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Article Critique. Presented by: Confidential Group Members and Kaitlin Deason. Niacin and Statins in Patients with Dyslipidemia. - PowerPoint PPT Presentation
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Article Critique
Presented by:Confidential Group Members and Kaitlin Deason
Karas, R.H., Kashyap, M.L., Knopp, R.H., Keller, L.H., Bajorunas, D.R., & Davidson, M.H. (2008) Long-term safety and efficacy of a combination of niacin extended release and simvastatin in patients with dyslipidemia. American Journal Cardiovascular Drugs, 8 (2),69-81.
Niacin and Statins in Patients with Dyslipidemia
Background Reducing LDL-cholesterol reduces major fatal
and non-fatal cardiovascular complications High-dose HMG-CoA inhibitors (statins) fail to
prevent two-thirds of cardiovascular events Statin monotherapy provides an effect on serum
HDL-cholesterol Non-HDL-cholesterol is a secondary target of
therapy in patients with serum triglyceride >200 mg/dL
Background Epidemiologic and clinical trials shown benefit
from concurrent LDL-C reducation and HDL-C elevation
15 years of study the combination of niacin and simvastatin
OCEANS study: Open-label evaluation of the safety and efficacy of a Combination of niacin ER and simvastatin in patients with dyslipidemia
Purpose Evaluation of the long-term safety profile of
Niacin Extended Release/Simvastin (NER core coated with simvastin)
Focus on treating abnormalities of non-HDL-C, HDL-C and triglycerides
Intensification in combination therapy in national guidelines
Methods Open-label, randomized, parallel-group study Screened: 1718 men & women >21 years old
w/ elevated non-HDL-C (mixed dyslipidemia) Simvastatin run-in phase Lipid qualification phase 520 Randomized TLC diet
Methods◼ Inclusion criteria: triglyceride <500 mg/dL; LDL-
C<250 mg/dL◼ Exclusion criteria: an allergy, hypersensitivity, or
intolerance to niacin, statins; pregnancy◼ Treatment received (n=509): NER/S tablets once
daily at bedtime with low fat snack◼ Assessment Safety: frequency, type and severity
of adverse events, flushing◼ Assessment Efficacy: clinical labs
Methods: Study Design
Results: Safety 509 received NER/S Flushing:
71% experienced at least one episode 61% experienced mild or moderate intensity Gender, race, or history of prior lipid-lowering
therapy did not affect the proportion Adverse events: pruritis, nausea, elevated
HbA1c, serum CPK, blood glucose: 40(7.9%): only 3 (0.6%) treatment related
Results: Efficacy
Results◼ A simvastatin run-in phase group: NER/S
group: 52 wks: Clinically meaningful improvements in non-HDL-C, LDL-C, triglyceride, HDL-C, apo A-I, apo B, and Lp (a)
◼ No lipid-lowering drug group: NER/S group: 24 wks: reduced serum of non-HDL-C, LDL-C, and triglyceride by 50% and increased HDL-C by 25%
Discussion Long term safety and efficacy of the
combination of NER/S of up 2000/40 mg/day in a population at high risk of CHD
The rate of discontinuation due to treatment related adverse events was greater for 12 wk
Discussion Concerns persist regarding the possibility that
niacin might worsen glycemic control or contribute to insulin resistance
Recent large-scale studies shown that niacin only slightly increases fasting blood glucose levels in patients w/ or w/out DM.
Conclusion OCEANS study demonstrated that NER/S
provides additional , clinically relevant benefits on multiple lipid parameters, beyond of simvastatin monotherapy over 24-52 wks
The safety profile of the combination of NER/S up to maximum dosage of 2000/40 mg/day is consistent with safety profile of each component given individually
Strengths and weaknesses
+ Research question is clear identified
+ Long term study+ Randomized clinical trial+ Large sample size+ Time frame is adequate to
objective+ Figures and tables are
visual
− No control group− Bias when safety was
evaluated− TLC is hard to assess− No discussion of alternative
explanation
Nicotinamide and Alzheimer’s Disease
Green, K. N., Steffan, J. S., Martinez-Coria, H., Sun, X., Schreiber, S. S., Thompson, L. M., & LaFerla, F. M. (2008). Nicotinamide restores cognition in Alzheimer's disease transgenic mice via a mechanism involving sirtuin inhibition and selective reduction of Thr231-phosphotau. The Journal of Neuroscience, 28(45), 11500-11510.
Background Alzheimer’s disease (AD) is a neurodegenerative
disorder Primarily effects hippocampus, amygdala, and cortex
brain regions No known cure Most prevalent ND disorder in the elderly
Histone deacetylase (HDAC) causes deacetylating of proteins
Background con’t. HDAC inhibitors have previously been shown
to offer neuroprotection Nicotinamide is a class III HDAC and may
improve specific protein structure
Purpose To determine if nicotinamide is an effective
treatment in mice induced with AD Precursor to future human studies to
determine if this is possibly a safe and effective therapeutic agent
Methods 3xTg-AD mice were used as the treatment
group and were compared with normal mice All mice were 4 months old
8 mice from ea. group were given 200 mg/kg/day of NAM in their water for 4 months
8 mice from ea. group were used as a control Several tests were conducted to test brain
function from specific brain regions
Morris water maze (MWM) test
Depends on hippocampus brain region Mice were trained in a maze to reach a
hidden platform located within the maze Measured by how many days it took the mice
to learn where the hidden platform was located
Contextual fear conditioning
Dependent on hippocampus and amygdala Tested how long it would take mice to stay
away from a dark compartment where they would receive a shock
Novel object recognition
Depends on cortex brain region Tests whether mice prefer to explore new
objects or familiar objects
Mechanism of NAM Following tests, the mice were killed and there
brains were studied to determine mechanism of action
Results are complicated but can be found in the article if interested
There were a variety of mechanisms determined to have been in effect
Results MWM:
Untreated 3xTg-AD mice took 6 days to learn maze where treated took only 4 days
Both untreated normal mice and treated normal mice took 4 days
Contextual fear conditioning 3xTg-AD mice treated with NAM completely avoided the dark
room after training Statistically significant results after 24-hr trial
Results con’t. Novel object recognition
No difference was observed between treatment groups
Shows that there is no effect in cortex function Overall nicotinamide improves both short and long
term memory in AD-mice Also improves hippocampus-dependent learning
and amygdala-dependent contextual learning Even show NAM improves short term memory in
mice without AD
Results con’t Brain analysis showed improved microtubule
stability which improves neuron transport Take home message: NAM improves cognitive
deficits in mice with AD
Strengths and weaknesses+ By using mice safety is
determined for future human studies
+ Researchers able to control adherence to treatment
+ Findings are first of their kind and show a lot of potential in future human models
− Effect on humans is yet to be determined
− Tests were complicated and difficult allowing for possible error or bias
− Early AD is tested so these results may not be the same for late stages of AD
Comparison of studiesNiacin and Dyslipidemia
Human model More generalizable More variability and
less adherence Collected blood samples
and assessed lipid profile
Looks at niacin’s effect on lipid levels
Niacin and Alzheimer’s Animal model
Less generalizable Less variability and
control over adherence Observational tests and
collected brain for analysis
Looks at niacin’s effect on Alzheimer’ disease
Comparison of studies con’t
Niacin and Dyslipidemia P-values determined
using ANOVA, Fisher’s exact test for adverse events, Wilcoxon sign-ranked test to determine % change from baseline
Well established finding and not a lot more research needed
Niacin and Alzheimer’s Behavioral scores
evaluated using ANOVA, Bonferroni correction to determine individual differences b/w groups, biochemical data assessed by planned student t-tests
Novel findings with a lot more research needed especially in human models