Ndei Beta Cell Slide Kit Clinical Implications

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  • Clinical Implications This module addresses clinical and management issues related to type 2 diabetes.

Transcript

  • 1. Section 4 Clinical Implications
  • 2.  -Cell Adaptation and Failure: Opportunities for Prevention and Treatment of Type 2 Diabetes
  • 3. Disclosure
    • This slide kit is intended to provide current information on issues concerning  -cells in patients with type 2 diabetes.
    • Some of the information and agents mentioned may include discussions of off-label, non–FDA-approved, or investigational uses. Please refer to each manufacturer’s full prescribing information before prescribing any of the agents mentioned in this program.
    • Slides that include discussion of off-label uses are identified with the symbol .
  • 4. Treatment of Type 2 Diabetes: Getting Back on the Curve Reestablishing Insulin Sensitivity-Secretion Relationships Resistant Insulin sensitivity Sensitive Insulin level Normal curve Diabetes Insulin or Secretagogue Diet+Exercise, Metformin, TZDs Combination Therapy
  • 5. Short-term Methods to Improve  -Cell Insulin Secretion
    • Reverse glucotoxicity in severely decompensated individuals
    • Add insulin secretagogues
    • Administer exogenous insulin
  • 6. Lowering Glucose Levels Improves  -Cell Function
    • 14 subjects
      • age: 50 ± 3 years
      • diabetes duration: 7.8 ± 2.1 years (new onset to 20 years)
      • fasting glucose: 286 ± 17 mg/dL
      • plasma insulin: 15 ± 2 U/mL
    • 22 days of CSII
      • euglycemic clamp and hepatic glucose output
      • insulin secretion over 24 hrs and IV glucose and glucagon
    Garvey WT et al. Diabetes. 1985;34:222-234.
  • 7. Increased Insulin Secretion Following Elimination of Glucotoxicity Garvey WT et al. Diabetes. 1985;34:222-234. Glucose (mg/dL) Insulin (  U/mL) 450 400 350 300 250 200 150 100 50 40 30 20 10 Before After After Before Time 8 am 12 pm 4 pm 8 pm 12 am 4 am 8 am Meals
  • 8. Insulin Secretagogues: Sulfonylureas and Glitinides
    • Bind to K ATP channels on the  -cell and directly increase insulin secretion
      • sulfonylureas (longer half-life)
        • glimepiride
        • glipizide
        • glyburide
      • glitinides (shorter half-life)
        • nateglinide
        • repaglinide
    Krentz AJ et al. Drugs . 2005;65:385-411.
  • 9. Effect of Glyburide in Hyperglycemia: Enhanced  -Cell Responsiveness Shapiro ET et al. J Clin Endocrinol Metab . 1989;69:571-576. Solid red line (left graph) and shaded red area (right graph) represent mean ± SEM for a group of subjects without diabetes. Clock time Clock time Before glyburide After glyburide 6 am 10 am 2 pm 6 pm 10 pm 2 am 6 am 0 100 200 300 400 500 600 700 800 6 am 12 pm 6 pm 12 am 6 am 20 15 10 5 0 Glucose (mmol/L) Insulin secretion (pmol/min) Meals Meals Before glyburide After glyburide
  • 10. Long-term Improvement or Stabilization of Islet Function
    • All therapies for diabetes appear to lose effectiveness with time, primarily due to a progressive decline in  -cell function
    • Therapies that decrease  -cell secretory demand can prevent or possibly reverse islet dysfunction
  • 11. Progressive Hyperglycemia in Type 2 Diabetes Despite Therapy 0 6 7 8 9 2 4 6 8 10 A1C (%) Years after randomization 0 Conventional (diet) Intensive: Upper Normal The UKPDS Study UKPDS Group. Lancet. 1998;352:854-865. Chlorpropamide Glibenclamide Insulin Metformin
  • 12. Prevention and Early Treatment of Type 2 Diabetes: Changing the Focus  -Cell function (%) UKPDS Data Prevention and Early Treatment -12 -10 -8 -6 -4 -2 0 2 4 6 0 20 40 60 80 100 Years from diagnosis Holman RR. Diabetes Res Clin Pract. 1998;40(suppl):S21-S25.
  • 13. Prevention and Early Treatment of Type 2 Diabetes: Three Levels of Opportunity 3  -Cell Failure Hyperglycemia Robust  -Cells Hyperinsulinemia Weak  -Cells Adipose Tissue Adipokines Fatty Acids Insulin Resistance 2 Insulin Resistance Liver & Muscle 1 Obesity Energy Balance Negative Positive Lifestyle Interventions Fat Accumulation
  • 14. Weight Loss Can Improve Diabetic Control and Prevent the Deterioration in  -Cell Function
    • Lifestyle interventions (diet and exercise) are the mainstays of treatment for type 2 diabetes
    • Exercise and weight loss improve insulin sensitivity, resulting in reduced insulin secretion
  • 15. Effect of Weight Loss on  -Cell Function in Obese Patients With Type 2 Diabetes Gumbiner B et al. J Clin Endocrinol Metab . 1990;70:1594-1602. 0 60 120 180 300 250 200 150 100 50 0 Insulin secretion (pmol/min/m²) Minutes 0 60 120 180 0 6 8 10 12 14 16 18 22 20 Glucose (mmol/L) Before (mean BMI 35.5 kg/m 2 ) After (mean BMI 29.5 kg/m 2 ) Minutes
  • 16. Weight Loss Improves Insulin Secretion in Obese Patients With Type 2 Diabetes Gumbiner B et al. J Clin Endocrinol Metab . 1990;70:1594-1602. Minutes Minutes 25 20 15 10 5 0 Glucose (mmol/L) 0 60 120 180 240 300 360 300 250 200 150 100 50 0 Insulin secretion (pmol/min/m 2 ) 0 60 120 180 240 300 360 Before (mean BMI 35.5 kg/m 2 ) After (mean BMI 29.5 kg/m 2 )
  • 17. Prevention of Type 2 Diabetes Results of Recent Randomized Trials Buchanan TA et al. Diabetes. 2002;51:2796-2803. Chiasson JL et al. Lancet. 2002;359:2072-2077. Knowler WC et al. N Engl J Med. 2002;346:393-403. Torgerson JS et al. Diabetes Care . 2004;27:155-161. Toumilehto J et al. N Engl J Med . 2001;344:1343-1350. Relative Risk Study Subjects Intervention Reduction Finnish DPS IGT Lifestyle 58% US DPP IGT Lifestyle 58% US DPP IGT Metformin 31% Stop-NIDDM IGT Acarbose 25% TRIPOD Prior GDM Troglitazone 55% XENDOS IGT Orlistat 45% Behavior Medication
  • 18. Finnish Diabetes Prevention Study: Effect of Lifestyle Intervention Cumulative probability of remaining free of diabetes Toumilehto J et al. N Engl J Med . 2001;344:1343-1350. 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 5 6 Years on trial Intensive Lifestyle (11%) Control (23%) 58% Relative Risk Reduction
  • 19. US Diabetes Prevention Program: Effect of Lifestyle Intervention Years from randomization Cumulative incidence of diabetes (%) 0 1 2 3 4 0 10 20 30 40 Placebo Lifestyle 58% Relative Risk Reduction Adapted from Knowler WC et al. N Engl J Med. 2002;346:393-403.
  • 20. US Diabetes Prevention Program: Effect of Metformin 0 1 2 3 4 0 10 20 30 40 Placebo Metformin 31% Relative Risk Reduction Years from randomization Adapted from Knowler WC et al. N Engl J Med. 2002;346:393-403. Cumulative incidence of diabetes (%)
  • 21. Metformin and Islet Function
    • Metformin directly reduces glucose production by the liver, resulting in lower insulin levels
    • Metformin has a minimal peripheral insulin-sensitizing effect
    • Metformin does not directly affect insulin secretion
    • Metformin usually results in modest weight loss
    Krentz AJ et al. Drugs . 2005;65:385-411.
  • 22. Metformin in Type 2 Diabetes: Improved Glucose Without Changes in Insulin Secretion Wu MS et al. Diabetes Care . 1990;13:1-8. Before After 8 12 1 11 9 10 2 3 4 Plasma glucose (mg/dL) 300 250 200 150 100 50 0 20 40 60 Plasma insulin (  U/mL) Time of day Time of day 8 12 1 11 9 10 2 3 4
  • 23.  -Glucosidase Inhibitors
    • Decrease the rate of digestion of complex carbohydrates in the small intestine
    • Delay glucose absorption and attenuate postprandial rises in blood glucose and insulin
    • Efficacious as first-line therapy and in combination with sulfonylureas, metformin, and insulin
    • Beneficial effects on hyperglycemia and hyperinsulinemia
    • Do not cause weight gain
    • May lower triglyceride levels
    Krentz AJ, Bailey CJ. Drugs . 2005;65:385-411.
  • 24. The STOP-NIDDM Study: Effect of Acarbose Cumulative probability of remaining free of diabetes Days after randomization Acarbose Placebo 25% Relative Risk Reduction Chiasson JL et al. Lancet. 2002;359:2072-2077. 1.00 0.95 0.90 0.85 0.80 0.75 0.70 0.65 0.60 0.55 0.50 0.45 0.40 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300
  • 25. Lipase Inhibitor: Orlistat
    • Inhibits intestinal lipase, decreasing the absorption of fat in the small intestine
    • In clinical trials, orlistat-treated patients lost 5% to 10% of body weight vs 2% to 7% in placebo-treated patients following 6 to 48 months of treatment
    • Reduces LDL cholesterol and insulin levels
    Curran MP, Scott LJ. Drugs . 2004;64:2845-2864.
  • 26. The XENDOS Study: Effect of Orlistat Week Cumulative incidence of diabetes (%) Placebo + lifestyle - IGT patients Orlistat + lifestyle - IGT patients Placebo + lifestyle - all patients Orlistat + lifestyle - all patients 45% Relative Risk Reduction P =0.0024 P =0.0032 0 26 52 78 104 130 156 182 208 0 5 10 15 20 25 30 Torgerson JS et al. Diabetes Care . 2004;27:155-161. 37% Relative Risk Reduction
  • 27. PPAR  Activators and Islet Function
    • The thiazolidinediones and other PPAR  activators
      • improve insulin sensitivity in muscle and liver primarily by redirecting FFAs to adipose tissue, reducing TG levels
      • improve insulin sensitivity by reducing insulin concentrations
      • improve  -cell secretion patterns
      • prevent diabetes in high-risk populations
    Krentz AJ et al. Drugs . 2005;65:385-411.
  • 28. TRIPOD Study: Effect of Troglitazone Buchanan TA et al. Diabetes. 2002;51:2796-2803. Months on study 55% Relative Risk Reduction 50 40 20 0 0 12 24 36 48 60 Placebo Troglitazone 30 10 Patients with diabetes (%) 12.1% Annual Incidence Rate 5.4% Annual Incidence Rate
  • 29. Stabilization of  -Cell Function at IGT Stage: Evidence From the TRIPOD Study P =0.01 between groups Baseline 8 Months post-trial Placebo (n=40) 0 2 4 6 MINMOD S i Acute insulin response (  U/mL x min) 200 400 600 800 0 0 2 4 6 MINMOD S i 39% decrease in  -cell compensation Stable Buchanan TA et al. Diabetes. 2002;51:2796-2803. 1,000 200 400 600 800 0 1,000 Troglitazone (n=44)
  • 30. Stabilization of  -Cell Function at Early Diabetes: Evidence From the TRIPOD Study Years Disposition index ( S i x AIRg) 0 1 2 3 4 5 0 200 400 600 800 On Trial Off Trial Troglitazone Placebo P =0.82 -3% P =0.02 -35% Xiang AH et al. J Clin Endocrinol Metab . 2004;89:2846-2851.
  • 31. Effect of Troglitazone on  -Cell Function in PCOS Ehrmann DA et al. J Clin Endocrinol Metab . 1997;82:2108-2116. P <0.005 P <0.005 NS S i (10 -5 min -1 /pmol/L) AIR glucose (pmol/L) 0 100 200 300 400 500 600 700 800 900 0 250 500 750 1,000 1,250 1,500 1.25 1.00 0.75 0.50 0.25 0 Data are the mean±SEM. Disposition index Before treatment After treatment
  • 32. Prevention of Type 2 Diabetes
    • Tools for identification of high-risk people
    • Step 1: Find Insulin Resistance
      • Overweight by BMI (ethnicity-specific)
      • Increased waist circumference
      • Components of the metabolic syndrome
      • Family history of type 2 diabetes and/or metabolic syndrome
    • Step 2: Find  -Cell Dysfunction
      • Impaired fasting glucose (100-125 mg/dL)
      • Impaired 2-hour postprandial glucose (140-199 mg/dL)
      • Rising glucose levels over time
  • 33. Prevention of Type 2 Diabetes: One Clinical Strategy At-Risk Clinical Characteristics Higher Risk Impaired Continue Lifestyle Intervention Stable Glycemia Consider Pharmacologic Treatment Rising Glycemia Measure Glucose Lower Risk Normal Lifestyle Advice Follow-up Glucose Testing Diabetes Treat to Achieve an A1C <6.5%-7% Diabetic Lifestyle Intervention