132,137). In men, some studies have shown increased colon cancer (91,112), but others have not (105,139,153,156).

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Cross-sectional studies have reported an association between obesity and osteoarthritis of the knees (1,6,22,39,46,59,77,120). A twin study in which one twin weighed more than the other showed a strong association between obesity and osteoarthritis (58). This report concluded that every 5 kg of gain in weight increased the risk of knee arthritis by 35%. The evidence for the relationship of obesity to osteoarthritis of the hip is much less strong (59,77,144).

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Association between Fat Distribution and Medical Conditions

A considerable literature is now available with regard to the association of central or upper body fat distribution and health risk. Most of the epidemiological studies that have been published have been done using anthropometric measurements as surrogates for fat distribution.

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There have been a number of cross-sectional (29,53,68,110) and longitudinal (66) epidemiological studies that have reported an association between central fat distribution and hypertension.

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Type II diabetes mellitus.

There are a number of studies, both cross-sectional (44,56,60,67) and longitudinal (55,57,76,95,106), that have shown an association between obesity and diabetes mellitus. The increased central fat distribution leads to insulin resistance and impaired glucose tolerance (28,35,36,80,111,126).

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There have been a number of studies that have described dyslipidemia in patients with central fat distribution. The syndrome is similar to that seen for obesity per se, with hypertriglyceridemia, low HDL-cholesterol, and an increased number of small dense LDL particles, which are very atherogenic (24–27,107,135). In addition, increased apoB lipoprotein levels have been described (89).

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Cardiovascular disease.

Cross-sectional studies have shown a relationship between central fatness and CHD (89). Longitudinal studies have reported similar findings (19,29,32,33,62,86,87,121,134).

There is also a report of enhanced risk for stroke with central obesity (148).

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Other medical conditions.

Gall bladder disease has been reported to be associated with central fat distribution (56).

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There are many unanswered questions on the association of obesity and central fat distribution with health risks. Research priorities with regard to these associations are numerous. Most important is the fact that all of the above cited studies show an association or correlation between obesity, central fat distribution, and morbidity, but correlation does not necessarily indicate causality (5). Three studies have suggested that obesity and cardiovascular risk factors are not pleiotropic (51,104,122). In addition, within person changes in fatness lead to changes in morbidity (71,103,140). Also, there is a report of a negative relationship between baseline cardiovascular risk factors and future fatness, suggesting that these risk factors are not elevated before weight gain (15). Clear confounders are physical activity, composition of the diet, caloric intake, and smoking. The role of each of these confounders on comorbid conditions needs to be investigated.

More investigation is also needed on the following:

1. The relation of central fat to comorbidities, with better characterization of the central fat so as to be able to sort out the contribution of central versus subcutaneous fat tissue to each comorbidity.

2. The genetics of the relationship between obesity, fat distribution, and each of the comorbidities.

3. The impact of gender, race, intensity, and duration of obesity and fat distribution on each of the comorbidities.

4. The interaction between obesity and central fat distribution and other potential associated factors responsible for particular comorbidities.

5. The relationship between obesity and psychiatric disease.

6. The independent contribution of diet and of sedentariness to the development of each of the comorbidities.

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The evidence for the relationship of obesity to a number of comorbidities is strong, but much more research is necessary on causation and on what other factors play a role.

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