Type 2 diabetes is a progressive. status

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1 Type 2 diabetes is a progressive disease: its treatment the current status Associate Professor Jonathan Shaw

2 Why is type 2 diabetes so hard to treat? How to choose the right glucose-lowering g drug? Page 2: Baker IDI

3 Why is type 2 diabetes so hard to treat? Multiple pathophysiological abnormalities Page 3: Baker IDI

4 E TIOL OGY OF T2D M Im Secr paire dins etion ulin Incre ased Lipo lysis Hy perg lycem ia IncrH GP eased De Upcreas edglu take cose DEF N75-3/9 Decreased Insulin Secretion Multiple causes of T2 diabetes Decreased Incretin Effect Increased Lipolysis Islet α cell HYPERGLYCEMIA /04 Increased Glucagon Secretion Increased HGP Neurotransmitter Dysfunction Decreased Glucose Uptake Courtesy of Ralph de Fronzo

5 Why is type 2 diabetes so hard to treat? Multiple pathophysiological abnormalities Hard to know which is important in each patient Multiple l abnormalities may require multiple l drugs Page 5: Baker IDI

6 Why is type 2 diabetes so hard to treat? Multiple pathophysiological abnormalities Hard to know which is important in each patient Multiple l abnormalities may require multiple l drugs Disease is progressive Page 6: Baker IDI

7 β Cell Function Declines Regardless of Intervention in T2DM 100 (%)* 80 Function β-cell Page 7: Baker IDI Sulfonylurea Diet Metformin Years Since Diagnosisi *β-cell function measured by HOMA Adapted from UKPDS Group. Diabetes. 1995;44:

8 HbA 1c 9 cross-sectional, median values HbA 1c (% %) 8 7 Conventional Intensive % upper limit of normal range Years from randomisation Page 8: Baker IDI ukpds

9 overweight patients HbA 1c cohort, median values 9 Conventional Insulin Chlorpropamide Glibenclamide Metformin ba 1c (%) H )8 7 Page 9: Baker IDI Years from randomisation ukpds

10 Why is type 2 diabetes so hard to treat? Multiple pathophysiological abnormalities Hard to know which is important in each patient Multiple l abnormalities may require multiple l drugs Disease is progressive Lifestyle change is hard Page 10: Baker IDI

11 Why is type 2 diabetes so hard to treat? Multiple pathophysiological abnormalities Hard to know which is important in each patient Multiple l abnormalities may require multiple l drugs Disease is progressive Lifestyle change is hard Drug compliance is often poor 43% of patients discontinue statins after 6 months Page 11: Baker IDI

12 Why is type 2 diabetes so hard to treat? Multiple pathophysiological abnormalities Hard to know which is important in each patient Multiple l abnormalities may require multiple l drugs Disease is progressive Lifestyle change is hard Drug compliance is often poor Drugs are not very potent Page 12: Baker IDI

13 Successful management will often require Multidisciplinary team addressing Pathophysiology Education Social setting of the disease within a patient s life Community beliefs about disease Multiple drugs Page 13: Baker IDI

14 Glucose lowering lowering drugs Metformin Sulphonylureas Glitazones Acarbose DPP4 inhibitors GLP1 agonists Insulin long-acting, mixed, short-acting Page 14: Baker IDI

15 How to select therapy Metformin remains the 1 st choice Evidence for micro and macrovascular benefit No hypos; no weight gain Sulphonylureas are 2 nd choice in many guidelines Evidence for micro and macrovascular benefit But hypos and weight gain Page 15: Baker IDI

16 What is 3 rd line therapy??? Insulin Most will need it eventually Evidence for micro and macrovascular benefit Hypos and weight gain Actos Treats insulin resistance Possible macrovascular benefit; no hypos Weight gain, fractures Page 16: Baker IDI

17 What is 3 rd line therapy??? GLP1 analogues Weight loss; no hypos Injections No long-term outcome data yet DPP4i Weight neutral; no hypos Oral No long-term outcome data yet Page 17: Baker IDI

18 Incretins and the cardiovascular system GLP 1 Page 18: Baker IDI 18 Sivertsen, J. et al. (2012) Nat. Rev. Cardiol. doi: /nrcardio

19 DPP4i and CVD risk 53 trials Mean duration ~8 months >30,000 patients DPP4i vs comparator 257 major CV events Risk reduction 31% Odds ratio: 069( ( ) Page 19: Baker IDI Monami. Curr Med Res Opin. 27, S3, 2011, 57 64

20 Principles for best management Start with drugs that have long-term outcome data Expect to use multiple l agents Avoid hypos in those with multiple comorbidities Assess compliance and reasons for non- compliance Glucose-lowering lowering is only 1 part of the puzzle Page 20: Baker IDI

21 Page 21: Baker IDI

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