Vitality Unleashed: The Functional Medicine Podcast

How NAD+ Lowers Cholesterol—With or Without Statins

• Dr. Kumar from LifeWellMD.com • Season 1 • Episode 84

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Navigating the complex landscape of NAD+ precursors just got easier. We're cutting through scientific noise to examine a massive meta-analysis combining 40 clinical studies with nearly 15,000 participants that reveals surprising truths about these popular supplements and their effects on cholesterol.

NAD+ isn't just another molecule—it's an essential coenzyme powering countless processes throughout your body, particularly fatty acid and cholesterol metabolism. The precursors that help your body produce NAD+—nicotinamide riboside (NR), nicotinamide mononucleotide (NMN), nicotinic acid (NA), and nicotinamide (NAM)—have generated tremendous interest in health circles, but with wildly varying claims about their benefits.

Our deep dive reveals that while these precursors collectively improved lipid profiles (reducing triglycerides, total cholesterol, LDL, and increasing HDL), the benefits weren't universal. The most striking finding? NAD+ precursors showed minimal impact in healthy individuals but produced significant improvements in those with existing cardiovascular disease or dyslipidemia. Nicotinic acid (niacin) emerged as the clear frontrunner for lipid management, working through multiple pathways to improve cholesterol markers and demonstrating real clinical benefits including reduced cardiovascular mortality.

We also explore the potential tradeoff—a slight increase in blood glucose levels associated with some precursors—and the evolving research suggesting NAM might offer lipid benefits without this downside. Whether you're considering supplementation or simply fascinated by metabolic health, this evidence-based exploration provides crucial context for understanding how these molecules might fit into your health strategy. What role might supporting NAD+ levels play in your long-term wellness plan?

Disclaimer:
The information provided in this podcast is for educational purposes only and is not intended as medical advice. Always consult with a qualified healthcare professional before making changes to your supplement regimen or health routine. Individual needs and reactions vary, so it’s important to make informed decisions with the guidance of your physician.

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If you enjoyed today’s episode, be sure to subscribe, leave us a review, and share it with someone who might benefit. For more insights and updates, visit our website at Lifewellmd.com.

Stay Informed, Stay Healthy:
Remember, informed choices lead to better health. Until next time, be well and take care of yourself.

Speaker 1:

Welcome to the Deep Dive. You're here, I think, because you want to get right to the heart of what matters in health and wellness without wading through tons of information.

Speaker 2:

Exactly Cut through the noise.

Speaker 1:

Right. So today we're doing just that for NAD plus precursors, specifically how they might impact cholesterol and well your overall health.

Speaker 2:

And we've got a pretty solid basis for this discussion.

Speaker 1:

We do. We're looking at a big meta-analysis, one that combined results from 40 clinical studies. We're talking almost 15,000 people involved.

Speaker 2:

Yeah, that's Zhang and colleagues from 2022. They really dug into how these NAD plus precursors affect glucose and, importantly for today, lipid metabolism in humans.

Speaker 1:

So our goal, our mission for this deep dive is pretty clear let's understand what these precursors are, how they connect to cholesterol and you know what the actual science is telling us about potential benefits.

Speaker 2:

Let's break it down, make it make sense.

Speaker 1:

OK, so let's start right at the beginning. Nad plus DOH what is it? Why should our listeners really care about?

Speaker 2:

it Right NAD plus DOH. It stands for nicotinamide adenine dinucleotide. Bit of a mouthful.

Speaker 1:

Yeah.

Speaker 2:

But basically it's absolutely essential. Think of it as a tiny critical helper molecule involved in well countless processes that just keep your body running.

Speaker 1:

Processes like.

Speaker 2:

Oh, all sorts Redox reactions which are fundamental for energy transfer, directly involved in energy production, but also, crucially for today, fatty acid and cholesterol synthesis.

Speaker 1:

Ah, so the cholesterol connection is direct.

Speaker 2:

Very direct. It's also involved in other energy-related things like ATP generation that's your main cellular fuel gluconeogenesis, making glucose and even producing ketone bodies. It's really central to metabolism.

Speaker 1:

Okay, central. How does our body actually get this NAD plus man? Where does it come from?

Speaker 2:

Well, there are two main routes. You can make it from scratch, what's called de novo synthesis, using tryptophan and an amino acid. But the main way, the really primary sorts for maintaining levels is through what we call salvage pathways.

Speaker 1:

Salvage pathways like recycling.

Speaker 2:

Exactly like recycling, the body is really efficient at taking NAD plus precursors the building blocks and just reusing them to make fresh NAD plus egging. That's the dominant pathway.

Speaker 1:

Efficient recycling always good. Now the study. It also mentions sirtuins. How do they link up with NAD plus?

Speaker 2:

Ah, sirtuins. They're a really fascinating family of proteins, and the key thing is they depend on NAD plus to do their job. They absolutely need it to function, and what is their job exactly? They're like master regulators for a huge range of cellular functions. We're talking about things like managing inflammation, controlling cell growth, energy metabolism, how your body uses fuel.

Speaker 1:

Wow, okay.

Speaker 2:

Yeah, and even things like your circadian rhythm. You know your internal body clock, nerve function, aging processes.

Speaker 1:

That's a massive portfolio for one protein family.

Speaker 2:

It really is. They're also implicated in things like cancer development, obesity, insulin resistance, how your body handles stress. So you see, a lot of the biological effects we associate with NAD+ actually happen through these sirtuins.

Speaker 1:

So NAD plus enables the sirtuins to do all this important work.

Speaker 2:

Precisely and interestingly, the research we're looking at highlights one specific sirtuin SART6. Lower levels of SART6 have been linked to abnormal glucose and lipid metabolism problems handling sugar and fats.

Speaker 1:

Okay, that ties it all together nicely. Nad plus is crucial. Sirtuins need NAD plus cell and sirtuins help manage metabolism, including cholesterol, which brings us logically to NAD plus precursors. What exactly are these supplements?

Speaker 2:

Right. So the precursors are basically the raw ingredients your body uses in those salvage pathways to make more NAD plus cell.

Speaker 1:

The building block.

Speaker 2:

The building blocks exactly. The meta-analysis focused on four main ones that get studied a lot Nicotinamide riboside, or NR, nicotinamide mononucleotide NMN, nicotinic acid NA and nicotinamide NAM.

Speaker 1:

And the idea behind taking these as supplements is just boost your NAD plus levels. That's the core idea Provide more raw material hoping the body makes more NAD plus S, which might support all those NAD plus C dependent processes like the ones involving sirtuins, makes sense. So what did this big meta-analysis actually find? Did taking these precursors help with health markers, especially cholesterol?

Speaker 2:

Okay, so the overall results, when they pulled all the studies together, were pretty interesting. It showed that, generally speaking, taking NAD plus precursors was linked to significant reductions in triglycerides. Okay dude Total cholesterol and LDL cholesterol, the bad kind, Also good and on the flip side, it was linked to an increase in HDL, the good cholesterol.

Speaker 1:

So positive effects on lipids overall.

Speaker 2:

Yes, but there was a catch. The analysis also showed a tendency for these precursors as a group to slightly increase plasma glucose levels, blood sugar.

Speaker 1:

Ah, so a potential trade-off there Improvements in fats, but maybe a negative nudge on sugar.

Speaker 2:

Potentially. Yeah, it's something to be aware of from the overall picture.

Speaker 1:

Did all the precursors behave the same way, or were there differences between NR, na and NAM? Nmn wasn't studied right.

Speaker 2:

Correct. Nmn wasn't included in the trials they analyzed and, yes, there were differences when they looked at each one individually. Nicotinic acid or NA really stood out.

Speaker 1:

How so.

Speaker 2:

NA seemed to have the most significant positive effects across the board on lipid markers, triglycerides, total cholesterol, ldl and HDL. It also had an effect on plasma glucose consistent with the overall trend.

Speaker 1:

So NA was the heavy hitter in this analysis for lipids. What about the other two, NR and NAM?

Speaker 2:

Well for NR and NAM. This specific meta-analysis didn't find statistically significant improvements in human lipid metabolism. Based on the studies they included.

Speaker 1:

Okay, so maybe less effective.

Speaker 2:

Not necessarily. The researchers themselves pointed out something important. There just weren't that many studies included. For NR and NAM specifically, the number was quite limited.

Speaker 1:

Ah, so lack of evidence isn't necessarily evidence of lack of effect.

Speaker 2:

Exactly. You can't definitively say they don't work based on this analysis alone, because the data pool was smaller for them and actually, as we might discuss a bit later, particularly for NA, some newer research outside this meta-analysis is suggesting potential benefits for lipids.

Speaker 1:

Okay, good to know. Let's focus on nicotinic acid NA for a bit, then, since it showed such strong results here. This isn't some brand new discovery. Is it NA or niacin?

Speaker 2:

Oh, absolutely not. Niacin has been around for a long time. It has a well-established role in managing dyslipidemia that's just unhealthy lipid levels and even in treating atherosclerotic cardiovascular disease.

Speaker 1:

The plaque buildup in arteries.

Speaker 2:

Right. It's known for lowering total cholesterol, triglycerides, ldl and, importantly, forin HDL.

Speaker 1:

And does that translate to actual health outcomes, not just better numbers?

Speaker 2:

Yes, absolutely. There are clinical trials showing that niacin therapy can actually reduce overall mortality, the risk of dying from cardiovascular diseases, and it can slow down the progression of atherosclerosis itself. So real, meaningful benefits.

Speaker 1:

That's significant. How does it work? What's the mechanism behind these cholesterol effects?

Speaker 2:

It seems to work through a few different routes. One key way is by promoting the breakdown of a protein called ApoB inside liver cells. Apob yeah, apob is a major structural protein in LDL cholesterol and other lipoproteins that can contribute to plaque buildup. Niacin seems to inhibit the liver's production of triglycerides the fats which in turn leads to more ApoB getting broken down.

Speaker 1:

Okay, so less triglyceride production means less packaging for these bad cholesterol particles.

Speaker 2:

That's part of it, yes, and it also seems to increase the degradation, the breakdown, of the ApoB protein itself. Another mechanism involves fat tissue. How so Niacin can reduce the activity of an enzyme in fat cells that releases fatty acids into the bloodstream, so fewer free fatty acids travel to the liver.

Speaker 1:

And less fuel for the liver to make triglycerides.

Speaker 2:

Exactly. Less fatty acid uptake by the liver means less triglyceride synthesis and, ultimately, less secretion of VLDL, which turns into LDL.

Speaker 1:

So it's hitting the supply line from fat tissue too.

Speaker 2:

Right, and there's even evidence. It directly inhibits a key enzyme within the liver that's crucial for making triglycerides, an enzyme called DGAT2. So it's working on multiple levels within the liver and related tissues.

Speaker 1:

Sounds really effective.

Speaker 2:

Right.

Speaker 1:

I feel like there's a but coming. Yeah, I seem to recall a common issue with niacin.

Speaker 2:

You're right. There is a well-known side effect. Especially at the doses needed for significant cholesterol effects, usually above 50 milligrams a day, it's flushing.

Speaker 1:

Ah, the niacin flush.

Speaker 2:

Yeah, that temporary redness, feeling of warmth, sometimes itching. It's generally harmless but it can be quite uncomfortable for people. Definitely something to be aware of with NA.

Speaker 1:

Okay, Now let's switch gears to nicotinamide riboside NR. It seems like this one gets a lot of buzz lately. What did the meta-analysis say about it again?

Speaker 2:

Well, as we mentioned, this specific analysis didn't find a statistically significant effect from NR on lipids in the human studies they looked at. But it's important context that NR is a naturally occurring form of vitamin B3, and it's definitely an NAD plus precursor, and animal studies have actually been quite promising.

Speaker 1:

What do they show in animals?

Speaker 2:

In rodent models, nr supplementation has been shown to improve glucose tolerance, how well they handle sugar and reduce various metabolic problems. So positive signs in animals.

Speaker 1:

Any hints of that in humans, even if not statistically significant in this particular analysis.

Speaker 2:

There is some other human research. Yes, suggesting NR might improve lipid metabolism. One potential way is by activating those sirtuin proteins we talked about earlier.

Speaker 1:

The NAD plus 2 dependent regulators.

Speaker 2:

Exactly. Sirtuins play roles in fat and sugar metabolism, so activating them could theoretically help. But the bottom line, as the meta-analysis authors noted, is that while NR seems pretty good at boosting NAD plus in animals, the human clinical trial data on its metabolic effects, especially lipids, is still relatively limited.

Speaker 1:

Some more research needed for NR in humans.

Speaker 2:

Definitely we need more robust human studies to really pin down its effects.

Speaker 1:

Okay, what about the last one, nicotinamide or NM you mentioned? It's related to NA, but different.

Speaker 2:

Yes, structurally similar but functionally distinct. Nm doesn't typically cause that flushing effect like NA does.

Speaker 1:

Okay, that's one difference.

Speaker 2:

And clinically it's often used for a specific purpose in dialysis patients to help manage high phosphate levels.

Speaker 1:

Interesting and its effect on lipids. You said earlier studies weren't that impressive.

Speaker 2:

Right. Historically, anacalia wasn't thought to have much impact on lipid metabolism. That was the general view reflected in some of the older studies possibly included in the meta-analysis baseline.

Speaker 1:

But you also hinted, there might be newer findings.

Speaker 2:

Yes, and this is where it gets interesting. While this meta-analysis didn't show a significant effect based on its included studies, some more recent research, particularly in hemodialysis patients, has shown that no M supplementation could actually improve blood lipid profile.

Speaker 1:

Improve lipids in dialysis patients.

Speaker 2:

Yes, lowering things like triglycerides or cholesterol and, crucially, these improvements were seen without causing an increase in blood glucose levels, which is a potential concern with NA and maybe the precursors.

Speaker 1:

Overall, so NA might offer lipid benefits without the blood sugar downside, at least in that specific group.

Speaker 2:

It's suggestive. Yeah, the mechanisms aren't fully clear yet, but these newer findings indicate NA might have some clinical promise for lipids, perhaps in specific situations. That wasn't apparent before.

Speaker 1:

So again, the science seems to be evolving, especially for NR and NA.

Speaker 2:

Very much so. It's an active area of research.

Speaker 1:

Now something you touched on earlier who actually benefits most? Did the meta-analysis look into different groups of people?

Speaker 2:

Yes, they did a subgroup analysis and this was a really key finding, I think.

Speaker 1:

What did it show?

Speaker 2:

It strongly suggested that NAD plus precursor supplementation didn't really move the needle much on lipid markers for people who are already healthy.

Speaker 1:

So if your cholesterol is fine, these might not do much for it.

Speaker 2:

Based on this analysis for lipid markers specifically, that seems to be the case. However, the story changed completely when they looked at patients with existing cardiovascular disease or dyslipidemia.

Speaker 1:

People who already have heart problems or abnormal lipid levels.

Speaker 2:

Exactly In those groups. The supplementation did show significant benefits, improving those lipid markers like triglycerides and cholesterol.

Speaker 1:

That makes a lot of sense. Actually, it suggests a more targeted effect, helping to correct existing imbalances, rather than being a general booster for everyone, at least for lipids.

Speaker 2:

Precisely. It really highlights that the potential benefit likely depends on your baseline health status.

Speaker 1:

Of course, no study, especially a meta-analysis combining different studies is perfect.

Speaker 2:

What were some of the limitations or things we should keep in mind about this research?

Speaker 1:

Good point. There were definitely a few factors. One is just the variability between the included studies. How so Well they use different doses of the precursors. Some studies combine the supplement with lifestyle changes like diet or exercise, or even with drugs like statins. Others looked at the precursor alone. That mix makes it harder to isolate the effect of just the precursor.

Speaker 2:

Yeah, lots of moving parts.

Speaker 1:

Another thing is they only included studies published in English, so potentially relevant research in other languages might have been missed.

Speaker 2:

A common limitation in these types of reviews. It is Also. The sample sizes of the individual studies varied quite a bit from small trials to larger ones. That kind of variation or heterogeneity can influence the overall pooled results Okay.

Speaker 1:

Anything else.

Speaker 2:

Just one more technical point. The researchers noted that different studies sometimes reported the biochemical results like cholesterol levels using different units. That adds a layer of complexity when trying to combine and analyze all the data accurately.

Speaker 1:

So while this meta-analysis gives us a really valuable big picture view, it sounds like the researchers themselves would say we still need more high-quality studies.

Speaker 2:

Absolutely. That was a clear conclusion. More research is needed to confirm these findings, to really clarify the specific effects of each different precursor NR, nam, na and figure out optimal doses, who benefits most and, importantly, the long-term effects.

Speaker 1:

Right, so let's try to wrap this up Based on our deep dive today. What are the key takeaways?

Speaker 2:

Okay, I'd say first NAD plus precursors, especially nicotinic acid, based on this large analysis, do show real promise for improving cholesterol and triglyceride levels.

Speaker 1:

But mainly in certain people.

Speaker 2:

Right, Particularly in individuals who already have cardiovascular disease or diagnosed dyslipidemia. The benefit seems less clear for generally healthy folks regarding lipids.

Speaker 1:

And we need to remember the potential impact on blood sugar.

Speaker 2:

Yes, that's the caveat. The overall trend suggested a possible increase in glucose, although recent NM studies hint it might avoid this issue in some cases. Definitely something to monitor.

Speaker 1:

What about NR and NM?

Speaker 2:

For NR and NM. This meta-analysis didn't show significant lipid effects, but that might be due to limited data for NR and for NM. Newer studies are actually suggesting potential benefits, so their story isn't fully written yet. More research is clearly needed for both.

Speaker 1:

A complex picture, but clearer than before, I think.

Speaker 2:

Hopefully. Yes, it gives a framework for understanding where the science currently stands.

Speaker 1:

Okay, so that leads us to our final thought. For everyone listening today, we know NAD plus is absolutely vital. We see these precursors have potential, particularly NA, but also maybe NAR and NAM down the line, especially for certain people. So the question to ponder is what are the bigger long-term implications of actively supporting healthy NAD plus levels throughout life, and what new questions does this raise for research and maybe even for your own personal health strategy?

Speaker 2:

Definitely food for thought. How do we best maintain this crucial molecule as we age?

Speaker 1:

Exactly Something to keep thinking about. Thanks for joining us for this deep dive.