Zetia and Byetta Can Kill (and other recent DM headlines) - Jennifer Beach, Pharm.D., CDE UWMC Diabetes Care Center Prandial Percolations Part 4 ...

Zetia and Byetta Can Kill (and
other recent DM headlines)

       Jennifer Beach, Pharm.D., CDE
        UWMC Diabetes Care Center
         Prandial Percolations Part 4
        November 18, 2008: Tacoma

ZETIA kills?
† Data from the Simvastatin and
  Ezetimibe in Aortic Stenosis (SEAS)
  study found an increased risk of
  cancer in those on the simvastatin
  combination vs placebo
† How big is this news?
† What is the role of ezetimibe?
† Can ezetimibe be harmful?

SEAS data
† Study in those with aortic valve
  stenosis who are at higher risk for CV
  death and MI with usual treatment of
  surgical replacement
† Question of condition development
  and if similar to atherosclerosis, could
  statins help?
† Not a diabetes trial, pts excluded

SEAS data related to cancer
            105 pts (11.1%) in treatment
            group vs 70 pts (7.5%) in placebo
            group (p=0.01)

SEAS Cancer data
† Not clustered at any one site
† Not associated with degree of LDL
  lowering
† No specific type of cancer more
  common
† Comment by authors:”long-term
  statin tx not associated with cancer …
  analysis of data from 14 statin trial
  involving 90K pts showed no
  increased incidence”

Remember ENHANCE?
† April 2008 NEJM, 24 month trial of
  80mg simva + placebo or ezetimibe
  in 720 pts with familial hyperchol
† Assessed intima media thickness
† Data showed combined tx resulted in
  no better IMT than simva alone
  despite decreases in LDL and CRP

Enter the SHARP/IMPROVE-IT trials
† Oxford researchers took 2 large
  ongoing trials using ezetimibe and
  unblinded the cancer data
† Adds 10,319 pts to active treatment
  and 10,298 pts to control treatment
† “Available results from these 3 trials
  do not provide credible evidence of
  any adverse effect of ezetimibe on
  rates of cancer”

NEJM Editorial Opinion
† Oxford researchers may prove to be
  right but appropriate to use caution.
† May be due solely to chance, but
  ezetimibe works to decrease GI
  absorption of cholesterol, and possibly
  other molecular entities that could
  conceivably affect cancer cell growth.
† Not assumed as chance until further
  data is in. SHARP and IMPROVE-IT
  trial final outcomes should help.

Questions regarding Zetia:
† Knowing only what you know now:
  „ What do you plan to tell patients when
    they ask about Zetia?
  „ Should this information change practice
    surrounding its use?
  „ Do you think it matters how you lower
    cholesterol or is it best to reach the goal
    no matter the method?

Bottomline:
† SEAS data suggests possible link with
  cancer though Oxford data refutes
† ENHANCE trial proves that add’l LDL
  lowering with Ezetimibe no benefit to IMT in
  those with familial hyperchol
† No true answer until IMPROVE-IT and
  SHARP data are completed, but until then,
  it may be best to use “tried and true”
  diet/exercise, statins, fibrates, niacin,
  reserving ezetimibe for failures/intolerance

Byetta History
† Approved on April 28, 2005
† FDA’s reporting system database logs 48
  cases of acute pancreatitis from release
  through December 31, 2006
† Reports on 18 cases were excluded due to
  other causes
† Of the 30 cases:
  „   mean age 58 years
  „   Onset ranged 4-300 days, mean 54
  „   70% required hospitalization
  „   90% has at least 1 other risk factor (obesity,
      alcohol use, hypertriglyceridemia, hyperlip)

Byetta/Pancreatitis history
† Since 2006, Byetta prescribing insert
  has included info about pancreatitis
† In 2007, amended to include
  pancreatitis as a Precaution
  „ Inform pts about pancreatitis sx
  „ Recommendations for subsequent pt
    management
  „ US Package insert updated at this time

Byetta kills?
† In August 2008, FDA issued an update
  referencing 6 cases of hemorrhagic or
  necrotizing pancreatitis that were
  associated with 2 deaths
  „ One fatal case morbidly obese man of 400
    lbs with extensive gallstones
  „ One fatal case with complicated medical
    course that included necrotizing
    pancreatitis, Byetta stopped months
    earlier

Byetta kills?
† Since launch of Byetta, a total of six
  cases with fatal outcome. The other
  4 cases did not appear directly
  attributable to pancreatitis.
† No definite causal relationship has
  been proven, the makers of Byetta
  vow to continue surveillance

Byetta Precautions section:
† “Patients should be observed for signs and
  symptoms of acute pancreatitis (persistent
  severe abdominal pain that may be
  accompanied by vomiting). If pancreatitis is
  suspected, Byetta and other potentially
  suspect drugs should be discontinued.
  Resuming treatment with Byetta is not
  recommended if pancreatitis is confirmed
  and an alternative etiology for pancreatitis
  has not been identified.”

Recommendations/Prevention
† Alert to signs/sx of pancreatitis:
  „   Persistent severe abdominal pain
  „   Pain may radiate to the back
  „   Pain may be accompanied by n/v
  „   Pain may worsen with meals
  „   Often look and feel very sick, “Toxic”
  „   Fever
  „   Rapid pulse

Recommendations/Prevention
† Do not use in those prone to developing
  pancreatitis:
  „   Active gallstones
  „   Heavy alcohol consumption
  „   Hypertriglyceridemia (>1,000 mg/dL)
  „   Obesity (Use with caution)
  „   Other medications such as estrogens,
      corticosteroids, thiazides, and Tylenol (use with
      caution)
† One other risk factor for pancreatitis may
  be Type 2 Diabetes

Questions regarding Byetta
† Knowing what you know now:
  „ Do you think that patient selection
    should be important when using Byetta?
  „ How much warning should be given in
    terms of pancreatitis?
  „ Should we use less Byetta, turning
    instead to insulin?

Bottomline:
† 80,000 cases per year, incidence
  0.03% of the population (1/3400)
† Byetta incidence not more than with
  general population (about 1 million
  Byetta users)
† However, use is in a high risk
  population and pt selection should be
  done very carefully with specific
  teaching on warning signs

JDRF Sensor study
† 322 patients with type 1 diabetes
† HbA1c 7-10%
† Stratified by age
  „ 8-14 years old
  „ 15-24 years old
  „ > 24 years old
† Use of CGM to determine value/benefit on
  diabetes endpoints
† Randomized to either CGM or home BGs

JDRF Sensor study
† Use of Dexcom, Medtronic, or
  Freestyle sensor systems
† Use of home BGs were to test QID+
† All insulin dosing based on meter
  „ Premeal target 70-130 mg/dL
  „ Peak postprandial < 180 mg/dL
  „ Bedtime 100-150 mg/dL
† Visits on 1,4,8,13,19, & 26 weeks
  with one phone call b/w visits

98 patients > 24 years
A1c mean difference -0.53% (-0.71
to -0.35%) p < 0.0001, favoring
CGM, more pts reach A1c goal

110 patients age 15-24
Mean difference A1c +0.08 (-0.17 to
0.33) p =0.52 b/w therapies, no
secondary differences b/w groups

114 patients age 8-14
Mean difference A1c -0.13 (-0.38 to
0.11) p =0.29 b/w therapies, more
pts reached goal

Discussion Questions for CGM
† Knowing what you know now:
  „ Does this data support the use of
    sensors in the population that you work
    with?
  „ Do you think you will recommend more,
    less, or the same amount of sensor use?
  „ Other thoughts?

JDRF Study discussion
† Benefit associated with age
† No differences in hypoglycemia in groups
  achieving better control
† 10% relative reduction in A1c felt important
  as DCCT showed a benefit of 40%+
  reduction in rate of early diabetic
  retinopathy
† Effects in age may be related to
  substantially greater sensor use in adults
  than in other 2 younger groups

UKPDS 10 year update:glucose
† Of the 4209 newly dx’d type 2 pts originally
  randomized to receive either conventional
  or intensive (insulin/SFU or metformin if
  overwt), 3277 pts asked to post-trial f/u
† No further attempt to control BGs but seen
  annually until 2002
† From 2002-2005, followup via
  questionnaires only
† Between group differences in A1c lost after
  the first year

UKPDS remembered
† Final results published in 1998
  showed with SFU/insulin:
  „ Reduced risk of microvasc complications
  „ Nonsignificant reduction in MI
  „ No improvement in all cause mortality
† Final results with metformin showed:
  „ Significant reductions in MI
  „ Significant reductions in mortality

10 year data UKPDS

9% reduction                21% reduction

15% reduction               33% reduction

10 year data UKPDS

24% reduction

13% reduction               27% reduction

Authors’ conclusions
† Intensive glucose control produces
  “legacy effects”
† A 15% reduction in MI may not be as
  impressive as a statin, but is a very
  substantial change
† Problems with ACCORD, ADVANCE,
  and VADT related to being “unable to
  stop a moving train”

UKPDS 10 year update: HTN
† No legacy effects seen at 10 years
  with HTN group
† One hypothesis behind disappointing
  results:
  „ Mechanical nature of HTN to cause
    complications as opposed to the
    inflammatory, atherosclerosis forming
    nature of glucose control affects over a
    longer-term