SECTION 1: The Clinical Challenges of Diabetes Management

Evidence of a Burgeoning Epidemic

In the United States, the interrelationship between weight gain, obesity, and diabetes mellitus (DM) and increased morbidity and death is well recognized. An estimated 300,000 deaths each year in the United States are attributed to obesity. Evidence-based medicine clearly demonstrates the connection between obesity and increased risk of type 2 DM (T2DM) diabetes.^1,2 In the United States, obesity prevalence increased from 12.0% in 1990 to 17.9% in 1998. This increase occurred in all states, regardless of sex, age, race, educational level, or smoking status.³ In 2000, 19.8% of the population was obese; diabetes prevalence was 7.3%, and 2.9% were obese and had diabetes.¹ These increases led researchers to suggest that the United States was trending toward an obesity epidemic.³

Worldwide diabetes prevalence also supports an epidemic description of diabetes for the first quarter of the 21st century. Over a 30-year period from 1995 to 2025, diabetes is projected to increase 122% from 135 million to 300 million adults, constituting a 35% increase in prevalence. In contrast, the worldwide population is expected to increase by 64%. The majority of people in developing countries with diabetes are 45 to 64 years of age, while most of those with diabetes in developed countries are 65 years and older.⁴

India, China, and the United States represent the 3 countries with the largest diabetes populations, and they are expected to retain these standings through 2025.

Prediabetes and Progression to T2DM

Table 1

In 1997 and 2003, the Expert Committee on Diagnosis and Classification of Diabetes identified an intermediate group of individuals whose glucose criteria did not specifically meet those for diabetes.⁵ Individuals within this group were diagnosed as having prediabetes; this classification was intended to alert patients and clinicians to their relatively high risk of developing diabetes and cardiovascular disease (CVD). These patients had impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) (), which are often associated with obesity (particularly visceral adiposity), dyslipidemia, hypertriglyceridemia, low high-density lipoprotein cholesterol (HDL-C), and hypertension. Glycosylated hemoglobin (A1C) level is routinely used in practice as a diagnostic criterion for diabetes in patients with CVD risk factors. When the committee met in 2009, they did not formally identify an intermediate A1C category; however, they noted that patients with A1C levels above normal but less than the diabetes threshold (6.0%-6.5%) were at very high risk of developing T2DM.⁵ Patients with an A1C level between 6.0% and 6.5% were more than 10 times more likely to develop T2DM than those with lower A1C levels. Increased diabetes risk is continuous, becoming disproportionately greater approaching the upper range limits as depicted in Table 1. Evidence indicates that when adjusted for age, sex, and follow-up duration, the relative risk of progressing from prediabetes to T2DM is 10.0 for patients with isolated IFG, 10.9 for patients with isolated IGT, and 39.5 for patients with both IFG and IGT compared with those with normal fasting glucose levels.⁶ For every 0.5% increase above the nondiabetic A1C mean (5.0% ±0.5%), the risk of developing diabetes nearly doubles.⁵

Risk Factors for T2DM

Figure 1

Increasing age: In general, the risk of developing T2DM increases with age. Among people 20 years and older, 23.5 million or 10.7% have diabetes; of those 60 years and older, 12.2 million or 23.1% have T2DM ().⁷ To determine the prevalence of T2DM among US adolescents, a total of 4370 subjects aged 12 to 19 years with self-reported diabetes and 1496 without self-reported diabetes (who fasted for at least 8 hours) were interviewed. A total of 0.5% of the full sample reported having diabetes. Of those, approximately 71% were categorized as having type 1 DM and 29% were characterized as having T2DM; of the 1496-patient subset, approximately 11% had IFG. Using these data, it was estimated that 39,005 US adolescents have T2DM and 2,769,736 have IFG.⁸P <.01).⁹ Age independently affects β-cell function, and may itself contribute to increased T2DM prevalence in older patients.¹⁰

Based on National Health Interview Survey data from 1997 to 2003, the multivariate-adjusted incidence of diabetes increased 41% in 6 years (

Increasing weight, decreasing activity: Increased intraabdominal fat plays a role in the insulin resistance associated with aging. The precise mechanisms by which visceral adiposity contributes to decreased insulin sensitivity and loss of beta-cell function are not entirely known; however, they may be mediated through free fatty acids. Hormones such as leptin, adiponectin, tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6) secreted by adipocytes may play a role, as many of them have both peripheral and central effects.¹⁰ Specifically, TNF-alpha and IL-6 stimulate the release of c-Jun amino-terminal kinases, which directly impairs insulin activity.¹¹

In addition, the leptin signaling pathway is particularly important in regulating human energy homeostasis. Defects in this pathway and leptin resistance have been implicated in excessive weight gain and obesity.¹² From 1967 to 1976 and 1987 to 1996, the prevalence of T2DM in Pima Indians aged 15 to 19 years increased 6-fold. Of African American and white youth in Ohio aged 10 to 19 years, 33% of all those with diabetes had T2DM, were obese, were members of minority populations, and had a family history of T2DM.¹³ Poor diet and lack of physical activity, which contribute to weight gain, have been cited together as the second leading modifiable risk factor for death.¹⁴ Such modifiable risk factors can be controlled to prevent middle-aged obesity, and evidencebased examples emphasize potential for success.¹⁵ In a 12-year study designed to investigate dietary influences on T2DM development, a Western diet (ie, more red and processed meats, french fries, high-fat dairy products, refined grains, sweets, and desserts) combined with low physical activity or obesity was associated with a high risk of T2DM, as opposed to a more prudent diet (ie, more vegetables, fruit, fish, poultry, and whole grains).¹⁶

Special populations: The National Health and Nutrition Examination Survey (NHANES) from 1999 to 2002 compared diagnosed and undiagnosed diabetes prevalence against data from 1988 to 1994 and found that minority groups were disproportionately affected by diabetes. While the prevalence of undiagnosed diabetes by race/ethnicity was similar, the prevalence of diagnosed diabetes was double that in non-Hispanic blacks and Mexican Americans compared with non-Hispanic whites.¹⁷ A comparable community-level study (NYC HANES) was undertaken by New York City (NYC) in 2004. In NYC, Asians had the highest prevalence of diabetes (16.1%) compared with all NYC adults (12.5%). Although 32.4% of Asians had IFG (compared with 23.5% of all NYC adults), they were significantly less likely to be obese.¹⁸

Consistent metabolic abnormalities have been identified as characteristic of schizophrenia, and because such abnormalities are associated with second generation antipsychotics, there is increased interest in this research. One study assessed metabolic abnormalities in patients with schizophrenia at 4 specific intervals: (1) at first episode or baseline (<1.5 years); (2) during recent onset (1.5 to 10 years); (3) sub-chronic stage (10 to 20 years); and (4) chronic stage (>20 years). Compared with the general population, the prevalence of diabetes in patients with schizophrenia increased dramatically and linearly-from 1.6% in those aged 15 to 25 years to 19.2% in those aged 55 to 65 years.¹⁹

Genetic and family risk: Genetic defects in beta-cell function or insulin action can result in diabetes, and relative risk of T2DM is significantly higher with a direct familial genetic association.^16,20 In general, 1 parent with diabetes accounts for a 40% lifetime diabetes risk, while both parents with diabetes elevates lifetime risk of diabetes to between 80% and 100%. Identical twins with diabetes generally develop the disease within a few years of each other, and overall lifetime risk of an identical twin developing T2DM after the other is 70% to 100%.

Table 2

Metabolic syndrome: The metabolic syndrome comprises a constellation of emerging and habitual lifestyle risk factors that include, but are not necessarily limited to, visceral adiposity, atherogenic dyslipidemia, hypertension, insulin resistance, and prothrombotic and pro-inflammatory states. It is closely associated with impaired and dysfunctional insulin actions such as insulin resistance.²¹ The National Cholesterol Education Program Expert Panel identified the metabolic syndrome criteria, and established that concomitance of any 3 of its comorbidities is diagnostic for the condition ().^21,22

Prediabetes: Most studies support that insulin resistance precedes hyperglycemia. In the early stages of T2DM, glucose levels remain normal due to increased insulin secretion (hyperinsulinemia) via compensatory beta-cell function. Over time, beta-cells can no longer compensate by maintaining a hyperinsulinemic state, leading to increased levels of postprandial glucose, increased hepatic glucose production, and clinical diagnosis of T2DM. Continued insulin resistance and decline in β-cell function result in overt T2DM.²³

Diabetes Contributes to Burgeoning Clinical Burden

The comorbidities of diabetes are well documented and include microvascular, macrovascular, and combined etiologies, many of which stem from dyslipidemia, hypertriglyceridemia, and hypertension. Heart disease and stroke are 2 to 4 times more likely in patients with diabetes compared with those without diabetes. In 2004, heart disease and stroke were listed 68% and 16% of the time, respectively, as comorbidities on diabetes-related death certificates in people greater than 65 years of age. Among adults 20 to 74 years of age, diabetes is the leading cause of blindness, and it results in 12,000 to 24,000 new retinopathy cases every year. Diabetes is the leading cause of new kidney disease and resulted in 44% of reported cases in 2005. That same year, in the United States and Puerto Rico, 178,689 people were living with end-stage renal disease and on chronic dialysis or had a kidney transplant due to diabetes. Approximately 60% to 70% of patients with diabetes have a diabetes-related neuropathy, and more than 60% of nontraumatic lower-limb amputations (about 71,000 in 2004) occur in patients with diabetes.²⁴ In 2007, the cost of treating only chronic diabetes-related complications in the United States was estimated at 58 billion dollars.²⁵

The Growing Economic Burden of Diabetes in the United States

Diabetes is the fifth leading disease that causes death in the United States; it also increases morbidity by increasing the risk for heart disease, blindness, kidney failure, extremity amputations, and other chronic conditions. Based on national health survey data, direct medical costs and indirect costs attributable to diabetes in 2002 were estimated at 132 billion US dollars. Direct medical costs alone totaled 91.8 billion US dollars: 23.2 billion for diabetes care, 24.6 billion for chronic diabetes complications, and 44.1 billion for excessive prevalence of general medical conditions.²⁶ Major expenditure groups by service settings consisted of inpatient days (43.9%), nursing home care (15.1%), and office visits (10.9%). Of the direct medical expenditures, 51.8% were incurred by people over 65 years of age. Indirect expenditures totaled 39.8 billion US dollars, and were attributable to lost workdays, restricted activity days, mortality, and permanent disability due to diabetes.²⁶

How Well Are We Managing T2DM?

The results of a recent self assessment survey demonstrate that most patients with T2DM feel they have "good" control over their blood glucose levels.²⁷ Generally, A1C levels less than 7% are considered acceptable measures of glycemic control. Recently, Ford et al conducted a study of A1C measures in 1334 patients with diabetes to assess A1C trends from 1999 through 2004. Of participants surveyed, in 1999 to 2000, 2001 to 2002, and 2003 to 2004, diabetes was diagnosed in 70.2%, 68.5%, and 74.6%, respectively. The geometric mean A1C concentration in 2003 to 2004 was lower than that of 1999 to 2000, and the percentage of diagnosed diabetic participants with A1C concentrations less than 7% increased significantly from 1999 (37.0%) to 2004 (56.8%). Compared with 1999 to 2000 NHANES participants, participants from 2001 to 2002 and those from 2003 to 2004 were more likely to have an A1C level less than 7% (adjusted prevalence ratios, 1.32 and 1.46, respectively) (P = .010 for linear trend). These results suggest that the concerted efforts of professional organizations and clinical practitioners may be positively affecting diabetes management, and they are consistent with other reports reflecting improved glycemic control in patients with diabetes in the United States. However, further assistance is required to help the approximately 40% of those with diabetes whose A1C levels are not well controlled.²⁸

Barriers to better diabetes management include factors related to patients, physicians, healthcare systems, and those related to the disease itself, such as its progressive nature which requires vigilant monitoring and an aggressive approach to therapy.²⁹ Patient issues include poor commitment to a proper diet and exercise plan, medication noncompliance, and fears of hypoglycemia and weight gain. Physician issues include lack of education or motivation, poor goal setting, time constraints, and poor communication skills. Healthcare system issues include lack of commitment to patient education, lack of support for the time (of doctor/healthcare practitioner) needed for good diabetes care, and limited formularies or difficulties accessing improved medication strategies.³⁰

Early Diagnosis, Intervention, and Therapeutic Optimization Can Improve Outcomes

Coupled with our failure to resolve societal issues of poor diet, physical inactivity, and obesity, the diabetes diagnosis is typically delayed, and in actual practice, therapy does not adequately address the progressive nature of the disease. These combined factors conspire against an aggressive, optimal approach to therapy. Testing and early intervention in prediabetes can prevent or delay manifestation of overt diabetes. Despite clear testing guidelines, however, the American Diabetes Association (ADA) estimates that nearly 25% of those with overt diabetes remain undiagnosed and therefore untreated.³¹

Clinical trials have demonstrated that CVD risk is often elevated before T2DM is diagnosed. Beginning in 1976, Hu et al followed 117,629 female nurses aged 30 to 55 years for 20 years. They documented 1556 new myocardial infarctions (MI), 1405 strokes (of which 300 were fatal), and 815 coronary heart disease fatalities. Among those who developed T2DM during follow-up and compared with those who developed T2DM, age-related relative risks (RRs) of MI were 3.75 for the period before diagnosis versus 4.57 for the period after diagnosis. The risk of stroke was significantly elevated (RR = 2.30) before T2DM diagnosis. Overall, data indicated that CVD risk was substantially elevated prior to T2DM diagnosis, suggesting that aggressive, multifactorial treatment with the goal of reducing macrovascular and microvascular risk factors secondary to diabetes is warranted in those at risk of T2DM.³²

Subsequent studies have indicated that aggressive, targeted, multifactorial intervention can significantly reduce modifiable CVD risk factors. The Steno-2 study compared the effects of targeted, intensified, multifactorial intervention (n = 80) with conventional therapy (n = 80) on modifiable CVD risk factors in patients (mean age, 55.1 years) with T2DM and microalbuminuria. Intensive treatment comprised stepwise implementation of behavioral modification and pharmacologic therapy (including aspirin for secondary CVD prevention) targeting hyperglycemia, hypertension, dyslipidemia, and microalbuminuria. After a mean follow-up of 7.8 years, levels of A1C, blood pressure, cholesterol, and triglycerides and albumin urinary excretion rate were significantly lower in the intensive treatment group compared with the conventional treatment group. The intensive treatment group also had significantly lower risk of CVD, nephropathy, retinopathy, and autonomic neuropathy. Overall, intensified, multifactorial intervention reduced CVD and microvascular events by approximately 50%.³³

Unfortunately, as these researchers also concluded, the exact roles and impact of specific interventions could not be determined due to study design. Duplicating their findings could prove problematic because numerous guidelines call for multiple risk factor reduction through similar, but not identical, strategies. More recent results, from well-known diabetes studies such as ADVANCE (Action in Diabetes and Vascular Disease), ACCORD (Action to Control Cardiovascular Risk in Diabetes), and VADT (Veterans Affairs Diabetes Trial), have suggested that lowering glycemic targets to nearnormal levels over the short term does not further reduce cardiovascular events in long-standing T2DM.^34-36 Also, in patients with ischemic heart disease, hypoglycemia should be avoided,³⁷ because this may have contributed in part to the lack of benefit observed in the aforementioned clinical outcome trials.

Download PDF: SECTION 1: The Clinical Challenges of Diabetes Management