Type 2 Diabetes in Practice An Expert Commentary With Clifford J. Bailey, PhD A Clinical Context Report

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This activity is supported by an independent educational grant from Boehringer Ingelheim Pharmaceuticals, Inc. which was made possible, in part, through a collaboration with Eli Lilly and Company. Clinical Context: Type 2 Diabetes in Practice Expert Commentary

Type 2 Diabetes in Practice Clinical Context Series The goal of this series is to provide up-to- date information and multiple perspectives on the pathogenesis, patient identification, symptoms, risk factors, and current and emerging treatments and best practices in the management of type 2 diabetes The goal of this series is to provide up-to- date information and multiple perspectives on the pathogenesis, patient identification, symptoms, risk factors, and current and emerging treatments and best practices in the management of type 2 diabetes.

Type 2 Diabetes in Practice Clinical Context Series Target Audience Endocrinologists, cardiologists, diabetes educators, primary care physicians, nurses, nurse practitioners, physician assistants, pharmacists, and other healthcare professionals involved in the care of patients with type 2 diabetes.

Activity Learning Objective

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Clifford J. Bailey, PhD Professor of Clinical Medicine Aston University Department of Life & Health Sciences Birmingham, UK Discussant

Disclosure Information Clifford J. Bailey, PhD, disclosed the following relevant financial relationships: disclosed the following relevant financial relationships: Board Member/Advisory Panel: Boehringer Ingelheim Pharmaceuticals; Bristol-Myers Squibb; GlaxoSmithKline; Merck Sharp & Dohme Limited; Novo Nordisk; Roche Pharmaceuticals. Research Support: sanofi-aventis.

Disclosure Information and have disclosed that they have no relevant financial relationships or conflicts of interest with commercial interests related directly or indirectly to this educational activity. Dori F. Zaleznik, MD, Associate Clinical Professor of Medicine, Harvard Medical School, Boston; Crystal Phend; and Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner, have disclosed that they have no relevant financial relationships or conflicts of interest with commercial interests related directly or indirectly to this educational activity. and have no relevant financial relationships or conflicts of interest with commercial interests related directly or indirectly to this educational activity. The staffs of Projects In Knowledge and MedPage Today have no relevant financial relationships or conflicts of interest with commercial interests related directly or indirectly to this educational activity.

Type 2 Diabetes Global Prevalence More than doubled worldwide from 1980 to 2008 —From 8.3% to 9.8% among adult men —From 7.5% to 9.2% among adult women Source: Danaei G, et al Lancet 2011; 378:

Microvascular Risk Reduction With Better Glycemic Control United Kingdom Prospective Diabetes Study (UKPDS) —Each percentage point decrease in hemoglobin A1c reduced microvascular complication risk by 35% Diabetes Control and Complications Trial (DCCT) —A two-percentage point reduction in hemoglobin A1c cut occurrence of microvascular complications by 39% to 76% Sources: UKPDS Group Lancet 1998; 352: DCCT Research Group N Engl J Med 1993; 329:

Recent Trials of More Intensive Glucose Control Mean diabetes duration at baseline: —Action to Control Cardiovascular Risk in Diabetes (ACCORD) – 10 years —Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) – 8 years —Veterans Affairs Diabetes Trial (VADT) – 11.5 years Sources: ACCORD Study Group N Engl J Med 2008; 358: ADVANCE Collaborative Group N Engl J Med 2008; 358: Duckworth W, et al N Engl J Med 2009; 360:

Early Start Matters UKPDS – Micro- and macrovascular benefits from more intensive glucose management in newly diagnosed type 2 diabetes VADT – No micro- or macrovascular benefits from more intensive glucose management in advanced type 2 diabetes Sources: Holman RR, et al N Engl J Med 2008; 359: Holman RR, et al N Engl J Med 2008; 359: Duckworth W, et al N Engl J Med 2009; 360:

Once-Weekly Exenatide (Bydureon) Extended release formulation of twice-daily exenatide (Byetta) FDA approval declined in October 2010 European Medicines Agency granted approval in June 2011

Dipeptidyl Peptidase-4 (DPP-4) Inhibitors Sitagliptin (Januvia) Saxagliptin (Onglyza) Linagliptin (Tradjenta) – Approved by FDA in May 2011

G-Protein-Coupled Receptor Stimulation Raises GLP-1 levels indirectly Oral delivery Early phase research

Type 2 diabetes prevalence is on the rise, bringing with it a pending tide of cardiovascular complications Deterioration of beta-cell function contributes to progression of type 2 diabetes, which often is marked by worsening insulin resistance as well. Both processes are typically well under way by the time of diagnosis Summary At the end of this activity, participants should understand:

Better glycemic control is linked to reduced risk of microvascular disease and, over the long term, lower risk of macrovascular disease as well Early intervention is key to these effects, as the ACCORD, VADT, and other trials have shown that more intensive efforts are largely ineffective later in the course of type 2 diabetes Animal studies have suggested that very early use of incretin drugs can delay beta-cell decline Summary

Incretin mimetics new to the clinic and on the horizon include the DPP-4 inhibitor linagliptin, which was approved by the FDA earlier this year, and a once-weekly formulation of the GLP-1 receptor agonist drug exenatide recently approved in Europe that is under review in the U.S. A novel class of oral drugs that raise GLP-1 indirectly through G-protein-coupled receptor stimulation is in early stage development Summary