6/1/2018. Lou Haenel, IV, DO, FACE, FACOI Endocrinology Roper St Francis Charleston, SC THE OMINOUS OCTET: HOW PATHOPHYSIOLOGY AND THERAPY MERGE

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1 Lou Haenel, IV, DO, FACE, FACOI Endocrinology Roper St Francis Charleston, SC THE OMINOUS OCTET: HOW PATHOPHYSIOLOGY AND THERAPY MERGE 1

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4 Sulfonylureas Glipizide Glyburide Glimeperide 4

5 Metformin Gold Standard Improves Insulin Resistance Decreases Hepatic Glucose Production Just missed ss of macrovascular rr in UKPDS First line pharmacotherapy in all algorithms MOA Activation of AMP activated protein kinase Influence on gut microbiome?? Glucagon Like Peptide 1 Agonists Dipeptidyl peptidase 4 Inhibitor INCRETIN THERAPY 5

6 Byetta (exenatide) Bydureon (exenatide) Victoza (liraglutide) Trulicity (dulaglutide) Tanzeum (albiglutide) Ozempic (semaglutide) GLP1 AGONISTS GLP-1 secreted upon the ingestion of food 6

7 Cardiac Data with GLP Tx Januvia (sitagliptin) - Janumet Onglyza (saxagliptin) - Kombiglyze Tradjenta (linagliptin).jentadueto Nesina (alogliptin) Kazano (alogliptin+pioglitazone) - Oseni DPP 4 INHIBITORS 7

8 Symlin Pramlintide AMYLIN Amylin: The Second -Cell Hormone Important regulator of glucose influx into bloodstream First reported in amino acid neuroendocrine hormone Colocated and cosecreted with insulin from pancreatic - cells Not synonymous with amyloid deposits Amylin Insulin Unger. Williams Textbook of Endocrinology Amylin Helps Regulate Postprandial Glycemia via Multiple Mechanisms Amylin _ Glucagon Pancreas Liver Insulin Brain Plasma Glucose Muscle and Fat Nutrient Delivery _ Food Intake _ Model derived from animal studies 8

9 Neurotransmitter Modification CYCLOSET

10 CYCLOSET : Proposed mechanism of action Diabetes patients may have low morning levels of hyothalamic dopamine, which is thought to lead to hyperglycemia and dyslipidemia CYCLOSET resets aberrant low morning hypothalamic dopaminergic activity, which may reset neuroendocrine metabolic control Decreased lipolysis in adipose tissue Decreased postprandial hepatic glucose output Decreased insulin resistance Meier, Diabetes Reviews 1996; 4 (4): Cycloset:A unique formulation CYCLOSET of bromocriptine 4.8 mg tablets Traditional formulations of bromocriptine Novartis Parlodel 5 mg tablets Mylan bromocriptine 5 mg tablets were not designed to provide the same pharmacokinetic/pharmacodynamic profile as CYCLOSET at equivalent dosing CYCLOSET is a novel quick-release formulation of bromocriptine that increases CNS dopaminergic activity CYCLOSET has no AB-rated equivalent *AB is the FDA therapeutic equivalence rating that indicates bioequivalence has been studied and demonstrated Data on file, Santarus, Inc 29 CYCLOSET : Summary of efficacy Following once-daily, early morning administration of CYCLOSET: CYCLOSET controlled glucose throughout the day, reducing postprandial glucose without increasing insulin levels CYCLOSET reduced HbA1c by 0.6% 0.9% vs. placebo when added to other oral antidiabetics CYCLOSET adds consistent glycemic control, with 35% to 40% of patients failing other oral antidiabetics reaching HbA1c goal in 24 weeks 30 10

11 CYCLOSET CV Safety Trial In a 3070-patient, 52 week safety study, CYCLOSET use was not associated with an increased risk for adverse CV events 42% relative risk reduction for composite CVD endpoint vs. placebo was observed 1.5% of patients on CYCLOSET vs. 3% on placebo experienced any composite CVD endpoint* 5.0 Cumulative % experiencing Composite CVD Endpoint HR 0.58 (95% CI, ) RRR=42% Placebo CYCLOSET p< n = Months *MI, stroke, hospitalization for unstable angina, Prescribing Information, CYCLOSET hospitalization for CHF, or coronary revascularization Gaziano et al, Diabetes Care 2010;33: CYCLOSET Safety trial: Summary Demonstrated cardiovascular safety In a 3070-patient, 52 week safety study, CYCLOSET use was not associated with an increased risk for adverse CV events 42% relative risk reduction for composite CVD endpoint vs. placebo was observed; Hazard ratio=0.58 (95% CI, ) 1.5% of patients on CYCLOSET vs. 3% on placebo experienced any composite CVD endpoint Demonstrated overall safety Rate of SAEs vs. placebo 8.5% vs. 9.6%, respectively No significant weight gain or severe hypoglycemia compared with placebo observed in clinical trials 32 Invokana (canagliflozin) - Invokamet Farxiga (dapagliflozin) - Xigduo Jardiance (empagliflozin) Steglatro (ertugliflozin) SGLT 2 INHIBITORS 11

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