1. Achieving Diabetes Targets Where are we, and how can we do better? Robert E. Ratner, MD MedStar Research Institute Georgetown University Medical School Washington, DC

2. Diabetes: The Numbers The National Diabetes Education Program www.ndep.nih.gov A joint program of NIH and CDC December 2006 EVERY 24 HOURS New Cases – 4,100 Amputations – 230 (60% of non-traumatic amputations annually) Blindness – 55 (#1 cause) Kidney Failure – 120 (#1 cause) Deaths – 810 - >60% due to CVD Derived from NIDDK, National Diabetes Statistics fact sheet. HHS, NIH, 2005.

3. $132 Billion for Total Excess U.S. Cost Attributable to Diabetes in 2002 American Diabetes Association. Diabetes Care 2003;26:917-932. Medication and Supplies Outpatient Care Institutional Care Indirect Costs Costs in Millions of Dollars

4. Projected impact of changing demographic characteristics on the national cost of diabetes: 2002–2020 (in 2002 billions of dollars) Source: Economic Costs of Diabetes in the U.S. in 2002, Lewin Group, Inc., for the American Diabetes Association, 2002. (http://care.diabetesjournals.org/cgi/content/full/26/3/9617)

5. Diabetes: The Numbers The National Diabetes Education Program www.ndep.nih.gov A joint program of NIH and CDC December 2006 Preventing Diabetes Complications Glucose control Blood pressure control Blood lipid control Preventive care practices for eyes, kidneys, feet, teeth and gums Aspirin as directed by physician NIDDK, National Diabetes Statistics fact sheet. HHS, NIH, 2005.

6. Number of Persons Initiating Treatment for End- Stage Renal Disease Related to Diabetes, United States, 1984–2002 Source: National Diabetes Surveillance System – CDC website (http://www.cdc.gov/diabetes/statistics/index.htm )

7. Incident ESRD patients; rates adjusted for age, gender, & race. Adjusted ESRD incident rates, by primary diagnosis, & diabetes in the general population USRDS, accessed July 13, 2007

8. Adjusted ESRD incident rates of ESRD due to diabetes lla illi lla illi Incident ESRD patients; adjusted for age, gender, & race. USRDS, accessed July 13, 2007

9. Prevalence of Visual Impairment per 100 Adults with Diabetes, by Age, United States, 1997–2003 Source: National Diabetes Surveillance System – CDC website (http://www.cdc.gov/diabetes/statistics/index.htm)

10. Hospital Discharge Rates for Nontraumatic Lower Extremity Amputation per 1,000 Diabetic Population, by Age, United States, 1980–2003 Source: National Diabetes Surveillance System – CDC website (http://www.cdc.gov/diabetes/statistics/index.htm)

11. Microvascular Endpoints 0.5 1 10 15 0567891011 37% decrease per 1% decrement in HbA1c p<0.0001 Updated mean HbA 1c Hazard ratio UKPDS 35. BMJ 2000; 321: 405-12

12. Fatal and Non-Fatal Myocardial Infarction 14% decrease per 1% decrement in HbA1c p<0.0001 0.5 1 5 0567891011 Updated mean HbA 1c Hazard ratio UKPDS 35. BMJ 2000; 321: 405-12

13. Fatal and Non-Fatal Stroke 0.5 1 5 0567891011 12% decrease per 1% decrement in HbA1c p=0.035 Updated mean HbA 1c Hazard ratio UKPDS 35. BMJ 2000; 321: 405-12

14. Myocardial Infarction and Microvascular Disease Myocardial infarction Microvascular disease Updated mean HbA 1c (%) Incidence per 1000 patient-years

15. A1c is a good biologic correlate to microvascular disease complications A1c is a less powerful correlate to macrovascular disease due to the multi- factorial nature of the CVD

16. Aggressive Control of Type 2 Diabetes is a Challenge 76% of patients surveyed had an A1C level recorded in the chart in the previous 12 months Distribution of A1C (%) Among Patients with Recorded Test Results (n=270,758) in Community Practice (n=122,453)(n=62,252)(n=35,472)(n=20,688)(n=29,893) Percent of Patients Graham, et al. Diabetes 2002;51(Suppl 2):A274.

17. 9.0 8.1 7.3 7.9 4 6 8 10 HbA 1c (%) 06.5+ 4+ 6 yrs DCCTEDIC DCCT EDIC (Type 1) Lessons from the DCCT and UKPDS: Sustained Intensification of Therapy is Difficult DCCT/EDIC Research Group. New Engl J Med. 2000; 342: 381-389. Steffes et al. Diabetes. 2001 (suppl. 2) 50: A63. 0 6 7 8 0246810 yrs HbA 1c (%) UKPDS (Type 2), Insulin Group Normal Baseline UK Prospective Diabetes Study Group (UKPDS) 33: Lancet. 1998;352:837–853.

18. Progress in Achieving A1C Goal % of adult patients with Diabetes Physician Recognition Program, average performance of applicants, 1997-2003 data. * Lower is better for this measure. www.ncqa.org

19. Secondary Failure of Monotherapy Overweight Patients in the UKPDS Turner RC et al. UKPDS 49. JAMA. 1999;281:2005-2012 Percent with A1C <7% on monotherapy Diet231211 Sulfonylureas452821 Metformin443413 3 years6 years9 years

20. Secondary endpoint : HbA1c *Significant difference rosiglitazone vs other treatment groups with Hochberg adjustment. Kahn SE, et al. N Engl J Med 2006;355:2427–2443. Years 6.0 7.6 8.0 6.8 012345 Glycated Hemoglobin (%) 7.2 0 Rosiglitazone, 0.07 (0.06 to 0.09) Metformin, 0.14 (0.13 to 0.16)* Glyburide, 0.24 (0.23 to 0.26)* 6.4 No. of Patients40123308299125832197822 Treatment difference (95% CI) Rosiglitazone vs metformin, -0.13 (-0.22 to -0.05); P=0.002 Rosiglitazone vs glyburide, -0.42 (-0.50 to -0.33); P<0.001 Annualized slope (95% CI)

21. Clinical Inertia: Failure to Advance Therapy When Required 0 20 40 60 80 100 DietSulfonylureaMetformin Percentage of Subjects advancing when HbA 1C >8% % Age of Subjects Combination 66.6% 35.3% 44.6% 18.6% 1 Brown et al. The Burden of Treatment Failure in Type 2 Diabetes. Diabetes Care 27. 1535-1540, 2004 At Insulin Initiation, the average patient had: 5 years with HbA 1C >8% 10 years with HbA1C >7%

22. Severe Adverse Effects Substantiated in Published Clinical Trials Hypoglycemia CV InsulinYes No No SulfonylureasYes Yes? No MetforminNo No Yes Lactic acidosis  -Glucosidase inhibitorsNo No No Glitazones (TZDs)No Yes(CHF) No Repaglinide, nateglinide*Yes No No Incretin Mimetics/Enhancers No No No * Recently available agents with few trials documenting long-term outcomes CV=cardiovascular; CHF=congestive heart failure

23. 1. Bristol-Myers Squibb. Glucophage ® Full prescribing Information. 2004. 2. Bristol-Myers Squibb. Glucovance ® Full prescribing Information. 2004. 3. Bristol-Myers Squibb. Metaglip ® Full Prescribing Information. 2002. 4. Malone M. Ann Pharmacother. 2005;39:2046-2055. 5. Eli Lilly. Actos ® Full Prescribing Information. 2004. 6. GlaxoSmithKline. Avandia ® Full Prescribing Information. 2005. 7. Novartis. Starlix ® Full Prescribing Information. 2004. 8. Novo Nordisk. Prandin ® Full Prescribing Information. 2004. 9. GlaxoSmithKline. Avandamet ® Full Prescribing Information. 2005. Weight Gain is a Common Side Effect of Most Oral Agents for Type 2 Diabetes TZDs 4-6 Metformin + TZD 5,6,9 Metformin + SU 1-3 Meglitinides 4,7,8 SUs 1-4 Metformin 1-3 Weight change (kg) Oral antidiabetic agent* -5-4-3-2-1012345 -3.8-0.5 -0.2-4.3 0.9-4.6 0.3-3.0 -0.3-1.9 0.8-2.1 *Data are not from head-to-head studies

24. Adherence to Prescribed Drugs in Patients with Type 2 Diabetes Drug classn% Adherent95% CI Oral antidiabetic drugs6650.037.9-62.1 Antihypertensive drugs6250.037.6-62.4 Lipid-lowering drugs3369.754.0-85.4 Antiplatelet drugs4077.564.6-90.4 All drugs8235.425.0-45.7 Mateo JF et al. Int J Clin Pract. 2006;60:422-428.

25. Diabetes Care. 2004 May 1; 27(5):1218-1224 Insulin adherence among patients with type 2 diabetes was 62-64%

26. Medical Benefits Substantiated in Published Clinical Trials MicrovascularCardiovascular InsulinYesYes? SulfonylureasYesNo MetforminYesYes?  -Glucosidase inhibitorsNoYes? Glitazones (TZDs)NoNo Repaglinide, nateglinide*NoNo Incretin Mimetics/Enhancers* No No * Recently available agents with few trials documenting long-term outcomes

27. Does Treatment of Diabetes impact Mortality? Kahler KH, et al. Diabetes Care 30:1689, 2007

28. Why do we need new therapies for Type 2 Diabetes? The epidemic of diabetes and its complications will soon swamp our medical delivery system A1c is a well validated short term target We are not currently achieving our glycemic targets Current therapies have either limited efficacy, marked complexity, or unacceptable side effects Therapies must be acceptable to patients and health care providers – They must be utilized!

29. What should drive diabetes drug development and approval?  Safety (Hepatic, CVD, Hypoglycemia – While realizing that diabetes is a serious disease!)  Efficacy (glycemic control, risk factor reduction)  Side Effects (weight gain)  Patient acceptability

30. MEAN CUMULATIVE 3-YEAR MEDICAL CHARGES FOR DIABETES PATIENTS BY CO-MORBIDITIES AND GLYCEMIC CONTROL DM + HTN + HD DM + HD DM + HTN DM Only HbA1c 6% HbA1c 7% HbA1c 8% HbA1c 9% HbA1c 10% 0 5000 10000 15000 20000 25000 30000 35000 40000 45000 50000 $ DM = Diabetes; HTN = Hypertension; HD = Heart Disease Gilmer, et al. Diab. Care, 1997; 20:1847-1853 The Business Case for a Comprehensive Approach

31. Cost/ QALY lifetime follow-up US cohort >=25 years Glycemia Hypertension Lipid Intervention type CDC JAMA 2002