Dietary Supplements for Diabetes: What's New?

Introduction
In the United States, around 38% of adults and 12% of children are using some form of complementary and alternative medicine (CAM), according to a National Institutes of Health survey.^[1] For people with diabetes, the estimate is 34%.^[2] Whether CAM is being used in conjunction with conventional medicine ("complementary") or as a replacement treatment ("alternative"), it is often considered by patients as "natural" and therefore safe. In the case of herbal and dietary supplements, the main risks for diabetics are hypoglycemia, potential adverse reactions with antidiabetes drugs, and uncertain long-term safety. Clinicians should be aware of their patients' use of such products and should inform them about whether the benefits have been scientifically confirmed. In 2013, the National Center for Complementary and Alternative Medicine (NCCAM) stated that there is not enough scientific evidence to suggest that any dietary supplements can help prevent or manage diabetes.^[3] But more studies have been published since. What do they say? This slideshow aims to give an update on some of the most popular supplements used to treat diabetes.

Traditional Chinese Medicine
When it comes to alternative medicine, Chinese medicinal herbs often come to mind. The herb huang lian (Rhizoma coptidis), which contains berberine, has been traditionally used in China to treat diabetic symptoms.^[4] In 2014, a randomized controlled trial (RCT) published in the Journal of Clinical Endocrinology & Metabolism showed that a combination of 10 Chinese herbs (named Tianqi, and which includes the huang lian herb), significantly decreased the risk for type 2 diabetes (T2D) by a third in subjects with impaired glucose tolerance. The effect, measured after 1 year of treatment vs placebo, was not associated with adverse effects or difference in safety.^[5] Both body weight and BMI remained unchanged. The authors noted that Tianqi had comparable results to metformin (31%) in reducing the progression to T2D. However, no direct comparison with pharmaceutical treatment was made in the study, and no information was provided about the degree to which glucose was lowered.^[6] Further studies are needed to confirm the long-term effect of this herbal combination.

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Cinnamon
Cinnamon has also been used traditionally in Chinese medicine to treat diabetic symptoms such as polydipsia and polyuria. It has been shown to be insulin mimetic,^[7] and some of its action mechanisms parallel those of statin drugs.^[8] Cinnamon appears to be the most widely studied CAM,^[9] but because most of the studies evaluated various types and extracts of cinnamon in a wide range of doses, conclusions are not uniform. Due to a lack of clinical evidence, neither NCCAM nor the American Diabetes Association recommends the use of cinnamon supplementation. So, what can be told to patients asking for those supplements?

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Cinnamon (cont'd)
A recent article published in the American Journal of Lifestyle Medicine^[10] summarized the clinical data released over the past 10 years and concluded that:

• Only cassia cinnamon (also called Chinese cinnamon, as opposed to Ceylon, Saigon, or Indonesian cinnamons) has demonstrated some clinical efficacy. Medicinal benefit is probably best obtained from capsules rather than the spice.
• The safety profile is relatively good. However, because cassia cinnamon contains coumarin, known to cause reversible hepatotoxicity when taken at high daily doses, use caution in patients taking warfarin or at risk for liver disease.
• Despite mixed results, a significant amount of favorable studies suggest that cinnamon could be a reasonable treatment option in patients with uncontrolled T2D. However, larger RCTs are needed to fully evaluate its efficacy.

In another recent meta-analysis of 10 studies, a daily dose of 1-6 g (1-2 teaspoons) of cassia cinnamon was suggested as a conceivable option for glucose lowering in conjunction with the use of evidence-based therapies.^[11]
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Chromium Picolinate
Chromium is an essential mineral found in such foods as whole grains, egg yolks, and broccoli. It plays an important role in facilitating glucose metabolism such that chromium deficiency is associated with insulin resistance and reversible diabetes.^[3,12] A small trial showed that a daily dose of 1 mg of chromium picolinate improved glucose sensitivity in diabetics,^[13] but newer studies concluded that the supplement doesn't ameliorate insulin resistance or impaired glucose metabolism.^[3,14,15] At best, when changes in glucose metabolism are observed, individual patient phenotypes may be a factor.^[2] NCCAM therefore has recommended that endocrinologists not endorse this therapy as part of a diabetes prevention strategy. In 2014, a systematic review and meta-analysis of 25 RCTs^[16] concluded that there is now enough evidence to suggest that chromium monosupplementation has favorable effects on glycemic control in diabetic patients. It could also improve triglycerides and HDL-C levels, with no increase in adverse events. Still, data on combined supplementation are limited, and long-term benefit and safety remain to be further investigated.

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Ginseng
The two most frequently used and studied varieties of ginseng are Asian ginseng (Panax ginseng) and American ginseng (Panax quinquefolius). Treatment claims for the popular root are numerous and include lowering blood glucose.^[17] In 2014, four small randomized, double-blind, placebo-controlled trials reported trends to beneficial effects of ginseng. The first one showed that acute administration of ginseng in T2D patients reduced the Augmentation Index, a surrogate measure of arterial stiffness and therefore a predictor of adverse cardiovascular events. However, no beneficial effects on other postprandial, vascular, or glycemic parameters were observed.^[18] The other trials focused on oral supplements; one showed that 4-week daily consumption of fermented red ginseng lowered postprandial glucose levels in persons with T2D or impaired fasting glucose (IFG), but fasting glucose, insulin, and lipid profiles remained similar.^[19] Meanwhile, 12-week daily supplementation with 5-g red ginseng decreased serum and whole blood levels of glucose, and tended to reduce serum insulin and C-peptide concentrations in persons with IFG, impaired glucose tolerance, or newly diagnosed T2D.^[20]

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Ginseng (cont'd)
In regard to safety, the fourth trial evaluated 12 weeks of supplementation with 3 g of American ginseng in 74 well-controlled T2D patients. The safety measures on kidney, liver, and hemostatic functions remained comparable to placebo.^[21] Finally, in a systematic review and meta-analysis of 16 RCTs, Canadian researchers concluded that ginseng modestly yet significantly improved fasting blood glucose in people with and without diabetes. They also call for larger and longer trials and ones that use standardized ginseng preparations.^[22] NCCAM recommends that people with diabetes use extra caution with Asian ginseng, especially if they are using medicines or taking other herbs.^[17] NCCAM-funded research on the herb's potential role in treating insulin resistance is ongoing.

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B Vitamins
Combination of active forms of vitamins B₉, B₁₂, and B₆ (namely L-methylfolate, methylcobalamin, and pyridoxal-5'-phosphate or LMF-MC-PLP [Metanx®]) is being used to improve sensory neuropathy in diabetic patients.^[23] LMF-MC-PLP may counteract oxidative stress in vascular endothelium and peripheral nerve.^[24] In a recent randomized, placebo-controlled trial, 24 weeks of supplementation with LMF-MC-PLP improved symptoms, sensory neuropathy, and quality of life in T2D patients with neuropathy.^[25] LMF-MC-PLP could also have some beneficial effects in reducing retinal edema and increasing light sensitivity in persons with nonproliferative diabetic retinopathy, according to a pilot study.^[26] However, in patients with diabetic nephropathy, B vitamin therapy may cause more harm than benefit.^[27] An RCT showed that high doses of oral B₆-B₉-B₁₂ vitamins decreased glomerular filtration rate and increased the risk for vascular events (myocardial infarction and stroke) or all-cause mortality in this patient population.^[28]

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Fish Oil
Because of its ability to lower triglyceride levels and the risk for arrhythmia, fish oil—and more specifically omega-3 polyunsaturated fatty acids (PUFAs)—may be used by diabetic patients.^[2,29] But could PUFAs prevent diabetes? A preview meta-analysis of RCTs did not show any significant changes in glycemic control nor fasting insulin with omega-3 PUFA supplementation in T2D patients.^[30] A 2014 epidemiologic study in Diabetes Care revived the idea of a link between fish oil and diabetes by reporting that higher serum concentrations of PUFAs were associated with lower risk for incident diabetes in Finnish men.^[31] Last October, a Swedish study suggested that fatty fish consumption may reduce the risk for latent autoimmune diabetes in adults.^[32] Finally, in the January 2015 issue of Journal of Clinical Medicine Research, a systematic review showed that intake of fish oils seemed not to affect insulin sensitivity, insulin secretion, beta-cell function, or glucose tolerance. The association between fish oil consumption and development of T2D could be partly explained by geographical differences.^[33]

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Fenugreek, Aloe Vera, and More
Beneficial effects on diabetes have been claimed for the guava leaf, garlic, bitter melon, gymnema, prickly pear cactus, fenugreek, and aloe vera, among others. They all have a long history of use in numerous parts of the world.^[2,34-36] Several can lower blood glucose, but most of the studies so far have lacked sufficient power or quality to conclude any recommendations in diabetic patients.^[3,9,37] In 2014, a systematic review of clinical trials supported beneficial effects of fenugreek seeds on glycemic control in diabetics, but at the same time the authors called for studies with higher methodology quality, using well-dosed and characterized fenugreek preparations to provide more conclusive evidence.^[38] As for aloe vera, it could help to reduce body weight, body fat mass, and insulin resistance in obese individuals with prediabetes or early untreated diabetes mellitus, according to a recent trial.^[39]

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Ask Patients About CAM Use
While nutritional supplements are now widely available, 50% of websites selling nutritional supplements for diabetes do not have a disclaimer from the US Food and Drug Administration (FDA), and 60% do not declare clearly that the product is not a substitute for medication, according to a study published in 2013. Adequate medical information about adverse effects and dosage, as well as strong scientific evidence, are generally lacking on those websites.^[40] In the same year, the FDA warned the public about 15 domestic and foreign companies selling (online and in retail stores) illegal products to treat diabetes and its complications.^[41] Some of the products may have significant effect, but the variations in potency, safety, and efficacy of various over-the-counter preparations call for caution. Until clinical consensus is established, CAM should be used under medical supervision. Considering that only one third of people using natural herbs or supplements tell their physicians about it,^[42] it is crucial that clinicians include this topic in their consultation discussion.

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