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Supplements Improving Treatment Success Rates for Type 2 Diabetes: Balancing Safety, Cost, and Outcome [CME/CPE]

Improving Care for Patients With Type 2 Diabetes: Applying Management Guidelines and Algorithms, and a Review of New Evidence for Incretin Agents and Lifestyle Intervention

Lawrence Blonde, MD, FACP, FACE

Diabetes affects an estimated 25.8 million US adults, or 8.3% of the population. By 2050, the prevalence of type 2 diabetes mellitus (T2DM) in the United States may be as high as 1 in 3 adults. This paper summarizes key national treatment goals, guidelines, and algorithms for T2DM management in a way that clarifies their similarities and areas of disparity, for use by managed care organizations and other healthcare professionals. In addition, the role of long-standing and newer classes of antihyperglycemic agents, including incretin-related agents, bromocriptine, and colesevelam, will be reviewed, as will emerging research on the role of lifestyle intervention in T2DM and prediabetes. Lastly, comparative and long-term clinical efficacy data on incretin therapy, reported at the American Diabetes Association’s 2011 71st Scientific Sessions, will be summarized. Although the treatment landscape for T2DM has increased substantially in complexity, major guidelines have similar goals. While established, relatively inexpensive, and thoroughly investigated antihyperglycemic agents maintain popularity, incretin-based agents offer glycemic efficacy along with other benefits relative to weight loss or neutrality and low rates of hypoglycemia. In addition, the feasibility of matching patients to appropriate lifestyle intervention, for both diabetes and diabetes prevention, is increasing.

(Am J Manag Care. 2011;17:S368-S376)

Diabetes affects an estimated 25.8 million US adults, or 8.3% of the population.1 By 2050, the US Centers for Disease Control and Prevention (CDC) estimates the prevalence of type 2 diabetes mellitus (T2DM) in the United States may be as high as 1 in 3 adults.2 Diabetes is the leading cause of adult blindness and end-stage kidney disease. It increases the risk for cardiovascular (CV) disease by 2- to 4-fold, and is the seventh leading cause of death for Americans.1 In 2007, total US medical costs attributable to diagnosed and undiagnosed diabetes were estimated at $174 billion; of this, $116 billion was spent on medical care and $58 billion was lost due to reduced productivity.3

This paper will summarize some key national treatment goals, and guidelines and algorithms for the management of T2DM that may be incorporated by managed care organizations into their internal T2DM treatment protocols. The role of some newer classes of antihyperglycemic agents, especially incretin-related agents, will be reviewed, as will some new clinical data reported at the American Diabetes Association's (ADA's) 71st Scientific Sessions (June 24-28, 2011; San Diego, CA). This paper will also discuss some emerging research on the role of lifestyle intervention in T2DM.

Type 2 Diabetes Pathophysiology and Therapeutics

In most patients who develop T2DM, peripheral insulin resistance in muscle and fat cells develops, along with insulin resistance in the liver. Initially, pancreatic beta-cells are able to compensate for this decreased insulin sensitivity via increased insulin production. Eventually, however, beta-cells fail to fully counteract insulin resistance, leading to the inability to maintain normal glucose homeostasis.4 In clinical practice, the relative contributions of beta-cell dysfunction and decreased beta-cell mass and insulin resistance to an individual patient's hyperglycemia will vary based on a number of factors, such as patient ethnicity, age, duration of disease, and physical activity and lifestyle habits. Diabetes does not develop, however, without at least a relative insulin secretory deficiency.5

Another contributor to the pathogenesis of T2DM is impairment of the postprandial insulin response, mediated by the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). In healthy, nondiabetic individuals, release of these hormones in response to oral intake is responsible for an estimated 70% of postprandial insulin secretion; in addition, at least in animals, data indicate that both GLP-1 and GIP promote beta-cell growth and prevent apoptosis. GLP-1 inhibits the secretion of glucagon by pancreatic alpha-cells, thus inhibiting the postprandial release of hepatic glucose; it also promotes the secretion of insulin in response to increasing plasma glucose, as does GIP. In T2DM, the insulinotropic effects of GIP are inhibited. While some studies indicate that diabetes-related diminished postprandial insulin secretion and glucagon suppression are due to a decrease in GLP-1 secretion, other research suggests that there is a decreased effect of GLP-1 which can be at least partially overcome by administering larger amounts of exogenous GLP-1 or increasing endogenous GLP-1 levels.6

Established T2DM antihyperglycemic medications have a strong, long-standing evidence base demonstrating their ability to address 1 or more of these core defects. The most commonly used drugs in T2DM are the biguanide metformin, sulfonylureas, thiazolidinediones (TZDs), and exogenous insulin therapy. The most commonly used newer therapies are the incretin-related agents (consisting of GLP-1 receptor agonists and dipeptidyl-peptidase-4 [DPP-4] inhibitors). Table 1 provides a summary of most available T2DM drug classes, developed by a writing group assembled by the American Association of Clinical Endocrinologists (AACE); treatments are classified based on their effects on fasting and postprandial glucose, as well as associated adverse effects.7

Metformin has a substantial beneficial effect on glycosylated hemoglobin (A1C) levels and can be associated with modest weight loss and favorable lipid reductions.8 However, metformin does not appear to exert any protective effect on beta-cells.4 Sulfonylureas have a potent initial A1C-lowering effect, but are associated with weight gain and relatively high rates of at least minor hypoglycemia.4,8,9 These drugs are now also recognized to often have a limited durability of antihyperglycemic efficacy.4,9 The TZDs contribute to improved insulin sensitivity (even in low doses) and may help to preserve beta-cell function.4 Recently, however, TZDs have been associated with risks for certain adverse events, including weight gain, edema, congestive heart failure, bone fracture, bladder cancer, and possible ischemic heart disease (rosiglitazone).8-10 Insulin is the most effective glucose-lowering agent available. Compared with multiple oral agent use, the earlier initiation of insulin may allow patients to achieve more rapid and/or better glycemic control. Insulin can also improve dyslipidemia, but may be associated with weight gain and hypoglycemia.11,12

In recent years, our understanding of T2DM pathophysiology in the gut, as well as the liver, kidney, pancreas, and brain, has broadened.4 Two classes of incretin-related therapies are available: GLP-1 receptor agonists and DPP-4 inhibitors.13 GLP-1 receptor agonists bind to GLP-1 receptors in the pancreas to stimulate pancreatic insulin release and suppress glucagon, both in a glucose-dependent manner. The drugs' glucose dependency reduces the risk for hypoglycemia. They also have effects on gastric emptying and satiety.11 GLP-1 receptor agonists are associated with substantial (0.8%-1.2%) improvements in A1C levels, reductions in weight and blood pressure levels, and evidence of improved beta-cell function.4,14,15 The DPP-4 inhibitors impede the function of DPP-4, the gut enzyme responsible for rapid degeneration of endogenous GLP-1 and GIP.6 These agents result in a 2- to 3-fold increase in endogenous levels of GLP-1, which results in a glucose-dependent increase in insulin secretion and suppression of glucagon secretion.11,16 DPP-4 inhibitors do not slow gastric emptying or have a significant effect on satiety, but are associated with improvements in A1C levels (0.5%-0.8%), weight neutrality, and there is some evidence of association with improved beta-cell function.11,17

Two additional more recently approved therapies for T2DM management are worth noting. Colesevelam is a bile acid sequestrant developed as a lipid-lowering agent; it also has blood glucose-lowering properties and was approved by the US Food and Drug Administration (FDA) in 2008 to treat hyperglycemia associated with T2DM. Colesevelam is weight neutral, and in clinical trials, the risk for hypoglycemia was similar to placebo.18 Quick-release bromocriptine is a sympatholytic D2 dopamine agonist recently approved for T2DM, with a low risk for hypoglycemia or weight gain. In addition to lowering A1C levels, quick-release bromocriptine reduces free fatty acid and triglyceride levels. Quick-release bromocriptine is the first agent to successfully complete the FDA-mandated cardiovascular safety trials for new antihyperglycemic medications; these trials found that the incidence of a composite cardiovascular end point was not increased with bromocriptine relative to placebo. In fact, the hazard ratio comparing quick-release bromocriptine to placebo for the time to first occurrence of the end point was 0.58 (0.35-0.96).4,19

Treatment Goals and Therapeutic Strategies

Despite some variance, current guidelines for blood glucose management in T2DM are more similar than they are different. For example, and as shown in Table 2, the ADA recommends an A1C goal of less than 7% for most patients, with preprandial plasma glucose goals of 70 to 130 mg/dL and a peak postprandial plasma glucose goal of less than 180 mg/dL.20 The AACE recommends an A1C goal of 6.5% or less, with preprandial plasma glucose less than 110 mg/dL, and 2-hour postprandial plasma glucose less than 140 mg/dL.16

Both organizations emphasize the need to individualize glycemic goals based on a number of patient-specific characteristics. These include the duration of diabetes, patient age, life expectancy, ethnicity, the presence of microvascular and macrovascular complications, other comorbid illnesses, CV risk factors, hypoglycemia unawareness, and patient risk for severe hypoglycemia.7,16,20 The ADA notes that lower A1C goals (if they can be achieved without hypoglycemia or other adverse effects) may be targeted in subjects with a short duration of diabetes, long life expectancy, no significant CV disease, and no significant hypoglycemia. In contrast, A1C targets should be less stringent in certain individuals, including those with a history of frequent or severe hypoglycemia or hypoglycemic unawareness, advanced vascular complications, and/or extensive comorbidities, as well as those with long-standing T2DM in whom lower A1C goals may be difficult to achieve despite optimal treatment.21

Expert groups assembled by the ADA (in collaboration with the European Association for the Study of Diabetes [EASD]) and by the AACE (in collaboration with the American College of Endocrinology [ACE]) have also developed T2DM treatment algorithms. While not official position statements, the goal of these algorithms is to identify and describe strategies to better utilize presently available antihyperglycemic agents. however, both algorithms emphasize the importance of lifestyle interventions (medical nutrition therapy and appropriately prescribed physical activity), as well as diabetes education and self-management training for all patients.16,20

In some cases, these algorithms place somewhat different emphasis on certain medication classes, discussed below. Regardless of drug choice, the primary objective of each algorithm is to enable patients to reach the recommended glycemic target with as few adverse effects as possible. For example, when considering combination regimens, both the ADA/EASD and the AACE/ACE algorithms recommend selecting drug classes with complementary mechanisms of action, so as to ensure the broadest glucose-lowering effect. In addition, both algorithms stress the importance of advancing therapy expeditiously, in order to reach and maintain A1C goals.7,11

 
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