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This article originally posted and appeared in  Issue 454Type 2 Diabetes

Recent Advances in GLP-1 Receptor Agonists in the Treatment of Type 2 Diabetes

A couple of months ago we had a review of GLP-1 mimetic therapies and studies form the European Association for the Study of Diabetes (EASD) 44th Annual Meeting convened in Rome, Italy, September 8-11, 2008. Many of you emailed me asking for more information on what the latest research shows as to how these compounds work and the results of the newer studies going on. Alan J. Garber, MD, PhD, prepared an in depth review of the things you asked for.


Recent Advances in GLP-1 Receptor Agonists in the Treatment of Type 2 Diabetes:
44th Annual Meeting of the European Association for the Study of Diabetes
Alan J. Garber, MD, PhD

The European Association for the Study of Diabetes (EASD) 44th Annual Meeting convened in Rome, Italy, September 8-11, 2008. Studies investigating glucagon-like peptide (GLP)-1-based therapies dominated the meeting, much as data on the same subject dominated the American Diabetes Association (ADA) 68th Scientific Sessions in June 2008. These agents appear to be the new frontier of antidiabetes therapies, and they have the greatest near-term potential to affect our management of patients with this disease within the next 1-3 years.

Incretin Mimetics
During an oral session entitled "GLP-1 Based Therapies," data were presented comparing the addition of liraglutide, a long-acting human GLP-1 receptor agonist, with the addition of insulin glargine to the therapeutic regimens of patients whose diabetes was poorly controlled with metformin-sulfonylurea combination therapy. The addition of liraglutide produced greater reductions in glycated hemoglobin (A1C; −1.33%) compared with the addition of insulin glargine (−1.09%). Furthermore, there was substantial weight loss associated with liraglutide treatment (−1.81 kg) vs weight gain with glargine (+1.62 kg). Thirteen percent of patients reported nausea with liraglutide.

In another study, the extent of A1C reduction produced by liraglutide was shown to be dependent, in part, on the level of initial hyperglycemia.[2] Higher baseline A1C levels were associated with greater reductions in A1C, and, conversely, lower A1C levels initially resulted in smaller degrees of A1C reduction. The greatest reductions in A1C were noted in patients previously treated with metformin plus rosiglitazone. This finding may reflect a state of maximal insulin sensitization, which might increase the response to the insulin secretory-stimulating properties of liraglutide.

Other papers in the session focused on exenatide, especially the once-weekly formulation -- exenatide long-acting release (LAR). In a direct comparison study, the once-weekly formulation reduced A1C by 1.9%, whereas the twice-daily formulation reduced A1C by only 1.5%. There was no difference in weight loss between the 2 exenatide formulations in this study, which was originally reported at the ADA 68th Scientific Sessions. At the EASD meeting, the 22-week, open-label follow-up to the original study was described. With the additional time, patients originally treated with exenatide LAR had a slight further improvement in A1C, for a final overall decrease of −2.0%. Patients who switched from exenatide twice daily to the LAR preparation showed a further decline in A1C levels to the same overall −2.0% decline. Nausea was low in both groups.

Another study investigated exenatide alone and in combination with metformin in obese insulin-resistant women with polycystic ovary syndrome. Exenatide twice daily alone or in combination with metformin was more effective than metformin alone in reducing androgen excess and abdominal girth.

A phase 2 dose-ranging study of AVE0010, an exenatide analog, demonstrated that this agent was somewhat more effective when given twice daily as 2 half doses compared with administration of the full dose once daily. However, the difference was small, and the agent appeared to be effective when administered as a once-daily injection.

Newer Incretin Therapies
New observations on patient-reported outcomes associated with liraglutide monotherapy were presented. Using previously developed instruments to assess parameters of mental health, well-being, and distress, the investigators found that liraglutide administration was associated with an increased sense of well-being and reduced concern about weight. These changes were judged to be quite positive for liraglutide in comparison with the changes reported for glimepiride, which were unchanged or negative in these areas. Despite the fact that liraglutide is administered once daily by injection, the weight-loss benefits of liraglutide -- especially the full 1.8-mg dose -- clearly overcame the negative impact of potential perceptions of ill health resulting from the injection per se. Thus, weight-loss benefits clearly overcame injection-associated negatives. This resulted in significantly improved quality-of-life scores for liraglutide compared with insignificant changes in the scores associated with glimepiride therapy.

The full data of the liraglutide monotherapy trial (Liraglutide Effect and Action in Diabetes [LEAD] 3 Mono) were also presented at the meeting. In this study, available online early from The Lancet, 2 groups of patients were studied: a cohort of drug-naive patients and a second cohort of patients on half-maximal doses of monotherapies directly switched to liraglutide. After a 52-week treatment period, liraglutide therapy reduced A1C by nearly twice the amount produced by glimepiride therapy (8 mg). In addition to its superior efficacy, liraglutide resulted in weight loss (−2.45 kg) compared with weight gain with glimepiride (+1.12 kg). There was also a 2- to 3-fold greater rate of minor hypoglycemia with glimepiride.

Trials of liraglutide in patients failing to respond to initial metformin monotherapy, prior metformin plus rosiglitazone combination therapy, and prior rosiglitazone plus sulfonylurea combination therapy were also presented. These studies all showed superior glycemic control with liraglutide compared with the addition of a conventional oral agent. Additionally, there was a significant weight benefit associated with liraglutide therapy that was not seen with other agents.

An analysis of all 5 phase 3 trials of liraglutide (the LEAD trials) with regard to systolic blood pressure was also presented. In all 5 studies, liraglutide reduced systolic blood pressure compared with comparators by 2.7-4.5 mm Hg. This finding was significant in 4 of 5 trials investigated and was independent of the adjuvant antidiabetes therapy used, if any.

Independent studies of liraglutide in animals demonstrated a direct effect of this GLP-1 agonist on endothelial cell dysfunction. Liraglutide reduced plasminogen activator inhibitor (PAI)-1 expression and the mRNA expression of the vascular adhesion molecules ICAM (intercellular cell adhesion molecule), VCAM (vascular cell adhesion molecule), and E-selectin. This direct effect of the agent may explain the observed clinical effect of liraglutide on clinical blood pressure within 2 weeks of its administration. Certainly, this timeframe precludes weight loss as the mechanism of blood pressure benefit and clearly implicates 1 or more direct effects of liraglutide on blood pressure regulatory functions.

Additional studies performed with liraglutide demonstrated a beta-cell function benefit of liraglutide compared with other antidiabetes therapies in the 5 LEAD trials. Two different methods of assessing beta-cell function were used. Indirect assessments with the Homeostasis Model Assessment (HOMA) equations showed a clear 28% to 34% improvement over baseline for liraglutide, regardless of concomitant antidiabetes therapies. This finding was confirmed by analyses of proinsulin:insulin in the trials as well. In all 5 trials, ratios were improved following liraglutide treatment. These findings suggest direct benefits of liraglutide on the beta cell that are not conferred by insulin secretagogues. These observations may also be important to the durability of glycemic control achieved with liraglutide treatment. As noted in LEAD 3 Mono, the 1.8-mg dose of liraglutide produced highly durable glucose control throughout the full 1-year period of the randomized trial. A1C values rapidly decreased to below 7.0% and remained less than 7% for the duration of the study. This result was in sharp contrast to the slow loss of control seen with glimepiride or the lower 1.2-mg dose of liraglutide.

Exenatide Updates
A number of studies with exenatide were also presented at the EASD meeting. Most notable was the finding that compliance and persistence with twice-daily exenatide therapy was significantly greater than compliance and persistence with once-daily administration of insulin glargine. The basis for this result is unclear, especially in view of the greater frequency of injection with exenatide. However, patients taking exenatide had fewer comorbidities than those taking insulin glargine.

Several large database studies were presented showing that exenatide therapy was associated with significant A1C reductions, weight loss, and reduction in concomitant medications in the populations studied. These were, of course, not randomized trials, but the findings were clearly consistent with prior smaller-scale randomized studies.

Clinical trials with exenatide reported better postprandial glucose control with exenatide than with the dipeptidyl peptidase (DPP)-4 inhibitor sitagliptin. This finding may have been the result of reduced gastric emptying or greater prandial insulin secretion or more effective prandial glucagon suppression seen with exenatide compared with sitagliptin. Because this was a 2-week study, A1C was not determined.

Four different studies compared exenatide with various insulin comparators, including basal or biphasic insulins In all instances, exenatide was more successful in attaining goals of tight glycemic control (A1C ≤ 6.5%) and in lowering postprandial glucose excursions. Exenatide therapy was associated with weight loss, and weight gain was associated with insulin therapy. Finally, like liraglutide, exenatide was shown to lower systolic blood pressure to a greater extent than insulin or placebo in patients with type 2 diabetes.

The mechanism of postprandial glucose normalization produced by exenatide was time-dependent with regard to acute vs chronic treatment. Acute exenatide exposure reduced postprandial glucose excursions by reducing gastric emptying and by decreasing and inhibiting endogenous glucose production, whereas chronic treatment with exenatide augmented hepatic glucose uptake and modestly reduced endogenous glucose production. This finding may or may not correspond to the conditioning effect seen by other investigators with respect to the effect of GLP-1 treatment on beta-cell function. Finally, exenatide effects on beta-cell function were demonstrated with respect to first-phase insulin secretion in terms of meal stimulation. This was assessed with an insulinogenic index rather than by rapid sampling for serum insulin levels or calculations of insulin secretion relying on deconvolution of C-peptide secretion responses.

Looking to the Future
An entire session was devoted to novel GLP-1-based therapies. One presentation dealt with the intranasal administration of exenatide. This novel route of administration resulted in rapid exenatide adsorption within 30 minutes, compared with peaks following subcutaneous injection of approximately 2 hours. Blood levels of exenatide were therapeutic following intranasal administration and were comparable to those achieved with subcutaneous administration. Similarly, the postprandial glucose effects of nasal vs injectable exenatide were similar.

Two papers dealt with pulmonary administration of GLP-1 by the use of Technosphere® (MannKind Corp, Paramus, New Jersey) technology. Pulmonary administration produced therapeutic blood levels of GLP-1 sufficient to lower blood glucose without associated nausea and vomiting, a result not seen for GLP-1 administered by subcutaneous injection.

Other GLP-1 analogs were also reported, including the results of studies with albiglutide, a human GLP-1 fused to albumin. The preliminary data showed good glucose lowering with once-weekly dosing of this agent. Results with taspoglutide were also presented. This is a human GLP-1 analog with 2 aminoisobutyric acid substitutions, which inhibit DPP-4 degradation of the molecule. Dose-ranging studies reported good efficacy at once-weekly or longer intervals.
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This article originally posted 03 February, 2009 and appeared in  Issue 454Type 2 Diabetes

Past five issues: Issue 796 | Diabetes Clinical Mastery Series Issue 255 | Issue 795 | SGLT-2 Inhibitors Special Edition August 2015 | Diabetes Clinical Mastery Series Issue 254 |

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