CPE

Natural products for the management of type 2 diabetes mellitus and comorbid conditions Jennifer Dixon Smith and Valerie B. Clinard

Objective: To provide pharmacists with practical information to guide consum- Jennifer Dixon Smith, PharmD, CPP, BC-ADM, CDE, is Associate Professor, ers in their choices of herbal products and dietary supplements for the manage- Pharmacy Practice, and Valerie B. Clinard, ment of type 2 diabetes mellitus (T2DM) and its comorbid disease states. PharmD, is Vice Chair, Experiential Summary: The herbal and dietary supplement market has grown exponentially Education, and Associate Professor, Pharmacy Practice, Campbell University over the past decade as Americans increasingly use such agents for generalized College of Pharmacy and Health Sciences, health and the prevention and treatment of chronic disease states.1 Pharmacist ad- Buies Creek, NC. vice is often requested on the use of these agents for the management of T2DM; Development: This home-study CPE activity however, this is an area that has insufficient evidence to support confident recom- was developed by the American Pharmacists mendations. Many published studies involving herbal agents and dietary supple- Association. ments are small and poorly designed, with heterogeneous results. Pharmacists Published concurrently in Pharmacy Today should be aware of the safety and efficacy data available for these agents, recognize and the Journal of the American Pharma- cists Association (available online at www. potential drug interactions, and identify acceptable manufactured products. japha.org). Conclusion: The strongest scientific evidence for blood glucose lowering effect is associated with alpha-lipoic acid and fenugreek. There is also good evidence supporting the use of ivy gourd, gymnema, and vitamin E for management of hyperglycemia; however, caution should be used when recommending vitamin E. Pharmacists should advise consumers to disclose use of any of these products to all of their health care providers. Keywords: Diabetes, herbal supplements, dietary supplements, botanicals Pharmacy Today. 2014(August);20(8):58–72.

Accreditation information Learning objectives At the conclusion of this knowledge-based Provider: American Pharmacists Association ACPE number: 0202-0000-14-161-H01-P activity, the pharmacist will be able to: Target audience: Pharmacists CPE credit: 2 hours (0.2 CEUs) ■■ Identify natural products and dietary Release date: August 1, 2014 Fee: There is no fee associated with this supplements associated with an anti- Expiration date: August 1, 2017 activity for members of the American Phar- hyperglycemic effect. Learning level: 1 macists Association. There is a $15 fee for ■■ Describe safety and efficacy data as- nonmembers. sociated with the most commonly used The American Pharmacists Association is accredited by the Accreditation Council agents for diabetes management. for Pharmacy Education as a provider of continuing pharmacy education (CPE). The ■■ Identify important drug–drug inter- ACPE Universal Activity Number assigned to this activity by the accredited provider actions associated with the most is 0202-0000-14-161-H01-P. Disclosures: Jennifer Dixon Smith, PharmD, CPP, commonly used agents for diabetes BC-ADM, CDE, has served as a consultant to AstraZeneca and Bristol-Myers Squibb. Valerie B. management. Clinard, PharmD, and APhA’s editorial staff declare no conflicts of interest or financial interests ■■ List three items that should clearly be in any product or service mentioned in this activity, including grants, employment, gifts, stock identified on the package labeling be- holdings, and honoraria. For complete staff disclosures, please see the APhA Accreditation fore recommending a particular herbal Information section at www.pharmacist.com/education. or dietary supplement.

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Preactivity questions lack of regulation, such products may be contaminated with Before participating in this activity, test your knowledge by answer- other substances, may not contain the intended ingredient, ing the following questions. These questions will also be a part of or may be ineffective. the CPE assessment. Adding to the problems of a growing, unregulated mar- 1. Which dietary supplement has data that demonstrate a possible ket is uncertainty about the generalized safety and efficacy benefit in A1C reduction in patients with T2DM? of these products. To date, only a few randomized clinical a. Chromium trials of product safety and efficacy have been conducted b. Pyridoxine and published, and the sample size of many of these stud- c. Selenium ies has been too small to draw reliable conclusions. Further, d. Zinc many of the studies on botanical products use different parts

2. Which fat-soluble vitamin has evidence suggesting that use of of the plant (e.g., root, stem, leaf), making it difficult to draw high doses may increase the risk of death and, thus, should not be reliable conclusions about the safety and efficacy of each recommended for management of T2DM? constituent.8 Given the limited data available, concern exists a. Pyridoxine regarding these products’ adverse effects, contraindications, b. Alpha-tocopherol and appropriate doses. c. Alpha-lipoic acid Thousands of plant-derived herbs have been implicated d. Zinc in the treatment of diabetes,1 and a plethora of natural prod-

3. Which herbal agent is more likely to increase bleeding risk when ucts—mostly in combination—are marketed for lowering used concomitantly with anticoagulants? blood glucose and treating comorbid conditions associated a. Bitter melon with diabetes.9 However, while limited data are available on b. Burdock the ability of many of these agents to safely and effectively c. Cinnamon lower blood glucose levels, health care professionals should d. Fenugreek not discount the use of such products. With more available information, it is possible that one or more of these agents may become an element of conven- Introduction tional treatment for patients with diabetes. Metformin—now The use of herbals and dietary supplements for generalized a cornerstone of diabetes prevention and treatment—is an health and the prevention and treatment of chronic disease example of how such a transition can occur. Metformin was states is increasing throughout the United States.1 The most discovered from use of the medicinal plant Galega officina- recent National Health and Nutrition Examination Survey lis to treat diabetes.10–12 Based on the recommendation of the (NHANES) data (2003–06) indicates that approximately 53% World Health Organization Expert Committee on Diabetes, of Americans aged 20 years and older use dietary supple- efforts are currently underway to determine the utility of ments, representing a 10% increase in use from the 1988–94 other traditional medicinal herbs in diabetes care.11 data.2,3 However, it is difficult to assess the use of herbal prod- Similarly, a secondary analysis of the complementary ucts and dietary supplements specifically for diabetes. Many and alternative medicine (CAM) supplement to the 2002 Na- studies report the use of CAM approaches to diabetes care, tional Health Interview Survey (NHIS) found that 57.3% of including dieting, relaxation techniques, herbal treatment, adult dietary supplement users took such products to treat prayer, and homeopathy.13 Available studies indicate that a specific medical condition in the previous 12 months.4 Ac- prayer and dietary measures are the primary types of CAM cording to a 2008 study, individuals with diabetes are 1.6 used in patients with diabetes. times more likely to use alternatives to traditional medicine In a study by Yeh et al.,10 CAM use in patients with diabe- compared with those without the disease.5 tes included prayer and spiritual practice (28%), herbal rem- Access to herbal and dietary supplements was greatly edies (7%), and commercial diets (6%). In a separate study by enhanced by passage of the Dietary Supplement Health and Bell et al.,14 a greater number of individuals with diabetes Education Act of 1994 (DSHEA).6 Prior to DSHEA, dietary were found to use CAM approaches compared with those supplements were held to the same regulatory requirements without the disease (73% vs. 61%); however, a significantly as other foods.7 Now, the manufacturer of a dietary supple- lower number of respondents with diabetes used non-vita- ment is responsible for ensuring product safety prior to mar- min, non-mineral natural products compared with respon- keting, while FDA is tasked with taking action against un- dents without diabetes (15.7% vs. 19.2%). Those with diabetes safe dietary supplements after products reach the market.7 who did use CAM mostly did so for non-diabetes conditions. Manufacturers do not require FDA approval to sell di- These findings underscore the need to determine the ac- etary supplements, and the agency does not maintain a list tual use of herbal remedies for diabetes care, as well as antic- of manufacturers or the dietary supplement products they ipated and actual outcomes. This review focuses on practical sell.7 FDA does call for “good manufacturing practices,” but information to aid pharmacists in guiding consumers on the the burden of proof for verifying product safety is left up use of herbals and dietary supplements for managing type to the government. Thus, herbals and dietary supplements 2 diabetes mellitus (T2DM) and its comorbid disease states. comprise part of a thriving, unregulated market. Given this www.pharmacist.com august 2014 • PharmacyToday 59 CPE natural products for t2dm and comorbid conditions

Herbal products avoided in patients with allergies to ragweed, chrysanthe- Bitter melon (Momordica charantia) mums, marigolds, or daisies. Animal studies suggest in- Bitter melon is also known as bitter gourd, karela, or balsam creased bleeding risk with burdock use; therefore, recom- pear.5 It is sometimes referred to as “vegetable insulin” be- mend caution with concomitant use of anticoagulants or cause its extract components share structural similarities antiplatelet agents.16 Of greatest concern is that burdock can with animal insulin.15,16 Purported mechanisms include en- be confused with belladonna alkaloids during harvesting, hanced pancreatic insulin secretion and decreased hepatic and atropine-like effects have been seen following the con- gluconeogenesis.16 sumption of contaminated burdock.16 Burdock itself does not Safety: Based on animal studies, isolated proteins from have atropine-like effects. bitter melon have abortifacient properties; therefore, bitter Known drug interactions: Burdock tinctures may contain melon should be used with caution in women of childbear- high concentrations of alcohol, which may induce vomiting ing age.5,16 Bitter melon should be avoided in nursing women, if combined with disulfiram or metronidazole.16 children, and those with allergies to foods in the gourd or Efficacy: Animal data and weak human data suggest the melon family.5 Additionally, ingestion of bitter melon seeds root or fruit of burdock may produce hypoglycemic effects, may cause favism—the onset of hemolytic anemia—in those but reliable data is lacking.16 Further studies are needed be- with glucose-6-phosphate dehydrogenase (G6PDH) deficien- fore recommending burdock for the management of T2DM. cy. 5 Known drug interactions: Bitter melon may be a p-glyco- Case study 1 protein inhibitor; concomitant use with digoxin should be A 28-year-old obese female with T2DM requests an herbal supplement 16 to use in addition to metformin for glycemic control. She has no other avoided. disease states but is allergic to grass, trees, and ragweed. Name two Efficacy: Bitter melon has shown hypoglycemic effects herbal supplements you would avoid recommending in this patient for in various animal models,12 some low-quality human trials, glycemic control. and one case report.16 A randomized controlled trial by Dans Bitter melon should be avoided in all women of childbearing et al.17 compared bitter melon extract (1000 mg three times age because of the risk of miscarriage. Additionally, burdock should daily) with placebo in patients with uncontrolled T2DM not be recommended at this time to any patient for glycemic control (glycosylated hemoglobin [A1C] levels of 7%–9%). The mean given the risk of contamination with belladonna alkaloids. Burdock should also be avoided in patients allergic to ragweed, chrysanthe- difference in treatment for A1C was 0.22% in favor of bitter mums, marigolds, daisies, or pectin. melon (non-significant); however, the study sample size was only 40 participants and power was not met. Cinnamon (Cinnamomum cassia) Fuangchan et al.18 published a study comparing dried bit- Cinnamon, also sometimes referred to as Chinese cinna- ter melon fruit powder doses of 500 mg/day, 1000 mg/day, mon,20 is derived from the dried inner bark of evergreen and 2000 mg/day with metformin 1000 mg/day. The four- trees grown in the tropical climates of Asia.5,21 The active week study based efficacy on lowered fructosamine levels, ingredients in cinnamon include cinnamaldehyde and pro- a measure of glycemic control over the past 2–3 weeks. Of cyanidin type-A polymers.5,21 It is purported that these con- the bitter melon doses, only the 2000 mg/day dose showed stituents enhance insulin sensitivity by improving glucose significant reduction in mean fructosamine levels, but there uptake and glycogen synthesis.21 was no effect on fasting or postprandial blood glucose levels. Safety: When used in natural food sources, cinnamon ap- Bitter melon reduction in fructosamine levels was less than pears to be safe. In clinical trials, gastrointestinal disorders that seen with a suboptimal metformin dose. were the most reported adverse effect associated with cin- Bitter melon in doses of 2 grams per day may have an namon use.16 It should be noted that cinnamon is a top food effect on long-term blood glucose lowering, but immediate allergen, so caution should be exercised when recommend- effects have not been observed. ing its use among mass populations. Known drug interactions: Cinnamon contains a coumarin Burdock (Arctium lappa) component, so caution should be used when recommending Burdock, which is rooted in traditional Chinese medicine, with concurrent administration of anticoagulants.5 has been examined for uses as an anti-inflammatory, anti- Efficacy: Results of randomized trials from human and cancer, antidiabetes, antimicrobial, and antiviral agent.19 Bur- animal studies have indicated hypoglycemic effects; how- dock root and fruit have been suggested as the parts of the ever, the results have been conflicting.16 To date, studies of plant that likely contribute the most to producing hypoglyce- patients with T2DM have involved the administration of 1, 3, mic effects.19 The root contains sitosterol-beta-D-glucopyran- or 6 grams per day of cinnamon in divided doses.22 oside, which is thought to have alpha-glucosidase inhibitor While there is currently insufficient data to recommend activity, and inulin, which helps to regulate blood glucose cinnamon for any human condition, its use in the treatment levels.19 Total lignin from the burdock fruit has suggested an- of T2DM seems to be the most desired field of research.16 The tidiabetic activity in animal studies.19 use of cinnamon increased substantially after 2003 when Safety: Different parts of the burdock plant contain vary- Khan et al.23 demonstrated a lowering of blood glucose val- ing levels of pectin complex. Avoid use in individuals with ues in patients with T2DM. Consequently, patients began allergy or intolerance to pectin.16 Burdock should also be questioning if cinnamon may be an appropriate alternative

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or supplement for diabetes management. Efficacy: Animal studies have suggested hypoglycemic Allen et al.22 conducted a systematic review and meta- effects of dandelion, but no human data is available. One analysis of randomized trials evaluating cinnamon (mono- published case report suspected that dandelion induced preparation or in combination) in patients with T2DM. A hypoglycemia when it was added to a neutral protamine total of 10 studies involving 543 participants met eligibility Hagedorn (NPH) insulin regimen.25 Dandelion may be criteria. Doses of aqueous cinnamon extract or raw cinna- considered safe when recommended as part of a natural mon powder ranged from 120 mg/day to 6 g/day over a pe- diet. However, given the lack of human data, dandelion riod of 4–18 weeks. Cinnamon was associated with a statisti- should not be recommended as a hypoglycemic agent at cally significant reduction in fasting plasma glucose levels of this time. 24.59 mg/dL. High degrees of heterogeneity were present for A1C levels, but no statistically significant effect was seen in Fenugreek (Trigonella foenum-graecum) A1C levels (−0.16%). Fenugreek is a fiber-rich plant that is a member of the Faba- Leach and Kumar24 conducted a Cochrane Review ceae family.5,15,16 It is commonly used for glycemic control in analysis of randomized controlled trials using cin- foreign countries such as Saudi Arabia and Canada.16 The namon as monotherapy for type 1 diabetes (T1DM) mechanism of action is thought to be a delay in gastric emp- or T2DM. A total of 10 studies met eligibility criteria tying, slowed carbohydrate absorption, and increased insu- (n = 577 participants), with only 2 of the studies dif- lin sensitivity of the tissues.8,15 Fenugreek seeds reportedly ferent from those evaluated in the Allen review. Cin- increase glucose-dependent insulin secretion.12 namon cassia was the predominant form of cinnamon Safety: The most commonly reported adverse effects used (mean dose of 2 g/d) for a period of 4–16 weeks. of fenugreek are gastrointestinal,5 including dyspepsia In the meta-analysis, no conclusions could be made re- and abdominal distention.26 Fenugreek also has a blood garding the efficacy of cinnamon on fasting blood glu- thinning effect5 and may cause hypokalemia.16 Fenugreek cose levels. Of the six trials reporting A1C levels (n = 405), should not be recommended for use in individuals aller- there was no statistically significant difference in A1C levels gic to members of the Fabaceae family (peanuts, chickpeas, (mean difference −0.06%). soybeans, or green peas).5,16 Further studies are needed before recommending cinna- Known drug interactions: Because it is rich in fiber, fenu- mon as an agent for glycemic control. greek may interfere with the absorption of some oral medi- cations. Therefore, it is recommended that the coadminis- Dandelion (Taraxacum officinale) tration of oral medications and fenugreek be spaced out by Dandelion is a member of the Asteraceae family.16 Found at least 2 hours.9 Additionally, caution should be exercised growing wild in meadows and pastures of temperate with concomitant use of potassium-depleting agents.16 zones, it provides fiber, potassium, iron, calcium, magne- Efficacy: Daily doses of 5–100 grams of fenugreek seed sium, phosphorus, thiamine, and riboflavin when ingested. powder have been shown to improve fasting blood glu- Dandelion has traditionally been used to treat gastrointes- cose, postprandial glucose, and A1C levels in patients with tinal disorders. FDA has approved dandelion fluid extract T2DM.26 and solid dandelion root extract as food additives; they are From a pooled analysis, Suksomboon et al.21 determined currently used as salad ingredients and coffee substitutes. that fenugreek had a statistically significant decrease in Safety: Dandelion is considered likely safe when taken A1C (1.13%), but no effect on fasting blood glucose. orally in amounts found naturally in foods,16 earning FDA’s Neelakatan et al.26 conducted a meta-analysis to assess “generally recognized as safe” designation. It has been the effect of fenugreek on glucose homeostasis; 10 trials met well-tolerated in human studies, with the most common- inclusion criteria, but only 8 were selective for patients with ly reported adverse effects being dermatologic in nature, T2DM. Results of the meta-analysis included significant following direct contact. However, safety data beyond 4 reductions in fasting blood glucose (−0.96 mmol/L), 2-hour months of use is lacking. Use should be avoided in indi- blood glucose (−2.19 mmol/L; 7 trials), and A1C levels viduals who are allergic to dandelion, honey, chamomile, (−0.85%; 3 trials). Significant reductions in glycemic mark- chrysanthemums, or any member of the Asteracae family. ers were only found with medium to high doses of fenu- A theoretical concern is that dandelion stimulates bile greek seed powder (≥5 g/d). secretion and therefore should not be used in individuals Fenugreek seed powder in daily doses of at least 5 with liver or gallbladder disease; however, supporting data grams appears to be a safe and effective option for glycemic for this is lacking. The prudent approach at this time would control in persons with T2DM. be to avoid recommending dandelion if liver or gallbladder disease is present. Ginseng—Korean red (Panax ginseng) and American Known drug interactions: Dandelion may cause increased (Panax quinquefolius) gastric acid secretion; therefore, it may reduce the effec- While several species of ginseng are used in herbal prod- tiveness of antacids.16 Dandelion may also increase the risk ucts, the most common are of the Panax genus.27 Other of bleeding, so caution is recommended with concomitant species of ginseng from different botanical families (e.g., use of anticoagulants or antiplatelet agents. Siberian) are sometimes sold as less expensive alternatives. www.pharmacist.com august 2014 • PharmacyToday 61 CPE natural products for t2dm and comorbid conditions

However, they lack the efficacy data associated with the Efficacy: Animal studies have demonstrated glucose- Panax genus.16 lowering effects in animals with residual pancreatic func- The glucose lowering effect of Panax is attributed to its tion, but not in pancreatectomized animals; however, ginsenosides, but the peptidoglycan and glycan constitu- gymnema has demonstrated efficacy in human trials in ents have also shown beneficial effects.1 However, there is both patients with T1DM and T2DM.8 great difficulty in standardizing Panax ginseng products. Baskaran et al.29 conducted a non-randomized study Currently, there are more than 30 identified ginsenosides, of 47 patients with T2DM. For 18–20 months, 22 of the pa- so there may be considerable variability in the composition tients were administered 400 mg/day of GS4, an extract of marketed ginseng products.1 from gymnema sylvestre leaves, in combination with oral Safety: Insomnia is the most commonly reported side hypoglycemic agents. Statistically significant reductions in effect. Anxiety, headache, and tachycardia have also been fasting blood glucose values (−2.78 mmol/L) and A1C lev- reported.5 els (-3.43%) were reported. Almost all patients in the treat- Known drug interactions: Caution should be exercised ment group required dose reduction or discontinuation of with concomitant use of agents that increase bleeding.16 sulfonylureas within several weeks (unspecified time). The Ginseng has also been linked to a plethora of potential drug study authors also observed elevations in serum insulin interactions (e.g., antihypertensives, antidepressants, pain levels in the fasting and postprandial state in those partici- relievers, antibiotics); however, data is lacking to definitive- pants treated with GS4. ly support these interactions.16 It may be safe to recommend gymnema for glycemic Efficacy: Vuksan et al.1 evaluated the acute and chronic lowering in T2M. However, further well-controlled trials effects of American and Korean red ginsengs using a stan- need to be conducted in this population to establish safety dardized ginsenoside component administered at specific and efficacy. times. The study found that doses of 1–9 grams of Ameri- can ginseng were equally effective in the acute and long- Ivy gourd (Coccinia indica) term reduction of postprandial hyperglycemia (~15–20%). Ivy gourd is an aggressive climbing vine found in tropical Chronic antihyperglycemic efficacy of American ginseng areas.16 Both human and animal studies have found that was evaluated using 1 gram of ginseng extract 40 minutes the fruit and leaves of ivy gourd can lead to reductions in before each meal (3 g/d). Similarly, the administration of fasting and postprandial blood glucose values. Ivy gourd 2 grams of Korean red ginseng rootlets 40 minutes before is a source of fiber, which may account for its ability to each meal (6 g/d) demonstrated acute and chronic anti- lower blood glucose levels, but it is also speculated to pos- hyperglycemic efficacy. Administration time of at least 40 sess insulin-like effects.12,16 Ivy gourd’s exact mechanism minutes prior to the meal was significant. of action remains unclear.8 A separate study evaluating the safety and efficacy of Safety: Published clinical trials report a lack of adverse Korean red ginseng observed acute efficacy for glycemic events associated with the use of ivy gourd.16 In a 2008 control, but did not see any long-term effects as measured study using an alcoholic extract of ivy gourd, participants by A1C levels.28 experienced mild disturbance of the gastrointestinal tract High variability in the composition of ginseng products (abdominal distention, flatulence, constipation, and gas- is linked to the inconsistent efficacy observed in studies, tritis). However, more participants in the placebo group with no standardization existing at this time for the differ- experienced these symptoms than those in the interven- ent ginsenosides and their ratios.1 Limited efficacy data and tion group, and the symptoms resolved within 1 week.30 lack of standardization limit the recommendation of Panax Known drug interactions: No known drug interactions ginseng products for glycemic control. exist.16 Efficacy: Evidence for the potential efficacy of ivy gourd Gymnema (Gymnema sylvestre) in lowering blood glucose dates back to a 1979 study con- Gymnema is a woody, climbing plant native to the tropi- ducted in Bangladesh, which found that 1800 mg/day of cal forests of central and southern India.8 In Hindu folk- ivy gourd decreased both fasting and postprandial blood lore, chewing gymnema leaves results in the inability to glucose values, with no reported side effects.8,31 A case se- taste sweets. It is therefore also known as “gurmar,” which ries published by Kamble et al.32 compared use of 6 g/day means “destroyer of sugar” in Hindi.8 The exact mechanism of ivy gourd to that of chlorpropamide and found that the of action is unknown, but suggested mechanisms include two treatments were similar in their ability to lower fast- enhanced insulin secretion, beta cell regeneration, and en- ing and postprandial blood glucose levels. hanced peripheral glucose utilization.8 Additional data are needed prior to recommending ivy Safety: Based on limited trial data, gymnema appears gourd for treatment of T2DM. to be safe, with the most notable side effect being taste al- teration.8 Patients may experience diminished perception of Nopal (Opuntia streptacantha) sweet taste and enhanced perception of bitter taste. Prickly pear cactus, known as nopal to the Mexican com- Known drug interactions: Gymnema may enhance the munity, has high soluble fiber and pectin content in its fresh lipid-lowering effects of antilipemic agents and the weight state,15 which may affect intestinal glucose uptake.8 loss effects of antiobesity agents.16 Safety: Diarrhea and increased stool volume have been

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reported with nopal use,5 as have allergic nasal inflamma- husk and leaves have been studied for potential blood glu- tion and asthma.16 Nopal is likely safe when used as a food cose lowering effects.16 While the exact mechanism of glu- source.16 cose lowering remains unclear,16 it has been suggested that Known drug interactions: Nopal may increase bleeding psyllium may enhance insulin action or insulin-independent when combined with anticoagulants or antiplatelet agents.16 effects.35 Additionally, nopal may cause increased drug levels of Safety: Adequate amounts of water should be consumed agents metabolized through the cytochrome P450 enzyme with psyllium-containing products to prevent swelling and system. Nopal may also help reduce cholesterol; thus an blockage of the throat and intestines.16 Health care workers additive effect is possible when combined with cholesterol- with repeated exposure to psyllium may be at increased risk lowering agents. for development of an allergy to the fiber. Efficacy:The leaves and stem of nopal have been studied Known drug interactions: Psyllium may reduce the absorp- for glycemic effects, with nopal shown to decrease glucose tion of some oral agents. Oral medications should be taken 1 in both pancreatectomized and nonpancreatectomized ani- hour before or 2 hours after psyllium. mals.8 Additionally, doses of 100–600 grams/day have pro- Efficacy: According to the American Diabetes Association vided hypoglycemic effects in individuals with T2DM.15 (ADA), fiber has lowered postprandial blood glucose levels Studies are generally limited on this readily available modestly in available trials.33 Other sources have associated plant. However, given the lack of significant side effects psyllium with lower mean daily glucose levels, lower post- seen in trials and the possible glucose-lowering effect of prandial blood glucose concentrations, and lower A1C lev- nopal, it can safely be recommended for consumption as a els.34 food source. Anderson et al.36 conducted a study to assess the safety and efficacy of psyllium in male patients with T2DM. For Onion (Allium cepum) 8 weeks, participants ingested 5.2 grams of psyllium seed Onion is part of the Allium species and contains allyl pro- husk twice daily (20–30 minutes before morning and eve- pyl disulphide.8 It is suggested that onion’s hypoglycemic ning meals). All-day blood glucose levels were significantly properties are attributable to enhanced pancreatic insulin lower in the psyllium group compared with the placebo secretion and/or improved hepatic storage of glycogen. group (−11%). As in previously published studies, Anderson Safety: Onion is likely safe when consumed as part of a et al. observed a “second meal effect” in the psyllium-treated normal diet,16 though increased dietary intake may induce group, with psyllium doses taken before morning meals re- heartburn or dyspepsia. Onion has resulted in lowered sulting in statistically significant lower post-lunch postpran- blood pressure in patients both with and without hyperten- dial blood glucose levels compared with the placebo group sion; therefore, its increased intake should be accompanied (−19.2%). by cautious monitoring of blood pressure. Ziai et al.37 evaluated the glycemic benefit of psyllium in Known drug interactions: P-glycoprotein substrates and persons with T2DM in a double-blind, placebo-controlled medications metabolized by the cytochrome P450 enzyme study. Psyllium dosing, dosing schedule, and study dura- system may interact with onion.16 Additionally, onion may tion were identical to the study conducted by Anderson et increase bleeding risk when combined with anticoagulants al. Of the 49 enrolled patients, 36 completed the study, with or antiplatelet therapy. no attrition in the treatment group due to adverse effects. A Efficacy: Onion has reduced fasting and postprandial statistically significant decrease in A1C levels from baseline blood glucose levels in both animal (rabbit) and human were reported in the psyllium-treated group [10.5% (±0.73) studies.12 Given as a single orally administered dose of 25, to 8.9% (±0.23)], while an increase was seen in the placebo- 50, 100, or 200 grams of aqueous onion extract (either boiled treated group [9.1% (±0.51) to 10.5% (±0.59)]. or raw), onion lowered fasting blood glucose levels in a dose- When either added to one’s regularly consumed diet or dependent manner and was comparable to tolbutamide—a used as fiber supplementation, psyllium may help benefit first-generation secretagogue. Additionally, an onion diet of glycemic control. 3 x 20 grams of fresh onion decreased or maintained blood glucose levels in study participants with T2DM.12 Dietary supplements Onion is considered safe when consumed as part of a Alpha-lipoic acid normal healthy diet. Therefore, pharmacists may safely rec- Alpha-lipoic acid (ALA) is an endogenous dithiol antioxidant ommend increased dietary intake for patients who do not that is naturally synthesized in the body.16 ALA acts as an an- take anticoagulants and are not currently being treated for tioxidant and coenzyme, and evidence exists that it may aid dyspepsia or heartburn. in the treatment of both T2DM and diabetic neuropathy.16,38 Safety: ALA is generally well tolerated when daily doses Psyllium (Plantago ispaghula) do not exceed 1200–1800 mg. Common adverse effects in- Fiber intake for the general population is recommended as 14 clude nausea, vomiting, and vertigo, especially at the higher g/1000 kcal, which for most individuals translates into 25–35 dose ranges (1200 mg or above).16,39,40 grams of fiber per day.33,34 The fiber consumption recommen- Use of ALA is a risk factor for the development of insulin dation for individuals with diabetes is the same as that for autoimmune syndrome (IAS), also known as Hirata disease, the general population.33 Psyllium is a soluble fiber; its seed a rare cause of hypoglycemia due to the production of auto- www.pharmacist.com august 2014 • PharmacyToday 63 CPE natural products for t2dm and comorbid conditions

antibodies to insulin in individuals who have not previously eficial effect of ALA on TSS. While no effect was seen for A1C been treated with insulin.16 Additional risk factors for IAS in- levels, significant effects in favor of ALA were observed for clude the use of sulfhydryl drugs (e.g., methimazole, mercap- neuropathy impairment score (17.1%), NIS of the lower limbs topropionyl glycine, and glutathione). Risk is also higher in (16%), pinprick sensation (OR = 1.57), touch pressure sensa- persons from East Asia and certain patients of native North tion (OR = 1.35), and ankle reflex (OR = 1.69). The rate of ad- American descent. verse effects, which included headache and nausea, did not Known drug interactions: Significant drug interactions differ between groups. Limitations of the review included have not been noted with ALA. the inclusion of select studies and the short duration of treat- Efficacy: ALA administered orally or via IV may improve ment. insulin sensitivity and glucose disposal in persons with It is also notable that that some studies have found no T2DM.41–46 benefit of ALA in the treatment of DPN.53,54 While ALA may Mazloom et al.46 conducted a randomized, placebo-con- provide benefit to some patients with DPN, additional stud- trolled study to assess the effect of ALA on A1C and blood ies are warranted to assess its effect on insulin sensitivity glucose levels in 70 patients with T2DM. Patients remained and glycemic control. on oral diabetes medications and were randomized to re- ceive 300 mg ALA or placebo three times daily for 8 weeks. Alpha-tocopherol/vitamin E Compared with baseline, patients in the ALA group showed Vitamin E is a fat-soluble vitamin that exhibits antioxidant significant reductions in mean fasting blood glucose levels properties.16 and 2-hour postprandial glucose levels. No significant dif- Safety: Evidence suggests that use of high-dose vitamin E ference between ALA and placebo treatment groups was supplements may increase the risk of death from all causes; observed. however, human research is inconsistent.16 Caution is war- A separate randomized, placebo-controlled trial43 as- ranted prior to recommending vitamin E supplementation sessed the effects of ALA on insulin sensitivity in non-insu- to patients. Vitamin E should not be used in patients with lin-dependent diabetes patients. Patients were randomized bleeding disorders or in those taking anticoagulants, and to 600 mg ALA (once to three times daily) or placebo. Com- high-dose vitamin E may increase the risk of congenital pared with baseline, patients administered 600, 1200, or 1800 heart defects.16 Additionally, vitamin E should not be used mg ALA daily demonstrated significantly increased insulin in patients with Alzheimer disease because of a significantly sensitivity of 15%, 14%, and 22%, respectively. However, a sta- increased risk of falls and syncope compared with placebo.5 tistically significant difference was not observed compared Known drug interactions: Possible drug interactions with with placebo. Mild hypoglycemic events were reported in a vitamin E include cyclosporine, paclitaxel, sucralfate, and few subjects, and their dose of oral diabetes medications had mineral oil.16 to be reduced. Efficacy: It has been suggested that vitamin E may aid Several studies have also confirmed that ALA is an effec- in the prevention of both T1DM and T2DM.56,57 Vitamin E tive treatment of diabetic peripheral neuropathy (DPN).39,40,47– may also improve glucose disposal in patients with T2DM, 50 ALA administered orally or intravenously at doses of nerve conduction in patients with diabetic neuropathy, and 600–1200 mg/day may reduce DPN symptoms.39,40,47–49,51 kidney function in patients with T1DM.58–59 Paoloisso et al.60 Symptoms such as burning, pain, numbness, and prickling, observed improved insulin action in non-insulin-dependent as well as attributes of nerve conduction, were improved patients with diabetes who were treated with vitamin E (900 with 3–5 weeks of supplementation. mg dl-alpha-tocopheryl acetate/d). Han et al.52 performed a meta-analysis of 15 clinical tri- Blum et al.61 performed a meta-analysis of two random- als to assess safety and efficacy of ALA in patients with ized trials to evaluate the cardiovascular protection effects of DPN. For 2–4 weeks, patients were intravenously adminis- vitamin E supplementation in patients with T2DM and hap- tered 300–600 mg ALA daily. Results from nine of the stud- toglobin 2-2 genotype (a cardiovascular disease risk marker ies showed significantly improved treatment efficacy in in diabetes). Patients were administered 400 IU daily of vita- the ALA treatment group compared with placebo. Most of min E. Endpoints included nonfatal myocardial infarction, the studies lacked information on adverse effects, adverse stroke, and cardiovascular disease death, in addition to a events, dropouts, and toxicity. Limitations to this review in- composite endpoint. A protective effect of vitamin E was sta- cluded the inclusion of studies with poor methodologies and tistically significant for all endpoints except stroke. Detailed limited information regarding study design. information about methodology of the trials was not includ- Ziegler et al.40 conducted a meta-analysis of four trials ed in the meta-analysis. Vardi et al.62 confirmed a possible (ALADIN I, ALADIN III, SYDNEY, and NATHAN II) to eval- benefit of vitamin E in patients with T2DM and haptoglobin uate the safety and efficacy of administering 600 mg ALA 2-2 genotype. over 3 weeks to patients with diabetes and symptomatic In a meta-analysis performed by Suksomboom et al.,63 polyneuropathy. Changes in total symptom score (TSS) was vitamin E supplementation did not improve glycemic con- assessed daily (except weekends). Patients treated with ALA trol in the overall group of patients with T2DM. However, demonstrated a significant relative improvement in TSS of vitamin E did improve glycemic control in patients with in- 24.2% compared with placebo. adequate glycemic control at baseline (A1C ≥8%) and baseline Three of the four trials included studies showing the ben- serum vitamin E levels below normal ranges.

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Other data suggest that vitamin E has no effect on serum responses. There was no association between chromium and glucose, A1C, or fructosamine levels.54,64–66 In the HOPE trial, glucose or insulin concentration in subjects without diabetes, treatment with vitamin E for an average of 4.5 years had no while data included in the analysis for patients with diabetes effect on cardiovascular outcomes.67 were inconclusive. Kleefstra et al.71 reported similar negative Some experts believe that vitamin E supplementation in results in a study evaluating chromium supplementation the form of alpha-tocopherol rather than gamma-tocopherol in patients with T2DM on oral agents. Many of the studies may be a factor in the observable negative effects or lack of evaluated were small and lacked defined methodology or in- effects reported.16 Gamma-tocopherol is believed to have formation critical to assessing the trial. more antioxidant effects compared with alpha-tocopherol. Additional research with more defined endpoints and Caution should be exercised prior to recommending vita- better methodology should be conducted prior to recom- min E to patients because of possible adverse effects and the mending chromium for the management of T2DM. lack of beneficial data.

Pyridoxine/vitamin B6

Chromium Pyridoxine (Vitamin B6) is required for the synthesis of sero- Chromium is an essential element in the metabolism of car- tonin and norepinephrine, as well as for myelin formation.16 bohydrates, lipids, and proteins.16 Chromium picolinate, the Pyridoxine supplementation has been assessed for improve- most common synthetic chromium product evaluated in ment of glucose metabolism and in the treatment of diabetic published literature, is thought to be more completely ab- neuropathy. sorbed and have a greater bioavailability than other chro- Safety: Pyridoxine is likely safe when used orally in doses mium formulations.68,69 Chromium picolinate has been ad- within the recommended dietary allowance.16 Doses greater ministered at doses ranging from 200 to 1400 mcg/day for a than 200 mg should be avoided, as reversible neuropathy has period of 6 weeks to 6 months. Other doses of varying forms been reported with high doses.16,78 of chromium have also been studied, including chromium Known drug interactions: Due to an additive hypertensive chloride, chromium-enriched yeast, and brewer’s yeast. effect, pyridoxine should not be used in combination with Safety: Trivalent chromium, typically found in food and other antihypertensives or in patients with cardiovascular supplements, appears to be safe, with very low toxicity.16 conditions.16 Patients treated for Parkinson disease should Many of the studies assessing the effects of chromium on pa- use caution before taking additional pyridoxine, as it may tients with T2DM reported either no adverse events or such enhance the metabolism of levodopa when levodopa is taken minimal effects as nausea, vomiting, constipation, headache, as a single agent. and vertigo.16,70,71 Efficacy: Pyridoxine may have a role in the treatment of Chromium is likely safe when used appropriately, al- diabetic neuropathy.38,78–80 In combination with thiamine 25 though shortened QTc intervals have been reported.16 mg daily, pyridoxine 50 mg may reduce the severity of symp- Known drug interactions: Theoretically, chromium may toms in patients with diabetic neuropathy.38,78 interact with selective serotonin reuptake inhibitors, mono- Abbas et al.80 assessed the effect of pyridoxine amine oxidase inhibitors, antiparkinsonian agents, and cen- 50 mg and thiamine 25 mg daily in patients with diabetes. A tral nervous system stimulants.16 Chromium picolinate may total of 100 control patients received a tablet identical to that affect the central nervous system metabolism of dopamine, provided to the treatment group but containing only 1 mg serotonin, and norepinephrine. Additionally, administration of pyridoxine and 1 mg of thiamine. Severity of peripheral of H2 blockers may inhibit the absorption of chromium. Ad- neuropathy symptoms decreased in 48.9% of patients in the ministration of levothyroxine sodium and chromium should treatment group, compared with 11.4% in the control group. be separated by several hours. Because patients’ pyridoxine levels were not reported, it is Efficacy: Chromium use in patients with T2DM has been difficult to determine the role of pyridoxine supplementation associated with beneficial effects on glucose, lipid metabo- in the trial. Conflicting evidence for use of pyridoxine in the lism, and insulin sensitivity.45,68,69,72–74 management of neuropathy in T2DM patients also exists.38,78 Balk et al.69 conducted a systematic review of randomized Researchers have also evaluated the use of pyridoxine controlled trials evaluating the effect of chromium supple- for impaired glucose tolerance in nonpregnant patients with mentation on glucose metabolism and lipid profile param- pyridoxine deficiency, with supplementation not found to eters. A total of 41 studies comprising 431 patients with ei- significantly improve either glucose tolerance or insulin re- ther T2DM or glucose intolerance met the eligibility criteria. sponse to glucose.81 This finding was affirmed by another Overall, chromium supplementation in patients with T2DM study in which 7 of 13 included patients had a pyridoxine proved statistically significant in reducing A1C by 0.6% and deficiency. 82 fasting glucose by −1.0 mmol/L; however, lipids were not im- At this time, pyridoxine should not be routinely recom- proved. None of the included studies reported differences in mended for glycemic control or peripheral neuropathy to pa- patients with glucose tolerance. tients without pyridoxine deficiency. Additional studies are However, the results of other studies are inconsistent with required. these findings.70,71,75,76 Althuis et al.77 conducted a systematic review and meta-analysis of 15 randomized controlled trials Selenium to determine the effect of chromium on glucose and insulin Selenium is an essential trace mineral found in soil, water, www.pharmacist.com august 2014 • PharmacyToday 65 CPE natural products for t2dm and comorbid conditions

and some foods.16 It functions as a cofactor for the antioxi- including healthy controls and those with poorly controlled dant enzymes. T2DM and diabetic neuropathy. Each day, participants re- Safety: Selenium should not be used in patients on hemo- ceived 660 mg of zinc sulfate orally. After 6 weeks of treat- dialysis or immunosuppressants, or in patients with hyper- ment, the group receiving zinc plus an oral antidiabetic ex- lipidemia, hypothyroidism, or high risk for development of perienced a significant decrease in fasting blood glucose and T2DM.16 preprandial blood glucose compared with before treatment. Known drug interactions: Possible drug interactions with Significant changes in motor nerve conduction velocity of selenium include HMG-CoA reductase inhibitors, barbitu- the median nerve and the common peroneal nerve were also rates, and erythropoietin.16 noted. Randomization, power calculations, adverse events, Efficacy: Data do not support use of selenium for the treat- and interactions were not discussed in the study manuscript. ment of T2DM.83–85 Interestingly, both low concentrations of Zinc’s potential benefits cannot be determined based on selenium in toenails and high serum levels of selenium have the available literature. Additional research is required to as- been associated with an increased risk for the development sess its effect on T2DM prior to making any recommenda- of T2DM.38,83,84 In one secondary analysis, patients who took tions to patients. selenium 200 mcg daily for an average of 7.7 years had a sig- nificantly increased risk for T2DM.83 Pharmacist-directed practical advice Selenium should not be recommended for the treatment Some of the most widely used agents in traditional medicine of T2DM. have derived from plant sources, including aspirin, antima- larials, anticancers, and digitalis.12 However, a current lack Case study 2 of scientific and clinical data establishing the safety and effi- A 74-year-old male patient with T2DM and benign prostatic hyperplasia cacy of many currently available “natural” products hinders (BPH) is currently taking selenium. He heard that selenium may be their use for medicinal purposes in the general population. helpful in controlling his BPH as well as his diabetes. His diabetes is well controlled with his current regimen, which includes metformin. He According to ADA, “there is limited evidence that the would like to stop taking his metformin and just continue the selenium. use of vitamin, mineral, or herbal supplements is necessary He asks you for your opinion. in the management of diabetes.”33 Therefore, ADA does not Selenium is an essential trace mineral that functions as a provide specific recommendations on the use of herbals and cofactor for the antioxidant enzymes. Data do not support the use of dietary supplements for glycemic control. selenium for the treatment of T2DM, and it has been implicated as a Of the natural products and dietary supplements dis- possible risk factor for the development of T2DM. cussed, alpha-lipoic acid and fenugreek demonstrate the strongest scientific evidence for lowering blood glucose lev- Zinc els. Additionally, good scientific evidence exists for use of Zinc is a trace mineral essential for the functioning of cellu- gymnema, vitamin E, and ivy gourd.16 lar processes, including enzymatic processes.16 Patients with Table 1 provides a summary and pocket guide for natural diabetes may be zinc deficient.16,86 Evidence exists that zinc products commonly used in the management of T2DM. Pa- may increase glucose transport into cells and thus assist with tients should be aware that these products may contain con- insulin-induced glucose transport.87 taminants or inappropriate amounts of active ingredients, as Safety: Zinc is likely safe when consumed at levels com- they are not required to undergo the same approval process monly found in food or at levels lower than the tolerable up- required for medications in the United States. per level: 4 mg for infants aged 0–6 months, 5 mg for infants Common dietary food sources designated by FDA as aged 7–12 months, 7 mg for children aged 1–3 years, 12 mg “generally recognized as safe” (e.g., cinnamon, dandelion, for children aged 4–8 years, 23 mg for children aged 9–13 and onion) can be safely recommended for use in the gen- years, 34 mg for children aged 14–18 years, and 40 mg for eral diet, with the potential benefit of lowering glucose with adults aged 19 years or older.16 minimal adverse effects. The most common adverse effects of zinc reported to the While some assume that consumers use complementa- California Poison Control System include nausea and vom- ry and alternative medicine because of their dissatisfaction iting.88 Caution should be used when zinc is administered with conventional treatment options, a 2004 U.S. study sug- as a supplement to patients with gastrointestinal disorders, gests otherwise.15 Study participants said they were more neurological disorders, hematological disorders, renal insuf- concerned with the inability of health care providers to un- ficiency, immunosuppression, and coagulation disorders, derstand the use of such products in the medical manage- and to men at risk for prostate cancer.16 ment of disease states than they were about providers’ poten- Known drug interactions: Possible drug interactions in- tial disapproval. This finding underscores the importance of clude fluoroquinolones, tetracyclines, and calcium salts.16 pharmacists being knowledgeable about the available litera- Efficacy: Zinc supplementation in patients with T2DM has ture on safety and efficacy of herbal and dietary supplement been shown to decrease fasting and postprandial blood glu- products, as well as the interaction of these products with cose.89 other pharmacologic treatments. Gupta et al.89 conducted a double-blind randomized trial Before recommending herbal or dietary supplementation assessing the efficacy of zinc supplementation in 50 patients, for patients with diabetes, consideration should be given to

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Table 1. Pocket guide for commonly used natural products in the management of type 2 diabetes mellitus5,16 Supplement Natural Standard Bottom line/counseling points Commonly studied doses evidence grade for T2DMa Alpha-lipoic acid A Alpha-lipoic acid is generally well tolerated when doses do not exceed 300–1800 mg/d 1200–1800 mg. Evidence exists that it may aid in the treatment of T2DM and peripheral neuropathy. Alpha-tocopher- B Caution is warranted prior to recommending vitamin E supplementation 400–600 IU/d ol/vitamin E because of a possible increased risk of death from all causes in patients who take high doses. Bitter melon C Bitter melon has been studied in humans as an oral and subcutaneous agent; 2–3 g/d however, safety and efficacy data are not readily available for specific doses. Use cautiously in women of child-bearing age (risk of miscarriage). Also avoid use in nursing women, children, patients with gourd/melon allergies, and those with G6PDH deficiency. Burdock C Given the potential of harvesters to confuse burdock with belladonna alkaloids, 90 g/d purity of burdock preparations cannot be guaranteed; contaminated burdock may produce atropine-like effects. Because of safety concerns and lack of efficacy data, burdock should not be recommended at this time. Avoid use in patients with allergies to ragweed, chrysanthemums, marigolds, daisies, or pectin. Use caution when taken with anticoagulants and antiplatelet agents. Chromium C Chromium is likely safe when used appropriately. Beneficial effects on glucose 200, 600 mcg/d in patients with T2DM have been documented; however, the results are inconsistent. Additional research is required before recommending to patients 500–1000 mcg/d (picolinate)

for glycemic control. Administration of H2 blockers may inhibit absorption of chromium. Additionally, coadministration of levothyroxine and chromium should be separated by several hours. Cinnamon C When consumed as a spice for food, cinnamon is likely safe and may lower 1–3 g/d blood glucose values in patients with diabetes. One gram of cinnamon is equal to approximately one-half teaspoonful per day.5 It should be noted, however, that cinnamon is a high-risk allergen. Also, avoid concomitant use with anticoagulants. Dandelion C Dandelion is likely safe when used as naturally found in food products. How- No human data available ever, human efficacy data for glycemic-lowering effects is severely lacking. Fenugreek A Fenugreek seed powder has more available positive evidence than other herbal 5–100 g/d supplements for reducing blood glucose levels in patients with T2DM. Gastro- (seed powder) intestinal effects may be experienced with its use. Space other oral medica- tions apart from fenugreek administration by at least 2 hours. Ginseng C Asian or American ginseng products may have efficacy as glucose-lowering 3, 6 g/d, agents; however, the inability to reliably reproduce efficacy results in trials divided into pre-meal doses limits the confident recommendation of these agents for glycemic control. Gymnema B It may be safe to recommend gymnema for glycemic lowering in patients 400 mg/d with T2DM, but further well-controlled trials need to be conducted. Counsel patients on the potential for enhanced perception of bitter taste. Ivy Gourd B Limited data in trials with small sample sizes suggest possible efficacy for 1800 mg/d; 6 g/d glycemic control in patients with T2DM. Ivy gourd is associated with possible minor gastrointestinal effects, but it has no known drug interactions. Nopal C Nopal is likely safe when consumed as part of a regular diet and may reduce 100–600 g/d blood glucose and cholesterol levels. Use with caution in patients taking anticoagulants, antiplatelet agents, or agents metabolized through the CYP450 system. Onion C Onion is likely safe when consumed as a part of regular dietary intake. Caution 20 g fresh onion consumed should be exercised when combined with anticoagulants, antiplatelet agents, three times daily; blood pressure lowering agents, or agents metabolized through the CYP450 25, 50, 100, and system. 200 g aqueous onion extract Psyllium C When added to one’s regular diet or used as fiber supplementation, psyllium 5.2 g seed husk two (hyperglycemia) may benefit glycemic control. Oral medications should be taken 1 hour before times daily or 2 hours after psyllium. Additionally, products containing psyllium should be consumed with adequate amounts of water.

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Table 1 continued from page 67 Pyridoxine C Pyridoxine is likely safe when used within one’s recommended dietary al- 50–100 mg/d; lowance. Dosages greater than 200 mg have been associated with reversible <200 mg/d recommended neuropathy. Selenium D Selenium should be avoided in patients on hemodialysis or immunosuppres- <800 mcg/d recommended (prevention) sants, as well as in those with hyperlipidemia or hypothyroidism. Selenium may increase risk for the development of T2DM. Zinc C Limited data is available on the efficacy of zinc in patients with T2DM. Zinc 600–660 mg/d should not be coadministered with fluoroquinolones, tetracyclines, or calcium salts. Abbreviations used: CYP450, cytochrome P450; G6PDH, glucose-6-phosphate dehydrogenase; T2DM, type 2 diabetes mellitus. aNatural Standard evidence-based grading scale key: A, strong scientific evidence; B, good scientific evidence; C, unclear or conflicting scientific evidence; D, fair negative scientific evidence; F, strong negative scientific evidence. the type and severity of disease, as well as other agents used for glycemic control. Patients should also be closely moni- Table 2. Elements that should be clearly identified on tored for adverse events. Optimal doses of natural products herbal and dietary supplement products prior to pharmacist are often unclear, many products are not standardized, and recommendation extensive variability can be seen from manufacturer to man- Common or scientific name of product ufacturer or batch to batch. Dosage of the botanical Pharmacists must be able to determine which brands of Part of the plant from which it was made herbal and dietary supplements can be reliably recommend- Active and other ingredients ed to consumers and use manufacturer labeling as a dosing Manufacturer’s name and address, lot number, and date of manufacture guide (Table 2).16 Pharmacists should look for products with and expiration recognized symbols of quality (e.g., United States Pharmaco- peia and the National Formulary, TruLabel, Consumer Lab) and avoid recommending foreign products unless the qual- 6. Dietary Supplement Health and Education Act of 1994, PL 103-417, 108 Stat 4325. ity is known.8 7. U.S. Food and Drug Administration. Dietary supplements. www. fda.gov/Food/DietarySupplements/default.htm. Accessed Janu- Conclusion ary 29, 2014. More than 400 herbal agents have been identified for their 8. Yeh GY, Eisenberg DM, Kaptchuk TJ, et al. Systematic review of potential antihyperglycemic effects.11,21 However, there is no herbs and dietary supplements for glycemic control in diabetes. Dia- conclusive evidence that these agents are safer or more ef- betes Care. 2003;26(4):1277–1294. fective than other agents currently used in modern medical 9. Shapiro K, Gong WC. Natural products used for diabetes. J Am practice. Pharmacists should encourage patients to seek ad- Pharm Assoc. 2002:42(2):217–226. vice about the addition of these agents for the management 10. Yeh GY, Eisenberg DM, Davis RB, et al. Use of complementary and of diabetes and consider these agents as adjuncts to pharma- alternative medicine among persons with diabetes mellitus: results cologic treatment. of a national survey. Am J Public Health. 2002;92(10):1648–1652. Though limited data are available for the use of herbals 11. Modak M, Dixit P, Londhe J, et al. Indian herbs and herbal and dietary supplements for diabetes care, health care con- drugs used for the treatment of diabetes. J Clin Biochem Nutr. sumers continue to turn to these agents as a means of supple- 2007;40(3):163–173. 12. Grover JK, Yadav S, Vats V. Medicinal plants of India with anti-dia- mentation and/or management of their disease state. It is es- betic potential. J Ethnopharmacol. 2002;81(1):81–100. sential that pharmacists recognize safety and efficacy issues 13. Garrow D, Egede LE. Association between complementary and al- prior to recommending herbals and dietary supplements for ternative medicine use, preventive care practices, and use of con- diabetes care. ventional medical services among adults with diabetes. Diabetes Care. 2006;29(1):15–19. References 14. Bell RA, Suerken CK, Grzywacz JG, et al. Complementary and al- 1. Vuksan V, Sievenpiper JL. Herbal remedies in the management of ternative medicine use among adults with diabetes in the United diabetes: lessons learned from the study of ginseng. Nutr Metab States. Altern Ther in Health Med.2006;12(5):16–22. Cardiovasc Dis. 2005;15(3):149–160. 15. Cicero AF, Derosa G, Gaddi A. What do herbalists suggest to diabet- 2. Bailey RL, Gahche JJ, Lentino CV, et al. Dietary supplement use in ic patients in order to improve glycemic control? Evaluation of scien- the United States, 2003–2006. J. Nutr. 2011;141(2):261–266. tific evidence and potential risks. Acta Diabetol. 2004;41(3):91–98. 3. Gahche J, Bailey R, Burt V, et al. Dietary supplement use among 16. Natural Standard. https://naturalmedicines.therapeuticresearch. U.S. adults has increased since NHANES III (1988–1994). NCHS com. Accessed January 29, 2014. Data Brief. 2011;61:1–8. 17. Dans AM, Villarruz MV, Jimeno CA, et al. The effect of Momordica 4. Kennedy J. 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Nutr Metab Cardio- diabetic polyneuropathy are improved with alpha-lipoic acid: the vas Dis. 2008;18(1):46 56. – SYDNEY trial. Diabetes Care. 2003;26(3):770–776. 29. Baskaran K, Kizar Ahamath B, Radha Shanmugasundaram K, et 50. McIIduff CE, Rutkove SB. Critical appraisal of the use of alpha lipoic al. Antidiabetic effect of a leaf extract from Gymnema sylvestre in acid (thiotic acid) in the treatment of symptomatic diabetic polyneu- non-insulin-dependent diabetes mellitus patients. J Ethnopharma- ropathy. Ther Clin Risk Manag. 2011;7:377–385. col. 1990;30(3):295 300. – 51. Ziegler D, Gries FA. Alpha-lipoic acid in the treatment of diabetic pe- 30. Kuriyan R, Rajendran R, Bantwal G, et al. Effect of supplementation ripheral and cardiac autonomic neuropathy. Diabetes. 1997;46(Sup- of Coccinia cordifolia extract on newly detected diabetic patients. pl 2):S62–S66. Diabetes Care. 2008;31(2):216–220. 52. Han T, Bai J, Liu W, et al. A systematic review and meta-analysis of 31. Shekelle PG, Hardy M, Morton SC, et al. Are Ayurvedic herbs for alpha-lipoic acid in the treatment of diabetic peripheral neuropathy. diabetes effective? J Fam Pract. 2005;54(10):876–886. Eur J Endocrinol. 2012;167(4):465–471. 32. Kamble SM, Jyotishi GS, Kamalakar PL, et al. Efficacy of Coccinia 53. Haritoglou C, Gerss J, Hammes HP, et al. Alpha-lipoic acid for indica W & A in diabetes mellitus. J Res Ayur Sid. 1996;17:77 84. – the prevention of diabetic macular edema. Ophthalmologica. 33. American Diabetes Association. Standards of medical care in dia- 2011;226(3):127–137. betes—2014. Diabetes Care. 2014;37(Suppl 1):s14-s80. 54. de Oliveira AM, Rondo PH, Luzia LA, et al. The effects of lipoic acid 34. Hall M, Flinkman T. Do fiber and psyllium fiber improve diabetic me- and alpha-tocopherol supplementation on the lipid profile and insu- tabolism? Consult Pharm. 2012;27(7):513 516. – lin sensitivity of patients with type 2 diabetes mellitus: a random- 35. AbouZid SF, Ahmed OM, Ahmed RR, et al. Antihyperglycemic effect ized, double-blind, placebo-controlled trial. Diabetes Res Clin Pract. of crude extracts of some Egyptian plants and algae. J Med Food. 2011;92(2):253 –260. 2014;17(3):400 406. – 55. Sano M, Ernesto C, Thomas RG, et al. A controlled trial of selegiline, 36. Anderson JW, Allgood LD, Turner J, et al. Effects of psyllium on alpha-tocopherol, or both as treatment for Alzheimer’s disease. N glucose and serum lipid responses in men with type 2 diabetes and Engl J Med. 1997;336(17):1216–1222. hypercholesterolemia. Am J Clin Nutr. 1999;70(4):466 473. – 56. Montonen J, Knekt P, Jarvinen R, et al. Dietary antioxidant intake 37. Ziai SA, Larijani B, Akhoondzadeh S, et al. Psyllium decreased se- and risk of type 2 diabetes. Diabetes Care. 2004;27(2):362–366. rum glucose and glycosylated hemoglobin significantly in diabetic 57. Arnlov J, Zethelius B, Riserus U, et al. Serum and dietary beta-caro- outpatients. J Ethnopharmacol. 2005;102(2):202 207. – tene and alpha-tocopherol and incidence of type 2 diabetes mellitus 38. Natural Medicines Comprehensive Database. http://naturaldata- in a community-based study of Swedish men: report from the Up- base.therapeuticresearch.com. Accessed February 1, 2014. psala Longitudinal Study of Adult Men (ULSAM) study. Diabetolo- 39. Ziegler D, Ametov A, Barinov A, et al. Oral treatment with alpha-li- gia. 2009;52(1):97–105. poic acid improves symptomatic diabetic polyneuropathy: the SYD- NEY 2 trial. Diabetes Care. 2006;29(11):2365–2370. www.pharmacist.com august 2014 • PharmacyToday 69 CPE natural products for t2dm and comorbid conditions

58. Bursell SE, Clermont AC, Aiello LP, et al. High-dose vitamin E sup- 74. Pei D, Hsieh CH, Hung YJ, et al. The influence of chromium chlo- plementation normalizes retinal blood flow and creatinine clearance ride-containing milk to glycemic control of patients with type 2 dia- in patients with type 1 diabetes. Diabetes Care. 1999;22(8):1245– betes mellitus: a randomized, double-blind, placebo-controlled trial. 1251. Metabolism. 2006;55(7):923–927. 59. Tutuncu NB, Bayraktar M, Varli K. Reversal of defective nerve con- 75. Krol E, Krejpcio Z, Byks H, et al. Effects of chromium brewer’s duction with vitamin E supplementation in type 2 diabetes: a prelimi- yeast supplementation on body mass, blood carbohydrates, and nary study. Diabetes Care. 1998;21(11):1915–1918. lipids and minerals in type 2 diabetic patients. Biol Trace Elem Res. 60. Paolisso G, D’Amore A, Giugliano D, et al. Pharmacologic doses of 2011;143(2):726 –737. vitamin E improve insulin action in healthy subjects and non-insulin- 76. Jain SK, Kahlon G, Morehead L, et al. Effect of chromium dinicocys- dependent diabetic patients. Am J Clin Nutr. 1993;57(5):650–656. teinate supplementation on circulating levels of insulin, TNF-alpha, 61. Blum S, Vardi M, Brown JB, et al. Vitamin E reduces cardiovascular oxidative stress, and insulin resistance in type 2 diabetic subjects: disease in individuals with diabetes mellitus and the haptoglobin 2-2 randomized, double-blind, placebo-controlled study. Mol Nutr Food genotype. Pharmacogenomics. 2010;11(5):675–684. Res. 2012;56(8):1333–1341. 62. Vardi M, Blum S, Levy AP. Haptoglobin genotype and cardiovas- 77. Althuis MD, Jordan NE, Ludington EA, et al. Glucose and insulin cular outcomes in diabetes mellitus- natural history of the disease responses to dietary chromium supplements: a meta-analysis. Am and the effect of vitamin E treatment. Meta-analysis of the medical J Clin Nutr. 2002;76(1):148–155. literature. Eur J Intern Med. 2012;23(7):628–632. 78. Head KA. Peripheral neuropathy: pathogenic mechanisms and al- 63. Suksomboon N, Poolsup N, Sinprasert S. Effects of vitamin E ternative therapies. Altern Med Rev. 2006;11(4):294–329. supplementation on glycaemic control in type 2 diabetes: sys- 79. Levin ER, Hanscom TA, Fisher M, et al. The influence of pyridoxine tematic review of randomized controlled trials. J Clin Pharm Ther. in diabetic peripheral neuropathy. Diabetes Care. 1981;4(6):606– 2011;36(1):53–63. 609. 64. Gomez-Perez FJ, Valles-Sanchez VE, Lopez-Alvarenga JC, et al. 80. Abbas ZG, Swai AB. Evaluation of the efficacy of thiamine and pyri- Vitamin E modifies neither fructosamine nor HbA1c levels in poorly doxine in the treatment of symptomatic diabetic peripheral neuropa- controlled diabetes. Rev Invest Clin. 1996;48(6):421–424. thy. East Afr Med J. 1997;74(12):803–808. 65. Ble-Castillo JL, Carmona-Diaz E, Mendez JD, et al. Effect of alpha- 81. Rao RH. Glucose tolerance in subclinical pyridoxine deficiency in tocopherol on the metabolic control and oxidative stress in female man. Am J Clin Nutr. 1983;38(3):440–444. type 2 diabetics. Biomed Pharmacother. 2005;59(6):290–295. 82. Rao RH, Vigg BL, Rao KS. Failure of pyridoxine to improve glucose 66. Kataja-Tuomola M, Sundell JR, Mannisto S, et al. Effect of alpha- tolerance in diabetics. J Clin Endocrinol Metab. 1980;50(1):198– tocopherol and beta-carotene supplementation on the incidence of 200. type 2 diabetes. Diabetologia. 2008;51(1):47–53. 83. Stranges S, Marshall JR, Natarajan R, et al. Effects of long-term 67. Yusuf S, Dagenais G, Pogue J, et al. Vitamin E supplementation selenium supplementation on the incidence of type 2 diabetes: a and cardiovascular events in high risk patients. N Engl J Med. randomized trial. Ann Intern Med. 2007;147(4):217–223. 2000;342(3):154–160. 84. Bleys J, Miller ER III, Pastor-Barriuso R, et al. Vitamin-mineral sup- 68. Albarracin CA, Fuqua BC, Evans JL, et al. Chromium picolinate and plementation and the progression of atherosclerosis: a meta-analy- biotin combination improves glucose metabolism in treated, uncon- sis of randomized controlled trials. Am J Clin Nutr. 2006;84(4):880– trolled overweight to obese patients with type 2 diabetes. Diabetes 887. Metab Res Rev. 2008;24(1):41–51. 85. Akbaraly TN, Arnaud J, Rayman MP, et al. Plasma selenium and 69. Balk EM, Tatsioni A, Lichtenstein AH, et al. Effect of chromium sup- risk of dysglycemia in an elderly French population: results from the plementation on glucose metabolism and lipids: a systematic review prospective Epidemiology of Vascular Ageing Study. Nutr Metab. of randomized controlled trials. Diabetes Care. 2007;30(8):2154– 2010;7:21. 2163. 86. Blostein-Fujii A, DiSilvestro RA, Frid D, et al. Short-term zinc sup- 70. Kleefstra N, Houweling ST, Jansman FG, et al. Chromium treatment plementation in women with non-insulin-dependent diabetes mel- has no effect in patients with poorly controlled, insulin-treated type litus: effects on plasma 5’-nucleotidase activities, insulin-like growth 2 diabetes in an obese Western population: a randomized, double- factor I concentrations, and lipoprotein oxidation rates in vitro. Am J blind, placebo-controlled trial. Diabetes Care. 2006;29(3):521–525. Clin Nutr. 1997;66(3):639–642. 71. Kleefstra N, Houweling ST, Bakker SJ, et al. Chromium treatment 87. Tang X, Shay NF. Zinc has an insulin-like effect on glucose transport has no effect in patients with type 2 diabetes in a Western popula- mediated by phosphoinositol-3-kinase and Akt in 3T3-L1 fibroblasts tion: a randomized, double-blind, placebo-controlled trial. Diabetes and adipocytes. J Nutr. 2001;131(5):1414–1420. Care. 2007;30(5):1092–1096. 88. Dennehy CE, Tsourounis C, Horn AJ. Dietary supplement-related 72. Singer GM, Geohas J. The effect of chromium picolinate and biotin adverse events reported to the California Poison Control System. supplementation on glycemic control in poorly controlled patients Am J Health Syst Pharm. 2005;62(14):1476–1482. with type 2 diabetes mellitus: a placebo-controlled, double-blinded, 89. Gupta R, Garg VK, Mathur DK, et al. Oral zinc therapy in diabetic randomized trial. Diabetes Technol Ther. 2006;8(6):636–643. neuropathy. J Assoc Physicians India. 1998;46(11):939–942. 73. Anderson RA, Cheng N, Bryden NA, et al. Elevated intakes of supplemental chromium improve glucose and insulin variables in individuals with type 2 diabetes. Diabetes. 1997;46(11):1786–1791.

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CPE Assessment Instructions: This exam must be taken online; please see “CPE information” for further instructions. The online system will present these questions in random order to help reinforce the learning opportunity. There is only one correct answer to each question.

1. Which botanical agent is a known abortifacient? 7. A female with T2DM asks for an herbal supplement a. Burdock to use as an adjunct to her metformin therapy for gly- b. Bitter melon cemic control. She takes no other medications and has c. Fenugreek no other disease states at this time. Based on the avail- d. Gymnema able safety and efficacy data, which herbal supplement 2. Due to theoretical concerns, dandelion use should be would be the most appropriate to recommend? avoided in patients with: a. Burdock a. Gastric ulcers b. Dandelion b. Pancreatitis c. Fenugreek c. Anemia d. Ivy gourd d. Liver disease 8. Which statement is true regarding ginseng? 3. An important counseling point for consumers wish- a. Siberian ginseng is an acceptable alternative to ing to purchase gymnema would be: Panax ginseng. a. Significant potential for weight gain b. Studies have demonstrated efficacy when given 40 b. Enhanced perception of bitter taste minutes after meals. c. Avoid combination with anticoagulants c. Products are standardized according to the ginsen- d. Take 40 minutes prior to meals osides and their ratios. 4. Based on available data, which agent has good scien- d. Doses of 1–9 grams have reduced blood tific evidence for glucose-lowering efficacy? glucose values acutely and long term. a. Gymnema 9. Which agent has demonstrated hypoglycemic effects b. Onion comparable to tolbutamide when given as a single oral c. Cinnamon dose? d. Nopal a. Dandelio 5. Which herbal agent is more likely to increase bleeding b. Onion risk when used concomitantly with anticoagulants? c. Cinnamon a. Bitter melon d. Psyllium b. Burdock 10. Which agent should be cautiously recommended in c. Cinnamon persons with cardiovascular disease because of the d. Fenugreek potential for contamination during harvesting? 6. Which agent has a more notable drug–drug interaction a. Bitter melon with dandelion? b. Burdock a. Calcium carbonate c. Fenugreek b. Furosemide d. Dandelion c. Ciprofloxacin d. Orlistat

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CPE instructions: 1. Log in or create an account at pharmacist.com and select LEARN from the top of the page; select Continuing Education, then Home Study CPE to access the Library. 2. Enter the title of this article or the ACPE number to search for the article and click on the title of the article to start the home study. 3. To receive CPE credit, select Enroll Now from the left navigation and successfully complete the assessment (with randomized questions) and evaluation. 4. To obtain your CPE credit, click “Claim” on the right side of the page. You will need to provide your NABP e-profile ID number to obtain your CPE credit. Your CPE transcripts will be stored on CPE Monitor. Live step-by-step assistance is available Monday through Friday, 8:30 am to 5:00 pm ET from APhA Member Services at 800-237-APhA (2742) or by e-mailing [email protected].

www.pharmacist.com august 2014 • PharmacyToday 71 CPE natural products for t2dm and comorbid conditions

11. A reliable brand of herbal supplements to recommend c. Higher doses (>200 mg) of alpha-lipoic acid have will contain: been associated with reversible neuropathy. He a. Manufacturer’s phone number should discontinue the alpha-lipoic acid and see his b. Notice of FDA approval primary care provider. c. Treatment statement for condition d. Peripheral neuropathy is a complication of T2DM. d. Recognized symbol of quality None of his current therapies have any effect on 12. Which dietary supplement has data that demonstrate symptoms of neuropathy. a possible benefit in A1C reduction in patients with 17. A patient at your pharmacy would like to start taking T2DM? selenium to help prevent T2DM. Her mother and two a. Chromium of her siblings have T2DM, and she is very concerned b. Pyridoxine about her risk for the disease. She currently has c. Selenium hypertension and hyperlipidemia. What would you d. Zinc recommend for this patient? 13. Which fat-soluble vitamin has evidence suggesting a. She should start selenium immediately to help pre- that use of high doses may increase the risk of death vent T2DM and to aid in treatment of her hyperlip- and, thus, should not be recommended for manage- idemia. ment of T2DM? b. Prior to starting selenium therapy, she should have a. Pyridoxine the concentration of selenium in her toenails deter- b. Alpha-tocopherol mined. If her concentration is high, she should start c. Alpha-lipoic acid selenium supplementation. d. Zinc c. She should not take selenium as a supplemental 14. Which should be avoided in patients being treated for therapy. Data demonstrate an increased risk for the Parkinson disease? development of T2DM in patients taking selenium. a. Selenium Additionally, selenium should be avoided in patients b. Chromium with hyperlipidemia. c. Alpha-lipoic acid d. She should not take selenium for prevention of d. Pyridoxine T2DM; however, if she is diagnosed with T2DM, she 15. A patient (JM) approaches your community pharmacy should begin selenium supplementation to aid in counter to ask about appropriate administration of glycemic control. chromium. She would like to try supplemental chro- 18. Which supplement has been implicated as a risk factor mium to aid in glycemic control of her T2DM. You in- for the development of insulin autoimmune syn- form her that that additional research is needed before drome? you can recommend chromium for glycemic control, a. Alpha-lipoic acid but she would still like to try the supplement. JM also b. Chromium has hypothyroidism and frequent heartburn. Which c. Onion counseling point would you provide JM? d. Pyridoxine a. Use of levothyroxine and chromium should be 19. Which statement regarding vitamin E is false? separated by several hours. a. Caution is warranted with the use of high-dose vita- b. Chromium should be administered at the same time min E because of a possible increased risk of death as JM’s ranitidine for maximum absorption. from all causes. c. Chromium is contraindicated in patients with hy- b. Vitamin E should be avoided in patients taking pothyroidism. anticoagulants. d. Chromium is contraindicated in patients taking c. Vitamin E has been shown to significantly reduce metformin. A1C levels in patients with T2DM in randomized, 16. A 62-year-old male patient started alpha-lipoic acid placebo-controlled clinical trials. 300 mg daily and pyridoxine 800 mg daily for treat- d. Vitamin E should be avoided in patients taking ment of his T2DM approximately 8 months ago. He cyclosporine. also takes metformin 1500 mg daily. His blood sugar 20. Which adverse event is frequently reported with the seems to be well controlled at this time. However, he use of supplemental zinc? is complaining of peripheral neuropathy pain today. a. Nausea He would like to know what could be causing this b. Encephalitis new symptom. Which is the most appropriate answer? c. Hemorrhage a. Alpha-lipoic acid has been proven to effectively treat d. Congenital heart defects neuropathy; thus, he should continue all of his cur- rent therapies at the current dose. b. Higher doses (>200 mg) of pyridoxine have been associated with reversible neuropathy. He should discontinue the pyridoxine and see his primary care provider.

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