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					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
                                                                               Diabetes: The Numbers


                              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.
                                                                                      December 2006

                               The National Diabetes Education Program
                                                     www.ndep.nih.gov
                                             A joint program of NIH and CDC
$132 Billion for Total Excess U.S.
Cost Attributable to Diabetes in 2002
                        Costs in Millions of Dollars

          Indirect                                    Institutional
                          $39,180                                         $54,215
          Costs                                               Care




  Medication            $17,516                                 $20,130
                                        Outpatient
  and Supplies
                                             Care


American Diabetes Association. Diabetes Care 2003;26:917-932.
 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)
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)
Adjusted ESRD incident rates,
by primary diagnosis, & diabetes
in the general population




 Incident ESRD patients; rates adjusted for age, gender, & race.


USRDS, accessed July 13, 2007
Adjusted ESRD incident rates of
ESRD due to diabetes




                                                illi
                                                illi
                                                lla
                                                lla


 Incident ESRD patients; adjusted for age, gender, & race.


  USRDS, accessed July 13, 2007
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)
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)
                     Microvascular Endpoints
         15
                   p<0.0001
         10
Hazard ratio




               1
                   37% decrease per 1% decrement in HbA1c
      0.5
         0 5             6       7       8        9       10   11
                             Updated mean HbA1c
                        UKPDS 35. BMJ 2000; 321: 405-12        ukpds
Fatal and Non-Fatal Myocardial Infarction
                 5
                     p<0.0001
  Hazard ratio




                 1


                     14% decrease per 1% decrement in HbA1c
        0.5
           0 5             6       7       8        9       10   11
                               Updated mean HbA1c
                          UKPDS 35. BMJ 2000; 321: 405-12        ukpds
                    Fatal and Non-Fatal Stroke
               5
                   p=0.035
Hazard ratio




               1


                   12% decrease per 1% decrement in HbA1c
      0.5
         0 5             6       7       8        9       10   11
                             Updated mean HbA1c
                        UKPDS 35. BMJ 2000; 321: 405-12        ukpds
Myocardial Infarction and Microvascular Disease
                           80


                           60                                  Microvascular
      1000 patient-years

                                                               disease
        Incidence per




                           40                                  Myocardial
                                                               infarction

                           20


                           0
                                0 5 6 7 8 9 10 11
                                  Updated mean HbA1c (%)
                                 UKPDS 35. BMJ 2000; 321: 405-12            ukpds
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
                         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

                             100
   Percent of Patients




                             75
                                       45
                             50
                                                     23
                             25                                   13            8           12
                              0
                                      <7%         7-7.9%       8-8.9%        9-9.9%       >9.9%
                                   (n=122,453)   (n=62,252)   (n=35,472)   (n=20,688)   (n=29,893)


Graham, et al. Diabetes 2002;51(Suppl 2):A274.
Lessons from the DCCT and UKPDS:
Sustained Intensification of Therapy is Difficult

                            DCCT     EDIC                                                             UKPDS (Type 2),
            10
                              (Type 1)                                                  8              Insulin Group
                      9.0

                                                          8.1
             8                                7.9




                                                                            HbA1c (%)
HbA1c (%)




                                  7.3
                                                                                        7
                                                                                                                             Baseline

             6


                                                                                        6                                    Normal

             4                                                                          0
                       0          6.5         +4           + 6 yrs                          0     2        4         6         8        10 yrs
                           DCCT                     EDIC
            DCCT/EDIC Research Group. New Engl J Med. 2000; 342: 381-389.        UK Prospective Diabetes Study Group (UKPDS) 33:
            Steffes et al. Diabetes. 2001 (suppl. 2) 50: A63.                    Lancet. 1998;352:837–853.
Progress in Achieving A1C Goal

                           % of adult patients with

                                     8                              2003
     Poor HbA1c                  7                                  2002
   Control* (>9.5%)                      10                         2000
                                                    21              1997

                                                                                 46
    Good HbA1c                                                                   45
   Control (<7.0%)                                                    37
                                                         25

                       0           10          20             30        40            50

      Diabetes Physician Recognition Program, average performance of applicants, 1997-2003 data.
      * Lower is better for this measure.
                                                                   www.ncqa.org
  Secondary endpoint : HbA1c
                                                              Treatment difference (95% CI)
                                                              Rosiglitazone vs metformin, -0.13 (-0.22 to -0.05); P=0.002
                                                    8.0
                                                              Rosiglitazone vs glyburide, -0.42 (-0.50 to -0.33); P<0.001


                                                    7.6
                          Glycated Hemoglobin (%)




                                                    7.2



                                                    6.8


                                                                                                       Annualized slope (95% CI)
                                                    6.4
                                                                                                          Rosiglitazone, 0.07 (0.06 to 0.09)
                                                                                                          Metformin, 0.14 (0.13 to 0.16)*
                                                                                                          Glyburide, 0.24 (0.23 to 0.26)*
                                                    6.0

                                                     0
                                                          0            1           2            3          4            5

                                                                                        Years

     No. of Patients                                  4012           3308        2991        2583        2197         822


*Significant difference rosiglitazone vs other treatment groups with Hochberg adjustment.
Kahn SE, et al. N Engl J Med 2006;355:2427–2443.
    Clinical Inertia: Failure to Advance
    Therapy When Required
                                   Percentage of Subjects advancing when HbA1C >8%

                                            At Insulin Initiation, the average patient had:
                             100                 • 5 years with HbA1C >8%
                                                 • 10 years with HbA1C >7%
                             80
         % Age of Subjects




                                    66.6%

                             60
                                                                       44.6%

                             40                      35.3%


                                                                                             18.6%
                             20

                              0
                                    Diet           Sulfonylurea      Metformin            Combination


1Brown   et al. The Burden of Treatment Failure in Type 2 Diabetes. Diabetes Care 27. 1535-1540, 2004
     Severe Adverse Effects
     Substantiated in Published Clinical Trials

                               Hypoglycemia              CV           Lactic
                                                                     acidosis
     Insulin                               Yes            No                 No
     Sulfonylureas                         Yes            Yes?               No
     Metformin                             No             No                 Yes
     -Glucosidase inhibitors              No             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
         Weight Gain is a Common Side Effect of
         Most Oral Agents for Type 2 Diabetes
                               Oral       antidiabetic agent*                                        Weight     change (kg)
                                                                                                  -3.8-0.5
                    Metformin1-3
                                                                                                                        -0.2-4.3
                    SUs1-4
                                                                                                                           0.9-4.6
                    TZDs4-6
                                                                                                                    0.3-3.0
                    Meglitinides4,7,8
                                                                                                                  -0.3-1.9
                    Metformin                +   SU1-3
                                                                                                                    0.8-2.1
                    Metformin                +   TZD5,6,9
1.   Bristol-Myers Squibb. Glucophage® Full prescribing Information. 2004.        -5   -4   -3     -2   -1   0     1      2   3     4   5
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.
                                                                                                              *Data are not from
5.   Eli Lilly. Actos® Full Prescribing Information. 2004.
                                                                                                                head-to-head
6.   GlaxoSmithKline. Avandia® Full Prescribing Information. 2005.
7.   Novartis. Starlix® Full Prescribing Information. 2004.
                                                                                                                   studies
8.   Novo Nordisk. Prandin® Full Prescribing Information. 2004.
9.   GlaxoSmithKline. Avandamet® Full Prescribing Information. 2005.
    Adherence to Prescribed Drugs in
    Patients with Type 2 Diabetes

     Drug class                                      n    % Adherent    95% CI

     Oral antidiabetic drugs                         66      50.0      37.9-62.1

     Antihypertensive drugs                          62      50.0      37.6-62.4

     Lipid-lowering drugs                            33      69.7      54.0-85.4

     Antiplatelet drugs                              40      77.5      64.6-90.4

     All drugs                                       82      35.4      25.0-45.7



Mateo JF et al. Int J Clin Pract. 2006;60:422-428.
    Diabetes Care. 2004 May 1; 27(5):1218-1224




Insulin adherence among patients
with type 2 diabetes was 62-64%
   Medical Benefits
   Substantiated in Published Clinical Trials

                                     Microvascular Cardiovascular

      Insulin                                     Yes                        Yes?
      Sulfonylureas                               Yes                        No
      Metformin                                   Yes                        Yes?
      -Glucosidase inhibitors                    No                         Yes?
      Glitazones (TZDs)                           No                         No
      Repaglinide, nateglinide*                   No                         No
      Incretin Mimetics/Enhancers*                No                         No
* Recently available agents with few trials documenting long-term outcomes
    Does Treatment of Diabetes impact
    Mortality?




Kahler KH, et al. Diabetes Care 30:1689, 2007
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!
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
The Business Case for a
Comprehensive Approach

                                                                      MEAN CUMULATIVE
                                                                        3-YEAR MEDICAL
       50000                                                              CHARGES FOR
       45000                                                           DIABETES PATIENTS
       40000                                                           BY CO-MORBIDITIES
       35000                                                             AND GLYCEMIC
   $   30000                                                                CONTROL
       25000
       20000                                             HbA1c 10%
       15000
                                                       HbA1c 9%
       10000
        5000                                         HbA1c 8%
           0                                      HbA1c 7%
                DM +                            HbA1c 6%
                     DM + DM +
                HTN
                      HD HTN DM
                                                     DM = Diabetes; HTN = Hypertension; HD = Heart Disease
                + HD           Only

Gilmer, et al. Diab. Care, 1997; 20:1847-1853
       Cost/ QALY lifetime follow-up
       US cohort >=25 years

                    60000
                    50000
  Cost/QALY (US$)




                    40000
                    30000
                    20000
                    10000
                        0
                    -10000
                             Glycemia     Hypertension      Lipid
CDC JAMA 2002
                                        Intervention type

				
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