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INTRODUCTION: Treating patients with type 2 diabetes: What is after lifestyle management and metformin? A focus on the glucagon-like peptide-1 receptor agonists

Although the prevalence of type 2 diabetes mellitus (T2DM) in the United States has increased over the past decade to approximately 24 million¹—an increase that is expected to continue—there is reason for optimism in addressing the challenges presented by this debilitating and costly disease. First, the percentage of patients achieving good glycemic control, defined as a glycosylated hemoglobin (A1C) level <7.0%, has actually increased: As reported in the National Health and Nutrition Examination Survey (NHANES), it has risen from 38.1% in 1999-2000 to 55.0% in 2001-2002, 57.8% in 2003-2004, and 59.1% in 2006.² Although this trend is encouraging, the care for patients with T2DM remains suboptimal. A second reason for optimism is that the array of medications available to manage patients with T2DM continues to grow and offers many important advances over the older medications. Some of the newer medications target pathophysiologic mechanisms of T2DM that have not previously been addressed. For example, medications such as the glucagon-like peptide-1 (GLP-1) receptor agonists and the dipeptidyl peptidase-4 (DPP-4) inhibitors act on the incretin system, which is integrally involved in glucose homeostasis. In addition to lowering blood glucose levels, incretin-based therapies modestly improve blood pressure^3-5 and lipid levels.^3,4,6 These therapies also offer benefits with regard to weight as well as a low incidence of hypoglycemia.^7-9 Unlike other agents, incretin-based therapies are glucose dependent and stimulate insulin secretion only in the presence of elevated levels of blood glucose. Weight gain and hypoglycemia associated with many of the older antihyperglycemic agents are major barriers to treatment adherence; however, these side effects have not been associated with incretin therapy, suggesting important treatment benefits.

  Combine lifestyle management and metformin

Initiating treatment with the combination of lifestyle management and metformin at the time of diagnosis of T2DM, unless contraindicated, is a major recommendation in the 2009 consensus algorithm developed by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).¹⁰ This approach is recommended because of the benefits of lifestyle management on blood glucose, blood pressure, lipid levels, and weight, and the benefits of metformin on blood glucose levels, as well as absence of weight gain or hypoglycemia, a high level of patient acceptance, and relatively low cost.¹⁰ Although metformin generally has a low level of side effects, some patients do not initially tolerate the gastrointestinal effects well. To improve patient adherence to metformin, it is generally recommended that patients start with a lower dosage and advance as tolerated. In addition, metformin should be used only in patients with normal renal function.

  Which medications? It depends on the patient

Although the combination of lifestyle management and metformin is initially effective in reducing blood glucose levels, the progressive nature of T2DM often requires that other medications be added over time. The question is, which medications? The answer, of course, must be individualized to the patient.

Recognizing the difficulty in managing patients with T2DM, the ADA/EASD developed a simplified algorithm “to help guide healthcare providers in choosing the most appropriate interventions for their [nonpregnant adult] patients with type 2 diabetes.”¹⁰ This consensus algorithm integrates the results of recent clinical trials, product labeling changes, and newly approved medications with the clinical experience of the panel. Because the panel considered all antihyperglycemic drugs currently available, the consensus algorithm compares the full array of treatment options, thereby giving clinicians the greatest opportunity to implement and modify treatment to meet the needs of each patient over the course of the disease.

To be sure, the treatment of patients with T2DM is challenging and many barriers remain. Managing the spectrum of diseases associated with T2DM, such as cardiovascular disease, is another crucial part of a comprehensive treatment plan. In addition, the goal of attaining acceptable glycemic control must be balanced with patient safety. Furthermore, patients’ needs, concerns, capabilities, and support systems, as well as the benefits offered by their health plans, are important factors in selecting and modifying treatment.

As a continuum of education for the primary care physician, this supplement builds on the basic and clinical information presented in The Journal of Family Practice September 2008 supplement, “The Role of Incretin Therapy for Type 2 Diabetes in Family Medicine”. The present supplement addresses the management of patients who do not achieve glycemic control with lifestyle management and metformin.

Primary care physicians encounter the challenge of managing a progressive disease that requires modification and intensification of therapy¹⁰ for the majority of their patients with T2DM. The first article by Dr Peterson provides a checklist of issues to consider in selecting the optimal add-on therapy for each patient. Dr McGill then discusses the advantages and limitations of the tier 1 (insulin, sulfonylurea) and tier 2 (thiazolidinediones, GLP-1 receptor agonists) treatment options considered the preferred therapies by the ADA/EASD for managing patients who do not achieve glycemic control with lifestyle management and metformin. In the third article, Dr Shomali illustrates these concepts using a patient-centered approach by discussing the accumulating clinical efficacy and safety evidence with the GLP-1 receptor agonists in combination with metformin and other antihyperglycemic agents. In the fourth article, Dr Haines continues the case study, addressing the patient education issues specific to the use of GLP-1 receptor agonists. The third and fourth articles focus on the GLP-1 receptor agonists, because they are 1 of the 4 preferred treatments recommended as add-on therapy by the ADA/EASD panel; of these preferred treatments, they are also the least familiar to family physicians. Treatment approaches for optimizing glycemic control in consideration of patient characteristics are also suggested. Not discussed are the alpha-glucosidase inhibitors, the glinides, or pramlintide, which were not included in the 2 tiers of preferred therapies by the ADA/EASD panel.

References

1. American Diabetes Association. Total prevalence of diabetes & pre-diabetes. www.diabetes.org/diabetes-statistics/prevalence.jsp. Accessed July 17, 2009.
2. McWilliams JM, Meara E, Zaslavsky AM, et al. Differences in control of cardiovascular disease and diabetes by race, ethnicity, and education: US trends from 1999 to 2006 and effects of Medicare coverage. Ann Intern Med. 2009;150:505–515.
3. Ratner RE, Maggs D, Nielsen LL, et al. Long-term effects of exenatide therapy over 82 weeks on glycaemic control and weight in over-weight metformin-treated patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2006;8:419–428.
4. Vilsboll T, Zdravkovic M, Le Thi T, et al. Liraglutide, a long-acting human glucagon-like peptide-1 analog, given as monotherapy significantly improves glycemic control and lowers body weight without risk of hypoglycemia in patients with type 2 diabetes. Diabetes Care. 2007;30:1608–1610.
5. Mistry GC, Maes AL, Lasseter KC, et al. Effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on blood pressure in nondiabetic patients with mild to moderate hypertension. J Clin Pharmacol. 2008;48:592–598.
6. Buse JB, Rosenstock J, Sesti G, et al. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet. 2009;374:39–47.
7. Buse JB, Henry RR, Han J, et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care. 2004;27:2628–2635.
8. Garber A, Henry R, Ratner R, et al. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase III, double-blind, parallel-treatment trial. Lancet. 2009;373:473–481.
9. Charbonnel B, Karasik A, Liu J, et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care. 2006;29:2638–2643.
10. Nathan DM, Buse JB, Davidson MB, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2009;32:193–203.

The Journal of Family Practice ©2009 Quadrant HealthCom Inc.