Fibrates may Cause an Abnormal Urinary Betaine Loss Which is Associated with Elevations in Plasma Homocysteine

Biochemistry Unit, Canterbury Health Laboratories, P.O. Box 151, Christchurch, 8140, New Zealand.
Cardiovascular Drugs and Therapy (Impact Factor: 3.19). 08/2009; 23(5):395-401. DOI: 10.1007/s10557-009-6188-1
Source: PubMed


Betaine is an osmolyte, supplies methyl groups, and controls plasma homocysteine. Abnormal urinary loss of betaine is common in patients with the metabolic syndrome or diabetes mellitus. These patients are often treated with fibrates which alter renal function and raise plasma homocysteine concentrations. We suggest there is a connection between fibrate treatment and betaine excretion.
We identified 32 fibrate-treated patients in several studies (total of 740 subjects) and compared the betaine excretion by these with the excretion by other patients, both in the separate studies and in the combined group. We investigated the correlation of betaine excretion with homocysteine in these groups.
Patients taking bezafibrate had higher betaine excretion than patients not taking fibrates, p < 0.00001 in some studies with n < 10. Of 32 patients taking bezafibrate, 20 had abnormal (>97.5 %-ile) betaine excretion. Plasma homocysteine correlated positively with betaine excretion in male patients with lipid disorders who were not taking fibrate (n = 68, p = 0.043), but the relationship was stronger if patients taking bezafibrate were included (n = 76, p < 0.00001). In elderly (>65 years) subjects with hypertension there was a similar correlation (n = 19, p = 0.047), which was stronger when a subject taking bezafibrate was included (n = 20, p = 0.013).
Abnormal betaine excretion is common in patients treated with bezafibrate. Bezafibrate appears to exacerbate betaine loss, which will cause a rise in plasma homocysteine. Betaine supplementation could be considered in conjunction with fibrate therapy.

52 Reads
  • Source
    • "The urinary betaine excretion, measured as the ratio to creatinine, is potentially more useful; as well as the abnormally high betaine excretion in diabetes and the metabolic syndrome, high excretion is common in chronic renal failure patients without diabetes, and interestingly, an abnormally low betaine excretion is also found in some patients with diabetes or with chronic renal failure, though so far the clinical significance of this is unknown. Fibrate therapy causes elevated excretions [108], especially in patients with features of the metabolic syndrome. Abnormal betaine excretions are often persistent for years [110]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Betaine is an essential osmolyte and source of methyl groups and comes from either the diet or by the oxidation of choline. Its metabolism methylates homocysteine to methionine, also producing N,N-dimethylglycine. Betaine insufficiency is associated with the metabolic syndrome, lipid disorders and diabetes, and may have a role in vascular and other diseases. Betaine is important in development, from the pre-implantation embryo to infancy. Betaine supplementation improves animal and poultry health, but the effect of long-term supplementation on humans is not known, though reports that it improves athletic performance will stimulate further studies. Subsets of the population that may benefit from betaine supplementation could be identified by the laboratory, in particular those who excessively lose betaine through the urine.Plasma betaine is highly individual, in women typically 20–60 μmol/L and in men 25–75 μmol/L. Plasma dimethylglycine is typically < 10 μmol/L. Urine betaine excretion is minimal, even following a large betaine dose. It is constant, highly individual and normally < 35 mmol/mole creatinine. The preferred method of betaine measurement is by LC-MS/MS, which is rapid and capable of automation. Slower HPLC methods give comparable results. Proton NMR spectrometry is another option but caution is needed to avoid confusion with trimethylamine-N-oxide.
    Clinical biochemistry 06/2010; 43(9-43):732-744. DOI:10.1016/j.clinbiochem.2010.03.009 · 2.28 Impact Factor
  • Source

    Cardiovascular Drugs and Therapy 10/2009; 23(5):341-2. DOI:10.1007/s10557-009-6201-8 · 3.19 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Fibrates or PPAR alpha agonists, in particular fenofibrate, are known to increase homocysteine levels (Hcy). A 3 to 5 micromol/L increase in Hcy is commonly observed within the first few weeks of fenofibrate treatment; it then persists in plateau when treatment is continued and is reversible upon its cessation. Since its description in 1999, this pharmacological effect attracted a great deal of attention as epidemiological studies in most populations have shown that elevated Hcy levels i.e.Hcy> or =15 micromol/L are associated with an increased risk of cardiovascular events (CVD), venous thromboembolic events (VTE) and possibly cognitive disorders and bone fractures. Chronic kidney disease is also associated with elevated Hcy levels and since fenofibrate increases creatinine levels by about 10-12 micromol/L, a relationship between Hcy and creatinine was postulated. Animal studies have shown that the Hcy increase is PPARalpha dependent but to date animal or human studies have not provided a clear mechanism. In particular, fenofibrate treatment does not change vitamin B levels; however, vitamin B supplements reduce fenofibrate-induced Hcy elevation but not the concomitant cysteine elevation. Similarly, the increase in creatinine with fenofibrate only partially accounted for by a reduction in glomerular filtration rate (GFR) since creatinine production is also increased by 5-10%. In the FIELD study, a placebo-controlled study in 9795 patients with type 2 diabetes, fenofibrate over 5 years reduced non-fatal cardiovascular events and microvascular events such as albuminuria, the need for laser treatment for proliferative retinopathy or maculopathy and amputations but did not reduce fatal events. The increase in Hcy was indeed much larger that what would be explained by creatinine elevation and independent from baseline kidney function. Although baseline Hcy and creatinine levels were associated with subsequent risk of CVD, as suggested by epidemiology, their respective elevation was not. Of interest, after withdrawal of fenofibrate, a potential renoprotective effect was unmasked, as estimated GFR was 5 ml/min/1.73 m2 higher in previous fenofibrate-allocated patients than in previous placebo-allocated patients. There was no suggestion that Hcy elevation was associated with VTE (which were increased by an unknown mechanism) or bone disorders. In conclusion, the discrepancy between the role of baseline Hcy levels in epidemiology and the absence of effect when altering its levels by either decreasing them with vitamin B supplements or increasing them with fenofibrate, suggests that the risk factor(s) behind homocysteine should be found. Nevertheless, other studies are also needed to understand the mechanism and the implications of the moderate homocysteine and creatinine elevations with fenofibrate and other PPARalpha agonists.
    Current Vascular Pharmacology 09/2010; 8(5):589-603. DOI:10.2174/157016110792006987 · 2.97 Impact Factor
Show more