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  1. What Is New In Diabetes: An Update David W. Gardner MD Director Cosmopolitan International Diabetes Center University of Missouri School of Medicine Columbia, MO

  2. What’s New and Important • How to diagnose diabetes • Identifying and treating prediabetes • Unusual forms of diabetes • What should glycemic goals be? • New and possible future treatments of diabetes • Obesity and diabetes

  3. Diagnosing Diabetes Mellitus

  4. Guidelines and Recommendations for Laboratory Analysis in the Diagnosis and Management of Diabetes Mellitus Any one of the following is diagnostic: 1. HbA1c >6.5% (48 mmol/mol) OR 2. FPG > 7.0 mmol/L (126 mg/dL) OR 3. 2-h Plasma glucose > 11.1 mmol/L (200 mg/dL) during an OGTT OR 4. Symptoms of hyperglycemia and casual plasma glucose > 11.1 mmol/L (200 mg/dL) Diabetes Care 34:e61–e99, 2011

  5. Recommendation of the International Expert Committee for the Diagnosis of Diabetes A1c > 6.5% = Diabetes Levels at which the Dx is made based on when the risk for retinopathy goes up

  6. CVD is the Leading Cause of Mortality in Patients With Diabetes The CV Risk Increases Dramatically When A1c is Between 5 and 6% • Followed 4662 men and 5570 women who were 45 to 79 for 6-8 years • Checked baseline A1c and risk factors • Followed until 2003 for CVD events and mortality • Relationship between A1c and CVD and all-cause mortality was continuos • With out known DM • Increase of 1% associated with mortality RR of 1.24 in men RR Coronary Heart Disease Event A1c Ann Intern Med. 2004;141:413-420.

  7. Prevalence of Diabetes and High Risk forDiabetes Using A1C Criteria in the U.S • Used NHANES data to look of incidence of DM (diagnosed and undiagnosed) and at risk for diabetes (IFG, IGT, Prediabetes) • Conclusion: Using the A1c criteria, there is a much lower prevalence of DM and Prediabetes than glucose criteria Diabetes Care 33:562–568, 2011

  8. Prevalence of Diabetes and High Risk forDiabetes Using A1C Criteria in the U.S Diabetes Care 33:562–568, 2011

  9. Performance of Glycated Hemoglobin for the Classification and Prediction of Diabetes • Objective: “assess the test performance of HbA1c against single and repeat glucose measurements for diagnosis of prevalent diabetes and for prediction of incident diabetes” • It was a Population-based analyses of 12,485 participants • Compared to a single fasting glucose the A1c had: • a sensitivity of 47% and • specificity (Sp) of 98% • An HbA1c cut-point of 6.5% is highly specific but has low sensitivity for the identification of prevalent undiagnosed diabetes Diabetes Care Publish Ahead of Print, published online September 20, 2010

  10. What Should We do? • 2 hr PP glucose has the highest specificity • Hard to do in office practice • FPG is better than A1c as single test • A1c is easy to do and has a high specificity • More expensive • Effected by hemoglobinopathies, hemolysis and anemia

  11. My Suggestion Screen with FPG and A1c • If FPG < 100 mg/dl and A1c <6.0%: Normal glucose tolerance • If FPG > 126 and A1c> 6.5%: Dx diabetes • If one is diagnostic of DM and other is not: repeat the high test and if still positive: Dx diabetes • If one or both in Prediabetic (FPG >100 and <126 mg/dl) or At risk range (A1c >6.0 and <6.5), do a 2hr PP glucose after 75 gm of glucose • If >200 mg/dl repeat to confirm Dx DM • If >140 and <200 mg/dl Dx with IGT, prediabetes or at risk for diabetes • Follow carefully

  12. Prediabetes Impaired Glucose Tolerance (IGT), Impaired Fasting Glucose (IFG), At risk for diabetes

  13. Previous Criteria IFG IGT New Guidelines 6.0-6.5% should be considered at “Higher Risk for Diabetes”

  14. Diabetes Prevention Program (DPP) Randomized 3234 subject with impaired glucose tolerance (prediabetes) to Intensive lifestyle intervention or Metformin and usual lifestyle intervention or Placebo and usual lifestyle Endpoint: development of diabetes mellitus Goal of intensive lifestyle intervention was 7% reduction in body weight and 150 minutes of physical activity a week NEJM 2002 346:393-403

  15. Diabetes Prevention Program (DPP) Intensive lifestyle intervention: One on one weekly instruction for 16 weeks Individualized diet and exercise program designed for each subject Monthly contact with a specially trained instructor for review of diet and exercise after initial 16 weeks Provide exercise facilities 3 times/week If not meeting goal, revising of the program to meet the individual needs of the subject NEJM 2002 346:393-403

  16. Diabetes Prevention Program (DPP) In the intensive lifestyle intervention group 74% met the goal of 150 minutes of physical activity per week at 24 weeks Daily energy intake decreased by 450 kcal Only fifty percent of the participants in the lifestyle intervention group had achieved the goal of weight loss of 7% or more by the end of 24 weeks 38 percent had a weight loss of at least 7% at the time of the most recent visit NEJM 2002 346:393-403

  17. Diabetes Prevention Program (DPP) NEJM 2002 346:393-403

  18. Diabetes Prevention Program (DPP) The intensive lifestyle intervention group had a 58% reduction in the risk of developing diabetes Metformin had a 31% decrease in risk of DM With Extensive education and resources devoted to education 74% maintaining 150 minutes of activity/week and Average decreased intake of 450 kcal/day Maximal weight loss was achieved at 6 months Average maximal weight loss was 13 lbs. (6.3%) Weight steadily increased for the remainder of the study NEJM 2002 346:393-403

  19. Diabetes Prevention Program (DPP) Sub Group Analysis In women with a history of Gestational DM Metformin and lifestyle intervention were similarly effective In older subjects (>60 years of age at baseline), the lifestyle intervention was particularly effective (72 percent reduction in diabetes compared with placebo), Metformin was relatively less effective. In younger subjects with BMIs > 35 metformin was as effective as intensive lifestyle intervention NEJM 2002 346:393-403

  20. DPP 10 Year Followup: Weight Change 4 lbs 5 10 Years Since Randomization Lancet 2009; 374: 1677–86

  21. DPP 10 Year Followup: Incidence of DM 10 5 Years Since Randomization Lancet 2009; 374: 1677–86

  22. Prediabetes (IGT, IFG, “At Risk For Diabetes”) • First have to diagnose it • Greatly underdiagnosed • Screen high risk individuals • Screen with FPG and A1c • Intensive life style intervention was very intensive • Sending to dietician and giving a book on exercise is not enough! • Likely to be expensive • If aggressive lifestyle not feasible or BMI > 35, Metformin is just as effective

  23. Secondary Types of DM Neither Type 1 or 2 DM

  24. Secondary Diabetes • Diseases of the Exocrine Pancreas • Pancreatitis/pancreatectomy • Neoplasia • Cystic fibrosis • Hemochromatosis • Endocrinopathies • Acromegaly • Cushing syndrome • Glucagonoma • Pheochromocytoma • Hyperthyroidism • Somatostatinoma • Aldosteronoma • Infections • Congenital rubella • Cytomegalovirus

  25. Secondary Diabetes • Drug- or Chemical-induced • Genetic Defects in Insulin Action • Type A insulin resistance • Leprechaunism • Rabson-Mendenhall syndrome • Lipoatrophic diabetes • Other Immune-Mediated Diabetes • Stiff man syndrome etc • Anti-insulin receptor antibodies • Other Genetic Syndromes • Down syndrome, Klinefelter syndrome, Turner syndrome, Wolfram syndrome, Friedreich ataxia, Huntington chorea, Laurence-Moon-Biedl syndrome, Myotonic dystrophy, Porphyria Prader-Willi syndrome

  26. Secondary Diabetes • Genetic Defects of ß-cell Function • Neonatal diabetes • Maturity-onset Diabetes of Youth (MODY) • MODY 1 - Chromosome 20, hepatocyte nuclear factor (HNF) -4α • MODY-2 Chromosome 7, glucokinase • MODY3 - Chromosome 12, HNF-1α • MODY4- Chromosome 13, insulin promoter factor-1 (IPF-1) • MODY5- Chromosome 17, HNF-1ß • MODY6 - Chromosome 2, neurogenic differentiation 1 • Mitochondrial DNA

  27. MODY • Heterogeneous group of monogenetic defects that usually limit the ability of the beta cell to produce insulin • Often diagnosed in adolescence • Very strong family history (Autosomal Dominant) • Often not obese and no ketones • Accounts for 1-5% of diabetes • Often do well with sulfourea monotherapy • Genetic testing can identify them • Importance: • 1-5% of patients can be treated with SU • Young adults might be Dx type 1 by mistake • Family screen can be done and Dx earlier

  28. Latent Autoimmune Diabetes of Adults (LADA)

  29. Latent Autoimmune Diabetes of Adults (LADA) • Different Names: • LADA • “Type 1.5 Diabetes,” • “Antibody-Positive Type 2 Diabetes,” • “Latent Type 1 Diabetes,” • “Double Diabetes,” and • “Youth Overt Diabetes of Maturity (YODM).” • LADA may comprise up to 10-15% of adults diagnosed with Type 2 diabetes. • Initially, it presents phenotypically as Type 2, • Autoimmune markers for Type 1 DM, such as anti-GAD antibodies, are present.

  30. Latent Autoimmune Diabetes of Adults (LADA) • LADA is generally considered to be a slowly progressive form of Type 1 diabetes • LADA patients do not require insulin early in the coarse of DM • Oral agents work initially but generally fairly early • Particularly sulfonylureas

  31. Keys to Recognize LADA • Negative family history for Type 2 DM • Positive family history for Type 1 DM • Non obese • Ketones in urine • Early failure of oral agents • Most type 2 patients do well on oral agents for several years Diagnosis • Measure GAD-65 anybody • Positive very likely LADA • Simultaneous glucose and C-Peptide or post meal C-Peptide • No national criteria for what is diagnostic values

  32. Treatment of LADA • If glycemic control is at goal on oral agents, continue them • Watch closely for worsening control on oral agents • If 2 agents are failing (A1c>7.0%) change to insulin • May continue metformin • Usually need to go to basal/bolus • If ketones persistently positive start insulin • Recognition is important so insulin treatment is not delayed as A1c climbs

  33. Glycemic Goals What should the A1c goal be?

  34. UKPDS: Results of Intensive Therapy With Sulfonylurea/Insulin P*= 0.029 0.0099 0.015 0.000054 0.052 *Difference in median HbA1c was 0.9% Lancet 352:837-853 1998

  35. A1c 10 Years After End of UKPDS Differences In Glycemic Control Lost in 1 year NEJM Published on line 9/10/08

  36. Myocardial Infarction 10 Years After End of UKPDS NEJM Published on line 9/10/08

  37. Mortality 10 Years After End of UKPDS Conventional Rx: SU & Insulin Conventional Rx: Metformin NEJM Published on line 9/10/08

  38. UKPDS 10 year Observation Differences In glycemic control were lost early In the Sulfonylurea Insulin group, Benefits of better glycemic control emerged for myocardial infarction, and overall survival All diabetic endpoints and microvascular outcomes continue to be significant In the metformin treated group Continued benefit in myocardial infarction, mortality, and all diabetic end points continued NEJM Published on line 9/10/08

  39. Metaanalysis of effects of Glycemic control, Cardiac events and all cause mortality • Published in Lancet may of 2009 • Looked at ACORD, ADVANCE, VADT, and added UKPDS (original results) and PROactive • The total numbers of events in each group was significantly less than predicted and this decreased the chance of finding a positive result • By combining the trials there were enough events to answer the question • In the metaanalysis the combined difference in A1c was 0.9% Lancet 2009; 373: 1765–72

  40. Probability of Non-Fatal Myocardial Infarction Intensive Glucose lowering A1c 6.6% vs 7.5% A1c 6.6 A1c 7.5 Lancet 2009; 373: 1765–72

  41. Aggressive Therapy of DM Saves Lives, Decrease Traditional Microvascular Complications and Decreases MIs!!!! The Benefit Persists Years After Control Gets Worse

  42. What About Hypoglycemia?

  43. The Year of Hypoglycemia! • Recent trials have emphasized the risk of hypoglycemia • The adverse effects may not be seen at the time the glucose is low but rather effects long term outcomes

  44. Hypoglycemic Episodes and Risk of Dementia in Older Patients With Type 2 Diabetes Mellitus • Longitudinal cohort study of 16,667 patients with type 2 DM • Mean age of 65 years • Looked at severe hypoglycemia requiring ED visit or hospitalization • Compared with patients with no hypoglycemia, patients with single or multiple episodes had a graded increase in risk for dementia • 1 episode HR, 1.26; • 2 episodes HR, 1.80; • 3 or more episodes HR, 1.94; JAMA. 2009;301(15):1565-1572 www.jama

  45. Hypoglycemia and Clinical Outcomes in Patients With Diabetes Hospitalized in the General Ward • This retrospective cohort study analyzed 4,368 admissions of 2,582 patients with diabetes • Looked at the associations between the number and severity of hypoglycemic (50 mg/dl) episodes and inpatient mortality, length of stay (LOS), and mortality within 1 year after discharge were evaluated Diabetes Care 32:1153–1157, 2009

  46. Hypoglycemia and Clinical Outcomes in Patients With Diabetes Hospitalized in the General Ward Risk of 1 year mortality Increase in length of Stay Diabetes Care 32:1153–1157, 2009

  47. Aggressive glycemic control: A two edged sword! • Lower glucose levels associated with improved outcomes • The lower the glucose levels and A1c, the greater the risk of hypoglycemia • 1% decrease in A1c results in a 3 fold increase in severe hypoglycemia • This is with agents that can cause hypoglycemia (insulin and sulfonylureas) • Increased hypoglycemia associated with increases in adverse outcomes

  48. Goals For Glycemic Control • AACE, A1c < 6.5% • ADA and EASD A1c <7% • If you can achieve lower A1c with increased risk of hypoglycemia or other adverse events, it should be considered • Important caveats: • Goals are patient directed • Benefit should outweigh risk in a given patient • Establish good control as early as possible and for as long as possible in DM • To avoid hypoglycemia with aggressive control, choose agents that have a low risk of hypoglycemia

  49. Therapy

  50. Therapeutic options • Metformin Hypoglycemia NO • Sulfonylureas Hypoglycemia YES • Insulin Hypoglycemia YES • TZD (Actos, etc) Hypoglycemia NO • Incretins Hypoglycemia NO • Bile acid sequestrant Hypoglycemia NO • Bromocriptine (Cycloset) Hypoglycemia NO • Bariatric surgery Hypoglycemia Possible Only 2 classes of agents cause hypoglycemia when used alone!