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GLP-1 Agonist Therapy

A new pharmacologic approach to type 2 diabetes

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Pharmacologic management of hyperglycemia associated with type 2 diabetes mellitus (T2DM) can be complex and challenging for both healthcare providers and patients.1 A wide array of treatment options are available, starting with lifestyle modifications and metformin monotherapy and progressing (with disease severity and failure to achieve glycated hemoglobin [A1c] goals) to two- and three-drug combinations that may or may not include an insulin regimen.1

Current consensus guidelines from the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) recommend that treatment decisions be made based on individual patient and drug characteristics, with a goal of optimizing glycemic control while minimizing adverse events (AEs).1 Due to the strong correlation between T2DM and cardiovascular disease, healthcare providers should customize individual treatment plans to modify factors including obesity, blood pressure and hyperlipidemia, promote smoking cessation, and incorporate regular exercise and healthy eating habits.2

In patients with longstanding T2DM, it is usually necessary to normalize both fasting plasma glucose (FPG) and postprandial plasma glucose (PPG) levels to reach glycemic goals.2,3 When combination therapy is required, ADA/EASD guidelines recommend choosing drugs with complementary mechanisms of action, such that effects on both fasting and postprandial glucose are maximized.1

Metformin, thiazolidinediones (TZDs), and basal insulin primarily target FPG,4 which is the major contributor to hyperglycemia at high A1c levels.3,5 Non-prandial glucagon-like peptide-1 (GLP-1) agonists, including exenatide long-acting release (LAR), liraglutide and albiglutide also have a stronger effect on FPG via their insulinotropic and glucagonostatic properties.6-9 In contrast, prandial GLP-1 agonists such as exenatide and lixisenatide, dipeptidyl peptidase-4 (DPP-4) inhibitors and prandial insulin have a greater effect on reducing postprandial glucose excursions,4 which contribute more to overall hyperglycemia relative to FPG when A1c is closer to 7.0%.3-6

Prandial GLP-1 agonists and prandial insulin generally provide moderate to marked PPG reductions,4 but unlike insulin, GLP-1 agonists are not associated with a significant risk of hypoglycemia.10,11 Another important difference between GLP-1 agonists and insulin is their effect on body weight. GLP-1 agonists are associated with clinically meaningful weight loss, while insulin is associated with weight gain.11

This article provides information about the role of GLP-1 agonists in current diabetes treatment algorithms and the importance of PPG management, especially for patients who are not achieving glycemic control on traditional regimens that primarily target FPG.

Patient Presentation

A 52-year-old Hispanic woman presents with a 6-year history of T2DM and a body mass index (BMI) of 32 kg/m2. The patient has a history of hypertension and hyperlipidemia, and her social history includes variable work hours, irregular eating times, rare alcohol consumption, and no regular exercise. She is a nonsmoker. Her medications include metformin 1,000 mg twice daily, lisinopril 10 mg once daily, atorvastatin 20 mg once daily, and aspirin 81 mg once daily.

Laboratory testing shows her A1c is 8.7%, total cholesterol is 185 mg/dL, low-density lipoprotein (LDL) cholesterol is 90 mg/dL, high-density lipoprotein cholesterol (HDL) is 40 mg/dL, and triglycerides are 210 mg/dL. The patient is concerned about weight gain and the risk of hypoglycemia given her irregular schedule and eating times, which could become problematic if a complex insulin strategy is needed.

Treatment & Management

The patient's A1c is quite high with metformin monotherapy, suggesting that FPG is the main contributor to her hyperglycemia.3,5 Because the patient is still a long way from a glycemic goal of A1c below 6.5% to 7.0%, addition of basal insulin is a logical next step. Insulin can be expected to provide the most robust glycemic response given her longstanding history of T2DM,1 and a simple basal insulin regimen is a better option than more complex mixed insulin regimens at this stage given the irregular schedule and concerns about hypoglycemia.

At the patient's 3-month follow-up visit after initiation of basal insulin, her A1c has fallen to 7.3%, which is still above the recommended A1c goal of less than 7.0%. She continues to experience significant postprandial glucose excursions (180 mg/dL or higher). For these reasons, additional antihyperglycemic therapy is needed.

Current ADA/EASD guidelines recommend the following therapies as possible add-ons to metformin and basal insulin: a thiazolidinedione (pioglitazone), a DPP-4 inhibitor, or a GLP-1 agonist.1 If the patient is experiencing excessive PPG excursions, adding a prandial GLP-1 agonist is a logical next step, because these agents can significantly lower PPG levels both as monotherapy and in combination with oral agents or basal insulin (e.g., exenatide twice daily and lixisenatide once daily).12,13 In addition, of the recommended treatments, only GLP-1 agonists have been shown to provide clinically meaningful weight loss of about 1 kg to 5 kg (about 3% of body weight),1,14,15 which is important for this patient given her BMI and concerns about weight gain. In contrast, TZDs are associated with weight gain, and DPP-4 inhibitors have neutral effects on body weight.1

GLP-1 agonists may also have beneficial effects on the cardiovascular system. Based on analyses of clinical studies of exenatide and liraglutide, it can be expected that GLP-1 agonists will reduce systolic blood pressure by about 1 mm Hg to 7 mm Hg, reduce LDL cholesterol by 1 mg/dL to 17 mg/dL, and reduce triglyceride levels by roughly 12 mg/dL to 40 mg/dL.10 However, large-scale randomized controlled cardiovascular outcomes studies are necessary to confirm the cardiovascular benefits of GLP-1 agonists.

GLP-1 agonists are generally well tolerated. They are associated with a low risk of mild or moderate hypoglycemia, and severe hypoglycemia is rare.10 GLP-1 agonists can cause mild to moderate gastrointestinal AEs (e.g., nausea and vomiting),1,10 but these usually subside after 4 to 8 weeks of treatment and can be minimized with dose escalation strategies.10

Given this patient's need to lose weight, concern about hypoglycemia and history of hypertension and hyperlipidemia, addition of a GLP-1 agonist to metformin plus basal insulin would be a good treatment option. Indeed, previous clinical trials have shown that the combination of a GLP-1 agonist with basal insulin can further lower A1c levels significantly compared with each agent alone. In patients with T2DM uncontrolled on insulin glargine, reduction of A1c from baseline was greater with exenatide twice daily plus optimized insulin glargine (1.74%) compared with placebo (1.04%), corresponding to an additional 0.7% decrease.12

In another study, the addition of liraglutide to metformin, followed by insulin detemir intensification in patients with A1c 7% or higher, led to a further 0.5% A1c reduction compared with 0.02% increase without insulin detemir.16 Such additional A1c reductions should be sufficient for the patient to reach a target A1c of less than 7.0%. Importantly, when GLP-1 agonists are used in combination with basal insulin (with or without metformin), additional A1c and PPG lowering can be achieved without significantly increasing the risk of hypoglycemia and often allowing for lower basal insulin requirements.12,13,17,18

Three GLP-1 agonists are FDA-approved for the management of hyperglycemia in patients with T2DM: exenatide (Byetta), exenatide LAR (Bydureon) and liraglutide (Victoza). Exenatide is approved as add-on to basal insulin in the United States;17,19 another GLP-1 agonist, lixisenatide is approved in Europe. The addition of basal insulin to liraglutide has also been studied and approved for use in the United States.6-8 Both lixisenatide and albiglutide are in late-stage clinical development and awaiting regulatory approval in the United States.

Exenatide twice daily and lixisenatide once daily are prandial GLP-1 agonists,20 whereas liraglutide once daily, exenatide LAR once weekly and albiglutide once weekly are nonprandial GLP-1 agonists.15 The prandial GLP-1 agonists produce more marked reductions in PPG than the nonprandial drugs because they slow gastric emptying. In contrast, the nonprandial GLP-1 agonists provide better FPG control because patients maintain consistently high plasma levels of these drugs.15

Patient Education

Successful long-term management of T2DM requires that patients take an active role in decisions about their treatment and daily self-management.1 Thus, patient education should be a foundation of all T2DM treatment plans and, when possible, certified diabetes educators should be included.1

Before initiating treatment with a GLP-1 agonist, discuss the dosing and administration requirements of these agents. The different GLP-1 agonists have distinct dosing schedules, and healthcare providers should work with patients to find the treatment that best accommodates their schedule and lifestyle.10 The potential for gastrointestinal AEs with GLP-1 agonists should be communicated to patients before initiating therapy. It should be explained that these adverse effects are usually mild and typically subside in about 4 to 8 weeks.15 Patients should also be educated about the possibility of rare but serious risks of pancreatitis with GLP-1 agonists and the black-box warning about thyroid cancer specific for liraglutide and exenatide LAR.7,8

Medication costs are a common concern for patients with T2DM and should be discussed when determining the best treatment plan. Newer T2DM treatment options, including GLP-1 agonists and DPP-4 inhibitors, can be costly, so healthcare providers should work with the patient to determine whether insurance coverage may reduce out-of-pocket costs or whether the patient qualifies for prescription assistance programs or discounts.10 If costs are prohibitive, patients may not adhere to their medication, placing them at high risk for diabetes complications.21

Discussion

Patient-centered care that provides individualization of therapy should be a cornerstone of chronic disease management. Because there is a wide range of treatment options for T2DM, healthcare providers can work with patients to determine the best treatment choices to fit their lifestyle, preferences, values and individual treatment goals.1

For many patients, GLP-1 agonists are a good treatment option because they effectively reduce A1c and have safety profiles that are more favorable than other antihyperglycemic agents (e.g., sulfonylureas, TZDs, insulin).10 GLP-1 agonists, particularly the prandial drugs exenatide and lixisenatide, act to control PPG, which is important for regulating glycemia.12,13 The nonprandial GLP-1 agonists exenatide LAR and liraglutide have a stronger effect on FPG, likely due to suppression of hepatic glucose output during the night.6-8

Unlike most other T2DM treatment options, GLP-1 agonists are associated with weight loss of about 1 kg to 5 kg (~3%).14,15 The importance of this weight loss should not be underestimated given the high rate of obesity among patients with T2DM and the clinical benefits of even modest (5% to 10%) weight loss in improving glucose control and potentially reducing cardiovascular risk.1 The improved glycemic control and weight loss achieved with GLP-1 agonists can improve quality of life, including psychological well-being and health perceptions, in part by reducing anxiety associated with weight gain.22

Adding a GLP-1 agonist to basal insulin is a promising T2DM treatment option because this combination provides substantial A1c lowering without an increased risk of hypoglycemia.17 The PPG-lowering effects of prandial GLP-1 agonists may provide a complementary and more physiological approach to glycemic control when combined with basal insulin (which primarily targets FPG), and addition of a GLP-1 agonist may lower the required dose of basal insulin.17

Christopher E. Sadler is a physician assistant and diabetes educator at Diabetes and Endocrine Associates in La Jolla, Calif. He is the president of the American Society of Endocrine Physician Assistants. Sadler has completed a disclosure statement and reports that he is a consultant for sanofi-aventis and Boehringer Ingelheim/Lilly. He serves on speaker bureaus for Bristol-Myers Squibb, Novo Nordisk and Takeda. Medical writing assistance was provided by Cherie Koch, PhD, of MedErgy and was funded by sanofi-aventis. The author received no compensation and retained full editorial control over the content of the manuscript.

References

1. Inzucchi SE, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012;35(6):1364-1379.

2. Aryangat AV, Gerich JE. Type 2 diabetes: postprandial hyperglycemia and increased cardiovascular risk. Vasc Health Risk Manag. 2010;6:145-155.

3. Riddle M, et al. Contributions of basal and postprandial hyperglycemia over a wide range of A1C levels before and after treatment intensification in type 2 diabetes. Diabetes Care. 2011;34(12):2508-2514.

4. Rodbard HW, et al. Statement by an American Association of Clinical Endocrinologists/American College of Endocrinology consensus panel on type 2 diabetes mellitus: an algorithm for glycemic control. Endocr Pract. 2009;15(6):540-559.

5. Monnier L, et al. Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients: variations with increasing levels of HbA1c. Diabetes Care. 2003;26(3):881-885.

6. Fineman MS, et al. GLP-1 based therapies: differential effects on fasting and postprandial glucose. Diabetes Obes Metab. 2012;14(8):675-688.

7. BYDUREON (exenatide extended-release for injectable suspension) [package insert]. San Diego, CA: Amylin Pharmaceuticals, Inc.; 2012.

8. Victoza (liraglutide [rDNA origin] injection) [package insert]. Bagsvaerd, Denmark: Novo Nordisk A/S; 2012.

9. Rosenstock J, et al. Potential of albiglutide, a long-acting GLP-1 receptor agonist, in type 2 diabetes: a randomized controlled trial exploring weekly, biweekly, and monthly dosing. Diabetes Care. 2009;32(10):1880-1886.

10. Campbell RK, et a ;. Distinguishing among incretin-based therapies. Pathophysiology of type 2 diabetes mellitus: potential role of incretin-based therapies. J Fam Pract. 2010;59(9 Suppl 1):S5-S9.

11. Stonehouse AH, et a ;. Incretin-based therapies. J Diabetes. 2012;4(1):55-67.

12. Buse JB, et al. Use of twice-daily exenatide in basal insulin-treated patients with type 2 diabetes: a randomized, controlled trial. Ann Intern Med. 2011;154(2):103-112.

13. Riddle MC, et al. Adding Once-Daily Lixisenatide for Type 2 Diabetes Inadequately Controlled by Established Basal Insulin: A 24-week, randomized, placebo-controlled comparison (GetGoal-L). Diabetes Care. 2013 ;36(9) :2489-2496.

14. Monami M, et al. Effects of glucagon-like peptide-1 receptor agonists on body weight: a meta-analysis. Exp Diabetes Res. 2012;2012:672658.

15. Meier JJ. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nat Rev Endocrinol. 2012;8(12):728-742.

16. Devries JH, et al. Sequential intensification of metformin treatment in type 2 diabetes with liraglutide followed by randomized addition of basal insulin prompted by A1C targets. Diabetes Care. 2012;35(7):1446-1454.

17. Berlie H, et al. Glucagon-like peptide-1 receptor agonists as add-on therapy to basal insulin in patients with type 2 diabetes: a systematic review. Diabetes Metab Syndr Obes. 2012;5:165-174.

18. Seino Y, et al. Randomized, double-blind, placebo-controlled trial of the once-daily GLP-1 receptor agonist lixisenatide in Asian patients with type 2 diabetes insufficiently controlled on basal insulin with or without a sulfonylurea (GetGoal-L-Asia). Diabetes Obes Metab. 2012;14(10):910-917.

19. BYETTA (exenatide for injectable suspension) [package insert]. San Diego, CA: Amylin Pharmaceuticals, Inc.; 2011.

20. Horowitz M, et al. Mechanisms and clinical efficacy of lixisenatide for the management of type 2 diabetes. Adv Ther. 2013;30(2) :81-101.

21. Williams J, et al. Cost-related nonadherence by medication type among Medicare Part D beneficiaries with diabetes. Med Care. 2013;51(2):193-198.

22. Bode BW, et al. Patient-reported outcomes following treatment with the human GLP-1 analogue liraglutide or glimepiride in monotherapy: results from a randomized controlled trial in patients with type 2 diabetes. Diabetes Obes Metab. 2010;12(7):604-612.




     

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