Potassium: Your Heart and Vasculature Will Love it! Meta-Analyses Show: Supplements Work, but Ain't Necessary

Foods, not supplements should be your go-to potassium source.

You've read about the importance of adequate potassium intakes and the lack of potassium (esp. in relation to sodium, where only 10% of the US adults meet the Na:K ratio the WHO recommends to reduce your overall mortality risk) in our diets at the SuppVersity, before (read more about potassium deficits). You've also learned that potassium supplements can be necessary during very low-calorie diets where they prevent the paradoxical induction of insulin resistance (read more about potassium and insulin resistance).

What you haven't read yet, however, is the number Tang et al. put on the effect of supplemental potassium on vascular function in their recent review and meta-analysis in the International Journal of Cardiology (Tang. 2016).

Learn more about potassium (K) in previous SuppVersity articles:

Potassium vs. Diet-Inducded Insulin Resis.

In the Lime Light: The Ill Effects of Low K Intakes

Bad News: Most Americans are Sign. K Deficient

Lean, Healthy ... Correlates of High Hair Potassium

Eeating a High Protein Diet? Better Watch K!

Potassium Bicarbonate = Anabolic!?

The scientists conducted a literature search on the PubMed database and included all articles that were published before April, 2016. As indices of vascular function, the researchers selected...

• the pulse wave velocity (PWV), which has a strong correlation with cardiovascular events and all-cause mortality (7.9x increased CVD death risk in Blacher et al. 1999a; 5.4x increased all-cause mortality risk in Blacher et al. 1999b; see also Cruickshank, 2002 and Laurent, 2001)
• the augmentation index (AI), which is a sensitive marker of arterial status and predictor of adverse cardiovascular events in a variety of patient populations, where a higher augmentation index is associated with target organ damage (Shimizu. 2008), 
• the pulse pressure (PP), which is the difference between the systolic and diastolic pressure readings and has been found to be associated w/ a significantly increased risk of cardiovascular disease and CV mortality (e.g. +20% with every 10 mm Hg increase in pulse pressure in Blacher et al. 2000),
• the flow mediated dilatation (FMD), of which a recent meta-analysis of Matsuzawa et al. (2015) shows that each meager 1% increase in FMD translates in a 12% reduction in predicted cardiovascular events,
• the glycerol trinitrate responses (GTN), which can tell you how effectively your arteries can relax when that's indicated, and
• the level of intercellular cell adhesion molecule-1 (ICAM-1), which is a soluble adhesion molecule and prediction of coronary heart disease that is associated with increased CHD risk (e.g. +68% in Malik et al. 2001 comparing the highest to lowest tertiles)

Data from all seven randomized controlled studies (409 patients in total) were pooled as standardized mean difference (SMD) with 95% confidence intervals. The dosage of potassium that was used in the studies ranged from 40 to 150 mmol/day (1.6-6g/day). The duration of the interventions was between 6 days and 12 months.

Figure 1: Forest plots of studies testing the effects of potassium supplementation on arterial stiffness: A. Pulse wave velocity (PWV); B. Augmentation index (AI); and C. Pulse pressure (PP). The results revealed a significant improvement in PP (p=0.010), but no improvement in PWV (p=0.391) and AI (p=0.184 | typos corrected in figure from Tang. 2016)

The results of the meta-analysis show benefits for all parameters of arterial stiffness, but a statistically significant effect only for one, but an important parameter: the pulse pressure (PP; Figure 1.C). From previous meta-analyses, we know that the overall effect on people's heart rate is only modest (potassium doses of 0.9–4.7 g/d for 2–24 weeks changed heart rate by 0.2 bpm according to Gijbers et al. 2016).

Figure 2: Forest plots of studies testing the effects of potassium supplementation on blood pressure: A. Systolic blood pressure (SBP); and B. Diastolic blood pressure (DBP). The results indicated a significant improvement in SBP (p=0.044), but no improvement in DBP (p=0.122 | typos corrected in figure from Tang. 2016

The effects on the subjects' systolic blood pressure which was also assessed by Tang et al. (2016), on the other hand, is quite significant (see Figure 2) and a logical mechanistic consequence of the improved vascular elasticity. Benefits for ICAM-1 and FMD exist, but don't reach statistical significance due to significant inter-study differences (data not shown).

Overall, the experimental evidence in favor of potassium supplementation is scarce and the "wide variation of evidences make it difficult to make a definitive conclusion" (Tang. 2016). 

That's in contrast to the epidemiological evidence, by the way. The latter, which describes the effect of high and low dietary potassium intake clearly indicates that high(er) potassium intakes are associated with a reduced risk of stroke (-24% | Aburto. 2013; 20% | D'Elia. 2014), and curvilinearly associated reduced risk of incident cardiovascular and all-cause mortality (e.g. O'Donnell. 2014 | see Figure 3).

Figure 3: Curvilinear association between urinary potassium, a good marker of your potassium balance with higher values being indicative of high intakes, and (A) risk of cardiovascular and (B) all-cause mortality (O'Donell. 2014). 

I guess I could keep enumerating studies, here, but in conjunction with previous articles about the beneficial effects of potassium you should have learned enough about this deficiency mineral to be incentivized to double-check your dietary intake and resort to potasium citrate or bicarbonate (check out what potassium bicarbonate may be able to do for your gains | "11% Increase in Type I Fiber Cross Sectional Area During 12 Weeks of KHCO3 Supplementation) in case you're coming short.

Highly Suggested Read: "Common Nutrient Deficiencies, Their Health Consequences and How You Can Fix Them - Part 1: Potassium Deficiency, Bone & Protein Loss, Stroke, Heart Disease & High Mortality" | learn more

So you suggest supplementing with potassium? No, I don't. Eventually, I will always recommend foods over supplements. With potassium this is all the more true, because the average potassium rich food will also make a beneficial contribution to your overall dietary quality. I mean, look at the next best TOP 10 foods list for potassium on the internet: (1) Avocado. 1 whole: 1068 mg (30% DV), (2) Spinach. 1 cup: 839mg (24% DV), (3) sweet potato. 1 medium: 952 mg (27% DV), (4) coconut water. 1 cup 600 mg (17% DV), (5) kefir or yogurt. 1 cup: 579 mg (15% DV); (6) white beans. ½ cup: 502 mg (15% DV); (7) banana. 1 large: 422 mg (12% DV); (8) acorn squash; (9) dried apricots
½ cup: 755 mg (22% DV), and (10) mushrooms 1 cup: 428 mg (27% DV | DV = recommended daily intake value).

All of the previously listed foods belong to the category of foods to eat more of if you want to improve your health and physique - and yes, by implication, this means that you should resort to supplements (best forms are citrate and bicarbonate for the added beneficial anti-acidosis effect only if you cannot get your optimal potassium intake of 5-6g/day from foods | Comment!

References:

• Aburto, Nancy J., et al. "Effect of increased potassium intake on cardiovascular risk factors and disease: systematic review and meta-analyses." (2013): f1378.
• Blacher, Jacques, et al. "Aortic pulse wave velocity as a marker of cardiovascular risk in hypertensive patients." Hypertension 33.5 (1999a): 1111-1117.
• Blacher, Jacques, et al. "Impact of aortic stiffness on survival in end-stage renal disease." Circulation 99.18 (1999b): 2434-2439.
• Blacher, Jacques, et al. "Pulse pressure not mean pressure determines cardiovascular risk in older hypertensive patients." Archives of internal medicine 160.8 (2000): 1085-1089.
• Cruickshank, Kennedy, et al. "Aortic pulse-wave velocity and its relationship to mortality in diabetes and glucose intolerance an integrated index of vascular function?." Circulation 106.16 (2002): 2085-2090.
• D'Elia, Lanfranco, et al. "Potassium-rich diet and risk of stroke: updated meta-analysis." Nutrition, Metabolism and Cardiovascular Diseases 24.6 (2014): 585-587.
• Gijsbers, L., et al. "Potassium supplementation and heart rate: A meta-analysis of randomized controlled trials." Nutrition, Metabolism and Cardiovascular Diseases (2016).
• Laurent, Stéphane, et al. "Aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in hypertensive patients." Hypertension 37.5 (2001): 1236-1241.
• Malik, Iqbal, et al. "Soluble adhesion molecules and prediction of coronary heart disease: a prospective study and meta-analysis." The Lancet 358.9286 (2001): 971-975.
• Matsuzawa, Yasushi, et al. "Prognostic Value of Flow‐Mediated Vasodilation in Brachial Artery and Fingertip Artery for Cardiovascular Events: A Systematic Review and Meta‐Analysis." Journal of the American Heart Association 4.11 (2015): e002270.
• Shimizu, Motohiro, and Kazuomi Kario. "Review: Role of the augmentation index in hypertension." Therapeutic advances in cardiovascular disease 2.1 (2008): 25-35.
• Tang, Xixiang, et al. "Effect of potassium supplementation on vascular function: A meta-analysis of randomized controlled trials." International Journal of Cardiology (2016).

Garlic & Red Yeast Rice: Manage Your Blood Lipids W/Out Statins - 12+1 Natural Alternatives Reviewed (Part I)

Red yeast rice is the "+1" in this SuppVersity Mini-Series because it is actually a "statin". Similar effects, similar side effects and all that (probably) because of the similar structure of its lipid lowering active ingredient(s).

"Twelve + 1"? I know that sounds odd, but I have my reason to single one of the natural alternatives, two scientists from the Chulalongkorn University in Thailand list in their 2016 review "A Review of the Efficacy, Safety, and Clinical Implications of Naturally Derived Dietary Supplements for Dyslipidemia", right from the start: red yeast rice (RYR).

While garlic, which will also be discussed in today's first installment of what is going to become a mini-series, also has the ability to decrease your HMG-CoA reductase activity, only RYR does that at a similar potency as statins do; which is why its use entails the risk of similar side effects as they have been reported for regular statin drugs Whether RYR is thus your best "natural alternative" is highly questionable.

All about cholesterol & related stories in previous SuppVersity articles:

Cholesterol Boosts Immunity

Eggs Promote Heart Health

All About Eggs (Focus on Yolk)

Silicon-Powered Anti-CVD Foods

Paleo Works W/ High Cholesterol

Coconut Oil to Control Chol.

On the other hand, the fact that the monacolins, the main bioactive compounds in RYR, is not debatable. Only recently, a meta-analysis by Li et al. (2014) reported no serious side effects and concluded based on 13 RCTs that "red yeast rice is an effective and relatively safe approach for dyslipidemia" (Li. 2014). Li et al. do yet also know that "further long-term, rigorously designed randomized controlled trials are still warranted before red yeast rice could be recommended to patients with dyslipidemia, especially as an alternative to statins" (Li. 2014).

Figure 1: Effects of 1,200mg/d red yeast rice (RYR) on blood lipids in statin-intolerant subjects (left | Venro. 2010) and subject-dependent reductions in LDL in the latest meta-analysis of the effects of RYR (right | Li. 2014).

If you are statin intolerant, however, Venro et al's study in 25 statin-intolerant subjects who received 1,200 mg RYR at bedtime, however, would suggest that you in particular could benefit from RYR as it appears to have a rather good tolerability in those subjects who cannot take regular statins.

Don't be a fool! This article is no statin or anti-cholesterol add. Nobody says that taking statins without a good reason would be wise. In fact, even the relatively well-tolerated RYR which works by the same mechanism, produced (albeit tolerable) muscle weakness and muscle pain as adverse effects in most clinical studies; a downside that points to the 'demusculizing' effects of HMG-CoA reductase inhibitors - even if the difference to placebo reached statistical significance only in few (albeit short-term) studies (Liu. 2006 & Li. 2014).

Further evidence that, as so often, individuality is key comes from the differential effects in European, Asian and US subjects (see Figure 1 showing data from Li. 2014). The latter, however, may be explained by both, the genetic configuration of the subjects, and the high ingredient variability of commercially available RYR preparations of which a comparative analysis of 10 commercial red yeast rice products reports a >30-fold range in total monacolin content. The authors of said study also highlight:

"Furthermore, compared with the full spectrum of monacolins expected in a red yeast rice dietary supplement, with monacolin K representing 55% to 60%, 4 of the 10 products were >90% monacolin K, suggesting that they were actually food-grade red yeast rice “spiked” with lovastatin, the prescription statin that is chemically identical to monacolin K" (Mark. 2010).

And Mark et al. are not the only ones reporting an intolerable degree of cutting in the snake oil industry. Similar results have been presented by Gordon et al. who tested 12 products that are regularly sold and consumed in the US and found total monacolin contents ranging from 0.31 to 11.15 mg/capsule. Just like Mark et al. Gordon et al. also found monacolin K (lovastatin | 0.10-10.09 mg/capsule), which could occur naturally, albeit not at very high doses, in many and the kidney-damaging citrinin in four of the twelve tested products (33%).

Garlic is a HMG-CoA inhibitor that doesn't have the problems of statins & RYR ...

...or, we simply don't know about them yet, because the currently available garlic supplements all suffer from the pathetic bioavailability of allicin (which is broken down enzymatically before it reaches your bloodstream | Lawson. 2001), which could - in very high doses that have not been tested in studies yet - possibly have similar negative side effects as the monocalins in RYR.

More recently, however, studies have suggested that allicin may not even be necessary for some of the beneficial effects of garlic. In particular, its general anti-oxidant and anti-inflammatory effects appear to be mediated mainly by S-allyl cysteine. Furthermore, "various chemical constituents in garlic products, including nonsulfur compounds such as saponins, may contribute to the essential biological activities of garlic" (Amagase. 2006) - including their anti-lipidemic effect.

I want to try it - What's the optimal dosing for garlic and RYR? While the evidence for the more powerful RYR is relatively conclusive and says that effective dosage(s) range from 600 and 3600 mg (depending on product quality and how significant your 'cholesterol-problem' is), reliable dosage suggestions are hard to make for garlic. In the previously cited recent review from Thailand (Thaipitakwong & Aramwit. 2016), the suggestion is 2–5 g of fresh garlic, 0.4–1.2 g of dried powder, 2–5 mg of oil and 300–1000 mg - "any other preparations should correspond to 4–12 mg of alliin or 2–5 mg of allicin" (ibid.). As previously pointed out, however, there's probably one study to refute the efficacy of real-food or supplemental garlic at the given dosages for every two studies that support it. Eventually, you will thus have to self-experiment to find out if and at which dosages garlic can exert a significant effect on your blood lipids.

In contrast to their active ingredient, however, the efficacy of garlic and garlic supplements as anti-hyperlipidemic drugs is well-established. One of the most cited meta-analyses (39 RCTs with 2298 participants | Ried. 2013) found that, overall, garlic consumption caused significant changes in serum levels of total cholesterol (–15.25 mg/dl; p < 0.0001), LDL-C (–6.41 mg/dl; p = 0.02), and HDL-C (1.49 mg/dl; p = 0.02), whereas the triglyceride levels appeared to be unaffected (I will address this in a follow-up, but if you eat your garlic with fatty fish, this should address the triglyceride issue). In addition, a more recent meta-analysis revealed that it will also reduce the level of lipoprotein (a) in the blood of hyperlipidemic subjects (Sahebkar. 2016).

Figure 2: Effects of garlic supplements on LDL (left, red) and HDL (right, green) according to a 2013 meta-analysis of  39 RCTs with 2298 participants (Ried. 2013) - the results have generally been confirmed more recently (Ried. 2016). 

Needless to say that, for garlic, just like RYR and any other drug or supplement, conflicting evidence exists. Early studies, for example, didn't report consistent effects on LDL and HDL. Whether that's due to different types (raw, powder, oil, and aged extract), processing and doses of garlic products used, or the subjects' baseline lipid levels and the study duration is something neither Thaipitakwong & Aramwit (2016), in their review, nor I can tell you due to the lack of studies that directly investigate the individual effects of these parameters. studies. The latter is also true for the bioavailability of raw garlic vs. supplements and the various types of 'garlic products' on the market. As the previously cited study from Thailand rightly concludes: the individual bioavailability simply has not been studied, yet (Thaipitakwong & Aramwit. 2016).

It should never be your goal to eradicate cholesterol. What you want is to control your levels within a rationale range that is probably much higher (esp. for total cholesterol) than the US recommendations to reap the benefits this essential hormone precursor and building block of your cells will have on endocrine, immune, muscle and brain function.

To be continued: If you miss the promised 11 'true' alternatives that won't mess with your HMG-CoA enzyme activity, I can reassure you, there will be a follow-up in which you can learn more about phytosterols, sesame, green tea, probiotics, fiber, chitosan, soy, flaxseed, guggul, krill and fish oil.

Until then, I would like to leave you with the conclusion that garlic is both, the less effective, and less side-effect prone natural alternative to statins. In contrast to red yeast rice, which is practically a "natural statin", it is yet able to control only "slightly elevated" (Ried. 2016) cholesterol levels; and not those you will see irrespective of your diet due to an inheritable genetic disposition and/or known or unknown pathologies (oftentimes one or several of the other components of the metabolic syndrome) | Comment!

References:

• Amagase, Harunobu. "Clarifying the real bioactive constituents of garlic." The Journal of nutrition 136.3 (2006): 716S-725S.
• Gordon, et al. "Marked variability of monacolin levels in commercial red yeast rice products." Arch Intern Med 170.19 (2010): 1722-1727.
• Lawson, Larry D., and Z. Jonathan Wang. "Low allicin release from garlic supplements: a major problem due to the sensitivities of alliinase activity." Journal of agricultural and food chemistry 49.5 (2001): 2592-2599.
• Li, Yinhua, et al. "A meta-analysis of red yeast rice: an effective and relatively safe alternative approach for dyslipidemia." PloS one 9.6 (2014): e98611.
• Liu, Jianping, et al. "Chinese red yeast rice (Monascus purpureus) for primary hyperlipidemia: a meta-analysis of randomized controlled trials." Chinese medicine 1.1 (2006): 1.
• Mark, David A. "All red yeast rice products are not created equal—or legal." The American journal of cardiology 106.3 (2010): 448.
• Venero, Carmelo V., et al. "Lipid-lowering efficacy of red yeast rice in a population intolerant to statins." The American journal of cardiology 105.5 (2010): 664-666.
• Sahebkar, Amirhossein, et al. "Effect of garlic on plasma lipoprotein (a) concentrations: A systematic review and meta-analysis of randomized controlled clinical trials." Nutrition 32.1 (2016): 33-40.
• Ried, Karin, Catherine Toben, and Peter Fakler. "Effect of garlic on serum lipids: an updated meta-analysis." Nutrition reviews 71.5 (2013): 282-299.
• Ried, Karin. "Garlic lowers blood pressure in hypertensive individuals, regulates serum cholesterol, and stimulates immunity: an updated meta-analysis and review." The Journal of nutrition 146.2 (2016): 389S-396S.