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Diabetes Medication: Initiation and Intensification

Diabetes Medication: Initiation and Intensification. Gregory A. Nichols, PhD Annual Collaborative Diabetes Education Conference for Health Professionals January 21, 2012. Disclosures. Employed by Kaiser Permanente Center for Health Research, Portland, Oregon Government Research Funding:

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Diabetes Medication: Initiation and Intensification

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  1. DiabetesMedication: Initiation and Intensification Gregory A. Nichols, PhD Annual Collaborative Diabetes Education Conference for Health Professionals January 21, 2012

  2. Disclosures Employed by Kaiser Permanente Center for Health Research, Portland, Oregon Government Research Funding: National Institute of Diabetes and Digestive and Kidney Disorders (NIDDK) National Heart, Lung and Blood Institute (NHLBI) Agency for Healthcare Research and Quality (AHRQ) Industry Funding: GlaxoSmithKline Merck & Co. Novartis Pharmaceuticals Tethys Bioscience Takeda Pharmaceuticals America Novo Nordisk AstraZeneca Amgen

  3. The Need for Diabetes Pharmacotherapy • Diabetes is a metabolic condition characterized by hyperglycemia • Insulin Resistance • Insufficient insulin production • Progressive, typically requiring ongoing therapy intensification

  4. General Benefits of Metformin • Reduces hepatic glucose production in the presence of insulin • At least weight neutral • May be cardioprotective • May reduce cancer risk • Definitely prevents/delays diabetes in some at-risk individuals

  5. Metformin Initiation at Diabetes Diagnosis • Recommended by EASD/ADA • Does early vs. late metformin initiation and more intensive dosing: • Increase the likelihood of successful metformin therapy? • Prolong its success?

  6. Study Site and Sample Selection • Kaiser Permanente Northwest • All diabetes patients who initiated metformin monotherapy as first-ever anti-hyperglycemic drug, 2004-2006 • Members for > 1 year pre- and 6 months post-metformin initiation • HbA1c measured pre- and post-metformin initiation

  7. Study Sample n = 3,116

  8. Study Sample n = 3,116 Primary Failure or Non-Adherence n = 518 (16.6%) Continued Metformin n = 2,598 (83.4%)

  9. Study Sample n = 3,116 Primary Failure or Non-Adherence n = 518 (16.6%) Continued Metformin n = 2,598 (83.4%) No Refills, n=210 < 90 Days Supply, n=289 Added 2nd Agent, n=19

  10. Study Sample n = 3,116 Primary Failure or Non-Adherence n = 518 (16.6%) Continued Metformin n = 2,598 (83.4%) No Refills, n=210 A1C Measured 6 Months Post-Metformin n = 2,508 < 90 Days Supply, n=289 Added 2nd Agent, n=19

  11. Study Sample n = 3,116 Primary Failure or Non-Adherence n = 518 (16.6%) Continued Metformin n = 2,598 (83.4%) No Refills, n=210 A1C Measured 6 Months Post-Metformin n = 2,508 < 90 Days Supply, n=289 Added 2nd Agent, n=19 Never Achieved <7% n = 709 (28.3%) Achieved < 7% n = 1,799 (71.7%)

  12. Characteristics of Patients Who Did and Did Not Achieve A1C < 7% Adapted from Nichols et al. Curr Med Res Opin 2010;26:2127-2135

  13. Characteristics of Patients Who Did and Did Not Achieve A1C < 7% Adaptedfrom Nichols et al. Curr Med Res Opin 2010;26:2127-2135

  14. Factors Associated with Probability of Attaining A1C < 7% Adapted from Nichols et al. Curr Med Res Opin 2010;26:2127-2135

  15. A1C at Metformin Initiation and Probability of Attaining A1C < 7%* *Controlling for age, BMI, Initial Dose, MPR, and duration of diabetes at initiation Adapted from Nichols et al. Curr Med Res Opin 2010;26:2127-2135

  16. Best A1C Achieved by A1C at Metformin Initiation

  17. Diabetes Duration and Probability of Attaining A1C < 7%* *Controlling for age, BMI, Initial Dose, MPR, and A1C at initiation Adapted from Nichols et al. Curr Med Res Opin 2010;26:2127-2135

  18. Best A1C Achieved by Diabetes Duration at Metformin Initiation Adapted from Nichols et al. Curr Med Res Opin 2010;26:2127-2135

  19. Study Sample n = 3,116 Primary Failure or Non-Adherence n = 518 (16.6%) Continued Metformin n = 2,598 (83.4%) No Refills, n=210 A1C Measured 6 Months Post-Metformin n = 2,508 < 90 Days Supply, n=289 Added 2nd Agent, n=19 Never Achieved <7% n = 709 (28.3%) Achieved < 7% n = 1,799 (71.7%)

  20. Definitions of Secondary Failure • Added/switched to another anti-hyperglycemic agent • Subsequent HbA1c > 7.5% • Composite of the above

  21. Study Sample n = 3,116 Primary Failure or Non-Adherence n = 518 (16.6%) Continued Metformin n = 2,598 (83.4%) No Refills, n=210 A1C Measured 6 Months Post-Metformin n = 2,508 < 90 Days Supply, n=289 Added 2nd Agent, n=19 Never Achieved <7% n = 709 (28.3%) Achieved < 7% n = 1,799 (71.7%) Secondary Failure n = 748 (41.6%) Continued Success N = 1,051 (58.4%)

  22. Sample Characteristics Adapted from Brown et al. Diabetes Care 2010;33:501-506

  23. Probability of Secondary Failure Adapted from Brown et al. Diabetes Care 2010;33:501-506

  24. Secondary Failure of Metformin by HbA1c at Initiation Adapted from Brown et al. Diabetes Care 2010;33:501-506

  25. Secondary Failure of Metformin by Diabetes Duration at Initiation Adapted from Brown et al. Diabetes Care 2010;33:501-506

  26. Summary • In KPNW clinical practice, 72% of drug naïve patients attained the goal of A1C<7% • After attaining goal, metformin monotherapy secondary failure rates are high • But…

  27. Summary • Initiation at diagnosis greatly improves chances of achieving A1C < 7% • Patients who initiate metformin at diagnosis and attain A1C < 7% remain in good glycemic control for longer periods than those who delay initiation • Achieving good control with metformin is possible even in patients with relatively high pre-therapy A1C

  28. Conclusions • The EASD/ADA recommends initiating metformin when diabetes is diagnosed • The KPNW experience confirms the wisdom of that recommendation • Simultaneous lifestyle changes should also be initiated at diagnosis, but exercise may reduce metformin effectiveness

  29. Sulphonylureas • Been around since 1954 • Enhance beta cell production by allowing release of insulin at lower glucose levels • May cause weight gain • More likely to cause hypoglycemia • Have been associated with cardiovascular disease

  30. Study Site and Sample Selection • Kaiser Permanente Northwest • Diabetes patients who initiated SU (glyburide) monotherapy as first-ever anti-hyperglycemic drug • Members for > 1 year pre- and post-SU initiation • Therapeutic success defined as achievement of A1C < 8% • Failure defined as subsequent A1C > 8%

  31. Characteristics Associated with Initial Success of SUs Adapted from Nichols et al. Endocr Pract 2007;13:37-44

  32. Characteristics Associated with Secondary Failure of SUs Adapted from Nichols et al. Endocr Pract 2007;13:37-44

  33. A1C Prior to Initiation and Secondary Failure of SUs Adapted from Nichols et al. Endocr Pract 2007;13:37-44

  34. Time to A1C > 8% by A1C Achievement with SUs Adapted from Nichols et al. Endocr Pract 2007;13:37-44

  35. Summary and Conclusions (SUs) • Patients are highly responsive to SU’s • Initiation of SU’s at lower A1C levels increases likelihood and durability of response • SU’s fail faster when A1C reductions are smaller

  36. Metformin/Sulphonylurea Combination Therapy • Typically initiated by adding one agent to the other—rarely initiated simultaneously • Despite different mechanisms of action, glycemic benefits aren’t additive • Durability of 2nd agent less than when initiated as 1st agent • Some evidence that the combination raises CVD risk

  37. Study Site and Sample Selection • Kaiser Permanente Northwest • Diabetes patients who initiated SU/metformin combination therapy (SU/MET) • Members for > 6 months pre- and post-SU/MET initiation • Therapeutic success defined as achievement of A1C < 8% • Time to insulin initiation when A1C > 8%

  38. Patient Characteristics by Whether A1C < 8% was Attained or Maintained with SU/MET Adapted from Nichols et al. J Gen Intern Med 2007;22:453-458

  39. Glycemic History by Whether A1C < 8% was Attained or Maintained with SU/MET Adapted from Nichols et al. J Gen Intern Med 2007;22:453-458

  40. Time to Insulin Addition on SU/MET Nichols et al. J Gen Intern Med 2007;22:453-458

  41. Summary and Conclusions (SU/MET) • SU/MET works for most patients, but not for long • Most patients on SU/MET delay adding insulin for WAY too long, incurring tremendous glycemic burden

  42. Insulin • A question of when (not if) • Can theoretically lower any level of A1C • Causes weight gain • Hypoglycemia • Has been associated with heart failure • “Psychological Insulin Resistance”

  43. Study Site and Sample Selection • Kaiser Permanente Northwest • Diabetes patients who newly initiated insulin therapy • Members for > 1 year pre- and 270 days post insulin initiation • Early response defined as achievement of A1C < 7% at first measurement within 90-270 days

  44. Characteristics Associated with Early Glycemic Response to Insulin Adapted from Nichols et al. Diabetes Care (submitted)

  45. Characteristics Associated with Early Glycemic Response to with Insulin Adapted from Nichols et al. Diabetes Care (submitted)

  46. Probability of Early Glycemic Response to Insulin Adapted from Nichols et al. Diabetes Care (submitted)

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