Managed Care - October 2008 - (Page 43) betes treatment according to this approach. To utilize this idea, physicians must match the characteristics of a particular drug or therapy to specific patient characteristics such as preexisting cardiovascular compromise, CHF, renal or hepatic compromise, advanced age, obesity, and whether the patient is symptomatic. Clinicians also need to evaluate patient characteristics that would make the potential for hypoglycemia particularly threatening. We will briefly consider a number of drugs and the patients for whom they may be appropriate (see figure 4 and table 4). Metformin improves hepatic insulin resistance. It is clearly effective at enhancing glycemic control. Potential gastrointestinal side effects necessitate gradual dose increase for maximal effectiveness. Metformin is not appropriate for patients with underlying renal disease because of the threat of lactic acidosis. Thiazolidinediones act via the PPARγ receptor. They decrease insulin resistance in the periphery and in the liver, resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output. Insulin action is enhanced, leading to a reduction in insulin secretion. Consequently, serum glucose is reduced TABLE 3 A novel approach to diabetes treatment Goals of therapy • Reduce HbA1c levels as low as possible without undue hypoglycemia • Select agents that will aid weight loss, or at least result in no weight gain • Consider potential cardiovascular benefits of any agents • Utilize agents with the potential to preserve β-cell function • Employ combination therapy to address multiple pathophysiologic defects • Minimize potential side effects TABLE 4 Pathophysiologic basis for combination therapy of type 2 diabetes • Diminish insulin resistance • Weight redistribution: thiazolidinediones • Weight loss: diet; exercise • Hepatic insulin resistance: metformin decreases hepatic glucose production • Minimize β-cell dysfunction • Potentiate insulin release: incretins; secretagogues • Decrease insulin demand: thiazolidinediones, metformin, α-glucosidase inhibitors • Stimulate new β-cells: incretins; thiazolidinediones • Replace insulin (when endogenous production is inadequate) • Prevent, delay or reverse long-term complications • Treat hypertension, dyslipidemia, dysfibrinolysis, endothelial dysfunction, pro-inflammatory state; encourage smoking cessation due to increased peripheral glucose utilization and decreased hepatic glucose production. β-cell function is enhanced as well. As outlined above, both pioglitazone and rosiglitazone are comparable with respect to glycemic effectiveness but clear differences exist with regard to changes in lipid parameters and cardiovascular safety. Data from the PROactive trial suggests that pioglitazone may reduce macrovascular events. Thiazolidinediones are safe for patients with renal insufficiency, hypoglycemia is not an issue, and glycemic benefits are durable over time. Incretin mimetics are another class of agents for treating diabetes. Animal studies demonstrate that these drugs act to improve β-cell function. Both the GLP-1 analog, exenatide, and the DPP-4 inhibitor, sitagliptin, improve glucose-dependent insulin secretion and suppress glucagon release. Sitagliptin is not associated with nausea or other gastrointestinal side effects, and patients usually experience no weight loss or gain. On the other hand, exenatide use may be complicated by nausea, the result of a central satiety effect. Patients who continue with exenatide typically lose weight. The insulin secretagogues — sulfonylureas and glinides — were discussed earlier. They act rapidly to lower glucose by driving insulin release. Hypoglycemia may occur with these agents, and weight gain is common. The α-glucosidase inhibitors delay absorption of glucose from the duodenum to farther along in the intestines, and represent an effective way to decrease postprandial glucose levels. However, side effects are considerable and include bloating and diarrhea. Nevertheless, among certain populations, such as patients in nursing homes who are typically constipated, increased gastrointestinal motility could represent a potential benefit of therapy. The current treatment paradigm is too simple; a single algorithm cannot possibly take into account the many different and evolving patientand drug-related factors that impact treating the pathophysiologic defects in diabetes. Some consider the current treatment approach as offering “too little, too late.” The interval between initiating a treatment, evaluating it, and possibly changing dose or adding another agent needs to be shortened. By treating aggressively, physicians can safely help patients achieve optimal glycemic control while diminishing insulin resistance and preserving β-cell function. In this way, the development of complications can be delayed or even pre- OCTOBER 2008 / MANAGED CARE 43
For optimal viewing of this digital publication, please enable JavaScript and then refresh the page. If you would like to try to load the digital publication without using Flash Player detection, please click here.