Pathophysiology in the Treatment of Type 2 Diabetes Newer Agents Part 1 of 5

Addressing Pathophysiology in the in Treatment of Type 2 Diabetes: Newer Agents Objectives Islet-Cell Defects:Incretins, &Amylin State the modes of action and clinical potential of amylin agonists, and incretin-based therapies, Hepatic and Peripheral Insulin Resistance State the modes of action and clinical potential of other more recently introduced agents in the management of patients with type 2 diabetes: bromocryptine and colsevalam Differentiate New andTraditional Treatment Strategies Re: A1c lowering potential, route of administration, effects on weight and/or CV risk factors, and whether or not they can be used as part of mono- or combination therapy strategies.

Type 2 Diabetes: Two Principal Defects; Overview Reaven GM. Physiol Rev. 1995;75: Reaven GM. Diabetes/Metabol Rev. 1993;9(Suppl 1):5S-12S; Polonsky KS. Exp Clin Endocrinol Diabetes. 1999;107 Suppl 4:S124-S127. Insulin resistance- lipotoxicity  -cell dysfunction/ Failure; dec. mass ± Environment± IFGIGT Genes Type 2 diabetes Glucose Toxicity Glucose Toxicity hepatic peripheral Abn. First phase 1 st & 2nd DM will NOT occur if B-cells not genetically predisposed

AACE/ACE: Recommendations Based on A1C at Diagnosis Rodbard HW, et al. Endocr Pract. 2009;15: A1C 6.5%-7.5%A1C 7.6%-9.0% A1C > 9.0% If under treatment If drug naive Insulin plus other agent(s)* Insulin plus other agent(s)* Symptoms No symptoms Lifestyle Modifications *Pramlintide can be used with prandial insulin, but insulin secretagogues should be discontinued with multidose insulin Monotherapy Dual therapy Triple therapy Dual therapy Triple therapy AACE: American Association of Clinical Endocrinologists

Non-Insulin Therapy for Hyperglycemia in Type 2 Diabetes, Treating Defronzo’s Octet: WITHOUT HYPOGLCEMIA: Match Patient Characteristics to Drug Characteristics 5. Gut CHO Absorption: Incretin, Pramlintide, Glucosidase inh. Peripheral glucose uptake Pancreatic insulin Secretion: Incretin, 2.Pancreatic glucagon Secretion- Incretin HYPERGLYCEMIA 6.Fat- TZD, metformin 7.Brain- TZD,INCRETIN, bromocriptine 8.Kidney - SGLT2 3. Muscle- TZD, Incretin 4.Liver Hepatic glucose production: Metformin, incretin, colesevelam De

Other Therapies: Likely Effects on Hepatic and Peripheral Insulin Resistance Bromocriptine

IR begets IR: hyperinsulinemia in hypothalamus reduces nutrient sensing via increased NE/5HT, overcoming nml spring rise in dopa/decreasing dopa in spring

Bromocryptine QR: Proposed mechanism of action Morning administration (within 2 hours of waking) of AGENT Corrects Restoration of morning peak in dopaminergic activity (via D2 receptor-mediated activity) Decreased postprandial glucose levels Reduction in insulin resistance Day-long reduction in plasma glucose, TGs and FFAs  Sympathetic tone  HPA axis tone  Hepatic gluconeogenesis  FFA and TG  Insulin resistance  Inflammation/hypercoagulation Low dopaminergic tone in hypothalamus in early morning in diabetes  Sympathetic tone  HPA axis tone  Hepatic gluconeogenesis  FFA and TG  Insulin resistance  Inflammation/hypercoagulation Impaired glucose metabolism, hyperglycemia and insulin resistance Adverse cardiovascular pathology 9 Fonseca. Use of Dopamine agonists in Type-2-Diabetes. Oxford American Pocket Cards. OUP, 2010 Cincotta. Hypothalamic role in Insulin Resistance and insulin Resistance Syndrome. Frontiers in Animal Diabetes Research Series. Taylor and Francis, Eds Hansen, B Shafrir, E London, pp , 2002

Bromocriptine-QR (quick release) The dopamine receptor agonist is indicated as an adjunct to diet and exercise to improve glycemic control in adults with diabetes. The specific mechanism by which bromocriptine mesylate improves glycemic control is not known. Patients with type 2 diabetes should take bromocriptine mesylate within two hours of waking in the morning. An initial daily dose of 0.8 mg should be titrated weekly until a maximum tolerated dose of 1.6 mg to 4.8 mg is achieved. Possible decreased risk for CV events with bromocriptine. Holt RIG, et al. Diabetes, Obesity and Metabolism 12: 1048–57, 2010

Bromocriptine In Treatment of Type 2 Diabetes H PijlH Pijl, S Ohashi, M Matsuda,Y Miyazaki,S OhashiM MatsudaY Miyazaki A Mahankali, V Kumar, R Pipek, P Iozzo, A MahankaliV KumarR PipekP Iozzo J L Lancaster, A H Cincotta and R A DeFronzo J L LancasterA H CincottaR A DeFronzo Diabetes Care 23:1154–1161, 2000

Bromocriptine-QR Holt RIG, et al. Diabetes, Obesity and Metabolism 12: 1048–57, 2010 Tolerability PlaceboBromocriptine-QR Severe adverse events14%17% Nausea7%22% Orthostatic hypotension0.8%2.2% Somnolence1.3%4.3% Psychosis - may exacerbate psychotic disorders or reduce effectiveness of drugs that treat psychosis; not reported with QR formulation to date Safety Cardiovascular Event rate lower in Bromocriptine-QR than placebo [1.8% vs. 3.2%] in 1-year safety study. Fibrosis Associated with ergot-derived dopamine receptor agonists, maybe less in Bromocriptine-QR. Drug interactions (Caution combining) Other ergot-related drugs Dopamine receptor agonists or antagonists Strong inhibitors/agnoists/substrates of CYP3A4.

*MI, Stroke, hospitalization unstable angina, hospitalization CHF, or coronary revasc. KM Curve: the separation in favor of Bromocriptine begins 3 months and persists through the end of the study HR 0.58; 95% CI, RRR=42% KM Curve – Fast-Acting Bromocriptine Safety Trial Cumulative Percent Composite CVD Endpoint Gaziano M. Diabetes Care 2010, March 23 online Bromocriptine