Meeting Perspectives: The ADA Scientific Sessions: Advances in the Pharmacologic Management of Type 2 Diabetes Mellitus

Commentary by  Howard Furst MD and Mitchell Charap MD

We will focus our review of the 2008 ADA meetings on new data regarding the GLP-1 analogues and the DPP 4 inhibitors. Before describing the clinical data, we will review the basic science that led to interest in these new classes of drugs for the treatment of diabetes mellitus.

Background
Incretins are peptides released from the gastrointestinal tract in response to nutrient ingestion. They enhance glucose-dependent insulin secretion from the pancreas and aid in the overall maintenance of glucose homeostasis. The 2 principal incretins are glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP). GLP-1 and GIP are small peptides, 30 and 42 amino acids in length, respectively,

The intestinal L cell secretes GLP-1 as a gut hormone. GLP-1 secretion by L cells is dependent on the presence of nutrients in the lumen of the small intestine. The secretagogues include major nutrients like carbohydrate, protein and lipid. GLP-1 has a half life of less than 2 minutes, due to rapid degradation by the enzyme dipeptidyl peptidase-4 (DPP-4).

DPP-4 is associated with immune regulation, signal transduction and apoptosis. It is an indiscriminate enzyme for which at least 62 substrates are known. Furthermore, it appears to work as a suppressor in the development of cancer and tumors. Dipeptidyl peptidase-4 plays a major role in glucose metabolism because it is responsible for the degradation of incretins such as GLP-1.
GLP-1 possesses several physiological properties that have made it a subject of intensive investigation as a potential treatment of diabetes mellitus. The known physiological functions of GLP-1 include:

• Increasing insulin secretion from the pancreas in a glucose-dependent manner.
• Decreasing glucagon secretion from the pancreas.
• Increasing beta cell mass and insulin gene expression.
• Inhibiting acid secretion and gastric emptying in the stomach.
• Decreasing food intake by increasing satiety.

So the trick is to find a way to extend the half-life of GLP-1 and, as expected, industry steps in…

Attracted by the lure of a potentially novel and thus, lucrative, agent in the treatment armamentarium for diabetes and potentially as an weight loss agent, Amylin Corporation discovered that a modern descendant of the dinosaur, the Gila monster, had in its saliva a toxin, exendin-4, that was structurally homologous to GLP-1. They worked their magic in the lab and structurally modified exendin-4 such that the resultant compounds were resistant to the action of endogenous dipeptidyl dipeptidase (DPP 4). Thus, they were capable of prolonging the action of GLP-1 from minutes to hours or even the whole day. With this discovery was borne the first GLP-1 analog: exenatide, known commercially as Byetta.

GLP-1 analogs represent one approach to maintaining GLP-1 levels. The other is to decrease its degradation by blocking the enzyme, DPP 4, aka a DPP 4 inhibitor. Sitagliptin, known commercially as Januvia, is the only inhibitor available now, but many more are in clinical trials or being reviewed by the FDA. Though a potential concern is that DPP 4 inhibition might affect immune function, this has not been borne out in the trials.

ADA Meeting Summary
With the above as a background, the following studies were highlighted at this year’s ADA meeting.

Comparison of Long acting release exenatide (LAR) and Byetta
Reported was a 30 week randomized, open label study comparing the efficacy of two formulations of exenatide. LAR exenatide is administered intramuscularly once a week and Byetta is administered twice daily. The patients were either treatment naive or were treated with one or more oral agents. Benefits in LAR were seen at ten weeks as measured by the study’s endpoints, including HgA1C (decrease of 1.9 in the LAR group and 1.5 in the byetta group P<0.005) and fasting glucose.

Furthermore, LAR exenatide was well tolerated with 90% of patients completing the trial and nausea, the most frequent side effect, noted less often in the LAR group. We believe that LAR exenatide will play a significant role in the management of Type 2 Diabetes Mellitus. It appears to be at least as good as the shorter acting formulation and may offer some advantages. However, because of the increased viscosity of the drug, a larger bore needle is necessary and therefore more painful to administer to the patient. There will be competition with Liraglutide (discussed below), which is a once daily GLP 1 analog whose FDA approval is expected in 2009.

Efficacy of Exenatide therapy over two years in a “Real World” setting
This oral presentation described the realities of using exenatide in the “real world.” However, it described the experience of only 30 patients. The patients were on a variety of different regimens, including oral agents and insulin and were then started on exenatide. At two years post initiation of exenatide, the following observations were made:
1. Despite initial significant weight loss, the majority regained it. Average weight loss was -1.53 kg (P=0.786).
2. 13 of 30 patients discontinued exenatide secondary to drug failure ( no improvement in HgA1c) and 6 of 30 stopped secondary to side effects.
3. 11 of 30 had a HgA1c decrease of only 0.78% and a minimal weight loss of 3.68 kg.

This data is clearly different from the initial phase III trial data. Little is known about the patient population and because of the small numbers, it is difficult to draw meaningful conclusions. The one exception may be that in both the phase III data and this small study, there is wide variability in weight loss and HgA1c change in patients taking exenatide.

New Formulation: Intranasal Exenatide
Exenatide cannot be effectively administered orally, thus creating an opportunity for an intranasal delivery route as an alternative to multiple daily injections. Phase I data was presented. Twenty patients with type II diabetes mellitus were given varying doses of the intranasal formulation. Tmax was reached at 15 minutes and levels were comparable to SC dosing. Post prandial glucose decreased significantly. Nausea was a complaint in 6 patients and vomiting in 5.
This is interesting early data. If the intranasal drug does not have to be refrigerated as do the parenteral formulations, then it may have a role in the GLP-1 marketplace

Liraglutide compared with Glimepiride
Liraglutide is a once daily GLP 1 analog. Reported at the ADA meeting was a 52 week RCT that compared efficacy and safety of two doses of liraglutide to glimepiride, a sulfonylura, in 746 patients. The findings were similar to the original phase II and III results of extenatide with comparable HgA1c lowering from baseline vs glimepiride and similar changes in weight (decrease in liraglutide and increased in glimepiride). Nausea, the most common side effect was noted in almost 30% of patients randomized to liraglutide. This data looks surprisingly similar to the data from exenatide in phase II and III trials. There was the same magnitude of effect on HbA1c and weight as well as a similar percentage of patients experiencing nausea.

R1583 improves glycemic control and lowers body weight
R1583 is another long acting GLP-1 analog in Phase II trial. The drug is a two amino acid substitution from GLP1. 306 patients on metformin (BMI 32.7; HgA1C 7.9) were randomized to placebo or to receive different doses of weekly or every other week R1583 for 8 weeks. The HgA1c decrement was about 1 in the treatment arm and .2% in the placebo arm. Body weight decreased progressively and dose-dependently (~2kg). This drug is in Phase IIII trials and will compete against LAR. It is not clear at present what advantage this drug might have except that it may be administered every two weeks.

The Bad News
Unfortunately, since its introduction two years ago, there have been at least 30 reported cases of acute pancreatitis and the FDA believes there is an association between Byetta and some of the cases of pancreatitis. On August 18th, 2008, the FDA updated health professionals, stating that since their last report in October 2007, they received reports of 6 additional cases of necrotizing or hemorrhagic pancreatitis. All 6 patients required hospitalization and 2 died. The FDA has stated that unless an alternative etiology is identified following confirmed pancreatitis, Byetta should not be restarted.

DPP 4 inhibitors
By inhibitring DPP 4, the potential exists for the progressive beta-cell loss of type 2 diabetes to slow or abate. Maintaining and regenerating beta-cell mass is the final therapeutic goal for the treatment of diabetes. To that end, known commercially as Januvia, is the only DPP 4 inhibitor FDA approved. As reported at the ADA metings, many pharmaceutical companies are in various phases of development on identifying similar inhibitors. Initial reports reveal that they do not appear terribly different from one another. To generalize, DPPIV inhibition results in slightly improved glycemic control (~0.5mg/dl), and the drugs are well tolerated with very few side effects.

Take Home Points
The GLP 1 analogues play a role in the management of type 2 diabetes mellitus. They are associated with modest weight loss and lower HgbA1c by approximately 2mg/dl under optimal conditions. The drugs are easy to dose, but oral administration is not possible and the drugs require refrigeration. Once daily dosing of Liraglutide and LAR exenatide will potentially improve compliance and is thus promising. The claim that these drugs maintain beta cell mass is based on experimental and preliminary clinical observations (the drugs are effective over long periods of time), and their clinical importance remains to be seen.

The DDP 4 inhibitors are safe and marginally effective. Soon there will be many choices for the practitioner. Initial observations do not reveal any significant differences between them, though this is extremely preliminary. Moreover, it does not appear that this class of drugs will have the same clinical impact as the GLP 1 analogues

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