Norris SL, Carson S, Thakurta S, et al.

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Diabetes mellitus (diabetes) is a group of diseases characterized by high levels of blood glucose resulting from defects in insulin production, insulin action, or both.1 There are 4 main categories for the etiology of diabetes. Type 1 diabetes accounts for 5% to 10% of all diagnosed cases of diabetes and is the result of a failure of the pancreatic beta cells to produce insulin. The onset of type 1 diabetes is often in childhood or in young adulthood, but can occur in adults as well. Insulin treatment is required to supplement the body’s abnormally low or nonexistent endogenous insulin. Gestational diabetes is a form of glucose intolerance that is diagnosed during pregnancy and has important implications for the health of the mother (who has an increased risk of having or developing type 2 diabetes) and of the fetus and newborn. The third category consists of other specific types of diabetes caused by genetic defects in insulin action or beta cell function, diseases of the exocrine pancreas, endocrinopathies, and various other causes of impaired insulin secretion or action.2

The fourth category, type 2 diabetes, accounts for 90% to 95% of all diagnosed cases of diabetes. It is characterized by insulin resistance initially, but over time inadequate pancreatic production of insulin occurs. Type 2 disease is associated with obesity, family history of diabetes, history of gestational diabetes, impaired glucose tolerance or impaired fasting glucose, physical inactivity, and race or ethnicity.1

The prevalence and incidence of diabetes is increasing both in the United States and worldwide. The prevalence of diabetes in the United States for all ages is estimated at 7.8%, or 23.6 million people. Approximately 5.7 million of those cases are undiagnosed.1

The prevalence of type 2 diabetes varies among racial and ethnic groups: In non-Hispanic blacks 20 year or older the prevalence is 14.7%; Hispanic/Latino Americans, 9.5%; American Indians and Alaska natives, 14.2%; and non-Hispanic whites, 9.8%.1 The prevalence of type 2 diabetes is increasing among children and adolescents. True prevalence data are not available as yet; however, the percentage of children with newly-diagnosed diabetes who are classified as having type 2 diabetes has risen from <5% before 1994 to 30% to 50% subsequent to that year.3

Diabetes has a major impact on the health and welfare of affected individuals. Diabetes was the seventh leading cause of death listed on United States death certificates in 2006. This statistic likely underestimates the mortality rates from diabetes, which is often not listed on the death certificate of an affected person.1 Individuals with diabetes have an overall risk of death about twice that of individuals without diabetes.1 Heart disease is the leading cause of diabetes-related deaths. Adults with diabetes have a death rate from heart disease that is 2 to 4 times higher than adults without diabetes.1 The risk for stroke is 2 to 4 times higher among people with diabetes and two-thirds of people with diabetes die of heart disease or stroke. Diabetes is associated with other diseases and cardiovascular risk factors including hypertension.1

In addition to macrovascular sequelae, diabetes leads to numerous microvascular complications: Diabetes is the leading cause of end-stage renal disease and new cases of blindness among adults age 20–74 years; 60% to 70% of people with diabetes have peripheral neuropathy; more than 60% of nontraumatic lower limb amputations occur among persons with diabetes; periodontal disease is more common; and pregnancy is complicated.1 The cost of diabetes in America is enormous. It is estimated that the total costs (2007) are $174 billion, with direct medical costs accounting for $116 billion. The remainder of costs are indirect, including those attributed to disability, work loss, and premature mortality.1

Diabetes treatment

Diabetes is a chronic condition that requires continuing medical care and self-management in order to minimize the risk of complications and mortality. The goals of treatment are to (1) achieve optimal glycemic control; (2) reduce other cardiovascular risk factors, including hypertension, hyperlipidemia, and overweight and obesity; and (3) diminish complications such as heart disease, peripheral vascular disease, renal disease, and neuropathy.

Type 2 diabetes may be treated by diet and exercise, often combined with 1 or more oral hypoglycemic agents. Optimal treatment, however, may require the use of insulin with or without oral agents. Among adults with diagnosed diabetes, the current distribution of types of treatment is as follows: 12% use both insulin and oral drugs, 16% use insulin only, 57% use oral agents only, and 15% do not use pharmacotherapy.1


Prediabetes refers to the condition of having impaired fasting glucose, impaired glucose tolerance, or both. The term prediabetes was coined as it was recognized that both impaired fasting glucose and impaired glucose tolerance are associated with a significant risk of developing diabetes.4 Impaired fasting glucose is diagnosed when the fasting blood glucose level is elevated (100 to 125 mg/dL) after an overnight fast, but the glucose level does not fit criteria for diabetes (≥126 mg/dL). Impaired glucose tolerance is defined as blood glucose level of 140–199 mg/dL after a 2-hour oral glucose tolerance test (diabetes is diagnosed if the blood glucose level is ≥200 mb/dL).2

Prediabetes has a high prevalence: In 1988–1994, 33.8% of US adults aged 40 to 74 years had impaired fasting glucose, 15.4% had impaired glucose tolerance, and 40.1% had prediabetes (impaired fastng glucose, impaired glucose tolerance, or both).1 The risk increases with age and reaches a peak in people aged 60 to74 years. The risk also increases with increased body mass index.4

Prediabetes may be the most important risk factor for progression to type 2 diabetes. The cumulative 5- to 6-year incidence of developing type 2 diabetes in persons with either impaired glucose tolerance or impaired fasting glucose is 20% to 34%.5 The risk of diabetes is even higher among persons with both impaired glucose tolerance and impaired fasting glucose. Impaired glucose tolerance is associated with an increased risk for cardiovascular and all-cause mortality; the association with impaired fasting glucose is not as strong.5

Lifestyle changes can prevent or delay the onset of type 2 diabetes among high-risk persons. In the Diabetes Prevention Project (DPP),6 a lifestyle intervention decreased by 58% the development of diabetes at follow-up of over 3 years. Similar results were noted in the Diabetes Prevention Study.7

Pharmacotherapy, such as metformin, acarbose, and thiazolidinediones, has also been shown to delay the progression of prediabetes to diabetes. In the Diabetes Prevention Project6 metformin was particularly effective in persons 25 to 40 years of age and 50 to 80 pounds overweight. In the STOP-NIDDM trial8 acarbose decreased the risk of developing diabetes by 25% over 3 years.

In the Troglitazone in Prevention of Diabetes (TRIPOD) study, troglitazone was associated with a decrease in the progression to type 2 diabetes among Hispanic women with impaired glucose tolerance when compared with placebo after approximately 30 months of treatment and 8 months of post-treatment follow-up.9

Metabolic syndrome

The metabolic syndrome has been proposed as a compilation of metabolic disturbances that are risk factors for cardiovascular disease. The concept of the metabolic syndrome has existed for at least 80 years and terminology and definitions have evolved.10 In 1988 Reaven11 noted that several risk factors for cardiovascular disease commonly cluster together. He called this cluster syndrome X; its components are dyslipidemia, hypertension, and hyperglycemia.

Today the term “metabolic syndrome” is most frequently used for the cluster of cardiovascular risk factors that co-occur in individuals more often than might be expected by chance. The abnormalities involved in the metabolic syndrome include glucose intolerance (type 2 diabetes, impared fasting glucose, or impaired glucose tolerance), insulin resistance, central obesity, dyslipidemia, and hypertension. A variety of definitions have been put forward10 that vary with respect to specific components as well as criteria.

The National Cholesterol Education Program’s Adult Treatment Panel III report (ATP III)12 identified 5 components of the metabolic syndrome (Table 1). The World Health Organization proposed a working definition of the metabolic syndrome in 1999, which differed somewhat from ATP III in that insulin resistance was a required component for diagnosis and a higher blood pressure was required.13 The American Association of Clinical Endocrinologists proposed a third set of clinical criteria, which appears to be a hybrid of the APTP III and the World Health Organization criteria.14 Efforts are underway to achieve a universal definition.10

Table 1

Table 1

National Cholesterol Education Program’s Adult Treatment Panel III definition of the metabolic syndrome

The prevalence of the metabolic syndrome varies widely, in part due to differing definitions. Prevalence also varies between sexes and across ethnicities, geographic settings, and age. The prevalence in the United States was reported as 7% among persons 20 to 29 years, 44% among persons 60 to 69 years (data collected 1988–1994),15 and 4.2% among adolescents.16

The metabolic syndrome is associated with an increased risk of diabetes and cardiovascular disease.10 The risk of cardiovascular disease mortality in persons with the metabolic syndrome compared to those without is 2.26 in men and 2.78 in women.17

The pathogenesis of the metabolic syndrome has not been defined. It appears to be associated with obesity, insulin resistance, deregulation of adipocyte-derived hormones, a proinflammatory state, and other endocrine factors.18

Management of the metabolic syndrome involves careful appraisal of cardiovascular risk and appropriate management of the underlying risk factors.10


There are 2 thiazolidinediones approved for prescription use in the United States, rosiglitazone maleate (Avandia) and pioglitazone hydrochloride (Actos®) (Table 2). A third thiazolidinedione (Troglitazone) was removed from the market in 1999 due to adverse hepatic effects.

Table 2

Table 2

Characteristics of thiazolidinediones approved for use in the United States and Canada

Both rosiglitazone and pioglitazone are approved by the United States Food and Drug Administration for use in adults for the treatment of type 2 diabetes, either as monotherapy or in combination with insulin, metformin, or sulfonylurea when diet, exercise, and a single agent does not result in adequate glycemic control. Neither drug is currently approved for use in prediabetes or the metabolic syndrome.

The mechanisms of action of thiazolidinediones in lowering plasma glucose among persons with type 2 diabetes are thought to include the following: increase in insulin sensitivity, decrease endogenous glucose production and postprandial gluconeogenesis, increase fasting and postprandial glucose clearance, and have beneficial effects on beta-cell function.20 In addition to hypoglycemic effects, thiazolidinediones may have cardioprotective effects that are independent of glucose lowering and may be due to anti-oxidant, anti-inflammatory, or calcium channel-blocking properties.21 Much of the data for these mechanisms are based on animal models.

The glycemic effects of thiazolidinediones are thought to be mediated by binding to the peroxisome proliferators-activated receptor (PPAR) gamma receptors. These receptors are expressed in the liver, heart, adipose tissue, skeletal muscle, and smooth muscle, and endothelial cells of the vasculature of the kidneys and the gut.22

Other uses of thiazolidinediones

Thiazolidinediones have been studied in several other clinical conditions where insulin resistance is a central part of the pathophysiology. These conditions are not included in this review, although studies show that thiazolidinediones may be useful in these conditions:25 polycystic ovary syndrome,26 nonalcoholic steatohepatitis,27 and HIV-infected patients using antiretroviral therapy. Persons with these conditions are only included in this review if they have been diagnosied with one or more of prediabetes, type 2 diabetes, or the metabolic syndrome.

Scope and Key Questions

The objectives and scope of the updated report were modified from those of the original report. For this update, our objective was to update the recent Comparative Effectiveness Review produced by the Agency for Healthcare Research and Quality, Comparative Effectiveness and Safety of Oral Diabetes Medications for Adults with Type 2 Diabetes.28 The Agency for Healthcare Research and Quality report compared available oral medications for the treatment of adults with type 2 diabetes for efficacy, effectiveness, and adverse events. Studies that included comparison with insulin were excluded. The key questions for this Drug Effectiveness Review Project updated report were thus modified from the prior Drug Effectiveness Review Project report in order to address both within- and between-class comparisons encompassing rosiglitazone and pioglitazone.

The participating organizations of the Drug Effectiveness Review Project approved the following key questions for this update:

  1. For persons with type 2 diabetes, do pioglitazone and rosiglitazone differ from each other, from placebo, and from other oral hypoglycemic agents in the ability to reduce and maintain A1c levels?
  2. For persons with type 2 diabetes, do pioglitazone and rosiglitazone differ from each other, from placebo, and from other oral hypoglycemic agents in their effects on macrovascular and microvascular complications, and mortality from diabetes?
  3. (NOT UPDATED) For patients with prediabetes or the metabolic syndrome, do thiazolidinediones differ from one another or from placebo in improving weight control
    1. when used as monotherapy?
    2. when added to metformin?
  4. For persons with pre-diabetes or the metabolic syndrome, do pioglitazone and rosiglitazone differ from one another or from placebo in delaying or preventing the occurrence of type 2 diabetes?
  5. (NOT UPDATED) For patients with prediabetes or metabolic syndrome, is the use of different thiazolidinediones associated with reversal or slower progression of cardiac risk factors, including lipid levels, central obesity, or elevated blood pressure?
  6. For persons with type 2 diabetes what are the adverse events related to pioglitazone and rosiglitazone, and how do these differ from each other, from placebo, and from other oral hypoglycemic agents?
  7. (NOT UPDATED) How do thiazolidinediones compare to sulfonylureas in serious hypoglycemic events, functional status, and quality of life?
  8. Are there subgroups of persons with type 2 diabetes based on demographic characteristics or co-morbidities for which the benefits and adverse effects of pioglitazone or rosiglitazone differ from those in general populations, compared to each other and to other hypoglycemic agents?