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