1. Supported by Day Summary Friday, September 18 th ©AstraZeneca 2015 Intended for non-US healthcare professionals only Atlas approval ID: 892624.011 Preparation date: September 2015 Expiry date: September 2016

2. Supported by Utility of Older Antidiabetes Agents Kunavisarut and colleagues presented a study that examined the effectiveness of SUs in patients who have failed on SU therapy ‒ Analysed both patients with T2DM and individuals with normal glucose tolerance ‒ Even in patients who have failed on SU therapy, SU still elicited a dose-dependent effect on glycemic control, albeit to a lesser extent than in patients with normal glucose tolerance Dujic and colleagues studied the association of organic cation transporter 1 (OCT1) reduced- function polymorphisms with metformin-induced side effects in patients with T2DM ‒ OCT1 reduced-function variants were associated with a 2-fold higher incidence of common metformin- induced gastrointestinal side effects SU, sulfonylurea; T2DM, Type 2 diabetes mellitus Kunavisarut T. et al. EASD 2015; Oral Presentation 217; Dujic T. et al. EASD 2015; Oral Presentation 218

3. Supported by Utility of Older Antidiabetes Agents Hansen and colleagues presented a study evaluating the acute effects of metformin on postprandial glucose excretion and to evaluate the dependence of this effect on GLP-1 using the GLP-1RA, exendin 9-39 ‒ Metformin increased postprandial GLP-1 and glucagon excretion compared with placebo ‒ This effect appeared to be, in part, dependent on GLP-1 Out and colleagues presented data from the HOME trial examining the effect of metformin on methylmelonic acid (MMA) and the risk of neuropathy (a symptom of vitamin B12 deficiency) in patients with T2DM ‒ Metformin decreased vitamin B12 and increased MMA dose-dependently and progressively ‒ This was associated with worsening of the neuropathy score ‒ The authors recommended the routine monitoring of vitamin B12 and MMA in users of metformin GLP-1 glucagon-like peptide-1; GLP-1 RA glucagon-like peptide-1 receptor agonist; T2DM, Type 2 diabetes mellitus Hansem M, et al. EASD 2015; Oral Presentation 219; Out M, et al. EASD 2015; Oral Presentation 220

4. Supported by We need more choices Current insulin titration and intensification is suboptimal in real life Free mixing requires optimization and titration so simpler options are needed The titration algorithm of fixed dose combinations is easier Patients require only one injection per day to deliver both agents Fixed dose combinations have fewer gastrointestinal side effects The physiological rationale is questionable: GLP-1RAs and insulin work via the same metabolic pathway Benefits are small, especially outside of clinical studies Individualisation is not possible with fixed doses The costs of fixed doses are higher than individual agents when properly titrated There are cheaper options than insulin and GLP-1RAs, such as lifestyle changes and low carbohydrate diets Michael Berger Debate: Do We Need Fixed Combinations of GLP-1RAs and Insulin? GLP-1RA, glucagon-like peptide-1 receptor agonist Michael Berger Debate. EASD 2015 (available at: http://www.easdvirtualmeeting.org/contentsessions/2036)http://www.easdvirtualmeeting.org/contentsessions/2036 Yes (Stephen Gough) No (Leszek Czupryniak)

5. Supported by Studies on Combination Therapy Juris Meier talked about the concept of combining metabolic hormones/proteins and highlighted that there are other gut hormones, that may be worth exploring as therapeutic targets in combination with GLP-1. Examples included ‒ Glucagon, GIP, VIP, secretin, and gastrin David Russell-Jones and John Buse presented results from the DUAL program studying fixed-dose combination of insulin degludec and liraglutide (IDegLira) ‒ IDegLira treatment led to significant and durable reductions in HbA 1c and improvements in quality of life compared with the individual components ‒ IDegLira was associated with lower rates of hypoglycemia than insulin degludec ‒ Weight change with IDegLira comprised a reduction compared with insulin degludec ‒ Nausea rates were lower with IDegLira than with luraglutide GIP, gastric inhibitory peptide; GLP-1 glucagon-like peptide-1; GLP-1 RA glucagon-like peptide-1 receptor agonist; T2DM, Type 2 diabetes mellitus Symposium. EASD 2015 (available at: http://www.easdvirtualmeeting.org/contentsessions/2042)http://www.easdvirtualmeeting.org/contentsessions/2042

6. Supported by Insulin in the Central Nervous System Tamas and his group carried out a series of in vitro experiments in an attempt to identify sources and effects of insulin in the cerebral cortex: 1 ‒ Authors concluded that insulin mRNA is expressed by neurogliaform interneurons of the rat cerebral cortex and that external insulin supresses excitation in the cortical circuits. In addition, neurogliaform cells release insulin in response to glucose and glibenclamide ‒ Human interneurons also express insulin mRNA and proinsulin, and insulin-expressing subpopulations of inhibitory interneurons are positioned to match neuronal activity and metabolic supply Labouebe and colleagues identified novel thalamo-accumbal circuits that control motivated sucrose-seeking behaviour in mice: 2 ‒ Authors also speculated that this behaviour may not be suppressed by artificial sweeteners and may be over-activated in obese individuals ‒ This circuit may also be inactivated in people experiencing anorexia leading to reduced motivation to eat mRNA, messenger ribonucleic acid. 1. Tamas G, EASD 2015; EASD symposium (available at: http://www.easdvirtualmeeting.org/contentsessions/2039); 2. Labouebe G. EASD 2015; EASD symposium (available at: http://www.easdvirtualmeeting.org/contentsessions/2039).http://www.easdvirtualmeeting.org/contentsessions/2039

7. Supported by Logistics of Diabetes Care O’Hara and colleagues carried out a systematic review to evaluate interventions aimed at improving outcomes for young adults with T1DM: 1 ‒ Structured transition, continuity of care, as well as education and support were identified as some of the areas that could be improved when caring for patients with diabetes Petrov and his group investigated the impact of education on physical exercise, metabolic control and quality of life in patients with T2DM: 2 ‒ An educational program was associated with benefits such as higher exercise capacity, decreased body weight and HbA 1c, and increased quality of life Odnoletkova and her group demonstrated that nurse-led target-driven telecoaching by diabetes nurse educators improved glycemic control, total cholesterol, and body mass index at 6 months in people with T2DM in Belgian primary care 3 Ismailov and colleagues demonstrated that diabetes training improved glycemic control compared with untrained individuals, and was also associated with more patients achieving HbA 1c <7.5% after 5 years 4 HbA1c, glycated hemoglobin; T1DM, type 1 diabetes; T2DM, type 2 diabetes. 1. O’Hara MC, EASD 2015; Oral presentation 245; 2. Petrov A, EASD 2015; Oral presentation 246; 3. Odnoletkova I, EASD 2015; Oral presentation 248; 4. Ismailov S. EASD 2015; EASD symposium (available at: http://www.easdvirtualmeeting.org/contentsessions/1994).http://www.easdvirtualmeeting.org/contentsessions/1994

8. Supported by From β to α: Shifting the Diabetes Paradigm Malmgren and colleagues investigated the interaction between glucagon, clock genes and the circadian rhythm of glucose homeostasis in mice 1 ‒ Glucose receptor knockout mice had higher insulin sensitivity than wild type mice at the start of the light phase of the 12 hour light cycle and a lower glucagon response to OGTT at the start of the 12 hour dark cycle, demonstrating that glucagon signalling is important for the circadian glucose rhythm Lund and colleagues evaluated glucagon response in totally pancreatectomized patients following OGTT and IIGI 2 ‒ A hyperglucagonemic response was observed in pancreatectomized patients following OGTT and this was suppressed by intra-venous glucose administration, indicating that gut-derived glucagon may play a role in diabetic pathophysiology Moede and colleagues demonstrated that glucokinase is the only glucose phosphorylating enzyme in rat pancreatic  -cells 3 ‒ >90% of pancreactic α cells tested positive for glucokinase, the majority of which was functional ‒ The threshold for the decrease in glucagon release in response to glucose was increased by glucokinase inhibitors and glucose responsiveness was decreased by glucokinase knockdown IIGI, intravenous glucose infusion; OGTT, oral glucose tolerance test 1. Malmgren S, et al. EASD 2015; Abstract 242; 2. Lund M, et al. EASD 2015; Abstract 243; 3. Moede T, et al. EASD 2015; Abstract 244

9. Supported by Conclusion Older antidiabetes agents still have an important place in the treatment of diabetes and there is still considerable scope for studies to understand their mechanisms of action but for efficacy and safety Fixed-dose combinations of GLP-1 RAs and insulin have a place in the modern treatment paradigm ‒ Fixed dose combination therapy resulted in greater glycemic efficacy than individual components with a an acceptable safety profile However, individual GLP-1 RA and insulin components allow for greater individualization of treatment Education for both patients and prescribers is essential to improve communication and has been shown to improve treatment outcomes GLP-1 RA, glucagon-like peptide-1 receptor agonist