1. Supported by Daily Bulletin: Summary Wednesday, September 16 th ATLAS Approval ID: 889840.011; Date of Preparation: September 2015; Expiry Date: September 2016

2. Supported by Updated Data on GLP-1 Receptor Agonists Nauck and colleagues 1 presented data on the efficacy and tolerability of liraglutide from two randomized trials ‒ Liraglutide reduced mean HbA 1c significantly more than lixisenatide and more patients reached HbA 1c goals of <7% and ≤6.5% with liraglutide than with lixisenatide both added to metformin, despite a similar tolerability profile for both agents Lind and colleagues 2 outlined a study of liraglutide versus placebo in patients with T2DM receiving multiple daily insulin injections ‒ Liraglutide reduced HbA 1c significantly more than placebo, and more patients receiving liraglutide achieved a target HbA 1c of <7% ‒ Compared with placebo, liraglutide treatment led to significant improvements in weight, fasting plasma glucose, total daily insulin dose, and scores on the Treatment Satisfaction Status Scale ‒ There was no difference in the hypoglycemia profiles between groups GLP-1, glucagon-like peptide-1; HbA 1c, glycated hemoglobin; T2DM, Type 2 diabetes mellitus 1. Nauck MA, et al. EASD 2015; Abstract 75; 2. Lind M, et al. EASD 2015; Abstract 74

3. Supported by Updated Data on GLP-1 Receptor Agonists Roy-Duval and colleagues 1 presented data from the GetGoal-Duo2 study of the addition of lixisenatide to basal insulin ‒ Lixisenatide was non-inferior to insulin glulisine for HbA 1c reductions and statistically superior for body weight reduction Ferdinand and colleagues presented a meta-analysis of nine clinical trials of dulaglutide 2 ‒ Dulaglutide was not associated with any increase in the 4-point composite MACE endpoint. However, we await the results of the REWIND CV outcomes trial for more information Finally, Jendle and colleagues 3 presented a substudy from the AWARD-4 trial comparing dulaglutide with insulin glargine, both in combination with insulin lispro ‒ In a substudy of patients undergoing continuous glucose monitoring, dulaglutide treatment resulted in a greater increase in the amount of time spent in the normoglycemic range, and with lower glycemic variability, compared with glargine, whereas glargine was associated with a larger amount of time spent in the hypoglycemic range CV, cardiovascular; GLP-1, glucagon-like peptide-1; HbA 1c, glycated hemoglobin; MACE, major adverse cardiovascular event 1. Roy-Duval C, et al. EASD 2015; Abstract 78; 2. Ferdinand K, et al. EASD 2015; Abstract 77; 3. Jendle J, et al. EASD 2015; Abstract 76

4. Supported by Insulin Pumps Bilous and colleagues 1 provided results from testing a new device incorporating a glucose meter and an insulin pump that allows wireless control of the pump functions ‒ Glycemic control improved when switching from MDI therapy and was maintained in previous pump users ‒ User acceptance of this system was high Meanwhile, Thabit and colleagues 2 looked at closed-loop insulin delivery during free daily living in adults with T1DM over 12 weeks ‒ Prolonged home use of unsupervised day-and-night closed loop under free living conditions resulted in improved glucose control and reduced exposure to hypoglycemia without increasing total daily insulin requirements MDI, mixed-dose insulin; T1DM, Type 1 diabetes mellitus 1. Bilous R, et al. EASD 2015; Abstract 982; 2. Thabit H, et al. EASD 2015; Abstract 987

5. Supported by Treatment Inertia In a retrospective database analysis, Paul and colleagues 1 evaluated the prevalence of TI, the extent of potentially avoidable glycemic and BP burden, and the association of TI and TI- associated glycemic and BP burden with the risk of composite of MI, HF, and stroke in a cohort of 1,145,979 patients ‒ There was a high prevalence of TI, a significant glycemic burden over 2 years even with intensified treatment, and an association of TI with an increased CV risk over 4 years Similarly, Placzkiewicz-Jankowska and colleagues 2 conducted a cross-sectional nationwide study in Poland assessing T2DM treatment efficacy ‒ The authors concluded that, despite a widely accepted need for progressive and multifactorial treatment of T2DM, many patients are still not treated intensively enough, even with old and relatively inexpensive therapies BP, blood pressure; CV, cardiovascular; HF, heart failure; MI, myocardial infarction; T2DM, Type 2 diabetes mellitus; TI, treatment inertia 1. Paul S, et al. EASD 2015; Abstract 127; 2. Placzkiewicz-Jankowska E, et al. EASD 2015; Abstract 843

6. Supported by CV Safety of Diabetes Therapies Sheehan and colleagues 1 analyzed data from a large US claims database to determine the risk of hospitalization for HF in patients with T2DM receiving a DPP-4 inhibitor versus an SU and patients treated with saxagliptin versus sitagliptin ‒ There was no evidence of increased risk of hHF in DPP-4 versus SU or saxagliptin versus sitagliptin Potentially conflicting data were presented by Eriksson and colleagues 2 who compared the risk of CVD, all-cause mortality, and severe hypoglycemia in T2DM patients who initiated second-line treatment with either SUs or DPP-4 inhibitors in Sweden ‒ They found that second-line treatment with SUs compared with DPP-4 inhibitors was associated with an increased risk of subsequent CV events, all-cause mortality, and severe hypoglycemia Meanwhile, Anyanwagu and colleagues 3 looked at the effects of dual therapy intensification with insulin versus GLP-1 analogs on CV events and all-cause mortality ‒ Intensification of dual oral therapy by adding insulin was associated with a higher risk of CV events, irrespective of weight, compared with adding a GLP-1 analogue therapy as the third agent CV, cardiovascular; CVD, cardiovascular disease; DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; HF, heart failure; hHF, hospitalization for heart failure; SU, sulfonylurea; T2DM, Type 2 diabetes mellitus 1. Sheehan JJ, et al. EASD 2015; Abstract 370; 2. Eriksson JW, et al. EASD 2015; Abstract 129; 3. Anyanwagu U, et al. EASD 2015; Abstract 937

7. Supported by Lessons from CV Outcomes Trials Del Prato 1 explained that glucose lowering remains an effective measure for preventing microvascular complications ‒ Glucose lowering reduces the incidence of coronary heart disease, and should be considered as an element of a more comprehensive approach for reducing CV risk; however, one size does not fit all, so an individualized approach to patient care is crucial Furthermore, Currie 2 suggested that achieving HbA 1c between 7.0 and 8.5% without hypoglycemia is necessary to minimize the risk of CVD and maximize survival in patients with T2DM; controlling blood pressure and lipids is also important ‒ Current CV outcomes trials could have been designed differently to answer important safety questions Perhaps controversially, McGuire 3 suggested that detecting rare but serious adverse events requires greater drug exposure, which may not have been achieved in the CV outcomes trials conducted to date CV, cardiovascular; CVD, cardiovascular disease; HbA 1c, glycated hemoglobin; T2DM, Type 2 diabetes mellitus 1. Del Prato S. EASD 2015; http://www.easdvirtualmeeting.org/resources/glucose-lowering-and-cvd-risk-do-targets-matter ; 2. Currie C. EASD 2015; http://www.easdvirtualmeeting.org/resources/glucose-lowering-and-cvd-risk-do-strategies-matter; 3. McGuire D. EASD 2015; http://www.easdvirtualmeeting.org/resources/diabetes-and-cv-outcome-trials-lessons-learned Accessed September 17, 2015http://www.easdvirtualmeeting.org/resources/glucose-lowering-and-cvd-risk-do-targets-matter http://www.easdvirtualmeeting.org/resources/glucose-lowering-and-cvd-risk-do-strategies-matter http://www.easdvirtualmeeting.org/resources/diabetes-and-cv-outcome-trials-lessons-learned

8. Supported by Everyday Consequences of Hypoglycemia Thomas 1 explained that diabetes and renal impairment often coexist, and achieving adequate glycemic control without hyperglycemia is particularly important and challenging in this patient population ‒ Hypoglycemia is not only common in patients with CKD, but it may also be dangerous ‒ Current generation antihyperglycemic agents, such as the DPP-4 inhibitor class, may be more suitable for this patient population, compared with SUs Heller 2 went on to explain how experimental hypoglycemia has lasting effects on rheology and markers of inflammation in individuals with T2DM ‒ Asymptomatic nocturnal hypoglycemia is common, prolonged, and associated with cardiac arrhythmias, which can sometimes be fatal Finally, Frier highlighted that severe hypoglycemia at any time of day poses a risk of accidents when driving, with a history of severe events in the past 12 months suggesting a valid driving risk 3 ‒ Many drivers with insulin-treated diabetes may conceal events to protect their driving license CKD, chronic kidney disease; DPP-4, dipeptidyl peptidase-4; SU, sulfonylurea; T2DM, Type 2 diabetes mellitus 1. Thomas M. EASD 2015; http://www.easdvirtualmeeting.org/resources/kidney-disease-and-risk-of-hypoglycaemia; 2. Heller SR. EASD 2015; http://www.easdvirtualmeeting.org/resources/who-is-at-risk-from-the-cardiovascular-effects-of-hypoglycaemia 3. Frier BM. EASD 2015; http://www.easdvirtualmeeting.org/resources/hypoglycaemia-and-driving-are-the-eu-licensing-regulations-fit-for-purpose Accessed September 17, 2015http://www.easdvirtualmeeting.org/resources/kidney-disease-and-risk-of-hypoglycaemia http://www.easdvirtualmeeting.org/resources/who-is-at-risk-from-the-cardiovascular-effects-of-hypoglycaemia http://www.easdvirtualmeeting.org/resources/hypoglycaemia-and-driving-are-the-eu-licensing-regulations-fit-for-purpose

9. Supported by Conclusion The GLP-1 receptor agonist class continues to develop, with new agents and new findings adding to our armamentarium for the treatment of diabetes Equally, developments in the field of treatment devices are providing new scope in the day-to- day management of blood glucose control Nonetheless, patients are still confronted by the potential impact of hypoglycemic events However, treatment inertia is common and must be overcome to ensure the best possible long-term outcome Although there are some conflicting reports, the weight of evidence suggests that the CV safety profile of the newer antidiabetes agents is acceptable CV, cardiovascular; GLP-1, glucagon-like peptide-1; HbA 1c, glycated hemoglobin; NAFLD, non-alcoholic fatty liver disease