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