1. Diabetes Medication: 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 Employed by Kaiser Permanente Center for Health Research, Portland, Oregon Government Research Funding: 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: 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 hyperglycemiaDiabetes is a metabolic condition characterized by hyperglycemia – Insulin Resistance – Insufficient insulin production Progressive, typically requiring ongoing therapy intensificationProgressive, typically requiring ongoing therapy intensification

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

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

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

8. Study Sample n = 3,116

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

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 < 90 Days Supply, n=289 Added 2 nd 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 < 90 Days Supply, n=289 Added 2 nd Agent, n=19 A1C Measured 6 Months Post-Metformin n = 2,508

12. 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 2 nd Agent, n=19 A1C Measured 6 Months Post-Metformin n = 2,508 Never Achieved <7% n = 709 (28.3%) Achieved < 7% n = 1,799 (71.7%)

13. Characteristics of Patients Who Did and Did Not Achieve A1C < 7% Did Not Achieve < 7% Achieved A1C < 7% P value P value Age at Metformin Initiation 55.258.6<0.001 Duration of Diabetes (years) 2.42.0<0.001 % Men 52.6%48.4%0.059 Body Mass Index 36.735.60.002 Adapted from Nichols et al. Curr Med Res Opin 2010;26:2127-2135

14. Characteristics of Patients Who Did and Did Not Achieve A1C < 7% Did Not Achieve < 7% Achieved A1C < 7% P value P value A1C at Initiation 8.9%8.1%<0.001 Months to 7% or Lowest A1C 9.26.3<0.001 Dose When A1C < 7% (or last dose) 1,7451,283<0.001 Medicine Possession Ratio 64.2%88.0%<0.001 Adapted from Nichols et al. Curr Med Res Opin 2010;26:2127-2135

15. Factors Associated with Probability of Attaining A1C < 7% Odds Ratio 95% CI P value Age at Initiation (per year) 1.02 1.01 – 1.03 <0.001 BMI (per kg/m 2 ) 0.98 0.97 – 0.99 0.010 Initial Dose > 1000mg 1.71 1.33 – 2.20 0.004 MPR > 80% 4.59 3.60 – 5.85 <0.001 Adapted from Nichols et al. Curr Med Res Opin 2010;26:2127-2135

16. A1C at Metformin Initiation and Probability of Attaining A1C < 7%* A1C at Initiation Odds Ratio 95% CI P value < 7.0% (n=522) 6.81 4.56 – 10.2 <0.001 7 – 7.9% (n=840) 1.67 1.27 – 2.19 <0.001 8 – 8.9% (n=455) ref---- > 9.0% (n=691) 0.67 0.50 – 0.88 0.005 *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

17. Best A1C Achieved by A1C at Metformin Initiation

18. Diabetes Duration and Probability of Attaining A1C < 7%* Duration of Diabetes Odds Ratio 95% CI P value 0–3 Months (n=935) 2.85 2.04 – 3.98 <0.001 4–11 Months (n=262) 1.73 1.13 – 2.64 0.011 12–23 Months (n=335) ref---- 24–35 Months (n=281) 1.10 0.74 – 1.63 0.630 > 36 Months (n=695) 0.82 0.60 – 1.14 0.234 *Controlling for age, BMI, Initial Dose, MPR, and A1C at initiation Adapted from Nichols et al. Curr Med Res Opin 2010;26:2127-2135

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

20. 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 2 nd Agent, n=19 A1C Measured 6 Months Post-Metformin n = 2,508 Never Achieved <7% n = 709 (28.3%) Achieved < 7% n = 1,799 (71.7%)

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

23. 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 2 nd Agent, n=19 A1C Measured 6 Months Post-Metformin n = 2,508 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%)

24. Sample Characteristics Failed Metformin Did Not Fail P value N(%) 748 748(41.6%) 1,051 1,051(58.4%)-- Age in Years 57.759.20.008 % Men 50.0%47.3%0.257 Duration of Diabetes at Metformin Initiation, Months 26.521.4<0.001 HbA1c at Metformin Initiation 8.2%7.9%<0.001 Months to Failure or End of Follow-up 16.927.6<0.001 Adapted from Brown et al. Diabetes Care 2010;33:501-506

25. Probability of Secondary Failure Odds Ratio95% CIp value Age at metformin initiation (per year)0.980.97 - 0.99<0.001 Duration of Diabetes at Metformin Initiation: 0 - 3 Months (reference)1.00-- 4 - 11 Months1.561.12 - 2.180.008 12 - 23 Months2.091.53 - 2.87<0.001 24 - 35 Months1.591.13 - 2.240.007 > 36 Months2.201.68 - 2.87<0.001 HbA1c prior to metformin: < 7% (reference)1.00-- 7 - 7.9%1.531.19 - 1.980.001 8 - 8.9%1.731.27 - 2.35<0.001 > 9.0%2.041.54 - 2.72<0.001 Adapted from Brown et al. Diabetes Care 2010;33:501-506

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

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

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

29. Summary Initiation at diagnosis greatly improves chances of achieving A1C < 7% 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 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 Achieving good control with metformin is possible even in patients with relatively high pre-therapy A1C

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

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

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

34. Characteristics Associated with Initial Success of SUs Achieved A1C < 8% Did Not Achieve 8% P value N (%) 4,091 (89.9%) 462 (11.1%) -- Age60.355.4<0.001 A1C prior to SU 9.2%10.4%<0.001 1 Year Weight Change with SU (kg) -0.021.01<0.001 Initial Dose (mg) 3.74.6<0.001 Last Dose (mg) 5.07.8<0.001 Adapted from Nichols et al. Endocr Pract 2007;13:37-44

35. Characteristics Associated with Secondary Failure of SUs Subsequent A1C >= 8% A1C Never >= 8% P value N (%) 1,769 (43.2%) 2,322 (56.8%) -- Age58.961.6<0.001 A1C prior to SU 9.6%8.9%<0.001 Diabetes Duration at SU Initiation (months) 11.614.80.011 Months of follow-up 24.839.1<0.001 Dose > 10mg 56.6%21.5%<0.001 Adapted from Nichols et al. Endocr Pract 2007;13:37-44

36. A1C Prior to Initiation and Secondary Failure of SUs Hazard Ratio 95% CI P value < 7.0% 1.00---- 7.0 – 7.9% 1.25 0.93 – 1.67 0.135 8.0 – 8.9% 1.50 1.13 – 1.99 0.005 > 9.0% 1.81 1.37 – 2.38 <0.001 Adapted from Nichols et al. Endocr Pract 2007;13:37-44

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

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

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

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

42. Patient Characteristics by Whether A1C < 8% was Attained or Maintained with SU/MET Maintained < 8% Attained, Did not Maintain < 8% Never Attained < 8% N (%) 944 (24.3%) 2,241 (57.6%) 706 (18.1%) Age at SU/MET Initiation 61.959.253.8 Last SU Dose 11.313.814.4 Last Metformin Dose 1,6751,9131,865 SU MPR 0.790.820.81 Metformin MPR 0.780.750.70 Adapted from Nichols et al. J Gen Intern Med 2007;22:453-458

43. Glycemic History by Whether A1C < 8% was Attained or Maintained with SU/MET Maintained < 8% Attained, Did not Maintain < 8% Never Attained < 8% A1C Prior to SU/Met 8.9%9.1%10.3% Best A1C on SU/Met 6.3%6.7%9.2% Mean A1C on SU/Met 7.2%8.1%10.0% Months on SU/Met 54.962.130.1 Months A1C < 8% 44.617.10 Glycemic Burden 11.131.863.9 Adapted from Nichols et al. J Gen Intern Med 2007;22:453-458

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

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

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

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

48. Characteristics Associated with Early Glycemic Response to Insulin Achieved A1C < 7% Did Not Achieve <7% P value P value N (%) 464 (40.7%) 675 (59.3%) -- Mean Age 66.162.6<0.001 Duration of Diabetes 8.59.00.050 Long-Acting Insulin Only 24.1%39.6%<0.001 Short-Acting Insulin Only 19.2%5.6%<0.001 Long- and Short-Acting Insulin 56.7%54.8%0.043 Concomitant Oral Agents 67.2%73.0%0.035 Adapted from Nichols et al. Diabetes Care (submitted)

49. Characteristics Associated with Early Glycemic Response to with Insulin Achieved A1C < 7% Did Not Achieve <7% P value P value A1C Prior to Insulin 8.2%9.2%<0.001 1 st A1C 90 Days Post-Insulin 6.3%8.0%<0.001 Change in A1C 1.9%1.2%<0.001 Units per Day 47.453.2<0.001 Adapted from Nichols et al. Diabetes Care (submitted)

50. Probability of Early Glycemic Response to Insulin Odds Ratio 95% CI P value Long-Acting Insulin Only 1.00---- Short-Acting Insulin Only 3.131.96-5.01<0.001 Long- and Short-Acting Insulin 2.041.53-2.74<0.001 Pre-Insulin A1C 0.740.68-0.80<0.001 Diabetes Duration 0.960.94-0.990.007 Units per Day 0.990.98-1.000.024 Concomitant Oral Agents 0.840.63-1.110.208 Adapted from Nichols et al. Diabetes Care (submitted)

52. Study Site and Sample Selection Kaiser Permanente Northwest Kaiser Permanente Northwest Diabetes patients who newly initiated insulin therapy (n=2,417) Diabetes patients who newly initiated insulin therapy (n=2,417) Members for > 1 year pre- and up to 7 years post insulin initiation Members for > 1 year pre- and up to 7 years post insulin initiation Glycemic response, usage and weight changes analyzed each quarter (90 days) post-insulin Glycemic response, usage and weight changes analyzed each quarter (90 days) post-insulin

53. Glycemic Response to Insulin Over Time Nichols et al. Curr Med Res Opin 2010;26:9-15

54. Insulin Usage Over Time Nichols et al. Curr Med Res Opin 2010;26:9-15

55. Change in Weight with Insulin Nichols et al. Curr Med Res Opin 2010;26:9-15

56. Summary and Conclusions (Insulin) Initiation of insulin at lower levels of A1C increases glycemic response Initiation of insulin at lower levels of A1C increases glycemic response Ongoing dosage increases will probably be necessary to maintain glycemic control Ongoing dosage increases will probably be necessary to maintain glycemic control Weight gain occurs rapidly but levels off Weight gain occurs rapidly but levels off

57. Other Anti-Hyperglycemics Meglitinides (Starlix, Prandin) Meglitinides (Starlix, Prandin) Thiazolidinediones (Actos, Avandia) Thiazolidinediones (Actos, Avandia) Αlpha-glucosidase Inhibitors (Precose, Glyset) Αlpha-glucosidase Inhibitors (Precose, Glyset) DPP-4 Inhibitors (Januvia, Onglyza) DPP-4 Inhibitors (Januvia, Onglyza) Pramlintide (Symlin) Pramlintide (Symlin) Incretin mimetics (Byetta) Incretin mimetics (Byetta)

58. Summary and Conclusions Early initiation of pharmacotherapy improves response to and durability of the therapy Early initiation of pharmacotherapy improves response to and durability of the therapy This pattern continues as therapy escalates to oral combination and then insulin This pattern continues as therapy escalates to oral combination and then insulin Adherence also plays a role Adherence also plays a role Does minimizing cumulative glycemic burden reduce risk of complications? Does minimizing cumulative glycemic burden reduce risk of complications?