Treating Pre-Diabetes Which choices really matter

1. 1 Treating Pre-DiabetesWhich choices really matter? Miles Hassell, MD Medical Director, Department of Integrative Medicine Providence Cancer Center, Portland, Oregon www.providence.org/integrativemedicine Comprehensive Risk Reduction Clinic Providence St. Vincent Medical Center, Portland, Oregon www.goodfoodgreatmedicine.com Co-Author: Good Food, Great Medicine DM2 09.30.2011

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3. Should our goal be to prevent diabetes, or reverse insulin resistance? 3

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5. 5 Mortality and glycemic control:a continuum, not a threshold

6. 6 Causes of insulin resistance Diets high in refined carbohydrates and sugars Diets low in fiber Certain micronutrient deficiencies, like vitamin D, magnesium, carotenoids (vegetables, whole fruit) Sedentary lifestyle Central obesity and excessive non-muscle weight Lack of sleep, alcohol Certain medications, aging Choosing parents poorly

7. 7 Reversing pre-diabetes, preventing diabetes Medications Diet and exercise programs Diabetes Prevention Program Finnish Diabetes Prevention Study Mediterranean Diet Identifying and applying the most valuable lifestyle choices

8. 8 Pharmacological intervention to avoid type 2 diabetes (DM2)

9. 9 Metformin for DM2 prevention Metformin is cheap, fairly safe, relatively minor side effects Inhibits gluconeogenesis Improves muscle insulin sensitivity Does not increase insulin secretion or preserve � cell function DeFronzo R. et al. Diabetes Care 2011;34(Suppl.2):S202-9

10. 10 Metformin for DM2 prevention Metformin 850 mg bid reduced IGT conversion to DM2 by 31% DPP, Knowler WC et al, NEJM 2002;346:393-403 2.8y Reduced incidence of metabolic syndrome Associated with progressive rise in HbA1c ADA recommends using it for high risk individuals : HbA1c = 6.0%, BMI > 30, =60yo Diabetes Care 2007;30:753-59 Same study: Lifestyle: goals of 7% weight loss, 150 minutes of exercise/week reduced conversion by 58% Consider combining metformin 1000mg/d with piogltazone 15-30 mg/d DeFronzo R. et al. Diabetes Care 2011;34(Suppl.2):S202-9

11. 11 Thiazolidinediones to prevent diabetes Reduce insulin resistance, TZDs preserve � cell function, improve glucose control Rosiglitazone 8mg reduced progression of IGT to DM2 by 62% (DREAM, $25M, 11.6%/26%, trend towards more CV events) , pioglitazone by 72% (ACT NOW, 45mg/d, 2.4y, n=602, DeFronzo, R. NEJM 2011;364:1104-15) Safety issues troublesome, lower doses and combination with metformin may be reasonable Review: DeFronzo R. et al. Diabetes Care 2011;34(Suppl.2):S202-9 ACT-NOW using pioglitazone. Improved DBP, less CIMT, better HDL, more weight gain and edema. No reduction in CV eventsACT-NOW using pioglitazone. Improved DBP, less CIMT, better HDL, more weight gain and edema. No reduction in CV events

12. 12 Incretin ideas for preventing DM2 (Exenatide, Liraglutide) GLP-1 Analogues: Insulin secretagogues, inhibit glucagon secretion, delay gastric emptying, promote weight loss, improve � cell function (but not �cell mass) Once-weekly formulation seems attractive! DPP-4 inhibitors share similar promise: Sitagliptin, Saxagliptin Clinical disease outcome data lacking Review in DeFronzo R. et al. Diabetes Care 2011;34(Suppl.2):S202-9

13. 13 Other drugs to prevent DM2 Acarbose reduces carbohydrate absorption, increases incretin secretion 25% less DM2 STOP-NIDDM ,100mg tid, 3.3y, Chiasson, JL et al. Lancet 2002;359:2072-77 Colesevelam (Welchol) and ACEI have modest potential for benefit Valsartan decreased DM2 incidence by 14%, no reduction in CV outcomes NAVIGATOR, 5y, up to 160mg valsartan/d NEJM 2010;362:1477-90

14. 14 But frankly�. How much benefit do these medications really have for patients with insulin resistance in terms of reducing micro-and macro-vascular outcomes? Boussageon, R et al. BMJ 2011;343:d4169, Editorial BMJ 2011;343:d4243 Even microvascular benefits are modest for patients with DM2: intensive drug treatment of 32-142 patients prevents one case of microalbuminuria, at the cost of 1 episode of hypoglycemia for every 15-52 patients, and with a slight trend to increased mortality and CV death. Can we expect more of pharmaceuticals for patients with IFG?

15. 15 Bariatric surgery and insulin resistance In severely obese patients (e.g. BMI >35) bariatric surgery Reduces mortality 25% SOS 10y data, Sjostrom A.J. et al Lancet 2006;368:1660-72 92% reduction in diabetic mortality, 59% less cardiac death 2y data, Adams T.D et al NEJM 2007;357:753-61 RCT for bariatric surgery in recently diagnosed DM2: 73% remission DM2 vs. 13% remission in conventional arm Dixon JB et al. JAMA 2008;299:839-47

16. 16 Lifestyle and Diabetes Prevention

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18. 18 AHA/NHLBI: Updated Metabolic Syndrome GuidelinesDiagnose when ?3 of these risk factors present AHA/NHLBI: Updated Metabolic Syndrome Guidelines The American Heart Association (AHA) and the National Heart, Lung, and Blood Institute (NHLBI) released revised guidelines to help physicians diagnose and treat the metabolic syndrome (MetS). The new guidelines confirm the NCEP ATP III recommendations issued in 2001 on MetS, but lower the thresholds of some of the risk factors. The guidelines reinforce that individuals with abnormal levels of three or more out of the five criteria should be considered as having MetS. The panel of experts who wrote the statement clarified several issues based on new scientific evidence. The new guidelines recognize that some individuals who are not obese by traditional measures are nonetheless insulin resistant (IR) and have other metabolic risk factors, ie, persons with one or both parents with diabetes or first- or second-degree relatives with diabetes. This is also true in individuals of Asian ethnicity, who are more prone to IR. In persons who are genetically predisposed to IR, a marginally increased waist circumference of 37-39 inches in men and 31-35 in women may place them at greater risk. Therefore, the updated guidelines lowered the threshold for waist circumference in individuals or ethnic groups, such as Asian Americans, who are prone to IR. The guidelines state that TG, HDL-C, and blood pressure (BP) levels be considered abnormal when a person is on drug treatment for these risk factors. In addition, it clarifies the definition of elevated BP as exceeding the threshold for either systolic (130 mm Hg) or diastolic (85 mm Hg) BP. The threshold for elevated fasting glucose was reduced from >=110 mg/dL to >=100 mg/dL in line with the ADA�s definition of impaired fasting glucose. The panel emphasized that the primary goal of clinical management of MetS is to reduce the risk for atherosclerotic cardiovascular disease and the risk of developing type 2 diabetes. If these conditions are present, treatment of MetS must be intensified. Grundy SM et al. Circulation. 2005;112.AHA/NHLBI: Updated Metabolic Syndrome Guidelines The American Heart Association (AHA) and the National Heart, Lung, and Blood Institute (NHLBI) released revised guidelines to help physicians diagnose and treat the metabolic syndrome (MetS). The new guidelines confirm the NCEP ATP III recommendations issued in 2001 on MetS, but lower the thresholds of some of the risk factors. The guidelines reinforce that individuals with abnormal levels of three or more out of the five criteria should be considered as having MetS. The panel of experts who wrote the statement clarified several issues based on new scientific evidence. The new guidelines recognize that some individuals who are not obese by traditional measures are nonetheless insulin resistant (IR) and have other metabolic risk factors, ie, persons with one or both parents with diabetes or first- or second-degree relatives with diabetes. This is also true in individuals of Asian ethnicity, who are more prone to IR. In persons who are genetically predisposed to IR, a marginally increased waist circumference of 37-39 inches in men and 31-35 in women may place them at greater risk. Therefore, the updated guidelines lowered the threshold for waist circumference in individuals or ethnic groups, such as Asian Americans, who are prone to IR. The guidelines state that TG, HDL-C, and blood pressure (BP) levels be considered abnormal when a person is on drug treatment for these risk factors. In addition, it clarifies the definition of elevated BP as exceeding the threshold for either systolic (130 mm Hg) or diastolic (85 mm Hg) BP. The threshold for elevated fasting glucose was reduced from >=110 mg/dL to >=100 mg/dL in line with the ADA�s definition of impaired fasting glucose. The panel emphasized that the primary goal of clinical management of MetS is to reduce the risk for atherosclerotic cardiovascular disease and the risk of developing type 2 diabetes. If these conditions are present, treatment of MetS must be intensified. Grundy SM et al. Circulation. 2005;112.

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21. 21 Combined lifestyle choices mortality outcomes in women Good diet (veg >5s/d, fruit >4/d, nuts or soy daily, fish/poultry>red meat, cereal fiber >15g/d, rare hydrogenated oils, PS:S >1.0) BMI <25: Get a waist! 30min/day brisk walking or equivalent Light alcohol intake (Consumption of up to 1 drink /day, excluding non-drinkers) 31% of cancer, 12% of CAD, 23% of all cause mortality Previously identified with 90% less diabetes incidence Compared to being sedentary, overweight smoker with poor diet. Non-smokers, 24 year follow up, 78k, Nurses Health Study van Dam, R. BMJ 2008;337:a1440doi:10.1136/bmj.a1440

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23. 23 Finnish Diabetes Prevention Study 58% lower diabetes incidence (11% vs. 23%) despite modest goal attainment: 47 % for fat intake, 43% reached weight loss goal, 25% reached saturated fat or fiber goal; but 86% for exercise Subgroups: 4 hours exercise/week: 80% less risk; 5% weight loss: 70% less risk. No diabetes developed in patients who achieved 4 of the 5 goals! 3.2y, Tuomilehto NEJM 2001;344:1343-50 At 7 years, further 36% reduction in risk of DM2 p=0.04 Tuomilehto Diabetes Care 2007;30:435-38

24. 24 From the USA (DPP) NEJM 2002;346:393-403 3234 people with IGT, average BMI 34, average follow-up 2.8y randomized to placebo, metformin 850 bid, or lifestyle: 7% weight loss (Food Pyramid, NCEP Step 1), 150 minutes exercise/w Individualized lifestyle counselling: 16 classes in 24 w, subsequent monthly individual and group classes Weight loss: lifestyle 5.6kg, metformin 2.1 kg, placebo 0.1kg

25. 25 Diabetes Prevention Program (DPP) NEJM 2002;346:393-403 Diabetes reduction: lifestyle 58% , metformin 31% 4.8 (L), 7.8 (M) and 11 (placebo) cases per 100 person years At 10 years, diabetes incidence was reduced 34% in lifestyle group, 18% in metformin compared to placebo. Lancet 2009 DOI:10.1016 Lifestyle saved $2600 per person, metformin $1700 per person cf placebo Herman, ADA 2011

26. 26 From Japan�Saito, T et al. Arch Intern Med 2011;171:1352-60 341 people with IFG, average BMI 27 Randomized to control (4 visits in 36 months) or frequent intervention: 9 visits in 36 months. Goal: Reduce energy intake with less fat and carbohydrate, increase activity, 5% weight reduction Weight loss 1.1kg controls vs. 2.5 kg treatment, Waist loss 1.3cm vs. 3.1cm, 50 � 100% increase in activity in treatment group

27. 27 Japanese diabetes prevention Observed changes towards goals: 57% reduced energy (controls 49%) 37-48% increased activity (controls 28-40%) At 36 months DM2 observed in 12.2% of intervention, 16.6% of controls, overall 44% reduction (adjusted) 76% reduction in those with baseline HbA1c > 5.6% Saito, T et al. Arch Intern Med 2011;171:1352-60, also see Knowler, W. Arch Intern Med 2011;171: 1361-2.

28. 28 The Mediterranean diet lowers: Prospective Cohort Studies Lower total mortality: 8% less for every 2 points greater adherence on a 10 point scale Myocardial infarction and stroke: 10% Neurodegenerative disease 13% Risk of cancer, or cancer death:6% Sofi, F. AJCN 2010;92:1189-96 12% lower incidence in Greek EPIC data Benetou, V. B J Cancer 2008;99:191-95

29. 29 Whole-food Mediterranean diet Increased use of vegetables and whole fruits daily: �5 a day� is a reasonable minimum, potatoes don�t count Increased legumes/beans, raw nuts, coarse whole grain Extra-virgin olive oil typically used rather than other vegetable oils and fats Increased fish, especially oily fish Dairy variable, often whole fat Less preserved meats, meat, potatoes Not typically low in fat or cholesterol

30. 30 Mediterranean diet, insulin resistance, and type 2 diabetes Mediterranean diet associated with: 31% lower risk of metabolic syndrome overall Meta-analysis of 50 studies, n=534k. Kastorini, CM. JACC 2011;57:1299-313 80% lower risk of developing DM2 in healthy participants Observational, high vs. low adherence, n= 13,380, 4.4y, Martinez-Gonzalez, MA. BMJ 2008;336:1348-51 37% less need for diabetes medications in those with diabetes Esposito, K Annals Intern Med 2009;151:306-314 50% reduction in incidence of metabolic syndrome after 2 years Med diet vs. �prudent low fat diet� p<.001 Esposito, K. JAMA 2004;292:1440-46

31. 31 Mediterranean diet for preventing DM2 Salas-Salvado, J. et al. PREDIMED-Reus. Diabetes Care 2011;34:14-19 418 people with at least 3 CV risk factors, without CV disease, average BMI 30, FPG 100 mg/dl Randomized to �low fat diet�, or Med diet with 7 goals including 1. Increased olive oil 2. More fruit, veges, legumes, fish 3. Reduction in total meat and processed meat, prefer white meat, 4. Preparation of homemade sauces, 5. Reduced fast foods, sweets, pastry, butter, cream, sweet drinks, 6. Moderate red wine, 7. Either 1 liter olive oil/w, or 30g nuts/d. Med diet assessed on a 14 point scale

32. 32 Mediterranean diet for preventing DM2 Salas-Salvado, J. et al. PREDIMED-Reus. Diabetes Care 2011;34:14-19 51% adjusted risk reduction in diabetes incidence at 4y (10% in olive oil group, 11% in nut group, 17.9% in low fat) 70% reduction for those with baseline HbA1c >6.1 6.3% incidence in those who achieved 4+ goals, 15% in those who achieved <4 goals Weight loss and physical activity were not interventions, and there was no calorie restriction Weight loss and activity similar between groups

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36. 36 Exercise and Diabetes Risk

37. 37 Benefit of moderate exercise in patients with insulin resistance and type 2 diabetes Improves � cell function Slentz, C. Diab Care 2009;32:1807-11 30-70% lower risk of developing DM2 Better blood sugar control, TG Lower risk of cardiovascular disease Lower total mortality Less steatohepatitis Perseghin Diabetes Care 2007;30:683-88 Antioxidant and anti-inflammatory Teixara-Lemos Cardiovasc Diabetology 2011;10:12 Improved endothelial function Diabetes Care 2007;30:719 And T cell populations Diabetes Care 2007;30:716-18

38. 38 Be careful what you measure� 593 newly diagnosed diabetics, randomized to usual care, intensive diet support, or intensive diet + walking 30min 5d/w (pedometer) Intensive diet improved HbA1c at 6 and 12 months (0.3%) despite less med, no apparent benefit from exercise. Andrews RC et al. Lancet 2011;378:129-39 Hmmmmph.

39. 39 Exercise, type 2 diabetes and stayin�alive High level of activity associated with >4 years longer life Jonker Diabetes Care 2006;29:38-43 In DM2 men, 1 MET increased exercise capacity improved survival 10% No assoc with BMI. N=831 veterans, 4.8y, McAuley, P Diabetes Care 2007;30:1539-43 One fewer death yearly for every 61 diabetics who walk 2 h/week Brisker and 3-4h/week even better. 8y prospective study. Gregg. Arch Int Med 2003;163:1440-4

40. 40 Exercise: will they do it? 340 sedentary patients with DM2, randomized to usual care or 30 min counseling re exercise benefits, 15min telephone call 1mo later, clinic visits q3mo. 69% vs 18% compliance with exercise BMI better by 1, HbA1c by 0.5 in exercise group. DiLoreto Diabetes Care 2003;26:404-8

41. 41 Exercise recommendations ACSM and AHA 2007, healthy adults <65 Moderately intense cardio 30min/d, 5d/ w or Vigorous cardio 20min/d, 3d/w; and 8-10 strength training exercise, 8-12 reps of each, twice a week www.acsm.org Physical Activity Guideline CDC, older adults www.cdc.gov/physicalactivity 150 min/week moderate aerobic and strength training 2 or more days/w; or 75 min/w vigorous aerobic and strength training 2 d/w

42. 42 Particular targets for enhancing insulin sensitivity

43. 43 If your patient doesn�t learn to minimize concentrated carbs, success will be limited Most sweets and sweet drinks, including juice Honey (sparingly) is probably the best alternative Most refined and finely ground grains Includes most breads, pasta, pastries, crackers Cold breakfast cereals, even �whole grain� Meal replacement (�Protein�) bars and drinks White rice, potatoes, corn, dried fruit Brown Basmati rice or quinoa likely better

44. 44 Sweet drinks are harmful: Sugar sweetened and diet drinks! 1 soft drink daily, regular or diet, associated with more obesity, central weight gain, higher blood sugar and blood pressure, higher triglycerides, lower HDL Dhingra, R. Circulation 2007;116:480-88 67% more DM2 Diet soda Nettleton, J. Diabetes Care 2009;32:688-94 61% more vasc events Diet soda. Gardner Int Stroke Conf. 2/11 Artificial sweeteners seem to increase total calorie intake through increased appetite For rats, anyway. Swithers, S. Behavioral Neuroscience 2008;122:161-73

45. 45 Dairy foods and type 2 diabetes risk Dairy food consumption associated with lower risk of type 2 diabetes Enhances weight loss Shahar Diabetes Care 2007;30:485-89 9% lower risk per daily serving Insulinotropic effects or increased magnesium? Choi Arch Intern Med 2005;165:997-1003 Dairy (incl. whole fat!) associated with less adiposity, lower insulin resistance, dyslipidemia 60% less incident diabetes for highest vs. lowest consumption. Circulating trans palmitoleate, Cardiovasc Health Study, n=3736, Mozaffarian, D. Ann intern Med 2010;153:790-99

46. Other particularly beneficial lifestyle elements Raw nuts Fish, and maybe fish oil Minimally processed whole grains Greens Probiotic foods Apple cider vinegar Alcohol Coffee/tea Dark chocolate Adequate sleep 46

47. Lifestyle factors that seem particularly troublesome Preserved meats Red meat itself is probably not a risk factor Highly refined grain products, even �whole grain� such as cold breakfast cereals Sweets, even �no-calorie� or low GI (e.g. agave) Possibly hydrogenated oils Screen time and other sedentary behaviors 47

48. 48 A real life example: S.B. 52 yo male Presented to urgent care with blurry vision, polyuria, polydipsia Long history of dyslipidemia Strong family history of type 1 and 2 diabetes Consulted with Susanna Reiner, CDE at Providence Advised regarding Mediterranean diet, exercise, processed foods and refined carbohydrates Good Food, Great Medicine Initial findings Weight 212 BP 137/107 Total cholesterol 217 HDL 13 Triglycerides first 6701, then 1570 LDL ? TC:HDL ratio 17 Random glucose 939 HbA1c 11.5%

49. 49 S.B. took advice seriously!Able to stop insulin, fibrate, statin, metformin. Only medicine is ASA Initial findings Weight 212 Blood pressure 137/107 Total cholesterol 217 HDL 13 Triglycerides 6701/1570 LDL ? TC:HDL ratio 17 Random glucose 939 HbA1c 11.5% 11 months later: Weight 155 Blood pressure 110/70 Total cholesterol 152 HDL 39 Triglycerides 75 LDL 98 TC:HDL ratio 3.9 Fasting glucose 102 HbA1c 4.9%

50. 50 A real hero: S.B.

51. Create a plan for the patient What are the patient�s goals? Discuss life in 10, 20 years Educate regarding the disease, complications, and modest benefits of pharmacological therapy Review the power of diet and exercise Educate regarding whole-food Med diet It is not low fat! Written plan, with specific goals, frequent follow-up 51

52. Modified whole food Mediterranean diet Emphasize: vegetables, raw nuts and seeds, dairy, beans/legumes, minimally processed whole grains, fish and other animal proteins Minimize refined grain foods and concentrated starches (�high glycemic load�): Breads, pasta, polenta, potatoes, rice Avoid sweets, sweet drinks, even if �diet� Mixed meal effect: fat and protein with every meal and snack Second meal effect: Frequent small meals 52

53. Exercise The best exercise: the one the patient does What will patient do? What do they like? Consider pedometer 10 minutes 3 times/day might be a great start Exercise for health, not weight loss Exercise daily Tell the patient what YOU do! 53

54. Weight loss Take a dietary history � I use 3 day history Food and activity journal helps Daily weights, call weights to office weekly 1lb/week weight loss Bring own lunch to work, make own food Frequent follow up with a health professional, and/or a sturdy unpaid buddy Ask: What did and didn�t work, and why? Cut all portions 10-20% 54

55. 55 How health care professionals can make a difference� Be an example of good lifestyle choices Have written materials for the patient See following link for a tool we use: http://goodfoodgreatmedicine.com/resources/resources.htm Clarify for the patient why the management of Insulin Resistance and Type 2 Diabetes needs more than medication Put the patient in charge, hold them accountable

56. 56 Recommended reading The New Mediterranean Diet Cookbook A Delicious Alternative for Lifelong Health - Nancy Harmon Jenkins Food Rules, An Eater�s Manual � Michael Pollan The Schwarzbein Principle � Diana Schwarzbein, MD The South Beach Diet � Arthur Agatston, MD The Diabetes Solution - Richard Bernstein, MD Good Food, Great Medicine - Miles Hassell, MD and Mea Hassell See recommended reading on page 34 for additional book reviews and recommendations

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