1. Type II Diabetes Gil C. Grimes, MD Assistant Professor Community and Family Medicine Scott and White Memorial Hospital September 2007

2. Objectives Discuss Complications Discuss Therapy Oral Agents Insulin Highlight Texas Flow-sheets Provided

4. 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]

5. Complications Prospective cohort 4,662 men aged 45- 79 followed 2-4 years 1 Increase HbA1c 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]

6. 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

7. 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]

8. 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]

9. 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]

10. 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]

11. 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}

12. 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]

13. 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]

15. Treatment Goals American Diabetes Association Recommendations Control of glycemia is important Goal is HgA1c less than 7% Pre-meal glucose 5-7.2 mmol/l Post-meal glucose <10 mmol/l Blood pressure less than 130/80 Lipid control LDL < 2.6 mmol/l Triglycerides <1.7 mmol/l HDL >1.1 mmol/l Diabetes Care 2006 Jan;29(suppl 1):S4-S42

16. 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]

17. 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

18. 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]

19. 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]

20. 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

21. 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

22. Medications When monotherapy fails Add second drug with different mechanism of action Metformin (vs. pioglitazone) probably better choice for 2 nd 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]

23. 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)

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

25. 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

26. 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

27. 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]

28. Metformin Mechanism Decreased endogenous glucose production Decreased hepatic gluconeogenesis 1 Improves response to insulin Enhanced insulin-mediated glucose uptake Increased use of glucose in intestine and adipose Reduced GI glucose absorption Does not stimulate insulin secretion Requires insulin to be effective 1- NEJM 1998;338(13):867-72 Level 1c

29. Metformin Side effects Gastrointestinal upset Nausea, anorexia, diarrhea, abdominal discomfort, metallic taste Dose-related Minimized by taking with meals and gradually increasing the dose 0.003% lactic acidosis

30. Metformin Risk factors for lactic acidosis Renal impairment (Creat> 1.5 mg/dL men >1.4 mg/dL women) CHF on medications Hepatic insufficiency Hypoxia Perioperative from major surgery Binge drinking Iodinated contrast agents

31. Metformin Preventive measures Hold prior to procedure Restart after 48 hours if renal function is normal Dissent on contraindications exists 1-3 Use in pt with CHF associated with decreased mortality 1,883 patients with DM and CHF HR 0.66 for metformin vs. sulfonylurea and metformin 0.54 1- CMAJ 2005 30:173(5):502-05 Level 5 2- BMJ 2003;326(7379):4 Level 5 3- Diabetes Care 2005;28(10):2345 Level 2b

32. Metformin Systematic review 29 RCT 5,259 patients mean follow-up 3 years Reduction of mortality from MI in obese or overweight patients Improves glycemic control, weight, lipids, insulinemia, and diastolic pressure Cochrane Library 2005 Issue 3:CD002966 Level 1c

33. Insulin Therapy Bedtime NPH with sulfonylurea Better than NPH alone for control Allows for lower insulin dose Based on metanalysis of 16 studies 1 Metformin as well reduces weight gain 2 Addition of PNH vs.. 70/30 reduces hypogylcemia, reduces weight gain, not as effective 3 1- Arch Intern Med 1996;156:259 [Level 1c] 2- Cochrane 2004:CD003418 [Level 1a] 3- J Fam Pract 2004;53:393 [Level 2a]

34. Insulin Therapy Long acting glargine insulin With sulfonylurea/metformin may be better than NPH for glycemic control 1 Second study 70/30 associated with improved control vs. glargine but more hypoglycemic episodes 2 1- Diabetes Care 2005;28:254 [Level 3] 2- Diabetes Care 2005;28:260 [Level 3]

35. Aspirin Prospective 5.2 year follow up on 2,368 pts with CAD and DM-2 Observational study Cardiac mortality 10.9% those taking Aspirin Cardiac Mortality 15.9% for those not taking aspirin Am J Med 1998;105(6):494-9 Level 2c

36. ACE Inhibitors Reduce albumin excretion rate in normotensive diabetics but no evidence of effect on ESRD, glomerular filtration rate, or side effects 1 Enalipril has long term reduction of frequency and severity of albuminuria and reduces the rate of rise of creatinine 2 HOPE trial discloses that ACE inhibitors help with a wide range of morbidity and mortality 3 1- Cochrane 2001;1:CD002183 [Level 1a] 2- Arch Intern Med 1996;156:286 [Level 1c] 3- Lancet 2000;355:253 [Level 1c]

37. Cardiovascular Disease Prevention Meta-analysis of placebo controlled RCTs 7 lipid lowering trials 6 hypertension trials 5 glucose control trial Results for risk reduction combined outcome coronary heart disease death and non-fatal MI Lipid lowering 0.75 (0.61-0.93) Hypertension control 0.73 (0.57-0.94) Glucose control 0.87 (0.74-1.01) 69-300 person-years of Lipid tx or HTN tx to prevent one cardiovascular event Am J Med 2001;111(8):633-42 Level 1a

38. American College of Physicians EB guidelines Recommendation 1: Lipid-lowering therapy should be used for secondary prevention of cardiovascular mortality and morbidity for all patients (both men and women) with known coronary artery disease and type 2 diabetes. Recommendation 2: Statins should be used for primary prevention against macrovascular complications in patients (both men and women) with type 2 diabetes and other cardiovascular risk factors. Recommendation 3: Once lipid-lowering therapy is initiated, patients with type 2 diabetes mellitus should be taking at least moderate doses of a statin. Recommendation 4: For those patients with type 2 diabetes who are taking statins, routine monitoring of liver function tests or muscle enzymes is not recommended except in specific circumstances. Ann Intern Med 2004;140(8):644-649 Level

39. Lipid Management Statin therapy for patients with DM-2 Coronary artery disease (Grade A) Age >40 plus CV risk factors LDL>2.59 mmol/l with lifestyle changes (Grade A) Routine use in others (Grade C) Am Fam Physician 2005;72(5):866 FPIN questions

40. Lipid Management 2,838 Patients 40-75 with DM-2 for 6 months LDL <4.182 mmol/lL 1 other risk factor, no prior CAD RCT of Atorvastatin 10 mg vs. placebo Median f/u 3.9 years Risk Reduction Tx vs. placebo 3.6% vs. 5.5% for composite (MI, USA, CHD Death, Cardiac arrest) 1.7% vs. 2.4% coronary revascularization 1.5% vs. 2.8% stroke 5.8% vs. 9% primary end point (any of above) NNT31 Lancet 2004;364(9435):685-96 Level 1c

41. Control the Blood Pressure Aggressive blood pressure control pays off for diabetics 1 Goal of less than 135 and less than 80 Decreases clinically relevant macrovascular events Decreases clinically relevant microvascular events Prolongs life 1- Ann Intern Med 2003;138:593 [Level 1a]

42. Blood pressure and Lipids Meta-analysis of 18 trials looking at Lipid control, HTN control, and Glucose control Primary aggregate end point (CHD, death non-fatal MI) Lipid management RR 0.75 NNT 106 HTN management RR 0.87 NNT 157 Glucose management RR0.87 NS Am J Med 2001;111:633-42 Level 1a

43. Texas Flow-sheets

44. Questions?