Obesity-Related Comorbidities

Introduction

A vast body of data unequivocally documents the direct and indirect links between excessive body weight and a wide spectrum of comorbidities (Figure 3-1). Although the underlying pathophysiologic mechanisms are not yet fully elucidated, many of these mechanisms involve an array of factors secreted by metabolically dysfunctional adipose tissue (Figure 3-2). Obesity is also associated with an increased risk of all-cause mortality, with the hazard ratio (HR) increasing from 1.45 for class I obesity to 1.94 for class II and 2.76 for class III obesity.

Obesity and Inflammation

Obesity has been linked to a chronic state of inflammation which may be involved in the development of comorbidities such as metabolic syndrome, cardiovascular disease, non-alcoholic steatohepatitis and cancer. The association of obesity and levels of inflammatory biomarkers has been demonstrated in an analysis of data from the 1999-2004 National Health and Nutrition Examination Study (NHANES). Serum concentrations of C-reactive protein (CRP) and fibrinogen were compared across different weight classes. With CRP levels for normal weight individuals as a reference, CRP levels nearly doubled with each increase in weight class from +0.11 mg/dL for overweight to +0.73 mg/dL for class III obesity (BMI ≥40; Table 3-1). Similarly, with normal weight individuals as a reference, fibrinogen levels also increased with increasing weight class and were highest for individuals with class III obesity (+93.5 mg/dL). Furthermore, individuals with hypertension or diabetes have higher levels of CRP and fibrinogen levels compared with individuals without hypertension or diabetes, even when stratified according to BMI (Table 3-2).

Prevalence of Major Comorbidities

The associations between obesity and its common comorbidities, such as diabetes, hypertension, dyslipidemia and obstructive sleep apnea, have been reported by a considerable number of epidemiologic studies. The results from a selected sample of such studies are summarized below. Overall, the results from these studies indicate that the prevalence of the major comorbidities of obesity tend to increase with increases in body weight.

Diabetes

Obesity, and particularly central adiposity, is the dominant risk factor for the development of type 2 diabetes (T2D). It is also one of the most important modifiable risk factors for the prevention of T2D.

In an analysis of data from adults with diabetes who participated in NHANES 1999-2006, the prevalence of diabetes increased with increasing weight classes, from 8% for normal weight individuals to 43% for individuals with class III obesity. Moreover, a separate study using the data from NHANES surveys determined that from 1999/2000 to 2013/2014 the prevalence of obesity and T2D has increased by 9.8% and 2.9%, respectively. The increase in the prevalence of T2D was limited to individuals with abdominal obesity, with no significant change in prevalence in the group without obesity. These findings highlight that obesity is a critical risk factor for developing diabetes, and imply that targeting obesity may slow the rise in T2D cases.

A considerable body of evidence demonstrates that the long-term risk of T2D increases significantly with increasing body weight. For example, according to data from the Behavioral Risk Factor Surveillance System, the prevalence of diabetes and mean body weight both increased by 49% from 1990 to 2000 (Figure 3-3A). The effect of long-term weight change on the risk for clinical diabetes was evaluated in 114,281 women enrolled in the Nurses’ Health Study. As shown in Figure 3-3B, after adjusting for age, body weight was the major risk factor for diabetes during 14-year follow-up. Among women with a 5 to 7.9 kg weight gain, the relative risk for diabetes was 1.9 and for those with an 8.2 to 10.9 kg weight gain, the relative risk was 2.7.

Consistent with these observations, several studies have shown that weight loss is associated with a significant reduction in the risk of diabetes. In a prospective, 20-year study of 7176 British men, the rate of new diabetes was 11.4 per 1000 person-years among subjects with obesity vs 1.6 among normal-weight subjects (P <0.0001), but the effect of weight change during a 5-year follow-up on the development of diabetes found a relative risk of 0.62 among those losing weight compared with 1.0 for stable weight and 1.76 among those gaining >10% body weight (P <0.0001).

Not only is weight reduction associated with lower risk of developing diabetes, but weight loss may help achieve remission of existing T2D. A study in the UK (DiRECT) demonstrated that following an intensive weight-management program, 46% of participants in the intervention group and 4% participants in the control group (P <0.0001) achieved diabetes remission after 12 months. Remission varied with weight loss in the whole study population, with achievement in none of the 76 participants who gained weight, six (7%) of the 89 participants who maintained 0–5 kg of weight loss, 19 (34%) of the 56 participants with 5–10 kg loss, 16 (57%) of 28 participants with 10–15 kg loss and 31 (86%) of 36 participants who lost 15 kg or more. After 24 months, 53 (36%) intervention participants and five (3%) control participants had sustained remission of diabetes. Thus, a diabetes remission can be achieved with weight management programs delivered by primary care practices, for patients with T2D diagnosed within past 6 years.

Dyslipidemia

Obesity and elevated BMI are associated with higher prevalence of dyslipidemia. Data analysis from 1999-2006 NHANES shows the prevalence of abnormal total cholesterol level (>200 mg/dL) increased from 40% for BMI <25 to 48% for a BMI ≥35. Dyslipidemia is common in patients with hypertension, T2D and metabolic syndrome, and elevated serum levels of total cholesterol, LDL cholesterol and non-HDL cholesterol are all associated with an increased risk of hypertension. One study verified the additive interaction between dyslipidemia and overweight or obesity in relation to developing hypertension. Compared with normal-weight individuals without dyslipidemia, those with dyslipidemia and obesity had the highest risk of hypertension (adjusted OR: 5.82, 95% CI: 3.08–10.99) and those with dyslipidemia and overweight had a 4.77 times higher risk of hypertension compared to the reference group. Therefore, people who have overweight or obesity and suffer from dyslipidemia are at higher risk of hypertension. Treatment of a comorbidity such as dyslipidemia is an integral part of care for patients with obesity in order to reduce their risk of developing cardiovascular disease.

Hypertension

Excess body weight is one of the major risk factors for hypertension. According to an American Heart Association (AHA) estimate, at least 75% of the incidence of hypertension is related directly to obesity. The results of many studies indicate that the prevalence of hypertension increases with increasing body weight. Although reported prevalence rates have varied somewhat between studies likely due to differences in study populations, the relationship of hypertension prevalence and increasing body weight remains. In one study, the prevalence of hypertension increased from 18.1% in normal weight individuals to 52.3% in those with class III obesity. Thus, individuals with class III obesity had a nearly five times higher risk (adjusted odds ratio [OR] 4.8) for hypertension.

Other Coronary Heart Disease Risk Factors

Obesity is a well-documented risk factor for the development of coronary heart disease (CHD) and stroke, especially when coincident with hyperglycemia, hypertension and/or dyslipidemia. Changes in 10-year CHD risk associated with levels of obesity and the prevalence of hypertension and abnormal total cholesterol level (>200 mg/dL) were assessed using data from 12,500 participants in the 1999-2006 NHANES. The prevalence of hypertension increased according to increases in BMI, from 24% for BMI <25 to 54% for BMI ≥35. Among men, these changes resulted in an increase in 10-year CHD risk of 3.1% with a BMI <25 to a peak of 5.6% for a BMI of 30 to 34.9. The 10-year CHD risk for women increased from 0.8% with BMI <25 to a peak of 1.5% for BMI ≥35.

One study quantified how much of the effects of BMI on CHD and stroke are mediated through blood pressure (BP), cholesterol and glucose and how much is independent of these factors. Using data from 97 prospective cohort studies that collectively enrolled 1.8 million participants between 1948 and 2005, and included 57,161 CHD and 31,093 stroke events, the hazard ratios (HRs) of BMI on CHD and stroke with and without adjustment for all possible combinations of BP, cholesterol and glucose were estimated. For each cohort, the authors excluded participants who were younger than 18 years, had a BMI lower than 20, or who had a history of CHD or stroke. The HR of BMI on CHD and stroke with and without adjustment for all possible combinations of BP, cholesterol and glucose was estimated. The HR for each 5 kg/m2 higher BMI was 1.27 for CHD and 1.18 for stroke after adjustment for confounders. These findings suggest that 46% of the excess risk of BMI for CHD and 76% the excess risk for stroke is mediated by these factors. BP was the most important mediator, accounting for 31% of the excess risk for CHD and 65% for stroke. Both overweight (BMI ≥25 to <30) and obesity (BMI ≥30) were associated with a significantly increased risk of CHD and stroke compared with a BMI of ≥20 to <25.

Since obesity, hypertension, diabetes and dyslipidemia are clinical markers of the metabolic syndrome, an analysis of data from 13,745 adults who participated in NHANES 1999-2004 assessed the relationship of body weight and changes in the prevalences of these comorbidities and the metabolic syndrome itself. With increasing overweight and obesity class, there were increases in the prevalences of hypertension, diabetes, dyslipidemia and the metabolic syndrome (Table 3-3). The adjusted ORs of these comorbidities in individuals with class III obesity were also significantly greater compared with normal weight individuals (Table 3-3).

Obstructive Sleep Apnea

Obstructive sleep apnea (OSA) is a syndrome characterized by repetitive episodes of upper airway obstruction that occur during sleep. Associated features include loud snoring, fragmented sleep, repetitive hypoxemia/hypercapnia and daytime sleepiness. Obesity, particularly central adiposity, are potent risk factors for sleep apnea since they can increase pharyngeal collapsibility through mechanical effects on pharyngeal soft tissues and lung volume and also through the central nervous system (CNS) via different interactions of adipokines and adipocyte-binding proteins on binding receptors that may affect airway neuromuscular control.

An OSA “event” can be either an apnea, characterized by complete cessation of airflow for at least 10 seconds, or a hypopnea in which airflow decreases by 50% for 10 seconds or decreases by 30% if there is an associated decrease in the oxygen saturation or an arousal from sleep. To assess the severity of OSA, the number of events per hour is reported as the apnea-hypopnea index (AHI). An AHI of <5 is considered normal. An AHI of 5-15 is mild; 15-30 is moderate and >30 events per hour is severe sleep apnea.

In the general adult population, the prevalence of OSA is 2% to 3% among middle-aged women and 4% to 5% among middle-aged men. In contrast, the prevalence among individuals with obesity has been reported to be ≥30% and from 50% to 98% among those with class III obesity. Among individuals referred for diagnostic sleep studies for OSA, 60% to 90% have overweight; the relative risk for the development of OSA among patients with obesity has been reported to be ≥10.

The impact of changes in body weight on OSA has been demonstrated by the Wisconsin Sleep Cohort Study and the Sleep Heart Health Study. The overall incidence of moderate to severe OSA over a 5-year period was 11.1% in men and 4.9% in women, respectively. Men with >10 kg weight gain during the follow-up period had a 5-fold risk of increasing their severity of OSA. In contrast, for the same degree of weight gain in women, there was a 2.5-fold risk associated with a similar degree of weight gain. Complementing the available body of observational data are studies on the effects of weight loss which show that reducing OSA severity is possible with a decrease in body weight. Although often limited by few small study samples and the lack of appropriate control groups, the unvarying observation is that weight loss can improve severity of disease in many patients and may be completely curative in some.

Additional Comorbidities

Since many individuals with obesity may have multiple concurrent comorbidities, one study analyzed the primary care electronic health records of 223,089 adults aged ≥30 years to assess the prevalence and impact of BMI category on the probabilities of concurrent comorbidities.

The presence of concurrent comorbidities was found to be strongly associated with levels of obesity. In normal weight men, the prevalence of multiple comorbidities was 23%, with increases to 27% in overweight, 33% in class I obesity, 38% in class II and 44% in class III obesity. In women, the pattern was similar except the increases with each stage were higher than those in men (28%, 34%, 41%, 45% and 51%, respectively). The odds of multiple comorbidities increased successively with each BMI category (Table 3-4). For participants with overweight, the odds of one disease, compared with none, were 25% higher than for normal weight patients. In patients with class I obesity, the relative odds were 54% higher and higher by 81% with class II obesity and 124% with class III obesity. The effect of increasing BMI category on concurrent comorbidities was similar to that of ageing, with patients with obesity having a prevalence of concurrent comorbidities similar to that of normal weight patients several decades older.

Osteoarthritis

An increasing body of evidence supports the role of obesity as an independent modifiable risk factor for the development of osteoarthritis (OA), particularly in weight-bearing joints such as the hips and knees. In one study, 2764 Italian general practitioners provided data from 10 consecutive patients with OA pain. In these 12,827 patients, the most painful joints were the knee (53.6%), the hip (23.6%) and the hand (22.8%). An association with a BMI of ≥25 was found in 74.8% of men and in 68.3% of women. The BMIs associated with knee and hip OA were consistently higher than those associated with hand OA. A case control study also found that relative to a BMI of 24, the risk of knee OA increased progressively from 0.1 in individuals with a BMI <20 to 13.6 in those with a BMI of ≥36.

Although the link between obesity and OA is well established, the etiological relationship has yet to be fully defined since OA has a multifactorial etiology. The biomechanical relationship is well known: increased loads on articular cartilage result in subsequent wear and cartilage breakdown. Conversely, clinical studies have shown that weight loss can have a favorable effect on OA. For instance, one study reported that for every one pound of weight lost, there was a four-pound reduction in the load exerted on the knee for each step taken during daily activities. However, since obesity-related OA can affect not only the weight-bearing joints (hips and knees) but also the hands, this suggests a role for circulating cytokines associated with adipose tissue, including leptin, adiponectin and resistin, which may influence OA through direct joint degradation or control of local inflammatory processes.

Cancer

Many prospective cohort studies and systematic reviews have confirmed a significant association between obesity and cancer. The strongest association is between an elevated BMI and cancer risk and mortality. Historical data from the past 25 years indicate that obesity is a cause of approximately 14% of cancer deaths in men and up to 20% of cancer deaths in women. The American Cancer Prevention Study II followed >900,000 subjects who were free from cancer in 1982 and had a mean follow-up of 16 years. Among those with a BMI ≥40, mortality from all causes of cancer was 52% higher in men and 62% higher in women compared with those with a normal BMI.

The Million Women Study from the United Kingdom recruited over 1.2 million women, aged 50 to 64 years during 1996 to 2001 and followed for a mean of 5.4 years for cancer incidence and 7 years for cancer mortality. Increasing BMI was associated with a significant increase in risk for 10 out of 17 of the most common types of cancer. A prospective study among 287,700 men in the NIH-AARP Diet and Health Study found that during a mean follow-up of 5 to 6 years, the relative risk for mortality from prostate cancer was 1.46 and 2.12 for a BMI ≥30 and ≥35, respectively.

A systematic review and meta-analysis of 221 datasets from 141 publications that included 282,137 incident cancer cases determined the RRs for 20 cancer types associated with each five-point increment in BMI. For example, in a man with a BMI of 28, the RR for colon cancer would be 1.24 compared with a man with a BMI of 23. Similarly, in a man with a BMI of 32, the RR for colon cancer would be 2.48 compared with a man with a BMI of 23. In a woman with a BMI of 28, the RR for colon cancer would be 1.09 compared with a woman with a BMI of 23. If that women had a BMI of 32, her RR for colon cancer would be 2.18 compared with a woman with a BMI of 23.

In the European Prospective Investigation into Cancer and Nutrition (EPIC) study that followed more than 368,000 men and women who were cancer-free at for a mean of 6.1 years, a BMI ≥29.4 was significantly associated with the risk of colon cancer in men but not women. Conversely, the RR for renal cell carcinoma associated with increased BMI in women was 2.25, but no significant increase was observed for men (RR, 1.22). Therefore, these results indicate a progressive increment in RR by BMI that can differ by cancer type and gender.

Depression

A reciprocal association between obesity and major depressive disorder (MDD) has long been recognized, specifically that obesity increases the risk of MDD (and other psychiatric disorders) and conversely, the presence of MDD increases the risk of weight gain. For example, the National Epidemiologic Survey on Alcohol and Related Conditions evaluated the relationship between BMI and psychiatric disorders in 41,654 individuals. Compared with normal weight subjects, BMI was significantly associated with mood, anxiety and personality disorders. The odds ratio for a psychiatric disorder was 1.21- to 2.08-fold greater among individuals with class I/II obesity and individuals with class III obesity, respectively and the OR for a lifetime prevalence of MDD was 1.53 and 2.02 among those with class I/II obesity and class III obesity, compared with normal weight subjects.

Another major survey of 217,379 US community-dwelling adults found that individuals with current depression or a lifetime diagnosis of depression or anxiety were significantly more likely to have unhealthy behaviors including obesity, smoking, physical inactivity, binge drinking and heavy drinking. The adjusted OR for coincident depression and obesity (BMI ≥30) was 1.6 vs 1 for individuals without obesity and the OR increased with increasing severity of MDD. In a study among 4,641 middle-aged women, the prevalence of moderate or severe MDD increased from 6.5% with a BMI <25 to 25.9% with a BMI >35. The OR for having MDD was 4.4 for a BMI of 30 to 35 and 4.95 for a BMI of ≥35.

A systematic review and meta-analysis of 15 studies (n = 58,745) found that obesity at baseline increased the risk of onset of depression at follow-up (OR 1.55; P <0.001). This association was more pronounced for MDD than for depressive symptoms (P = 0.05). Overweight also increased the risk of onset of depression at follow-up (OR 1.27; P <0.01). Conversely, depression at baseline increased the odds for developing obesity (OR 1.58; P <0.001).

Anxiety

Anxiety is an important part of the association between obesity and mental health. A series of interviews, conducted internationally as part of the World Mental Health Surveys initiative, examined the association of mental disorders and obesity and the effect of demographics on this association. The study noted a significant relationship between BMI ≥30 or >35 and anxiety, with a pooled odds ratio of 1.2 for BMI ≥30 and 1.4 for BMI >35. This relationship was even stronger than that of obesity and depressive disorder, which showed a pooled odds ratio of 1.1 for BMI ≥30 and 1.3 for BMI >35. The relationship between obesity and anxiety disorder was significant for women and for respondents who have not completed secondary education, with pooled odds ratios of 1.3 and 1.2, respectively. Overall, the association between obesity and anxiety observed in the study was modest but significant.

Gallbladder Disease

The prevalence of cholesterol gallstones is increased in persons with obesity, more commonly in women than in men. The risk is especially high in those with the highest BMI. The increased prevalence of stones is mostly due to supersaturation of bile with cholesterol because of an increased synthesis by the liver and secretion into bile.

The effects of overweight and obesity (BMI >30) on symptomatic gallstones were assessed in the 58,400 participants in a Swedish Twin Study. Overweight and obesity were both associated with a significant increase in the risk of symptomatic gallstones (OR = 1.86 and 3.38, respectively). A separate analysis of the Health Professionals Follow-Up Study, a prospective cohort study in 29,847 US men, sought to determine whether abdominal obesity, as measured by abdominal circumference and/or waist-to-hip ratio, is a separate risk factor for symptomatic gallstones. Men with waist circumference ≥102.6 cm (40.4 in) had a significantly greater risk (RR 2.29; P <0.001 for trend) for symptomatic gallstones compared with men with waist circumference <86.4 cm (34 in). Men with a waist-to-hip ratio ≥0.99 also had a significantly greater risk for symptomatic gall stones (RR 1.78; P <0.001 for trend) compared with men with a waist-to-hip ratio <0.89.

Gallbladder disease is a common cause of hospitalization, especially among women and has a considerable impact on health care costs. A large epidemiologic study from England and Scotland found a significant association between obesity and symptomatic gall-bladder disease among 1.3 million women (mean age, 56 years). Women with a higher BMI at study entry were more likely to be admitted and to spend more days in the hospital for symptomatic gallbladder disease. For each 1000 person-years of follow-up, women with BMI 18.5 to 24.9 spent a mean of 16.5 days hospitalized vs 44 days for women with BMI 30 to 39.9.

Weight loss also increases the risk of gallstones. The prevalence of new gallstones reaches 10% to 12% after 8 to 16 weeks of a low-calorie diet and more than 30% within 12 to 18 months after gastric by-pass surgery. About one third of the stones are symptomatic. Risk factors for gallstones during weight loss are; a relative weight loss >24% of initial body weight, weight loss rate of >1.5 kg per week, a very low calorie diet with no fat, a long overnight fast period and a high serum triglyceride level.

Non-alcoholic Fatty Liver Disease (NAFLD)

Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of disorders that range from simple steatosis to nonalcoholic steatohepatitis (NASH) and, ultimately, cirrhosis and hepatocellular carcinoma. Studies of NAFLD prevalence and incidence indicate that the diagnosis is heterogeneous and relies on a variety of assessment tools, including liver biopsy, radiological tests such as ultrasonography, and blood testing such as liver enzymes. NAFLD affects ~15% to 30% of the general population, and has a prevalence of ~70% in people with T2D.

Many studies have identified obesity as a risk factor for NAFLD. In an analysis of data from 832 Hispanic adults in which the diagnosis of NAFLD was based on ultrasound and no history of alcohol abuse or hepatitis C infection, a BMI >26.9 was significantly and independently associated with NAFLD with an odds ratio of 6.2. In a cross-sectional study of 326 Israelis who participated in a National Health Survey, the prevalence of NAFLD was 30%; NAFLD was more common in men (38%) than in women (21%), and obesity (BMI ≥30) was independently associated with NAFLD (odds ratio 2.9). A meta-analysis found that NAFLD has an increased overall mortality (OR 1.57) deriving from liver-related and CV disease, and a 2-fold risk of diabetes.

Polycystic Ovarian Syndrome (PCOS)

Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism and chronic oligo-anovulation. However, many features of metabolic syndrome are inconsistently present in the majority of women with PCOS. Approximately 50% of women with PCOS have overweight or obesity and most of them have the abdominal obesity phenotype. However, obesity is not a part of the PCOS phenotype in many parts of the world. Given the high prevalence of PCOS among relatively normal weight populations, obesity per se is likely not a direct cause of PCOS. However, obesity does exacerbate many aspects of the phenotype, especially CV risk factors such as glucose intolerance, insulin resistance and dyslipidemia. It is also associated with a poor response to infertility treatment and an increased risk for pregnancy complications in those women who do conceive.

While many women with PCOS have overweight, obesity, or central obesity, the effect of excess weight on the outcomes of PCOS is inconsistent. A systematic review and meta-analysis of studies that enrolled a total of 15,129 women described the prevalence of overweight, obesity and central obesity in women with and without PCOS. Women who have overweight or obesity and concomitant PCOS had decreased sex hormone-binding globulin (SHBG), increased total testosterone, free androgen index, hirsutism, fasting glucose, fasting insulin, homeostatic model assessment-insulin resistance index and worsened lipid profile. Obesity significantly worsened all metabolic and reproductive outcomes measured except for hirsutism compared with normal weight women with PCOS. In women with overweight there were no differences in total testosterone, hirsutism, total cholesterol and low-density lipoprotein cholesterol compared with normal weight women and no differences in SHBG and total testosterone compared with women with obesity. Central obesity was associated with higher fasting insulin levels. The Australian Longitudinal Study on Women’s Health was a community-based observational study that enrolled 9145 women aged 28-33 years. Self-reported PCOS prevalence was 5.8%. Women reporting PCOS had higher weight, mean BMI (32.5), and greater 10-year weight gain (2.6 kg). BMI was the strongest correlate of PCOS status with every BMI increment increasing the risk of reporting PCOS by 9.2%.

The relationship between PCOS and obesity is a complicated one. Not all women who have PCOS also have obesity, and not all women with obesity have PCOS. Thus, it is not clear whether PCOS leads to weight gain, or if the excess weight contributes to developing PCOS. Certainly, obesity is a common finding in PCOS and aggravates its metabolic features such as insulin resistance.

Chronic Renal Failure (CRF)

Although obesity has been implicated as a possible risk factor for microalbuminuria in individuals with hypertension and diabetes, general population studies suggest that obesity also may be harmful to the kidneys in individuals without hypertension, diabetes, or preexisting renal disease. A nationwide, population-based, case-control study in Sweden assessed the effect of body weight and the risk of moderately severe CRF. Eligible cases were men (n =597) and women (n = 329) whose serum creatinine levels, for the first time and permanently were ≥3.4 mg/dL (300 μmol/L) and 2.8 mg/dL (250 μmol/L), respectively. Using the World Health Organization (WHO) cut points for BMI levels, there were significant 3-fold increases in both men and women with a BMI ≥35. Men and women who reported a BMI ≥25 at age 20 had a significant 3-fold elevated risk for CRF compared with patients with BMI <25. BMI at age 40 and at age 60 showed similar relationships with CRF risk as did highest lifetime BMI.

GERD

Gastroesophageal reflux disease (GERD) is a common condition that has been steadily increasing in prevalence, disproportionately so in the younger population. According to several studies, obesity increases the risk of developing GERD and related erosive esophagitis by 1.5-2.0. In a meta-analysis of 9 studies that examined association between GERD symptoms and obesity, data from 8 studies yielded a pooled adjusted odds ratios for GERD symptoms of 1.43 (95% CI, 1.158 to 1.774) for BMI of 25-30 and 1.94 (CI, 1.468 to 2.566) for BMI >35. These findings suggests that the risk progressively increases with an increase in BMI.

Stress Urinary Incontinence (SUI)

Urinary incontinence is a condition that affects almost half of middle-aged women and has profound negative impacts on the quality of life. Studies on the association of urinary incontinence and obesity suggest that for every 5 units of BMI increase, there is a 20% to 70% increase in the risk of daily urinary incontinence. In women with obesity (BMI ≥ 40), the prevalence of incontinence was 60% to 70%, with pure stress incontinence accounting for 28%, pure urge incontinence for 4% and mixed incontinence for 32%, suggesting a stronger association with stress-induced incontinence compared to urge incontinence or overactive bladder syndrome. Another study identified maximal cough pressure as a possible mechanism for the relationship between obesity and stress urinary incontinence (SUI). Maximal cough pressure was significantly associated with SUI for women with obesity (OR 3.191 [95% CI: 1.326-7.683], P<0.01), but not for women with normal weight or overweight. Further path model analyses demonstrated a significant relationship between BMI and SUI through maximal cough pressure (indirect effect, P=0.038), compared to other possible mechanisms.

Infertility

Infertility affects one in seven couples, and there is a well-documented link between obesity and infertility in both men and women. The risk of female infertility is three times higher in women with obesity than in women of normal weight, with fertility being impaired in both natural and assisted conception. Although there are several mechanisms by which obesity impacts fertility, studies have uncovered a strong association between obesity and anovulatory infertility. Male fertility is also affected by high BMI. One meta-analysis revealed an inverse association between excess weight and sperm count. Men with overweight had significantly increased odds of having oligozoospermia (OR 1.11 [95% CI: 1.01-1.20]) or azoospermia (OR 1.39 [95% CI: 0.98-1.97) compared with normal-weight men. Men with obesity also had a higher risk of oligozoospermia (OR 1.42 [95% CI: 1.12-1.79]) or azoospermia (OR 1.81 [95% CI: 1.23-2.66]) compared with normal-weight men.

Pregnancy Complications

As in every other demographic bracket obesity is becoming increasingly prevalent in women of childbearing age. Maternal obesity, regardless of weight before the pregnancy, is an independent risk factor for complications in pregnancy. In a systematic review of 22 reviews and meta-analyses, maternal obesity was found to be associated with gestational diabetes, pre-eclampsia, gestational hypertension, depression and instrumental and caesarean birth. Maternal obesity was also linked with adverse outcomes for the fetus, including preterm birth, large-for-gestational-age babies, fetal defects, congenital anomalies and perinatal death.

Lower Limb Venous Disease (LLVD)

Lower limb venous disease affects up to 50% of the population worldwide, and is thus commonly comorbid with obesity. A number of epidemiologic studies have established obesity as a risk factor for LLVD, including varicose veins, chronic venous insufficiency, chronic venous ulceration, deep vein thrombosis and venous thromboembolism. Obesity is thought to contribute to LLVD via several mechanisms, including increased coagulation, venous stasis and the transmission of intraabdominal pressure to the legs by femoral veins.

Metabolic syndrome

Metabolic syndrome is a collection of metabolic conditions that increase the risk of cardiovascular disease, stroke and T2D. The metabolic risk factors are all closely related to weight gain. Metabolic syndrome now affects 30–40% of people by age 65, and is largely driven by weight gain, specifically the increase in intra-abdominal fat accumulation. A study analyzing the NHANES data from 2003-2004 to 2013-2014 revealed that cardiovascular risk factors, diabetes and obesity were all increasing among US adults during the period. While metabolic syndrome doubles the risk of CVD, the individual constituents of metabolic syndrome are reversible, and therefore can be treated by weight management.

Metabolically Healthy Obesity?

Although obesity is typically accompanied by unfavorable metabolic profiles, it has been reported that this may not always be the case. The term “metabolically healthy obesity” (MHO) has been used to describe obesity that does not have the burden of any metabolic abnormalities. Although the definitions of and criteria for MHO vary considerably, one study examined the MHO phenotype using NHANES, a nationally representative sample of adults living in the United States, and found a prevalence of 32% among adults with obesity over the age of 20.

Several epidemiologic studies have shown that participants with MHO are not at increased risk of developing CV disease over 3 to 13 years of follow-up compared with healthy individuals without obesity and are at lower risk compared with participants with non-MHO obesity. However, there are inconsistencies in the data, and other studies with an extended follow up period (>15 years) showed that participants with obesity but without metabolic syndrome at baseline were still at increased risk of major CV disease events compared with healthy participants without obesity

A systematic review and meta-analysis of eight studies (n = 61,386; 3988 events) that evaluated participants for all-cause mortality and/or CV events found that individuals with MHO had an increased risk (RR; 1.24) for events only when compared with metabolically healthy normal-weight individuals in studies with 10 or more years of follow-up were considered. All metabolically unhealthy groups had a similarly elevated risk: normal weight (RR: 3.14), overweight (RR: 2.70) and obesity (RR: 2.65). The authors conclude that individuals with obesity have an increased risk for death and CV events over the long-term regardless of metabolic status, and that metabolically unhealthy overweight is also associated with these adverse outcomes.