B Vitamins in Diabetes: Just “Expensive Urine”?
....one of the most controversial... questions... is the issue of the importance of homocysteine in cardiovascular health.
In Part 1 of this article series, we discussed the topic of B vitamins in diabetes, including some of the relevant clinical research evaluating B vitamins in the treatment of various concerns in diabetes. Yet one of the most controversial, and still unresolved, questions regarding B vitamins in diabetes, and more broadly in cardiovascular disease, is the issue of the importance of homocysteine in cardiovascular health. In this article, I will provide some background on homocysteine, including why the medical community thought is was of concern, and then following the progression of our knowledge on homocysteine to the present, where the danger of homocysteine is being challenged. In addition, I will write briefly about special clinical considerations for B vitamins in diabetes.
What the Heck is Homocysteine Anyway?
Homocysteine is a by-product of our metabolism of sulphur-containing amino acids (amino acids strung together in various combinations form proteins- which we eat!). Homocysteine is converted to methionine (another amino acid) and back again; it is also converted to cysteine (yet another amino acid) by a separate process. The conversion of homocysteine to methionine requires vitamins B12 and folic acid, while the conversion of homocysteine to cysteine requires vitamin B6.
Homocysteine is a by-product of our metabolism of sulphur-containing amino acids...
This process is important for several reasons; it serves a role in the interconversion between different forms of folic acid, each with specific jobs; it assists in the availability of specific amino acids, namely cysteine and methionine, which have biologic functions of their own; and some methionine gets converted to S-adenosylmethionine (SAMe) which serves as an important intermediate (methyl group donation) in numerous biologic processes including detoxification in the liver.
Is Homocysteine Dangerous?
The short answer is, we don’t really know. As is usually the case in medical research, we are limited by the answers different types of research methodology are able to give us, and by the studies that have been performed. Specifically, many times in medicine “risk factors” are identified based on following large groups of people for long periods of time and waiting for them to get sick. Studying people in large groups like this allows epidemiologists to look for exposures that increase risk. A key limitation of this type of research is that observational studies cannot say a risk factor causes disease, only that the risk factor is associated with the disease. This limitation occurs because although researchers try to control for other possible contributors (or confounders) to any observed change in risk, no one study can control for all confounders. In some cases, these risk factors stick around and in some cases they do not. Although it may sound like a waste of time to do this type of observation study, they spawn hypotheses to be tested in clinical trials. Clinical trials, when properly designed, do not suffer from the same influence of confounding. Confounding is controlled in clinical trials by “placebo-controlling” trials and by randomization. For this reason, only clinical trials can determine causality.
Findings suggesting homocysteine was associated with harm to the heart were further supported in 1998 by a study by researchers Wald et al.
Now back to homocysteine. Back in the 1990s, several epidemiologists published papers on the risk of heart attack (myocardial infarction) relative to homocysteine levels. Stampfer et al. published a study demonstrating a greater than 3-fold increased risk of heart attacks in males with elevated homocysteine levels. Supporting these findings was a published report by Verhoef et al. in the American Journal of Epidemiology based on research in the Netherlands showing an 11% increase in risk of heart attack from elevated homocysteine, and the risk seemed to increase as the level of homocysteine increased, i.e. there was graded risk.
Findings suggesting homocysteine was associated with harm to the heart were further supported in 1998 by a study by researchers Wald et al. studying homocysteine in over 1300 men in the United Kingdon; this study showed men with the highest levels of homocysteine had 3.7 times the risk of developing ischemic heart disease compared to those with lower levels. Wald et al. also reported that the risk seemed to increase by 41% for every 5 umol/L increase of homocysteine in the blood. These researchers went out on a limb in their study and said, because the associations seemed so strong, that elevated homocysteine appeared causal.
The story continues in 1999 (although many other papers were published during 1997-1999 adding further support to the “homocysteine hypothesis”) when research was published evaluating homocysteine and risk of death in 1933 elderly participants in the Framingham cohort (the Framingham cohort study followed - and still follows - thousands of American men and women in order to determine risk factors for cardiovascular disease; Framingham remains important in determining risk factor reduction guidelines). The study, published by Bostom et al. in the Archives of Internal Medicine, reported over a doubling of risk of cardiovascular death and all-cause death from homocystiene levels greater than 14.26 umol/L.
By the 2000s, enough observational data was accumulating showing that homocysteine was associated with an increased risk of heart disease and death that researchers began pooling this data together, performing meta-analyses. In 2002, the Homocysteine Studies Collaboration published their meta-analysis in the Journal of the American Medical Association showing an 11% reduced risk for ischemic heart disease and a 19% reduced risk for stroke by lowering homocysteine levels 3 umol/L.
In addition to these (and many other) observational studies, animal and bench researchers discovered many possible mechanisms for the observed increase in risk. Included in the probable mechanisms were:
increased endothelial dysfunction (the endothelium is the innermost lining of arteries and serves an important role in responding to chemical signals to dilate or constrict to regulate blood flow)
increased smooth muscle cell proliferation (smooth muscle cells are in the middle of our larger arteries and therefore proliferation of these cells contribute to reduced blood flow)
increased pro-clotting factors and reduced anti-clotting factors in the blood
All of this data fueled the fire for the “homocysteine hypothesis”. Everyone loved homocysteine. Cardiologists loved it because it was something else to measure and easy to treat. Complementary medicine providers loved it because there was finally a strong case for extra B vitamins in the diet, typically through supplements. The public loved it because it supported theories of reduced quality in the food supply. Everyone was happy.
The primary question... was: will lowering homocysteine after first heart attack reduce the risk of having a second heart attack? or reduce the risk of death?
All of this data also fueled the development of clinical trials - the necessary step to determine causality. In 2004, The Vitamin Intervention for Stroke Prevention (VISP) trial was published in the Journal of the American Medical Association. This trial randomized 3680 adults with history of stroke to receive either high (5 mg of B6, 0.4 mg of B12, and 2.5 mg of folic acid) or low (200 micrograms of B6, 6 micrograms of B12 and 20 micrograms of folic acid) dose B vitamins for 2 years. The outcomes of interest were recurrent stroke and death. The results of the study showed that B vitamins do reduce homocysteine (with the high dose arm ending up with lower levels than the low dose group), however the study did not find any reduction in risk of second stroke or for death. The study did still see a baseline association between high homocysteine levels and risk of recurrent stroke and death. These findings suggested 2 years was not long enough to reduce stroke risk by lowering homocysteine.
Following the VISP trial, was the NORVIT trial which randomized 3749 men and women with history of heart attack to one of four arms: 0.8 mg of folic acid, 0.4 mg of B12, and 40 mg of B6; 0.8 mg of folic acid and 0.4 mg of B12; 40 mg of B6; or placebo. The primary question in this trial was: will lowering homocysteine after first heart attack reduce the risk of having a second heart attack? or reduce the risk of death? Disappointingly, the NORVIT trial also produced negative findings, there seemed to be no beneficial effect of B vitamin supplementation to lower homocysteine on risk of second heart attack or death. Alarmingly, the arm of the NORVIT trial that received folic acid, B12 and B6 seemed to have an increased risk of second heart attack!
Alarmingly, the arm of the NORVIT trial that received folic acid, B12 and B6 seemed to have an increased risk of second heart attack!
The findings of the homocysteine-lowering elements of the HOPE2 study were also published in 2006 in the New England Journal of Medicine. HOPE2 randomly assigned 5522 men and women with known vascular disease to 2.5 mg of folic acid, 50 mg of vitamin B6, and 1 mg of vitamin B12 or with placebo for an average of five years. The primary aim of the study was to determine if lowering homocysteine reduced the risk of heart attack, stroke or risk of death during the study. The findings of the HOPE2 study similarly showed no benefit for death or cardiac event. The study did show a 25% reduced risk for stroke, however it also showed a 24% increase in risk for unstable angina, a significant risk factor for heart attack.
The data to date still suggests lowering homocysteine has some benefit on reducing the risk for stroke.
Obviously there is unsettled business surrounding the issue of homocysteine and the risk of vascular disease. The data to date still suggests lowering homocysteine has some benefit on reducing the risk for stroke. However, what is still not clear is whether assessing and treating homocysteine in patients with or without known heart disease does any good in reducing their risk for cardiovascular events (ischemic heart disease, heart attack, heart-related death). There are still unanswered questions regarding homocysteine, including time. Does lowering homocysteine levels for longer periods of time reduce risk, i.e. does preventing homocysteine elevation reduce risk? How long is necessary before benefits are seen? Do extra B vitamins cause cardiovascular harm - or was this finding an anomaly? We’ll have to wait and see.
What do I do about Homocysteine?
I must admit, I have been less aggressive in my approach to homocysteine lowering since the NORVIT and HOPE2 trials were released last year. However I do think homocysteine is still worth checking and treating in patients with diabetes. We know people with diabetes have an increased risk for stroke, and to date the data seem to suggest treating elevated homocysteine is still protective. My rules of thumb are to lower homocysteine down to less than 10-12 umol/L whenever possible, ideally through dietary B vitamins.
When Do I Recommend Extra Supplemental B Vitamins?
Megaloblastic Anemia - Deficiencies of either folic acid or vitamin B12 can cause a characteristic anemia. “Anemia” is a category of conditions that all have a reduced ability to deliver oxygen in the body, often due to changes in red blood cell number or oxygen saturation. The anemia resulting from deficiencies of vitamin B12 and/or folic acid is characterized by larger than normal red blood cells, or megaloblasts. Your physician can check for this type of anemia by checking for simple characteristics in your blood.
Neuropathy - As discussed in Part 1, patients with diabetes who experience reduced sensation or have known nerve complications of their diabetes often benefit from vitamin B12 treatment.
Special Considerations with Metformin - Metformin is one of the first line medications for the treatment of diabetes. However, a small percentage (estimates vary) of patients can end up with deficiencies of vitamin B12 and elevations in homocysteine.
Thiamine vs. Benfotiamine (See Part 1) - The safety of benfotiamine is still too unknown in my opinion. If you have reason to suspect thiamine deficiency, discuss testing and trial treatment with your physician care provider.
B vitamins have vital functions in human health that may be disrupted in conditions like diabetes. Although some clinical trials suggest benefit, the consumption of large (much larger than diet) doses of nutrients should always be discussed with your physician. In the meantime, enjoying fresh vegetable foods that are rich in these nutrients is a sure bet to health improvement/risk reduction in cardiovascular disease and diabetes. Until more research steers me otherwise, I will continue checking and discussing homocysteine in an effort to assist in the optimal health of my patients.Part 1 >>
Ryan Bradley, ND, MPH is a naturopathic doctor, clinical researcher and epidemiologist in San Diego, CA. He is an Associate Professor and Assistant Director of Research at the National University of Natural Medicine in Portland, OR and an Assistant Professor in the Department of Family Medicine and Public Health at the University of California, San Diego.
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