Ординатура / Офтальмология / Английские материалы / Diabetes and Ocular Disease Past, Present, and Future Therapies 2nd edition_Scott, Flynn, Smiddy_2009

4Diabetes and Ocular Disease

Figure 1.1. Global prevalence of diabetes 2000–2025. (Source: King H. Diabetes Care. 1998;21:1414–1431.)

skyrocket to approximately 121.8 million over the next 25 years [2]. Most of the increase in total numbers of diabetic patients is expected to occur in developing countries. Worldwide, about 300 million people are expected to have diabetes by 2025, affecting 5.4% of the world’s population [3]. Changing dietary and exercise trends appear to play a major role in the increasing prevalence of diabetes mellitus. Figure 1.1 summarizes the changing prevalence of diabetes worldwide.

In the United States, diabetes mellitus has increased at a staggering rate. While in 1990, only 5 states reported an incidence of diabetes exceeding 6% of the population, by 1998, a total of 22 states reported an incidence of diabetes greater than 6% of the population (Fig. 1.2) [4]. In the United States, there are 18.2 million people (6.3% of the population) with diabetes [5]. The prevalence of diabetes in African Americans has doubled in slightly more than a decade to 18.2%, with type 2 accounting for nearly 95% of cases [6] as per estimates of 2002.

Figure 1.2. Diabetes trends in the United States: 1990–1998. (Source: Mokdad AH et al. Diabetes Care. 2000;23:1278–1283.)

Dyslipidemia

Microalbuminuria

Figure 1.3. The insulin resistance (metabolic) syndrome and its components. (Source: Groop et al. Front Horm Res. 1997;22:131–156.)

DIABESITY: THE METABOLIC SYNDROME

The increasing prevalence of obesity is a critical factor associated with the growing numbers of people with diabetes, particularly type 2 diabetes. The WHO has recognized what it refers to as a “global epidemic of obesity” that is emerging in developing nations. In the United States, the Centers for Disease Control estimates that about 65% of Americans are either overweight or obese with about 23% characterized as “obese” [7]. The prevalence of type 2 diabetes appears to be rising in parallel with the global trend towards obesity [8]. It has been estimated that a weight gain of 11 to 15 pounds increases the risk of diabetes by 50% [9]. Data suggest that this increase is particularly prevalent in women, with the age-adjusted prevalence of the metabolic syndrome increasing 24% in women and only 2% in men between the years 1988 and 1999 [10]. Obesity is a critical element of the “metabolic syndrome,” also referred to as “insulin resistance syndrome.” This entity combines insulin resistance, whether in the form of glucose intolerance or frank type 2 diabetes with a variety of factors. These factors include coronary heart disease (CHD), central or truncal obesity, hypertension, and dyslipidemia [11]. A model of the insulin resistance syndrome and its components is shown in Figure 1.3.

From a global perspective, the increasing incidence of the metabolic syndrome is due to changing dietary patterns, the trend toward obesity, and sedentary lifestyle. Interaction with other risk factors for diabetes has resulted in a changing pattern of public health and disease status. Figure 1.4 demonstrates how these interactions

Figure 1.4. The metabolic syndrome.

6Diabetes and Ocular Disease

Presence of classic symptoms (fatigue, thirst, polyuria) and:

Type 2 diabetes affects about 18 million Americans

Figure 1.5. Diabetes: diagnostic criteria.

lead to development of the metabolic syndrome and the impact on public health. In the past, nomenclature often referred to diabetes as juvenile-onset or adult-onset. Since the metabolic syndrome and obesity can also affect children and adolescents, the incidence of type 2 diabetes is accelerating in these populations as well. In one large U.S. metropolitan area, 33% of new cases of diabetes in adolescents were type 2, representing a ten-fold increase between 1982 and 1994 [12]. Just as in the adult population, the primary risk factor appears to be obesity [13]. Therefore, insulin deficient or type 1 diabetes versus insulin resistant or type 2 diabetes are better descriptors for these diseases.

As the medical understanding of diabetes improves, the diagnostic criteria have become more focused and better defined. Eighteen million Americans are classified as having type 2 diabetes mellitus determined by elevated plasma glucose levels and classic symptoms such as fatigue, polydipsia, polyphagia, and polyuria. Current definitions include an elevated fasting plasma glucose level greater than 126 milligrams per deciliter (mg/dL), or a random plasma glucose in excess of 200 mg/dL. These criteria are summarized in Figure 1.5.

An additional 41 million Americans are currently classified as pre-diabetic. These patients have a fasting plasma glucose level between 100 and 125 mg/dL, or an impaired glucose tolerance test. These individuals are at increased risk for atherosclerosis and eventual conversion to type 2 diabetes. Figure 1.6 shows the current diagnostic criteria for pre-diabetes.

PRE-DIABETES: THE HIDDEN EPIDEMIC

Currently, patients diagnosed with diabetes represent only the tip of the diabetic epidemic iceberg. Studies show that patients with impaired glucose tolerance (the

Impaired fasting glucose (IFG)

Fasting glucose 100–125 mg/dL

Impaired glucose tolerance (IGT)

2 h glucose in glucose tolerance test: 140–199 mg/dl

Pre-diabetes affects about 41 million Americans. They are at risk of accelerated atherosclerosis and type 2 diabetes.

Figure 1.6. Prediabetes: diagnostic criteria.

Age (years)

Figure 1.7. Prevalence of undiagnosed and diagnosed diabetes and impaired glucose tolerance (IGT) in a US population (20–74 year of age). (Source: Adapted from Harris ML. Diabetes Care. 1993;16:642–652.)

incidence of which is associated with advancing age) represent the largest group of potential diabetic patients. This represents an undiagnosed patient subgroup that far exceeds the number of diagnosed and undiagnosed persons with diabetes in the United States today (Fig. 1.7) [14].

Risk factors for type 2 diabetes are well recognized and include such uncontrollable issues as age, family history, and ethnicity. However, factors such as truncal obesity and dyslipidemia may be the result of physical inactivity and sedentary lifestyle (Fig. 1.8).

Prevention or delay of type 2 diabetes mellitus is of key concern when the population of persons with pre-diabetes is considered. Over a ten year period, 33% of patients with impaired glucose tolerance will progress to frank type 2 diabetes without intervention. Indeed, it is estimated that diabetes is undiagnosed in 30% to 50% of people with the disease and more than 50% of persons with newly diagnosed diabetes will have diabetic complications at the time of their diagnosis as a result of delayed detection. Obviously, delaying or reducing the conversion rate of people with pre-diabetes to type 2 diabetes would eliminate much of the end organ damage, and would reduce the great health care expense associated with treating these

Risk factors for type 2 diabetes

increasing age

overweight, especially central adiposity

physically inactive

family history of diabetes

high risk ethnic group

low birth weight

in women, child weighing >9 lbs at birth

medical conditions, e.g., PCOS, pancreatitis, hypertriglyceridemia, acanthosis nigricans

Figure 1.8. Risk factors for type 2 diabetes.

8Diabetes and Ocular Disease

Trial was discontinued 1 year early because of clear results

Figure 1.9. Diabetes Prevention Program preliminary results.

complications. The Diabetes Prevention Program (DPP) study looked at the role of the oral hypoglycemic agent metformin, as well as diet and exercise, in preventing progression to type 2 diabetes in patients with pre-diabetes. In the study, patients were divided into three groups. One was a control group. The second received metformin. The third group was treated with diet and exercise alone. While metformin was accompanied by a 31% reduction in the rate of development of disease, the diet and exercise group attained a 58% reduction. This decreased the rate of conversion to type 2 diabetes from 29% to 14% over a 3-year period [15]. This study confirms the fact that by addressing controllable risk factors, the rate of progression can be modified. The results of the DPP trial are summarized in Figure 1.9.

CONSEQUENCES OF DIABETES: COMPLICATIONS AND COSTS

Treatment of complications due to diabetes is a growing source of health care expenditures. While ophthalmologists focus on the retinal and ophthalmic complications of diabetes and their treatment costs, it is important to note that these represent only a fraction of the overall cost of uncontrolled diabetes. Chronic complications of diabetes include accelerated atherosclerosis and its associated macrovascular disease processes of CHD, stroke, and peripheral vascular disease. These are responsible for the majority of diabetes-associated morbidity and mortality. Peripheral and autonomic neuropathy, renal impairment and failure, and diabetic retinopathy are associated with the microvascular complications of diabetes. As an example, Haffner and colleagues compared the 7-year incidence of myocardial infarction (MI) in diabetic and nondiabetic subjects with and without prior CHD (Fig. 1.10). Their data suggest that diabetic patients without a previous MI have a higher risk of MI than nondiabetic patients who have had a previous history of MI. Persons with diabetes have a nearly seven-fold increase in heart disease compared to nondiabetic patients [16]. CHD is the number one cause of death in the

P<0.001.

*7-year incidence of fatal/nonfatal myocardial infarction in the East West Study.

Figure 1.10. Type 2 diabetes and coronary heart disease. (Source: Haffner SM et al. N Engl J Med. 1998;339:229–234.)

developed world, and accounts for over 500,000 deaths per year in the United States alone [17]. It is clear that the emerging diabetic epidemic facing the developing nations of the world will significantly change rates of CHD and associated mortality in coming years.

In the United States alone, the cost of treating uncomplicated diabetes is over 6 billion dollars per year. Acute complications of diabetes, such as emergent hypoglycemia or hyperglycemia, raise that cost significantly. The chronic complications of diabetes, as mentioned above, totaled over 44.1 billion dollars in 1997. That represented 10,071 dollars per each diabetic patient in the United States [18]. The total cost related to diabetic complications in the United States is estimated to be at least 100 billion dollars per year. Figure 1.11 shows that eye care expenditures are only a fraction of the total cost of treating diabetic complications in the United States.

Numerous studies have shown that the key to decreasing diabetic complications lies with strict glucose control. The Diabetes Control and Complications Trial (DCCT) has shown the benefits of intensive blood glucose control in patients with type 1 diabetes [19]. Intensive glucose control reduced the risk of developing

Figure 1.11. Cost of treating complications of diabetes. (Source: American Diabetes Association.

Diabetes Care. 1998;21:296–309.)

Figure 1.12. United Kingdom Prospective Diabetes Study: loss of long-term glycemic control. (Source: UKPDS. Lancet. 1998;352:837–853.)

retinopathy by 54%. Neuropathy was reduced by 60% and albuminuria by 54%, respectively. With regards to type 2 diabetes mellitus, the United Kingdom Prospective Diabetes Study (UKPDS) was a randomized clinical trial involving 3867 newly diagnosed patients with type 2 diabetes [20]. After 3 months of diet treatment alone, patients with a mean of two fasting plasma glucose concentrations of 6.1 to 15.0 mmol/L were randomly assigned to either an intensive glycemic control group or a conventional control group. This study showed a 21% reduction in risk for progression of diabetic retinopathy over a 12-year period in the intensive group. In addition, there was a 29% reduction in the need for retinal photocoagulation in the intensive group compared to the conventional group. Overall, there was a 37% reduction in the risk of an adverse microvascular complication with intensive control that was less strict than current guidelines. The UKPDS study also demonstrated that glycemic control appears to diminish with time (Fig. 1.12). Clearly, the best indicator of glycemic control continues to be hemoglobin A1C (HgbA1C). Skyler and associates have demonstrated that HgbA1C levels correlate in a direct relationship with the relative risk of diabetic microvascular complications (Fig. 1.13) [21]. Strict glucose control, weight

Figure 1.13. Relationship of HbA1c to risk of microvascular complications. (Source: Skyler. Endocrinol Metab Clin. 1996;25:243–254, with permission.)

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Classification of Diabetic

Retinopathy

CHARLES P. WILKINSON, MD

CORE MESSAGES

•The prevalence of vision loss due to diabetic retinopathy can be expected to increase with growing numbers of patients with diabetes unless there is more effective screening of these patients.

•There is a need for improved communication between eye care professionals and physicians managing patients with diabetes.

•Development of a simplified classification system for diabetic retinopathy should lead to improved communication and improved patient outcomes.

•A 5-stage disease severity scale regarding diabetic retinopathy is proposed. This ranges from “no retinopathy” to “proliferative diabetic retinopathy.”

•A 3-stage severity scale regarding edema of the central macula is proposed, and this is based upon the location and extent of the retinal thickening.

Diabetes mellitus is a significant public health issue. The World Health Organization (WHO) has estimated that there are approximately 150 million people with this disorder and that this number could double by the year 2025 [1]. In the U.S., diabetes affects over 18.2 million people (6.3% of

the total population), and 800,000 new cases of type 2 diabetes are diagnosed each year [2]. As a frequent complication of diabetes, diabetic retinopathy can be expected to remain a significant cause of visual disability in an increasing number of patients.

In the U.S., diabetic retinopathy is the leading cause of blindness among adults aged 20 to 74 years of age; it is estimated that more than 10,000 individuals become legally blind from diabetic macular edema (DME) and/or proliferative diabetic retinopathy (PDR) each year [2]. The duration of diabetes is a strong

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