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

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

Indicated as an adjunct to diet and exercise to improve glycemic control in adults with DM2 Not indicated as treatment for DM1 or DKA Mechanism of action uncertain Contraindications: –History of bowel obstruction –Serum triglycerides >500 mg/dL –History of hypertriglyceridemia-induced pancreatitis

Potential Mechanism of Action of Colesevelam Staels,B,

Zieve FJ et al. Clin Ther. 2007;29:74. Bays H et al. Presented at: AACE 16th Annual Meeting & Clinical Congress; April Abstract 204. Fonseca VA et al. Presented at: AACE 16th Annual Meeting & Clinical Congress; April Abstract 409. Goldberg RB, Truitt K. Presented at: AHA Scientific Sessions; November 2006; Chicago, IL. Poster Effects of Colesevelam on A1C Levels in Add-On Therapy Trials: ≥0.50% Reductions Mean Change in A1C (%) GLOWS Week 12 Metformin Week 26 Sulfonylurea Week 26 Insulin Week 16 * P≤0.007 n=>1, * * *

Colesevelam: Dosage and Administration Recommended dose with meals and a liquid: –625-mg tablets: Take 6 tablets QD OR 3 tablets BID –Suspension preparation (powder mixed with water): Take 3.75 g packet QD OR g packet BID As with all LDL-C lowering agents, serum lipid levels should be monitored periodically No special considerations or dosage adjustments with hepatic impairment or renal disease LDL-C=low-density lipoprotein cholesterol; Welchol ® (colesevelam HCl) prescribing information. Daiichi Sankyo, Inc., Parsippany, NJ. February 2010.

Colesevelam in Type 2 DM: Adverse Reactions * Event DescriptionNumber of Patients (%) Colesevelam N = 566 Placebo N = 562 Constipation49 (8.7)11 (2.0) Nasopharyngitis23 (4.1)20 (3.6) Dyspepsia22 (3.9)8 (1.4) Hypoglycemia17 (3.0)13 (2.3) Nausea17 (3.0)8 (1.4) Hypertension16 (2.8)9 (1.6) *Placebo-Controlled Clinical Studies of Colesevelam Add-on Combination Therapy with Metformin, Insulin, Sulfonylureas: Adverse Reactions Reported in ≥2% of Patients and More Commonly than in Patients Given Placebo, Regardless of Investigator Assessment of Causality. Colesevelam HCl prescribing information, January 2008.

Addressing Pathophysiology in the 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 colesevelam Differentiate New and Traditional 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.

The Incretin Hormones GLP-1GIP  L cells in ileum and colon 1,2  K cells in duodenum 1,2  Glucose-dependent β-cell stimulated insulin response 1  Inhibits gastric emptying 1,2  Minimal effect on gastric emptying 2  food intake & body weight 2  No effect on satiety or weight 2  Glucose-dependent inhibition of α-cell glucagon secretion 1  No inhibition of α-cell glucagon secretion 1,2 1.Meier JJ et al. Best Pract Res Clin Endocrinol Metab. 2004;18:587– Drucker DJ. Diabetes Care. 2003;26:2929–2940.

Time, min IR Insulin, mU/L nmol/L The Incretin Effect Control Subjects (n=8) Type 2 Diabetes (n=14) Time, min IR Insulin, mU/L nmol / L Oral glucose loadIntravenous (IV) glucose infusion Incretin Effect Adapted from Nauck M et al. Diabetologia. 1986;29:46–52. Copyright © 1986 Springer-Verlag. Permission pending.