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Future Directions

 

Drugs need to counter DM with its co-morbidities like HTN,DYSLIPIDEMIA AND OBESITY All drugs need to first prove safety first before moving on to efficacy and finally disease modification.
e.g. Incretin mimetic helps with weight neutrality, PPAR gamma helps with NAFLD,dyslipidemia, SGLT2 inhibitors may have a role in reno protection.

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There are many new drugs and drug delivery targets that are under investigation currently. Insulin receptor agonists seems to be the most active center for new molecule research. New additions that are imminent could be SGLT2 inhibitors.

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This slide compares the possible use positioning for GLP-1 agonist when compared with insulin. Though Insulins have better efficacy they also come with higher side effect profile of more hypos.


GLP-1 agonist due to their weight neutrality, and low side effect profile scores over insulin in patient compliance. With its B preservation effects it may help in disease modification too. With long acting versions it may lead to even better compliance.

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Long acting compounds not only help with patient adherence but also with smoothness of control. They may also be have a lower side effect profile, with similar efficacy results.

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Slide background:
Subjects continued any pre-existing treatment regimens of metformin and/or diet and exercise throughout the study

Discussion points:
Mean A1C was reduced by -1.4% and -1.7% for 0.8 mg and 2.0 mg exenatide LAR, respectively, compared to +0.4% for placebo


At Week 15, mean A1C values were 9.0%, 7.2%, and 6.6% in the placebo, 0.8 mg, and 2.0 mg exenatide LAR groups, respectively. fter a 3-day lead-in (placebo or exenatide 5 mg BID), subjects received placebo LAR, 0.8 mg, or 2.0 mg exenatide LAR subcutaneously once weekly for 15 weeks

Following Week 15 measures, subjects were followed for an additional 12 weeks during which no study medication was administered

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Slide background:
Subjects continued any preexisting treatment regimens of metformin and/or diet and exercise throughout the study.

After a 3-day lead-in (placebo or exenatide 5 mg BID), subjects received placebo LAR, 0.8 mg, or 2.0 mg exenatide LAR subcutaneously once weekly for 15 weeks.

Following Week 15 measures, subjects were followed for an additional 12 weeks during which no study medication was administered

Discussion points:
Treatment with 2.0 mg exenatide LAR resulted in progressive reduction in body weight over 15 weeks

No change in weight was observed for those patients treated with 0.8 mg exenatide LAR or placebo LAR

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The active form of native GLP-1 is rapidly degraded by peptidase. Aminioisobutylic acid (Aid) substitutions block enzymatic degradations
The Agonist activity was comparable with native form and Once weekly dosing was supported by zinc-based formulation

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Newer DPP4 inbitors will always find favor, however their incremental benefits over the older ones have to be seen. Alogliptin is one of the newer DPP4 inhibitors that could hit the market in 2012. Here are some of the clinical trials that showcase the efficacy and issues related with this molecule.

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Problems with current treatments necessitate new therapies to treat type 2 diabetes. In particular, new treatments to retain normal (i.e., glucose-dependent) insulin secretion are needed. Given glucagon-like peptide-1's ("GLP-1") role in promoting glucose-regulated insulin secretion in the pancreas, GLP-1 receptor agonists are potentially valuable in the treatment of such diseases. Moreover, glucagon receptor antagonists should prove valuable in treating type 2 diabetes given glucagon's role in elevating plasma glucose by stimulating hepatic glycogenolysis and gluconeogenesis

Peptide analogs of glucagon have been identified which act as glucagon antagonists and reduce hyperglycemia in diabetic rats. However, no peptide glucagon antagonist has, moved beyond preclinical development. A number of structurally diverse non-peptide glucagon receptor antagonists have been reported in the scientific and patent literature. However, attempts to identify small molecule inhibitors of the glucagon receptor have met with limited success in vivo. The only antagonist of glucagon action known to be active in a clinical study is a compound identified as BAY 27-9955. A potential side effect of glucagon antagonism is hypoglycemia.

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Problems with current treatments necessitate new therapies to treat type 2 diabetes. In particular, new treatments to retain normal (i.e., glucose-dependent) insulin secretion are needed. Given glucagon-like peptide-1's ("GLP-1") role in promoting glucose-regulated insulin secretion in the pancreas, GLP-1 receptor agonists are potentially valuable in the treatment of such diseases. Moreover, glucagon receptor antagonists should prove valuable in treating type 2 diabetes given glucagon's role in elevating plasma glucose by stimulating hepatic glycogenolysis and gluconeogenesis


This invention provides novel polypeptides that function both as an agonist of the GLP-1 receptor and an antagonist of the glucagon receptor and which are effective in the treatment of diseases and conditions that can be ameliorated by agents having both GLP-1 receptor agonist and glucagon receptor antagonist activity. Polypeptides of the present invention provide a new therapy for patients with, for example, metabolic disorders, such as those resulting from decreased endogenous insulin secretion, in particular type 2 diabetics, or for patients with impaired glucose tolerance, a prediabetic state that has a mild alteration in insulin secretion or impaired fasting glucose, or obesity.

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The action of peroxisome proliferators is thought to be mediated via specific receptors, called PPARs, which belong to the steroid hormone receptor superfamily. PPARs affect the expression of target genes involved in cell proliferation, cell differentiation and in immune and inflammation responses. Three closely related subtypes (alpha, beta/delta, and gamma) have been identified. This gene encodes the subtype PPAR-alpha, which is a nuclear transcription factor. Multiple alternatively spliced transcript variants have been described for this gene, although the full-length nature of only two has been determined.

Peroxisome proliferator-activated receptor (PPAR)-alpha is a ligand-activated transcriptional factor that belongs to the family of nuclear receptors. PPAR-alpha regulates the expression of genes involved in fatty acid beta-oxidation and is a major regulator of energy homeostasis. Fibrates are PPAR-alpha agonists and have been used to treat dyslipidemia for several decades because of their triglyceride (TG) lowering and high-density lipoprotein cholesterol (HDL-C) elevating effects. More recent research has demonstrated anti-inflammatory and anti-thrombotic actions of PPAR-alpha agonists in the vessel wall as well. Thus, PPAR-alpha agonists decrease the progression of atherosclerosis by modulating metabolic risk factors and by their anti-inflammatory actions on the level of the vascular wall. This is confirmed by several clinical studies, in which fibrates have shown to reduce atherosclerotic plaque formation and the event rate of coronary heart disease (CHD), especially in patients suffering from metabolic syndrome (MS). MS is characterized by a group of metabolic risk factors that include obesity, raised blood pressure, dyslipidemia, insulin resistance or glucose intolerance, and a prothrombotic state, and its incidence in the Western world is rising to epidemic proportions.

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Inhibition of SGLT2 is a rational approach to therapy for type 2 diabetes for the reasons listed on this slide.
First, SGLT2 inhibitors reduce glucose reabsorption in the renal proximal tubule, resulting in glucosuria. This decreases plasma glucose levels and reverses glucotoxicity.
This approach to therapy is simple and nonspecific and thereby would complement the action of all other antidiabetic agents, including insulin. As a result, even refractory type 2 diabetes will respond.

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This slide shows the basic mechanism of SGLT2. On the luminal side of the early proximal tubule S1 segment, absorption of sodium across the cell membrane creates an energy gradient that in turn allows glucose to be absorbed. On the other side of the cell, sodium is reabsorbed through an ATPase-mediated sodium-potassium pump into the bloodstream in order to maintain intravascular volume. This exchange alters the concentration gradient within the cell so that glucose is reabsorbed into the bloodstream via the GLUT2 transporter.

The GLUT2 transporter is present in red blood cells, the brain, and other tissues and thus is not a candidate for pharmacologic intervention. In contrast, SGLT2 is specific to the proximal tubule, so that pharmacologic inhibition will affect glucose reabsorption in the kidney but not in other tissues. Hediger MA, Rhoads DB. Molecular physiology of sodium-glucose cotransporters. Physiol Rev. 1994;74:993-1026.

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SGLT2 inhibitors improve glucose control by reducing plasma glucose levels, which in turn reverses the effects of glucotoxicity, as follows:

Insulin sensitivity in muscle increases via increased GLUT4 translocation and insulin signaling as well as other mechanisms.

Insulin sensitivity also improves in the liver, with a decrease in glucose-6-phosphatase levels.

Gluconeogenesis in the liver decreases as a result of a reduction in the Cori cycle and decreased PEP carboxykinase.

β-Cell function improves.

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In a phase II, randomized, double-blind, placebo-controlled, dose-ranging study, 12 weeks of dapagliflozin treatment significantly reduced HbA1c in patients with type 2 diabetes, across all doses tested (P<0.01 versus placebo).

Baseline HbA1c values ranged from 7.7% to 8.0% across all groups. Placebo-subtracted HbA1c reductions ranged from 0.5% to 0.7% and were similar to that achieved with metformin XR (-0.6%; no statistical comparisons were made among active treatments).

List JF, Woo V, Morales E, Tang W, Fiedorek FT. Sodium-glucose co-transport inhibition with dapagliflozin in type 2 diabetes mellitus. Diabetes Care. 2009;32:650-657.

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A large number of SGLT2 inhibitors are under investigation.

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Impaired insulin action is important in the Pathophyisiology of multiple metabolic abnormalities such as obesity and type 2 diabetes. Protein tyrosine phosphatase 1B (PTP1B) is considered a negative regulator of insulin signaling. The notion that insulin signaling can been enhanced by the inhibition of PTP1B providing an attractive target for therapy against type 2 diabetes and obesity. In addition, recent genetic studies support the association between PTP1B with insulin resistance. The development of PTP1B inhibitors has already begun although it has become clear that is not easy to find both a selective, safe and effectivePTP1B inhibitor.

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Thus, small molecule glucokinase activators have been demonstrated to be effective glucose-lowering agents in animal models of type 2 diabetes and have advanced into clinical studies.

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Glycogen synthase kinase 3 (GSK-3) is a serine/threonine protein kinase that has recently emerged as a key target in drug discovery. It has been implicated in multiple cellular processes and linked with the pathogenesis of several diseases. GSK-3 inhibitors might prove useful as therapeutic compounds in the treatment of conditions associated with elevated levels of enzyme activity, such as type 2 diabetes and Alzheimer's disease. The pro-apoptotic feature of GSK-3 activity suggests a potential role for its inhibitors in protection against neuronal cell death, and in the treatment of traumatic head injury and stroke. Finally, selective inhibitors of GSK-3 could mimic the action of mood stabilizers such as lithium and valproic acid and be used in the treatment of bipolar mood disorders.

Insulin resistance is an early change associated withthe onset of non-insulin-dependent diabetes mellitus(NIDDM) or type 2 diabetes. The major defect ininsulin resistance is the inability of peripheral tissues,such as muscle, liver and fat, to respond normally tophysiological concentrations of insulin. Since one ofthe major characteristics of diabetic muscle is thesevere inhibition of glycogen synthase and the loss ofglycogen synthesis, it is reasonable to assume thata defect in GSK-3 regulation might be associated withinsulin resistance. Furthermore, a role for GSK-3 inregulating adipogenesis was proposed in view of its ability to phosphorylate C/EBPα

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The metabolic syndrome consists of a constellation of co-associated metabolic abnormalities such as insulin resistance, type 2 diabetes, dyslipidaemia, hypertension and visceral obesity. For many years endocrinologists have noted the striking resemblance between this disease state and that associated with Cushing's syndrome.

The enzyme that mediates this activation, conversion of cortisone (11-dehydrocorticosterone in rodents) to cortisol (corticosterone in rodents), locally within tissues is 11 -hydroxysteroid dehydrogenase type 1 (11 -HSD1). In order to determine whether elevated tissue 11 -HSD1 contributed to obesity and metabolic disease, transgenic mice overexpressing 11 -HSD1 in adipose tissue or liver were studied.
Early data using non-selective 11 -HSD1 inhibitors to insulin sensitise humans, this corroborated the notion that the enzyme may be a good therapeutic target in the treatment of the metabolic syndrome.

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Technologies and drugs that were once only on paper are reality today. Thus the future hold great promise.

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Newer insulins, newer methods of manufacturing, newer sources for insulin like plants or even ideas like the SMART insulin concept could be our future.

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Needle technology has also advanced greatly. Nowadays, needle are virtually painless and getting smaller as we progress. Intradermal methods of insulin injections that are as fine as a mosquito bite could be the wave of the future.

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rHuPH20 is a genetically engineered soluble version of the naturally-occurring human hyaluronidase enzyme. Over 60 years of clinical use support the safety of animal extract forms of hyaluronidase . First hyaluronidase FDA approved in 1948 rHuPH20 is the first and only recombinant human hyaluronidase enzyme FDA approved for improving "dispersion and absorption" of injected drugs

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Increasing heat at the site of injection may help the rapid dispersion of prandial insulin. Thus rapid delivery of regular human insulin, via this heating method may mimic the rapid acting analogues that are available today. Also patches could be made available, that are fitted to the skin which aids the injection method not only to be painless but faster.

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An ideal basal insulin is one that last for 24 hours and is peakless. Lantus was the first insulin basal analogue that aimed to be an ideal basal insulin. However, newer insulins are on the way that are longer acting and more flatter. Not only would they give more timing flexibilty but lower side effects due to their peakless profiles.

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Imagine an insulin that works as a basal insulin for uptp 120 days. Supramolecular insulins being developed in India, could see this coming to the market in the near future. It could also be given IM. Very useful for type 1 DM patients who need a constant basal level.

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If an oral insulin was made available today, then many other molecules would have no place in DM therapy. There would be many benefits to the ORAL insulin. However, there are many companies working on this oral technology but none has proved successful till now. Its difficult to bring the correct dose and time this dose with oral insulin formulations for the diabetic patient. Bioavailability is an issue.

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Exubera tried the bold step of introducing Insulin through the inhaler. However, dosing, bioavailability and adherence was an issue that prevented the market success of this product. However, do we rest all inhaled insulin methods.

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There are some companies that use the Technosphere technology to improve on some of the failings of Exubera. Certain drugs, such as insulin, can be loaded onto these particles by combining a mildly acidic solution of the drug with a suspension of Technosphere® material, which is dried to a powder. When the particles contact the moist lung surface with its neutral pH, the Technosphere® particles dissolve immediately.
This releases the insulin molecules, which then diffuse across a thin layer of cells into the bloodstream

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This slide shows that Technosphere technology can help delivery a very rapid shot of insulin. The GIR rate, or the infusion of glucose that was required to maintain a certain level of glucose in the blood was maximum with Technosphere and then rapidly tapered of. This showed that was better than Rapid acting analogues as a ideal prandial insulin.

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Smart Insulin™ consists of a layered, biocompatible and biodegradable polymer-therapeutic that is bound to an engineered glucose-binding molecule. Insulin is released from Smart Insulin only when the polymer-therapeutic is unbound from Insulin by the presence of a specific glucose concentration. Imagine: Once-a-day injection,No hypoglycemia,Near-perfect glucose control,Significantly fewer finger pricks,Minimal dietary restrictions. On demand insulin release! Number of patents filed for such insulin's Number of companies are quite active

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