It is estimated that 29.1 million people or 9.3% of the US population have diabetes, which contributes to considerable medical and financial burden.1 Type 2 diabetes mellitus is characterized by insulin resistance, and by some impairment in insulin secretion leading to hyperglycemia. The presence of insulin resistance is strongly correlated with obesity.1
A significant challenge in the treatment of diabetes is avoiding the development of hypoglycemia, particularly with sulfonylureas and insulin. Complications of hypoglycemia include unconsciousness, brain damage, and even death if untreated.1 Another adverse effect associated with the treatment of diabetes is weight gain, which occurs with most antidiabetes agents, including sulfonylurea, insulin, and thiazolidinediones.2 Because obesity is closely linked to diabetes, these agents’ efficacy in treating diabetes become partly limited because of their link to weight gain.2
Cost is also an important consideration when selecting among the many antidiabetes medications. Table 1 compares the costs of diabetic agents. Glucagon-like peptide (GLP)-1 receptor agonists are generally the most expensive agents. Of note, the cost of Soliqua 100/33 (insulin glargine and lixisenatide injection), which is a combination of insulin glargine and a GLP-1 receptor agonist, is comparable to other GLP-1 receptor agonists that are given as monotherapy. The cost of individual antidiabetes agents may vary depending on insurance coverage, although coupons are often available for a significant cost reduction. Although the cost of diabetes medications (and associated supplies) is significant (12% of the overall cost of treating diagnosed diabetes), the costs of treating the complications of diabetes (18%) and of diabetes-related inpatient care (43%) are even greater.3 Therefore, it is more cost-effective for patients when their diabetes is appropriately controlled with medications, as necessary.
The Rationale for GLP-1 Receptor Agonists
The pathology of type 2 diabetes involves inherited traits and environmental factors. The vast majority of patients with type 2 diabetes have a genetic risk for insulin resistance; however, the risk for diabetes also worsens with increasing age and weight.2 Obese patients have more adipocytes, which release leptin, adiponectin, tumor necrosis factor–alpha, and resistin, and these hormones are thought to further contribute to insulin resistance.
During periods of hyperglycemia, there is an increase in glucose transport into beta-cells of the pancreas, which leads to insulin secretion. It is well-recognized that continued poor control of hyperglycemia leads to a decline in beta-cell function, which is likely a result of decreased insulin gene expression and decreased production of insulin. Therefore, it is important that lifestyle changes and treatments are implemented to maintain euglycemia. Uncontrolled diabetes will eventually lead to complications, such as microvascular disease (ie, retinopathy, nephropathy, and neuropathy), and cardiovascular (CV) events and hypertension.
Insulin secretion occurs in 2 phases. The first phase occurs after a meal, manifested as an immediate rise in insulin lasting approximately 10 minutes. This is followed by a second phase, in which insulin is released more slowly for a prolonged period. Patients with type 2 diabetes have markedly reduced first-phase insulin secretion, which likely explains why the majority have persistently elevated postprandial glucose concentrations despite relatively normal fasting glucose levels.4,5 The beta-cells in the pancreas respond to this by increasing second-phase insulin response.6 However, prolonged elevation of insulin from persistent hyperglycemia leads to beta-cell toxicity and ultimately contributes to insulin resistance.7 Interventions that mimic normal first-phase insulin secretion, rather than the second phase, have been correlated with improved glucose tolerance.8
GLP-1 is a naturally occurring hormone responsible for the incretin effect. The incretin effect is a response to release more insulin because of high glucose levels after a meal. Studies suggest that patients with type 2 diabetes have an attenuated incretin effect, possibly because of reduced levels of active GLP-1.9 Evidence shows that GLP-1 regulates the expression of beta-cell genes by inhibiting beta-cell apoptosis, preventing beta-cell glucolipotoxicity, and improving beta-cell function.10 GLP-1 has been shown to suppress glucagon release and hepatic glucose output.10 GLP-1 also decreases the rate of gastric emptying and acid secretion, thereby reducing appetite and contributing to weight loss. GLP-1 is degraded by dipeptidyl peptidase (DPP)-4, resulting in a shorter half-life, as shown in patients with type 2 diabetes and in healthy volunteers.11 This has led to the development of DPP-4 inhibitors, which inhibit the degradation of GLP-1. GLP-1 had been considered a treatment modality, but it has a very short half-life and would require continuous infusions.11 This has led to the development of GLP-1 receptor agonists, which are structurally similar to the natural hormone to provide beneficial effects but differ structurally to prevent breakdown by DPP-4.
This article reviews the evidence available for current GLP-1 receptor agonists.
Exenatide (Byetta) is a synthetic derivative of exendin-4 (isolated from salivary secretions of the Gila monster lizard) with a 53% amino acid sequence overlap.12 In 2005, it became the first GLP-1 receptor agonist to receive approval by the US Food and Drug Administration (FDA) for the treatment of type 2 diabetes. As an agonist of pancreatic beta-cells and resistance from DPP-4 inactivation, exenatide has a longer duration of action than GLP-1 and more than 1000-fold potency for lowering glucose than GLP-1.12 Exenatide has been shown to stimulate insulin production in response to blood glucose concentration, inhibit postprandial glucagon release, slow the rate of gastric emptying, slow the rate of nutrient absorption in the bloodstream, and reduce appetite.12 It is also found to promote the proliferation of beta-cells and islet-cell neogenesis from precursor cells.12
Exenatide was first introduced as a twice-daily injection of 5 mcg for 1 month followed by 5 mcg or 10 mcg. Pharmacokinetics demonstrated a plasma level reaching peak concentrations at 2 to 3 hours after administration with levels remaining detectable for 6 hours after administration. Patients with type 2 diabetes who were inadequately controlled with a sulfonylurea and/or metformin were given 0.08-mcg/kg subcutaneous injections of exenatide, which showed significant reductions in postprandial plasma glucose (PPG) and glycated hemoglobin (HbA1c).12
Exenatide was studied in the phase 3 clinical trials AMIGO I, II, and III.12,13 In all 3 trials, the continuation of previous therapy (with metformin alone, sulfonylurea alone, or the combination of both) was compared between the addition of exenatide and placebo. The exenatide treatment group demonstrated a significant reduction in PPG concentrations and HbA1c compared with the placebo group. Nausea was the most common adverse effect, with an increased rate of nausea in the exenatide groups versus the placebo groups. The rates of hypoglycemia in AMIGO I, which included patients who had received metformin, were equal between the exenatide and the placebo groups; however, in the AMIGO III study, which included patients who had received sulfonylurea and metformin combination therapy, patients receiving 10-mg exenatide had increased hypoglycemia (28% vs 13% in the placebo group). No changes in heart rate, blood pressure, and electrocardiograms were noted. The small increase in cortisol levels normalized by day 28.12,13
Buse and colleagues compared exenatide 5 μg twice daily for 4 weeks and then 10 μg twice daily thereafter with placebo in patients receiving insulin glargine.14 Insulin glargine was titrated to achieve a fasting glucose of <100 mg/dL on the basis of the Treat-to-Target Trial algorithm. The study showed an HbA1c reduction of 1.74% with exenatide versus 1.04% with placebo. No significant increase in hypoglycemia or weight gain occurred. Similar to the AMIGO trials, exenatide was associated with more events of nausea (41% vs 8%, respectively) and vomiting (18% vs 4%, respectively) than placebo.14
A new formulation of exenatide, exenatide extended-release (ER; Bydureon) 2-mg once-weekly injection was approved by the FDA in 2012 as an adjunct therapy or monotherapy in patients with type 2 diabetes.15 Exenatide ER reaches therapeutic levels after 2 weeks, and after 6 weeks the drug attains a maximum concentration higher than that attained by a single injection of exenatide 10 mcg.15 Six weeks after stopping treatment, the serum concentration of exenatide once weekly declines to insignificant levels.
The phase 3 clinical trials of exenatide ER included the DURATION series, and are summarized in Table 2.16-22 DURATION-1 and -5 compared exenatide twice daily versus exenatide ER, showing that exenatide ER had a greater HbA1c reduction and better glucose control compared with the twice-daily formulation. DURATION-2 and -4 compared exenatide ER with other diabetic oral medications, including pioglitazone, sitagliptin, and metformin, which demonstrated comparable efficacy in reducing HbA1c and significantly reducing weight.16-21
Exenatide was associated with an increase in gastrointestinal (GI) adverse effects, including nausea, vomiting, and diarrhea,16-21 as is expected of the GLP-1 class. Nausea was most notable during the first few weeks of therapy and was minimized by gradual dose titration. In DURATION-2 and -4, no significant differences were reported in the rates of hypoglycemia between exenatide ER and metformin, pioglitazone, or sitagliptin.18,20 DURATION-3 compared exenatide ER with insulin glargine, showing 3 times fewer hypoglycemic events with the GLP-1 inhibitor than in the insulin glargine group.19
Mild injection-site pruritus was observed more often with exenatide ER, but it resolved with treatment continuation.17 Despite concerns for a possible association of exenatide and the other GLP-1 receptor agonists with increased risk for pancreatitis, this was not observed in the DURATION trials.15
Liraglutide (Victoza) is an acylated analog of GLP-1 that has 97% amino acid sequence identity to the endogenous GLP-1 analog. In 2009, it was the second GLP-1 agonist to be approved by the FDA for the treatment of type 2 diabetes. Liraglutide is a long-acting GLP-1 receptor agonist that is administered once daily as a subcutaneous injection in contrast to twice-daily injections of the first exenatide formulation.23 Liraglutide has been reported to increase beta-cell mass in animal models via increased beta-cell replication and reduced apoptosis.24 In a study with normal-weight and obese rats, liraglutide was associated with a reduction in food intake, resulting in weight loss of approximately 15%.25 Preclinical studies showed improvement in first- and second-phase insulin secretion, implying that liraglutide leads to improved biphasic insulin secretion in response to hyperglycemia.26,27
The Liraglutide Effect and Action in Diabetes (LEAD) program is comprised of 6 phase 3 clinical trials, which are summarized in Table 3.28-33 Liraglutide, given as adjunct therapy and as monotherapy, was associated with significant reductions in HbA1c levels, blood pressure, fasting plasma glucose (FPG), and PPG levels.28-33 Liraglutide is superior to insulin glargine and to twice-daily exenatide in HbA1c reduction. Weight loss was similar between the liraglutide and the exenatide groups, but greater weight loss was seen with liraglutide compared with insulin glargine.28-33
The LEAD trials showed that the risk for hypoglycemia is low with liraglutide and is significantly lower than with a sulfonylurea or twice-daily exenatide.28-33 Like exenatide, liraglutide was associated with increased GI side effects, including nausea and vomiting, which were generally mild and transient. A total of 3.4% of the patients receiving liraglutide in the phase 3 trial withdrew because of nausea.30 In general, the GI adverse effects can be managed by starting at lower doses of liraglutide and then gradually increasing the dose. Liraglutide was associated with a lower antibody formation than exenatide, likely because of the greater (97%) amino acid sequence identity than human GLP-1.34 Exenatide has a lower sequence identity than liraglutide, which may explain the incidence of anti-exenatide antibody formation in up to 43% of exenatide-treated patients.35
There have been few case reports of liraglutide-associated pancreatitis. Studies in rodents have shown that liraglutide induces C-cell proliferation and medullary thyroid adenomas and carcinomas via GLP-1 receptor agonist activation and calcitonin release, but this pattern was not seen in humans. Follow-up studies have been inconclusive to definitively define a cause-and-effect relationship between liraglutide and pancreatitis, because patients with type 2 diabetes already have a 3-fold increased risk for pancreatitis.36 In the LEADER trial, liraglutide taken for 3.5 years was associated with a 23% reduction in CV events, a 22% reduction in CV mortality, and a 15% reduction in all-cause mortality.37
Albiglutide (Tanzeum) is a GLP-1 agonist that was approved by the FDA in 2014 as an adjunct treatment for diabetes; it is administered as a weekly injection.38 Albiglutide has 97% homology to the amino acid sequence of GLP-1. A single amino acid substitution (alanine to glycine) renders albiglutide resistant to DPP-4–mediated protein degradation, resulting in a longer half-life. After subcutaneous injection of a single 30-mg dose, patients with type 2 diabetes achieved mean maximum plasma concentration 3 to 5 days after administration. Plasma concentrations reach steady state within 3 to 5 weeks of repeated once-weekly administrations. Albiglutide is currently available as a 30-mg and a 50-mg once-weekly injection.38
Albiglutide was tested in the HARMONY phase 3 clinical trials, which comprised 8 studies (Table 4).39-46 HARMONY-2 demonstrated the superiority of albiglutide monotherapy to diet and exercise in glycemic control.40 In HARMONY-3, once-weekly albiglutide add-on therapy was noninferior to once-daily sitagliptin and once-daily glimepiride at reducing HbA1c levels in patients inadequately controlled with metformin alone,41 whereas HARMONY-4 and -6 demonstrated that albiglutide was noninferior to insulin therapy in patients inadequately controlled with oral antidiabetes therapy.42,44 However, in HARMONY-5, albiglutide was found to be inferior to pioglitazone in HbA1c reduction.43 HARMONY-8 revealed that albiglutide was superior to sitagliptin in patients with and without renal impairment.46
Albiglutide demonstrated greater weight loss in all studies compared with sitagliptin, glimepiride, pioglitazone, and insulin therapy, although more GI adverse effects were reported with albiglutide compared with other agents.39-46 All trials demonstrated no significant differences in rates of hypoglycemia, except in patients with impaired renal disease who used albiglutide and a sulfonylurea.39-46
Dulaglutide (Trulicity) is a once-weekly subcutaneously administered GLP-1 receptor agonist approved by the FDA in 2014 as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes.47 The initial dosage is 0.75 mg administered subcutaneously once weekly, which may be increased to 1.5 mg once weekly for additional glycemic control. Dulaglutide is comprised of 2 identical GLP-1 analog peptide chains (approximately 90% homologous to native human GLP-1) linked to an immunoglobulin (Ig) G4 heavy chain. The alteration of the GLP-1 analog provides protection against degradation by DPP-4, improved solubility, and reduced immunogenicity. The addition of IgG4 increases the size of the protein, which helps decrease the rate of renal clearance, and the Fc fragment of IgG4 prevents antibody formation to further reduce the potential for immunologic cytotoxicity.47
Dulaglutide has been studied in comparison with other antidiabetes agents and with placebo in the phase 3 AWARD trials (Table 5).48-54 These trials demonstrate that once-weekly dosing of 1.5-mg dulaglutide was superior to metformin, insulin glargine, and sitagliptin in reducing HbA1c levels; dosing with dulaglutide 0.75 mg was noninferior to these agents. Patients in these trials experienced greater loss with 1.5-mg and with 0.75-mg dosing of dulaglutide compared with other agents. In patients taking dulaglutide and insulin concomitantly, there was either attenuation of the weight gain or overall weight loss compared with patients receiving placebo.48-54 In AWARD-6, patients receiving liraglutide 1.8 mg experienced greater weight loss than those receiving dulaglutide 1.5 mg.53
Similar to other GLP-1 receptor agonists, the most frequently reported adverse events with dulaglutide were GI in nature, including nausea, vomiting, and diarrhea.48-54 These events were generally mild to moderate, peaked at 2 weeks, and rapidly declined over the next 4 weeks. The majority of adverse events were reported during the first 2 to 3 days after receiving the initial dose and declined with subsequent doses. Hypoglycemic events were not common in patients taking dulaglutide, and occurred less frequently compared with patients receiving insulin therapy, as was shown in AWARD-2 and -449,51; however, significantly more hypoglycemic events were reported with a sulfonylurea as background therapy compared with placebo as demonstrated in AWARD-8.48-54
Given its mechanism of action, dulaglutide was evaluated for pancreatic safety. Throughout the AWARD trials, 4 events were reported in patients taking dulaglutide (3 patients receiving dulaglutide 1.5 mg and 1 receiving the 0.75-mg dose). Laboratory studies of pancreatic amylase and lipase in these trials revealed a mean 14% to 20% increase in amylase and lipase levels in patients receiving dulaglutide; however, these events were not predictive of acute pancreatitis. Given the association of GLP-1 analogs with medullary thyroid carcinoma, thyroid safety was assessed as well. In the AWARD trials, only 1 case of medullary thyroid carcinoma in AWARD-5 was reported, although this case was determined to be preexisting.52
Lixisenatide (Adlyxin) is a once-daily subcutaneous GLP-1 receptor agonist that was approved by the FDA in July 2016 for the treatment of type 2 diabetes in adults.55 Lixisenatide is designed as C-terminal modification with 6 lysine residues and deletion of 1 proline, allowing it to withstand physiologic degradation by DPP-4. Lixisenatide is renally excreted, with a half-life of 2 to 4 hours. Despite its short half-life, lixisenatide is intended for once-daily dosing as a result of its strong binding affinity to the GLP-1 receptor. No clinically relevant difference was found in the rate of absorption if lixisenatide is injected into the abdomen, thigh, or arm. In a dose-dependent manner, lixisenatide tested at 5-mcg, 10-mcg, and 20-mcg doses reached peak concentrations between 1 and 2 hours.55 Preclinical trials have also shown that the addition of a GLP-1 receptor agonist to insulin analog–like glargine demonstrated a protective effect on beta-cells, suggesting that the combination of these medications may preserve beta-cell mass in patients with type 2 diabetes.56 Thus, in November 2016, the FDA approved the combination of lixisenatide with insulin glargine (Soliqua 100/33).
Lixisenatide was studied in the 10 phase 3 GETGOAL clinical trials that assessed its efficacy and safety profile (Table 6).56-64 In these trials, the 20-mcg dose of lixisenatide was selected, because it had demonstrated in previous trials the best efficacy-to-tolerability ratio. The phase 3 studies assessed lixisenatide in a 1-step titration as a 10-mcg dose for 2 weeks, then a 20-mcg dose once-daily subcutaneously, and in a 2-step titration as a 10-mcg dose for 1 week, 15-mcg dose for 1 week, and then as a 20-mcg dose. In all these trials except GETGOAL-M,64 lixisenatide was administered in the morning. No significant differences were seen in efficacy and adverse events between the 1- and 2-step titration groups.56-64
Lixisenatide demonstrated superiority in reducing HbA1c, PPG, and FPG compared with placebo monotherapy or adjunct therapy. In GETGOAL-X, lixisenatide demonstrated noninferiority with HbA1c reduction compared with exenatide 10 mcg twice daily. Weight loss was superior with lixisenatide treatment in all trials, except GETGOAL-M,64 compared with placebo56-64; however, in GETGOAL-X, lixisenatide treatment resulted in an average 2.8-kg weight loss compared with 3.8 kg in the exenatide group.63
As with other GLP-1 analogs, there was an increase in GI adverse effects with lixisenatide, including nausea and vomiting, as reported in GETGOAL-F1,58 GETGOAL-S,59 GETGOAL-L,60,62 GETGOAL-P,61 and GETGOAL-M64; however, there were fewer reports of nausea compared with exenatide. In all trials where lixisenatide was not combined with insulin, pioglitazone, or a sulfonylurea, no increase in hypoglycemic events was seen compared with placebo. If combined with these agents, the lixisenatide groups exhibited more hypoglycemic events. Compared with exenatide, fewer hypoglycemic events were reported in the patients receiving lixisenatide.56-64
CV outcomes were studied with lixisenatide in the separate phase 3 ELIXA trial.65 Patients who take lixisenatide do not have any increase in CV adverse effects after an acute coronary syndrome compared with placebo. In addition, no significant CV benefit was seen compared with placebo.65
Semaglutide is an investigational agent that was developed as a once-weekly subcutaneous formulation, as well as the first oral GLP-1 analog formulation. The manufacturer applied for regulatory approval by the FDA of the injectable formulation in December 2016, after the phase 3 clinical trial SUSTAIN-6 showed promising results, including HbA1c reduction, weight loss, and CV benefit.66 The oral formulation is still in phase 3 clinical trials.67
The SUSTAIN-6 trial showed the weekly subcutaneous formulation of semaglutide to have a significant HbA1c reduction of 0.7% with the 0.5-mg dose, and 1% with the 1-mg dose, compared with placebo.68 Patients in the 0.5-mg group had a weight loss of 2.9 kg, and the 1-mg group had a 4.3-kg weight loss. Nonfatal myocardial infarction occurred in 2.9% of patients receiving semaglutide versus 3.9% in patients receiving placebo. Nonfatal stroke occurred in 1.6% and 2.7% of the patients, respectively. The rate of death from a CV cause was similar in both groups. The rate of new or worsening nephropathy was lower in the semaglutide group than in the placebo group, although the rate of retinopathy complications was significantly higher with semaglutide.68
Perhaps the most exciting development in the GLP-1 class is the oral formulation of semaglutide that has shown promising results in its phase 2 trial and is currently undergoing a phase 3 study.69 This oral formulation is combined with the absorption enhancer SNAC (sodium N-[8-(2-hydroxybenzoyl)amino] caprylate), which causes a localized increase in pH. This enables higher solubility and protects from enzymatic degradation. The patients in the phase 2 study experienced dose-dependent decreases in their HbA1c and had similar results in their weight loss and other secondary outcomes.69 Mild-to-moderate GI side effects were the most frequently reported adverse events, which included nausea (13%-34%), vomiting (6%-22%), and diarrhea (7%-23%).69
Comparison of GLP-1 Receptor Agonists
Currently, 5 GLP-1 receptor agonists are FDA-approved in the United States for the treatment of patients with type 2 diabetes. Their formulations vary from the twice-daily injection of exenatide to once-weekly formulations of albiglutide, exenatide ER, and dulaglutide. Several head-to-head comparison studies have compared the GLP receptor agonists. A new drug is currently under FDA review.
Comparing exenatide twice daily with exenatide once weekly showed a significantly greater reduction of HbA1c with exenatide ER (difference, 0.7%)17; the adverse effects were similar, but injection-site reactions were more common with exenatide ER. In DURATION-6, once-daily treatment with liraglutide 1.8 mg resulted in significantly greater reduction of HbA1c (difference, 0.21%) and greater weight loss (difference, 0.90 kg) in comparison with once-weekly exenatide 2 mg, although GI adverse events occurred more often with patients taking liraglutide.22
Similarly, in LEAD-6, liraglutide 1.8 mg had a significantly greater HbA1c reduction (difference, –0.33%) and less adverse effects, including hypoglycemia, than exenatide 10 mcg twice daily.33 HARMONY-7 compared once-weekly albiglutide 50 mg with liraglutide 1.8 mg and showed greater HbA1c reduction with liraglutide (difference, 0.21%; noninferior).45 There were more injection-site reactions with albiglutide (difference, 7.5%), but more GI events with liraglutide (difference, 13.1%).45 AWARD-6 compared once-weekly dulaglutide 1.5 mg with liraglutide 1.8 mg, showing greater HbA1c reduction with dulaglutide (difference, –0.06%; noninferior), although liraglutide had significantly greater weight loss (difference, 0.71 kg). No significant differences in the adverse-effect profile were noted in the study.53
GETGOAL-X compared lixisenatide 20 mcg with exenatide 10 mcg twice daily and showed similar HbA1c reduction, although there was less hypoglycemia and nausea with lixisenatide.63 Lixisenatide is currently marketed mainly as a 5-mcg dose in combination with insulin glargine (Soliqua).
The GLP-1 receptor agonists are valuable options for the treatment of type 2 diabetes as adjunctive therapy or as monotherapy. There is robust evidence supporting the indication for the use of GLP-1 receptor agonists if patients are overweight or obese, have CV disease or renal disease, or are at high risk for hypoglycemia—common comorbidities of type 2 diabetes. Clinical trials demonstrate the superiority of GLP-1 receptor agonists to other antidiabetes drugs in HbA1c reduction, blood pressure reduction, and weight loss, without hypoglycemia risk. Unlike metformin, there is no contraindication to giving patients with renal disease a GLP-1 receptor agonist. Although some significant differences exist among the agents in this class, the efficacy of the individual agents is generally comparable. Choosing among the available GLP-1 receptor agonists will likely depend on patient preferences, reaction to adverse effects, and cost.
Author Disclosure Statement
Dr Tran, Dr Park, Dr Pandya, Dr Muliyil, Dr Jensen, and Dr Huynh reported no conflicts of interest. Dr Nguyen is on the Speaker’s Bureau for AstraZeneca, Janssen, and sanofi-aventis.
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