Vitamins to Mitigate Diabetes Risk: Message in a Bottle?
Vitamins to Mitigate Diabetes Risk: Message in a Bottle?
Abstract & Commentary
By Susan T. Marcolina, MD, FACP. Dr. Marcolina is a physician at the HealthPoint Community Health Clinic in Kent, WA; she reports no financial relationship to this field of study.
Synopsis: Middle-age female health professionals at risk for cardiovascular disease and type 2 diabetes derived no benefit from more than 7 years of daily supplementation with a combination pill composed of folic acid, vitamin B6, and vitamin B12 designed to decrease serum levels of homocysteine. Although homocysteinemia has been recognized as a risk factor for diabetic vascular disease due to its effects on promotion of endothelial dysfunction, systemic inflammation, and oxidative stress, it appears that simply decreasing levels does not prevent progression to type 2 diabetes and cardiovascular events. Such high-risk individuals, perhaps not surprisingly, will require additional interventions to optimize cardiometabolic parameters such as blood pressure, lipid levels, body mass index (BMI), and waist circumference to prevent progression to type 2 diabetes and cardiovascular events.
Source: Song Y, et al. Effect of homocysteine-lowering treatment with folic acid and B vitamins on risk of type 2 diabetes in women: A randomized trial. Diabetes 2009;58: 1921-1928.
Diabetes currently affects 236 million persons worldwide and is projected to affect 380 million by 2025. Up to 80% of type 2 diabetes is preventable by adopting a healthy diet and increasing physical activity.1 Cardiovascular disease is the leading cause of death for both women and men in the United States and diabetes is a major risk factor.2 Therefore, it is important for primary care physicians to target susceptible individuals for effective therapies to mitigate the risk for developing type 2 diabetes. Intensive lifestyle modifications, such as daily physical aerobic exercise, calorie and dietary fat restriction, and weight loss, have been proven effective strategies to improve insulin resistance and delay progression to type 2 diabetes. Long-term maintenance of these habits, however, can be problematic for many patients.3
For this reason, nutritional or pharmacologic supplementation strategies are attractive options for primary prevention of type 2 diabetes. Although medications such as metformin are currently being considered for use in "prediabetic" patients at high risk to progress to type 2 diabetes, adverse effects can limit its routine use for this population.4 On the other hand, an elevated serum homocysteine level (hyperhomocysteinemia) represents a novel risk factor, which may promote insulin resistance and pancreatic beta-cell dysfunction through its adverse metabolic effects, which include promotion of oxidative stress, endothelial dysfunction, and systemic inflammation. Such adverse metabolic effects have been described by Cho et al in a 4-year prospective study of women with gestational diabetes.5 Since plasma homocysteine levels decrease in response to supplementation with the B vitamins responsible for its metabolism, namely, folic acid and vitamins B6 (riboflavin) and B12,6 Song et al undertook the present randomized, double-blind, controlled trial to evaluate whether specific supplementation with these three nutrients to decrease homocysteine levels could mitigate progression of high-risk individuals to frank type 2 diabetes.
This large cardiovascular prevention trial, the Women's Antioxidant and Folic Acid Cardiovascular Study (WAFACS), was begun in 1998 as a cohort of the Women's Antioxidant Cardiovascular Study, an ongoing randomized, placebo-controlled study of 8,171 female health professionals randomized to receive three antioxidant vitamins, namely vitamin C, vitamin E, and beta-carotene, or matching, respective placebos. More than 4,200 nondiabetic female health professionals were randomized for WAFACS to receive either a combination pill containing 2.5 mg folic acid, 50 mg vitamin B6, and 1 mg vitamin B12 as active treatment, or a matching placebo, and both groups were followed for a median period of 7.3 years for the development of type 2 diabetes.
The key finding from the study was that the folate and B vitamin supplementation given to the treatment group did not mitigate their risk of developing type 2 diabetes (11.5% developed incident diabetes) compared to placebo group (12.2% developed incident diabetes), despite the fact that supplementation resulted in an 18.5% lowering of homocysteine levels from baseline (27.7% of study subjects had homocysteine levels ≥ 15 mmol/L). Although the authors cited declining compliance (failure to take at least two-thirds of their study medications) with the supplementation over the course of the study, a subgroup analysis of compliant subjects from both treatment and control arms failed to show any significant differences between groups with respect to progression to type 2 diabetes.
Commentary
This study's results do not support the use of folic acid/B vitamin supplementation for diabetes prevention, but it does address a relevant issue. This now leaves us with the knowledge that the most effective strategy for the prevention of diabetes involves not primarily the use of supplemental vitamins but rather intensive lifestyle modification with the goal of increasing exercise and decreasing weight, which has been shown to improve cardiometabolic parameters such as blood pressure, lipid levels, and inflammatory markers such as high-sensitivity C-reactive protein levels, as well as anthropomorphic measurements such as waist circumference and BMI. The question is how to motivate patients to successfully implement and maintain intensive lifestyle modifications to mitigate the risk of future progression to type 2 diabetes.
Barnard et al notably advocate the use of a low- fat, plant-based dietary intervention to promote and maintain weight loss and improve insulin sensitivity.7 Individuals adherent to this diet consume low-fat, vegan foods with a low glycemic index with the advantage of decreased restrictions on portion sizes except for vegetable oils and nuts; the result is relatively early (within 2-3 weeks) and sustained weight loss with improvement in cardiometabolic parameters. Such individuals, however, do require vitamin B12 and D supplementation.
Studies such as the Community Diabetes Prevention Project (CDPP) in Minnesota have identified low cardiorespiratory fitness (as measured by maximal oxygen consumption [VO2max] using continuous gas exchange measurement on a maximal, symptom-limited exercise tolerance test on a bicycle ergometer) as a prevalent baseline abnormality in patients at risk for type 2 diabetes. Leite et al performed a cross-sectional study of 369 persons (79% women; age range, 20-65 years) at risk for insulin resistance and type 2 diabetes from the CDPP in Minnesota and 177 control subjects matched for age, gender, activity level, and BMI.8 They found that 96% of individuals from the CDPP cohort (at risk for type 2 diabetes or insulin resistance) had VO2max results that were moderately (11%) to severely decreased (85%) for their age and sex. In contrast, the mean VO2max value of 26 mL O2/kg/min for control subjects without the risk factors for type 2 diabetes or insulin resistance averaged 15% higher than the CDPP subjects (P < 0.001). Previously, Eriksson et al showed a progressive decrease in VO2max with a decline in glucose regulation from normal to impaired glucose tolerance and type 2 diabetes mellitus.9
This finding of decreased VO2max as an early marker for insulin resistance or type 2 diabetes may encourage patients at risk to participate in daily physical activity to improve cardiovascular fitness and mitigate the development of insulin resistance, type 2 diabetes, and the associated cardiovascular morbidity and mortality.8
Given that diabetes is a devastating and costly public health problem with serious associated impacts on quality of life, it is important to arm susceptible patients at an early stage in the disease process with information they need to minimize their risk of progression to type 2 diabetes and to carefully guide and monitor their progress through changes in diet, body weight, and exercise to maximize their success. Results of the current trial suggest that B vitamin supplementation does not have a significant role in reducing the risk of type 2 diabetes.
References
1. Diabetes Atlas. 3rd edition. Brussels, Belgium: International Diabetes Federation, 2007.
2. Kung HC, et al. Deaths: Final Data for 2005. National Vital Stat Rep 2008;56:1-120.
3. Leite SAO, et al. A1C predicts type 2 diabetes mellitus and impaired glucose tolerance in a population at risk: The community diabetes prevention project. Diabetol Metab Syndr 2009;1:5. Available at: www.ncbi.nlm.nih.gov/pmc/articles/PMC2761297/?tool=pubmed. Accessed Nov. 1, 2009.
4. Sharma MD, et al. What is the best treatment for prediabetes? Curr Diab Rep 2009;9:335-341.
5. Cho NH, et al. Elevated homocysteine as a risk factor for the development of diabetes in women with a previous history of gestational diabetes mellitus: A 4-year prospective study. Diabetes Care 2005;28: 2750-2755.
6. McNulty H, et al. Homocysteine, B-vitamins and CVD. Proc Nutr Soc 2008;67:232-237.
7. Barnard ND, et al. The effects of a low-fat, plant-based dietary intervention on body weight, metabolism and insulin sensitivity. Am J Med 2005;118:991-997.
8. Leite SAO, et al. Low cardiorespiratory fitness in people at risk for type 2 diabetes: Early marker for insulin resistance. Diabetol Metab Syndr 2009;1:8. Available at: www.ncbi.nlm.nih.gov/pmc/articles/PMC 2762992/?tool=pubmed. Accessed Nov. 2, 2009.
9. Eriksson K, et al. Prevention of type 2 (non-insulin-dependent) diabetes mellitus by diet and physical exercise. The 6-year Malmo feasibility study. Diabetologia 1991;34:891-898.
Middle-age female health professionals at risk for cardiovascular disease and type 2 diabetes derived no benefit from more than 7 years of daily supplementation with a combination pill composed of folic acid, vitamin B6, and vitamin B12 designed to decrease serum levels of homocysteine.Subscribe Now for Access
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