Primary Care Corner with Geoffrey Modest MD: Uric Acid Lowering Cardiovasc Benefit, And An Evolutionary Perspective

By Dr. Geoffrey Modest

  1. There have been a slew of articles over the years either implicating or exonerating uric acid as a cardiovascular risk factor. Some studies have found it to be an independent risk factor, and some have suggested that its role was through its association with metabolic syndrome/diabetes, obesity, hypertension, endothelial dysfunction, oxidative stress and/or low-level chronic inflammation. A recent observational study from Taiwan strongly supports a more direct relationship between uric acid and cardiovascular disease (CVD), with amelioration by uric acid lowering agents (see J Rheumatol 2015; 42: 1694)​.
  • Results:
    • Patients with gout not treated with ULT vs controls had increased CVD mortality [HR 2.43 (1.33-4.45)] and all-cause mortality [HR 1.45 (1.05-2.00)]
    • Patients with gout treated with ULT vs those with gout not treated by ULT had strikingly decreasedCVD mortality [HR 0.29 (0.11-0.80)] and all-cause mortality [HR 0.47 (0.29-0.79)]​
    • Overall, there was no significant difference between survival in patients with gout but on ULT, and the reference group without gout
    • ​Results were independent of whether allopurinol or benzbromarone was used
  • Assessed:
    • Mortality rates compared 1189 patients with gout who did not receive ULT vs those with neither gout nor ULT (matched for age, sex)
    • Mortality rates compared 764 patients with gout who received ULT vs 764 patients with gout who did not receive ULT
  • Details:
    • 40,623 adults (mean age 50, 62% male, BP 128/76, chol/HDL=200/44, eGFR 75, BMI 24, 10% daily drinkers, 10% daily smokers) in prospective case-matched cohort study, followed 6.5 years
    • Gout was treated with uric acid lowering therapy (ULT) with either allopurinol or benzbromarone (a potent uricosuric med which was withdrawn from the market because of serious hepatotoxicity, though was still used in some countries – esp. in Asia where HLA-B*5801 haplotypes are common, which are associated with allopurinol hypersensitivity reactions)
    • Baseline uric acid levels were: those with gout on ULT was 8.1 and those with gout not on ULT was 6.5, and for non-gout reference patients was 5.7. It is not clear what the achieved uric acid level was with meds (the article and the supplementary tables are remarkably opaque. not sure what the on-therapy uric acid numbers are).

2. An interesting article was just published in Scientific American on “The Fat Gene” which implicates uric acid in obesity, diabetes, hypertension… (see​). Their argument is as follows:

  • Over the past 50 years, the “thrifty gene” hypothesis has been in and out of vogue, the hypothesis being that in times of food shortage there was a selection bias to a genetic variant which made the body more efficient in handling food, with increased storage of food as fat to be used in times of scarcity, but then leading to obesity in our modern era of high caloric processed food being plentiful and a more sedentary lifestyle. However, there was a lack of evidence of prolonged periods of human starvation
  • But, more recent data has suggested that in fact there were significant changes in food availability and starvation of great apes in global cooling periods around 10-20 million years ago
  • These authors hypothesize that the genetic change in great apes and humans was a nonfunctional mutation of the uricase enzyme, which seems to have occurred at about this same time period (and suggests that great apes and humans had a common ancestor)
  • Consistent with this, humans (even those with non-Western habits) and great apes do have higher uric acid levels than other animals, though uric acid levels are much higher in humans with Western diets and sedentary habits
  • Early animal studies (rats) found that blocking uricase activity led to hypertension, and lowering the uric acid decreased the blood pressure
  • There are also several human studies. Uric acid levels in obese adolescents with newly diagnosed hypertension are high, 90% in one study. 30 individuals who had new hypertension and uric acid >6 mg/dl in a double-blind, placebo controlled crossover trial were treated with allopurinol 200mg bid vs placebo for 4 weeks and had significant decreases in blood pressure, with 20 of the 30 achieving normal blood pressure on allopurinol vs 1 while on placebo (see JAMA 2008; 3000(8): 924). These same authors wrote a longer treatise in NEJM, presenting lots of data suggesting that hyperuricemia is a cause of hypertension, animal studies finding that uric acid can cause microvascular renal disease independent of hypertension, hyperuricemia precedes and seems to be related to development of the metabolic syndrome (animal studies show that decreasing uric acid levels can prevent or reverse the metabolic syndrome), and that in humans, part of the cardioprotection of losartan in the LIFE study and atorvastatin in the GREACE study​ is related to their ability to lower uric acid levels (see N Engl J Med 2008; 359: 1811 for a pretty exhaustive/exhausting review of the data).
  • Fructose, largely from fruits and honey (and now often from high-fructose corn syrup!!) does a few things:
    • It is the only sugar which is metabolized to form uric acid
    • In animals, it is associated with increased appetite and fat accumulation (fructose blunts the effects of leptin, a hormone which decreases appetite)
  • So, the proposed mechanism evolutionarily is: eating fructose, mostly from fruits (which many hibernating animals do prior to hibernation) leads to more fat deposition, and in animals with non-functioning uricase (which they think is the “Fat Gene”), leads to higher uric acid levels. These increasing uric acid levels provide an evolutionary advantage in times of starvation (adding to the effect of the fructose itself), resulting in an insulin resistant state, which decreases immediate energy production and leads to more accumulated fat for future energy, and also by increasing the blood sugar, giving the brain more glucose for its function in times of food scarcity. And there are some animal data suggesting that the main culprit may be the uric acid produced by the fructose: giving the animals a high-fructose diet and also allopurinol blocks many of the features of the metabolic syndrome.​

So, it seems from the above studies that there really is a plausible role of uric acid per se playing a major part in our current prevalent issues of obesity, metabolic syndrome/diabetes, hypertension, and cardiovascular disease. Of concern, average daily intake of fructose has doubled in past 30 years, with adolescents consuming 73 grams/d (12% of their caloric intake). There is a linear trend of increasing fructose consumption and decreasing HDL levels and increasing triglycerides. Small studies and the above Taiwan observational study support the efficacy of lowering uric acid levels. But, it really would be helpful to have a large clinical trial testing the clinical efficacy of lowering uric acid levels.  Then we might target lowering uric acid levels themselves, even without gout or the various uric acid-related nephropathies. The first approach would be to limit fructose and especially high-fructose corn syrup from the diet. My experience over the past couple of years confirms that just by eliminating sodas (high in high-fructose corn syrup), there is a significant decrease in serum uric acid levels (I just saw a patient whose uric acid went from 8.5 to 6.9 by eliminating sodas). And, in general promoting a healthy lifestyle with more exercise and more freshly prepared foods.

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