ADVERTISEMENT

Advances in therapy for type 2 diabetes: GLP–1 receptor agonists and DPP–4 inhibitors

December 1, 2009 | Cleveland Clinic Journal of Medicine
Jaime A. Davidson, MD
Author and Disclosure Information

Jaime A. Davidson, MD
Clinical Professor of Internal Medicine, Division of Endocrinology, University of Texas Southwestern Medical School, Dallas, TX

Correspondence: Jaime A. Davidson, MD, 7777 Forest Lane, Suite C204, Dallas, TX 75230; davidsonmd@sbcglobal.net

Dr. Davidson reported that he has received grant support from Bristol-Myers Squibb, Eli Lilly and Company, GlaxoSmithKline, MannKind Corporation, Novo Nordisk, Pfizer Inc., and Sanofi-Aventis; consulting/advisory fees from AstraZeneca, Boehringer Ingelheim GmbH, Bristol-Myers Squibb, Eli Lilly and Company, F. Hoffmann-La Roche Ltd., Generex Biotechnology Corporation, Johnson & Johnson, Novo Nordisk, and Takeda Pharmaceutical Company Limited; and speakers’ bureau fees from Eli Lilly and Company, Novo Nordisk, and Takeda Pharmaceutical Company Limited. He reported that he has stock ownership interest in Eli Lilly and Company, Generex Biotechnology Corporation, GlaxoSmithKline, and Pfizer, Inc., managed by Royal Alliance Associates, Inc. Dr. Davidson reported that he received no honorarium for writing this article.

Dr. Davidson reported that he wrote this article and received no assistance with content development from unnamed contributors. He reported that BlueSpark Healthcare Communications, a medical communications company, assisted with preliminary literature searches, reference verification, proofing for grammar and style, table and figure rendering based on author instructions, copyright permission requests, and identification of topical overlap with other manuscripts in this supplement.

ABSTRACT

Type 2 diabetes mellitus (T2DM) is intrinsically connected to overweight and obesity. It is a complex metabolic disorder that predisposes patients to, and is associated with, cardiovascular disease. In addition to the triumvirate of core defects associated with T2DM (involvement of the pancreatic beta cell, the muscle, and the liver), other mechanisms including hyperglucagonemia, accelerated gastric emptying, and incretin deficiency/resistance are also involved. This has led to the development of incretin-based therapies, such as glucagon-like peptide–1 (GLP-1) receptor agonists and dipeptidyl peptidase–4 (DPP-4) inhibitors. These newer therapies have beneficial effects on glycosylated hemoglobin A1c (HbA1c) levels, weight, and pancreatic beta-cell function.

KEY POINTS

  • Hormonal deficiencies in T2DM are related to abnormalities in the secretion of amylin, glucagon, and incretin hormones.
  • In clinical trials, GLP-1 receptor agonists reduced HbA1c levels, had beneficial effects on weight, and caused less hypoglycemia than insulin analogues.
  • Both GLP-1 receptor agonists and DPP-4 inhibitors improve pancreatic beta-cell function.
  • Incretin-based therapies have been incorporated into recently updated clinical guidelines for treatment of T2DM.

Meta-analysis conclusions

The published clinical trial data presented in this review expand the body of evidence on the safety and efficacy of incretin-based therapy in patients with T2DM. These data include the results of a meta-analysis by Amori et al,17 which examined randomized controlled trials of 12 weeks’ or longer duration that compared incretin-based therapy with placebo or other diabetes medications and reported HbA1c changes in adults with T2DM. The meta-analysis showed that incretin-based therapies reduced HbA1c more than placebo (weighted mean difference, –0.97% [95% confidence interval (CI), –1.13% to –0.81%] for GLP-1 receptor agonists and –0.74% [95% CI, –0.85% to –0.62%] for DPP-4 inhibitors) and were noninferior to other antidiabetes agents. Treatment with a GLP-1 receptor agonist (ie, exenatide) caused weight loss (–1.4 kg and –4.8 kg vs placebo and insulin, respectively) while DPP-4 inhibitors (ie, sitagliptin, vildagliptin) were weight neutral.17

Beta-cell function

Evidence regarding the effects of incretin-based therapies, particularly the exendin-4 GLP-1 receptor agonists, on beta-cell function in patients with T2DM continues to accumulate. When assessing long-term (1 year) exenatide treatment in patients with T2DM, a trial (n = 69) comparing exenatide with the basal insulin analogue insulin glargine showed that exenatide and insulin glargine resulted in similar reductions in HbA1c (–0.8% vs –0.7%; P = .55).64 However, exenatide significantly reduced body weight while insulin glargine resulted in weight gain (–3.6 kg vs +1.0 kg; P < .0001). In terms of beta-cell function, arginine-stimulated C-peptide secretion during hyperglycemia increased 2.46-fold from baseline after 52 weeks of exenatide treatment compared with 1.31-fold with insulin glargine treatment (P < .0001).64

With respect to the direct beta-cell effects of liraglutide, a preclinical study reported that liraglutide improved glucose homeostasis in marginal mass islet transplantation in diabetic mice.65 In this study, liraglutide was shown, in a mouse model, to reduce the time to normoglycemia after islet cell transplantation (median time, 1 vs 72.5 days; P < .0001). The effects of liraglutide on beta-cell function also were assessed in 13 patients with T2DM. After 7 days of treatment, liraglutide improved beta-cell function, which was associated with improvement in glucose concentration.66 Liraglutide improved potentiation of insulin secretion during the first meal, owing in part to restoration of the potentiation peak (which is markedly blunted in T2DM), in a phenomenon similar to that observed with exenatide.67

Beneficial effects on beta-cell function have also been reported with DPP-4 inhibitors. In a model-based analysis of patients with T2DM, it was shown that sitagliptin improved basal, static, and dynamic responsiveness of pancreatic beta cells to glucose. The results were observed when sitagliptin was administered both as an add-on to metformin therapy and as monotherapy.68 A 52-week, double-blind, randomized, parallel-group study compared vildagliptin 50 mg/day and placebo in 306 patients with T2DM and mild hyperglycemia (HbA1c, 6.2% to 7.5%). Vildagliptin was shown to significantly increase fasting insulin secretory tone, glucose sensitivity, and rate sensitivity, all of which are aspects of beta-cell function.69

Summary

Based on the ability of incretin-based therapies to address various disease mechanisms, including beta-cell defects (ie, hyperglycemia), hormone-related abnormalities (ie, hyperglucagonemia, incretin deficiency/resistance), and accelerated gastric emptying (especially with GLP-1 receptor agonists); their favorable effects on weight (reduction with GLP-1 receptor agonists and neutral with DPP-4 inhibitors); their beneficial effects on CV risk factors; and their good safety profile (ie, hypoglycemia risk comparable with metformin), these agents could be considered therapeutic advances for the treatment of patients with T2DM.

INCRETIN-BASED THERAPIES IN GUIDELINES AND ALGORITHMS

The 2007 AACE medical guidelines for clinical practice for the management of diabetes recognized the place of the incretin-based therapies and included them among the pharmacologic options.5 Exenatide was specifically recommended for combination therapy with metformin, a sulfonylurea (secretagogue), a sulfonylurea plus metformin, or a TZD. Sitagliptin was recommended for use as monotherapy or in combination with metformin or a TZD.5

In 2009, the American Diabetes Association (ADA) and the European Association for the Study of Diabetes convened a consensus panel to produce an algorithm for the initiation and adjustment of therapy for patients with T2DM. In this algorithm, GLP-1 receptor agonists were considered appropriate in certain clinical scenarios (eg, when hypoglycemia was an issue or weight loss was a major consideration during treatment). However, the groups also noted a need for more data on long-term safety and the cost of treatment with incretin-based therapies.70

The AACE and the American College of Endocrinology recently developed “road maps” for managing patients with T2DM. In patients with T2DM who are naïve to therapy, DPP-4 inhibitors are among the recommended first options when the initial HbA1c is 6.0% to 7.0% and as a combination therapy component when HbA1c reaches 7.0% to 9.0%. In patients who have already received monotherapy for 2 to 3 months and whose HbA1c is 6.5% to 8.5%, treatment options include combination therapy with a DPP-4 inhibitor and metformin or a TZD. Another option includes the initiation of treatment with a GLP-1 receptor agonist in combination with a TZD, with metformin or a sulfonylurea, or with metformin and a sulfonylurea.71

The role of GLP-1 receptor agonist therapies and their incorporation into T2DM treatment algorithms was noted at the 2008 annual meeting of the ADA. In the Banting lecture, Ralph A. DeFronzo, MD, advocated the early use of triple-drug therapy with metformin, exenatide, and a TZD in the management of patients with T2DM.9

CONCLUSION

T2DM, which is linked to weight gain and obesity, is a complex disease that predisposes patients to and is associated with CVD. A better understanding and appreciation of the role of the incretin system in the pathogenesis of T2DM has led to the development of incretin-based therapies, such as the GLP-1 receptor agonists and DPP-4 inhibitors. As more experimental and clinical evidence becomes available, subtle nuances are emerging that distinguish the roles of these two therapeutic classes.

ADVERTISEMENT
ADVERTISEMENT
ADVERTISEMENT