GLP-1 Receptor Agonists vs. DPP-4 Inhibitors for Type 2 Diabetes

Is One Approach More Successful or Preferable Than the Other?

S. Brunton

Disclosures

Int J Clin Pract. 2014;68(5):557-567. 

In This Article

Abstract and Introduction

Abstract

Background: In patients with type 2 diabetes (T2D), incretin-based therapies improve glycaemic control with low incidence of hypoglycaemia and without weight gain, both advantages over traditional add-ons to metformin. Dipeptidyl peptidase-4 (DPP-4) inhibitors are administered orally and provide a physiological increase in glucagon-like peptide-1 (GLP-1) levels, while GLP-1 receptor agonists (GLP-1RAs) are injectable and deliver pharmacological levels of GLP-1RA. This review aims to distinguish between GLP-1RAs and DPP-4 inhibitors, and discuss when each may be favoured in clinical practice.

Methods: A MEDLINE search, limited to human clinical trials and using the search criteria 'GLP-1RA' or 'DPP-4 inhibitor', identified seven head-to-head studies and one relevant post hoc analysis (all a GLP-1RA vs. the DPP-4 inhibitor sitagliptin). In combination with treatment algorithms, product prescribing information and personal clinical experience, these studies were used to compare the efficacy and suitability of GLP-1RAs and DPP-4 inhibitors in patients with T2D.

Results: In head-to-head clinical trials, GLP-1RAs provided greater glycaemic control, weight loss and overall treatment satisfaction vs. the DPP-4 inhibitor sitagliptin. Transient nausea was more frequent with GLP-1RAs and should be addressed through patient education and an incremental dosing approach. Current treatment algorithms recommend incretin-based therapy use after metformin failure, but local guidance may restrict their use.

Conclusion: GLP-1RAs provide superior glycaemic control and weight loss vs. DPP-4 inhibitors in patients with T2D. DPP-4 inhibitors may sometimes be preferred to a GLP-1RA if weight is not a concern, oral administration is a desirable feature or when a GLP-1RA cannot be tolerated.

Introduction

Traditional therapies available to patients with type 2 diabetes (T2D) after metformin failure [sulphonylureas (SUs), thiazolidinediones (TZDs)] are often associated with drawbacks such as weight gain, hypoglycaemia or poor long-term efficacy. The incretin-related therapies dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) not only improve glycaemic control with a low risk of hypoglycaemia but can also have beneficial non-glycaemic effects such as avoidance of weight gain, reduced blood pressure and improvements in beta-cell function and cardiovascular risk biomarkers.[1–3]

From personal experience, it appears that there is a misconception among some clinicians that DPP-4 inhibitors are essentially orally administered GLP-1RAs. This review aims to distinguish between the two treatment classes.

Incretin Physiology

The incretins are a group of hormones produced by the gastrointestinal system that enhance insulin secretion in a glucose-dependent manner; the combined incretin response accounts for 50–70% of total postprandial insulin production.[4,5] The two main human incretins are GLP-1 and glucose-dependent insulinotropic peptide (GIP). In addition to direct insulinotropic action, animal data suggest that incretin hormones may also have protective effects on the beta-cell by enhancing proliferation and resistance to apoptosis.[6] GLP-1 also promotes satiety and inhibits glucose-dependent glucagon secretion, as well as reducing hepatic glucose production.[6,7] Within the gut, GLP-1 exerts a motility-inhibiting effect and slows gastric emptying.[6]

In patients with T2D, the response to GIP is impaired. Unlike GLP-1, GIP infusion in patients with T2D does not amplify the late-phase insulin response to glucose.[8,9] Furthermore, the addition of GIP to a concurrent GLP-1 infusion not only provides no further glycaemic benefit but also antagonises GLP-1-induced glucagon suppression.[9] Therefore, incretin-based therapeutic intervention has focused on GLP-1. However, native GLP-1 has limited pharmacological value because of its short half-life (1–2 min), attributable to degradation by the peptidase enzyme DPP-4.[10] Two strategies have been employed to elevate and sustain GLP-1-mediated effects over prolonged periods: inhibition of DPP-4, which extends the half-life of endogenous GLP-1, and is therefore dependent on endogenous GLP-1 production (DPP-4 inhibitors); and use of GLP-1RAs resistant to DPP-4 degradation that can provide supraphysiological stimulation of the GLP-1R. The therapeutic potential of DPP-4 inhibitors and GLP-1RAs is dependent on their different modes of action.

DPP-4 Inhibitors and GLP-1RAs: What is the Difference?

DPP-4 inhibitors are small molecular-weight drugs that inhibit ≥ 90% of DPP-4 activity and are orally administered on a once-daily (OD) basis [vildagliptin twice daily (BID)].[11,12] There are currently three Food and Drug Administration (FDA)-approved DPP-4 inhibitors: sitagliptin, saxagliptin and linagliptin. In the European Union (EU), a fourth, vildagliptin, is also available.

The GLP-1RAs are peptide-based therapies and therefore, such as insulin, require subcutaneous injection to avoid degradation by gastrointestinal enzymes. There are currently three approved DPP-4-resistant GLP-1RA therapies: exenatide, a GLP-1-like xenopeptide and two GLP-1RAs – liraglutide, a human GLP-1 analogue, and the recently approved exendin-4-based agent lixisenatide. Exenatide and lixisenatide are synthetic forms of the naturally occurring peptide exendin-4 and both share approximately 50% sequence identity with native GLP-1.[13,14] Exenatide is available as a BID or once-weekly (OW) formulation where the latter comprises exenatide encapsulated in microspheres of poly (d,l lactic-co-glycolic acid) for gradual drug delivery.[15] Lixisenatide is administered OD.[16] Liraglutide is a human GLP-1 analogue that shares 97% amino acid sequence identity with native GLP-1. Liraglutide reversibly binds to albumin, increasing plasma half-life and allowing OD dosing.[17] Unlike exenatide and lixisenatide, which are predominantly eliminated by glomerular filtration with subsequent proteolytic degradation, liraglutide is largely metabolised prior to excretion, with no specific organ identified as a major route of elimination.[16,18,19]

The main patient-perceived difference between DPP-4 inhibitors and GLP-1RAs is likely to be their mode of administration: oral (DPP-4 inhibitors) vs. injection (GLP-1RAs). Although it is believed that patients generally oppose injectable therapies, evidence suggests that this is not always the case, especially if the injectable therapy has greater efficacy.[20–22]

Efficacy of DPP-4 Inhibitors and GLP-1RAs in Clinical Trials

In clinical trials, comparable HbA1c reductions of 0.4–0.7% have been reported with sitagliptin (100 mg OD), vildagliptin (50 mg BID), saxagliptin (5 mg OD), or liniagliptin (5 mg OD) monotherapy for 26 weeks.[23] GLP-1RAs (liraglutide 1.2 or 1.8 mg OD, exenatide 10 μg BID, exenatide OW, or lixisenatide 20 μg OD), by comparison, result in HbA1c reductions of 0.6–1.9% following 24/26/30 weeks of treatment as dual (+metformin) or triple (+metformin + SU/TZD) therapy.[24–29] Comparing the individual GLP-1RAs, liraglutide 1.8 mg has been shown to provide greater reductions in HbA1c than both exenatide BID (−1.12% vs. −0.79%; p < 0.0001) and exenatide OW (−1.48% vs. −1.28%) in head-to-head studies.[30,31]

GLP-1RAs are typically associated with weight loss (1–3 kg after 26/30 weeks), whereas DPP-4 inhibitors are generally weight-neutral, again possibly reflecting the limited increase in GLP-1R stimulation with DPP-4 inhibitors.[23,25,32,33] Direct comparisons of the GLP-1RAs have suggested that liraglutide 1.8-mg treatment may result in greater weight loss than exenatide BID [−3.24 vs. −2.87 kg; estimated treatment difference (ETD) −0.38 kg (95% CI −0.99 to 0.23); p = 0.22] and exenatide OW [−3.58 vs. 2.68 kg; ETD 0.90 kg (95% CI 0.39–1.40); p < 0.001].[30,31] Because of their glucose-dependent mechanism of action, the risk of hypoglycaemia is low with both GLP-1RAs and DPP-4 inhibitors. However, the risk of hypoglycaemia is higher when either is used in combination with a SU.[24,34–38]

Studies of GLP-1RAs in Asian populations have shown reductions in HbA1c that are comparable to or greater than those seen in global large randomised trials.[39] Likewise, clinical evidence suggests that DPP-4 inhibitors exhibit greater HbA1c-lowering efficacy in Asians than in other ethnic populations.[40] The mechanisms underlying these effects remain unclear, although they may potentially be caused by differences in pathophysiology of T2D among Asian patients, particularly in relation to body weight.[39,40] However, as yet, no head-to-head studies have been conducted that compared the use of GLP-1RAs and DPP-4 inhibitors in Asian populations.

Aim of the Review

Numerous clinical trials have compared the efficacy and safety of GLP-1RAs and DPP-4 inhibitors with placebo or oral antidiabetic drugs (OADs); however, few trials directly compare the two treatment classes. This review will focus on the results of trials directly comparing GLP-1RAs and DPP-4 inhibitors with the aim of distinguishing between the two treatment classes, and will also discuss clinical situations when each of the drug classes might be preferable.

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