Article Critique

1. Article Critique Presented by: Confidential Group Members and Kaitlin Deason

2. Niacin and Statins in Patients with Dyslipidemia 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.

3. 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 • Statinmonotherapy provides an effect on serum HDL-cholesterol • Non-HDL-cholesterol is a secondary target of therapy in patients with serum triglyceride >200 mg/dL

4. 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

5. 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

6. 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

7. 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

8. Methods: Study Design

9. 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

10. Results: Efficacy

11. 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%

12. 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

13. 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.

14. Conclusion • OCEANS study demonstrated that NER/S provides additional , clinically relevant benefits on multiple lipid parameters, beyond of simvastatinmonotherapy 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

15. 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

16. 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.

17. 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 • Histonedeacetylase (HDAC) causes deacetylating of proteins

18. Background con’t. • HDAC inhibitors have previously been shown to offer neuroprotection • Nicotinamide is a class III HDAC and may improve specific protein structure

19. 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

20. 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

21. 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

22. 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

23. Novel object recognition • Depends on cortex brain region • Tests whether mice prefer to explore new objects or familiar objects

24. 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

25. 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

26. 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

27. Results con’t • Brain analysis showed improved microtubule stability which improves neuron transport • Take home message: NAM improves cognitive deficits in mice with AD

28. 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

29. Comparison of studies Niacin 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

30. 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