MD Conference Express EASD 2012 - (Page 26)
n sElEcTEd UpdATEs On ORAl THERApiEs
Novel Oral Agents: The Search for Transformational Medicines
Written by Rita Buckley
In 2011, 366 million people had diabetes; by 2030, that figure is projected to rise to 552 million [International Diabetes Federation. IDF Diabetes Atlas. 5th ed. 2009]. The search for novel oral antidiabetic drugs (OADs) has taken on a growing sense of urgency. Richard D. DiMarchi, PhD, Indiana University, Bloomington, Indiana, USA, discussed efforts underway to develop glucagon-based incretin hybrids. Dr. DiMarchi focused his discussion on 2 glucagon-based single molecule coagonists: glucagon/glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP)/GLP-1. The clinical benefits of each are shown in Table 1. The glucagon/GLP-1 coagonist hypothesis is that chronic glucagon action decreases fat mass by increasing energy expenditure via the glucagon receptor, GLP-1 decreases fat mass by reducing food intake via the GLP1 receptor, a GLP-1/glucagon coagonist might decrease fat mass by synergistically affecting both components via 2 receptors, and a GLP-1/glucagon coagonist should minimize the diabetogenic risk of a pure glucagon analogue. Table 1. Summary of Glucagon-Based Single Molecule Coagonists.
Glucagon/GLP-1 High potency and balanced activity Enhanced activity compared with pure GLP-1 agonists In vivo activity (preclinical) • Body weight and fat mass reduction • Blood glucose, insulin improvement • Blood lipid and liver fat content GIP/GLP-1 High potency and balanced activity Enhanced activity compared with pure GLP-1 agonists In vivo activity (preclinical) • Body weight and fat mass reduction • Blood glucose, insulin improvement • Blood lipid and liver fat content • A potential basis for less nausea, emesis, and gastric stasis
Several parts of the hypothesis have been proven in preclinical and clinical studies. Day et al. [Nat Chem Biol 2009] reported a new peptide with agonism at the glucagon and GLP-1 receptors that has potent, sustained satiation-inducing and lipolytic effects. Two coagonist peptides that differ from each other only in their levels of glucagon receptor agonism were studied in rodent obesity models. Administration of PEGylated peptides once per week normalized adiposity and glucose tolerance in dietinduced obese (DIO) mice. Preclinical evidence also indicates that high-activity, longacting leptin analogues are additively efficacious when used with other weight-lowering agents, ie, extendin-4 or fibroblast growth factor 21 (FGF21; Figure 1) [Muller TD et al. J Pept Sci 2012]. Figure 1. High-Activity, Long-Acting Leptin Analogues May Be Additively Efficacious When Used with Other Weight-Lowering Agents.
Amylin or Exendin-4?
Leptin
+
Enhanced Body Weight Loss
Reproduced with permission from RD DiMarchi, PhD.
While Schelshorn et al. [Mol Pharmacol 2012] demonstrated that GLP-1 induces G-protein-coupled receptor heteromer formation, Christensen et al. [Diabetes 2011] found that GIP appears to be a physiological bifunctional blood glucose stabilizer with diverging glucose-dependent effects on the 2 main pancreatic glucoregulatory hormones in healthy human subjects. Based on the data, Dr. DiMarchi concluded that GLP-1 agonists provide significant clinical benefits, yet glucagon/
GIP=glucose-dependent insulinotropic peptide; GLP-1=glucagon-like peptide 1.
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November 2012
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Table of Contents for the Digital Edition of MD Conference Express EASD 2012
MD Conference Express EASD 2012
Contents
Understanding Incretin Hormone Action and the Treatment of Diabetes
New ADA/EASD Guidelines Focus on Patient-Centered Care
ORIGIN Trial: Insulin Glargine and n-3 Fatty Acids Fail to Reduce CV Events in Diabetic Patients
Exenatide Once Weekly Sustained Improvement in Glycemic Control with Weight Loss Through 4 Years
DiaPep277® Shows Promise as a Therapeutic Strategy for T1DM
Linagliptin Proves Safe and Effective as Add-on Therapy to Basal Insulin
12-Week Treatment with LY2409021 Significantly Lowers HbA1C and Is Well Tolerated in Patients with T2DM
Insulin Degludec Is Superior to Sitagliptin in Improving Glycemic Control in Uncontrolled Patients with Type 2 Diabetes on Oral Agents
Dapagliflozin Does Not Impact Renal Function in Patients with T2DM
Population-Based Screening for T2DM:The ADDITION-Cambridge Trial
The Challenges of Pharmaceutical Management of Painful Diabetic Peripheral Neuropathy
Enterovirus Infection
Novel Oral Agents
GLP-1
Genetics
Renal Denervation
Hypertension and Renal Function Are Risk Factors for CAD in T1DM
MD Conference Express EASD 2012
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