How to implement incretin therapy

Adjunct Faculty, University of Utah School of Medicine, Salt Lake City, Utah Canyons Medical Center, Sandy, Utah

Dr Cobble is on the advisory boards for abbott laboratories, eli lilly and company, and theraSim, inc; and is on the speakers bureau for abbott laboratories, astraZeneca, eli lilly and company, forest pharmaceuticals, and GlaxoSmithKline.

The roles of glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors are rapidly evolving, despite limited recommendations on their use in current guidelines.^1,2 This evolution is based on data from the large number of clinical trials demonstrating the clinical efficacy and favorable safety profile of these agents in individuals with type 2 diabetes mellitus (T2DM) (TABLE).^3-28 This article focuses on factors to consider when implementing the GLP-1 receptor agonists and DPP-4 inhibitors as monotherapy or in combination with other agents in the treatment of T2DM.

 

Patient selection

Because of their ability to restore biphasic insulin response, the GLP-1 receptor agonists provide a mechanism that is unique and helpful in the management of both elevated fasting plasma glucose (FPG) and postprandial hyperglycemia, and thus minimizes glycemic variability as well as improves β-cell function.^3-16 Although the DPP-4 inhibitors are weight neutral, the GLP-1 receptor agonists have the added benefit of promoting weight loss rather than weight gain, as is associated with many antidiabetic drugs.^6,17-21 Delayed gastric emptying and increased satiety associated with pharmacologic levels of GLP-1 may lead to weight loss over time, whereas physiological levels associated with DPP-4 inhibitors may be insufficient to affect gastric emptying and satiety.

Because of their positive actions on pancreatic β-cell function and mass, the incretins have the potential to address a primary defect in T2DM, specifically, β-cell dysfunction.^{7,14,15,19,25} Although the possible long-term benefits of these agents on pancreatic β-cells require further investigation, it is clear that the incretins are safe and effective as monotherapy in patients whose T2DM was previously managed with lifestyle modification (diet and exercise) alone.^{3,5,7,9,11,12,14,15,19,29,30} Patients unaware of their hypoglycemia may also benefit from treatment with incretins because these glucose-dependent agents are associated with a low incidence of hypoglycemia, especially severe hypoglycemia. In addition, incretins maintain normal hypoglycemia counterregulatory mechanisms.^{6,8,15,18,26-28} Patients with various types of dyslipidemia may benefit from treatment with incretins because they have been shown to significantly improve total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglyceride levels, as well as blood pressure.^5,9,27

Selection of incretins based on actions and patient type

 

Patient education

As with other medications used to lower blood glucose levels, patient education is critical for patients being treated with either GLP-1 receptor agonists or DPP-4 inhibitors. The importance of discussing safety issues with these patients should not be overlooked, despite the generally favorable adverse event profile of these agents. Although the incidence of hypoglycemia is generally low, which simplifies treatment and avoids associated costs, verifying that the patient can recognize the symptoms of hypoglycemia and knows how to respond is critical. It should be verified that the patient understands the importance of self-monitoring blood glucose levels and is willing and able to perform the test periodically as opposed to several times per day.

Treatment-associated weight gain is a concern among patients with T2DM. The weight reduction potential of the GLP-1 receptor agonists and the weight-neutral effect of the DPP-4 inhibitors will likely be greeted with enthusiasm and might be used to motivate the patient to adhere to the treatment regimen.

The patient should also be cautioned about using other prescription and nonprescription drugs and alternative medicines because of the possibility of drug interactions. Because GLP-1 receptor agonists can slow gastric emptying, the concomitant use of oral drugs that require rapid gastrointestinal absorption or a minimum threshold concentration (eg, oral contraceptives and antibiotics) should be administered cautiously and with appropriate monitoring. Check prescribing information for warnings regrding potential drug interactions.

 

Initiation and titration

The approach to initiating and titrating the GLP-1 receptor agonists and DPP-4 inhibitors stems from several key trials for each of these agents. The methodology in these clinical trials has been similar among the agents, with each agent having been investigated as monotherapy in treatment-naïve patients and compared with placebo or active comparators. Other subsequent trials compared the GLP-1 receptor agonist or DPP-4 inhibitor alone or in combiantion with 1 or 2 OADs.

Exenatide

The GLP-1 receptor agonist exenatide is injected subcutaneously twice daily before the 2 main meals of the day, preferably with ≥6 hours separating the doses. In my experience, administering the dose 45 to 60 minutes prior to the meal enhances the appetite-suppressant effect of exenatide. Administration of exenatide following a meal is contraindicated.³¹ Since exenatide is predominantly cleared by glomerular filtration, exenatide should not be used in patients with a creatinine clearance of <30 mL/min. Intolerable gastrointestinal side effects have also been observed in dialysis patients treated with exenatide.³¹ As noted previously, a once-weekly formulation is in development.¹³

Dosing. The recommended initial dose of exenatide is 5 mcg twice daily. The dose can be increased to 10 mcg twice daily after 1 month of therapy, if needed, to achieve glycosylated hemoglobin (A1C), FPG, and postprandial plasma glucose (PPG) goals. Although effective as monotherapy, exenatide is often combined with ≥1 glucose-lowering agent because of the additive benefits of combination therapy. The combination of exenatide and a sulfonylurea must be used cautiously because the actions of the sulfonylurea may impede the glucose dependence of GLP-1. The result may be a dramatic increase in insulin secretion at glucose levels below which insulin secretion is usually not stimulated, thereby increasing the risk of hypoglycemia.³² The addition of exenatide, 5 mcg or 10 mcg twice daily, to sulfonylurea therapy has been shown to increase the incidence of hypoglycemia by 14% and 36%, respectively, compared with 3% for the addition of placebo.³¹ Consequently, the dose of the sulfonylurea should be reduced by 50% to 75% to reduce the risk of hypoglycemia. When exenatide is added to metformin or TZD monotherapy, it is unlikely that the dose of metformin or TZD will require adjustment since metformin and the TZDs do not affect insulin secretion. This may make these combinations preferable to exenatide plus a sulfonylurea.³¹

Administration. Exenatide should be administered subcutaneously into the thigh, abdomen, or upper arm. Since some patients may resist the use of injectable drugs, it may be helpful to have the patient self-administer the first dose in the office. In our office, a nurse will show the patient how to administer the first shot, which the patient then performs on herself or himself. This helps the patient realize that the use of the pen is quite simple and that injection is relatively painless due to the fine gauge of the needle. It also allows the practitioner staff to observe the patient’s injection technique. Before leaving the office, the patient is again instructed on how (subcutaneously), where (thigh, abdomen, upper arm), and when (45-60 min before eating) to inject the drug. The need to eat within the first hour following injection of exenatide must be emphasized to reinforce the importance of appropriate timing of medication administration and eating.

Patient education. If exenatide is used in combination with a sulfonylurea, it is especially important to discuss with the patient how to recognize and treat hypoglycemia. As noted above, the importance of timing the dose in relation to meals should be emphasized. The patient should understand that transient gastrointestinal effects (nausea, vomiting, and diarrhea) occur commonly with exenatide.³³ Assuring the patient that the frequency and severity of nausea generally peaks in the first 8 weeks and decreases thereafter is important.³³ Assuming that exenatide is determined to be the cause of the nausea and/or vomiting, different approaches can be taken to reduce or prevent those side effects. One approach is to have the patient take the dose of exenatide during or near the end of the meal. Alternatively, if the dose is 5 mcg twice daily, it can be reduced to 5 mcg once daily. If the dose is 10 mcg twice daily, it can be reduced to 5 mcg twice daily. After 2 weeks or so, the dose can be increased. However, the patient should be instructed to seek immediate medical attention if persistent, severe abdominal pain occurs, with or without vomiting, as this can be the hallmark of acute pancreatitis. Cases of acute pancreatitis have been reported since the release of exenatide in 2005.³¹

Liraglutide

Currently an investigational once-daily agent under review by the FDA, liraglutide is a GLP-1 receptor agonist that has been studied in numerous clinical trials involving patients with T2DM.^6,38-44 Exenatide is a synthetic peptide originally identified in the Heloderma suspectum and only 53% homologous to human GLP-1, whereas liraglutide is a human GLP-1 analog that is 97% homologous to human GLP-1.^31,41

Dosing. Early clinical trials used single daily doses ranging from 0.045 to 0.75 mg.^19,21 However, more recent trials have generally used single daily doses of 1.2 or 1.8 mg, which are the doses proposed in the new drug application submitted to the FDA.^6,37,39,40 Liraglutide is effective as monotherapy but can be combined with one or more glucose-lowering agents because of the additive benefits of combination therapy. When liraglutide is combined with any oral antidiabetic drugs (OADs), the dose of liraglutide usually does not require adjustment after initial titration although adjustments may be needed to a sulfonylurea dose. This is based on data showing a similar risk of minor hypoglycemia with liraglutide 0.6 mg, 1.2 mg, or 1.8 mg once daily with glimepiride 2 to 4 mg once daily, compared with the combination of glimepiride and placebo (0.17 vs 0.51 vs 0.47 vs 0.17 events/year, respectively).³⁷ Similarly, the percentage of patients reporting minor hypoglycemia was not significantly different for liraglutide compared with placebo when either was used in combination with metformin 1 g twice daily and glimepiride 2 to 4 mg once daily (27% vs 17%, respectively).⁴⁰

Administration. Liraglutide is injected subcutaneously into the abdomen, thigh, or upper arm once daily preferably at the same time each day, independent of meals. Liraglutide can be taken with or without food.^{5,19,21,34,42}

Patient education. Once liraglutide becomes available, patients should be instructed regarding subcutaneous administration, as with exenatide, and any associated concerns. Patients should be advised that the addition of liraglutide to metformin with or without glimepiride may reduce body weight up to an additional 2.8 kg.^6,40

Sitagliptin

The DPP-4 inhibitor sitagliptin (Januvia) is administered orally once daily without regard to meals. The dose of sitagliptin should be reduced in patients with moderate or severe renal dysfunction.⁴³ Sitagliptin is also available as an oral formulation combined with metformin.

Dosing. In patients with normal renal function, the usual dose of sitagliptin is 100 mg. If a patient’s creatinine clearance (CrCl) is 30 to 50 mL/minute, the dose should be reduced to 50 mg, whereas 25 mg is recommended when the creatinine clearance is <30 mL/minute. Although in studies the pharmacokinetics of single-dose glyburide were not significantly altered when combined with multiple doses of sitagliptin, a lower dose of a sulfonylurea may be required when combined with sitagliptin to lower the risk of hypoglycemia. Dosage adjustment is not needed when sitagliptin is used with metformin or a TZD.⁴³

Patient education. Although the safety profile of sitagliptin is similar to placebo, the signs and symptoms of hypoglycemia—and the actions to be taken should it occur—should be discussed with the patient.⁴³ In addition, serious allergic and hypersensitivity reactions such as anaphylaxis, angioedema, and exfoliative dermatitis may occur in some patients. In such cases, the patient should be instructed to stop taking sitagliptin immediately and to seek medical care. Although no clinically meaningful drug interactions have been identified with sitagliptin, patients should be cautioned about beginning or changing any medications, including alternative medicines, without their physician’s or pharmacist’s knowledge.⁴³

Vildagliptin

Vildagliptin is an oral DPP-4 inhibitor that is approved in Europe and is currently under review by the FDA. Although vildagliptin generally possesses a good safety profile, the release of vildagliptin has been delayed due to FDA concerns regarding adverse skin events and elevated liver enzymes.⁴⁴

Dosing. Vildagliptin has been administered over a range of doses in clinical trials, but a daily dose of 100 mg, either once daily or in 2 divided doses, improves A1C and FPG levels.³⁰ Vildagliptin can be taken without regard to meals.⁴⁵

Alogliptin

A new drug application for alogliptin has been submitted to the FDA. Alogliptin is an oral, highly selective DPP-4 inhibitor that does not appear to cause dermal toxicity.⁴⁶

Dosing. Alogliptin has been investigated in doses ranging from 12.5 to 400 mg once daily, with recent investigations using doses from 12.5 mg or 25 mg once daily.^11,47-50 The total exposure to alogliptin increases with increasing doses, ranging from 25 mg to 100 mg once daily for 7 days, although in studies the elimination half-life did not change significantly (14.8 to 17.1 hours).⁵¹ Single-dose pharmacokinetic investigation in subjects with mild renal impairment (CrCl, 51-80 mL/min) indicates no need for dosage adjustment. However, the dose should be reduced by 50% in patients with moderate renal impairment (CrCl, 30-50 mL/min) and by 75% in patients with severe renal impairment (CrCl, < 30 mL/min).⁵²

Saxagliptin

Saxagliptin is an oral DPP-4 inhibitor that has been investigated in several phase 3 clinical trials, primarily involving drug-naïve patients with T2DM.^12,53

Dosing. The clinical efficacy of saxagliptin has been demonstrated using a wide range of doses, from 2.5 mg to 100 mg once daily. Pharmacokinetic studies demonstrate that subjects 65 years or older had a higher total exposure to saxagliptin as a result of a smaller volume of distribution and slower metabolic and renal clearances. No difference was observed between males and females.⁵⁴ Administration of saxagliptin to patients with hepatic impairment demonstrated a <2-fold difference in the pharmacokinetics of saxagliptin or its active metabolite, compared to healthy subjects.⁵⁵

 

Summary

The GLP-1 receptor agonists and the DPP-4 inhibitors can be used as part of a comprehensive plan for managing patients with T2DM. Although exenatide and liraglutide are both GLP-1 receptor agonists, the homology of liraglutide more closely resembles the human GLP-1 hormone. Both are administered subcutaneously, exenatide twice daily and liraglutide once daily. However, exenatide must be administered within 60 minutes of eating, whereas liraglutide can be given independent of meals. Decreasing the dose of a sulfonylurea should be considered when used in combination with a GLP-1 receptor agonist. Exenatide should not be used in patients with moderate to severe renal insufficiency. The DPP-4 inhibitors are generally administered orally once daily, although vildagliptin can also be given twice daily. Dose modification is needed in patients with moderate or severe renal impairment who are taking sitagliptin. The DPP-4 inhibitors are generally well tolerated, although concerns regarding skin toxicity and hepatic injury due to vildagliptin remain unresolved.

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