Presented by Ben Sherrill Doctor of Pharmacy Candidate UGA College of Pharmacy Class of 2012 The Lancet Vol. 378 July 9, 2011 Pages 182 – 195

 DMII is a complex disease state › Multifaceted endocrine and metabolic disorder › Environmental and genetic factors play roles in disease progression and severity  Ex: Obesity; Genes PPARG, CAPN10, etc. › Variable levels of insulin resistance and β-cell dysfunction › Many other hormones play roles in insulin resistance, insulin secretion, and hyperglycemia  Provide potential new targets for therapy

 Current therapies have drawbacks › Improvements in glycemia are not sustained › Side effects  GI upset  Weight gain  Hypoglycemia  Peripheral edema  Cardiovascular effects  New treatments are needed › Sustained glycemic control › Reversal of decline in β-cell function › Improve insulin action › Avoidance of negative side effects

The image to the right depicts the various systems, locations, and mechanisms within the body that are being targeted in current, new, and future medications for the treatment of Type II Diabetes (DMII). There are currently 8 classes of non-insulin medications used for DMII, each offering a different mechanism or approach for treating the disease. In the future, the number of classes available will potentially double, possibly even triple, as new research continues.

 Pancreatic contribution to serum glucose › α -cells  Secrete glucagon  Suppresses hepatic glycogen synthesis  Stimulates gluconeogenisis and glycogenolysis  Excess will prevent normal suppression of hepatic glucose output, leading to hyperglycemia › β-cells  Secrete insulin, C-peptide, and amylin  Bowels › L cells secrete incretins

 Renal contribution to serum glucose › Sodium-glucose-cotransporter-1 and -2 (SGLT1 & SGLT2)  Reabsorb glucose › Renal gluconeogensis contributes 20-25% of total glucose production  Hepatic contribution › Glycogen synthesis and metabolism

 Rationale: › High insulin response to glucose that is administered orally is brought about by incretins  Glucagon-like peptide 1 (GLP-1) & glucose- dependant insulinotropic peptide (GIP) › Reduced GLP-1 concentrations in DM II  Potency still remains, making it a potential target

 GLP-1 effects: › Potentiates glucose-dependant insulin secretion and glucagon suppression › Slows gastric emptying › Reduces food intake › In animal studies, it increased mass and decreased apoptosis of β-cells › Other potential effects:  Promote accumulation of glycogen in liver  Increase glucose uptake  Lower concentrations of triglycerides

 GLP-1 › Rapidly inactivated by dipeptidyl peptidase 4 (DPP- 4) › Short circulating t1/2 (<2 minutes)  GLP-1 mimetics › Exenatide (Byetta) and liraglutide (Victoza) › GLP-1 receptor agonists that are resistant to DPP-4  Achieved through different methods of preparation  DPP-4 inhibitors › Highly specific, block DPP-4 to increase endogenous GLP-1 › Sitagliptin (Januvia), saxagliptin (Onglyza), vildagliptin

 GLP-1 Mimetics  Advantages › Weight loss › Low risk of hypoglycemia › Possible effect on β- cell survival and decline  Disadvantages › Unknown long-term safety › Unconfirmed association with pancreatitis and medullary cell carcinoma › GI side effects (exenatide once- weekly) › Avoid in renal failure

 New GLP-1 mimetics in the pipeline: › Shortacting  Lixisenatide › Sustained-release  Exenatide once-weekly, taspoglutide, albiglutide, CJC-1134-PC

 Other new/potential incretin-based therapies › Oral S4P and Boc5  Activate GLP-1R › Chemical (non-peptide) GLP-1R agonist › Orally active GIP agonists › Linagliptin and alogliptin  New oral DPP-4 inhibitors  Linagliptin – low risk of hypoglycemia, no renal adjustment  Alogliptin – good GI tolerability

 Glucokinase Activators (GAs) › Once it enters the β-cell, glucose is phosphorylated by glucokinase  Affects the rate of glucose metabolism and ATP production › Effects in animal and human DM II models:  Increased insulin concentrations  Reduced glucose concentrations  Additional reduction of glucose by effects on hepatic glucose metabolism › Glucokinase activation is associated with increased triglycerides and risk of hypoglycemia › Drugs being studied:  Piragliptin  Compound 14  R1511  AZD1656  AZD6370  Compund 6  ID1101

 Excess glucagon management › Incretin based treatments  Reduce secretion in a glucose-dependant manner (only in association with hyperglycemia)  Don’t compromise hypoglycemia counter- regulation › Blocking of glucagon receptor or signaling pathway after binding with the hormone  Models show significant reduction in basal glycemia and improved glucose tolerance  Might reduce body’s ability to counteract hypoglycemia

 Dual-Acting Peptide for Diabetes (DAPD) › GLP-1R agonist that also binds to the glucagon receptor without activating it › In animal tests:  Extended duration, increased insulin secretion, improved glucose tolerance, reduced glucose concentrations  However, it increased glucagon concentration  Oxyntomodulin › Agonist at GLP-1R and Glucagon receptor › Induced weight loss, reduced food intake, and increased energy expenditure in rats

 These are mostly theorized drugs for now › Attempt to activate insulin receptor or post- receptor signaling intermediaries  Many belong to other regulatory pathways, including cell death, making these approaches difficult › Other potential mechanisms:  Attempt to prolong action of the insulin β subunit  Prevention of negative feedback

Sodium-glucose-cotransporter-2 (SGLT2) inhibitors

 Hepatic targets › Glucokinase activators  Stimulate insulin secretion and promote hepatic glucose storage  Will improve tolerance but can cause hypoglycemia › Fructose-1,6-bisphosphatase inhibitors  Inhibits gluconeogenisis, reduces serum glucose  Dose not induce hypoglycemia, nor cause hepatic steatosis › Glycogen phosphorylase inhibitors  Can prevent hyperglycemia without affecting fasting glucose

 GIP antagonists › Potentiates glucose-dependant insulin secretion, just like GLP-1 agonists  It also promotes fat deposition by adipocytes, does not inhibit glucagon secretion, and has little effect on food intake, satiety, gastric emptying, or bodyweight › In animal studies:  Increased energy expenditure  Reduced fat deposition and lipotoxicity  Enhanced glucose uptake  Improved β-cell function

 11β-hydroxysteroid-dehydrogenase-1 (11 BHD 1) inhibitors › Converts cortisone to cortisol › Phenotypic similarities between metabolic syndrome and Cushing’s syndrome  Inhibition reduced insulin resistance, prevented stress-induced obesity, improved tolerance, and enhanced insulin-secretory responsiveness in mice › 200mg of a test drug (INCB13739) added to metformin:  Reduced A1c by 0.6%  Reductions in total and LDL cholesterol and triglycerides

 PPAR modulators › Dual PPAR- and PPAR- γ agonists (glitazars) being developed for combo effect on lipids and glucose  Potentially better side effect profile than glitazones and fibrates

 Dopamine D2-receptor agonists › Bromocriptine  Produces effects on glycemic variables without increasing insulin concentrations  Bile acid sequestrants › Reduce glucose concentrations in DM II patients  Recent trial for colesevelam reduced A1c by % in combo with metformin  Unfortunately, it increases triglycerides

 Recent meta-analysis of 621 studies › 135,246 patients › 78.1% with DM II had resolution › Additional 8.5% had improved glycemic control  Issues › “Resolution” needs to be better defined, and needs to be more consistant › A more detailed investigation is needed

 Promising new medications for the future treatment of DMII  Possible benefits of bariatric surgery are exciting, and merit new research  Level of Evidence: › III B  Images and figures on slides 4, 14, and 18 were obtained from the article being reviewed: › Management of type 2 diabetes: new and future developments in treatment › The Lancet, Vol 378. July ,