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INTRODUCTION

As of 2014, an estimated 29.1 million people in the United States (U.S.) have diabetes. Unfortunately, approximately one-third of these people remain undiagnosed.¹ New cases of diabetes are being diagnosed at an alarming rate, with the majority of cases being diagnosed in adults over the age of 45 years. Annual direct medical costs related to diabetes in the U.S. exceed $175 billion and indirect costs total approximately $70 billion.¹ Patients with type 2 diabetes (T2DM) are typically overweight or obese and agents that are commonly used in the treatment of T2DM, such as sulfonylureas and insulin, can cause further weight gain. This article will review evidence supporting the use of glucagon-like peptide-1 (GLP-1) receptor agonists, a class of agents known to cause weight loss, in combination with insulin for the treatment of T2DM.

PATHOPHYSIOLOGY OF T2DM

The pathophysiology of T2DM is multifactorial, but insulin resistance and beta-cell dysfunction are the primary defects.^2,3 Insulin resistance is evident in the liver as hepatic glucose production that remains elevated despite elevated insulin concentrations. In the peripheral tissues, insulin resistance is evident as endogenous insulin that is not able to facilitate glucose uptake into the peripheral tissues. Beta-cell dysfunction results from the inability of beta-cells to compensate for insulin resistance and the resultant hyperglycemia is toxic to the cells. Inappropriate glucagon release is also present in patients with T2DM. Glucagon regulates the rate of gluconeogenesis and glycogenolysis to maintain glucose homeostasis. In patients with T2DM, exogenous insulin is unable to suppress glucagon release, which results in further hyperglycemia.^2,3

TREATMENT CONSIDERATIONS IN T2DM

Unless contraindications exist, all patients should be initiated on metformin and lifestyle interventions at the time of diagnosis with T2DM.^4,5 Metformin is considered first-line therapy due to its proven efficacy, as well as its low cost, general tolerability, low risk of hypoglycemia, neutral/beneficial effects on weight, and cardiovascular benefits. If metformin is not an option, the American Diabetes Association (ADA) guidelines recommend any of the following classes of agents for first-line treatment, in no preferential order: sulfonylureas, thiazolidinediones (TZDs), dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium glucose contransporter-2 (SGLT2) inhibitors, GLP-1 receptor agonists, or basal insulin.⁴ In contrast, the American Association of Clinical Endocrinologists (AACE) guidelines recommend the use of the following agents, in order of preference: GLP-1 receptor agonists, SGLT2 inhibitors, DPP-4 inhibitors, TZDs, alpha-glucosidase inhibitors, sulfonylureas, or meglitinides.⁵ The ADA recommends initial therapy with 2 agents in patients with a baseline hemoglobin A1c (A1c) of 9% or higher, and patients presenting with a baseline A1c of at least 10% to 12% should be initiated on basal insulin plus mealtime insulin or a GLP-1 receptor agonist.⁴ The AACE recommends a more aggressive treatment approach, with dual therapy recommended for patients with a baseline A1c of 7.5% or higher and dual therapy, triple therapy, or insulin with or without other agents when the baseline A1c is greater than 9%.⁵

After 3 months of treatment with the initial agent, if the A1c remains above goal, a second agent should be added.^4,5 Medications with different mechanisms of action for dual therapy and triple therapy should be chosen in order to target the various defects present in T2DM. The ADA recommends that a sulfonylurea, TZD, DPP-4 inhibitor, SGLT2 inhibitor, GLP-1 receptor agonist, or basal insulin be added to metformin for dual therapy.⁴ The AACE recommends, in order of preference, a GLP-1 receptor agonist, SGLT2 inhibitor, DPP-4 inhibitor, TZD, basal insulin, colesevelam, bromocriptine, alpha-glucosidase inhibitor, sulfonylurea, or meglitinide as add-on therapy to metformin.⁵ In general, the addition of a second agent will decrease the A1c no more than 1%. Insulin offers the most substantial lowering of A1c. Therefore, the higher the A1c, the more likely that treatment with insulin will be necessary.⁴ If the A1c goal is not met after 3 months with dual therapy, a third agent should be added. If the A1c remains above goal after 3 months of triple therapy, insulin should be initiated or the existing insulin regimen should be intensified.^4,5 The first insulin chosen should be a basal insulin. However, if basal insulin has already been initiated, prandial insulin or a GLP-1 receptor agonist should be added.^4,5 The benefits of adding a GLP-1 receptor agonist instead of prandial insulin include weight loss, a lower risk of hypoglycemia, and a simpler dosing regimen.⁴ According to the AACE guidelines, the addition of an SGLT2 inhibitor or a DPP-4 inhibitor may also be considered at this step.⁵

Basal insulins are categorized as intermediate-acting or long-acting insulins. Table 1 lists the characteristics of the basal insulins currently on the market in the U.S.⁶ Basal insulin is initiated at 10 units daily or 0.1 to 0.2 units/kg/day and titrated on the basis of fasting plasma glucose (FPG) levels.⁴

Table 1. Characteristics of currently available basal insulin products6

Abbreviations: NPH, neutral protamine Hagedorn

TARGETING POSTPRANDIAL GLUCOSE LEVELS

FPG and A1c levels are traditionally used to assess diabetes control. However, evidence exists to support the importance of postprandial glucose (PPG) as a treatment target. PPG excursions, defined as 2-hour glucose levels above 180 mg/dL, should be suspected when the FPG is normal but the A1c remains elevated.⁴ PPG excursions are a significant factor in glycemic control, especially when the A1c falls below 8.4%. Results from the DECODE trial and the Chicago Heart Association Detection Project revealed that post-load (i.e., after an oral glucose tolerance test) blood glucose levels were a better predictor of cardiovascular mortality than FPG.^7,8 In addition, data from the Diabetes Intervention Study showed that PPG, not FPG, significantly increased the risk of myocardial infarction and death.⁹

Agents that significantly reduce PPG levels include GLP-1 receptor agonists, DPP-4 inhibitors, alpha-glucosidase inhibitors, sulfonylureas, meglitinides, short-acting and rapid-acting insulins, and pramlintide.¹⁰ The GLP-1 receptor agonists are classified as either short-acting or long-acting agents. Short-acting agents include lixisenatide and twice-daily exenatide; dulaglutide, exenatide long-acting release (LAR), liraglutide, semaglutide, and albiglutide are long-acting agents. The short-acting GLP-1 receptor agonists have a more pronounced effect on gastric emptying and, therefore, reduce PPG to a greater extent than the long-acting agents.¹¹

GLP-1 receptor agonists

The GLP-1 receptor agonists are long-acting analogues of native GLP-1, an incretin hormone released by the gut. Active GLP-1 plays a role in glucose homeostasis by decreasing glucagon release, increasing glucose-dependent insulin synthesis and secretion, and improving beta-cell function. GLP-1 also decreases gastric emptying, increases satiety, and decreases food intake.¹² Currently, there are 5 GLP-1 receptor agonists on the market in the U.S.: exenatide (Byetta), exenatide LAR (Bydureon), liraglutide (Victoza), albiglutide (Tanzeum), and dulaglutide (Trulicity). Two additional agents are currently under development: semaglutide, which is in phase III clinical trials, and lixisenatide, which is under final review by the U.S. Food and Drug Administration (FDA). Dosing information for each of the available agents is listed in Table 2. All of the agents can be administered any time of the day, without regard to meals, with the exception of the exenatide twice-daily formulation, which should be administered 60 minutes before meals.^13-17 GLP-1 receptor agonists should be injected subcutaneously into the abdomen, thigh, or upper arm. GLP-1 receptor agonists are only approved for use in T2DM.

Table 2. Dosing guidelines and safety considerations for currently available glucagon-like peptide-1 receptor agonists13-17

Abbreviations: CrCl, creatinine clearance; LAR, long-acting release; MEN2, multiple endocrine neoplasia syndrome type 2; MTC, medullary thyroid carcinoma; URTI, upper respiratory tract infection

Although the A1c reduction is similar between short-acting and long-acting GLP-1 receptor agonists, the mechanisms by which they lower A1c are slightly different. Short-acting GLP-1 receptor agonists have less of an effect on FPG and more of an effect on PPG than long-acting agents; long-acting agents primarily affect FPG. A recent review of head-to-head clinical trials of GLP-1 receptor agonists showed significant differences in weight loss among agents.¹⁸ In trials that compared a short-acting agent to a long-acting agent, long-acting agents produced significantly more weight loss. Of the short-acting agents, twice-daily exenatide led to significantly more weight loss than lixisenatide.¹⁹ Head-to-head trials comparing long-acting GLP-1 receptor agonists showed that liraglutide caused significantly more weight loss than exenatide LAR,²⁰ albiglutide,²¹ and dulaglutide.²² Common adverse effects, reported in at least 5% of patients, for the GLP-1 receptor agonists are summarized in Table 2. Similarities among the adverse effects of the agents include diarrhea and nausea.^13-17 Patients should be warned that nausea has been reported in up to 40% of patients but that it does subside over time for most patients. The incidence of nausea is similar with short-acting and long-acting agents, but nausea appears to improve faster in patients using the long-acting agents.¹¹

The package inserts for the GLP-1 receptor agonists, with the exception of immediate-release exenatide, contain black box warnings concerning the risk of thyroid c-cell tumors. This concern arose from animal data; it is unknown whether GLP-1 receptor agonists cause these tumors in humans. Nonetheless, use of these agents is contraindicated in patients with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2. Patients should be educated about this risk and counseled regarding symptoms of thyroid tumors, which include a mass in the neck, dysphagia, dyspnea, and persistent hoarseness.^14-17 Postmarketing reports of pancreatitis have been associated with GLP-1 receptor agonist use, and clinicians should monitor patients for signs and symptoms of pancreatitis after initiation or dose increases of GLP-1 receptor agonists. Patients should be educated to seek medical help immediately if they experience persistent, severe abdominal pain, as this is a warning sign for pancreatitis.^13-17 Each of the GLP-1 receptor agonists are being monitored under an FDA Risk Evaluation and Mitigation Strategy program; fact sheets for each agent can be found on the FDA website.

Other precautions and warnings to consider before initiating a GLP-1 receptor agonist include renal impairment and severe gastrointestinal (GI) disease. Postmarketing reports of acute renal failure and worsening of chronic renal failure have been associated with GLP-1 receptor agonist use. Many of these events occurred in patients who reported severe GI adverse reactions including nausea, vomiting, diarrhea, and dehydration. Clinicians should consider monitoring renal function with the initiation and dose escalation of GLP-1 receptor agonists. Renal function should be closely monitored in patients complaining of severe GI adverse reactions.^13-17 Since GLP-1 receptor agonists affect gastric emptying, these agents should be avoided in patients with severe GI disease. However, none of the agents have been studied in such patients.^13-17

Combinations of GLP-1 receptor agonists and insulin

Studies have shown that combining a GLP-1 receptor agonist with insulin improves glycemic control and causes weight loss. Further, by combining these agents, patients are often able to decrease daily insulin requirements, which not only reduces weight gain but also affords the patient a simpler dosing regimen. The package inserts for the GLP-1 receptor agonists warn clinicians to exercise caution when combining these agents with insulin due to the potential for severe hypoglycemia. However, little to no hypoglycemia has been reported in studies of combination therapy. Table 3 summarizes the evidence supporting the use of GLP-1 receptor agonists in combination with insulin.

Table 3. Summary of clinical trials of combined glucagon-like peptide-1 receptor agonist and insulin

Abbreviations: ALB, albiglutide; ASP, insulin aspart; DEG, insulin degludec; DET, insulin detemir; EXE, exenatide; GLAR, insulin glargine; LIR, liraglutide; LIS, insulin lispro; LIX, lixisenatide; LixiLan, lixisenatide + insulin glargine; NON-DET, non-detemir-treated patients; PBO, placebo

Several studies have examined the effect of adding a GLP-1 receptor agonist to an existing insulin regimen in patients with T2DM. In one study, the addition of liraglutide or twice-daily exenatide in patients using various insulin regimens (multiple daily injections, basal only, or premixed) resulted in a mean A1c reduction of 1% and an average weight loss of 7.1 kg (p < 0.001 for both assessments).²³ Also, patients were able to significantly decrease their daily insulin requirements by an average of 38.6 units. A retrospective study examined the effect of twice-daily exenatide on glycemic control, weight, and insulin dose.²⁴ Similar to the previous study, patients in this study were on various insulin regimens. The mean decreases in A1c and weight were significant at each time period reported. Total daily doses of insulin were not significantly reduced, but, when prandial insulin doses were examined separately, it was discovered that exenatide led to significant decreases in prandial insulin doses at all time periods. An observational study examined the effect of adding liraglutide to patients currently using U-500 insulin.²⁵ This study involved 15 obese patients who were using an average of 192 units of U-500 insulin daily. Liraglutide (up to 1.8 mg daily) use resulted in a 1.4% reduction in A1c (p = 0.0001). In addition, weight decreased by an average of 5.1 kg and insulin doses decreased by approximately 28% (p = 0.0001 for both assessments).

The addition of a GLP-1 receptor agonist to patients on basal insulin only (with or without oral agents) has been examined in several studies. When liraglutide was added to patients inadequately controlled on basal insulin, patients experienced an average A1c decrease of 1.3% compared to placebo (p < 0.001).²⁶ Weight decreased significantly more in the liraglutide group with a between-group difference of approximately 3.1 kg (p < 0.001). A study investigating the use of twice-daily exenatide added to insulin glargine revealed a 0.7% reduction in A1c compared to placebo (p < 0.001).²⁷ Although insulin doses increased in both groups, they increased less in the group receiving concomitant exenatide than in the insulin glargine-only group (13 units and 20 units, respectively). Also, patients in the exenatide group experienced weight loss while those in the placebo group gained weight. Two studies examined the effect of adding lixisenatide to patients on basal insulin.^28,29 The results of one of these studies showed a decrease in A1c of 0.71% with lixisenatide and 0.4% with placebo (p < 0.001). PPG was also significantly decreased in the lixisenatide group compared to the placebo group, and significantly more patients taking lixisenatide achieved an A1c of less than 7%.²⁹ Similarly, the second study found a mean difference in A1c lowering of 0.88% with lixisenatide compared to placebo (p < 0.001).²⁸ Lixisenatide use also significantly improved PPG and FPG compared to placebo.

Lingvay et al³⁰ examined the effect of a fixed-dose combination of liraglutide plus insulin degludec (basal insulin) versus continuing insulin glargine alone. Mean A1c decreased by 1.81% in the insulin degludec/liraglutide group and by 1.13% in the insulin glargine group. These results showed that insulin degludec/liraglutide was superior to insulin glargine alone (p < 0.001). Body weight decreased by 1.4 kg in the insulin degludec/liraglutide group and increased by 1.8 kg in the insulin glargine group (p < 0.001). The results of this trial were similar to those reported in a pooled analysis of 5 other studies evaluating the use of insulin degludec plus liraglutide.³¹ The analysis found the combination to be non-inferior (and, in some cases, superior) to up-titration of basal insulin or basal/bolus insulin regimens and resulted in less hypoglycemia and weight gain in patients with T2DM. Another study examining the effect of a fixed-dose combination of a GLP-1 receptor agonist and basal insulin compared lixisenatide plus insulin glargine (LixiLan) to insulin glargine alone.³² The mean A1c decreased by 1.7% in the LixiLan group and by 1.5% in the insulin glargine group. These results showed LixiLan was superior to insulin glargine alone (p = 0.01). Improvements in body weight and PPG were also significant in the LixiLan group compared to insulin glargine alone (p < 0.001 for both assessments).

DeVries and colleagues³³ examined the effect of adding liraglutide to insulin-naïve patients on metformin (with or without a sulfonylurea); basal insulin was added if further treatment was required. After a 12-week run-in period with liraglutide, patients were randomized to receive open-label insulin detemir or no additional insulin for 26 weeks. Following randomization, the addition of insulin detemir led to a significant reduction in A1c of 0.5%; patients not using insulin detemir experienced an A1c increase of 0.02% (p < 0.001). Mean body weight decreased by 0.16 kg in patients who required additional insulin and by 0.95 kg in patients who did not require additional insulin. This study is the first to examine the effect of adding insulin to a GLP-1 receptor agonist versus adding a GLP-1 receptor agonist to an existing insulin regimen.

The addition of a GLP-1 receptor agonist compared to prandial insulin in patients not controlled on basal insulin has been evaluated in several studies. In a study comparing albiglutide to 3-times-daily prandial insulin (insulin lispro), A1c decreased by 0.82% in the albiglutide group and by 0.66% in the insulin lispro group.³⁴ The treatment difference between albiglutide and insulin lispro met non-inferiority criteria for albiglutide compared to insulin lispro. Weight decreased from baseline in the albiglutide group and increased in the insulin lispro group, with a between-group difference of -1.5 kg (p < 0.001). Hypoglycemia was twice as common in the insulin lispro group. A similar study compared the effects of adding twice-daily exenatide to 3-times-daily insulin lispro in patients uncontrolled on basal insulin.³⁵ After 30 weeks, the between-group difference in A1c was found to be non-inferior for exenatide compared to insulin lispro. In addition, significant improvements in weight and FPG were experienced by patients in the exenatide group (p < 0.001 and p = 0.002, respectively). Lixisenatide once daily was compared to insulin glulisine 1 or 3 times daily added to basal insulin in a 26-week trial.³⁶ Results of this trial were similar to the aforementioned trials, and, in terms of A1c improvement, the addition of lixisenatide was non-inferior to the addition of insulin glulisine 1 or 3 times daily. In addition, lixisenatide was superior to 3-times-daily insulin glulisine for changes in body weight. Finally, the addition of liraglutide was compared to a single daily dose of insulin aspart in patients uncontrolled on insulin degludec.³⁷ A1c improved significantly more in the group using liraglutide than in the group using insulin aspart, with a between-group difference of 0.32% (p = 0.0024). Weight loss was also significantly greater in the liraglutide group, with a between-group difference of 3.75 kg (p < 0.001).

MEDICATIONS CURRENTLY IN DEVELOPMENT THAT TARGET PPG

Lixisenatide is a GLP-1 receptor agonist currently approved in Europe as Lyxumia; it is under review by the FDA for approval in the U.S. Lixisenatide is administered once daily, 60 minutes before a meal.³⁸ Considering the European prescribing information, lixisenatide is likely to have the same warnings and precautions as the other GLP-1 receptor agonists. Sanofi expects a response from the FDA regarding lixisenatide approval in July 2016.³⁹

Combination products that include a basal insulin and a GLP-1 receptor agonist are currently under development. Sanofi has submitted a new drug application for a combination product including insulin glargine and lixisenatide.³⁹ Novo Nordisk's combination product, Xultophy, contains insulin degludec and liraglutide; it is currently approved in Europe and is awaiting approval by the FDA in the U.S.⁴⁰ Both combination products have been recommended for approval by an FDA Advisory Panel.^41,42 Combination products such as these would improve patient adherence due to simple dosing regimens.

SUMMARY

T2DM is a significant contributor to increasing health care costs in the U.S. With adequate control of glucose levels, complications associated with diabetes can be reduced. GLP-1 receptor agonists are safe and effective for controlling blood glucose levels and treating T2DM. These agents are also fairly well tolerated: GI effects are the most common adverse effects, but these symptoms abate over time. Safety concerns, including the risks of thyroid cancer and pancreatitis, should be considered before initiating a GLP-1 receptor agonist. Despite the warning found in the package labeling, clinical evidence supports the use of combining a GLP-1 receptor agonist with basal insulin. Recently, published guidelines for the treatment of diabetes have changed to reflect the role of this combination. Further, the use of GLP-1 receptor agonists is now considered an alternative to preprandial insulin, a former mainstay of diabetes therapy. The combination of GLP-1 receptor agonists and basal insulin offers patients a simple dosing regimen, weight reduction, and glycemic control of both FPG and PPG levels.

References

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