Preventing Diabetes K A R O L E. W A T S O N, M D, P H D, F A C C P R O F E S S O R O F M E D I C I N E / C A R D I O L O G Y

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1 Preventing Diabetes 2018 K A R O L E. W A T S O N, M D, P H D, F A C C P R O F E S S O R O F M E D I C I N E / C A R D I O L O G Y D A V I D G E F F E N S C H O O L O F M E D I C I N E A T U C L A CO-DIRECTOR, U C L A P R O G R A M I N P R E V E N T I V E C A R D I O L O G Y

2 Disclosures Research grants: NHLBI, NIDDK, NIH BD2K Consultant: Amarin, Amgen, Boehringher Ingelheim and Kowa Speaker s Bureau: Boehringher Ingelheim

Global Projections for the Diabetes Epidemic: 2003-2025 23.0 M 36.2 M 57.

8 M 79% World 2003 = 194 M 2025 = 333 M 72% 14.2 M 26.2 M 85% AFR 7.1M 15.

3 Global Projections for the Diabetes Epidemic: M 36.2 M 57.0% 48.4 M 58.6 M 21% 19.2 M 39.4 M 105% 39.3 M 81.6 M 108% 43.0 M 75.8 M 79% World 2003 = 194 M 2025 = 333 M 72% 14.2 M 26.2 M 85% AFR 7.1M 15.0 M 111% Diabetes Atlas Committee. Diabetes Atlas 2 nd Edition: IDF 2003.

*Source: Centers for Disease Control and Prevention. National diabetes statistics report: estimates of diabetes and its burden in the United States, 2014.

4 *Source: Centers for Disease Control and Prevention. National diabetes statistics report: estimates of diabetes and its burden in the United States, Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and Prevention, DIABETES 30.3 million Americans have diabetes * PRE-DIABETES 84 million American adults have prediabetes* That s more than 1 in 3 adults 9 out of 10 adults with prediabetes don t know they have it

5 *Source: Centers for Disease Control and Prevention. National diabetes statistics report: estimates of diabetes and its burden in the United States, Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and Prevention, Prediabetes: Targeting a population at risk Prediabetes: A reversible cardio-metabolic risk factor in which plasma glucose levels are above normal but not high enough to diagnose type 2 diabetes. 3-5 times higher risk of developing type 2 diabetes * Increased risk of cardiovascular disease and death

6 Prediabetes: Targeting a population at risk *Source: Centers for Disease Control and Prevention. National diabetes statistics report: estimates of diabetes and its burden in the United States, Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and Prevention, 2014.

7 Natural History of Type 2 Diabetes Glucose (mg/dl) Post-meal glucose Fasting glucose Years Adapted from: International Diabetes Center (Minneapolis, Minnesota).

8 Feasibility of Preventing Diabetes There is a long period of glucose intolerance that precedes the development of diabetes Screening tests can identify persons at high risk There are safe, potentially effective interventions that can address modifiable risk factors

9 Diabetes Prevention Program NIH-NIDDK sponsored study Primary Goal: To prevent or delay the development of type 2 diabetes in persons with impaired glucose tolerance (IGT)

10 Diabetes Prevention Program

11 DPP Eligibility Criteria Age > 25 years Elevated fasting and post prandial glucose Body mass index > 24 kg/m 2 All ethnic groups goal of up to 50% from high risk populations

12 DPP Study Interventions Eligible participants Randomized Standard lifestyle recommendations Intensive Metformin Placebo Lifestyle (n = 1079) (n = 1073) (n = 1082)

13 Metformin Metformin- 850 mg per day escalating after 4 weeks to 850 mg twice per day Placebo- Metformin placebo adjusted in parallel with active drugs

14 DPP Lifestyle Intervention An intensive program with the following specific goals: > 7% loss of body weight and maintenance of weight loss Dietary fat goal -- <25% of calories from fat Calorie intake goal kcal/day > 150 minutes per week of physical activity

15 MET-hours/week Mean Change in Leisure Physical Activity 8 Lifestyle Metformin Placebo Years from Randomization The DPP Research Group, NEJM 346: , 2002

16 Weight Change (kg) Mean Weight Change Placebo Metformin Lifestyle Years from Randomization The DPP Research Group, NEJM 346: , 2002

17 Cumulative incidence (%) Incidence of Diabetes Risk reduction 31% by metformin 58% by lifestyle Placebo (n=1082) Metformin (n=1073, p<0.001 vs. Placebo) Lifestyle (n=1079, p<0.001 vs. Metformin, p<0.001 vs. Placebo) Years from randomization The DPP Research Group, NEJM 346: , 2002

18 Diabetes Incidence Rates by Sex 12 Cases/100 person-yr 8 4 Lifestyle Metformin Placebo 0 Male (n=1043) Female (n=2191) The DPP Research Group, NEJM 346: , 2002

19 Diabetes Incidence by Age Cases/100 person-yr Lifestyle Metformin Placebo (n=1000) (n=1586) > 60 (n=648) Age (years) The DPP Research Group, NEJM 346: , 2002

20 Diabetes Incidence Rates by Ethnicity Lifestyle Metformin Placebo 12 Cases/100 person-yr Caucasian (n=1768) African American (n=645) Hispanic (n=508) American Indian (n=171) Asian (n=142) The DPP Research Group, NEJM 346: , 2002

21 Diabetes Incidence Rates by BMI Cases/100 person-yr Lifestyle Metformin Placebo < < 35 > 35 Body Mass Index (kg/m 2 ) The DPP Research Group, NEJM 346: , 2002

22 The DPP Research Group, NEJM 346: , 2002

23 Key Lesson # 1 Lifestyle trumps medication for preventing diabetes

24 DPP Lifestyle Intervention An intensive program with the following specific goals: > 7% loss of body weight and maintenance of weight loss Dietary fat goal -- <25% of calories from fat Calorie intake goal kcal/day > 150 minutes per week of physical activity

25 DPP Lifestyle Intervention Structure 16 session core curriculum (over 24 weeks) Long-term maintenance program Supervised by a case manager Access to lifestyle support staff Dietitian Behavior counselor Exercise specialist

26 The Core Curriculum (16 sessions) Education and training in diet and exercise methods and behavior modification skills Emphasis on: Self monitoring techniques Problem solving Individualizing programs Self esteem, empowerment, and social support Frequent contact with case manager and DPP support staff

27 DPP Post Core Program Self-monitoring and other behavioral strategies Monthly visits Supervised exercise sessions offered Periodic group classes and motivational campaigns Tool box strategies Provide exercise videotapes, pedometers Enroll in health club or cooking class

28 Key Lesson # 2 Lifestyle interventions to prevent diabetes should be comprehensive

29 T2DM incidence per 100 person-years Effect of Weight on T2DM Incidence in DPP % % % 7.3 Placebo Metformin Lifestyle DPP Research Group. N Engl J Med. 2002;346: to <30 30 to <35 35 BMI (kg/m 2 )

30 DPP and DPPOS : To prevent or delay the development of type 2 diabetes in persons with impaired glucose tolerance (IGT) ALL participants offered lifestyle seesions in between DPP and DPPOS : Prevention of diabetes complications such as kidney, eye and nerve problems, and heart disease

31 Crude Rate per 100 PYR DPP vs. DPPOS Diabetes Rates DPP DPPOS 8 6 Placebo Metformin Lifestyle DPP (n=3234) DPPOS (n=1994)

32 Diabetes Development in DPPOS Original Lifestyle participants continue to develop diabetes at about the same lower rate they developed diabetes during DPP. Original Placebo and Metformin participants lowered their rate of diabetes development to a similar rate as the Lifestyle group.

33 DPPOS Diabetes Risk Reduction Delay in diabetes onset after 10 years follow-up: 4 years for Lifestyle 2 years for Metformin The lower rate of diabetes development means: Original Lifestyle participants have a 34% lower risk of diabetes Original Metformin participants have a 18% lower risk of diabetes

34 Diabetes Frequency After 10 years 52% of Placebo participants developed diabetes 47% of Metformin participants developed diabetes 42% of Lifestyle participants developed diabetes Lancet Nov 14;374(9702):

35 Cost Effectiveness Over 10 years, metformin treatment reduced the costs of medical care by $1700 per person Over 10 years lifestyle treatment reduced the costs of medical care by $2600 per person

36 (These data) put diabetes prevention in the category of prenatal care or pediatric immunizations... It s dramatic when an intervention can improve the health of the population and potentially save money at the same time. William H. Herman -health services researcher with expertise is in the area of diabetes, University of Michigan

37 Key Lesson # 3 Preventing diabetes is costeffective

38 Keys to DPP Lifestyle Success Weight loss was the key to diabetes prevention -Every 2.2 pounds of weight loss decreased risk by 13% Reduction of total calories, especially fat calories Achieving 150 minutes of activity each week DPP intervention was key to prevention

39 Change in Weight (kg) Weight Change Over Time Placebo Metformin Lifestyle Year since DPP Randomization

40 Key Lesson # 4 Weight loss is very difficult to sustain

41 Key findings Prediction of weight loss Improvements in diet (calories and fat grams, or percent of calories from fat) predicted weight loss up to year 3 in DPP Increased activity became a stronger predictor of weight loss at each subsequent year so that by year 3 and beyond, an increase of 5 methours/week (approximately 1 hours walking/week) resulted in a.43 kg weight loss.

42 Preventing Diabetes Weight loss, largely determined by changes in diet and exercise, is the primary factor resulting in reduced diabetes incidence. An increase in physical activity helps sustain weight loss and independently reduces diabetes risk among those who do not lose weight. But exercise alone rarely results in weight loss Interventions to reduce the incidence of diabetes should aim at weight loss as the primary determinant of success.

43 Key Lesson # 5 Dietary changes are essential for weight loss; Regular physical activity is essential for weight maintenance

44 DPP Lifestyle Intervention An intensive program with the following specific goals: > 7% loss of body weight and maintenance of weight loss Dietary fat goal -- <25% of calories from fat Calorie intake goal kcal/day > 150 minutes per week of physical activity

45 DPP Lifestyle Intervention Structure 16 session core curriculum (over 24 weeks) Long-term maintenance program Supervised by a case manager Access to lifestyle support staff Dietitian Behavior counselor Exercise specialist

46 The Core Curriculum (16 sessions) Education and training in diet and exercise methods and behavior modification skills Emphasis on: Self monitoring techniques Problem solving Individualizing programs Self esteem, empowerment, and social support Frequent contact with case manager and DPP support staff

47 DPP Post Core Program Self-monitoring and other behavioral strategies Monthly visits Supervised exercise sessions offered Periodic group classes and motivational campaigns Tool box strategies Provide exercise videotapes, pedometers Enroll in health club or cooking class

48 Key Lesson # 6 Regular contact with the health care system appears essential for sustaining lifestyle changes

49 Change in BP (mm Hg) DPP Change in Blood Pressure Systolic Baseline BP Diastolic Lifestyle Metformin Placebo Lifestyle Metformin Placebo BP, blood pressure; DPP, Diabetes Prevention Program. Ratner R, et al. Diabetes Care. 2005;28:888.

50 Change in Lipids (%) DPP Change in Total and LDL Cholesterol Total Cholesterol Baseline (mg/dl) LDL-C Lifestyle Metformin Placebo Lifestyle Metformin Placebo DPP, Diabetes Prevention Program; LDL-C, low-density lipoprotein. DPP Research Group. Diabetes Care. 2005;28: Ratner R, et al. Diabetes Care. 2005;28:

51 Change in Lipids (mg/dl) DPP Change in Triglycerides and HDL Triglycerides Baseline (mg/dl) Lifestyle Metformin Placebo HDL-C Lifestyle Metformin Placebo DPP, Diabetes Prevention Program. DPP Research Group. Diabetes Care. 2005;28: Ratner R, et al. Diabetes Care. 2005;28:

52 Cardiovascular Risk Factors in DPPOS Lifestyle (n=910) Metformin (n=924) Placebo (n=932) Antihypertensive drugs 33% 37% 36% Lipid-lowering drugs 18% 23% 23% Blood pressure (mmhg) / / / 75 6 Serum cholesterol (mmol/l) Geometric serum triglycerides (mmol/l) DPP Research Group. Lancet. 2009; 374:

53 Key Lesson # 7 Prevention of diabetes is associated with improvement in almost all cardiovascular risk factors

54 Cardiovascular Risk in DPPOS All treatment groups have decreased blood pressure, cholesterol and triglycerides. Lifestyle participants had the same or lower blood pressure and lipid levels over time than other participants with less use of medicines.

55 Change in Weight (kg) Weight Change Over Time Placebo Metformin Lifestyle Year since DPP Randomization

56 BMI Change Over Time YOUNG people (25-44 y.o.) DPP Research Group. Lancet. 2009; 374:

57 BMI Change Over Time MIDDLE AGE (45-59 y.o.) DPP Research Group. Lancet. 2009; 374:

58 BMI Change Over Time OLDER ADULTS (> 60 y.o.) DPP Research Group. Lancet. 2009; 374:

59 Key Lesson # 8 After 60 years of age people tend to begin to lose weight

T2DM incidence per 100 person-years Effect of Age on Diabetes incidence in DPP 14 12 11.6 10.8 10.8 10 9.6 8 6 6.7 48% 6.2 7.

60 T2DM incidence per 100 person-years Effect of Age on Diabetes incidence in DPP % % % Placebo Metformin Lifestyle Age (years) DPP Research Group. N Engl J Med. 2002;346:

61 Key Lesson # 9 Lifestyle appears to have the greatest impact on older patients (possibly due to greater weight loss)

62 Now what about the age old question: What is more imporant our genes or our environment?

63 Genetic Variants and Progression to Diabetes Common genetic variants of the gene TCF7L2 have been found to be associated with development of type 2 diabetes We found that DPP participants with the TT genotype were more likely to develop diabetes than participants with the CC genotype We found that both metformin and lifestyle could mitigate the genetic risk In other words, if you had the TT genotype, you could reduce your chances of developing diabetes with lifestyle changes or with metformin Florez et al., N Engl J Med Jul 20;355(3):

64 Cases/100 person-yr Key findings CC CT TT Placebo Metformin Lifestyle Florez et al., N Engl J Med Jul 20;355(3):

65 Key Lesson # 10 Lifestyle (and metformin) can mitigate some of the genetic risk for development of diabetes

66 Preventing diabetes in community based settings

67 Percent Group Lifestyle Balance Program Intervention Phase 1 Post (n=51) Phase 2 Post (n=42) Weight Loss Achieved Completers Both phases (n=67) Phase 2 6 mo Weight Loss > 3.5% Weight Loss > 5% Weight Loss >7% Phase 2 12 mo DPP lifestyle intervention was adapted to a 12-session groupbased program Implemented in a community setting Significant decreases in weight, waist circumference, and BMI were found Average combined weight loss over the 3-month intervention was 7.4 pounds (3.5% relative loss, P<0.001) DPP, Diabetes Prevention Program; mo, month. Kramer MK, et al. Am J Prev Med. 2009;37:

8 Group-based DPP lifestyle 6 intervention vs brief 5 counseling alone (control) 0 among high-risk adults who -5 attended a diabetes riskscreening event at one of

68 Total Cholesterol (%) Translating the DPP Into the Community Standard (4-6 months) DPP (4-6 months) Standard (12-14 months) DPP (12-14 months) Pilot, cluster-randomized trial 11.8 Group-based DPP lifestyle 6 intervention vs brief 5 counseling alone (control) 0 among high-risk adults who -5 attended a diabetes riskscreening event at one of two semi-urban YMCA facilities The DEPLOY Pilot Study P<0.001 P=0.002 DEPLOY, Diabetes Education & Prevention with a Lifestyle Intervention Offered at the YMCA; DPP, Diabetes Prevention Program; YMCA, Young Men s Christian Association. Ackermann RT, et al. Am J Prev Med. 2008;35:

69 Translating DPP into the community Four additional studies utilizing the DPP lifestyle interventions in community settings demonstrated that: Weight loss could be achieved Reduction in glucose levels and HbA1c could be achieved Benefits were seen in high risk, underserved populations A new model of chronic, disease management is needed DPP, Diabetes Prevention Program. Boltri JM, et al. J Natl Med Assoc. 2011;103: Katula JA, et al. Diabetes Care. 2011;34: Ruggiero L, et al. Diabetes Educ. 2011;37: Santoyo-Olsson J, et al. Gerontologist. 2011;51(Suppl 1):S82-93.

70 LA County Diabetes Prevention Program

71 Key Lesson # 11 It is very feasible to translate a DPPlike intervention into the community

72 Gestational Diabetes and future DM risk Kim et al., Diabetes Care, 2002

73 Low birth weight is associated with Type 2 DM JAMA 2008; 300(24):

74 Incidence of Diabetes by Category of Glucose Intolerance Number of studies Regress to normal (%) Progress to Diabetes (%) Relative Risk of Diabetes Impaired Glucose Tolerance 26 8% 7% 6.4 ( ) IGT only on 1 occasion 3 n/a 6% 5.5 ( ) Impaired Fasting Glucose % 5-20%* 4.7 ( ) IFG only on 1 occasion 3 n/a 7% 7.5 ( ) IGT and IFG 3 n/a 10-15% 12.1 (4.3 20) Gerstein et al., Diab Res Clin Pract, 2007

75 Selected risk factors for development of DM Age Family History / genetics Gestational Diabetes Obesity / fat distribution Physical Activity / fitness Very low birth weight Antipsychotic medications Anti-Retrovial therapy

76 Key Lesson # 13 Targeting interventions to at risk populations is important

77 COFFEE 20 Years Ago Coffee (with whole milk and sugar) Today Mocha Coffee (with steamed whole milk and mocha syrup) 45 calories; 8 ounces 350 calories;16 ounces Calorie Difference: 305 calories

78 MUFFIN 20 Years Ago Today 210 calories 1.5 ounces 500 calories 4 ounces Calorie Difference: 290 calories

79 CHICKEN CAESAR SALAD 20 Years Ago Today 390 calories 1 ½ cups Calorie Difference: 400 calories 790 calories 3 ½ cups

80 Food intake per occasion, oz Portion Sizes Nielsen and Popkin, JAMA, 2003

81 Key Lesson # 14 We live in an obesogenic society

83 Key Lesson # 15 It takes a village

84 Association between statins and development of diabetes Statin Odds ratio (95% CI) Overall (n=91 140) 1.09 ( ) Rosuvastatin only (n=24 714) 1.18 ( ) Atorvastatin only (n=7773) 1.14 ( ) Simvastatin only (n=18 815) 1.11 ( ) Pravastatin (n=33 627) 1.03 ( ) Lovastatin (n=6211) 0.98 ( ) Sattar N et al. Lancet 2010;375:

Jupiter Trial: Statins and Diabetes No major risk factors for diabetes Major risk factors for diabetes Metabolic syndrome, IFG, HbA1c >6%, or BMI 30 kg/m 2 HR 0.99 (0.45-2.21) p=0.99 HR 1.

85 Jupiter Trial: Statins and Diabetes No major risk factors for diabetes Major risk factors for diabetes Metabolic syndrome, IFG, HbA1c >6%, or BMI 30 kg/m 2 HR 0.99 ( ) p=0.99 HR 1.28 ( ) p= deaths or vascular events prevented 0 excess cases of diabetes 134 deaths or vascular events prevented 54 excess cases of diabetes Ridker PM et al. Lancet 2012;380:565

86 CV Event Reduction vs. New-Onset Diabetes Incident Diabetes PROVE-IT - TIMI 22 A to Z TNT IDEAL SEARCH Pooled odds ratio Incident CVD PROVE-IT - TIMI 22 A to Z TNT IDEAL SEARCH Intensive dose Moderate dose OR (95% CI) 101/1707 (5.9) 65/1768 (3.7) 418/3798 (11.0) 240/3737 (6.4) 625/5398 (11.6) 1449/16,408 (8.8) 315/1707 (18.4) 212/1768 (12.0) 647/3798 (17.0) 776/3737 (20.8) 1184/5398 (21.9) 99/1688 (5.9) 47/1736 (2.7) 358/3797 (9.4) 209/3724 (5.6) 587/5399 (10.9) 1300/16,344 (8.0) 355/1688 (21.0) 234/1736 (13.5) 830/3797 (21.9) 917/3724 (24.6) 1214/5399 (22.5) 1.01 ( ) 1.37 ( ) 1.19 ( ) 1.15 ( ) 1.07 ( ) NTT: 155 patients to prevent 1 cardiovascular event 1.12 ( ) 0.85 ( ) 0.87 ( ) 0.73 ( ) 0.80 ( ) 0.97 ( ) NNH: 498 patients to see 1 new case of diabetes Pooled odds ratio 3134/16,408 (19.1) 3550/16,344 (21.7) 0.84 ( ) Odds ratio (95% CI) Preiss D et al. JAMA 2011; 305:

87 Conclusions There are now an estimated 18 million people with DM in the USA and even more with pre-diabetes. The lifetime risk of developing DM for people born in 2000 is 33% for men and 39% for women. For Hispanic women it is 50%. In this population CVD is the major cause of death. Preventing diabetes and cardiovascular disease is crucial

88 Questions?

Metabolic Syndrome. Shon Meek MD, PhD Mayo Clinic Florida Endocrinology

Metabolic Syndrome. Shon Meek MD, PhD Mayo Clinic Florida Endocrinology Metabolic Syndrome Shon Meek MD, PhD Mayo Clinic Florida Endocrinology Disclosure No conflict of interest No financial disclosure Does This Patient Have Metabolic Syndrome? 1. Yes 2. No Does This Patient