Thread by @Lpa_Doc

1/21 Saturday Morning Class #8 Lp(a) and niacin @OxPL_apoB

Basics: What is niacin?. It is vitamin B3 (i.e. essential nutrient) that is precursor of coenzymes NAD+ and NADP+, which shuttle around protons and electrons to mediate redox reactions for fat, carb, protein metabolism

2/21 How does niacin affect the lipid panel: at 2 gram/day: Lp(a) down 25%, LDL-C down 16%, TG down 32%, HDL up 24%. All modest, but going in right direction.

What is the niacin data before statins?
See excellent review by John Guyton- sciencedirect.com/science/articl…

3/21 6 trials done pre 1998, some outcomes, some angiography, all tended to show benefit. Most were combo with clofibrate, colestipol, prava, lova or gemfibrozil. Also other arms with different Rx. However only one with niacin monotherapy - Coronary Drug Project published 1975

4/21 CDP-8,341 men with MI, with TC 250, TG 177. Niacin 1-3g 3 times daily for 6 years, decreased TC 10% and TG 26% and primary endpoint recurrent nonfatal MI by 27% (p<0.004), secondary endpoint (stroke/TIA) by 26%. Number needed to treat 26 to prevent 1 MI (better than PCSK9i)

5/21 At 6 yrs, no effect on total mortality but at 15 yrs a 10.6% reduction was noted (p<0.001). To quote Guyton, “This means that treating 16 men for 6 years prevented 1 death at 15 years”. Of course, this is not primary evidence due to many potential confounders post trial

6/21 Interesting fact: 3 of 6 arms were stopped: estrogen at 5 mg/day for excess nonfatal cardiovascular events; estrogen at 2.5 mg/day for excess thromboembolism and cancer mortality; and dextrothyroxine for excess mortality. Giving estrogen to men = not a good idea...

7/21 2011: AIM-HIGH 3414 pts with CVD, LDL-74, HDL-35, TG-163, Lp(a)~15 mg/dL. Intervention: active control of LDL by simva during trial, 1-2g ext release niacin, 50 mg niacin to placebo: Result; no effect at 36 mo, trial stopped early for futility. Over 20% of pts d/c'd niacin

8/21 HPS2-THRIVE- 25,673 pts on with CVD statin, baseline LDL-64, HDL, 44, TG not given Lp(a) ~31 mg/dL. Intervention: 2 g of extended-release niacin and 40 mg of laropiprant vs placebo daily. Results- at 3.9 yrs no difference in groups.

9/21 More side effects with niacin/laropripant- GI, infection, bleeding, diabetes. Because there is no laropripant arm, we don’t know which drug caused these.

10/21 Question- has there been a study where patients with elevated Lp(a) (>50 mg/dL or >125nmol/L) were randomized to niacin vs placebo for outcomes? Answer is No.

1/21 What is Lp(a) data in these studies: ncbi.nlm.nih.gov/pubmed/23973688
In AIM-HIGH Lp(a) 4th quartile (>125 nmol/L or >50 mg/dL), 87% higher risk of events. Niacin decreased Lp(a) by 21% but no benefit. Critique, small number of events (<70 in this group) and short f/u = underpowered

12/21 In HPS2-THRIVE only a subgroup had Lp(a) measured and not evaluated for link to outcomes due to low power.

Finally, what is effect of PCSK9i on Lp(a)- its is widely reported to be 20-30% reduction, but in pts with Lp(a) >50 mg/dL its is only 15%. ncbi.nlm.nih.gov/pubmed/30561610

13/21 So, what to do in 2020 with niacin and Lp(a)?

1-Niacin clearly lowers Lp(a) modestly,
2-Niacin lowers Lp(a) more than PCSK9i (25-30% vs 14%) in pts with high Lp(a). Outliers exist either way
3-Primary evidence for outcomes in high Lp(a) is lacking either way

14/21 4- I use it selectively in subjects with prior MI or high risk as the ‘art’ of medicine. Some of my patients have been on it over 30 years, one with homozygous FH and high Lp(a) at 3 grams per day

15/21 - 5- Clearly not an ideal drug- side effects include increasing glucose by 5-10 mg/dL, potential for gout, bleeding, skin disorders and flushing, LFT increases. Patients need careful and frequent monitoring

16/21 6-Prior studies were done with crystalline pure niacin, there is a question whether extended release niacin give same results, as absorption is different and exposure to it is only at night for 8 hrs (vs 3x/day , thus it may not give same benefit

17/21- Clinical pearls:

1-If one uses it, make sure the ingredient is niacin: nicotinamide and niacinamide and inositol hexanicotinate (low flush) don’t lower lipids. Yes they reduce flushing but you are taking an expensive placebo

18/21- 2-If ones sees >40% reduction in Lp(a), check LFTs, several cases I have seen like this the LFTs also increase, so one needs to catch this and reduce dose or stop drug.
3-Tolerance to flushing occurs over 6 months and if pts can make it to 1 yr they usually do well

19/21 Fun fact: A pt told me they used to spike drinks with niacin in 1970s to get a flush effect, LOL

In an ideal world with a specific therapy to lower Lp(a), niacin would be relegated to medical history. Hopefully this will happen by 2025, so getting ready to write obituary

20/21 Q: 5 pts. Choose the incorrect choice:

1-Niacin lowers all lipid parameters
2-Niacin can be associated with significant side effects
3-It is clearly shown that pts with elevated Lp(a) don’t benefit from niacin
4-if LDL<70 and normal Lp(a), niacin = no benefit.

21/21 Bonus question: Choose the correct answer

Niacin deficiency results in:

A- beriberi
B- pellagra
C- scurvy
D- pernicious anemia and neural tube defects