Faculty. Identification and Treatment of Prediabetes to Prevent or Delay the Onset of T2DM. Learning Objectives. Disclosures

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1 Faculty Identification and Treatment of Prediabetes to Prevent or Delay the Onset of Sam Dagogo-Jack, MD, DM, FRCP A. C. Mullins Endowed Chair in Translational Research Professor of Medicine & Director Division of Endocrinology, Diabetes, and Metabolism Director, General Clinical Research Center University of Tennessee Health Science Center Memphis, Tennessee Ben Taylor, PhD, PA-C Georgia Regents University Clinical Faculty Augusta, Georgia Disclosures Learning Objectives Sam Dagogo-Jack, MD: Research Grants: NIH/NIDDK; Clinical Trial Contracts (UTHSC) AstraZeneca, Novo Nordisk, Boehringer Ingelheim; Consultant - Merck, Novo Nordisk, Boehringer Ingelheim, Janssen, Sanofi, Amgen, Perle Bioscience. Ben Taylor, PhD, PA-C has disclosed no relevant financial relationships with any commercial interests. Discuss the prevalence and complications of prediabetes and the importance of prediabetes as a clinicopathological entity Understand the key contributors to the pathophysiology of prediabetes and the predictors of progression from normoglycemia to prediabetes Define the diagnostic criteria and risk factors for prediabetes Discuss major health risks associated with prediabetes Explain the categories of glucose intolerance that are classified as prediabetic Discuss specific lifestyle approaches to diabetes prevention and reversal of prediabetes Analyze the role, indications and limitations of medications for diabetes prevention 29.1 Million People Have Diabetes Mellitus Prediabetes: Diagnosis, Pathophysiology, and Complications Sam Dagogo-Jack, MD, DM, FRCP Prediabetes 86.1 million (37%) 1

2 False-Positive and False-Negative Values for HbA1c vs OGTT Screening by Race Across Three Studies* White Black White Black White Black A1c should be considered as an additional criterion, not the primary criterion. *Screening for Impaired Glucose Tolerance study (n = 1581), and from the NHANES III (n = 214), and NHANES (n = 1111). Olson DE, Rhee MK, Herrick K, Ziemer DC, Twombly JG, Phillips LS. Diabetes Care. 21;33: Pathophysiology of Diabetes Mellitus Pima Study: Role of Insulin Action and Secretion Insulin Resistance Genes Dagogo-Jack S. Diabetes Care. 212;35: Type 1 Diabetes Mellitus -Cell Destruction Environment + Type 2 Diabetes Mellitus -Cell Dysfunction % Change Prediabetes (IGT) Diabetes mellitus Insulin action (M-low)* -6 Insulin action (M-high) -7 Insulin secretion *M-low: euglycemic clamp at physiologic insulin levels ( pmol/l) M-high: euglycemic clamp at supraphysiologic insulin levels (13, pmol/l); Weyer C, et al. J Clin Invest.1999;14: Glucoregulation in Normal vs Prediabetic Subjects by Glucose Criteria ISI-clamp( mol/kg.min -1 /pm) HOMA-IR Insulin Sensitivity * ** ** *** FPG < H PG <14 <14 <14 >14 IFG IFG-IGT * Insulin Resistance Disposition Index Insulin Secretion (pm) Cavaghan et al. J Clin Invest 1997;1:53-37 Disposition Index # # FPG < H PG <14 <14 >14 <14 IFG IFG-IGT Pathophysiological Defects in Prediabetes *P =.4. **.2, ***P <.1, #P =.2 Dagogo-Jack S, Askari H, Tykodi G. JCEM. 29;94: Brannick B, Wynn A, Dagogo-Jack S. Exp Biol Med (Maywood). 216 Jun;241(12):

3 (J Am Board Fam Med 216;29: ) The Continuum of Dysglycemia and Complications Analyzed data from the 212 National Ambulatory Medical Care Survey Identified adults >45 years without diagnosed DM who had an HbA1c test within 9 days of the visit (1,167,4 weighted visits) HbA1c results Normal 54.6% Prediabetes 33.6% Diabetes mellitus 11.9% Alerts/Reminders Lab reports EMR flags HMOs ACOs Of prediabetic HbA1c values, the number of patients diagnosed with prediabetes was too low (<1%) for a reliable population estimate Indication of treatment in the record (LS counseling and/or metformin) was present in 23% of those with diagnosed or undiagnosed prediabetes Microvascular Complications of Prediabetes Retinopathy in 7.9% of IGT subjects and 12.6% of new in DPP Documented increased risks of microalbuminuria and neuropathy Understanding the Continuum of Dysglycemia? 11%-25% of prediabetic subjects show evidence of peripheral neuropathy 13%-21% present with neuropathic pain 25%- 62% of idiopathic peripheral neuropathy patients have prediabetes U. S. DPP Da Qing FDPS IDPP DPP Research Group. Diabet Med. 27;24: Haffner SM, et al. Diabetologia. 1993;36: Papanas N, Vinik AI, Ziegler D. Nat Rev Endocrinol. 211;7: Pathobiology of Prediabetes in a Bi-racial Cohort (POP-ABC) Pathobiology of Prediabetes in a Bi-racial Cohort (POP-ABC) Baseline OGTT in NFG NGT Baseline OGTT in NFG NGT African- Americans Caucasians with parental NFG NGT Baseline/ repeated assessments every 3 months x 5 years IFG IGT IFG/ IGT Progressors African- Americans Caucasians with parental NFG NGT Baseline/ repeated assessments every, Lipid profile 3 months x 5 years IFG IGT IFG/ IGT Progressors Age: yr Age: yr NFG, Normal fasting glucose; NGT, Normal glucose tolerance IFG, Impaired fasting glucose; IGT, Impaired glucose tolerance Dagogo-Jack S, et al. Ethn Dis. 211;21: Dagogo-Jack S, et al. J Clin Endocrinol Metab. 213;98: NFG, Normal fasting glucose; NGT, Normal glucose tolerance IFG, Impaired fasting glucose; IGT, Impaired glucose tolerance Dagogo-Jack S, et al. Ethn Dis. 211;21: Dagogo-Jack S, et al. J Clin Endocrinol Metab. 213;98:

4 Progression from Normoglycemia to Prediabetes Predictors of Incident Prediabetes Prediabetes Survival Probability (P=.7855) White Black Mean Follow-up 2.62 yr Prediabetes: 11 (29.5%) ~11%/yr* : 1 (2.9%) Maintained NGR: 232 (67.6%) Pima Indians NGT IGT : ~8%/yr Weyer C, et al. Diabetes Care. 2;24: hr Plasma Glucose (mg/dl) Age Adiposity FPG 2-hrPG Behavioral Lipid profile Adiponectin Insulin sensitivity Insulin secretion NP * 18 * P 1 NP P Trunk Fat Mass (kg) P, Progressors; NP, Non-progressors * P =.3-<.1 Dagogo-Jack S, et al. J Clin Endocrinol Metab. 214;99(6):E Dagogo-Jack S, et al. JCEM. 214;99: Boucher A, et al. Metabolism. 215;64: Jiang Y, Owei I, Wan J, Ebenibo S, Dagogo-Jack S. BMJ. Open Diabetes Research and Care 216;4:e194. AACE Prediabetes Consensus Statement: Summary Prediabetes: Identification, Screening, and Monitoring to Reduce Risk Ben Taylor, PhD, PA-C 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. 215; In press. Garber AJ, et al. Endocr Pract. January 216;22(1): Rationale for Prediabetes Screening Risk Factors for Prediabetes and Epidemiologic evidence suggests the complications of diabetes mellitus begin early in the progression from normal glucose tolerance to frank type 2 diabetes mellitus Prediabetes and diabetes mellitus are both conditions in which early detection is of upmost importance because: Duration of hyperglycemia is a predictor of adverse outcomes There are effective interventions to prevent disease progression and to reduce complications associated with both Aged >45 years Family history of or CVD Overweight or obese Sedentary lifestyle Non-Caucasian ancestry Previously identified IGT, IFG, and/or metabolic syndrome PCOS, Acanthosis nigricans, or NAFLD Hypertension (BP >14/9 mm Hg) Dyslipidemia (HDL-C <35 mg/dl and/or triglycerides >25 mg/dl) History of gestational diabetes Delivery of baby weighing >4 kg (>9 lb) Antipsychotic therapy for schizophrenia or severe bipolar disease Chronic glucocorticoid exposure Sleep disorders Obstructive sleep apnea Chronic sleep deprivation Night shift work Garber AJ, et al. Endocr Pract. January 216;22(1): BP = blood pressure; HDL-C = high-density lipoprotein cholesterol; IFG = impaired fasting glucose; IGT = impaired glucose tolerance; NAFLD = nonalcoholic fatty liver disease; PCOS = polycystic ovary syndrome; = type 2 diabetes mellitus; CVD = cardiovascular disease. Handelsman YH, et al. Endocr Pract. January 216;22(1):

5 Criteria for Prediabetes IFG: FPG mg/dl IGT: 2-hour PPG mg/dl In patients with IFG, a 2-hour OGTT may further clarify the level of risk while also detecting undiagnosed diabetes mellitus Patients with impaired glucose metabolism identified by 2-hour OGTT were greater in number than patients discovered by routine FPG Metabolic syndrome diagnosed by the NCEP criteria should be considered a prediabetes equivalent 3 of 5 metabolic syndrome criteria are sufficient; recent evidence suggests even 2 of 5 metabolic syndrome criteria may be adequate Monitoring Patients with Suspected Prediabetes Patients suspected of having or diagnosed with prediabetes should get monitored at least every year to check the progress In addition to faithful yearly check-ups, Patients with prediabetes can also benefit from joining an ongoing support program Diabetes Prevention Support Center Excellent support group for those who have prediabetes or are very near to having impaired glucose tolerance WebMD Diabetes Community An elaborate discussion board for those who have questions about diabetes, want to post about their own experiences with the disease, or have information that they want to share with readers GlucoMenu Interactive website that gives the patient healthy options for building a diet based around the ADA s recommendations; meal plans are custom made around their dietary needs and are very easy to use FPG=fasting plasma glucose; IFG=impaired fasting glucose; IGT=impaired glucose tolerance; OGTT=oral glucose tolerance test; NCEP=national cholesterol estrogen program. Handelsman YH, et al. Endocr Pract. 215;21(suppl 1):1-87; Garber AJ, et al. Endocr Pract. January 216, Vol. 22, No. 1, pp Symptoms, Diagnosis and Monitoring of Pre-diabetes. (215, August 1). Retrieved June 24, 216, from Diagnosis-and-Monitoring-of-Pre-diabetes_UCM_461531_Article.jsp#.V3CTOGgrI1I. Normal FPG and Risk of Patients with normal FPG and any of the following comorbidities are at increased risk of developing Obesity Hypertension Low HDL-C High triglycerides Smoking Closer surveillance for the development of diabetes mellitus might be warranted in these patients FPG = fasting plasma glucose; HDL-C = high-density lipoprotein cholesterol; =type 2 diabetes mellitus. Nichols GA, et al. Am J Med. 28;121: Screening and Diagnosis of Prediabetes and Diabetes Mellitus Test Normal High Risk for Diabetes Mellitus Diabetes Mellitus* FPG, mg/dl < (IFG) h PG, mg/dl < (IGT) 2 Random PG, mg/dl 2 + symptoms of diabetes mellitus Hemoglobin A1C, % < (screening only) 6.5 Must also exclude iron deficiency with or without anemia *Confirm diagnosis on a separate day by repeating the glucose or A1C testing. Measured with an OGTT performed 2 hours after 75-g oral glucose load. AACE prefers use of glucose criteria for diagnosis of diabetes mellitus. When A1C is used for diagnosis, follow-up glucose testing should be done when possible to help manage diabetes mellitus. IFG = impaired fasting glucose; IGT = impaired glucose tolerance; OGTT = oral glucose tolerance test; PG = plasma glucose. Handelsman YH, et al. Endocr Pract. 215;21(suppl 1):1-87. Feasibility of Preventing There is a long period of glucose intolerance that precedes the development of diabetes mellitus 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 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. January 216, Vol. 22, No. 1, pp Garber AJ, et al. Endocr Pract. January 216, Vol. 22, No. 1, pp

6 What s the Take Home? New research shows that the deadly complications of this disease can be prevented through lifestyle modification and/or drug therapy Healthcare professionals need to be aware of the critical need for detecting both IGT and IFG in addition to diabetes mellitus More efficient screening guidelines and procedures need to be implemented so that we can detect more cases of prediabetes and start treatment earlier in efforts to delay and/or prevent diabetes mellitus in these patients Prediabetes: Approach to Management Sam Dagogo-Jack, MD, DM, FRCP The Continuum of Dysglycemia and Complications Population Prevalence (%) of CKD Stages 1 4 by Diabetes Mellitus and Prediabetes Status, NHANES CKD diagnosed with egfr by MDRD equation Plantinga L, et al. Clin J Am Soc Nephrol. 21;5: Relative Risk of MI or Stroke Risk of CVD Is Elevated Prior to Diagnosis of NHS: 117,629 female nurses aged 3-55 years who were free of diagnosed CVD at baseline were recruited in 1976 and followed for 2 years Diabetes Prevention Program Study Population Caucasian 1768 African-American 645 Hispanic-American 58 Asian-American & 142 Pacific Islander American Indian 171 Hispanic- American 16% African- American 2% Caucasian 55% Asian 4% American- Indian 5%. Nondiabetic Throughout Study 15 y or More Before Diagnosis y Before Diagnosis <1 y Before Diagnosis CVD=cardiovascular disease. Hu F, et al. Diabetes Care. 22;25: DPP Research Group. N Engl J Med. 22;346:

7 Study Interventions Eligible participants (IGT) Randomized Standard lifestyle recommendations Intensive (n = 179) Metformin (n = 173) DPP Research Group. N Engl J Med. 22;346: (n = 182) Elements of Intervention Dietary modification 5 to 7 Kcal/d reduction or weight-based Reduction in fat and total calorie intake Weight loss goal >7% Mediterranean, DASH Meal replacements Physical activity >15 min/wk Aerobic and resistance Frequent contacts Self-monitoring DPP Research Group. N Engl J Med. 22;346: Weight Change (kg) Activity Change (MET-hr/wk) % Medication Adherence Metformin Metformin Metformin Year Diabetes Prevention Program Research Group. N Engl J Med. 22;346(6): DPP Study 3234 individuals at risk for Randomized to: a), b) Metformin, or c) Increased activity Improved eating habits Mean follow-up of 2.8 years % Diabetes Mellitus Risk Reduction by Ethnicity Caucasian (n=1768) African- American (n=645) Metformin DPP Research Group. N Engl J Med. 22;346: Hispanic (n=58) American Indian (n=171) Asian (n=142) Baseline 8.2 fibers/mm After 1 Year 15.1 fibers/mm 32 subjects with symptomatic IGT neuropathy received individualized diet and exercise counseling Assessments at Baseline and after 1 year: Michigan Diabetic Neuropathy score Visual analog pain scale 75-g OGTT, Lipid profile 3-mm skin biopsies with measurement of IENFD Nerve conduction studies, quantitative sensory testing, Quantitative sudomotor axon reflex testing 32 subjects with symptomatic IGT neuropathy received individualized diet and exercise counseling Assessments at Baseline and after 1 year: Michigan Diabetic Neuropathy score Visual analog pain scale 75-g OGTT, Lipid profile 3-mm skin biopsies with measurement of IENFD Nerve conduction studies, quantitative sensory testing, Quantitative sudomotor axon reflex testing Smith AG, Hamwi J, Russell J, et al. Diabetes Care. 26;29: Smith AG, Hamwi J, Russell J, et al. Diabetes Care. 26;29:

8 Primary Prevention Trials Year Study Follow-up Intervention Outcome 1982 Bedford 1 yr Diet + SU Decrease 1991 Malmo 1 yr Diet + exercise Decrease 1997 Da Quing 6 yr Diet + exercise Decrease, 51% 21 DPS, Finland 3 yr Diet + exercise Decrease, 58% 22 DPP 2.8 yr Diet+Ex vs. Met Decrease, 58% 22 TRIPOD 2.6 yr Troglitazone Decrease, 59% 22 STOP-NIDDM 3.3 yr Acarbose + Diet Decrease, 25% 24 XENdos 4 yr Orlistat + Diet Decrease, 37% 26 DREAM 3 yr Rosiglitazone Decrease, 6% 28 ACT NOW 2-4 yr Pioglitazone Decrease, 72% 26 IDPP-1 3 yr L/S + Met Decrease, 26-28% 29 IDPP-2 3 yr L/S + Pio Pio not additive to L/S 21 Navigator 5 yr Nateglinide No effect Valsartan Decrease, 14% 21 CANOE 4 yr Rosi+Met Decrease 69% Primary Prevention Trials Year Study Follow-up Intervention Outcome 1982 Bedford 1 yr Diet + SU Decrease 1991 Malmo 1 yr Diet + exercise Decrease 1997 Da Quing 6 yr Diet + exercise Decrease, 51% 21 DPS, Finland 3 yr Diet + exercise Decrease, 58% 22 DPP 2.8 yr Diet+Ex vs Met Decrease, 58% 22 TRIPOD 2.6 yr Troglitazone Decrease, 59% 22 STOP-NIDDM 3.3 yr Acarbose + Diet Decrease, 25% 24 XENdos 4 yr Orlistat + Diet Decrease, 37% 26 DREAM 3 yr Rosiglitazone Decrease, 6% 28 ACT NOW 2-4 yr Pioglitazone Decrease, 72% 26 IDPP-1 3 yr L/S + Met Decrease, 26-28% 29 IDPP-2 3 yr L/S + Pio Pio not additive to L/S 21 Navigator 5 yr Nateglinide No effect Valsartan Decrease, 14% 21 CANOE 4 yr Rosi+Met Decrease, 69% Echouffo-Tcheugui JB, Dagogo-Jack S. Nat Rev Endocrinol 8: , 212 Echouffo-Tcheugui JB, Dagogo-Jack S. Nat Rev Endocrinol. 212;8: DPPOS: 1-year Follow-up of Diabetes Mellitus Incidence and Weight Loss DPP: Incidence of Metabolic Syndrome Change in weight (kg) Cumulative incidence (%) DPP Research Group. Lancet. 29;374: DPPOS DPPOS Legacy Effects Glycemic Non-glycemic BP Lipids Met. syndrome Adipocytokines CVD Other Cumulative Incidence of Metabolic Syndrome Risk reduction vs placebo 41% # Metformin vs placebo 17%* vs metformin 29% # Metformin *P<.5; # P<.1. Year from Randomization Adapted from Orchard TJ, et al. Ann Intern Med. 25;19;142: Da Qing Study: Cumulative Incidence of Diabetes Mellitus and Mortality in Intervention and Control Groups during 23 Years of Follow-up Prevention of : Current Recommendations Diabetes incidence CVD mortality Screen asymptomatic people for prediabetes Focus on overweight/obesity and DM risk Control group Intervention group HR.55, 95% CI(.4-.76) All-cause mortality Refer for ILI (-7% wt, -5 kcal, 15 min/wk) Selective use of metformin (age, BMI, GDM) Self-management education and support Annual assessment Identify and control CVD risk factors HR.71, 95% CI( ) Li G, et al. Lancet Diabetes Endocrinol. 214;2: American Diabetes Association. Diabetes Care. 216; 39 (Suppl 1):S14-17, S36. DPP Research Group. N Engl J Med. 22;346:393. 8

9 The Influence of Age on the Effects of Modification and Metformin in Prevention of Diabetes Mellitus What s the Take-Home? modification is the best documented, least toxic, and most appealing option for the prevention of diabetes mellitus Diabetes Mellitus Incidence per 1 P-Y 44% 31% 48% Metformin can be considered in special situations Currently, no compelling rationale or recommendation regarding other medications Prediabetes is predictable using simple heuristics (eg, waist, FPG, 2hPG) and reversible with lifestyle intervention Diabetes Prevention Program Research Group. N Engl J Med. 22;346: DPP Research Group. J Gerontol A Biol Sci Med Sci. 26;61: Identification and earlier intervention in persons at high risk for NGT IFG/IGT transition could provide a more comprehensive protection Questions? 9