New Therapeutic Approaches In Endocrinology and Metabolism
Zelia Francis-Tohme MD Fundamentals in Medical Research November 28, 2014 Novel Therapies and New Targets of Treatment for
Diabetes Mellitus: Type 2 Type 1 History of Diabetes Therapeutic Advances
The Ominous Octet
DeFronzo R A Diabetes 2009;58:773-795
Copyright © 2014 American Diabetes Association, Inc. Sites of Action of Currently Available Therapeutic Options
Physiology of GLP-1 and action on various tissues Incretin-based therapies result in
glucose-dependent insulin secretion
glucose-dependent glucagon suppression
low risk of hypoglycemia
are weight neutral in the case of DPP-4 inhibitors or cause weight loss in the case of incretin mimetics/analogues
prolong β cell survival in animal studies, which offers the theoretical possibility of slowing the progression to T2DM Two groups of incretin-based therapies are available
Dipeptidyl peptidase-4 (DPP-4) inhibitors (sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin): given orally
GLP-1 analogues/mimetics (exenatide, liraglutide, lixisenatide bid/ZP10 and albiglutide, dulaglutide, taspoglutide): given subcutaneously Cardiovascular effect of GLP-1 or GLP-1 receptors agonists
Include: Reduction in systolic blood pressure Improved endothelial function Reduced postprandial increases in plasma TG Protection against myocardial ischemia reperfusion injury Improved myocardial function
May have beneficial CV effects beyond glycemic control Ongoing incretin trials of cardiovascular disease outcomes in type 2 diabetes mellitus Two evolving trends in the area of GLP-1 agonists
The development of long-acting agents such as sus- tained-release exenatide and albiglutide, both of which are effective for at least 1 week between injections
The development of the potential of combining a GLP-1 agonist with basal insulin in a single injection Combination of basal insulin with a GLP- 1 agonist has a scientific logic Sites of Action of Currently Available Therapeutic Options Bromocriptine
Is a sympatholytic D2-dopamine agonist
Approved by the FDA for the treatment of T2DM
Has been shown to improve glycemic control and markers of insulin resistance in animal models of diabetes and obesity, an effect that has been duplicated in humans
A 1-year study that compared a quick release form of bromocriptine with conventional modes of diabetes therapy showed that Cycloset (Parlodel): reduced HbA1c level by 0.6% as monotherapy and 1.2% in combination with insulin or sulfonylurea lowered plasma triglycerides and free fatty acids by 30% Proposed mechanism of action of bromocriptine to improve glucose homeostasis and insulin sensitivity
Diabetes Care 2011 ADA, Inc Sites of Action of Currently Available Therapeutic Options Inhibitors of sodium-glucose co-transporter 2
Sodium-glucose transporter-2 (SGLT-2) inhibitors: dapagliflozin, canagliflozin, empagliflozin were recently introduced to the market ipragliflozin, luseogliflozin, and topogliflozin are under clinical investigation Sodium-glucose transporter-2 (SGLT-2) Sodium-glucose transporter-2 (SGLT-2) inhibitors:
Block glucose reabsorption resulting in glycosuria
Advantages: do not require functioning beta cells to be effective do not cause hypoglycemia cause weight loss
Disadvantages: increased risk of urinary tract infections and genital mycotic infections slight increase in LDL possible risk for bladder and breast cancer Sites of Action of Currently Available Therapeutic Options Colesevelam
Is a bile acid sequestrant used for the treatment of hyperlipidemia
Was approved by the FDA for the treatment of T2DM
Showed HbA1c reduction of up to 1.0% in patients with baseline HbA1c level greater than 8% over 12 weeks of treatment
The combined improvement in glycemic control and lipid profile gives colesevelam an advantage in the treatment of T2DM
It is administered orally, and its main side effects are gastrointestinal, particularly constipation
The mechanism of action is thought to be delayed or altered absorption of glucose in the intestines Investigational Agents For Type 2 DM
Long-acting GLP-1 receptor agonists Sodium-GLucose coTransporter (SGLT) {-1} & -2 inhibitors Ranolazine Dual (α/γ ) & Pan (α/γ /δ )-PPAR agonists 11β Hydroxysteroid Dehydrogenase (HSD)-1 inhibitors Fructose 1,6-bisphosphatase inhibitors Glucokinase activators G Protein-coupled Receptor (GPR) -40 & -119 agonists Protein Tyrosine Phosphatase (PTB)-1b inhibitors Carnitine Palmitoyltransferase (CPT)-1 inhibitors Acetyl CoA Carboxylase (ACC)-1 & -2 inhibitors Glucagon receptor antagonists Salicylate derivatives Immunomodulatory drugs G protein– coupled receptor (GPR) 40 agonist
Glucokinase (GK) activators Sirtuins
Are a group of NAD+-dependent enzymes that post- translationally modify histones and other proteins
Are enzymes implicated in many diseases associated with advancing age, such as atherosclerosis and T2DM
SIRT1 has been the most extensively studied and has been demonstrated to play a critical role in all major metabolic organs and tissues Sirtuins Sirtuins
Recently, SIRT3 has been demonstrated to modulate insulin sensitivity in skeletal muscle and systemic metabolism
Sirt3-null mice manifest characteristics of metabolic syndrome on a high-fat diet
Thus, it is reasonable to believe that enhancing the activities of SIRT1 and SIRT3 may be beneficial for Type 2 diabetes
Although it is controversial, the SIRT1 activator SRT1720 has been reported to be effective in improving glucose metabolism and insulin sensitivity in animal models Glucagon receptor antagonists
Glucagon, released by pancreatic alpha cells, acts to increase hepatic glucose output and, therefore, blood glucose levels particularly postprandially
High levels of glucagon have been demonstrated in patients with T2DM
A number of substances that block the glucagon receptor have been identified and have been shown to reduce the postprandial glucose rise seen with exogenous glucagon administration in healthy and diabetic animals as well as healthy humans
May provide a further group of medications targeting postprandial hyperglycemias Ranolazine
Is FDA approved for the treatment of angina
Inhibits sodium potassium channels, which promote release of calcium
Reduced HbA1c level by 0.6% over 4 months of therapy in patients who presented with diabetes and an acute coronary syndrome
Reduced HbA1c level and fasting glucose in non diabetic patients
The lowered HbA1C was thought to be due in part to increased insulin sensitivity and to increased insulin secretion Salsalate
Is an anti-inflammatory agent
Has been shown to reduce: levels of fasting glucose by 13%, post challenge glucose by 20% glycated albumin values by 17% after 1 month of therapy raise adiponectin levels by 57%
The glucose-lowering potential of salicylates appears to be due to effects on insulin concentration rather than improved insulin action
However, the mechanism by which salicylates increase insulin concentration and lower glucose remains to be determined Types of available insulin and their actions Late stage investigational basal insulins Investigational insulin technology Novel treatment strategies
Islet-cell transplantation produce insulin independence in a few patients with less hypoglycemias
Immunomodulation among people with type 1 diabetes, but these efforts have thus far failed to prevent diabetes
Monoclonal antibodies against the variety of immune-modulating substances for the treatment of diabetes in the early stages
Stem cell therapy offers hope for either regeneration of new cells in the pancreas or modulation of the immune process to allow self- cell function and thereby- ﰁregeneration or preservation of beta better glycemic control