1. Hot Topics in Nutrition for the Primary Care Physician Phillip Snider, RD, DO Bon Secours Medical Associates Virginia Beach, VA

2. Should Vitamins be Considered Drugs? Medline search of 4 online databases (Medline Plus, Drug Digest, Natural Medicine Comprehensive Database, and the database of the University of Maryland) 1966 through October 2009 Vitamins are used by over 1/3 of North Americans Vitamins have documented adverse effects and toxicities, and most have documented interactions with drugs Some vitamins (biotin, pantothenic acid, riboflavin, thiamine, vitamin B 12, vitamin K) have minor and reversible adverse effects Others, such as fat-soluble vitamins (A, E, D), can cause serious adverse events Two water-soluble vitamins, folic acid and niacin, can also have significant toxicities and adverse events

3. Should Vitamins be Considered Drugs? Vitamins A, E, D, folic acid, and niacin should be categorized as over-the-counter medications Labeling of vitamins, should include information on possible toxicities, dosing, recommended upper intake limits, and concurrent use with other products Vitamin A should be excluded from multivitamin supplements and food fortificants The Annals of Pharmacotherapy: Vol. 44, No. 2, pp. 311-324

4. Folic Acid Aka B9, Folacin or folate (natural form) – Name derived “folium” - Latin for leaf – Beans, peas, spinach, broccoli Functions – Synthesize, repair and methylate DNA Deficiency – Neural tube defects – Pernicious anemia – Accumulation of homocysteine – Theoretical increased risk of cancer

5. Folate Metabolism Intestinal Cells Folate reduced to tetrahydrofolate – Folate reductase inhibited by methotrexate Methylated to N 5 -methyl-THF – primary blood form

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7. Genetic polymorphism MTHFR C677T – 7 out of 10 depressed patients – 56% - C/T polymorphism 4 X more likely to have depression than general population 14% - T/T polymorphism Lifestyle – ETOH – Smoking – Poor nutrition Medications – anticonvulsants – oral contraceptives – lithium – fenofibrates, niacin – sulphasalazine – methotrexate – metformin Illness – diabetes – atrophic gastritis – crohn’s disease – hypothyroid – renal failure Risk Factors Associated with Low Folate Alpert M, et al. Jrnl Clin Psychopharmacology. 2003;23(3):309-13. Arinami T, et al. Am J Genetics. 1997;74:526-28. Fava M, et al. Am J Psychiatry. 1997;154(3):426-28. Procopciuc L.M., Poster Pres. P86 presented at Biol Psych. 2005. Popakostas G, et al. Psychiatry Research, 2005;140(3):301-7. Bjelland I. et al. Arch Gen Psychiatry. 2003;60(6):618-26. Bottigleri T. Prog Neuro-Psychopharmacology & Biol Psychiatry. 2005; 29:1103-12. Kelly B J, et al. Psychopharmacol. 2004 ;18(4):567-71.

8. Deplin as a Trimonoamine Modulator Stahl S.M. Novel Therapeutics for Depression: L-methylfolate as a Trimonoamine Modulator and Antidepressant Augmenting Agent. CNS Spectrums. 2007;12(10):739-744.

9. Bioavailability MTHFR C>T Polymorphism L-methylfolate Vs. 5, 10 Methylene THF L-methylfolate Tetrahydrofolat e Dihydrofolate (Dietary Folate) DHF Reductase Enzyme Folic AcidL-methylfolate Folic acid requires a 4 step transformation process to be converted to the active form of folate, L-methylfolate (5-MTHF). L-methylfolate is unaffected by the MTHFR C  T polymorphism.

10. Folic Acid (FA) Benefits Nurse’s Health Study (JAMA 1998) – 80,000 nurses, 14 yr follow-up – Relative Risk - highest vs lowest quintile – RR = 0.69 for folate – RR = 0.67 for B-6 – RR = 0.55 for folate + B-6 FA supplementation – vast majority of recent studies – Lowers homocysteine but this has not turned out to offer any clinical benefits

11. Folic Acid (FA) Benefits Depression – Deplin (L-methylfolatye) Stroke – Limited evidence shows moderate benefit Cancer – Complex relationship – High folate intake may protect against early carcinogenesis – High FA intake may promote advanced carcinogenesis – Dietary folate usually associated with lower risk – FA supplementation associated with higher risk

12. FA and Cancer A Finnish study – 29,133 older male smokers – Prostate CA risk - no relationship with serum folate levels Recent RCT – FA 1 mg/day Prostate CA increased – Dietary folate & plasma levels increased Prostate CA decreased

13. FA and Cancer Doubles the risk of prostate cancer 2006 prospective study – 81,922 Swedish adults – High dietary folate Associated with a reduced risk of pancreatic cancer

14. FA and Cancer 2007 RCT – Folic acid supplements Did not reduce the risk of colorectal adenomas Did significantly increase the presence of advanced adenomas by 67%

15. A Randomized Trial on Folic Acid Supplementation and Risk of Recurrent Colorectal Adenoma FA 1 mg/d (n = 338) vs placebo (n = 334) for 3-6.5 yr Primary endpoint: Any new diagnosis of adenoma during the study period (May 1996-March 2004) Secondary outcomes: Adenoma by site and stage and number of recurrent adenomas Low plasma FA = sig decrease (RR: 0.61; P = 0.01) Adequate plasma FA = no diff (RR: 1.28; P = 0.27) Am J Clin Nutr. 2009 Dec;90(6):1623-31.

16. Dietary Factors of One-carbon Metabolism & Prostate Cancer Risk 27,111 Finnish male smokers aged 50-69 End point = Diagnosis of prostate cancer between 1985 and 2002 Vit B6 intake inversely associated with prostate cancer risk (RR for highest versus lowest quintile: 0.88; P = 0.045) Vit B12 intake associated with sig incr risk (RR = 1.36; P = 0.01) FA or alcohol intake no association with prostate cancer risk FA or alcohol intake no association with risk according to stage of dz Am J Clin Nutr. 2006 Oct;84(4):929-35

17. FA and Cancer European Journal of Gastroenterology & Hepatology University of Chile, in Santiago Hospital-discharge data for two 4-year periods – before folic-acid fortification (1992–1996) – after (2001–2004) Significant increase colon cancer – 162% in people 45 to 64 years – 190% in people 65 to 79 years

18. FA and Cancer Aspirin/Folate Polyp Prevention Study J Natl Cancer Inst. 2009;101:432-435 3-fold increase in prostate cancer among men who took the folate supplement compared with men who took placebo

19. AARP Diet and Health Study Prospective study of 295,344 men 50 to 71 and free of cancer at enrollment in 1995 Multivitamin use assessed at baseline. 5% used multivitamins > 7 times a week 36% took a multivitamin daily 5 yr follow-up: 10,241 developed prostate cancer – 8,765 localized and – 1,476 advanced cancers – 179 cases of fatal prostate cancer

20. AARP Diet and Health Study  No association: multivitamin use and risk of prostate cancer overall (relative risk 1.06)  No association: multivitamin use and risk of localized prostate cancer (RR 1.02)  Increased risk of advanced prostate cancer (RR 1.32)  Elevated risk of fatal prostate cancers (RR 1.98) The associations were strongest in men with a family history of prostate cancer or those who took selenium, β-carotene, or zinc.

21. FA and Cancer Increased breast cancer risk at high plasma folate concentrations among women with the MTHFR 677T allele Nested case-control study included 313 cases (age 55– 73 y at baseline) with invasive breast cancer and 626 control subjects Malmö Diet and Cancer – 17,000 women followed 10 yr, 10% had mutation in MTHFR 677T allele Significant association of high plasma folate concentration with increased risk of postmenopausal breast cancer in carriers of the 677T allele Am J of Clin Nutr, Vol. 90, No. 5, 1380-1389, November 2009

22. Vitamins & Cancer Norwegian Vitamin Trial and Western Norway B Vitamin Intervention Trial 6837 patients with ischemic heart disease 1998 and 2005, and followed up through December 31, 2007 FA 0.8 mg + B12 0.4 mg + Vitamin B6 40 mg (n = 1708) FA 0.8 mg/d + B12 0.4 mg/d (n = 1703) B6 alone 40 mg/d (n = 1705) Placebo (n = 1721)

23. Vitamins & Cancer FA + B12 – 10.0% Dx cancer vs 8.4% HR 1.21; P =.02 – 4.0% Died-cancer vs 2.9%HR 1.38; P =.01 – 16.1% Died-all cause vs 13.8%HR 1.18; P =.01 Most common cancer was lung cancer Cancer Incidence and Mortality after Treatment with Folic Acid and Vitamin B12 JAMA. 2009 Nov 18;302(19):2119-26.

24. Food Fortification FDA started FA fortification in 1996 All flour in US fortified with FA at a level of 140 μg/100 gr Estimated to supply an extra 100 μg daily to the average diet

25. Food Fortification Study of 1480 subjects – FA intake actually increased by 190 µg/d – Total folate intake increased by 323 DFE/d Folic acid intake above the UL seen only among those taking FA supplements as well as folic acid found in fortified grain products Some researchers have advocated that this be increased to double and even four times this amount

26. Folic Acid Synthetic form ~2x bioavailable – 1 DFE 1 mcg folate 0.5 mcg folic acid (on empty stomach) WomenPregnant Women Men RDA400 DFE600 DFE400 DFE UL1,000 DFE

27. Folic acid fortification and public health: Report on threshold doses above which unmetabolized folic acid appear in serum BMC Public Health 2007, 7:41doi:10.1186/1471-2458-7-41 Electronic version of this article http://www.biomedcentral.com/1471- 2458/7/41 http://www.biomedcentral.com/1471- 2458/7/41

28. Vitamins and Cancer: Take Home Message Hickey and Roberts’ microevolutionary model for cancer describes how cells undergoing carcinogenesis respond to redox (antioxidant/oxidant) signaling and changes in redox state It predicts that nutritional doses of antioxidant supplements, required daily for maintenance of normal health, inhibit carcinogenesis

29. Vitamins and Cancer: Take Home Message Once a cancer is established, however, the model suggests that nutritional or pharmacologic doses of antioxidants may be contraindicated as they could accelerate tumor growth Large pharmacologic doses of nutrients, which produce specific physiologic or biochemical effects, are indicated for the treatment of cancer or other diseases

30. Vitamins and Cancer: Take Home Message In the oxidizing environment of a developing tumor, nutritional doses of antioxidants could lower oxidation levels and inhibit cancer cell death By contrast, pharmacologic doses of redox- active substances that alter the antioxidant– oxidant balance, such as vitamin C (acting as a pro-oxidant), have been shown to destroy cancer cells in vitro and in animal experiments

31. Vitamins and Cancer: Take Home Message People in good health should select only high- quality, natural, antioxidant supplements, or molecularly identical counterparts avoiding synthetic forms such as DL-alpha-tocopherol (synthetic vitamin E) In metastatic cancer, only those supplements that have been shown to provoke a differential redox response in cancer cells, are appropriate – Vitamin C, R-alpha-lipoic acid, and Vitamin K3

32. Interaction b/w FA and B12 FA can correct pernicious anemia from B12 deficiency FA does not correct the neurological impact – 3 carbon to 2 carbon conversion affected – MMA accumulates – Mixed neuropathy FA over the UL (1 mg/day) can mask B12 deficiency

34. Obesity and Overweight

35. Establish diagnosis:BMI BMI = weight / height 2 Correlates well with direct measures of adiposity Overweight child: BMI >85th and <95th percentile Obese child: BMI > 95th percentile If child < 3 years old, use weight for height

37. Pulmonary disease abnormal function obstructive sleep apnea hypoventilation syndrome Nonalcoholic fatty liver disease steatosissteatohepatitiscirrhosis Coronary heart disease Diabetes Diabetes Dyslipidemia Dyslipidemia Hypertension Hypertension Gynecologic abnormalities abnormal menses infertility polycystic ovarian syndrome Osteoarthritis Skin Gall bladder disease Cancer breast, uterus, cervix colon, esophagus, pancreas kidney, prostate Phlebitis venous stasis Gout Medical Complications of Obesity Idiopathic intracranial hypertension Stroke Cataracts Severe pancreatitis

38. Complications of Childhood Obesity

39. Relationship Between Weight Gain in Adulthood and Risk of Type 2 Diabetes Relative Risk Weight Change (kg) Willett et al. N Engl J Med 1999;341:427. -10-505101520MenWomen

40. Diagnosing the Metabolic Syndrome Diagnosis = 3 Risk FactorDefining Level Abdominal obesity Men Women >40 in >35 in TG  150 mg/dL HDL-C Men Women <40 mg/dL <50 mg/dL Blood pressure  130/  85 mm Hg Fasting glucose  110 mg/dL

41. Defining Cardiometaboilc Risk What is Abdominal Obesity ? Can be defined by Waist Circumference ATP- IIIIDF Male: > 42 Inch Female : > 35 Inch Male : > 37 Inch Female : > 31.5 Inch Better Method ? Waist < ½ Height

42. BMI Categories A BMI of:Classifies one as: – <18.5Underweight – 18.5-24.9Normal weight – 25-29.9Overweight – 30-34.9Obesity Class I – 35-39.9Obesity Class II – 40-49.9Obesity Class III – 50 and aboveSuper Obesity

43. Morbid Obesity BMI > 35 plus >2 Comorbidities – HTN, DM, Lipids, OSA, CAD, CVA, OA, SUI, GERD BMI > 40 > 100 lb over Ideal weight

44. Morbid Obesity Examples: BMI > 40 5’0” person > 204 lb 5’6” person > 247 lb 6’0” person > 294 lb

45. Morbid Obesity Examples: BMI > 35 5’0” person > 170 lb 5’6” person > 216 lb 6’0” person > 258 lb

46. Obesity is a BIG problem… 1.7 billion worldwide are overweight or obese The US has a higher percentage of overweight and obese people than any country in the world And the numbers are growing…

47. US Incidence of Obesity 2/3 is overweight – 50% are obese 5% of the US population is morbidly obese BMI subgroups growing the fastest – 35+ 40+

48. Why Are We So Fat & What Can We Do About It?

49. Obesity Treatment Pyramid Diet Physical Activity Lifestyle Modification Pharmacotherapy Surgery

50. Guide for Selecting Obesity Treatment The Practical Guide: Identification, Evaluation, and Treatment of Overweight and Obesity in Adults. October 2000, NIH Pub. No.00-4084 Treatment25-26.927-29.930-34.935-39.9>40 Diet, Exercise, Behavior Tx +++++ Pharmaco- therapy With co- morbidities +++ Surgery With co- morbidities + BMI Category (kg/m 2 )

51. “Hey Doc, I am fat because my hormones are out of whack. I know I don’t eat too much. Can’t you check out what’s wrong with me and give me a pill to fix it?”

52. Hormonal Causes of Obesity Cushings Syndrome Most treatments for Diabetes Mellitus NOT Hypothyroidism Very few (less than 1%) of patients are obese due to hormonal problems, but a substantial number are obese in part due to diabetes treatment or treatment with glucocorticoids

53. Medications That Can Cause Weight Gain Psychotropic medications – Tricyclic antidepressants – Monoamine oxidase inhibitors – Specific SSRIs – Atypical antipsychotics – Lithium – Specific anticonvulsants Older  -blockers Diabetes medications – Insulin – Sulfonylureas – Thiazolidinediones Highly active antiretroviral therapy Tamoxifen Steroid hormones – Glucocorticoids – Progestational steroids

54. “Yea, I know about balancing food and activity, but I don’t don’t eat that much.” “I don’t eat more than other people” “I only eat salads.”

55. Discrepancy Between Reported and Actual Energy Intake and Expenditure Kcal/d Reported *P<0.05 vs reported. Lichtman et al. N Engl J Med 1992;327:1893. Energy Intake ActualReportedActual Energy Expenditure * *

56. “My problem is my metabolism is slow. Everything I eat turns straight to fat.”

57. Relationship Between Resting Energy Expenditure and Fat-free Mass REE = Resting energy expenditure Fat-Free Mass (kg) REE (kcal/24 h) Owen. Mayo Clin Proc 1988;63:503. 309010004050607080 Lean females Obese females Lean males Obese males

58. “Any time I try to lose weight, my metabolism slows down so much that I can’t lose weight.”

59. Energy Metabolism Before & After Weight Loss Energy Expenditure (kcal/d) Before *P<0.05 vs before weight loss Amatruda et al. J. Clin Invest 1993;92:1236. Predicted Mean BMI Reduced from 31 to 23 kg/m 2 AfterBeforePredictedAfter Resting Energy Expenditure Total Energy Expenditure * * * *

60. “So obesity is all genetic. There’s nothing I can do.”

61. Gene-Environment Interaction in the Pathogenesis of Obesity Body Mass Index (kg/m 2 ) Ravussin E et al. Diabetes Care 1994;17:1067-1074. Pima Indians Maycoba, MexicoArizona P <0.0001

62. Effect of Portion Size on Energy Intake 500 Amount Consumed (g) Amount of Macaroni and Cheese Served (g) Rolls et al. Am J Clin Nutr. 2000 Dec;76(6):1207-13. 6257501000

63. Prevalence of Obesity by Hours of Daily TV NHES Youth Aged 12-17 in 1967-70 and NLSY Youth Aged 10-15 in 1990 4-53-42-31-20-1>5

64. “I don’t think I need to change what I am eating. I am going to work out and lose it that way.”

65. Physical Activity Alone Results in Minimal Weight Loss Wing. Med Sci Sports Exerc 1999;31(suppl):S547. *P<0.05 vs control group Duration of each study ranged from 4 to 12 months. Stefanick 1998 Stefanick 1998a Anderssen 1995 Hammer 1989 Verity 1989 Rönnemaa 1988 Wood 1988 Wood 1983 Weight loss (kg) Control Group Exercise Group * * * *

66. Relationship Between Physical Activity and Maintenance of Weight Loss Not Maintained Subjects Exercising (%) P<0.001 Kayman et al. Am J Clin Nutr 1990;52:800. Weight Loss Pattern Maintained

68. “Isn’t there some popular diet I can follow? One that makes it easy.”

69. Popular Diets Succeed short term because restriction in food choice reduces calories Fail long term because restriction of food choices becomes unacceptable Promote a cycle of euphoria and despair that discourages belief in the possibility of success

70. “Why can’t I just take a pill?”

71. Pharmacotherapy Used as an adjunct to diet/exercise Reserved for those with BMI>30 or those with BMI>27 and Comorbidities

72. Drugs Approved by FDA for Treating Obesity Generic Name Trade Names DEA Schedule Approved Use Year Approved OrlistatXenicalNoneLong-term1999 SibutramineMeridiaIVLong-term1997 DiethylpropionTenulateIVShort-term1973 Phentermine Adipex, lonamin IVShort-term1973 Phendimetrazine Bontril, Prelu-2 IIIShort-term1961 BenzphetamineDidrexIIIShort-term1960

73. Additive Effects of Behavior and Diet Therapy with Pharmacotherapy for Obesity Weight Change (%) Wadden et al. Arch Intern Med 2001;161:218. *P<0.05 vs medication alone. Time (months) 024812106 Medication alone Medication and behavior modification Medication, behavior modification and meal replacements * *

74. “What about surgery?”

75. Role of Surgery Evidence for long term effectiveness Is approved by most payers Requires life long committment

76. What are The Operative Results? 80% excess weight loss in 18 months Roux-en-Y Gastric bypass the most widely accepted and best results Higher volume centers and surgeons have best results. Still risk and complications 10 year weight loss maintenance best with surgery

77. Gastric Bypass

78. Lap Band

79. Who Qualifies for Surgery? BMI greater than 40 BMI greater than 35 with obesity co-morbidity Attendance in a plausible structured program for some period of time, without sustained and significant degree of weight loss Not impaired psychiatrically? BMI greater than 60?

80. Effect on Comorbid Conditions Diabetes – 76.8% - Completely resolved – 86.0% - Resolved or improved Hyperlipidemia – 70% - Improved HTN – 61.7% - Resolved – 85.7% - Resolved or improved Obstructive Sleep Apnea – 83.6% - Resolved – 85.7% - Resolved or improved Buchwald H, et al. Bariatric Surgery: A Systematic Review and Meta- analysis. JAMA, 14:1724-37, 2004

81. Long-Term Changes: Weight Regain One study of 342 gastric bypass pts showed excellent long-term weight maintenance: – % weight loss at: 1 year (89%) 2 years (87%) 5 years (70%) 10 years (75%) However, potential for pouch stretch, self- sabotage, etc. leading to weight regain over time. Surgery relatively new, will have to wait and reanalyze data in a few years.

82. Malabsorption Flintstones “Complete” Women who still have menstrual periods need iron. All women need calcium! Common deficiencies: Iron, Folate, B 12, Calcium, Vitamin D

83. Long-term implications Patient must commit to lifetime monitoring of height, weight, and nutritional status Women should not become pregnant up to 18 months after surgery Encourage patient to join a support group to celebrate and cope with weight loss

84. Other issues Depression – Many expect things to get better post-op – Pre-existing depression exacerbated by stress of surgery – Suicides increased post operatively in some series – Ask about mood post-op Too much weight loss too fast – Look for signs of volume depletion – Puts at risk for infection

85. Screening Recommendations First Year: – @3 months: CBC, Glu, Cr – @6 months: CMP, Ferritin, TIBC, B12, Folate, Ca [PTH] (if Ca elevated or to ensure Ca stable) [Vit D] (possibly to ensure adequate Ca) Every year thereafter: – All of the above Postmenopausal women: BMD Screening – Variable recommendations, probably worth screening and ensuring maximum calcium / vit D tx if low BMD

86. Impact of Weight Loss on Risk Factors ~5% Weight Loss 5%-10% Weight Loss HbA1c Blood Pressure Total Cholesterol HDL Cholesterol Triglycerides 1. Wing RR et al. Arch Intern Med. 1987;147:1749-1753. 2. Mertens IL, Van Gaal LF. Obes Res. 2000;8:270-278. 3. Blackburn G. Obes Res. 1995;3 (Suppl 2):211S-216S. 4. Ditschunheit HH et al. Eur J Clin Nutr. 2002;56:264-270. 1 2 3 3 1 2 3 3 4 Naaso – Modest Weight Loss

87. Conclusions Obesity is a chronic disease Modest weight loss (5% -10% of body weight) can have considerable medical benefits Lifestyle change (diet and physical activity) is the cornerstone of therapy Pharmacotherapy can be useful in properly selected patients Bariatric surgery is the most effective therapy for obesity

88. Metabolic Syndrome Treatment in the Overweight or Obese Weight loss induced by diet and increased physical activity is the cornerstone of therapy Weight loss induced by drug therapy can also improve specific features of the metabolic syndrome Bariatric surgery is the most effective weight loss therapy for extremely obese subjects and improves all features of the metabolic syndrome

89. Obesity-Related Resources Professional Associations North American Association for the Study of Obesity (NAASO) American Academy of Family Physicians (AAFP) American College of Sports Medicine (ACSM) American Diabetes Association (ADA) American Dietetic Association (ADA) American Gastroenterological Association (AGA) American Heart Association (AOA) American Obesity Association (AOA) American Society for Bariatric Surgery (ASBS) www.naaso.org www.aafp.org www.acsm.org www.diabetes.org www.eatright.org www.gastro.org www.americanheart.org www.obesity.org www.asbs.org