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Keywords:

  • antidiabetic drugs;
  • dipeptidyl peptidase 4 inhibitors;
  • glucagon-like peptide-1 receptor agonists;
  • incretin analogs;
  • type 2 diabetes therapy
  • 降糖药物,二肽基肽酶4抑制剂,胰高血糖素样肽-1受体激动剂,肠促胰岛素类似物,2型糖尿病治疗

Abstract

  1. Top of page
  2. Abstract摘要
  3. Discovery of the incretin effect
  4. Dipeptidyl peptidase-4 inhibitors
  5. GLP-1 receptor analogs
  6. Disclosure
  7. References

The present short review summarizes and updates clinical experience with two classes of drugs introduced for the management of type 2 diabetes mellitus over the past 8 years: (i) the glucagon-like peptide-1 receptor agonists; and (ii) the dipeptidyl peptidase 4 inhibitors. Both classes of agents address the so called “incretin defect” in patients with T2DM.

摘要

这篇简短的综述总结与更新了在过去的8年中引进的两类2型糖尿病治疗药物的临床经验: (i)胰高血糖素样肽-1受体激动剂;以及(ii)二肽基肽酶4抑制剂。这两种类型的药物都是针对T2DM患者的“肠促胰岛素缺陷”。


Discovery of the incretin effect

  1. Top of page
  2. Abstract摘要
  3. Discovery of the incretin effect
  4. Dipeptidyl peptidase-4 inhibitors
  5. GLP-1 receptor analogs
  6. Disclosure
  7. References

In 1964, Elrick et al.[1] described that oral glucose administration leads to greater insulin response than when glucose is delivered intravenously. That enhanced effect was called the “incretin” effect. Clearly, the difference between the oral administration of glucose and its delivery via the intravenous route was the presence of nutrient in the gastrointestinal track. In fact, the observation that factors released by the duodenum could stimulate insulin production predates discovery of insulin by 15 years. Moore et al.[2] stated then that “… the internal secretion of the pancreas might be stimulated and initiated (similarly to the external secretion) by a substance of the nature of a hormone or secretin yielded by the duodenal mucous membrane”, and it was La Barre who, in 1932, coined the term “incrétine” when he described a substance produced in the small intestine with the capacity to cause hypoglycemia without stimulating exocrine pancreatic secretion.[3] This idea was replicated in 1986 by the work of Nauck et al.[4] By definition, incretin hormones are secreted after nutrient ingestion and stimulate insulin secretion at the concentration that is reached by the ingestion. However, some time elapsed before a number of hormones, released from specific cells of the small intestine, were identified.

We now know that only two of the incretins identified truly meet that definition: glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic peptide, previously known as gastric inhibitory peptide (GIP). A 30–31-amino acid peptide, GLP-1 is secreted by enteroendocrine L cells in the ileum and colon, whereas GIP (a 42-amino acid peptide) is produced in the K cells of the duodenum and jejunum.[5] Both these peptides are released rapidly following nutrient ingestion and cleared by inactivation (by cleaving off the two N-terminal amino acids) by the ubiquitous enzyme dipeptidyl peptidase (DPP)-4.[6] As a result, the residence life of active incretins in plasma is under 2 min. These peptides act by binding to their respective specific receptors located in many tissues. Upon binding to the seven membrane-spanning G-protein-coupled surface receptors, adenylate cyclase is activated, leading to intracellular cAMP generation and intracellular calcium release.[7]

The reasons behind the observed diminished incretin effect in patients with type 2 diabetes mellitus (T2DM)[4] have been thoroughly examined over the past 25 years. Although many different possibilities have been proposed, a consensus is slowly emerging (see, for example, the elegant review by Meier and Nauck[8]). It is apparent that it is not necessarily decreased secretion of GLP-1 and GIP in response to nutrient ingestion that is responsible for the diminished incretin effect. Rather, it seems that there is a less potent insulinotropic response to the physiologically induced GLP-1 and GIP levels in those patients. This deficit seems to be secondary to the overall decline in β-cell secretory ability brought about by long-standing hyperglycemia inherent in established T2DM. Interestingly, if one elevates the GLP-1 levels into the supraphysiological range, the incretin effect can be enhanced in a subject with T2DM to approach that seen in healthy people.[9] In contrast, even heroic concentrations of GIP cannot bring insulin levels up to those seen in healthy individuals.[10] It was speculated that hyperglycemia itself leads to downregulation of GIP receptors and this hypothesis was confirmed in a study of eight patients with poorly controlled T2DM (mean HbHbA1c 8.6%) whose glycemia was near-normalized over 4 weeks by insulin treatment.[11] The late phase (10–120 min) C-peptide response to both GLP-1 and GIP was increased three- to fourfold. Interestingly, no such effect on β-cell responsiveness to glucose alone was seen. Thus, efforts to achieve euglycemia by any means should by themselves enhance the incretin effect.

In clinical practice there are two major ways to address this defect: (i) enhance the incretin effect by administering a pharmacological dose of a GLP-1 receptor activator (GLP-1 RA); or (ii) inhibit the enzyme DPP-4, which is responsible for the inactivation of incretins after their secretion. In the former case one achieves a pharmacological excess (eight- to ninefold the circulating levels of GLP-1 present throughout the day) of the incretin analog,[12] whereas the latter represents a more “physiological” approach by allowing the patient to “keep” their own secreted incretins longer in the circulation and achieving approximately a doubling of the postprandial concentrations of both GLP-1 and GIP.[13] Because there is a hierarchy of incretin effects, the resulting incretin concentrations will lead to different clinical effects among patients with diabetes. The high concentrations achieved by injections of GLP-1 RA activate specific central nervous system GLP-1 receptors and result in effects such as increased satiety, diminished appetite, decreased food intake, and resulting weight loss. There is also a slowing of gastric emptying, leading to diminished postprandial glycemic excursions.[14]

The use of incretin analogs could be potentially wide given their unique mechanism of action. They can be used as initial monotherapy in those in whom control has not been achieved by lifestyle modifications and across the entire spectrum, from patients in whom one or two oral agents have failed to those patients already receiving insulin therapy. The effects have not been seen to be diminished according to the stage of diabetes at which these agents have been used. In addition, the incretin analogs possess the advantage of not being associated with either hypoglycemia or weight gain.

Dipeptidyl peptidase-4 inhibitors

  1. Top of page
  2. Abstract摘要
  3. Discovery of the incretin effect
  4. Dipeptidyl peptidase-4 inhibitors
  5. GLP-1 receptor analogs
  6. Disclosure
  7. References

The DPP-4 inhibitors selectively inhibit DPP-4, which is responsible for removing the last two N-terminal amino acids of incretins, resulting in inactivation of GLP-1 and GIP. Blockade of DPP-4 results in increased circulating concentrations of incretins,[13] leading to enhanced glucose-dependent insulin secretion and diminished glucagon secretion. In patients with T2DM, favorable clinical results have been generally observed, as determined by lower fasting and postprandial glucose and HbHbA1c levels.

The DPP-4 inhibitors are approved for use in patients with T2DM who have not achieved their glycemic targets using lifestyle modifications (Fig. 1) as monotherapy or in combination with one or more oral agents or with basal insulin. They are easy to use, being once daily oral drugs that can be administered regardless of the time of the day or mealtime. In general, they carry a low risk of mild hypoglycemia, have been relatively free of adverse clinical effects thus far, and are weight neutral.

figure

Figure 1. Structure of the five dipeptidyl peptidase-4 inhibitors currently in clinical use.

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Monotherapy

Sitagliptin

In an 18-week trial, it was reported that sitagliptin (100 mg/day) lowered HbA1c by 0.48% from a baseline of 8.04%,[15] whereas in a 24-week long study it decreased HbA1c from 8.01% to 7.39% (0.61% decrease).[16] In another 24-week long trial, it was reported sitagliptin lowered HbA1c by 0.66% (from a mean baseline of 8.87% to 8.18%).[17] In all studies, as expected, the higher the baseline HbA1c, the larger the absolute decrease in HbA1c seen.

Saxagliptin

Saxagliptin was used in drug-naïve patients as monotherapy in a 24-week long study and showed 0.43% and 0.46% (for the 2.5 and 5 mg/day doses, respectively) declines in HbA1c from a mean baseline of 7.9%.[18]

Vildagliptin

There have been at least 19 different studies published using vildagliptin as monotherapy.[19] In one such example of monotherapy experience with vildagliptin, 459 patients who had been randomized to vildagliptin, 50 mg b.i.d., showed an average reduction in HbA1c of 1.1% from a baseline level of 8.7% (see Dejager et al.[19]).

Linagliptin

Both the 18- and 24-week long studies of linagliptin as monotherapy resulted in 0.4% HbA1c reductions from baseline values of 8.1% and 8.0%, respectively.[20] In an open-label 78-week extension study of 5 mg/day linagliptin, after the initial 24-week double-blinded trial (for a total of 102 weeks exposure to the drug), a sustained HbA1c reduction of 0.5% was seen (from a baseline of 7.4%).[21]

Alogliptin

Alogliptin monotherapy of poorly controlled patients with T2DM (baseline HbA1c 7.9%) for 26 weeks resulted in decreases in HbA1c of 0.56% and 0.59% for doses of 12.5 and 25 mg/day alogliptin, respectively.[22]

Combination studies

Many studies have been published regarding the use of DPP-4 inhibitors in combination with other antidiabetic drugs, both from the registration trials and from the post-approval phase. Study designs have included add-on and initial drug combinations in drug-naive patients. What follows is a brief synopsis of these trials.

Sitagliptin

Initial combination of sitagliptin (100 mg/day) and metformin (either 1000 or 2000 mg/day) demonstrated additivity compared with either drug alone over 24 weeks; specifically, decreases were seen in HbA1c of 0.66%, –0.82%, –1.40%, –1.13%, and –1.90% for sitagliptin monotherapy, 1 g/day metformin, sitagliptin + 1 g metformin, 2 g/day metformin, and sitagliptin + 2 g/day metformin, respectively.[17] Two-year double-blinded extension substantiated the claims of the durability of this effect.[23] The addition of sitagliptin for 24 weeks in patients uncontrolled on pioglitazone monotherapy (baseline HbA1c ∼8%) lowered HbA1c by 0.7% more than in patients randomized to placebo, to a mean HbA1c of 7.2%.[24] When sitagliptin was added to metformin for 24 weeks, HbA1c decreased by a mean of 0.67% in 701 patients with a mean HbA1c of 8%.[25] In the subset of patients on glimepiride plus metformin, sitagliptin addition reduced HbA1c by 0.89% relative to placebo, compared with a reduction of 0.57% in the subset of patients on glimepiride alone.[26]

Sitagliptin is also approved for use in combination with basal insulin. In one supporting study,[27] patients inadequately controlled on long-acting, intermediate-acting, or premixed insulin (HbA1c ≥7.5% and ≤11%; mean baseline HbA1c 8.7%) were randomized 1:1 to the addition of once-daily 100 mg sitagliptin or matching placebo over a 24-week period. Mean diabetes duration in this trial was longer (13 years) than in studies the assessing efficacy of sitagliptin in monotherapy or combination with oral agents (typical duration of T2DM of 4–6 years). The mean total daily insulin dose was 51 IU. At 24 weeks, the addition of sitagliptin significantly reduced HbA1c by 0.6% compared with placebo (0.0%).[27] In a Korean study assessing the effects of adding sitagliptin compared with continued increases in basal insulin, at 24 weeks HbA1c had decreased by 0.6 ± 0.1% (from a baseline of 9.2%) with added sitagliptin, but by 0.2 ± 0.1% in patients randomized to increasing insulin dose (P < 0.01).[28]

Sitagliptin is currently available in three different doses: the customary dose of 100 mg, and the lower 50 and 25 mg tablets recommended in patients with T2DM who have renal impairment (creatinine clearance 30–49 and <30 mL/min, respectively).

Saxagliptin

Saxagliptin has been studied in combination with metformin, sulfonylureas, thiazolidinediones (TZD), and insulin. Typical examples of its efficacy included a trial of 5 mg/day saxagliptin added to metformin for 24 weeks: in this study, a decline of 0.69% in HbA1c was seen (starting HbA1c between 7% and 10%).[29] In combination with 7.5 mg/day glyburide, 5 mg/day saxagliptin lowered HbA1c by 0.64% (from a mean baseline HbA1c of 8.4%) after 24 weeks.[30]

Patients with inadequately controlled T2DM (HbA1c 7.0–10.5%) receiving stable TZD monotherapy (30 or 45 mg/day pioglitazone or 4 or 8 mg/day rosiglitazone) were put on 2.5 or 5 mg/day saxagliptin plus TZD for 24 weeks and demonstrated significant adjusted mean decreases in HbA1c compared with placebo (–0.66% or –0.94% vs –0.30%, respectively).[31]

Patients uncontrolled (HbA1c 7.5–11%) on stable insulin therapy (30–150 U/day insulin ± metformin) for at least 8 weeks were randomly assigned 2:1 to receive saxagliptin 5 mg/day or placebo once daily for 24 weeks.[32] Patients treated with saxagliptin had significantly greater reductions in adjusted mean HbA1c compared with placebo (difference: –0.41%). Treatment with saxagliptin resulted in similar reductions in HbA1c relative to placebo, irrespective of metformin treatment.[32]

Saxagliptin is available in two strengths: 5 mg/day for patients with normal renal function and 2.5 mg/day for those whose creatinine clearance is <50 mL/min.

Linagliptin

Linagliptin, added to ongoing metformin therapy, was assessed in patients with T2DM who had inadequate glycemic control (HbA1c ≥7.5 to ≤10%) on metformin therapy alone.[33] After 12 weeks treatment, there was a mean placebo-corrected lowering in HbA1c of 0.73% for 5 mg/day linagliptin. In another study, patients with HbA1c levels of 7–10% were randomized to linagliptin (5 mg/day) or placebo in addition to metformin therapy for 24 weeks.[34] Approximately two-thirds of patients had been treated previously with metformin alone, and one-third had received metformin in combination with another oral antidiabetic agent (OAD). After 24 weeks treatment, patients receiving linagliptin in addition to metformin had significantly greater changes in HbA1c (–0.64%). Another trial assessed the efficacy of linagliptin in patients whose glycemia was insufficiently controlled with metformin plus a sulfonylurea.[35] After a 2-week placebo run-in, patients were randomized to 5 mg/day linagliptin or placebo for 24 weeks, in addition to their established metformin plus sulfonylurea regimen, which was continued at unchanged doses. After 24 weeks, patients receiving add-on linagliptin had significantly greater changes in HbA1c (placebo-corrected mean change of –0.62%).[35] In an additional linagliptin combination trial,[36] patients were randomized to 5 mg/day linagliptin or placebo as initial therapy in combination with pioglitazone (30 mg/day) for 24 weeks. Treatment-naïve patients were eligible if screening HbA1c levels were between 7.5% and 11.0%; patients receiving treatment with any other OAD were eligible if HbA1c levels were between 7.0% and 9.5% at screening and between 7.5% and 11.0% after a 4-week washout of all OADs. Adjusted mean changes in HbA1c for linagliptin plus pioglitazone were significantly greater than with placebo plus pioglitazone after 24 weeks (–0.51%).[36]

For approval of linagliptin in combination with basal insulin, a study of 1261 patients with T2DM inadequately controlled (baseline HbA1c 7–10%) on insulin glargine, insulin detemir, or NPH insulin was conducted.[37] Subjects were randomized to receive either 5 mg linagliptin once daily or placebo. Additional background therapy combinations included basal insulin plus metformin (75.5%), basal insulin plus metformin and pioglitazone (7.4%), and basal insulin plus pioglitazone (1%). After 24 weeks, linagliptin plus basal insulin demonstrated a placebo-adjusted reduction in HbA1c of 0.65% from a baseline HbA1c of 8.3%.[37]

Linagliptin is excreted primarily via the bile and gut[38] and does not require dose adjustment in patients with renal impairment.[39] Dose adjustment is also not necessary for hepatic impairment, coadministration with food, body weight, sex, or age.[40] Thus, only a 5 mg dose of linagliptin is marketed.

Vildagliptin

The addition of vildagliptin to metformin improves glucose control. For example, when placebo or vildagliptin (50 mg once daily) was added to ongoing metformin treatment (1500–3000 mg/day), HbA1c (baseline 7.7%) decreased at Week 12 by –0.6%.[41] At the endpoint of the extension study, HbA1c did not change from Week 12 to Week 52 in vildagliptin-treated patients, but increased in participants given placebo.[41] The between-group difference in HbA1c after 1 year was –1.1%. In another double-blind randomized multicenter parallel group study of 24-weeks treatment with 50 mg vildagliptin daily, 100 mg vildagliptin daily, or placebo in patients continuing metformin (≥1500 mg/day) but achieving inadequate glycemic control (HbA1c 7.5–11%),[42] the between-treatment difference (vildagliptin – placebo) in adjusted mean change in HbA1c from baseline to endpoint was –0.7% and –1.1% in patients receiving 50 or 100 mg vildagliptin daily, respectively. Another 24-week double-blind active-controlled study assessed the effects of vildagliptin (100 mg/day), pioglitazone (30 mg/day), and vildagliptin combined with pioglitazone (100/30 mg/day or 50/15 mg/day) in 607 drug-naïve patients with T2DM.[43] After 24 weeks treatment, adjusted mean changes in HbA1c from baseline (∼8.7%) in patients receiving pioglitazone monotherapy, the 50/15 mg combination, the 100/30 mg combination, and vildagliptin monotherapy were –1.4%, –1.7%, –1.9% and –1.1%, respectively. In yet another 24-week randomized parallel-group study comparing the effects of vildagliptin (50 or 100 mg daily) with placebo as an add-on therapy to pioglitazone (45 mg/day) in 463 patients with T2DM inadequately controlled by prior TZD monotherapy,[44] the adjusted mean change in HbA1c from baseline (mean HbA1c 8.6%) to endpoint was –0.8% (vs placebo) and –1.0% (vs placebo) in patients receiving 50 or 100 mg/day vildagliptin, respectively.

Finally, a 24-week double-blind randomized placebo-controlled study in patients with T2DM that was inadequately controlled by insulin (HbA1c 7.5–11%; mean baseline 8.4%), patients received vildagliptin (50 mg twice daily) or placebo while continuing insulin therapy.[45] The adjusted mean change from baseline to endpoint in HbA1c was –0.5% and –0.2% in patients receiving vildagliptin or placebo, respectively. Adverse events were similar in both groups, but those receiving vildagliptin reported fewer hypoglycemic events than those receiving placebo.

Alogliptin

Combination therapy with alogliptin–pioglitazone has been examined in conjunction with various background therapies. In a randomized double-blind placebo-controlled 26-week study, DeFronzo et al. investigated the combination of alogliptin–pioglitazone in subjects inadequately controlled on metformin.[46] The arms of the study included placebo, 12.5 and 25 mg/day alogliptin, 15, 30, and 45 mg/day pioglitazone, and 12.5 or 25 mg/day alogliptin combined with 15, 30, or 45 mg/day pioglitazone. Pooled analysis looked at all doses of pioglitazone, 12.5 mg/day alogliptin plus any dose of pioglitazone, and 25 mg/day alogliptin plus any dose of pioglitazone. The mean change in HbA1c from baseline (mean HbA1c 8.5%) was –0.89% in the pioglitazone groups, –1.43% in the 12.5 mg alogliptin + pioglitazone groups, and –1.42% in the 25 mg alogliptin + pioglitazone groups.

In a 26-week double-blind placebo-controlled study,[47] patients were randomized to receive 12.5 mg alogliptin, 25 mg alogliptin, or placebo once daily, as add-on to stable insulin therapy with or without metformin. At Week 26, mean HbA1c changes from the mean baseline value of 9.3% were significantly greater for 12.5 and 25 mg alogliptin compared with placebo (–0.63% and –0.71% vs –0.13%, respectively).[47]

Conclusion

To summarize the efficacy of drugs in this class, the five available DPP-4 inhibitors brought about approximate 0.5–0.7% decreases in HbA1c from the baseline levels of 8–8.5% in the various trials. Importantly, this clinically significant improvement in glycemic control has occurred in the general absence of hypoglycemia and weight gain. Further, these agents have been well tolerated with acceptable adverse event profile (see below for more details).

GLP-1 receptor analogs

  1. Top of page
  2. Abstract摘要
  3. Discovery of the incretin effect
  4. Dipeptidyl peptidase-4 inhibitors
  5. GLP-1 receptor analogs
  6. Disclosure
  7. References

Three GLP-1 receptor agonists are currently in use in the US: exenatide twice daily, exenatide once weekly and liraglutide (Fig. 2).

figure

Figure 2. Structure of native human glucagon-like peptide-1 (GLP-1), exenatide, and liraglutide.

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Exenatide

Exenatide is a synthetic form of exendin-4 (originally identified in the salivary gland enzyme of the Gila monster).[48] 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.[49] 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,[55] 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.[55] In addition, exenatide twice daily has been reported to improve glycemic control in a study of patients uncontrolled on TZD and TZD + metformin.[56]

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).[57] 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.[60] 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.[61] 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.[62] 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.[63] 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%.[64] 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.[64]

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).[65] 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.[65] 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.[66] 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.[66]

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.[67] 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,[68] 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.

Liraglutide

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.[69] 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,[70] 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).[70] 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.[71] 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,[71] 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).[72] 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.[73] 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.[74] 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.[75] 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.[81] 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).[82]

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.,[85] Butler et al.,[86] and Mudaliar and Henry.[87]

Disclosure

  1. Top of page
  2. Abstract摘要
  3. Discovery of the incretin effect
  4. Dipeptidyl peptidase-4 inhibitors
  5. GLP-1 receptor analogs
  6. Disclosure
  7. References

The author has received research grants from Novo Nordisk, Amylin, and GSK, and participates in the Speakers Bureau for Novo Nordisk, Amylin, Merck, Boehringer Ingelheim, and Takeda.

References

  1. Top of page
  2. Abstract摘要
  3. Discovery of the incretin effect
  4. Dipeptidyl peptidase-4 inhibitors
  5. GLP-1 receptor analogs
  6. Disclosure
  7. References
  • 1
    Elrick H, Stimmler L, Hlad CJ et al. Plasma insulin response to oral and intravenous glucose administration. J Clin Endocrinol Metab. 1964; 24: 10761082.
  • 2
    Moore B, Edie ES, Abram JH. Further observations on the treatment of diabetes mellitus by acid extract of duodenal mucous membrane. Biochem J. 1906; 1: 446454.
  • 3
    La Barre J. Sur les possibilities d'un traitement du diabète par l'incrétine. Bull Acad R Med Belg. 1932; 12: 620634.
  • 4
    Nauck M, Stöckmann F, Ebert R et al. Reduced incretin effect in type 2 (non-insulin-dependent) diabetes. Diabetologia. 1986; 29: 4652.
  • 5
    Nauck MA, Homberger S, Siegel EG et al. Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses. J Clin Endocrinol Metab. 1986; 63: 492498.
  • 6
    Deacon CF, Nauck MA, Toft-Nielsen M et al. Both subcutaneously and intravenously administered glucagon-like peptide I are rapidly degraded from NH2-terminus in type II diabetic patients and in healthy subjects. Diabetes. 1995; 44: 11261131.
  • 7
    Nauck MA, Heimesaat MM, Behle K et al. Effects of glucagon-like peptide 1 on counterregulatory hormone responses, cognitive function, and insulin secretion during hyperinsulinemic, stepped hypoglycemic lamp experiments in healthy volunteers. J Clin Endocrinol Metab. 2002; 87: 12391246.
  • 8
    Meier JJ, Nauck MA. Is the diminished incretin effect in type 2 diabetes just an epi-phenomenon of impaired beta-cell function? Diabetes. 2010; 59: 11171125.
  • 9
    Vilsbøll T, Krarup T, Madsbad S, Holst JJ. Defective amplification of the late phase insulin response to glucose by GIP in obese type II diabetic patients. Diabetologia. 2002; 45: 11111119.
  • 10
    Nauck MA, Heimesaat MM, Ørskov C, Holst JJ, Ebert R, Creutzfeldt W. Preserved incretin activity of glucagon-like peptide 1 [7–36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type 2 diabetes mellitus. J Clin Invest. 1993; 91: 301307.
  • 11
    Højberg PV, Vilsbøll T, Rabøl R et al. Four weeks of near-normalisation of blood glucose improves the insulin response to glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes. Diabetologia. 2009; 52: 199207.
  • 12
    Agersø H, Jensen LB, Elbrønd B et al. The pharmacokinetics, pharmacodynamics, safety and tolerability of NN2211, anew long-acting GLP-1 derivative, in healthy men. Diabetologia. 2002; 45: 195202.
  • 13
    Herman GA, Bergman A, Stevens C et al. Effect of single oral doses of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on incretin and plasma glucose levels after an oral glucose tolerance test in patients with type 2 diabetes. J Clin Endocrinol Metab. 2006; 91: 46124619.
  • 14
    Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care. 2003; 26: 29292940.
  • 15
    Raz I, Hanefeld M, Xu L et al. Efficacy and tolerability of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes mellitus. Diabetologia. 2006; 49: 25642571.
  • 16
    Aschner P, Kipnes MS, Lunceford JK et al. Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care. 2006; 29: 26322637.
  • 17
    Goldstein B, Feinglos MN, Lunceford JK et al. Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin on glycemic control in patients with type 2 diabetes [published erratum appears in Diabetes Care. 2008;31:1713]. Diabetes Care. 2007; 30: 19791987.
  • 18
    Rosenstock J, Aguilar-Salinas C, KLein E et al. Effect of saxagliptin monotherapy in treatment-naive patients with type 2 diabetes. Curr Med Res Opin. 2009; 25: 24012411.
  • 19
    Dejager S, Schweizer A, Foley JE. Evidence to support the use of vildagliptin monotherapy in the treatment of type 2 diabetes mellitus. Vasc Health Risk Manag. 2012; 8: 339348.
  • 20
    Del Prato S, Barnett AH, Huisman H et al. Effect of linagliptin monotherapy on glycaemic control and markers of β-cell function in patients with inadequately controlled type 2 diabetes: A randomized controlled trial. Diabetes Obes Metab. 2011; 13: 258267.
  • 21
    Gomis R, Owens DR, Taskinen MR et al. Long-term safety and efficacy of linagliptin as monotherapy or in combination with other oral glucose-lowering agents in 2121 subjects with type 2 diabetes: Up to 2 years exposure in 24-week Phase III trials followed by a 78-week open-label extension. Int J Clin Pract. 2012; 66: 731740.
  • 22
    DeFronzo RA, Fleck PR, Wilson CA, Mekki Q. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes and inadequate glycemic control: A randomized, double-blind, placebo-controlled study. Diabetes Care. 2008; 31: 23152317.
  • 23
    Williams-Herman D, Johnson J, Teng R et al. Efficacy and safety of sitagliptin and metformin as initial combination therapy and as monotherapy over two years in patients with type 2 diabetes. Diabetes Obes Metab. 2010; 12: 442451.
  • 24
    Rosenstock J, Brazg R, Andryuk PJ et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy on patients with type 2 diabetes: A 24-week multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Clin Ther. 2006; 28: 15561568.
  • 25
    Charbonnel B, Karasik A, Liu J et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care. 2006; 29: 26382643.
  • 26
    Hermansen K, Kipnes M, Luo E et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride and metformin. Diabetes Obes Metab. 2007; 9: 733745.
  • 27
    Vilsbøll T, Rosenstock J, Yki-Järvinen H et al. Efficacy and safety of sitagliptin when added to insulin therapy in patients with type 2 diabetes. Diabetes Obes Metab. 2012; 12: 167177.
  • 28
    Hong ES, Khang AR, Yoon JW et al. Comparison between sitagliptin as add-on therapy to insulin and insulin dose-increase therapy in uncontrolled Korean type 2 diabetes: CSI study. Diabetes Obes Metab. 2012; 14: 795802.
  • 29
    DeFronzo RA, Hissa MN, Garber AJ et al. The efficacy and safety of saxagliptin when added to metformin therapy in patients with inadequately controlled type 2 diabetes with metformin alone. Diabetes Care. 2009; 32: 16491655.
  • 30
    Chacra AR, Tan GH, Apanovitch A et al. Saxagliptin added to submaximal dose of sulphonylurea improves glycaemic control compared with uptitration of sulphonylurea in patients with type 2 diabetes: A randomised controlled trial. Int J Clin Pract. 2009; 63: 13951406.
  • 31
    Hollander P, Li J, Allen E et al. Saxagliptin added to a thiazolidinedione improves glycemic control in patients with type 2 diabetes and inadequate control on thiazolidinedione alone. J Clin Endocrinol Metab. 2009; 94: 48104819.
  • 32
    Barnett AH, Charbonnel B, Donovan M, Fleming D, Chen R. Effect of saxagliptin as add-on therapy in patients with poorly controlled type 2 diabetes on insulin alone or insulin combined with metformin. Curr Med Res Opin. 2012; 28: 513523.
  • 33
    Forst T, Uhlig-Laske B, Ring A et al. Linagliptin (BI 1356), a potent and selective DPP-4 inhibitor, is safe and efficacious in combination with metformin in patients with inadequately controlled type 2 diabetes. Diabet Med. 2010; 27: 14091419.
  • 34
    Taskinen MR, Rosenstock J, Tamminen I et al. Safety and efficacy of linagliptin as add-on therapy to metformin in patients with type 2 diabetes: A randomized, double-blind, placebo-controlled study. Diabetes Obes Metab. 2011; 13: 6574.
  • 35
    Owens DR, Swallow R, Dugi KA, Woerle HJ. Efficacy and safety of linagliptin in persons with type 2 diabetes inadequately controlled by a combination of metformin and sulphonylurea: A 24-week randomized study. Diabet Med. 2011; 28: 13521361.
  • 36
    Gomis R, Espadero R-M, Jones R, Woerle HJ, Dugi KA. Efficacy and safety of initial combination therapy with linagliptin and pioglitazone in patients with inadequately controlled type 2 diabetes: A randomized, double-blind, placebo-controlled study. Diabetes Obes Metab. 2011; 13: 653661.
  • 37
    Yki-Järvinen H, Duran-Garcia S, Pinnetti S et al. Efficacy and safety of linagliptin as add-on therapy to basal insulin in patients with type 2 diabetes. Diabetes. 2012; 61 (Suppl. 1): A255. (Abstract).
  • 38
    Blech S, Ludwig-Schwellinger E, Grafe-Mody EU, Withopf B, Wagner K. The metabolism and disposition of the oral dipeptidyl peptidase-4 inhibitor, linagliptin, in humans. Drug Metab Dispos. 2010; 38: 667678.
  • 39
    Graefe-Mody U, Friedrich C, Port A et al. Effect of renal impairment on the pharmacokinetics of the dipeptidyl peptidase-4 inhibitor linagliptin. Diabetes Obes Metab. 2011; 13: 939946.
  • 40
    Graefe-Mody U, Giessmann T, Ring A, Iovino M, Woerle HJ. A randomized, open-label, crossover study evaluating the effect of food on the relative bioavailability of linagliptin in healthy subjects. Clin Ther. 2011; 33: 10961103.
  • 41
    Ahrén B, Gomis R, Standl E, Mills D, Schweizer A. Twelve- and 52-week efficacy of the dipeptidyl peptidase IV inhibitor LAF237 in metformin-treated patients with type 2 diabetes. Diabetes Care. 2004; 27: 28742880.
  • 42
    Bosi E, Camisasca RP, Collober C, Rochotte E, Garber AJ. Effects of vildagliptin on glucose control over 24 weeks in patients with type 2 diabetes inadequately controlled with metformin. Diabetes Care. 2007; 30: 890895.
  • 43
    Rosenstock J, Kim SW, Baron MA et al. Efficacy and tolerability of initial combination therapy with vildagliptin and pioglitazone compared with component monotherapy in patients with type 2 diabetes. Diabetes Obes Metab. 2007; 9: 175185.
  • 44
    Garber AJ, Schweizer A, Baron MA, Rochotte E, Dejager S. Vildagliptin in combination with pioglitazone improves glycaemic control in patients with type 2 diabetes failing thiazolidinedione monotherapy: A randomized, placebo-controlled study. Diabetes Obes Metab. 2007; 9: 166174.
  • 45
    Fonseca V, Schweizer A, Albrecht D, Baron MA, Chang I, Dejager S. Addition of vildagliptin to insulin improves glycemic control in type 2 diabetes. Diabetologia. 2007; 50: 11481155.
  • 46
    DeFronzo RA, Burant CF, Fleck P, Wilson C, Mekki Q, Pratley RE. Effect of alogliptin combined with pioglitazone in glycemic control in metformin-treated patients with type 2 diabetes. J Clin Endocrinol Metab. 2012; 97: 16151622.
  • 47
    Rosenstock J, Rendell MS, Gross JL, Fleck PR, Wilson CA, Mekki Q. Alogliptin added to insulin therapy in patients with type 2 diabetes reduces HbA(1C) without causing weight gain or increased hypoglycaemia. Diabetes Obes Metab. 2009; 11: 11451152.
  • 48
    Eng J, Kleinman WA, Singh L, Singh G, Raufman JP. Isolation and characterization of exendin-4, an exendin-3 analogue, from Heloderma suspectum venom. J Biol Chem. 1992; 267: 74027405.
  • 49
    Thorens B, Porret A, Buhler L, Deng SP, Morel P, Widmann C. Cloning and functional expression of the human islet GLKP-1 receptor. Demonstration that exendin-4 is an agonist and exendin (9–39) an antagonist of the receptor. Diabetes. 1993; 42: 16781682.
  • 50
    Nelson P, Poon T, Guan X, Schnabel C, Wintle M, Fineman M. The incretin mimetic exenatide as a monotherapy in patients with type 2 diabetes. Diabetes Technol Ther. 2007; 9: 317326.
  • 51
    Moretto TJ, Milton DR, Ridge TD et al. Efficacy and tolerability of exenatide monotherapy over 24 weeks in antidiabetic drug-naive patients with type 2 diabetes: A randomized, double-blind, placebo-controlled, parallel-group study. Clin Ther. 2008; 30: 14481460.
  • 52
    Buse JB, Henry RR, Han J, Kim DD, Fineman MS, Baron AD. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care. 2004; 27: 26282635.
  • 53
    DeFronzo RA, Ratner RE, Han J, Kim DD, Fineman MS, Baron AD. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care. 2005; 28: 10921100.
  • 54
    Kendall DM, Riddle MC, Rosenstock J et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea. Diabetes Care. 2005; 28: 10831091.
  • 55
    Derosa G, Maffioli P, Salvadeo SA et al. Exenatide versus glibenclamide in patients with diabetes. Diabetes Technol Ther. 2010; 12: 233240.
  • 56
    Zinman B, Hoogwerf BJ, Durán García S et al. Effect of adding exenatide to a thiazolidinedione in suboptimally controlled type 2 diabetes: A randomized trial. Ann Intern Med. 2007; 146: 477485.
  • 57
    Heine RJ, Van Gaal LF, Johns D, Mihm MJ, Widel MH, Brodows RG. Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes: A randomized trial. Ann Intern Med. 2005; 143: 559569.
  • 58
    Barnett AH, Burger J, Johns D et al. Tolerability and efficacy of exenatide and titrated insulin glargine in adult patients with type 2 diabetes previously uncontrolled with metformin or a sulfonylurea: A multinational, randomized, open-label, two-period, crossover noninferiority trial. Clin Ther. 2007; 29: 23332348.
  • 59
    Nauck MA, Duran S, Kim D et al. A comparison of twice-daily exenatide and biphasic insulin aspart in patients with type 2 diabetes who were suboptimally controlled with sulfonylurea and metformin: A non-inferiority study. Diabetologia. 2007; 50: 259267.
  • 60
    Buse JB, Bergenstal RM, Glass LC 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: 103112.
  • 61
    Violante R, Oliveira JH, Yoon KH et al. A randomized non-inferiority study comparing the addition of exenatide twice daily to sitagliptin or switching from sitagliptin to exenatide twice daily in patients with type 2 diabetes experiencing inadequate glycaemic control on metformin and sitagliptin. Diabet Med. 2012; 29: e417424.
  • 62
    Drucker DJ, Buse JB, Taylor K et al. Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: A randomised, open-label, non-inferiority study. Lancet. 2008; 372: 12401250.
  • 63
    Buse JB, Drucker DJ, Taylor KL et al. Exenatide once weekly produces sustained glycemic control and weight loss over 52 weeks. Diabetes Care. 2010; 33: 12551261.
  • 64
    Bergenstal RM, Wysham C, Macconell L et al. Efficacy and safety of exenatide once weekly versus sitagliptin or pioglitazone as an adjunct to metformin for treatment of type 2 diabetes (DURATION-2): A randomised trial. Lancet. 2010; 376: 431439.
  • 65
    Diamant M, Van Gaal L, Stranks S et al. Once weekly exenatide compared with insulin glargine titrated to target in patients with type 2 diabetes (DURATION-3): An open-label randomised trial. Lancet. 2010; 375: 22342243.
  • 66
    Russell-Jones D, Cuddihy RM, Hanefeld M et al. Efficacy and safety of exenatide once weekly versus metformin, pioglitazone, and sitagliptin used as monotherapy in drug-naive patients with type 2 diabetes (DURATION-4): A 26-week double-blind study. Diabetes Care. 2012; 35: 252258.
  • 67
    Blevins T, Pullman J, Malloy J et al. DURATION-5: Exenatide once weekly resulted in greater improvements in glycemic control compared with exenatide twice daily in patients with type 2 diabetes. J Clin Endocrinol Metab. 2011; 96: 13011310.
  • 68
    Buse JB, Nauck M, Forst T et al. Exenatide once weekly versus liraglutide once daily in patients with type 2 diabetes (DURATION-6): A randomised, open-label study. Lancet. 2013; 381: 117124.
  • 69
    Marre M, Shaw J, Brändle M et al. Liraglutide, a once-daily human GLP-1 analogue, added to a sulphonylurea over 26 weeks produces greater improvements in glycaemic and weight control compared with adding rosiglitazone or placebo in subjects with type 2 diabetes (LEAD-1 SU). Diabet Med. 2009; 26: 268278.
  • 70
    Nauck M, Frid A, Hermansen K et al. Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: The LEAD (liraglutide effect and action in diabetes)-2 study. Diabetes Care. 2009; 32: 8490.
  • 71
    Garber A, Henry R, Ratner R et al. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): A randomised, 52-week, Phase III, double-blind, parallel-treatment trial. Lancet. 2009; 373: 473481.
  • 72
    Zinman B, Gerich J, Buse JB et al. Efficacy and safety of the human glucagon-like peptide-1 analog liraglutide in combination with metformin and thiazolidinedione in patients with type 2 diabetes (LEAD-4 Met+TZD) [published erratum appears in Diabetes Care. 2010; 33(3): 692]. Diabetes Care. 2009; 32: 12241230.
  • 73
    Russell-Jones D, Vaag A, Schmitz O et al. Liraglutide vs insulin glargine and placebo in combination with metformin and sulfonylurea therapy in type 2 diabetes mellitus (LEAD-5 met+SU): A randomised controlled trial. Diabetologia. 2009; 52: 20462055.
  • 74
    Buse JB, Rosenstock J, Sesti G et al. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: A 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet. 2009; 374: 3947.
  • 75
    Buse JB, Sesti G, Schmidt WE et al. Switching to once-daly liraglutide from twice-daily exenatide further improves glycemic control in patients with type 2 diabetes using oral agents. Diabetes Care. 2010; 33: 13001303.
  • 76
    Mari A, Sallas WM, He YL et al. Vildagliptin, a dipeptidyl peptidase-IV inhibitor, improves model-assessed beta-cell function in patients with type 2 diabetes. J Clin Endocrinol Metab. 2005; 90: 48884894.
  • 77
    Ahren B. Vildagliptin: An inhibitor of dipeptidyl peptidase-4 with antidiabetic properties. Expert Opin Investig Drugs. 2006; 15: 431442.
  • 78
    Degn KB, Juhl CB, Sturis J et al. One week's treatment with the long-acting glucagon-like peptide derivative liraglutide (NN2211) markedly improves 24-h glycemia an α- and β-cell function and reduces endogenous glucose release in patients with type 2 diabetes. Diabetes. 2004; 53: 11871194.
  • 79
    El-Ouaghlidi A, Rehring E, Holst JJ et al. The dipeptidyl peptidase 4 inhibitor vildagliptin does not accentuate glibenclamide-induced hypoglycemia but reduces glucose-induced glucagon-like peptide 1 and gastric inhibitory polypeptide secretion. J Clin Endocrinol Metab. 2007; 92: 41654171.
  • 80
    Deacon CF, Wamberg S, Bie P, Hughes TE, Holst JJ. Preservation of active incretin hormones by inhibition of dipeptidyl peptidase-IV suppresses meal-induced incretin secretion in dogs. J Clin Endcorinol. 2002; 172: 355362.
  • 81
    Nauck MA. Incretin-based therapies for type 2 diabetes mellitus: Properties, functions and clinical implications. Am J Med. 2011; 124 (Suppl.) S318.
  • 82
    Gooßen K, Gräber S. Longer term safety of dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes mellitus: Systematic review and meta-analysis. Diabetes Obes Metab. 2012; 14: 10611072.
  • 83
    Bloomgarden Z. Diabetes treatment: The coming paradigm shift. J Diabetes. 2012; 4: 315317.
  • 84
    Cobble ME, Frederich R. Saxagliptin for the treatment of type 2 diabetes mellitus: Assessing cardiovascular data. Cardiovasc Diabetol. 2012; 11: 6.
  • 85
    Drucker DJ, Sherman SI, Bergenstal RM, Buse JB. The safety of incretin-based therapies: Review of the scientific evidence. J Clin Endocrinol Metab. 2011; 96: 20272031.
  • 86
    Butler PC, Dry S, Elashoff R. GLP-1-based therapy for diabetes: What you do not know can hurt you. Diabetes Care. 2010; 33: 453455.
  • 87
    Mudaliar S, Henry RR. The incretin hormones: From scientific discovery to practical therapeutics. Diabetologia. 2012; 55: 18651868.