Exenatide is a synthetic form of exendin-4 (originally identified in the salivary gland enzyme of the Gila monster). Despite sharing only 53% amino acid sequence identity with human GLP-1, it fully activates the human GLP-1 receptor and is resistant to degradation by DPP-4. Thus, exenatide can be used twice daily by subcutaneous injections (rather than continuously, as would be needed with native human GLP-1, which has a plasma half-life of <2 min). Exenatide received regulatory approval in the US in 2005 for use in patients with T2DM as an adjunct to lifestyle modifications, as monotherapy, or in combination with other oral agents, and later also with basal insulin based on a series of registration trials. To summarize, as monotherapy, exenatide (10 μg, s.c., twice daily) reduces HbA1c by approximately 0.9–1% from a mean baseline HbA1c of 7.8%,[50, 51] reduces fasting glucose by approximately 18 mg/dL, and reduces weight by approximately 3 kg. In a series of 30-week placebo-controlled trials as add-on to sulfonylurea, metformin, and sulfonylurea + metformin, exenatide (5 μg b.i.d. for 4 weeks, then 10 μg b.i.d.) resulted in a decrease in HbA1c of 0.8–0.9% from a baseline of 8.2–8.6% and mean weight reductions of 1.6–2.8 kg.[52-54] In an interesting study of patients failing metformin monotherapy (HbA1c 8.8–8.9%) who were randomized either to added exenatide or glibenclamide for 1 year, there was no difference in glucose lowering between subjects placed in either arm (mean HbA1c decrease 1.0–1.3% with exenatide and glibenclamide), but weight was reduced by exenatide (mean –6.3 kg) but increased with sulfonylurea (+1.3 kg). β-Cell function and high sensitivity C-reactive protein (hs-CRP) were also improved to a greater extent by exenatide. Hypoglycemia was reported more frequently in the group receiving the sulfonylurea. In addition, exenatide twice daily has been reported to improve glycemic control in a study of patients uncontrolled on TZD and TZD + metformin.
Before the introduction of GLP-1 receptor agonists, clinicians often placed patients uncontrolled on dual oral antidiabetic therapy (e.g. metformin + sulfonylurea) on basal insulin as the next step in an attempt to improve glucose control. When twice-daily exenatide was compared with insulin glargine in such a group of patients (baseline HbA1c 8.2%), the glycemic improvements were comparable (HbA1c decreased by ∼ 1% from baseline). However, there was significant weight loss on exenatide (∼2.3 kg) and weight gain on glargine (+1.8 kg) over 26 weeks. Not surprisingly, there was better postprandial glucose control in the exenatide arm and better fasting glucose in the glargine arm. Nausea, vomiting and diarrhea were more common in the exenatide group (57.1% vs. 8.6%, 17.4% vs 3.7%, and 8.5% vs 3.0%, respectively). Exenatide was also compared with glargine in a cross-over trial design and to biphasic premixed insulin aspart, with similar results.[58, 59]
The use of twice-daily exenatide in combination with basal insulin was recently approved in the US. In a study submitted for the regulatory approval of such a combination, adults with T2DM and an HbA1c level of 7.1–10.5% on insulin glargine alone or in combination with metformin or pioglitazone (or both agents) were randomized to receive either exenatide or placebo. The HbA1c level decreased by 1.7% with exenatide and by 1.0% with placebo (between-group difference –0.69%). Weight decreased by 1.8 kg with exenatide and increased by 1.0 kg with placebo (between-group difference –2.7 kg). There was no difference in the incidence of minor hypoglycemia between patients in the two groups. Average increases in insulin dosage with exenatide and placebo were 13 and 20 U/day, respectively. Thus twice-daily exenatide improved glycemic control without increased hypoglycemia or weight gain in participants with uncontrolled T2DM who were receiving insulin glargine. The most common adverse events associated with the use of exenatide included nausea (41% vs 8% in the placebo group), diarrhea (18% vs 8%), vomiting (18% vs 4%), headache (14% vs 4%), and constipation (10% vs 2%). Approximately 10% of patients in the exenatide arm did not finish the 30-week study.
An intriguing question has long been asked: would combining a DPP-4 inhibitor (which would prolong the half-life of all incretins) with a GLP-1 receptor agonist (which provides pharmacological excess of GLP-1 only) provide an additional benefit? Most studies have concluded that there would be no significant benefit; the GLP-1 effect is so powerful that any additional effect from another incretin (such as GIP) would provide no meaningful clinical benefit. The controversy has been reignited by results of a study published by Violante et al. In that study, patients with T2DM uncontrolled with the DPP-4 inhibitor sitagliptin plus metformin were randomly assigned to 20 weeks treatment with twice-daily exenatide (a GLP-1 receptor agonist) plus placebo and metformin or twice-daily exenatide plus sitagliptin and metformin. A greater reduction (P = 0.012) in HbA1c was experienced by patients in the triple-agent therapy group (–0.68%) compared with those who switched from sitagliptin to exenatide (–0.38%). By study end, more patients in the exenatide + sitagliptin group had reached HbA1c <7.0% compared with those in the group on exenatide without sitagliptin (41.7% vs 26.6%, respectively; P = 0.027). Patients in the combined treatment group also saw greater fasting and mean postprandial self-monitored blood glucose reductions compared with patients who switched from the DPP-4 inhibitor to exenatide by Week 20. Whether these results can be extrapolated to wider groups of patients with T2DM will need to be explored.
Exenatide once weekly (long-acting release)
Exenatide once weekly (ExQW) is based on a proprietary polymer microsphere technology. It is administered subcutaneously by patients or their caregivers. This technology allows encapsulation of a medication of interest in microspheres, which slowly degrade in situ and release drug into the circulation in a sustained fashion. The structural matrix of the microsphere is composed of a medical-grade biodegradable polymer called poly-(d,l-lactide-co-glycolide) (PLG). These polymers have been used in surgical sutures, bone plates, and orthopedic implants for decades. Degradation of the PLG polymer occurs by natural (i.e. non-catalysed) hydrolysis of the ester linkages into lactic acid and glycolic acid, which are naturally occurring substances that are easily eliminated as carbon dioxide and water. The encapsulated exenatide in ExQW that is released into the circulation is identical to exenatide twice daily injections. Thus, the technology allows for controlled drug delivery over an extended period of time and facilitates once-weekly administration and continuous exposure to the drug above the therapeutic threshold.
Studies with ExQW demonstrated its potency as an antidiabetic agent associated with weight loss in most users (the entire series of studies was called Diabetes Therapy Utilization: Researching Changes in HBA1C, Weight, and Other Factors Through Intervention with Exenatide Once Weekly or “DURATION”). For example, a 30-week of trial of 2 mg ExQW (DURATION-1) led to a decline in HbA1c by 1.9% from a mean baseline HbA1c of 8.3%, whereas those in the exenatide b.i.d. arm saw a 1.5% reduction. Seventy-seven percent of patients achieved HbA1c <7% (vs 61% in the exenatide b.i.d. group). Patients who finished the study were then invited to continue treatment for another 22 weeks (i.e. total 52 weeks treatment) in such a manner that those on the ExQW formulation continued receiving the drug once weekly, whereas those originally randomized to the short-acting formulation switched to the once weekly formulation. The group on ExQW for the entire period had a 2% reduction in HbA1c after 1 year, whereas those who switched to ExQW exhibited a further improvement after the switch. Both groups achieved the same HbA1c lowering at 52 weeks (mean HbA1c 6.6% and weight loss ∼4 kg).
When used on the background of metformin (DURATION-2; 26 weeks) ExQW lowered HbA1c significantly more (by 1.5%) than either sitagliptin or pioglitazone from a baseline HbA1c of 8.5%. Similarly, weight loss (∼2.3 kg) was greater in patients on ExQW than those who used sitagliptin or pioglitazone. No episodes of major hypoglycemia occurred. The most frequent adverse events with exenatide and sitagliptin were nausea (24% and 10%, respectively) and diarrhea (18% and 10%, respectively), whereas upper respiratory tract infection (10%) and peripheral edema (8%) were the most frequent events with pioglitazone.
In DURATION-3, patients with T2DM uncontrolled on oral agents were randomized for 26 weeks into arms adding either insulin glargine (titrated from 10 units to an average 31 units/day by study end) or ExQW (2 mg weekly). Both agents reduced HbA1c: glargine by 1.3% and exenatide by 1.5% from a baseline of 8.3%. Weight loss was recorded in patients taking ExQW (∼2.6 kg), whereas those on insulin gained approximately 1.4 kg on average. Minor hypoglycemia was reported in 8% of 233 exenatide patients compared with 26% of 223 insulin glargine patients. Among the adverse events reported, nausea was more frequent in the ExQW than glargine recipients (13% vs 1%, respectively), as was diarrhea (9% vs 4%). In total, 5% of patients in the ExQW arm withdrew because of adverse events, compared with 1% of those randomized to insulin.
In DURATION-4, ExQW (2 mg weekly) was compared in drug-naïve patients with T2DM with metformin, sitagliptin, or pioglitazone as initial monotherapy in a 26-week double blind study. Baseline HbA1c was 8.5% and diabetes duration averaged 2.7 years. HbA1c reductions at 26 weeks (least-squares means) with ExQW compared with metformin, pioglitazone, and sitagliptin were –1.53% versus –1.48%, –1.63%, and –1.15%, respectively; weight changes were –2.0 versus –2.0, +1.5, and –0.8 kg, respectively. Minor (confirmed) hypoglycemia was rarely reported. No major hypoglycemia occurred. Exenatide weekly was thus not inferior to metformin, but not to pioglitazone, and superior to sitagliptin with regard to the HbA1c reduction at 26 weeks. Both ExQW and metformin provided similar improvements in glycemic control along with the benefit of weight reduction and no increased risk of hypoglycemia as initial treatment. The most frequent adverse events reported for the respective treatment arms were nausea (11.3%) and diarrhea (10.9%) for ExQW, diarrhea (12.6%) and headache (12.2%) for metformin, nasopharyngitis (8.6%) and headache (8%) for pioglitazone, and nasopharyngitis (9.8%) and headache (9.2%) for sitagliptin.
In DURATION-5, the effects of ExQW (2 mg weekly) and ExBID (5 μg b.i.d. for 4 weeks, followed by ExBID 10 μg for 20 weeks) on glycemic control, body weight, and safety were compared. That 24-week randomized open-label comparator-controlled study included patients with T2DM (baseline HbA1c 8.4 ± 1.2%) who were drug naïve or were previously treated with one or multiple oral antidiabetic medications. ExQW produced significantly greater reductions in HbA1c from baseline than ExBID (–1.6 ± 0.1% vs –0.9 ± 0.1%, respectively) and fasting plasma glucose (–35 ± 5 vs –12 ± 5 mg/dL, respectively). Mean body weight declined from baseline to Week 24 in both the ExQW and ExBID groups (–2.3 ± 0.4 and –1.4 ± 0.4 kg, respectively). Transient, and predominantly mild to moderate, nausea, the most frequent adverse event, was less common with ExQW than with ExBID (14% vs 35%, respectively). Injection-site reactions were infrequent, but more common with ExQW. No major hypoglycemia occurred.
Finally, in DURATION-6, a 26 week open-label randomized parallel-group study that included patients with T2DM treated with lifestyle modification and oral antihyperglycemic drugs, subjects were randomly assigned to receive injections of once-daily liraglutide (1.8 mg) or ExQW (2 mg weekly). Mean change HbA1c was greater in patients in the liraglutide than exenatide group (–1.5% vs –1.3%, respectively) with the treatment difference (0.21%; 95% confidence interval [CI] 0.08–0.33) not meeting the predefined non-inferiority criteria (upper limit of CI <0.25%). The most common adverse events were nausea (21% in the liraglutide vs 9% in the exenatide group), diarrhea, and vomiting, which occurred less frequently in the ExQW group and with decreasing incidence over time in both groups.
The GLP-1 receptor agonist liraglutide has 97% homology with the native human incretin. There is only one amino acid substitution in the sequence and an addition of a fatty acid (palmitate) side chain that renders the molecule resistant to DPP-4 enzymatic degradation and protracts its action (half life ∼13 h, allowing once daily administration). As with exenatide, liraglutide is approved for use as an adjunct to diet and exercise in patients with T2DM, as monotherapy, or in combination with other oral agents and basal insulin. These indications were granted based on series of registration trials (collectively known as Liraglutide Effect and Action in Diabetes or “LEAD”). A brief summary of this program is given below. Liraglutide is injected subcutaneously once daily, regardless of the mealtime or time of day. To mitigate against possible adverse gastrointestinal events, it is started at 0.6 mg/day and then uptitrated in weekly intervals to the daily doses of 1.2 and 1.8 mg, as tolerated and required for optimal glycemic control.
In LEAD-1, liraglutide, rosiglitazone, or placebo were added to glimepiride for 26 weeks. Liraglutide (1.2 and 1.8 mg/day) reduced HbA1c by approximately 1.1% (from a baseline of ∼8.5%), whereas rosiglitazone reduced HbA1c only by 0.4%. The main adverse events for all treatments were minor hypoglycemia (<10%), nausea (<11%), vomiting (<5%), and diarrhea (<8%).
In LEAD-2, liraglutide decreased HbA1c by approximately 1% following its use once daily at a dose of1.2 or 1.8 mg. In that 26-week double-blind double-dummy placebo- and active-controlled parallel-group trial, subjects were randomly assigned to once-daily liraglutide, to placebo, or to glimepiride (4 mg once daily). All treatments were in combination therapy with metformin (1 g twice daily). Baseline HbA1c was 7–11% (when on previous antidiabetic monotherapy for ≥3 months) or 7–10% (when on previous antidiabetic combination therapy for ≥3 months). HbA1c values were significantly reduced in all liraglutide groups compared with the placebo group, with mean decreases of 1% for 1.8 mg liraglutide, 1.2 mg liraglutide, and glimepiride. Body weight decreased in all liraglutide groups (1.8–2.8 kg) compared with an increase in the glimepiride group (1.0 kg; P < 0.0001). The incidence of minor hypoglycemia with liraglutide (∼3%) was comparable to that with placebo, but was less than that with glimepiride (17%). Nausea was reported by 11–19% of the liraglutide-treated subjects compared with 3–4% of subjects in the placebo and glimepiride groups. The incidence of nausea declined over time.
The LEAD-3 study was a test of liraglutide as monotherapy for patients with uncontrolled early T2DM. Patients were randomly assigned to once daily liraglutide (1.2 or 1.8 mg) or 8 mg glimepiride for 1 year. After 52 weeks, HbA1c decreased by 0.5% with glimepiride, compared with 0.8% for 1.2 mg liraglutide, and 1.1% for 1.8 mg liraglutide, from a mean baseline HbA1c of 8.4%. Thus, liraglutide was deemed effective as initial pharmacologic therapy and, in that study, it resulted in greater reductions in HbA1c, weight, hypoglycemia, and blood pressure than glimepiride. Six patients in the liraglutide groups discontinued treatment because of vomiting, compared with none in the glimepiride group.
In LEAD-4, a 26-week double-blind placebo-controlled parallel-group trial, subjects were randomized to once-daily liraglutide (1.2 or 1.8 mg) or placebo in combination with metformin (1 g twice daily) and rosiglitazone (4 mg twice daily). Patients had T2DM and baseline HbA1c of 7–11% at enrollment. Mean HbA1c decreased significantly more in the liraglutide groups compared with placebo (mean –1.5% for both 1.2 and 1.8 mg liraglutide). Fasting plasma glucose decreased by 40, 44, and 8 mg/dL for 1.2 and 1.8 mg liraglutide and placebo, respectively, and 90-min postprandial glucose decreased by 47, 49, and 14 mg/dL, respectively. Weight loss occurred with 1.2 and 1.8 mg liraglutide (mean 1 and 2 kg, respectively) compared with weight gain with placebo (0.6 kg). Systolic blood pressure (SBP) decreased by 6.7, 5.6, and 1.1 mmHg with 1.2 and 1.8 mg liraglutide and placebo, respectively. Nausea occurred within the first 2 weeks more often in the liraglutide groups (29% and 40% with 1.2 and 1.8 g liraglutide, respectively) but mostly dissipated after the first few months. More patients exposed to liraglutide withdrew from the study, mostly because of gastrointestinal side effects (6% in the 1.2 mg liraglutide arm, 15% in the 1.8 mg liraglutide arm, and 3% in the placebo arm).
The LEAD-5 study compared the efficacy and safety of liraglutide in T2DM versus placebo and insulin glargine, all in combination with metformin and glimepiride. This was a randomized parallel-group controlled 26-week trial for patients on prior monotherapy and combination therapy. Patients were randomized to 1.8 mg liraglutide once daily, placebo, or open-label insulin glargine, all in combination with metformin (1 g twice daily) and glimepiride (4 mg once daily). Liraglutide reduced HbA1c significantly compared with glargine (1.3% vs 1.1%, respectively). There was greater weight loss with liraglutide compared with placebo (treatment difference –1.39 kg) and compared with glargine (treatment difference –3.43 kg). Liraglutide also reduced SBP (–4.0 mmHg) compared with glargine (+0.5 mmHg). The proinsulin : C-peptide ratio improved significantly in the liraglutide compared with insulin glargine and placebo arms. Nausea (13.9%) was reported by more patients randomized to liraglutide but, after 14 weeks, its incidence (1.5%) was identical to that for patients on insulin glargine or placebo. There was no difference in the rate of minor hypoglycemia (<3.1 mmol/L) between the liraglutide and insulin groups (27.4% vs 28.9%, respectively).
Finally, in the LEAD-6 study, adults with uncontrolled T2DM on maximally tolerated doses of metformin, sulfonylurea, or both were randomly assigned to additional 1.8 mg/day liraglutide or 10 μg exenatide twice a day for 26 weeks in an open-label parallel-group fashion. Mean baseline HbA1c was 8.2%. Liraglutide reduced HbA1c significantly more than did exenatide (–1.1% vs –0.8%, respectively) and more patients achieved HbA1c <7% with liraglutide than with exenatide (54% vs 43%, respectively). Liraglutide also reduced mean fasting plasma glucose more than exenatide (–1.61 vs –0.60 mmol/L, respectively) but postprandial glucose control was less effective after breakfast and dinner. Similar weight loss was seen for both liraglutide and exenatide (–3.24 vs –2.87 kg, respectively). Nausea was approximately 50% less persistent and minor hypoglycemia less frequent (1.93 vs 2.60 events/patient-year) with liraglutide than with exenatide. Thus, it can be concluded that liraglutide once daily provides greater improvements in glycemic control than exenatide b.i.d. To confirm that finding, patients in the LEAD-6 study participated in a 14 week extension. Patients in the original exenatide arm were switched to liraglutide, whereas the original liraglutide group continued with liraglutide throughout the extension phase. By the end of the study (40 weeks) there was further improvement in several parameters among the exenatide subjects, with HbA1c lowered by 0.32%, fasting glucose by 0.9 mmol/L, body weight by 0.9 kg, and SBP by 3.8 mmHg.
Comparisons of DPP-4 inhibitors and GLP-1 RAs
It is clear from the above summary of studies that GLP-1 RAs are more potent in reducing glucose levels than DPP-4 inhibitors. What is the difference between these two classes of agents affecting the incretin effect in T2DM? It has been said that DPP-4 inhibitors provide a “physiological” effect and GLP-1 receptor agonists a “pharmacological” effect. The addition of oral DPP-4 inhibitors leads to an approximate doubling[13, 76] of circulating incretin levels, whereas the use of GLP-1 analogs results in an approximate eight- ninefold increase..[12, 77, 78] Based on the dose–response of the incretin effect, the DPP-4-induced increase allows for improved glucose-dependent effects at the level of pancreatic islet cells (i.e. stimulation of β- and inhibition of α-cell activity) but is not sufficient to impact the GLP-1 receptors in the central nervous system. Thus, the effect on increased sense of satiety, decreased appetite (resulting in weight loss), and slowing down of gastric emptying is seen only with the use of GLP-1 receptor agonists. Although the effects of GLP-1 RAs can be explained by simply invoking their ability to bind directly to the cognate receptor, it has been much more difficult to elucidate the mechanism(s) by which the DPP-4 inhibitors achieve their glucose-lowering effect. Although it is true that they typically approximately double to triple the level of the biologically active GLP-1 in specific assays, they do not increase the total levels of circulating GLP-1 (as measured in non-specific assays). In contrast, the meal-stimulated secretion of GLP-1 is actually reduced up to 75% in dogs and humans.[79, 80] Nauck summarized the dilemma of trying to explain the improvement in glycemic levels with DPP-4 inhibition in this situation in the 2011 review of the topic. Speculations about the mode of action responsible for the benefits seen in the studies of DPP-4 in T2DM abound, such as protraction of effects of the other incretin hormones and neuropeptides regulated by DPP-4.
Given the relative potencies of these agents, it makes sense for the clinician to introduce DPP-4 inhibitors early in the treatment scheme for non-obese patients whose presenting HbA1c is <1% above their target HbA1c level. In contrast, the GLP-1 RAs would be more likely be started in those patients with T2DM who are more uncontrolled and in those who need to lose weight. Both classes share the advantage of being relatively free of hypoglycemic concerns (however, when used in combination with sulfonylureas or insulin, the dose of those hypoglycemic drugs may need to be decreased or even stopped entirely).
The DPP-4 inhibitors are once-daily oral medications, relatively free of adverse side effects. In a comprehensive review and meta-analysis of 67 randomized controlled trials including this class of drugs (four for alogliptin, eight for linagliptin, eight for saxagliptin, 20 for sitagliptin, and 27 for vildagliptin), “adverse events with gliptin treatment were at placebo level” (relative risk 1.02; 95% CI 0.99–1.04).
In contrast, the more potent GLP-1 RAs have to be injected subcutaneously and have more associated adverse events, mainly gastrointestinal in nature (nausea, vomiting, diarrhea), which have occurred in anywhere from 10% to 44% of patients depending on the trial. As pointed out above, these symptoms have usually been mild to moderate and dissipated over time, with their frequency approaching that seen in patients randomized to control arms by 8–12 weeks. These gastrointestinal symptoms have led to discontinuation of GLP-1 RAs in a relatively small number of patients (range 0.5–2% in different studies).
A review of the extrapancreatic effects of incretin-based therapies is beyond the scope of the present paper. However, large long-term global studies examining their effect on cardiovascular events are ongoing. The results of the first of these event-driven outcome studies are expected sometime between 2014 and 2018. There has been an intriguing possibility raised about the potential reduction in cardiovascular events by DPP-4 inhibitors, as reviewed elsewhere.[83, 84]
In addition, given some potential signals from in vitro and animal model preclinical studies, registries are kept for the incidence of acute pancreatitis, as well as certain types of cancers (medullary thyroid, pancreatic). To date, no confirmed increase in these events has been documented. Relevant recent reviews representing different views on these issues are referenced in Drucker et al., Butler et al., and Mudaliar and Henry.