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Dietary Supplements and Diabetes: What’s New?

Dietary Supplements and Diabetes: What’s New?. Laura Shane-McWhorter, PharmD , BCPS, BC-ADM, CDE, FASCP, FAADE University of Utah College of Pharmacy. Objectives. The educator will : Become familiar with information regarding popular supplements

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Dietary Supplements and Diabetes: What’s New?

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  1. Dietary Supplements and Diabetes:What’s New? Laura Shane-McWhorter, PharmD, BCPS, BC-ADM, CDE, FASCP, FAADE University of Utah College of Pharmacy

  2. Objectives The educator will : • Become familiar with information regarding popular supplements • Become familiar with information regarding the pharmacology of supplements, including theorized mechanism of action, side effects, and drug interactions • Become familiar with appropriate references to evaluate dietary supplements

  3. Which Agents? • Benfotiamine • Berberine • Cinnamon • Cranberry • Hibiscus • Magnesium • Mulberry • Vinegar CoQ10

  4. Challenge: What may decrease Vit B levels? • ETOH use • DM • Metformin • All of the above?

  5. DJ • DJ is a 51 y/o male with type 2 DM that is asking questions about his medications. He has DM and is having problems with burning feet at night. He can’t stand the sheets on his feet at night.

  6. Benfotiamine • Thiamine pro-drug; fat soluble form of Vit B1 (better absorbed) • Mechanism of action • Enhances transketolase activity (rate-limiting enzyme of pentose phosphate pathway) • Inhibits major pathways involved in damage (PKC, AGE, hexosamine) • Blocks hyperglycemia-induced activation of NF-кß • Normalizes cell division rates •  apoptosis

  7. Neuropathy: Pathophysiology  Glutathione  TGFβ, PAI-1  Vasodilators  Vasoconstrictors Activates NFK-B Modifies Proteins involved in gene transcription, Changes signaling  PARP Nature 2001;414:813-20 Diabetes 2005;54:1615-25

  8. Benfotiamine • Thiamine pro-drug; fat soluble form of Vit B1 (better absorbed) • Mechanism of action • Enhances transketolase activity (rate-limiting enzyme of pentose phosphate pathway) • Inhibits major pathways involved in damage (PKC, AGE, hexosamine) • Blocks hyperglycemia-induced activation of NF-кß • Normalizes cell division rates •  apoptosis

  9. Benfotiamine • Side effects • Potential allergies but unlikely • Drug interactions ( thiamine) • Metformin, diuretics • Antibiotics, OCPs, phenytoin, chemo • Herb interactions ( thiamine) • Horse tail • Betel nut

  10. Benfotiamine – Clinical Studies • RDBPCT in 165 pts with T1 and T2 DM • 300 mg, 600 mg, or PL daily (in divided doses) for 6 weeks • Evaluated neuropathy symptom scores, total symptom scores, and vibration sensation • Evaluated ITT and per protocol • Improved NSS in ITT and PP but significant only in the per protocol group Exp Clin Endocrinol Diabetes;2008;116:600-605

  11. Benfotiamine: Clinical Studies Neuropathy Symptom Score (5-9) ITT *p=0.055 between groups BF 600 mg BF 300 mg Placebo -1.35 -0.91 -0.63 Exp Clin Endocrinol Diabetes;2008;116:600-605

  12. Benfotiamine: Clinical Studies Neuropathy Symptom Score (5-9) PP *p=0.033 between groups BF 600 mg BF 300 mg Placebo -1.47 -0.79 -0.67 Exp Clin Endocrinol Diabetes;2008;116:600-605

  13. Benfotiamine: Clinical Studies • N=40 T2 DM pts randomized to 3 mo of 300 mg/day of thiamine or placebo1 • UAE ↓ to 30.1 mg/24h on thiamine and ↓ to 35.5 mg/24h on placebo (P<0.01) • N=82 T2DM randomized to 3 mo of 900 mg/day of BF or placebo2 • UAE ↓ by 18 mg/24 h (72) after 12 wks on BF; by 1 mg/24 on Pl (P=0.36); no impact on kidney tubule damage marker • Differences in the two studies: • Lower baseline UAE (45 vs 90) in first study and not all on ACEIs/ARBs • Perhaps BF is more appropriate earlier in nephropathy 1 Diabetologia 2009;52:208-12 2 Diabetes Care 2010;33:1598-1601

  14. Benfotiamine: Summary • BF, thiamine pro-drug, enhances transketolase and blocks major biochemical pathways implicated in complications • Emerging evidence: neuropathy, nephropathy • Retinopathy: murine tissue, human cells (prevents pericyte apoptosis) • Combined with ALA has shown benefit in experimental models of complication generating pathways • Dose is 120-600 mg/day in divided doses; dose-related benefits • Benign side effect profile • Many drugs may decrease thiamine levels • Should persons on metformin or diuretics or other drugs take this supplement?

  15. KC • KC is a 56 y/o male who wants to control his blood glucose and hyperlipidemia in a more “natural” way. He states he is currently thinking about using a natural product to treat his elevated glucose and LDL.

  16. Berberine • Coptischinensis (Huanglian or French) • Isoquinoline alkaloid • Ingredient of goldenseal, goldthread, European barberry, tree tumeric • Uses • Antibiotic, antidiarrheal • Discovered to have BG/lipid lowering effects • Mechanism of action • ↑ glucose stimulated insulin secretion • Facilitates glut-4 transport systems • Alpha glucosidase inhibitor activity

  17. Berberine • Side effects • Constipation • Kernicterus; do not use in pregnancy! • Drug interactions • Inhibits CYP 3A4 (↑ SDCs of CyA, certain statins) • P-glycoprotein modulator (caution with chemo, azoles, verapamil/diltiazem, some protease inhibitors) • Additive effects with diabetes drugs?

  18. Berberine • RDBPCT in 116 newly diagnosed T2DM with dyslipidemia • Given 0.5 gm bid or placebo x 3 months Ber Pl p FPG BL 126 mg/dL 122 mg/dL FPG End 101 115 <0.0001 PPG BL 216 mg/dL 220 mg/dL PPG End 160 198 <0.0001 A1C BL 7.5% 7.6% A1C End 6.6 7.3 <0.0001 J Clin Endocrinol Metab 2008;93:2559-65

  19. Berberine Ber Pl p WtBL 68.7 kg 71.8 kg Wt End 66.4 70.5 <0.001 TC BL 204 mg/dL 207 mg/dL TC End 167 203 <0.0001 TG BL 221 mg/dL 174 mg/dL TG End 142 181 0.001 LDL BL 124 130 LDL End 98 125 <0.0001 J Clin Endocrinol Metab 2008;93:2559-65

  20. Berberine • RCT in 2 groups of T2DM pts – newly diagnosed and poorly controlled (Ber or Met; Ber + other agents) • Gp A: 0.5 gm tid or metformin 500 mg tid x 3 months (N=36) Ber Met FPG BL 191 mg/dL 179 mg/dL FPG End 124 p<0.01 129 p<0.01 PPG BL 357 mg/dL 370 mg/dL PPG End 199 p<0.01 232 p<0.01 A1C BL 9.5% 9.2% A1C End 7.5 p<0.01 7.7 p<0.01 e.g., berberine = metformin Metabolism Clin Exper 2008;57:712-17

  21. Berberine • Gp B: 0.5 gm tid + other agents (insulin or orals) x 3 months • N=45 Ber + Other Agents FPG BL 173 mg/dL FPG End 137 p<0.001 PPG BL 266 mg/dL PPG End 194 p<0.001 A1C BL 8.1% A1C End 7.3 p<0.001 Metabolism Clin Exper 2008;57:712-17

  22. Berberine - Summary • Alkaloid contained in several different plants • Has insulin sensitizing and AGI activity • May ↑ SDCs of drugs metabolized by CYP 3A4 (CyA, some statins, CCBs, etc.) • Constipation is main side effect • Should not be used in pregnancy • Has shown benefit on A1C, FPG, PPG, lipids, weight, and even BP

  23. EL EL is a 52 y/o perimenopausal female who comes to the clinic. She is taking simvastatin 20 mg daily and lisinopril 20 mg daily. She states she has recently been diagnosed with “T2DM.” She does not want to take any more medications and is asking about using cinnamon.

  24. Cinnamon • Two major types: • Cinnamomum verum (true cinnamon) • Cinnamomum aromaticum (synonym Cinnamomum cassia) • The tree grows in tropical climates • The bark is used medicinally • Used for GI complaints and for flavoring http://www.theepicentre.com/Spices/cassia.html.

  25. Cinnamon • Active Ingredients1 • Polyphenolic polymers (hydroxychalcone) • Active constituent may be related to procyanidin type-A polymers • Mechanism1,2,3 •  insulin sensitivity •  cell/tissue glucose uptake • Glycogen synthesis • Delayed gastric emptying • May decrease PPG 1 J Am Coll Nutr 2001;20:327-36 2 Am J Health-Syst Pharm 2007;64:1033-35 3 Diabetes, Obesity, Metabolism 2009;11:1100-13.

  26. Cinnamon • Side effects1 • Topical allergic reactions • e.g., contact dermatitis • Rosacea • Drug Interactions1 • May  blood glucose if combined with glucose lowering agents • Anticoagulants2 • A coumarin-type component warrants caution 1 The Complete German Commission E Monographs: Therapeutic Guide to Herbal Medicines 2 Am J Health-Syst Pharm 2007;64:1033-35

  27. Cinnamon: Meta Analysis • Meta analysis of 5 RPCT clinical trials1 • N = 282 • Follow–up: 5.7 to 16 weeks • Dose – 1 to 6 g/day of cinnamon (cassia) • No significant decrease in mean A1C but:1 • FBG: - 17 mg/dL • TC: - 9.6 mg/dL • LDL: - 4.7 mg/dL • TGs: - 28.4 mg/dL • HDL: + 1.6 mg/dL • Under-powered (may need 1200-7000 persons) 1 Diabetes Care 2008;31:41-42

  28. Cinnamon • RPCT of N=109 T2DM pts with A1C > 7% that took 1 g daily of C. Cassia for 90 days • Pts on oral agents and/or insulin Cinnamon Placebo A1C BL 8.47% 8.28% A1C End 7.64 p<0.001 7.91 p< 0.04 vs placebo J Am Board Fam Med 2009;22:507-12

  29. Cinnamon - Summary • Cinnamon decreases fasting glucose and lipids and meta analysis shows benefit is not significant • 2009 study indicates it may be of greater benefit than thought, but 2010 study in 58 T2DM persons showed A1C ↓ 0.36% from baseline after 3 months (2 gm/day) vs 0.12% increase in Pl (p=0.002) (Diab Med 2010;27:1159-67) • Procyanidin type-A polymers are thought to be the active ingredient and it may enhance insulin sensitivity • May also delay gastric emptying and decrease postprandial glucose • Side effects are benign and there are no known interactions • Caution is warranted with concomitant anticoagulants • The dose is 1-6 g/day

  30. JF JF is a 44 y/o female who has T2DM and has recently been diagnosed with hyperlipidemia. She does not want to take a “statin” because “it may cause liver toxicity.” She also struggles with frequent UTIs.

  31. Cranberry • Vaccinium macrocarpon • Part used – ripe fruit • Close relative of American blueberry, Europen bilberry

  32. Cranberry • Uses • UTIs • Lipid lowering? • Chemical constituents • Nondialyzable polymeric compound • Rich in benzoic acid, which is excreted as hippuric acid in the urine (although this is not its MOA) • Fructose • Juice contains resveratrol

  33. Cranberry • Mechanism • Polymeric compound inhibits bacterial adhesion and inhibits adherence of E coli to cells lining bladder wall • Unique theorized effect in lipid modulation •  in hepatic cholesterol uptake through induction of LDL receptor expression in hepatocytes •  intestinal cholesterol absorption because cranberry binds bile acids and  fecal cholesterol excretion

  34. Cranberry • Adverse Effects • GI - diarrhea • High sugar content may affect diabetes; have patients use sugar free product • Calcium oxalate renal stones? • Drug interactions • Warfarin? • Flavonoids in cranberry may inhibit CYP2C9 • Several case reports (includes new case with cranberry sauce)

  35. Cranberry • 1994 RDBPCT in 153 elderly women • Women prone to UTIs • Measured bacteriuria + WBCs at baseline and periodically • Measured probability of change from bacteriuric-pyuric to non-infected JAMA 1994;271:751-54

  36. Urine Samples Each Month With Bacteriuria plus Pyuria for Cranberry or Placebo Infected Urine Samples, % Time, Months JAMA 1994;271:751-54

  37. Cranberry • Cranberry does decrease bacteriuria/pyuria, but it takes about 4-8 weeks to see change • Average 1 mo probability of change from bacteriuric-pyuric to non-infected • Cranberry – 0.54 • Placebo – 0.28 • Average 1 mo probability of change from non-infected to bacteriuric-pyuric • Cranberry – 0.09 • Placebo – 0.12 JAMA 1994;271:751-54

  38. Cranberry - Cochrane Evaluation • Identified 10 studies with RCT or quasi RCT • 5 were crossover • 5 were parallel • 7 compared cranberry/cranberry-ligonberry with Pl, juice or water • 4 compared cranberry tablets with Pl • N=1049 Cochrane Database Syst Rev 2008

  39. Cranberry - Cochrane Evaluation • Results analyzed for: • Pts with h/o recurrent UTIs • Elderly • Pts requiring intermittent catheterization • Pregnant women • Pts with indwelling catheter or urinary tract abnormality • Also did meta-analysis of 4 parallel studies (N=665) • For meta analysis: RR of UTIs at 12 mo with cranberries vs Pl/Control: • 0.65 (95% CI 0.47-0.92; p=0.01) Cochrane Database Syst Rev 2008

  40. Cranberry - Cochrane Evaluation • Cranberry more effective in: • Women vs elderly men and women • Women with recurrent UTIs • Less effective in those requiring catheterization • Use had to be at least 1 month to reduce recurrent UTIs • Studies had high withdrawal rates Cochrane Database Syst Rev 2008

  41. Cranberry – Effect on Lipids in T2DM • RDBPCT in 30 persons with T2DM on oral agents: • 16 males, 14 females, mean age 65 y/o • Given cranberry extracts 500 mg tid after meals or placebo x 12 wks • Evaluated changes in lipids, BG, CRP, UAE • Results for lipids: • LDL  from 127 mg/dL to 112 mg/dL (Cran) • LDL  from 127 mg/dL to 123 mg/dL (Pl) • No significant change in TC, TGs, or HDL Diabet Med 2008;25:1473-7

  42. Cranberry – Effect on Lipids in T2DM • Changes in BG and A1C (NS) • FBG  from 160 mg/dL to 149 mg/dL (Cran) • FBG  from 149 mg/dL to 142 mg/dL (Pl) • A1C  from 8.1% to 7.7% (Cran) • A1C  from 8% to 7.9% (Pl) • No changes in CRP, UAE Diabet Med 2008;25:1473-7

  43. Cranberry - Summary • Cranberry juice/tablets may be used to prevent UTIs • May have a role in lipid profile in DM • Devoid of side effects - caution in patients who have diabetes with juice products • Caution: • Patients on warfarin • Recurrent calcium oxalate stones • Dose is 300 mL/day all at once or in divided doses; may use equivalent dose of tablets or capsules to decrease sugar/calorie content

  44. Hibiscus (Hibiscus sabdariffa L.) • “Agua de Jamaica” “Karkade” “Sour tea” • Part used: calyx • Uses: BP, liver disease, fever • Active ingredients: anthocyanins • Delphidin-3-sambubiosides • Cyanidin-3-sambubiosides • Mechanism: • ACE inhibition • Vasorelaxation (CCB-like effect?) • Diuretic

  45. Hibiscus (Hibiscus sabdariffa L.) • Adverse effects • Bitter taste • Hepatic, renal function assessed in short-term trials and no problems reported • Drug interactions • ↓ elimination half-life of APAP • ↓ elimination of diclofenac • Additive effects in combo with ACE Is

  46. Hibiscus: Effects on BP in T2DM • DBRCT in 53 T2DM persons with mild HTN (<160/100 mm Hg; not on BP meds) • N=27 on Sour Tea N=26 on Black Tea x 1 mo • Given one tea sachet and added 240 mL of boiling water (allowed to steep 20-30 min) • SBP Results (mm Hg) Tea BL 4 weeks P (vs BL) ST 134.4 112.7 <0.001 BT 118.6 127.3 0.002 P < 0.001 for ST vs BT Results not significant for DBP J Hum Hypertens 2009;23:48-54

  47. Hibiscus: Effects on Lipids in T2DM • DBRCT in 53 T2DM persons (not on antilipidemics) • N=27 on Sour Tea; N=26 on Black Tea x 1 mo • Given one tea sachet and added 240 mL of boiling water (allowed to steep 20-30 min) • Lipid Results (mg/dL) Sour Tea Black Tea BL 4 wks BL 4 wks P (ST vs BT) LDL 137.5 128.5 124.9 130.1 0.003 HDL 48.2 56.1 46.2 52.01 0.6 TG 246.1 209.2 247.5 247.8 0.09 J Alt Compl Med 2009;15:899-903

  48. Hibiscus - Summary • Commonly used product • Studies evaluating use lack optimal design • Best study is use in mild HTN; better effect on SBP than DBP • Has been compared to ACEIs (less effective) • Studies don’t do a good job of reporting SEs • More study is needed

  49. Magnesium • Cofactor for enzymes in glucose metabolic pathways, phosphorylation reactions • Hypomagnesemia: • Diminished insulin action • Insulin resistance, T2DM • ADRs – GI, hypermagnesemia in renal dysfunction • Mg depleters – PPIs, diuretics, steroids, digoxin, beta-2 agonists • Drug interactions -↓ BP with CCBs, ↑ Mg with K-sparers; may impair absorption of tetracyclines, FQs, Ca, bisphosphonates • Benefit is varied Natural Medicines Comprehensive Database 12th ed. Stockton, Calif., Therapeutic Research Faculty, 2010

  50. Magnesium • Meta Analysis of 9 DBRCTs • N=370 persons with T2DM taking 360 mg/d for 4-16 wks (median duration 12 wks) • Results • FBG ↓ 10 mg/dL vs control (95% CI -1.1 to -0.01; p=0.03) • A1C ↓ 0.31% vs control (95% CI -0.81 to 0.19; p=0.22) • HDL ↑ 3 mg/dL (95% CI 0.03 to 0.14; p=0.001) • No effects on other lipids, BP, or weight • No severe ADRs; only GI side effects Diabet Med 2006;23:1050-56

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