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Insulin Therapy in Type 2 DM Earlier = Better

Insulin Therapy in Type 2 DM Earlier = Better. דר' אוהד כהן המכון האנדוקריני המרכז הרפואי ע"ש שיבא, תל-השומר. Three issues addressed: Which treatment achieves the best long term metabolic goals? Which treatment has a more favorable effect beyond glycemic control?

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Insulin Therapy in Type 2 DM Earlier = Better

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  1. Insulin Therapy in Type 2 DM Earlier = Better דר' אוהד כהן המכון האנדוקריני המרכז הרפואי ע"ש שיבא, תל-השומר Three issues addressed: Which treatment achieves the best long term metabolic goals? Which treatment has a more favorable effect beyond glycemic control? Which treatment is safer?

  2. Therapeutic Goals • Achieving safe euglycemia • A1c<7% • Mean BG 120 + 40 • FBG 90-120 • No hypo’s • No side effects (cardiac,obesity,lipids,bp etc.) • Improving QOL • Prevention-CVD,DM. Can this be achieved without insulin?

  3. What's your average A1c? • MyoTrack 8.0% • Maccabi 7.8% • Schneider (1) 9.5% • Germany 9.0% • NHANES III 7.6% (norm -6.0%) • MOST TYPE 2 POPULATONS A1c WAS 8.1%-10.%

  4. What’s Your A1c

  5. Insulin resistance Carbohydrate Compensatory increase in insulin secretion Gut Digestive enzymes Excessive fat breakdown leading to increase in free fatty acids Blood Glucose Pancreas Insulin Adiposetissue Excess glucose production Muscle Liver Decreased insulin-dependent glucose uptake

  6. TYPE 2 DIABETES . . . A PROGRESSIVE DISEASE Progressive Decline of -Cell Function in the UKPDS 100 80 60 -Cell Function (% ) 40 20 0 10 9 8 7 6 5 4 3 2 1 0 1 2 3 4 5 6 Years Adapted from UK Prospective Diabetes Study (UKPDS) Group. Diabetes. 1995; 44:1249-1258. 6-4

  7. Over time,most patients will needinsulinto control glucose TYPE 2 DIABETES . . . A PROGRESSIVE DISEASE 6-7

  8. Can oral agents achieve normoglycemia? • Monotherapy does not achieve HbA1c<7% in the majority of patients • Improvement in glucose control is transient.

  9. Can insulin treat to target? • VA CSCM Diabetes Care 1998 MDI in Obese TYPE 2 ;mean A1c 7% (140 u/d). • Treat to Target Trial Diabetes Care 2003 Bed time glargine/NPH in Obese TYPE 2; mean A1c 7% (47 u/d).

  10. 120 severe hypoglycaemia 1.2 1.0 per 100 patient years 0.8 per 100 patient years 60 0.6 risk of retinopathy 0.4 0.2 0 0 5 6 7 8 9 10 5.5 6.5 7.5 8.5 9.5 10.5 HbA1c (%) The balance between control and tolerability: data from DCCT New Engl J Med 1993;328:977

  11. CSII (Insulin Pump) Improved Control:-Decreased Hypoglycemia Episodes per 100 pt yrs N=55 Bode et al: Diabetes Care 1996; 19:324-7

  12. 3.0 2.5 2.0 1.5 Insulin Detemir NPH insulin 1.0 0.5 0 Overall hypoglycaemic event rate by study Event rate / patient / month during maintenance periods Study no. 1243 1316 1335 1336 (type 2) HbA1c (%) 7.88 7.78 7.53 7.59 8.26 8.38 7.63 7.48

  13. Reducing weight gain with insulin analogues • Treat to target : 3 kg weight gain • Mix 25: No weight gain vs 30/70 • Asp 30: • Lantus vs NPH Insulin glargine was associated with significantly less weight gain 0.4 vs 1.4 kg; P < 0.001).

  14. Insulin has an anti-inflammatory and potential anti atherogenic effect . • Mechanisms are related to the inhibition of cytokines such as TNF-a, CRP, macrophage inhibitory factor and others. • Suppression of the expression of ICAM-1 and MCP-1 • Suppression of the intranuclear binding activity of NFk-B and an increase in IkB expression. • Insulin has a suppressive effect on regulatory factors of the matrix metalloproteinases .

  15. Improvement of Glycemic Control by 1 Year of Insulin Therapy Leads to a Sustained Decrease in sE-Selectin Concentrations in Type 2 Diabetes

  16. These data suggest that: • 1) Early insulin treatment can overcome the tissue resistance to its anti-inflammatory and antithrombotic action. • 2) Given the effects of insulin on several cytokines in addition to its effect on free fatty acids and glucose, it seems that insulin itself has therapeutic advantages on atherosclerosis beyond tight blood glucose control.

  17. Are Sulphonylureas (SU) cardiotoxic? • The DIGAMI trial found a 30% reduction in mortality when intensive insulin treatment was initiated. The reduced mortality was maintained even at a mean follow-up of 3.4 years. Speculation whether the benefits were secondary to the use of the insulin versus the withdrawal of sulphonylureas brought back into focus the debate regarding the cardiovascular safety of the SU • Potential underlying mechanism for the cardiovascular risk associated with sulfonylureas has been the process of myocardial ischemic preconditioning, by which the myocardium protects itself from impending ischemic injury. This process depends on opening KATP channels, the same channels that are blocked by glyburide.

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