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Type 2 diabetes mellitus: Prevalence and risk factors

AUTHOR: R Paul Robertson, MD
SECTION EDITOR: David M Nathan, MD
DEPUTY EDITOR: Katya Rubinow, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Nov 2023.

This topic last updated: Sep 15, 2023.

INTRODUCTION

Type 2 diabetes mellitus is characterized by hyperglycemia, insulin resistance, and relative

impairment in insulin secretion. Its pathogenesis is only partially understood, but is
heterogeneous and both genetic factors affecting insulin release and responsiveness and
environmental factors, such as obesity, are important.

The prevalence of and risk factors for type 2 diabetes will be reviewed here. The pathogenesis,
including genetic susceptibility, and the diagnostic criteria for diabetes are discussed elsewhere.
(See "Pathogenesis of type 2 diabetes mellitus" and "Clinical presentation, diagnosis, and initial
evaluation of diabetes mellitus in adults".)

PREVALENCE

Diabetes is estimated to affect approximately 530 million adults worldwide, with a global
prevalence of 10.5 percent among adults aged 20 to 79 years [1,2]. Type 2 diabetes represents
approximately 98 percent of global diabetes diagnoses, although this proportion varies widely
among countries [3]. In an analysis of data from the National Health Interview Survey (2016 and
2017), the prevalence of diagnosed type 2 diabetes among adults in the United States was 8.5
percent [4]. Other national databases, such as the Center for Disease Control and Prevention
Diabetes Surveillance System, reported in 2022 a prevalence of diagnosed diabetes of
approximately 11.3 percent of adults (37.3 million people; 28.7 million with diagnosed diabetes,
an estimated 8.5 million undiagnosed, and 95 percent of whom have type 2 diabetes) [5,6].
Given the marked increase in childhood obesity, there is concern that the prevalence of
diabetes will continue to increase substantially. Global data appear to substantiate this concern
as the worldwide incidence rate of type 2 diabetes among adolescents and young adults (aged
15 to 39 years) rose from 117 to 183 per 100,000 population between 1990 and 2019 [7]. (See
"Definition, epidemiology, and etiology of obesity in children and adolescents", section on
'Epidemiology'.)

The prevalence of diabetes is higher in certain populations [8,9]. As examples:

● Using data from a national survey for people aged 20 years or older, the prevalence of
diagnosed type 2 diabetes in the United States (2018) was 7.5 percent in non-Hispanic
White Americans, 9.2 percent in non-Hispanic Asian Americans, 12.5 percent in Hispanic
Americans, 11.7 percent in non-Hispanic Black Americans, and 14.7 percent in Native
Americans/Alaska Natives [8].

● In an analysis of data from the 2011 to 2014 Behavioral Risk Factor Surveillance System,
the prevalence of self-reported diabetes was higher among Asian persons (9.9 percent)
and Native Hawaiian or other Pacific Islander individuals (14.3 percent) than in White
individuals (8 percent) [10].

● Outside the United States, type 2 diabetes is most prevalent in Polynesia and other Pacific
islands (approximately 25 percent) with similarly high rates in the Middle East and South
Asia (Kuwait and Pakistan, in particular) [11,12]. In China, the most populous country in
the world, an estimated 13 percent of the adult population has diabetes, with
approximately one-half undiagnosed [1,13].

ABNORMAL GLUCOSE METABOLISM

Abnormal glucose metabolism can be documented years before the onset of overt diabetes.
Although the risk of developing type 2 diabetes follows a continuum across all levels of
abnormal glycemia, when classified categorically, the individuals demonstrably at highest risk
include those with impaired fasting glucose (IFG), impaired glucose tolerance (IGT), or a
glycated hemoglobin (A1C) level of 5.7 to 6.4 percent (39 to 46 mmol/mol) ( table 1) [14,15].
The criteria for defining diabetes and impaired glucose regulation are reviewed in greater detail
separately. (See "Clinical presentation, diagnosis, and initial evaluation of diabetes mellitus in
adults".)
Although the natural history of IFG and IGT is variable, approximately 25 percent of subjects
with either will progress to diabetes over three to five years [14]. Individuals with isolated IFG
have hepatic insulin resistance, whereas those with isolated IGT predominantly have muscle
insulin resistance and normal or slightly reduced hepatic insulin sensitivity [14]. Individuals with
abnormalities in both IFG and IGT have hepatic and muscle insulin resistance, which confers an
even higher risk of progressing to diabetes compared with having only one abnormality.
Individuals with additional diabetes clinical risk factors, including obesity and family history, are
also more likely to develop diabetes. (See 'Clinical risk factors' below.)

Impaired glucose tolerance — The term IGT describes subjects who, during an oral glucose
tolerance test (OGTT), have blood glucose values between those in normal subjects and those in
patients with overt diabetes (140 to 199 mg/dL [7.8 to 11 mmol/L]) ( table 1). The rate of
progression from IGT to overt diabetes varies among different populations. In six prospective
studies, for example, the incidence rates of type 2 diabetes among patients with IGT ranged
from 36 to 87 per 1000 person-years [16]. The rates were higher among Hispanic, Pima, and
Nauruan people than among White people. Estimates of obesity (including body mass index
[BMI], waist-to-hip ratio, and waist circumference) were positively associated with the incidence
of type 2 diabetes. In contrast, sex and family history of diabetes were not related to the rate of
progression in most studies.

Subjects who have only IGT generally do not develop clinically significant microvascular
complications of diabetes such as retinopathy and nephropathy [17]. They are, however, at
substantially increased risk (when compared with matched subjects with normal glucose
tolerance) for developing macrovascular disease (such as coronary artery disease). (See "Clinical
presentation, diagnosis, and initial evaluation of diabetes mellitus in adults", section on 'A1C,
FPG, and OGTT as predictors of cardiovascular risk'.)

Impaired fasting glucose — IFG is defined as a fasting blood sugar of 100 to 125 mg/dL (5.6 to
7 mmol/L) ( table 1). IFG increases the risk of developing type 2 diabetes [18].

Although fasting glucose levels less than 100 mg/mL (5.55 mmol/L) are considered normal by
the 2003 criteria of the Expert Committee on the Diagnosis and Classification of Diabetes
Mellitus, subjects with fasting glucose values in the higher quintiles of normal range are at
increased risk for developing type 2 diabetes. In a prospective cohort study (over 46,500
subjects followed for a mean of 81 months), the overall incidence of diabetes in those with
normal fasting glucose was low (4 percent) [19]. However, there was an increased risk of
diabetes incidence in those with fasting plasma glucose of 95 to 99 mg/dL (5.3 to 5.5 mmol/L)
compared with <85 mg/dL (4.7 mmol/L) (hazard ratio [HR] 2.33, 95% CI 1.95-2.79) [19].
Similar results were reported in a study of 13,163 healthy male Israeli army recruits [20]. There
was a progressive increased risk of diabetes for those with fasting plasma glucose levels greater
than 87 mg/dL (4.83 mmol/L) compared with those in the lowest quintile with fasting glucose
levels less than 81 mg/dL (4.5 mmol/L). The risk of diabetes was even greater (HR 8.23, 95% CI
3.6-19.0) in those with high normal glucose levels (91 to 99 mg/dL) in combination with elevated
serum triglycerides (greater than 150 mg/dL) and elevated BMI (>30 kg/m2), and may indicate
subjects for whom preventive measures would be most effective.

Glycated hemoglobin — A1C measurements are also helpful in predicting diabetes ( table 1)
[15,21-23]. In a systematic review of 16 prospective studies examining the relationship between
A1C and future incidence of diabetes mellitus, risk of diabetes increased sharply with A1C
across the range of 5 to 6.5 percent (31 to 48 mmol/mol) [24]. For persons with A1C between 5.5
to 6.0 percent and 6.0 to 6.5 percent, the projected five-year risk of diabetes ranged from 9 to
25 and 25 to 50 percent, respectively. In the largest prospective cohort study of 26,563 women
without diagnosed diabetes followed for 10 years, baseline A1C, at levels considered to be
within the normal range, was an independent predictor of future type 2 diabetes [22]. In those
individuals with baseline A1C in the highest quintile (A1C >5.22 percent [34 mmol/mol]), the
adjusted relative risk (RR) of diabetes was 8.2, 95% CI 6.0-11.1.

The international standardization of the A1C assay and biological and patient-specific factors
(eg, low red cell turnover in iron deficiency anemia, rapid red cell turnover in patients treated
with erythropoietin, hemoglobinopathies) that may cause misleading results are reviewed in
detail elsewhere. (See "Measurements of chronic glycemia in diabetes mellitus", section on
'Glycated hemoglobin (A1C)'.)

CLINICAL RISK FACTORS

Family history — Compared with individuals without a family history of type 2 diabetes,
individuals with a family history in any first degree relative have a two to three-fold increased
risk of developing diabetes [25,26]. The risk of type 2 diabetes is higher (five- to sixfold) in those
with both a maternal and paternal history of type 2 diabetes [25,26]. The risk is likely mediated
through genetic, anthropometric (body mass index [BMI], waist circumference), and lifestyle
(diet, physical activity, smoking) factors. The genetics of type 2 diabetes is reviewed separately.
(See "Pathogenesis of type 2 diabetes mellitus", section on 'Genetic susceptibility'.)

Ethnicity — Data from the prospective Nurses' Health Study (NHS) collected over 20 years
found that the risk for developing diabetes in women, corrected for BMI, was increased for
Asian, Hispanic, and Black Americans (relative risk [RR] 2.26, 1.86, and 1.34, respectively)
compared with White Americans [27]. In an analysis of 2011 to 2012 data from the National
Health and Nutrition Examination Survey (NHANES), the age-standardized prevalence of total
diabetes (using the A1C, fasting plasma glucose, or two-hour oral glucose tolerance test [OGTT]
definition) was higher among non-Hispanic Black, non-Hispanic Asian, and Hispanic individuals
(21.8, 20.6, and 22.6 percent, respectively) than among non-Hispanic White individuals (11.3
percent) [28].

The ethnic disparity in diabetes incidence may be related in part to modifiable risk factors. As an
example, in a retrospective analysis of a cohort study of 4251 Black and White young adults
without diabetes at baseline (median follow-up 30 years), the racial disparity in diabetes risk
was primarily associated with biological risk factors (eg, BMI, waist circumference, blood
pressure) but also with neighborhood, psychosocial, socioeconomic, and behavioral factors
during young adulthood [29].

Obesity — The risk of impaired glucose tolerance (IGT) or type 2 diabetes rises with increasing
body weight ( figure 1) [30-34]. In an analysis of five NHANES spanning over thirty years,
increase in BMI over time was the most important of the three covariates studied (age,
race/ethnicity, BMI) for the increase in diabetes prevalence, accounting for approximately 50
percent of the increase in diabetes prevalence in males and 100 percent in females [35]. In
addition, the NHS demonstrated an approximately 100-fold increased risk of incident diabetes
over 14 years in nurses whose baseline BMI was >35 kg/m2 compared with those with BMI <22
kg/m2 [36].

The risk of diabetes associated with body weight appears to be modified by age. In a
prospective cohort study of over 4000 males and females >65 years of age, the risk of diabetes
associated with BMI in the highest tertile was greater in subjects less than 75 years of age
compared with those 75 years and older (hazard ratio [HR] 4.0 versus 1.9) [37].

Obesity acts at least in part by inducing resistance to insulin-mediated peripheral glucose

uptake, which is an important component of type 2 diabetes, likely unmasking the part of the
population with limited insulin secretion [38-40]. Reversal of obesity decreases the risk of
developing type 2 diabetes and, in patients with established disease, improves glycemic
management and can lead to remission. (See "Prevention of type 2 diabetes mellitus", section
on 'Lifestyle intervention' and "Nutritional considerations in type 2 diabetes mellitus" and
"Initial management of hyperglycemia in adults with type 2 diabetes mellitus", section on
'Weight management'.)

Fat distribution — The distribution of excess adipose tissue is another important determinant
of the risk of insulin resistance and type 2 diabetes. The degree of insulin resistance and the
incidence of type 2 diabetes are highest in those subjects with central or abdominal obesity, as
measured by waist circumference or waist-to-hip circumference ratio ( figure 2) [34,37,41,42].
Intra-abdominal (visceral) fat rather than subcutaneous or retroperitoneal fat appears to be of
primary importance in this regard. This 'male' type obesity is different from the typical 'female'
type, which primarily affects the gluteal and femoral regions and is not as likely to be associated
with glucose intolerance or cardiovascular disease. Why the pattern of fat distribution is
important and the relative roles of genetic and environmental factors in its development are not
known [41,42]. (See "Obesity in adults: Prevalence, screening, and evaluation", section on 'Waist
circumference' and "Obesity: Genetic contribution and pathophysiology", section on 'Body fat
distribution'.)

Birth and childhood weight — There is an apparent U-shaped relationship between birth
weight and risk of type 2 diabetes. This issue is discussed in detail elsewhere. (See
"Pathogenesis of type 2 diabetes mellitus", section on 'Role of intrauterine development'.)

Above-average childhood BMI also is a risk factor for diabetes, independent of birth weight
[43,44]. Remission of overweight or obesity before puberty appears to negate the risk. In a
population-based study from Denmark, men who had been overweight at seven years of age,
but who were normal weight by 13 years of age (and remained normal weight), had a similar
risk of developing type 2 diabetes in adulthood as men who had never been overweight as
children or in early adulthood [44]. Remission of overweight after age 13 years but before early
adulthood (17 to 26 years) was associated with increased risk, but risk was lower than that
among men who were overweight at every age. (See "Epidemiology, presentation, and
diagnosis of type 2 diabetes mellitus in children and adolescents", section on 'Risk factors'.)

Lifestyle factors — Although insulin resistance and, in particular, impaired insulin secretion in
type 2 diabetes have a substantial genetic component, they can also be influenced, both
positively and negatively, by behavioral factors, such as physical activity, diet, smoking, alcohol
consumption, body weight, and sleep duration. Improving these lifestyle factors can reduce the
risk of diabetes mellitus [45].

Exercise — A sedentary lifestyle lowers energy expenditure, promotes weight gain, and
increases the risk of type 2 diabetes [46]. Among sedentary behaviors, prolonged television
watching is consistently associated with the development of obesity and diabetes [47].

Physical inactivity, even without weight gain, appears to increase the risk of type 2 diabetes. In a
cohort study of Swedish men, low aerobic capacity and muscle strength at 18 years of age was
associated with an increased risk of type 2 diabetes 25 years later, even among men with
normal BMI [48].
Physical activity of moderate intensity reduces the incidence of new cases of type 2 diabetes,
regardless of the presence or absence of IGT. (See "Prevention of type 2 diabetes mellitus",
section on 'Exercise'.)

Smoking — Several large prospective studies have raised the possibility that cigarette smoking
increases the risk of type 2 diabetes [49-57]. In a meta-analysis of 25 prospective cohort studies,
current smokers had an increased risk of developing type 2 diabetes compared with
nonsmokers (pooled adjusted RR 1.4, 95% CI 1.3-1.6) [58]. The risk appears to be graded, with
increasing risk as the number of cigarettes smoked per day and pack-year history rises. In one
study, the risk was also increased for non-smokers who have been exposed to secondhand
smoke, compared with those who have not been exposed [55].

While a definitive causal association has not been established, a relationship between cigarette
smoking and diabetes mellitus is biologically possible based upon a number of observations:

● Smoking increases the blood glucose concentration after an oral glucose challenge [59].

● Smoking may impair insulin sensitivity [60].

● Cigarette smoking has been linked to increased abdominal fat distribution and greater
waist-to-hip ratio that, as mentioned above, may have an impact upon glucose tolerance
[61,62].

The effect of smoking cessation on diabetes risk is variable and may depend upon individual
patient factors. Smoking cessation may reduce diabetes risk by reducing systemic
inflammation. On the other hand, smoking cessation is often associated with weight gain,
which will increase the risk of diabetes. (See "Pathogenesis of type 2 diabetes mellitus", section
on 'Role of diet, obesity, and inflammation'.)

In an analysis of three cohort studies in the United States (mean follow-up 19.6 years), smoking
cessation was associated with an increased risk of type 2 diabetes compared with continuing to
smoke (HR 1.22, 95% CI 1.12-1.32) [63]. The risk peaked five to seven years after cessation and
did not drop to that among individuals who had never smoked until 30 years after quitting. The
increased risk of diabetes was directly proportional to weight gain. Nevertheless, quitters had
significantly lower rates of overall and cardiovascular mortality compared with current smokers,
irrespective of weight gain.

Similar findings were noted in other cohort studies [64,65]. The increased risk of type 2 diabetes
after smoking cessation does not outweigh the overall benefits of giving up smoking. Smoking
cessation efforts should be accompanied by additional lifestyle interventions, such as increasing
physical activity and reducing weight.

Sleep duration — Sleep quantity, quality, and chronotype may be associated with
development of type 2 diabetes mellitus, but causality is uncertain [66]. In a meta-analysis of 10
prospective studies, compared with approximately eight hours/day of sleep, short (≤5 to 6
hours/day) and long (>8 to 9 hours/day) duration of sleep were significantly associated with an
increased risk of type 2 diabetes (RR 1.28 and 1.48, respectively) [67]. Difficulty initiating and
maintaining sleep were also associated with an increased incidence. In a subsequent report
from the European Prospective Investigation into Cancer and Nutrition (EPIC) study of more
than 23,000 participants across Europe, short sleep duration (<6 hours/day compared with 7 to
<8 hours/day) was associated with an increased risk of chronic disease, including type 2
diabetes (6.7 cases versus 4.2 cases per 1000 person-years, HR 1.44, 95% CI 1.10-1.89) [68]. The
effect was largely attenuated by adjusting for BMI and waist-to-hip ratio (HR 1.08, 95% CI 0.82-
1.42).

Whether the putative association between disordered sleep and development of diabetes is
causal or not is unknown. Since the association loses statistical significance after adjusting for
obesity, it is not clear if there is a unique relationship between sleep patterns and diabetes risk,
whether sleep disruption associated with obesity (eg, sleep apnea) has some pernicious effects
on diabetes risk, or whether other mechanisms may play a role in diabetes development. One
possible mechanism whereby short sleep duration increases the risk of diabetes is through its
effect on melatonin secretion. Sleep disruption is associated with decreased melatonin
secretion, and in an observational study, lower melatonin secretion was independently
associated with a higher risk of developing type 2 diabetes [69].

DIETARY PATTERNS

Dietary patterns affect the risk of type 2 diabetes mellitus. Consumption of red meat, processed
meat, and sugar sweetened beverages is associated with an increased risk of diabetes, whereas
consumption of a diet high in fruits, vegetables, nuts, whole grains, and olive oil is associated
with a reduced risk [70-73]. A healthy cardiac diet (high in cereal fiber and polyunsaturated fat,
and low in trans fat and glycemic load) had more impact on diabetes risk in Asian, Hispanic, and
Black than among White Americans (relative risk [RR] 0.54 versus 0.77) in a 20-year prospective
study [27]. It is important to recognize that most studies have used food frequency
questionnaires to capture dietary patterns and that none of the food stuffs examined can be
considered in isolation. For example, higher meat intake always means more saturated fat
intake, relatively lower fruit and vegetable intake, and frequently, higher body mass index (BMI).
Although some lifestyle and dietary factors are considered in multivariable analysis, other
unmeasured lifestyle or dietary factors may account for the findings in the observational
studies described below.

Increased risk

Western versus prudent diet — In a study of over 42,000 male health professionals, a
western diet (characterized by high consumption of red meat, processed meat, high fat dairy
products, sweets, and desserts) was associated with an increased risk of diabetes independent
of BMI, physical activity, age, or family history (RR 1.6, 95% CI 1.3-1.9) [71,72]. The risk was
markedly increased (RR 11.2) among subjects who ate a western diet and were obese (BMI ≥30
kg/m2 versus <25 kg m2) [71]. In contrast, men who ate a prudent diet (characterized by higher
consumption of vegetables, fruit, fish, poultry, and whole grains) had a modest reduction in risk
(RR 0.8, 95% CI 0.7-1.0).

Similar results have been described in women [74,75] and in European populations [76]. (See
"Nutritional considerations in type 2 diabetes mellitus" and "Healthy diet in adults".)

Sugar-sweetened beverages — Sugar-sweetened beverages, in particular soft drinks, have

been associated with obesity in children. Most [77-84], but not all [85], studies report an
increased risk of diabetes with consumption of sugar-sweetened beverages. As examples:

● In a prospective, cohort study of adult women, higher consumption of sugar-sweetened

beverages was associated with both greater weight gain and risk of type 2 diabetes [77].
After adjustment for potential confounders, women consuming one or more sugar-
sweetened soft drinks per day had a higher risk of developing type 2 diabetes when
compared with women who had less than one soft drink per month (RR 1.83, 95% CI 1.4-
2.4).

● Similar findings were noted in a prospective study of 59,000 African American women [78].
Compared with women who consumed less than one sugar-sweetened soft drink per
month, women who had two or more drinks each day had a higher risk of developing type
2 diabetes (incidence rate ratio [IRR] 1.24, 95% CI 1.06-1.45). For fruit drinks (fortified fruit
drinks, Kool-Aid, and fruit juices other than orange or grapefruit), the IRR was 1.31, 95% CI
1.13-1.52. Consumption of orange or grapefruit juice and diet soft drinks did not increase
risk of diabetes.

It is unclear whether the described association is due to increased caloric intake and weight
gain, other lifestyle factors (smoking, exercise, other food choices), or excess consumption of
refined carbohydrates, such as high-fructose corn syrup (used to sweeten beverages) [86]. In
the two studies described above, women who increased their consumption of soft drinks over
the study period experienced greater weight gain than women with stable consumption
patterns, suggesting that the primary mechanism for increased diabetes risk is weight gain
[77,78].

Vitamin D deficiency — Several prospective observational studies have shown an inverse

relationship between circulating 25-hydroxyvitamin D levels and risk of type 2 diabetes. The
causality of this relationship remains unclear as interventional trials have failed to demonstrate
a significant benefit of vitamin D therapy on the risk of developing diabetes [87]. Obesity is also
associated with low 25-hydroxyvitamin D concentrations, and a relationship between vitamin D
deficiency and type 2 diabetes may be related to obesity, rather than vitamin D deficiency. This
topic is reviewed in detail elsewhere. (See "Vitamin D and extraskeletal health", section on
'Diabetes'.)

Selenium — Although animal models suggest that low doses of the antioxidant selenium may
improve glucose metabolism, these findings have not been demonstrated in humans [88]. In an
exploratory analysis of the Nutritional Prevention of Cancer trial, 1202 individuals who did not
have diabetes at baseline and who were randomly assigned to selenium (200 mcg daily) or
placebo were evaluated for incident type 2 diabetes [89]. After 7.7 years of follow-up, the
cumulative incidence of diabetes was higher in those taking selenium than placebo (incidence
12.6 versus 8.4 cases per 1000 person-years, respectively, hazard ratio [HR] 1.55, 95% CI 1.03-
2.33). Thus, selenium supplementation does not confer benefit and may increase the risk of
type 2 diabetes. Potential mechanisms for this association are unknown, but may be related to
the effects of selenium on glucagon (stimulatory) and insulin-like growth factor 1 (IGF-1)
(inhibitory) [90].

Other

● Iron intake – An association between serum ferritin levels [91,92], high iron intake [93],
and type 2 diabetes has been reported, but the association is not well understood. Low
iron diets are not recommended.

● Chromium deficiency – Chromium deficiency is generally limited to hospitalized patients

with increased catabolism and metabolic demands in the setting of malnutrition. Other
patients at risk for chromium deficiency include patients with short bowel syndrome,
burns, traumatic injuries, or those on parenteral nutrition without appropriate trace
mineral supplementation. An association has been suggested between low chromium
levels and impaired glucose tolerance (IGT) and unfavorable lipid profiles. Randomized
trials on this subject are of fair quality and have conflicting results, but generally suggest
 that chromium supplementation improved glycemia among patients with diabetes, but
not among those with normal glucose tolerance [94]. (See "Overview of dietary trace
elements", section on 'Chromium'.)

Reduced risk

Mediterranean diet — In prospective cohort study of over 13,000 Spanish graduate students
without diabetes at baseline, high versus low adherence to a Mediterranean diet (high in fruits,
vegetables, nuts, whole grains, and olive oil) was associated with a lower risk of diabetes over
4.4 years (median) of observation [95]. Similar findings were noted in a large European case-
cohort study [96]. (See "Metabolic syndrome (insulin resistance syndrome or syndrome X)",
section on 'Diet'.)

Dairy products — There is an inverse association between consumption of dairy products and
the metabolic syndrome (obesity, glucose intolerance, hypertension, dyslipidemia) in
overweight, but not lean adults. In the Coronary Artery Risk Development in Young Adults
(CARDIA) study, overweight subjects with the highest consumption of dairy products (≥35 per
week) had a significantly lower risk of the metabolic syndrome as compared with those with the
lowest dairy consumption (<10 per week, adjusted odds ratio [OR] 0.3, 95% CI 0.1-0.6) [97]. In
other prospective studies, low-fat, but not high-fat dairy intake, was associated with a lower risk
of type 2 diabetes (independent of BMI) in men [98] and in women [99].

The beneficial effects of dairy product consumption on diabetes risk may be mediated by trans-
palmitoleic acid, a fatty acid derived primarily from naturally occurring dairy and ruminant trans
fats. In a subset of subjects participating in the Cardiovascular Health Study, higher plasma
trans-palmitoleic acid levels were associated with lower risk for new onset diabetes [100].

Nuts — Nut and peanut butter consumption may lower the risk of type 2 diabetes in women.
In a prospective cohort study of over 83,000 women, increasing nut consumption was inversely
associated with the risk of type 2 diabetes (for ≥5 one-ounce servings per week compared with
no nut consumption, RR 0.7, 95% CI 0.6-0.9) [101]. In addition, women consuming more than
five servings of peanut butter per week had a similar reduction in risk compared with those who
never/rarely ate peanut butter (RR 0.8, 95% CI 0.7-0.9).

Whole grains and cereal fiber — There appears to be an inverse association between whole
grain consumption and the risk of type 2 diabetes [84,102,103]. As an example, among males
and females participating in the Health Professionals Follow-up Study and the Nurses' Health
Study (NHS), high brown rice intake was associated with a lower risk of type 2 diabetes (RR 0.89,
95% CI 0.81-0.97 for two or more servings per week versus less than one serving per month)
[104]. In contrast, consumption of white rice was associated with a higher risk of type 2 diabetes
(RR 1.17, 95% CI 1.02-1.36). A meta-analysis of prospective cohort studies showed that high
intake of white rice was more strongly associated with risk of type 2 diabetes in Asian than
Western populations (RR 1.55, 95% CI 1.20-2.01 versus 1.12, 95% CI 0.94-1.33, for highest versus
lowest category of white rice intake) [105]. Consumption levels of white rice were much lower
overall in the Western populations (112.9 versus 5.3 g/day for high and low intake groups
compared with ≥750 versus <500 g/day for Asian populations). The meta-analysis was limited by
significant heterogeneity in the size of the effect estimates obtained.

Some of the beneficial reduction in type 2 diabetes associated with intake of whole grains may
be mediated by cereal fiber [103]. Cereal fiber is linked to a reduced risk of type 2 diabetes [106-
108]. Increased insoluble fiber consumption for three days improved insulin sensitivity in a
randomized cross-over study of 17 overweight subjects with normal glucose metabolism [109].

Fruit — Increased consumption of fruit has not been associated consistently with a decreased
risk of developing type 2 diabetes [110,111]. The heterogeneity in the findings may be due to
the differences in patient populations, study design, or even to the type of fruit consumed. In
one study, greater consumption of specific fruits (blueberries, grapes, apples, bananas, and
pears) was significantly associated with a reduced risk of type 2 diabetes, whereas greater
consumption of strawberries, cantaloupe, peaches, and oranges was not [112]. The glycemic
index of the individual fruits did not account for the differences in the associations.

Coffee and caffeinated beverages — Long-term coffee consumption may be associated with
a decreased risk of type 2 diabetes [85,113-117]. In a systematic review of nine cohort studies
(combined n = 193,473), compared with those with minimal coffee consumption (less than two
cups per day), diabetes risk was lowest in subjects who drank greater than six cups daily (RR
0.65, 95% CI 0.54-0.78) and significantly reduced for subjects who consumed four to six cups
daily (RR 0.72, 95% CI 0.62-0.83) [115]. These associations did not differ by sex, obesity, or
region including the United States, Europe, and Asia. A modest inverse association was also
seen for decaffeinated coffee.

A prospective study of over 88,000 women aged 26 to 46 years in the NHS found that the risk of
diabetes was lower even for small amounts of daily coffee consumption [118]. RR was 0.87 (95%
CI 0.73-1.03) for one cup per day, 0.58 (0.49-0.68) for two to three cups, and 0.53 (0.41-0.68) for
four or more cups, compared with non-drinkers. Associations were similar for non-caffeinated
and caffeinated coffee; tea consumption did not affect risk.

In contrast, in a survey of over 17,000 subjects age 40 to 65 years of age from Japan, where
diabetes prevalence has increased twofold in the past two decades, participants who frequently
drank green tea (six or more cups daily) were less likely to develop diabetes over a five year
follow-up period (odds ratio [OR] 0.67, 95% CI 0.47-0.94) [119]. The correlation with green tea
consumption was dose-related and reflected caffeine intake.

These observational data do not prove a cause-and-effect relationship, and we do not

recommend increasing coffee or green tea intake as a prevention strategy.

Other

● In meta-analyses of prospective cohort studies, there was a lower risk of type 2 diabetes in
both males and females with higher magnesium intake [107,120]. Sources of dietary
magnesium include nuts, whole grains, and green leafy vegetables.

● Moderate alcohol intake (defined for females and males as <2 and <3 drinks per day,
respectively) has also been associated with a lower risk of type 2 diabetes. (See "Overview
of the risks and benefits of alcohol consumption", section on 'Diabetes mellitus'.)

ENVIRONMENTAL EXPOSURES

Epidemiologic studies have reported an increased risk of type 2 diabetes after exposure to
some environmental toxins and contaminants [121-124]. As examples:

● Chronic exposure to inorganic arsenic in drinking water (adjusted odds ratio [OR] 3.58,
95% CI 1.18-10.83, for type 2 diabetes in individuals at the 80th versus the 20th percentiles
for the level of total urinary arsenic) [125]. (See "Arsenic exposure and poisoning".)

● Exposure to bisphenol A, a monomer used to make hard, polycarbonate plastics, and

some epoxy resins (adjusted OR 1.39, 95% CI 1.21-1.60, per one standard deviation
increase in urinary bisphenol A concentration) [126]. (See "Occupational and
environmental risks to reproduction in females: Specific exposures and impact", section on
'Bisphenol A and other phenols'.)

● Chronic exposure to organophosphate and chlorinated pesticides (OR 1.17, 95% CI 0.99-
1.38, for type 2 diabetes in those with the highest quartile of cumulative days of use
compared with lowest quartile) [127].

MEDICATIONS

A large number of drugs can impair glucose tolerance or cause overt diabetes mellitus; they act
by decreasing insulin secretion, increasing hepatic glucose production, or causing resistance to
the action of insulin ( table 2). This topic is reviewed elsewhere. (See "Pathogenesis of type 2
diabetes mellitus", section on 'Drug-induced hyperglycemia'.)

MEDICAL CONDITIONS ASSOCIATED WITH INCREASED RISK

Gestational diabetes — The risk for type 2 diabetes is higher in women who have had
gestational diabetes [128-131]. These women have defects in both insulin secretion and insulin
action, the severity of which correlate with the future risk of diabetes [128,129]. In a meta-
analysis of observational studies, the cumulative incidence of type 2 diabetes in women with
and without gestational diabetes was 16 and 2 percent, respectively, by 10 years (RR 8.09, 95%
CI 4.34-15.08) [131]. (See "Gestational diabetes mellitus: Glucose management and maternal
prognosis", section on 'Maternal prognosis'.)

Cardiovascular disease — Heart failure and myocardial infarction (MI) appear to be associated
with an increased risk of type 2 diabetes. In one study of 2616 nondiabetic patients with
coronary artery disease, those with advanced heart failure (New York Heart Association [NYHA]
class III) had nearly twice the risk of developing diabetes during 6 to 12 years of follow-up (17
versus 8 percent in NYHA class I patients; relative risk [RR] 1.7, 95% CI 1.1-2.6) [132]. Worsening
obesity is an unlikely explanation, as weight loss is common in severe heart failure. (See "Heart
failure: Clinical manifestations and diagnosis in adults".)

Similar findings were noted in a retrospective analysis of 8291 nondiabetic patients with MI
[133]. During a mean observation period of three years, 12 percent developed diabetes,
representing an annual incidence rate of 3.7 percent compared with 0.8 to 1.6 percent in
population-based cohorts. Independent predictors of diabetes included markers of metabolic
dysfunction (body mass index [BMI], hypertension, high triglycerides, low high-density
lipoprotein [HDL], smoking) and medications (diuretics, beta blockers, lipid-lowering drugs).

In some studies, there has also been an association between elevated blood pressure and
increased risk of developing type 2 diabetes [134,135]. As an example, in one large prospective
cohort study, women with self-reported high-normal (130 to 139/85 to 89 mmHg) and elevated
(≥140/90 mmHg or on antihypertensive therapy) blood pressure were at increased risk of
developing diabetes compared with women with normal blood pressure (multivariate adjusted
hazard ratios [HRs] 1.4 [95% CI 1.2-1.7] and 2.0 [95% CI 1.8-2.3] for high-normal and elevated
blood pressure, respectively) [135]. The association persisted after adjustment for several
metabolic dysfunction variables, such as BMI, hypercholesterolemia, age, exercise, smoking,
and family history of diabetes. However, these results do not prove causality, and other
confounders not controlled for during statistical analysis (insulin resistance or other genetic
polymorphisms linking endothelial dysfunction, inflammation, and type 2 diabetes) may explain
the observed association.

Hyperuricemia — Several prospective studies have found an association between higher levels
of serum uric acid and an increased risk of developing type 2 diabetes [136-140]. After
controlling for other diabetes risk factors (eg, BMI, alcohol consumption, smoking, physical
activity) the RR was attenuated but remained significant. Proposed mechanisms for such an
increase in risk include development of endothelial dysfunction, oxidative stress, and insulin
resistance [86]. Although the association is plausible, these observational studies do not prove
causality.

Polycystic ovary syndrome — Polycystic ovary syndrome is associated with an increased risk
for type 2 diabetes, independent of BMI, particularly in women with a first degree relative with
type 2 diabetes. This topic is reviewed separately. (See "Clinical manifestations of polycystic
ovary syndrome in adults", section on 'IGT/type 2 diabetes'.)

Metabolic syndrome — Patients with the metabolic syndrome, including those without
hyperglycemia as an element of the definition, are at particularly high risk for type 2 diabetes.
(See "Metabolic syndrome (insulin resistance syndrome or syndrome X)", section on 'Risk of type
2 diabetes'.)

OTHER

Breastfeeding — Breastfeeding has been associated with a decreased risk of maternal type 2
diabetes [141,142]. As an example, in two large cohorts from the Nurses' Health Study (NHS),
with data collected prospectively in 83,585 parous women and retrospectively in 73,418, each
additional year of lactation reduced the risk of diabetes in women who had been pregnant
within the prior 15 years by 14 to 15 percent [141]. Risk reduction began to accrue with a
minimum of six months of lactation, and longer durations of breastfeeding per pregnancy were
associated with a greater benefit. In this study, the incidence of diabetes in women with a
history of gestational diabetes was not affected by lactation. However, in a subsequent
prospective study of women with recent gestational diabetes, breastfeeding reduced the two-
year incidence of type 2 diabetes mellitus [143]. (See "Gestational diabetes mellitus: Obstetric
issues and management", section on 'Breastfeeding'.)

Endogenous sex hormones — Levels of endogenous sex hormones may influence the risk of
type 2 diabetes differently in males and females. A systematic review found that, after adjusting
for body mass index (BMI), high testosterone levels were associated with an increased risk for
type 2 diabetes in women but a decreased risk in men [144]. Decreased levels of sex hormone-
binding globulin (SHBG) were associated with an increased risk for type 2 diabetes; this
association was stronger in women than in men. In a subsequent study that included a
genotype analysis, SHBG polymorphisms were associated with plasma levels of SHBG and were
predictive of risk of type 2 diabetes in males and females [145]. Carriers of an rs6257 allele had
lower plasma levels of SHBG and increased risk of type 2 diabetes, whereas carriers of an
rs6259 variant allele had higher plasma levels and lower risk. Sex differences in the action of
testosterone on lipolysis, and the production of cytokines such as tumor necrosis factor alpha,
have been suggested.

PREDICTION MODELS

There are several diabetes-prediction models that incorporate clinical risk factors and/or
metabolic factors to generate a prediction score [146]. These models vary in complexity and
most have not been validated in varied populations.

Simple clinical models may be more effective in predicting diabetes than complex models
[147,148]. As an example, in the Framingham Offspring Study, several models to predict
incident diabetes were compared [148]. The simple clinical model included information typically
available at clinic evaluations, such as age, parental history of diabetes, body mass index (BMI),
blood pressure, high-density lipoprotein (HDL), triglycerides, and impaired fasting glucose (IFG).
Each of the metabolic syndrome traits (elevated blood pressure and triglyceride concentrations,
low HDL levels, and IFG), obesity, and parental history were highly associated with developing
diabetes. Adding more complex measurements (oral glucose tolerance, insulin sensitivity,
insulin resistance) did not improve the model, nor did adding a genotype score based upon the
presence of a number of risk alleles confirmed to be associated with type 2 diabetes [149].

In other models, the addition of genetic data to the simple clinical model (and other clinical
models) had a minimal effect on prediction of type 2 diabetes [150,151]. In one such model,
genetic data were incorporated based upon low and high genetic risk groups (quintiles with the
lowest and highest number of risk alleles, respectively) [150]. The improvement in prediction
was too small to allow for individual risk prediction. Thus, at the current time, there is
insufficient evidence to support genotyping for risk assessment in clinical practice.

The genetics of type 2 diabetes, including a discussion of the risk alleles confirmed to be
associated with it, are reviewed elsewhere. (See "Pathogenesis of type 2 diabetes mellitus",
section on 'Genetic susceptibility'.)
SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Diabetes mellitus in
adults" and "Society guideline links: Diabetes mellitus in children".)

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics."
The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading
level, and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and who prefer
short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more
sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading
level and are best for patients who want in-depth information and are comfortable with some
medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print
or e-mail these topics to your patients. (You can also locate patient education articles on a
variety of subjects by searching on "patient info" and the keyword(s) of interest.)

● Basics topics (see "Patient education: Type 2 diabetes (The Basics)" and "Patient education:
Treatment for type 2 diabetes (The Basics)" and "Patient education: Lowering your risk of
prediabetes and type 2 diabetes (The Basics)")

● Beyond the Basics topics (see "Patient education: Type 2 diabetes: Overview (Beyond the
Basics)" and "Patient education: Type 2 diabetes: Treatment (Beyond the Basics)" and
"Patient education: Exercise and medical care for people with type 2 diabetes (Beyond the
Basics)")

SUMMARY

● Abnormal glucose metabolism – Patients with impaired fasting glucose (IFG), impaired
glucose tolerance (IGT), or a glycated hemoglobin (A1C) level of 5.7 to 6.4 percent (39 to 46
mmol/mol) are at increased risk of developing type 2 diabetes ( table 1). Patients with
both IFG and IGT have hepatic and muscle insulin resistance, which confers an increased
risk of progressing to diabetes compared with having only one abnormality. Although
 most of the high risk groups have been defined categorically (eg, IFG or IGT), the risk for
developing diabetes follows a continuum across the entire spectrum of subdiabetic
glycemic values. Higher fasting or two-hour oral glucose tolerance test (OGTT) values or
higher A1C values convey higher risk than lower values. (See 'Abnormal glucose
metabolism' above.)

● Clinical risk factors

• Obesity – Obesity is the most important modifiable risk factor for type 2 diabetes. (See
'Obesity' above.)

• Genetic susceptibility – Genetic susceptibility is an important contributor to the risk of

developing diabetes. Insulin resistance and impaired insulin secretion in type 2
diabetes have a substantial genetic component. (See "Pathogenesis of type 2 diabetes
mellitus", section on 'Genetic susceptibility'.)

• Lifestyle factors – Insulin resistance and impaired insulin secretion can also be
influenced, both positively and negatively, by behavioral factors, such as physical
activity, diet, smoking, alcohol consumption, body weight, and sleep duration. (See
'Lifestyle factors' above and 'Dietary patterns' above.)

● Dietary patterns – Adherence to a diet high in fruits, vegetables, nuts, whole grains, and
olive oil is associated with a lower risk of type 2 diabetes. (See 'Mediterranean diet' above.)

● Medical conditions – Medical conditions associated with an increased risk of type 2

diabetes include gestational diabetes, polycystic ovary syndrome, and metabolic
syndrome. (See 'Medical conditions associated with increased risk' above.)

● Prevention – Identification of individuals at risk for diabetes is important as lifestyle

modification (predominantly exercise and weight loss) successfully decreases the
development of diabetes. (See "Prevention of type 2 diabetes mellitus".)

ACKNOWLEDGMENT

The UpToDate editorial staff acknowledges David McCulloch, MD, who contributed to earlier
versions of this topic review.

Use of UpToDate is subject to the Terms of Use.

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Topic 1771 Version 63.0
GRAPHICS

Categories of increased risk for diabetes (prediabetes)*

FPG 100 to 125 mg/dL (5.6 to 6.9 mmol/L) – IFG

2-hour post-load glucose on the 75 g OGTT 140 to 199 mg/dL (7.8 to 11.0 mmol/L) – IGT

A1C 5.7 to 6.4% (39 to 46 mmol/mol)

FPG: fasting plasma glucose; IFG: impaired fasting glucose; OGTT: oral glucose tolerance test; IGT:
impaired glucose tolerance; A1C: glycated hemoglobin.

* For all 3 tests, risk is continuous, extending below the lower limit of the range and becoming
disproportionately greater at higher ends of the range.

Reprinted with permission from the American Diabetes Association. Standards of medical care in diabetes—2011. Diabetes Care
2011; 34:S11. Copyright © 2011 American Diabetes Association. Table also published in: American Diabetes Association. Standards
of medical care in diabetes—2013. Diabetes Care 2013; 36 Suppl 1:S11. The content within this table is still current as of the 2020
version of the Standards of Medical Care in Diabetes.

Graphic 82479 Version 16.0

Importance of body weight and exercise on development of type 2 diabetes

Adjusted incidence of type 2 diabetes mellitus in 5990 males in relation to BMI (in kg/m 2 ) and the level of
physical activity (in kcal/week). The risk of type 2 diabetes was directly related to BMI, while regular
exercise was protective except for in males with a BMI below 24 kg/m 2 .

BMI: body mass index.

Data from: Helmrich SP, Ragland DR, Leung RW, Paffenbarger RS Jr. Physical activity and reduced occurrence of non-insulin-
dependent diabetes mellitus. N Engl J Med 1991; 325:147.

Graphic 79316 Version 5.0

Obesity and fat distribution impair glucose tolerance

Serial changes in blood glucose concentrations during an oral glucose tolerance test in 9 patients with
upper body obesity, 16 patients with lower body obesity, and 9 control subjects without obesity. The
groups with obesity had impaired glucose tolerance, but the abnormality was more pronounced in the
group with upper body obesity. The degree of glucose intolerance underestimated the degree of insulin
resistance since peak serum insulin concentrations were also much higher in the group with upper body
obesity (225 microU/mL versus 115 and 65 microU/mL in the other 2 groups). To convert blood glucose to
mmol/L, divide by 18; to convert serum insulin to pmol/L, multiply by 6.

Data from: Kissebah A, Vydelingum N, Murray R, et al. Relation of body fat distribution to metabolic complications of obesity. J Clin
Endocrinol Metab 1982; 54:254.

Graphic 56394 Version 3.0

Drugs that can impair glucose tolerance or cause overt diabetes mellitus

Category Agents Mechanism*

Anti-infectives

Fluoroquinolones Gatifloxacin ¶ (not available in Altered insulin secretion.

United States), moxifloxacin Association with moxifloxacin is
rare.

HIV antiretrovirals Protease inhibitors Increased peripheral insulin

resistance. Part of antiretroviral-
Nucleoside reverse transcriptase
associated metabolic syndrome.
inhibitors (NRTIs)

Other anti-infectives Pentamidine Altered pancreatic beta cell

function. Following initial
hypoglycemic effect, beta cell
destruction can occur.

Antipsychotics

First-generation Chlorpromazine ¶ , perphenazine, Mechanism not established.

other phenothiazines Appears to involve increased
insulin resistance and diminished
insulin secretion.

Second-generation Clozapine ¶ , iloperidone, Mechanism not established.

olanzapine ¶ , paliperidone, Appears to involve increased
quetiapine, risperidone insulin resistance and diminished
insulin secretion.

Cardiovascular

Beta blockers Atenolol, metoprolol, Decreased insulin sensitivity

propranolol [1] (moderate effect).

Carvedilol does not appear to

impair glucose tolerance.

Refer to UpToDate topic on

treatment of hypertension in
patients with diabetes mellitus.

Hypolipidemic Niacin (nicotinic acid) ¶ , statins Niacin – Altered hepatic glucose

metabolism, probably greater
with extended-release form.

Statins – Evidence of impaired

glucose tolerance due to statins
is conflicting, and overall risk
appears low.
 Thiazide diuretics Hydrochlorothiazide, Reduced total-body potassium,
chlorthalidone, chlorothiazide, decreased insulin secretion, and
indapamide increased insulin resistance [2] .

Infrequent with low dosages (ie,

hydrochlorothiazide ≤25 mg or
equivalent).

Potassium supplementation may

decrease thiazide-associated
glucose intolerance.

Vasodilators Diazoxide Reduced insulin secretion and

sensitivity, increased hepatic
glucose production.

Vasopressors Epinephrine ¶ , norepinephrine [3] Activation of glycogenolysis,

increased hepatic
gluconeogenesis, stimulation of
glucagon and cortisol, inhibition
of insulin secretion.

Gonadotropin-releasing Class effect in males receiving Refer to UpToDate topic on side

hormone agonists androgen deprivation therapy for effects of androgen deprivation
metastatic prostate cancer therapy.

Glucocorticoids, systemic* Class effect Multifactorial, including

increased hepatic glucose
NOTE: Glucocorticoids are a
production, increased insulin
particularly common cause of
resistance, increased expression
clinically significant drug-
of peroxisome proliferator
induced hyperglycemia
activated gamma receptors
(PPAR-gamma).

Refer to UpToDate topic on majo

side effects of systemic
glucocorticoids.

Hormones, growth Somatropin, tesamorelin Increased counterregulatory

responses.

Refer to UpToDate topics on

treatment of growth hormone
deficiency and treatment of HIV-
associated lipodystrophy.

Immune checkpoint inhibitors

Programmed cell death Nivolumab, pemprolizumab, PD-1 and PD-L1 inhibitors

receptor 1 (PD-1) inhibitors cemiplimab overcome immune suppression
of cytotoxic T cells in the tumor
milieu; CTLA-4 inhibitors
 Programmed cell death ligand
1 (PD-L1) inhibitors
Cytotoxic T-lymphocyte
associated protein 4 (CTLA-4)
inhibitors
Atezolizumab, avelumab,
durvalumab
Iipilimumab, tremelimumab
overcome immune suppression
of cytotoxic T cells in secondary
lymphoid tissues. Immune
checkpoint inhibitors promote
activation of cytotoxic T cells that
act "off target" to attack and
destroy islet cells.

Immunosuppressants Cyclosporine (cyclosporin), Decreased insulin synthesis and

sirolimus, tacrolimus release.

Refer to UpToDate topic on new-

onset diabetes after transplant in
renal transplant recipients.

* Degree or incidence of hyperglycemia is generally related to dose.

¶ Among agents listed, these have been more frequently associated with hyperglycemia and/or diabetes
mellitus.

Data from:
1. Sarafidis PA, Bakris GL. Antihypertensive treatment with beta-blockers and the spectrum of glycaemic control. QJM 2006;
99:431.
2. Luna B, Feinglos MN. Drug-induced hyperglycemia. JAMA 2001; 286:1945.
3. Thomas Z, Bandali F, McCowen K, Malhotra A. Drug-induced endocrine disorders in the intensive care unit. Crit Care Med
2010; 38:S219.

Graphic 67257 Version 13.0

Contributor Disclosures
R Paul Robertson, MD No relevant financial relationship(s) with ineligible companies to disclose. David
M Nathan, MD No relevant financial relationship(s) with ineligible companies to disclose. Katya Rubinow,
MD No relevant financial relationship(s) with ineligible companies to disclose.

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must
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