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

Jennifer Beach, Pharm.D., CDEUWMC Diabetes Care CenterPrandial 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 simvastatincombination vs placeboHow 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 replacementQuestion 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 siteNot associated with degree of LDL loweringNo specific type of cancer more commonComment 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 ezetimibein 720 pts with familial hypercholAssessed intima media thicknessData 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 dataAdds 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 refutesENHANCE trial proves that add’l LDL lowering with Ezetimibe no benefit to IMT in those with familial hypercholNo 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 HistoryApproved on April 28, 2005FDA’s reporting system database logs 48 cases of acute pancreatitis from release through December 31, 2006Reports on 18 cases were excluded due to other causesOf the 30 cases:

mean age 58 yearsOnset ranged 4-300 days, mean 5470% required hospitalization90% has at least 1 other risk factor (obesity, alcohol use, hypertriglyceridemia, hyperlip)

Byetta/Pancreatitis history

Since 2006, Byetta prescribing insert has included info about pancreatitisIn 2007, amended to include pancreatitis as a Precaution

Inform pts about pancreatitis sxRecommendations for subsequent pt managementUS 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 gallstonesOne 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 Byettavow 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 painPain may radiate to the backPain may be accompanied by n/vPain may worsen with mealsOften look and feel very sick, “Toxic”FeverRapid pulse

Recommendations/PreventionDo not use in those prone to developing pancreatitis:

Active gallstonesHeavy alcohol consumptionHypertriglyceridemia (>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 diabetesHbA1c 7-10%Stratified by age

8-14 years old15-24 years old> 24 years old

Use of CGM to determine value/benefit on diabetes endpointsRandomized to either CGM or home BGs

JDRF Sensor study

Use of Dexcom, Medtronic, or Freestyle sensor systemsUse of home BGs were to test QID+All insulin dosing based on meter

Premeal target 70-130 mg/dLPeak postprandial < 180 mg/dLBedtime 100-150 mg/dL

Visits on 1,4,8,13,19, & 26 weeks with one phone call b/w visits

98 patients > 24 yearsA1c mean difference -0.53% (-0.71 to -0.35%) p < 0.0001, favoring CGM, more pts reach A1c goal

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

114 patients age 8-14Mean 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 discussionBenefit associated with ageNo differences in hypoglycemia in groups achieving better control10% relative reduction in A1c felt important as DCCT showed a benefit of 40%+ reduction in rate of early diabetic retinopathyEffects in age may be related to substantially greater sensor use in adults than in other 2 younger groups

UKPDS 10 year update:glucoseOf 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/uNo further attempt to control BGs but seen annually until 2002From 2002-2005, followup via questionnaires onlyBetween group differences in A1c lost after the first year

UKPDS remembered

Final results published in 1998 showed with SFU/insulin:

Reduced risk of microvasc complicationsNonsignificant reduction in MINo improvement in all cause mortality

Final results with metformin showed:Significant reductions in MISignificant reductions in mortality

10 year data UKPDS

9% reduction 21% reduction

15% reduction 33% reduction

10 year data UKPDS

13% reduction

24% 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 changeProblems 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 groupOne 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