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[email protected] Rishma Walji, BSc, ND, PhD 1 Natural Health Products in Diabetes Agenda 2 Natural Health Product basics Regulations NHP definitions Efficacy and Safety peculiars Common NHPs for Diabetes Alpha lipoic acid Chromium Cinnamon Grape seed Gymnema sylvestre 3 NHP Basics Regulations Food and Drug Act Food and Drug Regulations Medical Device Regulations Cosmetics Regulation NHP Regulations Pre-NHP regulations 5 Food “Any article manufactured, sold or represented for use as food or drink by man, chewing gum, and any ingredient that may be mixed with food for any purpose whatever.” Drug “Any substance or mixture of substances manufactured, sold or represented for use in the diagnosis, treatment, mitigation or prevention of a disease, disorder, abnormal physical state, or the symptoms thereof, in man or animal, restoring, correcting or modifying organic functions in man or, disinfection in premises in which food is manufactured, prepared or kept.” Advantages/disadvantages? Why regulate? 6 Adulteration Exaggerated claims Mislabelling No standard labelling standards Contamination Impurities Quantity different than what was on the label No need to prove efficacy A new Health Canada directorate 7 NHPD – Natural Health Products Directorate Mandate: “To ensure that all Canadians have ready access to natural health products that are safe, effective, and of high quality, while respecting freedom of choice and philosophical and cultural diversity” NHP Regulations: January 1, 2004 NHP regulated as a subset of drugs http://canadagazette.gc.ca/partII/2003/20030618/html/sor196-e.html NHP Regulations 8 Product licensing Labelling Site licensing and GMP Definitions Clinical Trials NHP Regulations ADR reporting 9 Boon HS et al. Patient Education and Counseling 2007; 68:193-9. NHP definition 10 Includes: Herbal remedies Homeopathic medicines Materials from plants, algae, bacteria, fungi, or non-human animal material Amino acids Essential fatty acids Probiotics Vitamins and Minerals Synthetic duplicates of natural ingredients Excludes: Antibiotics, tobacco, marijuana, substances regulated under Food and Drug Regulations Efficacy 11 Traditional use Used for at least 50 consecutive years Require support from at least two independent references Non-traditional use More stringent requirements for scientific evidence Sources of evidence – clinical studies, pharmacopoeias, textbooks, peer-reviewed published articles, pre-clinical studies, reputable regulatory authority reports, expert opinion reports Standards of Evidence by Risk Level I - Well designed systematic reviews and metaanalyses of randomized controlled trials or other clinical trials, or at least one welldesigned randomized controlled trial (preferably multi-centred) Level II – Well-designed clinical trials without randomization and/or control groups Level III – Well-designed descriptive and observational studies, such as correlational studies, cohort studies, case-control studies Level IV – Peer-reviewed published articles, pharmacopoeias, conclusions of other reputable regulatory agencies, previous marketing experience, and expert opinion reports Level of Risk Associated with Health Claim Level of Risk Associated with Medicinal Ingredients EVIDENCE PYRAMID Level V – References to traditional uses (at least 50 consecutive years of use) © Health Canada Safety and Efficacy Peculiars 13 Recommended Dose • Based on available clinical trials and historical preparation Optimal Dose • Optimal doses to balance safety and efficacy are not often clear Variations • By manufacturer or batch or growing conditions Standardization Clinical effects • Not always possible • Not always comparable with different brands or product combinations 14 NHPs for Diabetes NHPs for Diabetes 15 Alpha lipoic acid Chromium Cinnamon Grape seed Gymnema sylvestre 16 Alpha Lipoic Acid Alpha-Lipoic Acid 17 Sulfur-containing free radical scavenger found in the mitochondria. Food sources: spinach, yeast, broccoli “Universal antioxidant” In Canada, approval related to: Providing antioxidants for the maintenance of good health Helping to promote healthy glucose metabolism Mechanism: Prevention of protein glycosylation Inhibition of aldose reductase enzyme Inhibits conversion of glucose and galactose to sorbitol Bliska, A. & Wlodek, L. Lipoic acid – the drug of the future? Pharmacological Reports, 2005; 57:570-577. Alpha-lipoic Acid - Evidence 18 Results of randomized, double-blind, placebo-controlled studies (ALADIN = Alpha Lipoic Acid in Diabetic Neuropathy) ALADIN: (n=328) ALADIN II: (n=65) Patients on 600mg and 1200mg per day of ALA (parenteral) had statistical improvements in pain, tingling and numbness vs. placebo at 3 weeks. Patients on 600mg and 1200mg per day of ALA (oral) showed statistically significant increase in nerve conduction velocity vs. placebo after 2 years. ALADIN III: (n=503) Patients on 600mg had significant reductions in neuropathic deficits at 3 weeks. Decreased neuropathy impairment scores after 6 months of 1800 mg ALA (oral), No significant differences were detected in glycohemoglobin levels or adverse side effects between the treatment groups. Ziegler, D., et al. (1995). Diabetologia, 38:1425–33.; Reljanovic, M. et al. Free Radic Res, 31:171–9.; Ziegler, D., et al. (1999). Diabetes Care, 22:1296–301. ALA – Evidence 19 Pilot study on patients with diabetes and chronic complications N=59; randomly assigned to: 1. Polarized Light treatment (n=19) 2. QALA group (antioxidants – 60 mg CoQ10, 100mg ALA, 200mg Vit E BID) (n=20) 3. QALAPL group (antioxidants with polarized light) (n=20) Antioxidants decreased plasma lipid peroxides, and improved echocardiographic parameters Conclusions: supportive therapy with polarized light and antioxidants (CoQ10, ALA and Vit E) is an effective way of controlling the complications of Type 2 Diabetes Pakacja P, et al. Complementary Therapy in diabetic patients with chronic complications: a pilot study. 2010; 111(4): 205-211. Alpha-lipoic Acid 20 Adverse Effects ALA appears to be safe in recommended doses Contact dermatitis (allergic reactions) May cause nausea, dizziness, vomiting Potential caution in hypothyroidism Avoid in patients with thiamine deficiency (alcoholism) Drug Interactions Anti-diabetic medications Thyroid medications Anti-cancer therapies, antibiotics, vasodilators, antiinflammatories Natural Standard. Natural Standard Monograph. www.naturalstandard.com 21 Chromium http://www.lookchem.com/ CHROMIUM 22 Essential trace element required for carbohydrate, lipid and protein metabolism Many people are deficient Due to higher consumption of refined foods and simple sugars, which increase urinary chromium losses by 10-300% Food processing methods which often remove naturally occurring chromium. Aging, pregnancy, strenuous exercise, infection, and physical trauma can further exacerbate chromium loss from the body Used to increase insulin sensitivity and facilitate blood glucose clearance Chromium 23 Mechanism Distributed to various tissues, in particular the kidney, muscle and liver Cofactor for insulin function: ↑ insulin binding, thereby ↑ glucose uptake. ↑ the number of insulin receptors. ↑ insulin receptor phosphorylation (enhances glucose transport into liver, muscle and adipose tissue). Cefalu, W., & Hu, F. (2004). Role of Chromium in Human Health and in Diabetes. Diabetes Care, 27(11):2741-2751 Chromium - Clinical Evidence 24 Chromium levels are reduced by >50% in both diabetic men and women. Systematic review (41 studies) Among participants with type 2 diabetes, chromium supplementation improved glycosylated hemoglobin levels by −0.6% and fasting glucose by −1.0 mmol/l but not lipids There was no benefit in individuals without diabetes There were some indications of dose effect and differences among chromium formulations. Balk, E., Tatsioni, A., Lichtenstein, A., Lau, J., & Pittas, A. (2007). Effect of Chromium Supplementation on Glucose Metabolism and Lipids. Diabetes Care, 30(8):2152-2136. Chromium - Clinical Evidence 25 RCT Type 2 diabetes (180 men and women) Three groups : 1) placebo, 2) 1000 µg Cr as chromium picolinate bid, or 3) 500 µg Cr bid. HbA1c values improved significantly after 2 months in 1,000µg group, and was lower in both chromium groups after 4 months. FBG was lower in the 1,000µg group after 2 and 4 months. Two-hour glucose values were also significantly lower for the subjects consuming 1000µg after both 2 and 4 months. Fasting and 2-h insulin values decreased significantly in both groups after 2 and 4 months. Plasma TC decreased after 4 months (1000µg). Anderson, RA., et al. (1997). Elevated intakes of supplemental chromium improve glucose and insulin variables in individuals with type 2 diabetes. Diabetes, 46(11):1786-91 Chromium 26 Adverse Effects Generally well-tolerated Gastrointestinal upset Very rarely, skin rashes, insomnia or sleep disturbances, headaches, mood changes, muscle damage, or anemia may occur Safe during pregnancy and breastfeeding: In gestational diabetes, chromium seems to be safely used in doses of 4-5µg/kg Does not seem to increase normal chromium concentration in human breast milk Broadhurst, C.L., & Domenico, P. (2006). Clinical Studies on Chromium Picolinate Supplementation in Diabetes Mellitus – A Review. Diabetes Technology & Therapeutics, 8 (6):677-687. Chromium 27 Drug Interactions Concurrent use with insulin and other hypoglycemic agents may cause additive hypoglycemia NSAIDs may increase chromium levels Antacids, H2 blockers and proton pump inhibitors may inhibit the absorption of chromium Corticosteroids may increase urinary chromium excretion. Natural Standard. Natural Standard Monograph. www.naturalstandard.com. 28 Cinnamon www.natures-health-foods.com Cinnamon (Cinnamonum spp.) 29 Cinnamonum cassia, C. zeylanicum Active ingredients: Cinnamaldehyde (90% of the volatile oil); coumarin is present in C. cassia (0.45%). Traditionally used for gastrointestinal complaints Recently used for treatment of Type 2 Diabetes Hypoglycemic effects Thought to improve glucose and insulin metabolism World Health Organization. WHO Monographs on Selected Medicinal Plants – Cortex Cinnamomi. Cinnamon - Mechanism 30 Volatile oils contain potential antibacterial, antioxidant and anti-inflammatory effects In animal studies: Potentiate insulin effects through the up-regulation of glucose uptake Reduce blood sugar and HbA1c levels Reduce activity of liver enzymes AST, ALT, LDH, ALP Activate insulin receptor kinase Khan, A., et al. (2003). Cinnamon Improves Glucose and Lipids of People With Type 2 Diabetes. Diabetes Care, 26:3215-3218. Cinnamon - Evidence 31 RCT on Type 2 diabetic patients (n=58) 2g cinnamon or placebo daily for 12 weeks Mean HbA1c was significantly decreased in cinnamon group Mean systolic and diastolic blood pressures were significantly reduced in the cinnamon group There were no significant differences in serum lipid profiles of total cholesterol, triglycerides, HDL and LDL cholesterols Akilen R et al. Glycated hemoglobin and BP lowering effect of cinnamon in a multi-ethnic Type 2 Diabetic patients in the UK: a randomized, placebo controlled double blind clinical trial. Diabet Med 2010; 27(10): 1159-67 Cinnamon 32 RCT (n=65) Aqueous cinnamon extract (= 3g of cinnamon powder daily) A statistically significant reduction (10%) of blood glucose was observed after 4 months of treatment No significant changes of HbA1c, total cholesterol, LDL, HDL or triacylglycerol Mang, B., et al (2006). Effects of a cinnamon extract on plasma glucose, HbA1C, and serum lipids indiabetes mellitus type 2. Eur J Clin Invest, 36(5):340-344. Cinnamon – Cautions 33 Adverse Effects No adverse effects have been associated with cinnamon. Pregnancy and breastfeeding? Drug Interactions May cause additive hypoglycemia Possible interaction with cardiovascular medications anticoagulants/antiplatelet lipid lowering drugs antihypertensives Naturalstandard.com medications 34 Grape seed www.grapeseedbenefits.com Grape seed 35 Traditionally used for skin and eye irritation, bleeding, varicose veins, diarrhea, cancer Contains oligomeric proanthocyanidins (OPCs) Preparations containing up to 475 mg grape seed extract, per day, standardized to 80-85% oligomeric proanthocyanidins (OPC) Grape seed - Evidence 36 RCT (n=32) patients with DM Received GSE (600 mg/day) or placebo for 4 weeks Following GSE (but not placebo), significant changes were noted in fructosamine; whole blood reduced glutathione and highly sensitive C-reactive protein Total cholesterol concentration also decreased No statistically significant changes were shown in endothelial function, HOMA-IR or TAOS. Conclusion GSE significantly improved markers of inflammation and glycaemia and a sole marker of oxidative stress in obese Type 2 diabetic subjects at high risk of cardiovascular events over a 4week period. Kar P et al. Effects of GSE in Type 2 diabetic subjects at high cardiovascular risk: a double blind placebo controlled trail examining metabolic markers, vascular tone, inflammation, oxidative stress and insulin sensitivity. Diabet Med 2009; 26(5): 526-31. Grape seed - Evidence 37 RCT, n=30 patients with diabetic retinopathy Received placebo or GSE 150mg for 3 months 80% of treated patients demonstrated stabilization of retinopathy (vs. 47% placebo) Case-series study, n=147 patients with atherosclerotic retinopathy 100mg proanthocyanidins daily for 1 year Improvements seen in visual acuity and overall positive effects, especially for ischemic lesions Arne JL. Gaz Med France 1982; 89(30):3610-3614; Verin MM et al. Bordeaux Medicale 1978; 11(16): 1467-1474 Grape seed 38 Side effects Reports of toxicity are lacking Seems well tolerated Reported effects include: dry scalp, nausea, indigestion Possible reduction of platelet aggregation Drug interactions Anticoagulants Methotrexate 39 Gymnema sylvestre www.sacredearth.com Gymnema sylvestre (Gurmar) 40 Traditional use (leaf) in the treatment of diabetes mellitus in for over 2000 years. Appears to: Lower serum glucose and HbA1c Lower lipid levels Antimicrobial action against Pseudomonas and S. aureus Indications: Hyperglycemia, IDDM and NIDDM, reduction of sweet cravings and appetite, weight loss, may benefit hyperlipidemia. Bone, K. Townsend Letter for Doctors & Patients. 2002;233:28-30.; Shigematsu, N., R. Asano, M. Shimosaka, and M. Okazaki, Effect of administration with the extract of Gymnema sylvestre R. Br leaves on lipid metabolism in rats. Biol Pharm Bull, 2001; 24(6): p. 713-7. Gymnema sylvestre 41 Active ingredients: Gymnemic acids, gymnema saponins and gurmarin Standardization varies, usually 25% gymnemic acids. Hypoglycemic Mechanism of Action: Enhances By insulin release from pancreatic ß-cells increasing cell number and improving cell function Improvements in hepatic and muscle glucose uptake The reversal of hemoglobin glycosylation Possible cholesterol-lowering effects Chattopadhyay RR. Possible mechanism of antihyperglycemic effect of Gymnema sylvestre leaf extract. Gen Pharm 1998;31(3):495-496. Gymnema sylvestre - evidence 42 In vitro studies In vitro measurements using isolated human islets of Langerhans direct stimulatory effects on insulin secretion from human ßcells (oral administration of GS) In studies of rats GS-treated diabetic rats demonstrated a 30% increase in total pancreatic weight, as well as a significant increase in the number of islets and number of cells per islet. Gymnemic acid extracts significantly increased the regeneration of β-cells in treated rats vs. diabetic rats. Shanmugasundaram, ER., et al. J Ethnopharmacol, 1990; 30:265–279.; Al-Romaiyan, A et al. Phytother Res 2010; 24(9): 1370-1376.; Ahmed AB, et al. Phytomedicine 2010; 17(13): 1033-1039. Gymnema sylvestre – clinical evidence 43 Open label trial (n=22) 400mg GS daily for 18–20 months + conventional drug Significant reduction of Fasting blood glucose, HbA1c and glycosylated plasma protein Cholesterol, triglycerides, phospholipids and free fatty acid levels Fasting and post-prandial serum insulin levels were significantly increased with GS. 21/22 patients reduced their intake of hypoglycemic drugs. 5 of these discontinued hypoglycemic drugs entirely and maintained their blood glucose homoeostasis with GS extract alone. Baskaran, K., et al. Antidiabetic effect of a leaf extract from Gymnema sylvestre in non–insulin-dependent diabetes mellitus patients. J Ethnopharmacol, 1990; 30:295–300. Gymnema sylvestre – Cautions 44 Adverse Effects Taste alteration Drug Interactions May cause additive hypoglycemia Possible interaction with lipid lowering agents due to cholesterol lowering effect Natural Standard. Natural Standard Monograph. www.naturalstandard.com Summary NHP 45 Indication Observed Clinical Effect Alpha-lipoic Acid Evidence Grade: A Diabetes; Neuropathy Statistically significant improvements blood sugar levels and nerve pain associated with diabetes. Chromium Evidence Grade: C Diabetes Cinnamomum cassia Evidence Grade: C* Diabetes Controlled trials have not consistently demonstrated statistical benefit. Systematic review indicates improved glycosylated hemoglobin levels by -0.6% and fasting glucose by -1.0 mmol/l. Inconsistent results and trials. Used to control blood sugar and shows promise in reducing HbA1c, and blood pressure. More human studies needed. Grape Seed Evidence Grade: B Diabetic retinopathy Several small studies demonstrated beneficial effects in halting the progression of retinopathy compared to placebo. Gymnema sylvestre Evidence Grade: B Diabetes Seems efficacious for serum glucose levels in T1DM and T2DM. Lower serum glucose and HbA1c levels following chronic use. Possible efficacy as a lipidlowering agent. Natural Standard www.naturalstandard.com
