1. Diabetes Mellitus type II Optimizing Glucose Control Andrea Shaylor Lock Haven University PA Program February 26, 2009

2. FACTS   Diabetes affects an estimated 24.1 million people -> an increase of more than 3 million in ~2 yrs 6.2 million remain undiagnosed/untreated   Another 57 million with prediabetes/ impaired FPG

3. Pathophysiology   Genetics + Environment Obesity!   defects in glucose uptake ↓ concentration of insulin receptors ↓ glycolytic enzymes glucokinase and hexokinase

4. Pathophysiology *Beta-cell dysfunction and loss vs. insulin resistance*   Chronic exposure to high glucose causes: -glucose-induced toxicity, resulting in irreversible beta-cell damage -generation of reactive oxygen species causing oxidative stress which affects the mRNA for insulin gene expression, resulting in less insulin production   UKPDS: only 50% of pancreatic islet function remains at time of diagnosis

6. Diagnosis   ADA offers 3 criteria: 1)* FPG > 126mg/dL on 2 random occasions 2) symptoms of hyperglycemia and a random plasma glucose >200mg/dL 3) 2-hour plasma glucose level >200mg/dL after a 75-gram oral glucose tolerance test

7. Current Management Lifestyle modification with diet and exercise ↓ FPG goal not met: monotherapy with metformin or sulfonylurea ↓ Combination of above, or another oral agent ↓ Addition of 3 rd agent, various combinations, or new agent ie incretin mimetic/Byetta or DPP-4 inhibitor/Januvia ↓ When all else fails: Insulin

9. Target for treatment   Glycosylated hemoglobin A1C, average blood glucose over past 3 mos, shows better correlation to micro and macrovascular complications than glycemic values   ADA and ACC recommendation: HgbA1C <6.5-7%   UKPDS: for every 1% reduction in A1C: - 21% reduction in death related to diabetes -14% reduction in risk for MI, 12% for stroke -32% reduction in risk for retinopathy -24-27% reduction in risk for nephropathy -30% reduction in risk for neuropathy   Intensive glycemic control associated with a 57% reduction in major CVD outcomes

11. Suboptimal Control   Causes irreversible micro and macrovascular complications, m & m   Despite this, 60% of pts do not meet goals   Prospective study of 7000 pts: Avg pt remained at A1C >8% for 5 yrs and >7% for 10 yrs   At time of all OA failure, many pts have had diabetes for 10-15 yrs, and long term complications have already developed Meneghini, L. (2007). Why and How to Use Insulin Therapy Earlier in the Management of Type 2 Diabetes. Southern Medical Association, 100: 164- 173.

12. PICO   Question: In the adult population with DM type II, should insulin be initiated earlier, after failure of just one oral agent, as measured by HbA1C, versus the further addition/combo of OAs, for better glycemic control thereby preventing or delaying the associated DM complications?

13.   Retrospective cohort study involving 2501 patients with DM type II above OGLA failure threshold   Found that 24% of patients had insulin delayed for at least 1.8 yrs, and 50% delayed for 5 yrs with polytherapy, even in the presence of diabetes-related complications   A1C levels were closer to 9% before intervention was triggered Rubino, A., McQuay, L., Gought, C., et al. (2007). Delayed initiation of subcutaneous insulin therapy after failure of oral glucose-lowering agents in patients with Type 2 Diabetes. Diabetic Medicine, 24: 1412-1418.

14. Evidence for Use   Although oral agents succeed at lowering glucose, there is still a continued loss of B-cell function with time.   Sulfonylureas have been to shown to possibly increase the risk of B-cell apoptosis.   TZDs associated with adverse effects   However, insulin is proven to prevent glucotoxicity and lipotoxicity, in addition to preserving B-cell functioning Tibaldi, J. (2008). Preserving Insulin Secretion in type 2 Diabetes Mellitus. Expert Review of Endocrinology & Metabolism : Medscape, 3(2): 147-159.

15. OADReduction in A1C Actos or Avandia.1-.9 Prandin1.1 Metformin1.4 Sulfonylureas1-2 Insulin~2+ Vinik, Aaron. (2007). Advancing Therapy in Type 2 DM with Early, Comprehensive Progression from OA to Insulin Therapy. Clinical Therapeutics, 29: 1236-1253.

16. A1C levels before and after insulin

17. Window of Opportunity   When blood glucose levels are normalized and maintained early, the glucotoxicity and oxidative stress causing B-cell deterioration and apoptosis can be reversed:   Clinical trials of short periods of intensive insulin therapy administered early have resulted in temporary remission due to restored B-cell functioning   However, when same intensive insulin therapy used in pts with avg of 7.6 yrs of DM, insulin response was much less Tibaldi, J. (2008). Preserving Insulin Secretion in type 2 Diabetes Mellitus. Expert Review of Endocrinology & Metabolism : Medscape, 3(2): 147-159.

18. ADA/ACE Goals & Algorithm   FPG<100mg/dL and 2hr PPG <140mg/dL   If HbA1C remains >7% following lifestyle changes + metformin after 3 mos-> consider insulin Metformin when combined with insulin has weight-ameliorating effects Vinik, Aaron. (2007). Advancing Therapy in Type 2 DM with Early, Comprehensive Progression from OA to Insulin Therapy. Clinical Therapeutics, 29: 1236-1253.

19. Regimen?   Elevated FPG-- basal   Elevated PPG-- basal/bolus or *premixed PP glycemic control accounts for 50% of overall glycemic control   INITIATE treat-to-target trial: Metformin+ premix BIAsp30: 66% reached <7% Metformin + basal glargine: 40% reached <7%   1-2-3 Trial: Failure on OA, with BIAsp30 added: 41% reached <7%, 21% reached <6.5% in 16 wks Fleury-Milfort, Evelyne. (2007). Practical Strategies to improve treatment of type 2 diabetes. Journal of the American Academy of Nurse Practitioners, 20: 295-304.

20.   55% of practitioners delay until absolutely necessary due to: ~Fear of hypoglycemia & weight gain ~More complicated and time consuming   PIR: DAWN study: 5000 DM pts, 3000 HCPs- >1/2 pts not using insulin worry about the time to start & >1/2 view the start as personal failure Ligthelm, R., Davidson, J. (2008). Initiating insulin in primary care- The role of modern premixed formulations. Primary Care Diabetes 2: 9-16.   Study published in Diabetes Educator found 50-77% of pts admitted to feelings of failure vs 35% with fear of injections Larkin, M., Capasso, V., Chen, C., et al. (2008). Measuring Psychological Insulin Resistance. The Diabetes Educator, 34: 511-517.

21.   Long term benefits outweigh   Newer insulin analogues are safer, simpler, better approximated to physiologic/endogenous insulin secretion, minimal weight gain   Smaller, more user-friendly needles   Diabetes Education!

22. Ultimate Goal for Outcome   Reducing glucose toxicity   Minimizing complications   Preventing m & m by improving CV profile   Limiting healthcare costs   Improving QOL

23. References   Brunton, S., Tenzer-Iglesias, P., Unger, J. (2008). Initiating and intensifying therapy in type 2 Diabetes. The Journal of Family Practice, 57, S17-26.   Fleury-Milfort, Evelyne. (2007). Practical Strategies to improve treatment of type 2 diabetes. Journal of the American Academy of Nurse Practitioners, 20: 295-304.   Larkin, M., Capasso, V., Chen, C., et al. (2008). Measuring Psychological Insulin Resistance. The Diabetes Educator, 34: 511-517.   Ligthelm, R., Davidson, J. (2008). Initiating insulin in primary care- The role of modern premixed formulations. Primary Care Diabetes 2: 9-16.   Meneghini, L. (2007). Why and How to Use Insulin Therapy Earlier in the Management of Type 2 Diabetes. Southern Medical Association, 100: 164-173.   Rubino, A., McQuay, L., Gought, C., et al. (2007). Delayed initiation of subcutaneous insulin therapy after failure of oral glucose-lowering agents in patients with Type 2 Diabetes. Diabetic Medicine, 24: 1412-1418.   Skyler, J., Bergenstal, R., Bonow, R., et al. (2008). Intensive Glycemic Control and the Prevention of Cardiovascular Events. Journal of the American College of Cardiology, 53: 298-304.   Tibaldi, J. (2008). Preserving Insulin Secretion in type 2 Diabetes Mellitus. Expert Review of Endocrinology & Metabolism : Medscape, 3(2): 147-159. Vinik, Aaron. (2007). Advancing Therapy in Type 2 DM with Early, Comprehensive Progression from OA to Insulin Therapy. Clinical Therapeutics, 29: 1236-1253.