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Type II Diabetes

Type II Diabetes. Gil C. Grimes, MD September 2006. Objectives. Define Diagnosis of Diabetes Describe Pathogenesis Describe risk factors for Type II diabetes Outline complications Delineate options for therapy. Definition. American Diabetes Association

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Type II Diabetes

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  1. Type II Diabetes Gil C. Grimes, MD September 2006

  2. Objectives • Define Diagnosis of Diabetes • Describe Pathogenesis • Describe risk factors for Type II diabetes • Outline complications • Delineate options for therapy

  3. Definition • American Diabetes Association • Fasting plasma glucose is the preferred test • Three criteria • Symptoms (polyuria, polydypsia, unexplained weight loss) and glucose ≥ 200 mg/dL • Fasting plasma glucose ≥ 126mg/dL on 2 occasions • 2 hour plasma glucose (after 75 g anhydrous glucose in water) ≥ 200 mg/dL • WHO prefers Oral glucose tolerance test National Guideline Clearing House 2002 Aug 22:6574 [Level 5]

  4. Definition • Results of ADA changes • Increased diagnosis of diabetes • Most of these ‘new’ diabetics have normal HgA1c 1 • No evidence that Tx at low range impacts quality of life 2 1- JAMA 1999;281:1203 [Level 1c] 2- Am Fam Physician 1998;58:1287 [level 5]

  5. Definition • Fasting vs. 2 hour glucose tolerance test • Fasting criteria less sensitive for predicting cardiovascular disease • Prospective analysis 4,515 pt over 8 years Cardiovascular Health Study • Sensitivity ADA fasting 28% • Sensitivity WHO criteria 54% Lancet 1999;345(9179):622-5 [Level 1b]

  6. Prevalence • Estimate 8.3% US adults >20 yo with diabetes1 • Estimate 14.4% have either DM or Impaired Glucose Tolerance1 • Estimated Lifetime Risk of Diabetes in US2 • 32.8% males • 38.5% female 1- MMWR 2003;52:833 [Level 1c] 2- JAMA 2003;290(14):1884 [Level 2c]

  7. Incidence • Disease of middle age • Mean age in US 46 years 1 • Prevalence similar in men and women • Fourth most common diagnosis during Family Physician visits 2 1- Ann Fam Med 2005;3(1):60 [Level 2c] 2- Ann Fam Med 2004;2(5):411 [Level 2c]

  8. Pathophysiology • Insulin resistance • Usually a receptor or post-receptor defect • Manifests as increased insulin requirement • Common cause • Obesity (especially abdominal) • Metabolic syndrome • Genetics and lifestyle • Decreased insulin secretion • Possible accelerated age-related loss beta cell • Amyloid deposits in > 70% pancreatic cells diabetics 1 • Unclear the role in disease 1- NEJM 2000;343(6);411 [Level 5]

  9. Risk Factor Obesity • Prospective cohort 37,878 female nurses followed 7 years • BMI more powerful predictor (HR 3.22) than activity 1 • Single most important predictor in prospective cohort 89,941 followed 16 years 2 1- JAMA 2004;292:1188 [Level 1b] 2- NEJM 2001;345:790 [Level 1b]

  10. Risk Factor Obesity • Adult diabetics • 85.2% obese or overweight • 54.8% obese 1 • Obese children 2 • Multicentric cohort 167 children and adolescents • BMI >95% for age • 25% age 4-10 impaired glucose tolerance • 21% age 11-18 impaired glucose tolerance • 4% age 11-18 type II DM 1- MMWR 2004;53:1066 [Level 1c] 2- NEJM 2002;346:802 [Level 2c]

  11. Risk Factor IGT • Population-based cohort study 1342 participants follow-up 6.4 years 1 • Performed FPG and 2 hour GTT • Odds Ratio for developing DM • 10 for IFG • 10.9 for isolated IGT • 39.5 for both 1- JAMA 2001;285:2109 [Level 2c]

  12. Risk Factor IGT • Prospective cohort study 1,197 VA patients over 3 years • HgA1c.7% led to testing fasting glucose • 73 patients developed dm (6.1%) • Annual incidence • 0.8% if HbA1c<5.5% • 2.5% if HbA1c 5.6-6% • 7.8% if HbA1c 6.1-6.9% J Gen Intern Med 2004;19(12):1175 [Level 1b]

  13. Risk Factor Activity • Prospective cohort from Nurses Health Study 68,497 women without DM 1 • 1515 new cases of DM • Each 2 hours/day sedentary increase risk obesity 5% and DM 7% • TV Watching associated with 23% increase risk obesity and DM 14% 1- JAMA 2003;289(14):1785 [Level 1b]

  14. Risk Factor Diet • Western Diet associated with increased risk of DM • 42,504 men age 40-75 followed 12 years • 1,321 developed DM • Relative Risk 1.59 diet alone • Relative Risk 1.96 diet and sedentary Ann Intern Med 2002;136:201 [Level 1c]

  15. Risk Factor Diet • Western Diet associated with increased risk of DM • 69,554 women age 38-63 followed 14 years • 2,699 developed diabetes • Relative Risk 1.49 diet • Relative Risk per increase serving • Red meat 1.38 • Processed meat 1.73 Arch Intern Med 2004;164(20):2235 [Level 1c]

  16. Risk Factor Diet • High glycemic index foods low fiber diet associated with increased risk of DM 1 • Prospective cohort 91,249 women, 741 cases of DM, followed 8 years • Higher glycemic index higher the risk for developing diabetes (RR 1.27) • Higher cereal fiber reduces risk (RR 0.64) 1- Am J Clin Nutr 2004;80:348 [Level 1c]

  17. Risk Factor Gestational DM • Prospective cohort 696 women with GDM 1 • Followed with GTT post-partum and every 5 years • Risk of abnormal GTT 42.4% at 11 years • Risk of DM 13.8% • Prospective cohort 481 women with diet controlled GDM 2 • 40% incidence after10 years • 27% impaired GTT 1- Diabetes Care 2003;26:1199 [Level 1c] 2- Diabetes Care 2004;27:1194 [Level 1c]

  18. Risk Factor PCOS • Prospective cohort 67 women with PCOS for 6.2 years 1 • 54 with normal GTT subsequently 17% developed DM • 13 with impaired GTT subsequently 54% developed DM 1- Hum Reprod 2001;16:1995 [Level 1c]

  19. Risk Factor Medications • Prospective double blind RCT 44 postmenopausal women not on HRT • Raloxifen or estrogen vs.. placebo • Looked at effects on insulin sensitivity • Used glucose tolerance test to check for insulin sensitivity • Insulin Sensitivity decreased in raloxifene J Am Geriatric Soc 2003;51(5):683-8 [Level 2b]

  20. Risk Factor Medications • Gatifloxacin et al may affect glycemic control as seen in two case control studies • 788 case patients in ED or hospital with hypoglycemia • Gatifloxacin OR 4.3 • Levofloxacin OR 1.5 • 470 case patients with hospital diagnosed hyperglycemia • Gatifloxacin OR 16.7 • Moxifloxacin OR 1.7 NEJM 2006 March 30 early release on-line [Level 3b]

  21. Complications • Prospective population study 13,105 subjects followed for 20 years 1 • 1.5-2 fold increase risk of death in men & women • 1.5-2 fold increase of MI in men • 1.5-4.5 fold increase risk of MI in women • 1.5-2 fold increase risk of Stroke in men • 2-6.5 fold increase risk in stroke in women 1- Arch Intern Med 2004;164:1422 [Level 1c]

  22. Complications • Prospective cohort 4,662 men aged 45-79 followed 2-4 years 1 • Increase HgA1c associated with increasing mortality • All cause RR 2.2 • Cardiovascular disease RR 3.3 • Ischemic disease RR 4.2 1- BMJ 2001;322:15 [Level 1c]

  23. Complication Macrovascular • Macrovascular complications • 75-80% diabetic deaths related to atherosclerosis • 75% accelerated CAD • 25% accelerated CVD and PVD • >50% diabetics hypercholesterolemic DynaMed accessed March 15 2006

  24. Complication CAD • Meta-analysis of 37 prospective studies 447,064 patients • Rate of Fatal CAD 5.4% vs. 1.6% for diabetics • Women RR 3.50 • Men RR 2.06 BMJ 2006;332(7533):73-8 [Level 1a]

  25. Complication CAD • Diabetes may be as risky as a prior MI 1 • Prospective cohort 9,434 men age 35-57 followed 25 years • Diabetes similar mortality to prior MI • Diabetics without prior MI= risk of prior MI 2 • Risk of MI • 3.5% in non-DM no prior MI • 18.8% for prior MI non-DM • 20.2% for DM without prior MI • 45% for DM with prior MI 1- Arch Intern Med 2004;164:1438 [Level 1c]] 2- NEJM 1998;339:229 [Level 2b]

  26. Complication HTN • Prospective cohort 49,582 Finish subjects without stroke or CAD at baseline followed 19.1 years followed for stroke • HTN Stage I HR 1.35 mortality 1.47 • HTN Stage II HR 1.98 mortality 2.62 • DM HR 2.54 mortality 3.06 • HTN I and DM HR 3.51 mortality 5.99 • HTN II and DM HR 4.50 mortality 9.27 Stroke 2005;36(12):2538-43 [Level 1b]

  27. Complication PAD • Prospective cohort 1,294 patients with DM-2 • Subgroup of 531 with sufficient screening for PAD • PAD at entry 13.6% (161 patients) • 14 developed PAD (75 patients) • Incidence of new PAD 3.7 per 100 pt years Diabetes Care 2206;29(3):575-80 [Level 2b]

  28. Complication Microvascular • Microangiopathy • Retinopathy (RR20) • #1 cause of new blindness • #3 cause of blindness • Neuropathy (ESRD RR25) • Nephropathy BMJ 2000;320(7241):1062 [Level 5}

  29. Complication Coma • Hyperosmolar Coma • Most common in elderly patients • Also occurs in children • 8 case reports in obese children • Causes • Infection 20-25% • New onset DM 30-50% • Drugs, Stress (MI etc.) • 20-30% mortality Endocr Pract 2005;11(1):23-9 [Level 4]

  30. Complication Hypoglycemia • Mild episodes common • Retrospective cross-sectional analysis of 1,055 outpatients • Prevalence of symptoms • Diet controlled 12% (9 of 76) • Oral agents 16% (56 of 346) • Insulin use 30% (193 of 633) • Severe Hypoglycemia 0.5% (5 of 1055) all using insulin • Risk factors • Younger age • Insulin use • Lower HbA1c at follow-up Arch Intern Med 2001;161(13):654-9 [Level 2b]

  31. Treatment Goals • American Diabetes Association Recommendations • Control of glycemia is important • Goal is HgA1c less than7%Grade B • Pre-meal glucose 90-130mg/dL • Post-meal glucose <180mg/dL • Blood pressure <130/80 • Lipid control • LDL <100 mg/dL • Triglycerides <150 mg/dL • HDL >40 mg/dL men or >50 mg/dL women Diabetes Care 2006 Jan;29(suppl 1):S4-S42

  32. Cost-effectiveness • CDC cost-analysis • Hypothetical cohort patients >25 yo new diabetes • Antihypertensive Therapy • Improved quality of life and cost savings age 25-84 • Very cost-effective 85-94 • Intensive Glycemic Control • Increase cost and improved outcome • Decreasing effect on quality of life • Decreasing cost effectiveness with increasing age • Lipid management improved quality of life at increased cost JAMA 2002;287(19):2542-51 [Level 2b]

  33. Lifestyle Changes • Dietary changes and exercise works • 20-50% of patients can control their diabetes with diet, exercise and weight reduction • Current trial lookAHEAD is recruiting patients for lifestyle management study

  34. Exercise • Exercise training reduces the HgA1c • Metanalysis of 14 trials duration 8 weeks • HgA1 c 7.65% vs. 8.31% 1 • Increased activity reduces risk of MI, Stroke • Walking 2 hours/week lower mortality NNT 61 for one year 2 1- JAMA 2001;286:1218 [Level 1a] 2- Circ 2003;163:1440 [Level 1c]

  35. Dietary Advice • Systematic review of 18 RCT lasting 6 months where dietary advice main intervention • Diets examined: low-fat/high –carb, high-fat/low-card, low-cal (1,000 kcal/day), very-low-calorie (500 kcal/day) • Data did no provide robust conclusions on effectiveness of dietary advice • Exercise improves glycemic control Cochrane Library 2004 Issue2:CD004097 [Level 1a]

  36. High Fiber Diet • 13 patients with DM-2 randomized in crossover fashion 6 week each arm • ADA diet 8gm soluble fiber 16 gm insoluble fiber • High-fiber 25 gm soluble fiber and 25 gm insoluble fiber • Mean pre-prandial glucose 142 vs. 130 (p=0.04) • Mean HbA1c 7.2% vs. 6.9% (p=0.09) • Mean LDL 142 mg/dL vs. 133 mg/dL (p=0.11) • May not be generalizable due to meals etc. NEJM 2000;342(19):1392-8 [Level 1b]

  37. Glycemic Index • 8 men with DM-2 at VA facility randomized in crossover trial • Low-biologically-available-glucose diet • HbA1c 9.8% vs. 7.6% • Took place in research center 1 • Low glycemic meals may reduce hyperinsulinism • Evidence limited • Small studies with methodological problems 1- Diabetes 2004;53(9):2375-82 [Level 1b] 2- JAMA 2002;287(18):2414-23 [Level 3a]

  38. Protein Restriction • ADA recommendation for patients with any chronic kidney disease • Limit protein intake 0.8g/kg/day • Grade B Diabetes Care 2006;29(suppl 1):S4-S42

  39. Medications • Initial Monotherapy • Sulfonylureas inexpensive • Metformin inexpensive • Rosiglitazone and pioglitazone are expensive and lacking long-term data • Nateglinide less effective than repaglinide • Acarobose and miglitol less effective poorly tolerated Medical Letter 2002;1:1

  40. Medications • When monotherapy fails • Add second drug with different mechanism of action • Metformin (vs. pioglitazone) probably better choice for 2nd agent 1 • Dual therapy fails add insulin with metformin • Less expensive than triple oral therapy • No difference in diabetic control compared 2 1- Diab Care 2004;27:141 [Level 1b] 2- Diab Care 2003;26:2238 [Level 1c]

  41. Medications • Systematic Review of 63 RCTs duration 3 months reporting HbA1c • Studied sulfonylureas, metformin, alpha-glucosidase inhibitors, thiazolidinediones, non-sulfonylurea secreatagogues • Medications at maximal doses were equally effective (except nateglinide and alpha-glucosidase inhibitors) • Only Sulfonylureas and metformin demonstrate long term vascular risk reduction • Metformin has advantage of lack of weight gain and lack of hypoglycemia JAMA 2002;287(3):360-72 Level 1a)

  42. Sulfonylureas • Increase insulin secretion by pancreas • Take before meals • Contraindicated in sulfa allergic patients • Second generation safer in renal disease • Multiple drug interactions

  43. Sulfonylureas • First generation have more interactions • Acetoheaxmide • Chlorpropamide • Disulfram reaction more likely • May aggravate CHF or fluid retention • May Cause SIADH • Tolazamide • Caution in renal dysfunction • Tolbutamide • BID dosing decreases GI side effects

  44. Sulfonylureas • Second-generation agents have fewer interactions • Glipizide and Glyburide are less likely to have disulfram reaction • Gluburide is renally eliminated watch in renal disease • Glipizide little benefit to doses >20mg/day

  45. Sulfonylureas and hypoglycemia • 52 sulfonylurea-treated subjects with DM mean age 65 RCT glyburide or glipizide 1 • Participated in 23 hour fasting study • 1 week placebo vs. 10mg/day or 20 mg/day of active drug • No hypoglycemia observed in 156 fasting studies • Second study glipizide similar results 2 1- JAMA 1998;279(2):1442-3 [Level 1b] 2- JAMA 1999;281(12):1084- [Level 1b]

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