. REPORTS. Current Treatment Approaches to Type 2 Diabetes Mellitus: Successes and Shortcomings Francis M. Collins, MD Abstract ly 30%. The implications of these findings Diabetes mellitus affects approximately 17 mil- are profound in terms of long-term com- lion adults in the United States and has profound plications and their associated costs. Most implications in terms of long-term microvascular primary care providers and endocrinolo- and macrovascular complications and their associ- gists acknowledge that good glycemic con- ated costs. In type 2 diabetes, insulin resistance trol can prevent or at least delay many of and a relative β-cell defect are the underlying pathologic problems leading to hyperglycemia. the complications of diabetes. However, Notably, insulin resistance is also associated with prior to the Diabetes Control and 2 obesity, dyslipidemia, and hypertension. Diabetes Complications Trial (DCCT) and the can be defined as a disease of accelerated cardio- United Kingdom Prospective Diabetes vascular deterioration associated with elevated Study (UKPDS),3 limited evidence was blood glucose levels. Glycemic control has been available to support this belief. Earlier shown to reduce the long-term complications studies failed to show a significant preven- associated with diabetes. Although medical nutri- tive benefit, for the most part because the tion therapy and appropriately prescribed definitions of good glycemic control used increased physical activity are important compo- in the studies were set too high. Even for nents of a diabetes management plan, most those who believed that tight glycemic patients need medication to lower glucose to near- normal levels. Therapeutic options for treating control was beneficial, therapeutic choic- hyperglycemia include sulfonylureas and other es for monitoring and treating hyper- insulin secretagogues, biguanides, α-glucosidase glycemia were limited. inhibitors, thiazolidinediones, and insulin. An Today, many new therapies with differ- antidiabetic agent that improves insulin sensitivity ent mechanisms of action are available for is an excellent choice for early treatment of type 2 treating hyperglycemia in patients with diabetes because it may delay or prevent compli- type 2 diabetes mellitus, although the cations associated with this disease. Because of increase in therapeutic options also the progressive nature of type 2 diabetes, aggres- increases the complexity of decision mak- sive intervention early in the course of the disease, ing. In this article, the pathogenesis of type including combination therapy, is often necessary. 2 diabetes is reviewed and the advantages (Am J Manag Care. 2002;8:S460-S471) and disadvantages of the various antidia- betic drug classes are discussed to identify the appropriate role for each drug class. iabetes mellitus affects approxi- . PATHOGENESIS OF TYPE 2 mately 17 million adults in the DIABETES. D United States, with the majority of these patients having type 2 diabetes mel- Type 2 diabetes mellitus is a complex, litus.1 In the past decade, the prevalence chronic, metabolic disease resulting from of diabetes has increased by approximate- insulin resistance in target tissues (prima- S460 THE AMERICAN JOURNAL OF MANAGED CARE OCTOBER 2002 Current Treatment Approaches to Type 2 Diabetes Mellitus: Successes and Shortcomings rily adipose, muscle, and liver) and impaired β-cell function.4 Insulin resist- Table 1. Criteria for the Diagnoses of Diabetes, Impaired ance is an early measurable defect in the Fasting Glucose, and Impaired Glucose Tolerance majority of patients who are destined to develop type 2 diabetes and often pre- Diabetes ■ Plasma glucose level ≥200 mg/dL and symptoms of diabetes such cedes the onset of the disease by 1 to 2 as polyuria, polydipsia, or unexplained weight loss 5 decades. To compensate for the decrease OR in insulin-mediated glucose metabolism, ■ Fasting plasma glucose level ≥126 mg/dL the pancreas increases its secretion of OR ■ ≥ insulin. After a period of compensated 2-hour plasma glucose level 200 mg/dL during an oral glucose tolerance test (OGTT) insulin resistance, impaired glucose toler- β Impaired Fasting Glucose ance develops as -cell function begins to ■ Fasting plasma glucose level 110 mg/dL to 125 mg/dL decrease and insulin concentrations are Impaired Glucose Tolerance not sufficient to compensate for the ■ 2-hour plasma glucose level 140 mg/dL to 199 mg/dL during an insulin resistance, despite often continued oral glucose tolerance test (OGTT) above-normal insulin concentrations (ie, hyperinsulinemia). Ultimately, pancreatic Source: Reference 12. β-cell failure results in decreased insulin secretion. When these 2 defects, insulin resistance and β-cell failure, occur simul- taneously, hyperglycemia and overt clini- During the 1990s, several key studies cal type 2 diabetes result.6 demonstrated that lowering blood glucose Insulin resistance is strongly linked to levels in patients with diabetes significant- obesity, and insulin-resistant individuals ly reduced the incidence of microvascular exhibit pathophysiologic characteristics complications. The DCCT demonstrated such as dyslipidemia, hypertension, and that intensive treatment of patients with increased cardiovascular risk.7 Because of type 1 diabetes achieved a mean blood the association between insulin resistance glucose level of 155 mg/dL and hemoglo- and cardiovascular disease, medications bin A1c (HbA1c) level of 7.2%. The improve- that improve insulin resistance may be ment in glycemic control resulted in risk useful earlier in the treatment of type 2 reductions for retinopathy, nephropathy, diabetes.8 and neuropathy ranging from 35% to more than 70% compared with patients who 2 . were treated conventionally. In the IMPORTANCE OF GLYCEMIC UKPDS, the rate of microvascular compli- CONTROL. cations was decreased by 25% in patients Guidelines for the diagnosis of type 2 with type 2 diabetes who were treated diabetes and goals for control have intensively with a sulfonylurea, met- evolved over time. The first nearly univer- formin, or insulin compared with patients sally accepted definitions of diabetes were on conventional diet therapy.3,11 Intensive published in 1979 by the National therapy achieved a median HbA1c of 7.0%, Diabetes Data Group9 and in 1980 by the whereas conventional therapy resulted in 10 World Health Organization. At that a median HbA1c of 7.9%. The UKPDS data time, diabetes was defined as a fasting showed a continuous relationship between blood glucose concentration greater than blood glucose levels and the risks of 140 mg/dL, a 2-hour postprandial glucose microvascular complications; for each level greater than 200 mg/dL, or 2 random percentage point decrease in HbA1c the blood glucose levels greater than 200 risk for microvascular complications was mg/dL. These guidelines were somewhat reduced by 35%. conservative in part because of the belief More recent definitions of and guide- that labeling an individual as a diabetic lines for type 2 diabetes have been devel- might have adverse emotional, social, or oped and are focused on health financial consequences. maintenance and prevention of long-term VOL. 8, NO. 16, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S461 REPORTS Table 2. Guidelines for Glycemic Control for Individuals With Diabetes Fasting Preprandial Postprandial Bedtime HbA1c (mg/dL) (mg/dL) (mg/dL) (mg/dL) (%) Normal 70-100 <100 <140 <110 <6.0 ADA 80-110 80-120 <180 100-140 <7.0 ACE/AACE <110 <110 <140 — <6.5 ACE/AACE indicates American College of Endocrinologists/American Association of Clinical Endocrinologists; ADA, American Diabetes Association; HbA1c, hemoglobin A1c. Sources: References 12, 13. complications of diabetes (Table 1).12 One patients 45 to 75 years of age ranges from goal for glycemic control is to achieve 40% to 60%.14 The UKPDS demonstrated essentially normal, nondiabetic blood glu- that in patients with type 2 diabetes, inten- cose levels when fasting, before meals, and sive control of blood pressure (defined as at peak after meals (Table 2).12,13 <150/85 mm Hg) reduced all diabetes As our understanding of insulin resist- complications by 24%, deaths by 32%, ance and the pathogenesis of type 2 dia- strokes by 44%, heart failure by 56%, and betes has evolved, so have treatment microvascular complications by 37%.11 goals. Indeed, appreciation of the impor- This study found that each 10-mm Hg tance of control of hypertension and lipid decrease in mean systolic blood pressure metabolism as part of diabetes manage- was associated with a 12% risk reduction ment is very recent. Today, type 2 dia- for any diabetes-related complication. betes can be defined as a disease of The Joint National Committee on accelerated cardiovascular deterioration Prevention, Detection, Evaluation, and associated with elevated blood glucose Treatment of High Blood Pressure recom- level. With the advent of home glucose mends that blood pressure be less than monitoring and with the availability of 130/85 mm Hg.15 The American Diabetes newer agents for control of type 2 diabetes Association recently recommended that mellitus and associated conditions, many individuals with type 2 diabetes decrease patients are now able to achieve and blood pressure to less than 130/80 mm Hg maintain improved glycemia, blood pres- (Table 3).16 sure, and lipid levels, which should In the UKPDS, both a β-blocker markedly decrease risk for both microvas- (atenolol) and an angiotensin-converting cular and macrovascular complications. enzyme (ACE)