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					THE ACCORD TRIAL: “IS LOWER HBA1C
 REALLY DANGEROUS, OR WHY DID
    PEOPLE DIE IN THIS STUDY?”
    (and other RECENT STUDIES)

  Jeffrey L. Probstfield, MD, for the ACCORD Study Group
       University of Washington Medical Center, Seattle, WA
   NHLBI/NIH decision:
    ◦ Discontinue intensive glycemia treatment
    ◦ Transition all participants to the standard glycemia
      treatment
    ◦ No interaction between BP and Lipid Trial
      Components and Glycemia Intervention.
    ◦ Continue the BP and Lipid trials
      “These trials continue to address important questions”



                               (NHLBI Press Release, February 6, 2008)
   To determine whether CVD event rates can be
    reduced in people with diabetes by intensively
    targeting three important CVD risk factors:
    hyperglycemia, dyslipidemia, and high blood pressure.
   Three trials in one research program
    ◦ Double 2 by 2 factorial design
   In middle aged/older people with type 2 DM at high risk
    for a CVD event, does a therapeutic strategy that targets
    an A1C < 6.0% reduce CVD event rates more than a
    strategy that targets an A1C between 7.0% & 7.9% (with
    the expectation of achieving a median level of 7.5%)?
                                                             Study          Mean A1C    Mean A1C    Relative Risk
       Observational studies                                               (Intense)   (Control)   Reduction for
        supportive                                                                                  CVD (95% CI)


         ◦ Each 1% higher A1C                                UKPDS (I/SU)   7.0%        7.9%        16% (0,29)

           associated with 18% greater                       UKPDS (Met)    7.4%        8.0%        39% (11,59)
           risk of CVD1
                                                             Kumamoto       7.1%        9.4%        46% (NS)
         ◦ CVD-glucose relationship
           extends into the normal                           VACSDM         7.1%        9.3%        -56% (-170,10)

           range                                             DIGAMI         7.1%        7.9%        29% (4,51)

       Clinical trials inconclusive2                        UGDP(IVAR)     FPG         FPG         9% (NS)
                                                                            130-146     170-186
                                                                            mg/dL       mg/dL

1. Selvin E, et al. Ann Intern Med. 2004;141:421-431.
2. Goff DC Jr, et al. Am J Cardiol. 2007;99[suppl]:4i-20i.
                          BP                        Lipid
               Intensive Standard           Statin +   Statin +
                                            Masked     Masked
               (SBP<120) (SBP<140)
                                            Study Drug Study Drug

Intensive
Glycemia
(A1C<6%)           1178         1193          1383         1374           5128*


Standard
Glycemia           1184        1178           1370         1391           5123*
(A1C 7-7.9%)


                  2362*        2371*          2753*       2765*           10,251
               *Primary analyses compare the marginals for main effects
   Stable Type 2 Diabetes for 3+ months
   A1C >7.5% AND <9% (more meds) OR <11% (fewer meds)
   Age 40-79 + previous CVD events OR
   Age 55-79 with:
     ◦ anatomical ASCVD, albuminuria, LVH OR
     ◦ > 2 CVD risk factors (dyslipidemia, hypertension, smoking, obesity)
   BMI < 45; Cr < 1.5 (133 uM)
   No frequent/recent serious hypoglycemia
   Able/willing to take insulin, do glucose monitoring
   Eligible for BP or Lipid Trial
   Primary:
    ◦ First occurrence of nonfatal MI OR Nonfatal Stroke OR CV
      Death
   Secondary/Other:
    ◦   Each component of 10
    ◦   Expanded CVD: 10 + Revasc & HF Hosp
    ◦   Total mortality
    ◦   Microvascular (nephropathy, neuropathy, eye)
    ◦   Eye photo substudy (N = 3537)
    ◦   HRQL (N = 2053); Cost (N = 4311)
    ◦   MIND: cognition, brain volume (MRI)
    ◦   Falls/Fractures/BMD
                      Intensive    Standard
                     (N = 5128)   (N = 5123)
Age                     62.2         62.2
Women                   38.7         38.4
Median DM Duration       10           10
Previous CVD Event      35.6         34.8
White/Black          64.4/19.7    64.5/18.9
Current Smoker          14.3         13.7
Mean BMI                32.2         32.2
Mean SBP/DBP         136.2/74.8   136.5/75.0
Mean/Median A1C       8.3 / 8.1    8.3 / 8.1
Mean FG                 175          176
Mean LDL / HDL        105 / 47     105 / 47
                    Intensive    Standard
                   (N = 5128)   (N = 5123)
Insulin (%)          34.1         35.7
Metformin (%)        59.7         60.0
Sulfonylurea (%)     50.8         49.4
TZD (%)              19.5         19.2
BP Drug (%)          84.9         86.0
ACE-I (%)            53.0         53.0
ASA (%)              54.8         54.1
Beta Blocker (%)     28.7         29.9
Thiazide (%)         26.5         26.4
Statin (%)           61.7         62.4
Intensive   Standard Rx Goal
Rx Goal
Intensive   Standard Rx Goal
Rx Goal




                               December 2007
 Metformin        Glargine Insulin
 Rosiglitazone    Aspart Insulin

 Glimepiride      70/30, N, R Insulin

 Repaglinide      Exenatide

 Acarbose
                                           Intensive    Standard
                                          (N = 5128)   (N = 5123)
Any Insulin (%)*                             77           55
Bolus Insulin (%)                            55           35
Metformin (%)                                95           87
Secretagogue (%)                             87           74
Thiozolidinedione%                           92           58
    Rosiglitazone (%)                        91           58
Acarbose (%)                                 23            5
Exenatide/Sitagliptin (%)                    18            5
    Exenatide (%)                            12            4
                    * % of Participants
             A1C
                        Intensification Thresholds
Group       Targets         A1C       > 50% of SMBG Results/4 Days

                                           Fasting > 100 (5.6)
Intensive     < 6%         > 5.9%                  OR
                                           2 Hr PP > 140 (7.8)


  Rx was reduced in the presence of      Even if the A1C is <6.0
  significant hypoglycemia.
                                        Action Required
            A1C
                                        Thresholds
Group      Targets         A1C

                          >8.0%               INCREASE RX

Standard    7-7.9%    6.5%-6.9% X 2        DECREASE Rx if**:
                           OR             Any Fasting < 90 (5.0)
                         < 6.5%         Symptomatic Hypoglycemia
                                        On Insulin or Secretagogue

           **Decrease only insulin or insulin secretagogues.
Decrease Increase
   Hypoglycemia requiring medical or
    paramedical attention, AND
    ◦ Documented blood glucose < 50 mg/dl (2.8 mmol/L), or
    ◦ Prompt recovery with administration of oral CHO, IV
      glucose, or subcutaneous glucagon
Each participant‟s „Glucose Diary‟ was reviewed at each clinic visit
to identify the occurrence of one of these hypoglycemic events
Number of Participants With One or More
Severe Hypoglycemia Events
Requiring Medical Assistance (n and %)

                   Intensive Group           Standard Group
 # Events **         n           %            n         %
      1             400         7.8          130       2.5

      2             82          1.6           34       0.7

    3 to 5          43          0.8           10       0.2

      >5             6          0.1           0         0

             **Cumulative number of events
                          Intensive     Standard
                                                        P
                            N (%)         N (%)
CHF                        152 (3.0)     124 (2.4)     0.10

MVA*                        9 (0.2)      14 (0.3)      0.31

Non-hypo SAE               113 (2.2)     82 (1.6)      0.03

Fluid Retention           3541 (70.1)   3378 (66.8)   <0.001

ALT > 3 X Normal           51 (1.0)      77 (1.5)      0.02

*Motor Vehicle Accident
1.41%/yr
           1.14%/yr

   HR = 1.22 (1.01-1.46)
   P = 0.04
                   Intensive    Standard
                     N (%)        N (%)       HR (95% CI)        P
Primary            352 (6.86)   371 (7.23)   0.90 (0.78-1.04)   0.16
Secondary
 Mortality         257 (5.01)   203 (3.96)   1.22 (1.01-1.46)   0.04
 Nonfatal MI       186 (3.63)   235 (4.59)   0.76 (0.62-0.92) 0.004
 Nonfatal Stroke   67 (1.31)    61 (1.19)    1.06 (0.75-1.50)   0.74
 CVD Death         135 (2.63)   94 (1.83)    1.35 (1.04-1.76)   0.02
 CHF               152 (2.96)   124 (2.42)   1.18 (0.93-1.49)   0.17
                          Intensive   Standard
                            N (%)       N (%)
Unexpected/Presumed CVD   86 (1.7)    67 (1.3)

MI                        19 (0.4)    13 (0.3)

CHF                       23 (0.5)    16 (0.3)

CV Procedure              10 (0.2)     3 (0.1)

Arrhythmia                 4 (0.1)    10 (0.2)

Non-CV Procedure          1 (0.02)     3 (0.1)

Stroke                     9 (0.2)    11 (0.2)

Other CVD                  8 (0.2)    10 (0.2)
                   Intensive    Standard
                     N (%)        N (%)       HR (95% CI)        P
Primary            352 (6.86)   371 (7.23)   0.90 (0.78-1.04)   0.16
Secondary
 Mortality         257 (5.01)   203 (3.96)   1.22 (1.01-1.46)   0.04
 Nonfatal MI       186 (3.63)   235 (4.59)   0.76 (0.62-0.92) 0.004
 Nonfatal Stroke   67 (1.31)    61 (1.19)    1.06 (0.75-1.50)   0.74
 CVD Death         135 (2.63)   94 (1.83)    1.35 (1.04-1.76)   0.02
 CHF               152 (2.96)   124 (2.42)   1.18 (0.93-1.49)   0.17
2.29%/yr


           2.11%/yr



 HR = 0.90(0.78-1.04)
 P = 0.16
Can the observed treatment group
 difference in mortality be explained by
 the observed post-randomization
 treatment group difference in severe
 hypoglycemia?
Severe Hypoglycemia Requiring Medical
Assistance




                   Intensive Group Annual Incidence Rate = 3.3%
                   Standard Group Annual Incidence Rate = 1.0%
Hypoglycemia requiring medical or paramedical attention
 Documented blood glucose < 50 mg/dl (2.8 mmol/L) or
 Prompt Recovery with administration of oral or IV CHO or
   glucagon


Each participant‟s „Glucose Diary‟ was reviewed at each clinic visit
to identify the occurrence of one of these hypoglycemic events
And we know
We know

     Intensive Strategy   Intensive Strategy




                          Higher Rates of
     Higher Mortality
                          Hypoglycemia
So – which situation do we have?

    Intensive Strategy              Intensive Strategy




     Higher Rates of
     Hypoglycemia




                         Higher Rates of
     Higher Mortality                            Higher Mortality
                         Hypoglycemia


                And can ACCORD
                distinguish these?                       No!
Background: Mortality By Severe Hypoglycemia

                      Never
                                                Experienced
                  Experienced a
                                             Hypoglycemic Event
                Hypoglycemic Event
  Overall
  Mortality
                  1.2% / year                  3.3% / year
  Rates            (409 Deaths / 9546 pts)        (51 Deaths / 705 pts)




        Mortality is higher among participants who had
         experienced a Severe Hypoglycemic Event
Background: Mortality By Severe Hypoglycemia

                        Never
                                           Experienced
                    Experienced a
                                        Hypoglycemic Event
                  Hypoglycemic Event
  Overall
  Mortality
                    1.2% / year           3.3% / year
  Rates

      Intensive
      Glycemia            1.3% / year           2.8% / year
Background: Mortality By Severe Hypoglycemia

                        Never
                                           Experienced
                    Experienced a
                                        Hypoglycemic Event
                  Hypoglycemic Event
  Overall
  Mortality
                    1.2% / year           3.3% / year
  Rates

      Intensive
      Glycemia            1.3% / year           2.8% / year

      Standard
      Glycemia            1.1% / year           4.9% / year
Background: Mortality By Severe Hypoglycemia

                        Never
                                           Experienced
                    Experienced a
                                        Hypoglycemic Event
                  Hypoglycemic Event
  Overall
  Mortality
                    1.2% / year           3.3% / year
  Rates

      Intensive
      Glycemia            1.3% / year           2.8% / year

      Standard
      Glycemia            1.1% / year           4.9% / year

         Again, mortality is higher among participants who
          had experienced a Severe Hypoglycemic Event,
                       regardless of treatment strategy
Mortality By Treatment Group


                 Overall


Intensive    1.4% / year
Glycemia          (257 Deaths)


Standard      1.1% / year
Glycemia          (203 Deaths)

Hazard      1.22 (1.01, 1.46)
Ratio
(95% CI)
Mortality By Treatment Group and
Severe Hypoglycemia
                                       Never
                 Overall           Experienced a
                                 Hypoglycemic Event

Intensive    1.4% / year            1.3% / year
Glycemia          (257 Deaths)              (223 Deaths)


Standard      1.1% / year           1.1% / year
Glycemia          (203 Deaths)              (186 Deaths)

Hazard      1.22 (1.01, 1.46)      1.24 (1.02, 1.50)
Ratio
(95% CI)                          1.22* (1.00, 1.48)

                      Mortality Higher in
                        Intensive Group



                                                * Adjusted for baseline factors
Mortality By Treatment Group and
Severe Hypoglycemia
                                       Never
                                                              Experienced
                 Overall           Experienced a
                                                           Hypoglycemic Event
                                 Hypoglycemic Event

Intensive    1.4% / year             1.3% / year               2.8% / year
Glycemia          (257 Deaths)              (223 Deaths)              (34 Deaths)


Standard     1.1% / year             1.1% / year               4.9% / year
Glycemia          (203 Deaths)              (186 Deaths)              (17 Deaths)

Hazard
Ratio       1.22 (1.01, 1.46)       1.24 (1.02, 1.50)         0.54 (030, 0.96)
(95% CI)

                                 Mortality Higher in       Mortality Higher in
                                  Intensive Group           Standard Group

                                         Interaction P < 0.01
Among participants who never had a severe
 hypoglycemic event during follow-up, mortality
 was greater in the intensive group.

 However, among participants who had a
 hypoglycemic event, mortality was greater in
 the standard group
Participants who had experienced a severe
 hypoglycemic event were more likely to die
        • True for both treatment groups
   Investigating the potential role that medications may
    have played in the mortality imbalance continues to
    be an important consideration for ACCORD
    Investigators.
   This is a difficult task because:
    ◦ Participants were not randomized to different
      medications
    ◦ Choice of medication in any participant was based on
      clinical judgment and characteristics of participants
   Examples of how baseline characteristics influenced
    choice of medications.
    ◦ Exenatide was less likely to be used if participants were
      already on insulin, as this was off label use.
    ◦ Insulins were more likely to be used in participants with a
      baseline history of CVD or longer duration of diabetes (see
      next slide)
    ◦ Rosiglitazone was less likely to be prescribed in those with
      prior CVD
   In general, these characteristics (longer duration,
    prior CVD) are also associated with a greater risk of
    mortality.
                    15 Years Duration of Diabetes
             3.50       (23% of Participants)

             3.00
Odds Ratio




                                                    More Likely
             2.50

             2.00

             1.50

             1.00




                                                    Less Likely
             0.50
                         Prior CVD
                    (35% of Participants)
             3.50

             3.00
Odds Ratio




                                            More Likely
             2.50

             2.00

             1.50

             1.00

             0.50




                                            Less Likely
   ACCORD investigators identified several combinations that
    were of interest.

   Estimated the risk of mortality for many medications in the
    presence or absence of a second medication. Does the
    addition of the 2nd medication magnify the risk associated
    with the 1st medication?

   Because of the high level of interest in the combination of
    rosiglitazone and insulin, we present those results on the next
    slide.
                      Any Insulin   Basal Insulin   Bolus Insulin   Premixed Insulin

                        p=0.53       p=0.19           p=0.68           p=0.93

               2.25
               2.00
Hazard Ratio




               1.75
               1.50
               1.25
               1.00
               0.75
               0.50
               0.25
   We have not been able to identify a single agent, or
    combination, that accounts for the imbalance in mortality.
    ◦ Exenatide  less mortality, but used rarely and more often in Intensive
      Glycemia group

    ◦ Premixed Insulin  greater mortality, but used more often in Standard
      Glycemia group

    ◦ Bolus Insulin  greater mortality, but no difference in mortality hazard
      ratios by randomized group and we don’t know if the relationship with
      mortality is a reflection of use or the participants to whom it was given

    ◦ Approximately a 20% increase in mortality associated with Intensive
      Glycemia even after controlling for participant characteristics and post-
      randomization use of glycemia medications.
Intensive glycemia strategy discontinued
early – after average 3.5 years
     Total mortality (prespecified secondary outcome
      and safety measure):
        22% higher rate in intensive group
        HR = 1.22 (95% CI =1.01-1.46), p = 0.04
     Prespecified primary CVD outcome (composite of
      nonfatal MI, nonfatal stroke, fatal CVD):
        10% lower rate in intensive group
         HR = 0.90 (95% CI = 0.78-1.04), p = 0.16
     DSMB judgment: “harm outweighs potential benefit”
      of intensive treatment, which should be discontinued
     NHLBI (sponsor) accepted DSMB recommendation
   Compared to a strategy targeting A1C levels of 7-7.9%, a
    therapeutic strategy using currently available therapies to
    target near-normal A1C levels in people with
    longstanding T2DM and either CVD or additional CVD
    risk factors
    ◦ Increased mortality
    ◦ Did not reduce a composite of major CVD events over 3.5
      years (primary outcome)
    ◦ Mortality results consistent across several subgroups
    ◦ Suggestion of reduced major CVD events in 2 subgroups:
      primary prevention and A1C <8% @ BL
  ADVANCE VADAT STUDY REVIEWS

WHAT TARGETS AND DRUGS FOR DIABETES?




             Irl B. Hirsch, M.D.
         University of Washington,
                 Seattle, WA
Differences in ACCORD/ADVANCE
 BASELINE                           ACCORD                     ADVANCE
          # patients                10,251                       11,140
          duration DM (yrs)            10                            8
          Hx macrovasc. Dz (%)         35                          32
          Baseline A1C (%)             8.1                         7.2
 Intervention
          target A1C (%)               <6                         <6.5
          insulin Rx (%)            77 vs. 55                 41 vs. 24
          TZD Rx (%)                92 vs. 58                  17 vs. 11
 Outcome (intensive vs. standard)
          Median A1C @ study end    6.4 vs. 7.5%             6.4 vs. 7.0%

          DEATH: any cause           5.0 vs. 4.0%*           8.9 vs. 9.6%



NEJM 2008;358, 2630                                *P<0.05
ADVANCE
ADVANCE Primary Outcomes
ADVANCE Primary Outcomes
ADVANCE: Secondary Endpoints
 ♦   All-cause mortality: P = NS
 ♦   Total renal events 11% RR with intensive, P < 0.001
 ♦   Eye events: P = NS
 ♦   CHF, PVD, neuropathy: P = NS
                  VA DAT
• Participants: 40% w prior CVD; 80% w HTN, vast
  majority obese; average age 60
• Participants had to have “failed simple therapy”
• Treatment: intensive group most on 2-3 orals plus
  insulin (90% on insulin)
• Achieved goals for lipids (LDL 78 mg/dL), BP
  (127/70) [these were background Tx]
• BL A1C mean 9.5%
• Achieved A1Cs: standard 8.4%, intensive 6.9% -
  delta 1.5%

                                        UNPUBLISHED
                    VA DAT
• “Reduction in CV events” [composite outcome,
  events and procedures] not statistically significant
• All components of the CVD composite outcome
  “favor good glucose control, except CV death, where
  there was a ….slight insignificant increase…”
• CVD events: standard 263, intensive 231; rates lower
  than predicted
• Microvascular outcomes not reported – analyses
  pending, to be reported in September in Rome
• Telling quote: “We think…A1C is a stronger marker
  for microvascular complications…than for
  macrovascular complications…”
                                         UNPUBLISHED
   Candidate Mechanisms:
    TGC and CVD Events
♦ Hypoxia (remember the PDR story!)
♦ Hypoglycemia (arrhythmias, brain
  dysfunction, vasoconstriction, new data
  leading to DAN)
♦ Obesity (3 drugs resulting in weight gain)
♦ Glucose variability in long-standing
  diabetes (insulin deficiency)
    Big Picture Messages
♦ T1 and T2DM: early meticulous glucose
  control can prevent microvascular and
  neuropathic complications
♦ T1DM: early meticulous glucose control
  appears to prevent CVD many years later
♦ T2DM: early meticulous glucose control does
  appear to prevent both micro- and
  macrovascular disease in T2DM
    The Benefit of Early
Aggressive Glycemic Control
♦ Metabolic memory
♦ “Legacy effect”
     Big Picture Message
♦ T2DM: patients with known CVD or long
  durations of DM may be harmed by
  meticulous control; although the
  mechanism(s) for this are not known, the
  leading candidate mechanism is
  hypoglycemia
More Big Picture Messages
♦ T1DM: impact of glycemia on microvascular
  disease not present after 20-25 years
  (probably true for T2DM too)
♦ After long duration of either T1 or T2DM (or
  known CVD), it appears BP, LDL-C and ASA
  use better predict CVD mortality than A1C
♦ Impact of hypoglycemia is not consistent
  between populations (under 5 year-olds,
  geriatrics, inpatient)
SO WHAT A1C TARGETS?
   My Take, At Least While We Are
   Awaiting ADA/AACE Consensus
    Statements on T2DM Targets
♦ < 10 years T2DM AND no CVD: Target at least < 7%
   ♦ 1st line: metformin
   ♦ 2nd line: SFU, sitagliptin, exenatide, basal insulin
     (A1C < 9%)
   ♦ 3rd line: physiologic insulin therapy
♦ 10-15 years T2DM AND no CVD:
   ♦ No change from above but this population will be
     more likely to require insulin to reach A1C target
           Possible Strategy
♦ > 15 years T2DM OR known CVD: 7-7.5% A1C
   ♦ Drugs with less risk of hypoglycemia
      ♦ Metformin, SFU unlikely to be effective with longer
        durations of DM
      ♦ Little data for TZDs, exenatide, sitagliptin
   ♦ Greatest risk of hypoglycemia with insulin, but also
     greatest likelihood of efficacy to consistent A1C levels
      ♦ Less hypoglycemia with basal insulin alone, but
        some prandial insulin required as duration of DM
        and A1C increases
      ♦ Don‟t use basal insulin to replace prandial needs!
                  Conclusions
♦ The recent studies do not negate the years of research from
  other clinical trials
♦ Different populations appear to have different A1C targets
   ♦ It appears the same in the inpatient population!
♦ It is difficult to recommend a generalization of one drug vs.
  another (depending on the situation) as there are so many
  variables and little clinical trial data to guide us
   ♦ General: hypoglycemia, weight gain, pregnancy, cost
   ♦ Specific: GI tolerability, edema, bone fx, increase CVD
     risk (?)
              Conclusion
♦ Insulin is always an option, is under-utilized,
  and needs to be used in a physiologic
  manner in patients with severe insulin
  deficiency
   ♦ In patients with known vascular disease,
     even more modest A1C targets require the
     use of insulin analogues (as opposed to
     human insulins) due to the consistent data
     showing less hypoglycemia even though
     there are no differences in A1C.

				
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