1. 1 Prediabetes Management

2. 2 AACE Prediabetes Consensus Statement: Summary Untreated individuals with prediabetes are at increased risk for diabetes as well as for micro- and macrovascular complications Treatment goals are to prevent deterioration in glucose levels and modify other risk factors such as obesity, hypertension, and dyslipidemia –The same blood pressure and lipid goals are suggested for prediabetes and diabetes Intensive lifestyle management is the cornerstone of all prevention efforts; pharmacotherapy targeted at glucose may be considered in high-risk patients Handelsman Y, et al. Endocr Pract. 2011;17(Suppl 2):1-53. Garber AJ, et al. Endocr Pract. 2008;14:933-946.

3. 3 Prediabetes Epidemiologic evidence suggests that the complications of T2DM begin early in the progression from NGT to frank diabetes Prediabetes and diabetes are conditions in which early detection is appropriate, because –Duration of hyperglycemia is a predictor of adverse outcomes –There are effective interventions to prevent disease progression and to reduce complications NGT, normal glucose tolerance ; T2DM, type 2 diabetes mellitus. Garber AJ, et al. Endocr Pract. 2008;14:933-946.

4. 4 Policy Paradigm Shifts Needed to Stem Global Tide of T2DM Integrating primary and secondary prevention along a clinical continuum Early detection of prediabetes and undiagnosed diabetes Implementing cost-effective prevention and control by integrating community and clinical expertise/resources within affordable service delivery systems Sharing and adopting evidence-based policies at the global level T2DM, type 2 diabetes mellitus. Narayan KM, et al. Health Aff (Millwood). 2012;31:84-92.

5. 5

6. 6 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: –Obesity –Body fat distribution –Physical inactivity –High blood glucose T2DM, type 2 diabetes mellitus. Garber AJ, et al. Endocr Pract. 2008;14:933-946. Feasibility of Preventing T2DM

7. 7 Interventions to Reduce Risks Associated With Prediabetes Therapeutic lifestyle management is the cornerstone of all prevention efforts No pharmacologic agents are currently approved for the management of prediabetes –Pharmacotherapy targeted at glucose may be considered in high-risk patients after individual risk-benefit analysis Garber AJ, et al. Endocr Pract. 2008;14:933-946.

8. 8 Lifestyle Intervention in Prediabetes Persons with prediabetes should reduce weight by 5% to 10%, with long-term maintenance at this level A diet that includes caloric restriction, increased fiber intake, and (in some cases) carbohydrate intake limitations is advised. A program of regular moderate-intensity physical activity for 30-60 minutes daily, at least 5 days a week, is recommended Garber AJ, et al. Endocr Pract. 2008;14:933-946.

9. 9 Primary Care-Based Counseling for T2DM Prevention: ADAPT ADAPT, Avoiding Diabetes Thru Action Plan Targeting; T2DM, type 2 diabetes mellitus. Mann DM, Lin JJ. Implement Sci. 2012;23:6.

10. 10 Self-Reported Risk Reduction Activities in Patients With Prediabetes (National Health and Nutrition Examination Survey Data) CDC. MMWR Morb Mortal Wkly Rep. 2008;57:1203-1205.

11. 11 Interventions Proven to Delay or Prevent T2DM Development T2DM, type 2 diabetes mellitus. Sherwin RS, et al. Diabetes Care. 2004;27,(Suppl 1): S47-S54. Eriksson K-F, Lindgärde F. Diabetologia. 1991;34:891-898. Ramachandran A, et al. Diabetologia 2006;49:289-297. Knowler WC, et al. N Engl J Med. 2002;346:393-403. Defronzo RA, et al. N Engl J Med. 2011;364:1104-15. Intervention Rate of Conversion to Normal Glucose Tolerance Lifestyle (3 trials)52%-58% Metformin (2 trials)26%-31% Acarbose (1 trial)25% Pioglitazone (1 trial)48%

12. 12 StudyCountryN Baseline BMI (kg/m 2 ) Intervention period (years) RRR (%)NNT Diabetes Prevention Program USA323434.02.85821 Diabetes Prevention Study Finland5233143922 Da QingChina57725.865130 BMI, body mass index; NNT, number needed to treat; RRR, relative risk reduction; T2DM, type 2 diabetes mellitus. DPP Research Group. N Engl J Med. 2002;346:393-403. Eriksson J, et al. Diabetologia. 1999;42:793-801. Li G, et al. Lancet. 2008;371:1783-1789. Lindstrom J, et al. Lancet. 2006;368:1673-1679. Prevention of T2DM: Selected Lifestyle Modification Trials

13. 13 T2DM Incidence in the Diabetes Prevention Program Intensive lifestyle intervention* (n=1079) T2DM incidence per 100 person-years Placebo (n=1082) Metformin 850mg BID (n=1073) 58% 31% *Goal: 7% reduction in baseline body weight through low-calorie, low-fat diet and ≥150 min/week moderate intensity exercise. IGT, impaired glucose tolerance; T2DM, type 2 diabetes mellitus. DPP Research Group. N Engl J Med. 2002;346:393-403.

14. 14 Effect of Age on Incidence of T2DM in the DPP T2DM incidence per 100 person-years 48% 59% Age (years) 71% *Goal: 7% reduction in baseline body weight through low-calorie, low-fat diet and ≥150 min/week moderate intensity exercise. DPP, Diabetes Prevention Program;. DPP Research Group. N Engl J Med. 2002;346:393-403.

15. 15 Effect of Weight on T2DM Incidence in the DPP T2DM incidence per 100 person-years 65% BMI (kg/m 2 ) 51% 61% *Goal: 7% reduction in baseline body weight through low-calorie, low-fat diet and ≥150 min/week moderate intensity exercise. DPP, Diabetes Prevention Program. DPP Research Group. N Engl J Med. 2002;346:393-403.

16. 16 10-Year Weight Loss in the DPP Outcomes Study DPP, Diabetes Prevention Program; T2DM, type 2 diabetes mellitus. DPP Research Group. Lancet. 2009;374:1677-1686. 1032 5476 8109 Years

17. 17 DPP, Diabetes Prevention Program; T2DM, type 2 diabetes mellitus. DPP Research Group. Lancet. 2009;374:1677-1686. 1032 5476 8109 Placebo Metformin Lifestyle Years 10-Year Incidence of T2DM in the DPP Outcomes Study

18. 18 DPP, Diabetes Prevention Program; DPPOS, Diabetes Prevention Program Outcomes Study; T2DM, type 2 diabetes mellitus. DPP Research Group. Lancet. 2009;374:1677-1686. 10-Year Incidence of T2DM in the DPP Outcomes Study

19. 19 The Chinese Prevention Study Incidence of Diabetes (%/yr) RRR=65% ControlMetformin The Effect of Metformin on the Progression of IGT to Diabetes Mellitus (N=321) IGT, impaired glucose tolerance; RRR, relative risk reduction. Yang W, et al. Chin J Endocrinol Metab. 2001;17:131-136.

20. 20 CI, confidence interval; DPP, Diabetes Prevention Program; T2DM, type 2 diabetes mellitus. Li G, et al. Lancet. 2008;371:1783-1789. Cumulative T2DM Incidence During Follow-up in the Chinese Da Qing Diabetes Prevention Study

21. 21 Effect of Lifestyle Modification and Metformin on Cumulative Diabetes Incidence The Indian DPP (N=531) n=136 n=133 Incidence (%) RRR (%) ControlLSMMETLSM & MET 28.5 P=0.018 26.4 P=0.029 28.2 P=0.022 n=133 n=129 DPP, Diabetes Prevention Program; LSM, lifestyle modification; MET, metformin; RRR, relative risk reduction. Ramachandran A, et al. Diabetologia 2006;49:289-297.

22. 22 T2DM Prevention in Women With a History of GDM: Effect of Metformin and Lifestyle Interventions Findings from the DPP: –Progression to diabetes is more common in women with a history of GDM vs those without, despite equivalent degrees of IGT at baseline Both intensive lifestyle and metformin are highly effective in delaying or preventing diabetes in women with IGT and a history of GDM DPP, Diabetes Prevention Program; GDM, gestational diabetes mellitus; IGT, impaired glucose tolerance; T2DM, type 2 diabetes mellitus. Ratner RE, et al. J Clin Endocrinol Metab. 2008;93:4774-4779.

23. 23 Effect of Acarbose on Reversion of IGT to NGT P<0.0001 Placebo Acarbose Number of Patients n=241 (35.3%) n=212 (30.9%) IGT, impaired glucose tolerance; NGT, normal glucose tolerance. Chiasson JL, et al. Lancet. 2002;359:2072-2077. The Study to Prevent Non-Insulin Dependent Diabetes Mellitus (STOP-NIDDM)

24. 24 Group Lifestyle Balance Program Intervention DPP lifestyle intervention was adapted to a 12-session group-based program Implemented in a community setting in 2 phases using a nonrandomized prospective design Significant decreases in weight, waist circumference, and BMI were noted in both phases vs baseline Average combined weight loss for both groups over the 3-month intervention was 7.4 pounds (3.5% relative loss, P<0.001) University of Pittsburgh Primary Care Practice and Diabetes Prevention Support Center DPP, Diabetes Prevention Program; mo, month. Kramer MK, et al. Am J Prev Med. 2009;37:505-511.

25. 25 Pilot, cluster-randomized trial Group-based DPP lifestyle intervention vs brief counseling alone (control) among high-risk adults who attended a diabetes risk-screening event at one of two semi-urban YMCA facilities 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;35:357-363. Translating the DPP Into Community Intervention The DEPLOY Pilot Study P<0.001 P=0.002

26. 26 Mean weight and physical activity min/week among participants by lifestyle intervention session CVD, cardiovascular disease; DPP, Diabetes Prevention Program. Amundson HA, et al. Diabetes Educ. 2009;35:209-223. Montana CVD and DPP

27. 27 Translation of the DPP’s Lifestyle Intervention Four additional studies utilizing the DPP lifestyle interventions in community settings provided the following findings: –Promising evidence of the prevention of diabetes by significantly decreasing glucose levels and adiposity –Statistically significant improvements in many behavioral outcomes and anthropometrics, particularly at 6 months –Decreased fasting glucose and weight in at-risk African Americans –Approaches that improve recruitment of participants from underserved communities into research, especially research related to chronic disease risk factors DPP, Diabetes Prevention Program. Boltri JM, et al. J Natl Med Assoc. 2011;103:194-202. Katula JA, et al. Diabetes Care. 2011;34:1451-1457. Ruggiero L, et al. Diabetes Educ. 2011;37:564-572. Santoyo-Olsson J, et al. Gerontologist. 2011;51(Suppl 1):S82-93.

28. 28 Pioglitazone for T2DM Prevention in IGT: ACT NOW ACT NOW, Actos NOW for the Prevention of Diabetes; IGT, impaired glucose tolerance; T2DM, type 2 diabetes mellitus. Defronzo RA, et al. N Engl J Med. 2011;364:1104-1115. Kaplan–Meier plot of hazard ratios for time to development of T2DM

29. 29 Effects of Exenatide and Lifestyle Modification on Body Weight and Glucose Tolerance in Obese Patients With and Without Prediabetes Patients –N=152, weight 108.6 +/- 23.0 kg, BMI 39.6 +/- 7.0 kg/m 2 (IGT or IFG 25%) Design –24-week randomized controlled trial: exenatide or placebo plus lifestyle intervention Results: –Exenatide-treated patients lost 5.1 kg from baseline vs 1.6 kg with placebo (P<0.001) –Both groups reduced their daily caloric intake –IGT or IFG normalized at end point in 77% and 56% of exenatide and placebo subjects, respectively BMI, body mass index; IFG, impaired fasting glucose; IGT, impaired glucose tolerance. Rosenstock J, et al. Diabetes Care. 2010;33:1173-1175.

30. 30 Garber AJ, et al. Endocr Pract. 2008;14:933-946. Special Concerns for Thiazolidinedione Use in Patients With Prediabetes Because of concerns about long-term safety, use of thiazolidinediones should be reserved for higher risk populations and those failing other, lower-risk strategies

31. 31 Medical Weight-Loss Strategies Orlistat may prevent progression from prediabetes to diabetes Lorcaserin, a selective serotonin 2C agonist, is indicated for use in obese patients with at least 1 weight-related comorbid condition (eg, hypertension, dyslipidemia, CVD, glucose intolerance, sleep apnea) Low-dose, immediate-release phentermine and controlled- release topiramate is recommended for obese or overweight patients with weight-related comorbidities such as hypertension, T2DM, dyslipidemia, or central adiposity CVD, cardiovascular disease; obese, BMI ≥30 kg/m 2 ; overweight, BMI ≥27 kg/m 2 ; T2DM, type 2 diabetes mellitus. Garber AJ, et al. Endocr Pract. 2008;14:933-946.

32. 32 Pharmacologic Weight-Loss Strategies Drug name Placebo- subtracted mean % body weight loss from baseline Patients (N) in clinical program/ patients (n) with diabetes % of patients losing ≥5% of body weight Clinical trial withdrawal rates Orlistat 2.4% (following 4 years of treatment with orlistat 120 mg TID) 7504/321 35.5%-54.8% (following 1 year of treatment with orlistat 120 mg TID) 8.8% Lorcaserin 3.3% at 52 weeks 6888/51047.1%36%-50% Phentermine/ topiramate) 3.5%-6.4%3678/80845%-70%31%-40% LOCF, last observation carried forward. Orlistat [package insert]. South San Francisco CA; Genentech USA; 2010. Belviq [package insert]. Woodcliff Lake, NJ; Eisai Inc.; 2012. Qsymia [package insert]. Mountain View, CA; VIVUS, Inc; 2012.

33. 33 DPP Year 1: Mean Change in Blood Pressure Change in BP (mm Hg) Baseline BP124124124797878 SystolicDiastolic BP, blood pressure; DPP, Diabetes Prevention Program. Ratner R, et al. Diabetes Care. 2005;28:888.

34. 34 Prevalence of Hypertension (% of patients) * Effects of Metformin, Lifestyle Modifications, and Placebo on Hypertension Over 36 Months in DPP P<0.001 P=0.08P<0.001 DPP, Diabetes Prevention Program; HTN, hypertension. Ratner R, et al. Diabetes Care. 2005;28:888-894.

35. 35 Hypertension defined as BP  140/90 mmHg Cumulative Incidence (%) 04 3 215 Years After Randomization 8 6 4 2 0 12 10 18 16 14 Acarbose Placebo RRR = 34% P=0.0059 BP, blood pressure; IGT, impaired glucose tolerance; STOP NIDDM, Study to Prevent Non-Insulin Dependent Diabetes Mellitus Trial Chiasson JL, et al. JAMA. 2003;290:486-494. STOP NIDDM: Incidence of New Cases of Hypertension in IGT Patients

36. 36 DPP Study: Mean Change in Total and LDL Cholesterol DPP, Diabetes Prevention Program; LDL-C, low-density lipoprotein. DPP Research Group. Diabetes Care. 2005;28:2472–2479. Ratner R, et al. Diabetes Care. 2005;28:888-894. Change in Lipids (%) Baseline (mg/dL) 202127 Total CholesterolLDL-C

37. 37 DPP Study: Mean Change in Triglycerides and HDL Cholesterol DPP, Diabetes Prevention Program. DPP Research Group. Diabetes Care. 2005;28:2472–2479. Ratner R, et al. Diabetes Care. 2005;28:888-894. Change in Lipids (mg/dL) Baseline (mg/dL)17240 TriglyceridesHDL-C

38. 38 DPP Study: Effects of Metformin, Lifestyle Modifications, and Placebo on Lipids: 3-year Timeframe DPP, Diabetes Prevention Program. Ratner R, et al. Diabetes Care. 2005;28:888-894.

39. 39 CVD Outcomes in Type 2 Diabetes Prevention Trials StudyOutcome DPP64 of 3234 patients (89 total events) DREAM0.5 events/100 patient-years STOP NIDDM1.4 events/100 patient-years CVD, cardiovascular disease; DPP, Diabetes Prevention Program; DREAM, Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication; STOP NIDDM, Study to Prevent Non-Insulin Dependent Diabetes Mellitus Trial. Ratner R, et al. Diabetes Care. 2005;28:888-894. DREAM Investigators. Diabetes Care. 2008;31:1007-1014. Chiasson JL, et al. JAMA. 2003;290:486-494.

40. 40 CVD, cardiovascular disease; IGT, impaired glucose tolerance; RRR, relative risk reduction; STOP NIDDM, Study to Prevent Non-Insulin Dependent Diabetes Mellitus Trial. Chiasson JL, et al. JAMA. 2003;290:486-494. Cumulative Incidence (%) 043215 Years After Randomization Acarbose Placebo 5 4 3 2 1 0 RRR = 49% P=.03 47 subjects with CVD events 32 placebo 15 acarbose STOP-NIDDM Study: Effect of Acarbose on Cardiovascular Event Incidence in Patients With IGT

41. 41 STOP NIDDM CVD Events Acarbose (N=682) Placebo (N=686) Hazard Rate Myocardial Infarction 1120.09* Angina5120.45 Revascularization11200.61 CVD Death 120.55 Cerebrovascular Event or Stroke 240.56 Peripheral Vascular Disease 111.14 Any CVD Event 15320.51* *P<0.05 CVD, cardiovascular disease; STOP NIDDM, Study to Prevent Non-Insulin Dependent. Chiasson JL, et al. JAMA. 2003;290:486-494.

42. 42 CVD, cardiovascular disease. Li G, et al. Lancet. 2008;371:1783-1789. Cumulative Incidence of CVD Death During Follow-up in China Da Qing Diabetes Prevention Study Control Intervention

43. 43 Pharmacotherapy for Cardiovascular Risk Factors TargetGoal First-Line Agents Comments LDL<100 mg/dLStatins Additional use of fibrates, bile acid sequestrants, ezetimibe, etc, should be considered as appropriate Blood pressure <130/80 mm/Hg ACE inhibitors, Angiotensin receptor blockers Calcium channel blockers are appropriate second-line treatment approaches Low-dose aspirin is recommended for all persons with prediabetes for whom there is no identified excess in risk for gastrointestinal, intracranial, or other hemorrhagic condition ACE, angiotensin converting enzyme; LDL, low-density lipoprotein. Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53. Garber AJ, et al. Endocr Pract. 2008;14:933-946.