Richard S. Crawford, MD Avera Medical Group Endocrinology and Diabetes April 11, 2014
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Richard S. Crawford, MD Avera Medical Group Endocrinology and Diabetes April 11, 2014 65 year old post-menopausal woman presents to clinic with newly diagnosed diabetes. Her hemoglobin A1c is 8.0 and she has just been placed on Metformin and will be attending diabetes education classes soon She mentions that she watches Dr. Oz and is interested in alternative medicine approaches to diabetes. Patient has started using cinnamon pills, ginseng, chromium, selenium and a “mega-antioxidant”with vitamin C, E and beta-carotene. She also takes calcium and vitamin D She asks if these supplements are a good idea to take. What do you tell your patient? •Herbal supplements and minerals and vitamins in Diabetes •Clinical importance in US •Reasons for use •Common plant based supplements used •Mineral supplements •Antioxidant vitamins •Advice for your patients? Plants have been used for medicinal purposes for thousands of years Two thirds of entries in first edition of US Pharmacopoeia were botanical substances By 1920, standardized pharmaceutical drugs replaced herbal therapies in USA 1960s saw beginning of resurgence of interest in natural and nonconventional medicines 1994- Dietary Supplement Health and Education Act (DSHEA) bill passed by Congress Defined dietary supplements as a product containing any one or more of the following: vitamin, herb, amino acid, mineral, other botanical, concentrate, extract or constituent DSHEA exempted such products from proving safety, efficacy or quality prior to market availability Data from the National Health Interview Survey (2007) 17.7 % of all US adults used an herbal or natural product Total sales of herbal/vitamins $4.8 billion 2008 Goldman, Pt Ann Int Med;135:594,2001 American Bot Council; 82:58, 2009 Number of Diabetics in US 1980 to 2010 (in millions) Over 400 traditional plants have been used in diabetes Plant remedies remain main therapies in underdeveloped countries In US, plant-based remedies have been used by patients and prescribed by alternative medicine practitioners Hypoglycemic action has been confirmed on some substances in animal models Few clinical studies performed to date Diabetes Care 12:8; Sept.1989 553-564 Gymnema sylvestre Fenugreek Bitter Melon Ginseng Cinnamon Gurmar in Hindi (sugar destroyer) Leaves of plants used in Ayurvedic medicine 2000+ years for diabetes, obesity and hyperlipidemia Gymneic acid is active compound lowering glucoses Mechanism of action is unknown Possible decreased intestinal glucose absorption and increases insulin secretion Anti-diabetic action supported by several small clinical studies Porchezian et al. Pharmazie 2003;58(1)5-12 Baskaran, K. et al. Ethnopharmacol1990;30(3): 295-305 Clinical Studies: 1. Baskaran et. al. 22 subjects with NIDDM on conventional oral diabetes medication place on 400 mg of GS4(gymnema extract) Monitored for 18-20 months Showed significant reductions in A1c 5 subjects able to discontinue OADs completely 2. Joffe D. et. al. 65 subjects with DM Diabetic subjects given 800 mg GS4 plus usual meds for 3 months Fasting glucoses lowered by 11% and A1c reduction by 0.6% No adverse events reported Baskaran, K. et al. Ethnopharmacol1990;30(3): 295-305 Joffe, D et al. Diabetes Control News 2001;76:1 Mechanism of action not clear No known serious side effects Small trials show reduction in FBG and hemoglobin A1c Larger clinical trials needed Typical dose: 200-250 mg BID Trigonella foenum-graecum Used as herb (dried or fresh leaves), spice (seeds) or vegetable (leaves, sprouts) Contains sotolon, a chemical producing sweet aroma Used commonly in Indian curries and Ethiopian and Middle Eastern dishes Seeds contain 45.4% fiber and galactose and mannose, agents that reduce glucose Can add as fiber source to muffins, breads, pizzas Dose in pill form 15-35 grams and up to 90 grams Concentrated forms over 100 grams cause GI upset Roberts, KT J Med Food 2011;14(12)1485-9 Trejo, B Natural news Oct 2009 Momordica charantia Plant components used to treat diabetes -Stems -Leaves -Fruit -Seeds Medicinal Compounds Isolated -Charantin- a steroidal saponin agent with insulin-like properties -Momordicin- an alkaloid (responsible for bitterness or fruit) Hypoglycemic effects shown -polypeptide- P (“plant-insulin” with insulin-like properties) Singh, et al. Open Med Chem Jour. 2011;5:70-77 Mechanism of Action for M. charantia Singh, et al. Open Med Chem Jour. 2011;5:70-77 Study comparing effect of bitter melon with Metformin in newly diagnosed type 2 DM subjects 4 week, multicenter randomized, double blind,active-control trial of 4 groups: Metformin 1000 mg/day Bitter Melon 500 mg/day Bitter Melon 1000 mg/day Bitter Melon 2000 mg/day Results: Metformin 1000 mg/day and Bitter Melon 1000 mg/day both reduced Fructosamine levels (-16.8% Metformin, -10.2% Bitter melon) Bitter melon 500 mg and 1000 mg had no significant effect Fuangchan, A. J Ethnopharmacol 201;134(2):422-8 Meta-analysis of studies thus far show modest glucose lowering benefits of bitter melon Bitter melon may have insulin-secretagogue like properties Onset of action reported as 30-60 minutes with peak effect at 4 hours Suggested dose is 3 to 6 tablespoons of bitter melon juice daily Gastrointestinal issues (diarrhea, mild abdominal pain) are possible side effects Need larger controlled trials to further assess clinical benefits and recommendations Raman, A. Phytomedicine. 1996;294 Baldwa, VS. Ups J Med Sci 1977;82:39-41 Ginseng refers to a variety of perennial plants found in the Northern Hemisphere Chinese Ginseng (Panax ginseng) American Ginseng (Panax quinquefolius) Ginseng traditionally used as a “tonic” for improving energy and vigor Evidence for glucose-lowering effects of ginseng Chinese and American ginseng both contain ginsenosides Ginsenosides acts as insulin sensitizers Pan SJ et al. Altern Ther 2001;7:S26 Vuksan et. al showed American ginseng reduces post-prandial glycemia in non-diabetic and type 2 diabetes subjects 19 subjects (10 non-diabetic and 9 diabetic) Receive placebo vs. 3 gm ginseng -at same time as 25-gm glucose load -40-minutes before 25-gm glucose load Measure fasting glucose thru 90 minutes (120 min. in diabetic group) Vuksan, V. et al. Arch Int Med.160; Apr 2010: 1009-13. Results: post-prandial glucose was lowered in both non-diabetic and type 2 diabetic subjects Non-diabetic subjects Diabetic subjects Vuksan, V. et al. Arch Int Med.160; Apr 2010: 1009-13. Vuksan,et al findings: Decrease in post-25 gm carb load glucose level in non-diabetes when ginseng given 40 minutes prior Decrease in post-25 gm carb load glucose level in diabetics both when ginseng given 40 minutes prior and at same time as carb loadboth by about 20% Lack of similar results in other studies could be due to lower glucose loads tested in those studies Possible mechanisms of action: 1. Ginseng slows gastric emptying 2. Ginseng increases insulin secretion via glucosedependent effect on islet cells through the NO pathway Vuksan, V. et al. Arch Int Med.160; Apr 2010: 1009-13. True cinnamon: Cinnamomum verum (Ceylon cinnamon) Most cinnamon in US: C Cassia (Chinese cinnamon) C cassia Natural insulin sensitizer Bioactive polyphenolic polymers act by: Activate insulin receptor kinase acitvity Autophosphorylation of the insulin receptor Activate glycogen synthase activity Benefits of cinnamon in diabetes showed mixed results Jarvill-Taylor, KJ et al. J AM Coll Nutr.2001;20:327-36 Baker, WL et al. Diabetes Care 2008;31(1):41-3. Khan et al. Randomized study comparing placebo vs. cinnamon effects on glucose and lipids 60 subjects with type 2 DM divided into six groups 1, 3 or 6 grams cinnamon remaining three groups on placebo Observed for 60 days total (40 days on cinnamon and then a 20 day post-cinnamon washout period) Assessed for change in FBG and fasting lipids Khan,A. et al. Diabetes Care 26; 12:2003. 3215-3218 Study Subjects: n=60 total 30 men and 30 women Mean age 52 years (all over age 40) 6.73 years of diabetes No subjects were on insulin All were on sulfonylureas at baseline Khan,A. et al. Diabetes Care 26; 12:2003. 3215-3218 Cinnamon reduced fasting glucose levels •18-29% reduction in glucose levels by day 40 in all treatment groups vs. placebo •At day 60, after 20 day washout, glucose level remained lower in 1 gm group Khan,A. et al. Diabetes Care 26; 12:2003. 3215-3218 Cinnamon reduced fasting serum triglyceride levels •At day 40 all cinnamon groups had lower triglyceride levels. •At day 60 (after 20 day washout) only 6 gm cinnamon group had lower TGs Khan,A. et al. Diabetes Care 26; 12:2003. 3215-3218 Cinnamon reduced fasting serum LDL cholesterol levels •At day 40 3 and 6 gram cinnamon groups had lower LDL levels. •At day 60 (after 20 day washout) 1 gm cinnamon group also had lower LDL level Khan,A. et al. Diabetes Care 26; 12:2003. 3215-3218 Conclusions from the Khan study •1-6 grams of daily cinnamon lowered fasting plasma glucose, triglycerides and LDL cholesterol •No adverse events from cinnamon •Sustained benefits even after cessation Khan,A. et al. Diabetes Care 26; 12:2003. 3215-3218 Baker, et al Meta-analysis of five clinical trials in human subjects all involving cinnamomum cassia in diabetes n= 282 subjects Follow-up range 5.7-16.0 weeks Doses ranged from 1-6 grams of cinnamon 4 studies powdered filled capsules and 1 aqueous-filled capsules Combined all of the doses in 1 meta-analysis since no dose-response differences were noted between 1-6 gm. Subjects had type 2 DM or adolescents with type 1 DM Baker, WL et al. Diabetes Care 2008;31(1):41-3. Meta-analysis of five clinical trials in human subjects all involving cinnamomum cassia in diabetes n= 282 subjects Follow-up range 5.7-16.0 weeks Doses ranged from 1-6 grams of cinnamon 4 studies powdered filled capsules and 1 aqueous-filled capsules Combined all of the doses in 1 meta-analysis since no dose-response differences were noted between 1-6 gm. Subjects had type 2 DM or adolescents with type 1 DM Baker, WL et al. Diabetes Care 2008;31(1):41-3. Baker, WL et al. Diabetes Care 2008;31(1):41-3. After analysis, no difference seen in FPG, A1c reduction, triglyceride or LDL levels Median duration of all treatment studies was 12 weeks Studies analyzed were small- estimated 1,166-6,583 patients needed to show differences were due to real effect rather than chance Could not explain Khan study discrepancy (aroma different for cinnamon pills vs. placebo, which could have affected results) Larger randomized double blinded studies are needed Baker, WL et al. Diabetes Care 2008;31(1):41-3. Hypoglycemic agents Banaba (Lagerstromia speciosa) Insulin Sensitizers Banaba (Lagerstromia speciosa) Agaricus mushroom (Agaricus blazei) Prickly pear (Opuntia ficus-indica) Soy (Glycine max) Carbohydrate Absorption Inhibitors Bean pod (Phaseolus vulgaris) Blond psyllium (Plantago ovata) Oat bran (Avena sativa) White mulberry (morus alba) Source: Clinical management series: Natural medicines comprehensive database Chromium Zinc Vanadium Selenium Antioxidant vitamins (vitamin C, beta-carotene and vitamin E) Other supplements for special diabetic patients Chromium is one of the most common element in the earth’s crust and seawater Exists as a metal, hexavalent oxidized state, and trivalent oxidized state Trivalent chromium is an essential nutrient, low in toxicity and most found in most foods and nutritional supplements 1950s –Brewer’s yeast contained “glucose tolerance factor” that prevented diabetes in animal models-this factor later found to be trivalent chromium 1970s- Malnourished patient on TPN showing severe signs of hyperglycemia refractory to insulin had marked improvement after 2 weeks of adding Tuman, RW et al Diabetes 26:820-26.1977 chromium Jeejeebhoy, KN et al Am J Clin Nutr 30:531-8. 1977 Chromium is a critical co-factor in action of insulin Chromium replacement in deficiency is necessary for glucose metabolism Trivalent chromium is found in egg yolks, wholegrains, high bran breakfast cereals, coffee, nuts, broccoli, green beans, brewer’s yeast, meats and certain wine and beers Chromium picolinate supplements: 200- 600 mcg of Chromium per tablet Chromium RDA for adults is 50-200 mcg/day One study shows adults may only be getting 50% of RDA of chromium in diets Cefalu, WT et al. Diabetes Care 27;11:2741-51.2004 Small studies have shown chromium supplementation Improves glucose tolerance and glucose control in diabetics 2 randomized placebo-controlled studies in Chinese diabetic subjects showed chromium improved glycemic control In these Chinese studies, chromium levels were not established at baseline or after treatment Cheng, N et al. J Trace Elements Exp Res 12:55-60,1999 Anderson, RA, Cheng N, et al Diabetes 46:1786-1791,1997 Chromium in gestational diabetes : Small study showed improvement in glucose and insulin metabolism in gestational diabetes 30 subjects treated with 4 or 8 mcg/kg CrP vs. placebo 8 weeks study Decreased FPG, insulin levels and c-peptide in chromium vs. placebo groups Jovanovic, L et al J Trace Elem Exp Med 12: 91-97,1999 Chromium in steroid-induced diabetes : Study showed that chromium administration reversed steroid-induced diabetes 3 patients in study -600 mcg/day of CrP -FPG fell from 250 mg/dl to 150 mg/dl -Anti-diabetic medication requirement reduced by 50% Ravina, A et al. Diabetes Med 16:164-167, 1999 No benefit seen in other studies 3 other randomized placebo-controlled studies showed no benefit of chromium in reducing glucose in diabetic subjects These studies all used lower chromium doses of 250 mcg/day or less Some studies use CrCl3 instead of more bio-available CrP Cefalu, WT et al. Diabetes Care 27;11:2741-51.2004 Recommendations: Must supplement in patient on TPN Adding supplementation to those with known deficiency and diabetes may be helpful Not recommended as a general tool for diabetes management Cefalu, WT et al. Diabetes Care 27;11:2741-51.2004 Pittler, MH et al. Int J Obes Relat Metab Disord 27:522-29, 2003 Increased urinary zinc losses seen in uncontrolled DM with marked glycosuria Gut absorption of zinc may not be able to compensate for urinary losses Small studies of elderly patients with DM have shown benefit in skin ulceration healing with zinc supplements Lab studies assessing zinc status may be unreliable If suspect zinc-deficiency, treat with Zinc Sulfate 220 mg for 3 months. Avoid longer term use as prolonged zinc use may inhibit copper absorption and worsen lipid status Chehade, JM, et al. Diabetes Spectrum;22:214-218,2009 Common mineral usually used to strengthen steel 1985- Canadian researchers discovered Vanadium salts in rats stimulate the uptake of glucose into tissues without raising insulin levels Clinical studies thus far do not show evidence for efficacy in treating diabetes Vanadium salts have risk of toxicity, including harming beta cells Newer organo-vanadium compounds with higher potency and less toxicity are being investigated Chehade, JM, et al. Diabetes Spectrum;22:214-218,2009 Srivastava, AK,et al. Diabet Med 22:2-13, 2005 Selenium is an important component in modulating oxidative stress Selenium implicated in regulating thyroid hormone activity Selenium anti-oxidant potentially could protect against diabetes Cross-sectional analysis study of 8,876 adults, and assessed for selenium levels -Those with the higher selenium levels were more likely to be diabetic -no conclusion or whether this correlation is associated with causation Bleys, J, et al Diabetes Care.30: 829-834, 2007 Benefits of selenium in diabetes are not clear Excess selenium may be associated with increased diabetes risk Excess selenium can cause a condition called selenosis (effects liver, skin, hair and nails) 55 mcg of selenium is a safe daily amount of selenium (1 egg=15 mcg, 1 bagel=27 mcg of selenium) Risk of microvascular and macrovascular complications in diabetes is linked to oxidative stress Vitamin C: Diabetics might be at higher risk of vitamin C deficiency Studies have shown that tissue uptake of vitamin C metabolites is hindered in hyperglycemic states No clinical evidence of vitamin C reducing cardiovascular risk in multiple studies Under certain conditions, vitamin C has been shown to be a prooxidant Doses in excess of 1 gram per day can cause abdominal bloating and osmotic diarrhea Diabetics can achieve adequate vitamin C intake through getting five daily servings of fruits and vegetables Chehade, JM, et al. Diabetes Spectrum;22:214-218,2009 Beta Carotene and Vitamin E Meta-analysis of seven randomized trials of vitamin E and eight randomized trials of beta carotene All trials had over 1000 or more participants Dose range for vitamin E 50-800 IU and beta carotene 15-50 mg Follow up ranged from 1.5 to 12 years Results: No benefit of vitamin E or beta carotene in terms of mortality reduction, CV death or stroke Beta carotene showed small but significant increase in all cause mortality Vivekananthan, DP et al Lancet.361:2017-23.2003 Beta Carotene Beta carotene supplementation linked to higher lung cancer in smokers and those with asbestosis High levels of beta carotene associated with increased belching and yellowing of skin Recommend against supplementing with beta carotene Lee, et al Natl Cancer Inst 91:2102-6. 1999 Bjeklovic, G. Cochrane Database Syst Rev2008:CD004183 Vivekananthan, DP et al Lancet.361:2017-23.2003 Vitamin E Diabetics may have increased vitamin E plasma and platelet concentrations Some studies may indicate increased mortality with vitamin E supplementation Retinitis pigmentosa progression and increased hemorrhagic strokes associated with excess vitamin E Limit supplementation to no more than 400 IU daily Mooradian, AD et al. Diabetes Care.17:464-79,2002 Belokjovic, G JAMA 297:842-857,2007 Chehade, JM, et al. Diabetes Spectrum;22:214-218,2009 Folate for pregnant diabetics -Folate deficiency associated with neural tube defects -pregnant diabetics at higher risk for birth defects -Some studies recommend 4,000 mg of folate before and 12 weeks into pregnancy -ADA Guidelines: 400 mcg in pregnant age diabetics, 600-800 IU if planning or actively pregnant Wilson, RD et al J Obst Gynaec Can 25:959-73,2003 •Vitamin D in older diabetics -Vitamin D important for skeletal health - May also benefit pancreatic insulin secretion and action •Vitamin D recommended amounts are same in diabetic population as non-diabetic: 200 IU daily for children and adults <50 400 IU daily for adults 51-70 600 IU daily for 71 and older Cholecalciferol (vitamin D3) preferred due to longer half life Ergocalciferol (vitamin D2) plant derived is more available Chehade, JM, et al. Diabetes Spectrum;22:214-218,2009 What do you tell your patient? Many plant and herbal sources have potential antidiabetic properties, but none have shown clinical efficacy to recommend routinely Larger clinical trials are needed Some supplements (vanadium, selenium) and vitamins (vitamin E and beta carotene) can have adverse/toxic effects Folic for pregnant or potential pregnant diabetics Vitamin D and calcium for post-menopausal diabetics What do you tell your patient? Stay on the Metformin Attend diabetes classes to work on recommendations for diet, exercise, and diabetes self-care Stay on the calcium and vitamin D and STOP the other supplements