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  • GLP has a half-life of < 2 min so it can’t be used as therapy. Necessary to use analogs exenatide clinical effects last up to 8 hours
  • At low titers, the antibodies do not affect the effectiveness of exenatide. Delays gastric emptying. Counsel patients to take their other meds 1 h before byetta
  • Most patients fail lifestyle interventions so the consensus panel decided they should be put on metformin at the same time
  • Important in both inpatient and outpatient setting
  • Secretagogues not considered synergistic when given with insulin
  • There aren’t many head-to-head comparisons of the ability of the different agents to achieve glucose control
  • Approximately 5,000 Patient included for 1,000 years of follow-up in this study Incidence rates and 95% confidence intervals for myocardial infarction and microvascular complications by category of updated mean haemoglobin A1c concentration, adjusted for age, sex, and ethnic group, expressed for white men aged 50­54 years at diagnosis and with mean duration of diabetes of 10 years
  • Atherosclerosis = plaque formation Essential hypertension = no identifiable cause for hypertension Part of syndrome X (metabolic syndrome) especially when hypertriglyceridemia and decreased HDL are included
  • If diabetic patient is initially between 130-140/80-90 you may begin lifestyle adjustment for 3 months if you feel your patient will return to clinic. If goal not achieved, then you must initiate pharmacotherapy management
  • ACE-I, ARB and Thiazide diuretic medications preferred combo = Monitor Renal function and Potassium (Hyper-K ACEI/ARB and Hypo-K HCTZ) ACE-I vasodilate at the efferent arteriole Non-DCCB = Verapamil/Diltiazem SBP > 160 or DBP > 100 requires immediate drug therapy
  • Treatment with aspirin: 30% decrease in myocardial infarction 20% decrease in stroke Not studied in person < 30 and person < 21 = increased chance of Reyes Symdrome
  • ACE-I vasodilate at the efferent arteriole Non-DCCB = Verapamil/Diltiazem
  • Pulses: dorsalis pedis and posterior tibialis
  • 131_1323.ppt

    1. 1. Management of the Patient with Type 2 Diabetes Gretchen M. Ray, Pharm.D. Cardiovascular Pharmacotherapy Resident University of New Mexico College of Pharmacy
    2. 2. Objectives <ul><li>Provide diabetes screening criteria for adults </li></ul><ul><li>Describe available pharmacologic treatment options for type 2 diabetes including advantages/disadvantages of therapy and contraindications </li></ul><ul><li>Given a patient case recommend appropriate lifestyle modifications and pharmacotherapy to achieve glycemic goals </li></ul>
    3. 3. Objectives <ul><li>Distinguish between microvascular and macrovascular complications </li></ul><ul><li>Provide screening criteria for nephropathy, neuropathy, and retinopathy </li></ul><ul><li>Provide treatment strategies for the prevention and treatment of micro and macrovascular complications </li></ul>
    4. 4. Epidemiology of Type 2 DM <ul><li>In 2005 20.8 million people (7% of the US population) had diabetes </li></ul><ul><ul><li>14.6 million diagnosed </li></ul></ul><ul><ul><li>6.2 million undiagnosed </li></ul></ul><ul><li>Type 2 diabetes accounts for 90-95% of patients with diabetes </li></ul><ul><li>In 2002 total indirect and direct medical costs for diabetes = $132 billion </li></ul>CDC. National diabetes fact sheet. 2005 available at www.cdc.gov/diabetes/pubs/pdf/ndfs_2005.pdf
    5. 5. Risk factors for type 2 diabetes <ul><li>Physically inactive </li></ul><ul><li>1 st degree relative with diabetes </li></ul><ul><li>Minority ethnic groups </li></ul><ul><li>Gestational diabetes or delivering a baby >9 lbs </li></ul><ul><li>Hypertension </li></ul><ul><li>HDL <35 mg/dL and/or triglycerides >250 mg/dL </li></ul><ul><li>Polycystic ovary syndrome </li></ul><ul><li>Previous impaired glucose tolerance (IGT) or impaired fasting glucose (IFG) </li></ul><ul><li>History of vascular disease </li></ul><ul><li>Psychiatric illness </li></ul>
    6. 6. Diagnosis of diabetes <ul><li>Symptoms of diabetes + casual plasma glucose ≥ 200 mg/dl </li></ul><ul><li>FPG ≥ 126 mg/dl </li></ul><ul><li>Oral glucose tolerance test (OGTT): 2-h postload glucose ≥ 200 mg/dl </li></ul>OR OR
    7. 7. Definition of “pre-diabetes” <ul><li>Impaired fasting glucose (IFG) = FPG 100-125 mg/dl </li></ul><ul><li>Impaired glucose tolerance (IGT) = 2-h post load glucose 140-199 mg/dl </li></ul><ul><li>IFG and IGT indicate a risk factor for diabetes and cardiovascular disease </li></ul>
    8. 8. Diabetes Screening <ul><li>Screening identifies asymptomatic patients who might have diabetes </li></ul><ul><li>Consider in patients ≥ 45 years especially if their BMI ≥ 25 kg/m 2 </li></ul><ul><li>Screen patients < 45 years old if they are overweight + an additional risk factor </li></ul><ul><li>FPG should be done initially </li></ul><ul><li>Repeat screening every 3 years </li></ul>
    9. 9. Oral Therapies
    10. 10. Metformin <ul><li> hepatic glucose production,  intestinal glucose absorption,  insulin sensitivity </li></ul><ul><li>Efficacy:  A1C 1.5% </li></ul><ul><li>Adverse effects </li></ul><ul><ul><li>Primarily GI (up to 50%) </li></ul></ul><ul><ul><ul><li>Diarrhea, abdominal bloating, nausea </li></ul></ul></ul><ul><ul><ul><li>Titrate dose at weekly intervals to minimize AEs </li></ul></ul></ul><ul><ul><ul><li>Give with meals </li></ul></ul></ul><ul><ul><li>Lactic acidosis- rare </li></ul></ul><ul><ul><ul><li>Monitor SCr </li></ul></ul></ul>
    11. 11. Contraindications to Metformin <ul><li>Renal impairment SCr >1.5 for men, >1.4 for women </li></ul><ul><li>Radiocontrast studies </li></ul><ul><li>Age >80 unless normal GFR </li></ul><ul><li>Hypoxia </li></ul><ul><li>Liver dysfunction </li></ul><ul><li>Alcoholism </li></ul><ul><li>Heart Failure requiring pharmacologic therapy </li></ul><ul><ul><li>According to package insert </li></ul></ul><ul><li>Should heart failure be a contraindication to metformin? </li></ul>
    12. 12. Improved Clinical Outcomes Associated with Metformin in Patients with Diabetes and Heart Failure <ul><li>Investigate the association between metformin and clinical outcomes in patients with HF and diabetes </li></ul><ul><li>Retrospective study </li></ul><ul><li>Primary outcome: all-cause mortality at 1 year and end of follow-up </li></ul><ul><li>Secondary outcome: all-cause hospitalizations at 1 year and end of follow-up </li></ul>Eurich DT, et al. Diabetes Care. 2005;28:2345-51
    13. 13. Improved Clinical Outcomes Associated with Metformin in Patients with Diabetes and Heart Failure Eurich DT, et al. Diabetes Care. 2005;28:2345-51 0.86 (0.77-0.96) 0.83 (0.70-0.99) 1.0 Combined endpoint 0.93 (0.83-1.05) 0.87 (0.73-1.05) 1.0 Adjusted all-cause hospitalization, HR (95% CI) 0.61(0.52-0.72) 0.70 (0.54-0.91) 1.0 Adjusted all-cause mortality, HR (95% CI) Combination therapy (n=852) Metformin monotherapy (n=208) Sulfonylurea monotherapy (n=773)
    14. 14. Improved Clinical Outcomes Associated with Metformin in Patients with Diabetes and Heart Failure <ul><li>Lower all-cause mortality with metformin </li></ul><ul><li>No increase in hospitalizations associated with metformin </li></ul><ul><li>Observational study </li></ul><ul><ul><li>Cannot prove that metformin is efficacious in this population </li></ul></ul>Eurich DT, et al. Diabetes Care. 2005;28:2345-51
    15. 15. Sulfonylureas <ul><li>↑ insulin secretion from pancreatic β -cells </li></ul><ul><li>Efficacy: ↓ A1C 1.5% </li></ul><ul><li>Glyburide </li></ul><ul><ul><li>Not recommended if CrCl < 50 ml/min (use a different sulfonylurea) </li></ul></ul><ul><li>Glipizide </li></ul><ul><ul><li>Not recommended if CrCl < 10 ml/min </li></ul></ul><ul><li>Glimepiride </li></ul><ul><ul><li>Not recommended if CrCl < 22 ml/min </li></ul></ul><ul><li>Response of sulfonylureas plateaus after half the max dose </li></ul><ul><li>Reduced GI absorption if blood glucose > 250 mg/dL </li></ul>
    16. 16. Sulfonylureas Adverse Effects <ul><li>Hypoglycemia </li></ul><ul><ul><li>Elderly patients </li></ul></ul><ul><ul><li>Hepatic/renal impairment </li></ul></ul><ul><ul><li>Combination therapy </li></ul></ul><ul><li>Weight gain </li></ul>
    17. 17. Thiazolidenediones (TZDs) Insulin Sensitizers <ul><li>TZDs are PPAR- gamma receptor activators </li></ul><ul><li>↑ insulin sensitivity </li></ul><ul><ul><li>Primarily in the peripheral tissue </li></ul></ul><ul><li>Efficacy:  A1C 0.5-1.4% </li></ul><ul><li>Effect may not be seen for 4 weeks </li></ul><ul><li>Rosiglitazone (Avandia ® ) </li></ul><ul><ul><li>Initial dose 4 mg/day, Max dose 8 mg/day </li></ul></ul><ul><li>Pioglitazone (Actos ® ) </li></ul><ul><ul><li>Initial dose 15-30 mg/day, Max dose 45 mg/day </li></ul></ul>
    18. 18. Adverse Effects/Contraindications of TZDs <ul><li>AE’s </li></ul><ul><li>Fluid retention and peripheral edema </li></ul><ul><li>Weight gain </li></ul><ul><ul><li>Fluid retention is a major contributor </li></ul></ul><ul><ul><li>Redistribution of adipose tissue </li></ul></ul><ul><li>New-onset heart failure </li></ul><ul><ul><li>< 1% </li></ul></ul><ul><ul><li>2-3% when combined with insulin </li></ul></ul><ul><li>CI’s </li></ul><ul><li>ALT > 2.5 x upper limit of normal </li></ul><ul><li>Hepatic disease </li></ul><ul><li>Alcohol Abuse </li></ul><ul><li>HF NYHA class III or IV (see following slides) </li></ul>Granberry MC, et al. Am J Health-Syst Pharm. 2007;64:931-6
    19. 19. TZD Use In Heart Failure <ul><li>Use of TZDs in patients with NYHA class I or II HF </li></ul><ul><ul><li>May be used with initiation of treatment at the lowest dosage (rosiglitazone 2 mg daily or pioglitazone 15 mg daily) </li></ul></ul><ul><ul><li>Observe for weight gain, edema, or exacerbation of HF </li></ul></ul><ul><li>Do not use TZDs in patients with NYHA class III or IV HF </li></ul>Nesto RW, et al. Diabetes Care. 2004;27:256-63
    20. 21. Meta-analysis of MI Risk With Rosiglitazone <ul><li>42 trials comparing rosiglitazone with placebo </li></ul><ul><ul><li>15,560 patients received rosiglitazone </li></ul></ul><ul><ul><li>12,283 patients assigned to comparator groups </li></ul></ul><ul><ul><li>24-52 week duration of trials </li></ul></ul><ul><ul><li>Mean baseline A1C 8.2% for both groups </li></ul></ul>Nissen SE, et al. N Engl J Med. 2007;356:1-15
    21. 22. Meta-analysis of MI Risk With Rosiglitazone Nissen SE, et al. N Engl J Med. 2007;356:1-15 0.06 1.64 (0.98-1.74) 22 39 Death from CV causes # events 0.03 1.43 (1.03-1.98) 72 86 Myocardial Infarction # events P value Odds Ratio (95% CI) Control n= 11,634 Rosiglitazone n= 14,371
    22. 23. PROactive Trial <ul><li>Primary objective: Determine if pioglitazone reduces CV morbidity and mortality in patients with diabetes </li></ul><ul><li>Pioglitazone vs. placebo </li></ul><ul><ul><li>↓ Triglycerides 11% vs. 1.8% ↑ </li></ul></ul><ul><ul><li>↑ LDL 7.2% vs. 4.9% </li></ul></ul><ul><ul><li>↓ LDL/HDL 9.5% vs. 4.2% </li></ul></ul><ul><li>Non-significant reduction in the primary endpoint </li></ul>Dormandy JA, et al. Lancet. 2005;366:1279-89
    23. 24. PROactive Sub-analysis <ul><li>Evaluated same endpoints in patients with prior MI </li></ul><ul><li>Significant ↓ in fatal/nonfatal MI excluding silent MI with pioglitazone </li></ul><ul><ul><li>5.3% pioglitazone vs. 7.2% placebo p=0.0453 </li></ul></ul><ul><li>Results for rosiglitazone and pioglitazone recently confirmed with two new meta-analyses </li></ul>Erdmann E, et al. J Am Coll Cardiol. 2007;49:1772-80
    24. 25. HF in PROactive Dormandy JA, et al. Lancet. 2005;366:1279-89 0.634 22 (1%) 22 25 (1%) 25 Fatal HF 0.007 108 (4%) 153 149 (6%) 209 HF with hospital admission 0.003 90 (3%) 117 132 (5%) 160 HF w/o hospital admission <0.0001 198 (8%) 302 281 (11%) 417 Any report of HF # Patients (%) # Events # Patients (%) # Events P value Placebo n = 2633 Pioglitazone n = 2605
    25. 26. FDA Updates- August 14, 2007 <ul><li>Rosiglitazone and pioglitazone received a “boxed warning” regarding CHF </li></ul>www.fda.gov Actos prescribing information. August 2007
    26. 27. FDA Updates: November 19, 2007 <ul><li>MI risk added to rosiglitazone boxed warning </li></ul>Avandia prescribing information. November 2007
    27. 28. Sitagliptin (Januvia ® ) <ul><li>DPP-4 inhibitor </li></ul><ul><ul><li>Prevents the degradation of endogenous GLP-1 </li></ul></ul><ul><ul><li>Results in a rise in postprandial endogenous GLP-1 levels </li></ul></ul>Lauster CD et al. Am J Health Syst Pharm. 2007;64:1265-73 Sitagliptin
    28. 29. Sitagliptin (Januvia ® ) <ul><li>Efficacy:  A1C 0.5-0.7% </li></ul><ul><li>100 mg PO once daily </li></ul><ul><ul><li>CrCl 30-50 ml/min 50 mg/day </li></ul></ul><ul><ul><li>CrCl <30 ml/min 25 mg/day </li></ul></ul><ul><li>Approved for monotherapy or combination therapy </li></ul><ul><li>Weight neutral </li></ul><ul><li>Side effects similar to placebo </li></ul><ul><li>No contraindications identified yet </li></ul>
    29. 30. Non-Oral Therapies
    30. 32. Glucagon-like peptide 1 (GLP-1) agonists <ul><li>Exenatide (Byetta ® ) </li></ul><ul><li>Glucagon-like-peptide-1 (GLP-1) analog </li></ul><ul><ul><li>Incretin mimetic </li></ul></ul><ul><ul><li>Resistant to degradation by dipeptidyl peptidase-4 (DPP-4) </li></ul></ul><ul><ul><li>Suppresses high glucagon levels </li></ul></ul><ul><ul><li>Delays gastric emptying (can affect absorption of other medications) </li></ul></ul><ul><li>Efficacy: ↓ A1C 0.5-1% </li></ul><ul><li>Dosing: </li></ul><ul><ul><li>5 mcg SC twice daily within 60 min of meals </li></ul></ul><ul><ul><li>Increase to 10 mcg bid after 4 weeks </li></ul></ul><ul><li>FDA approved for type 2 diabetes in patients on metformin, sulfonylurea, TZD, or a combination who are not at goal </li></ul><ul><ul><li>Not yet approved for use with basal insulin </li></ul></ul>
    31. 33. GLP-1 Physiology
    32. 34. Exenatide adverse effects/contraindications <ul><li>AE’s </li></ul><ul><ul><li>N/V, diarrhea (30-45%) </li></ul></ul><ul><ul><li>Modest weight loss (a good side effect) </li></ul></ul><ul><ul><li>Hypoglycemia especially in combination with sulfonylureas </li></ul></ul><ul><ul><li>Anti-exenatide antibodies </li></ul></ul><ul><li>Monitoring </li></ul><ul><ul><li>Renal function </li></ul></ul><ul><ul><li>A1C in 3 months </li></ul></ul><ul><li>CI’s </li></ul><ul><ul><li>Type 1 diabetes </li></ul></ul><ul><li>Precautions </li></ul><ul><ul><li>CrCl < 30 ml/min </li></ul></ul><ul><ul><li>Gastroparesis </li></ul></ul><ul><ul><li>Hypoglycemia </li></ul></ul>
    33. 35. Pramlintide (Symlin ® ) <ul><li>Synthetic analog of human amylin </li></ul><ul><ul><li>Suppresses glucagon secretion </li></ul></ul><ul><ul><ul><li>Suppression of endogenous glucose from liver </li></ul></ul></ul><ul><ul><li>Slows gastric emptying </li></ul></ul><ul><ul><ul><li>Less rapid glucose appearance in the circulation </li></ul></ul></ul><ul><ul><li>Regulates food intake due to central modulation of appetite </li></ul></ul><ul><ul><ul><li>Weight loss </li></ul></ul></ul>
    34. 36. Pramlintide (Symlin ® ) <ul><li>FDA approved for Type 1 or 2 diabetes in patients on optimal insulin therapy who are still not at goal </li></ul><ul><ul><li>With or without metformin and/or sulfonylurea therapy </li></ul></ul><ul><li>Efficacy:  A1C ~0.1-0.4% in type1 and 0.3-0.7% in type 2 </li></ul><ul><li>60 mcg (10 units) SC titrate to 120 mcg (20 units) before major meals (Type 2 dosing) </li></ul><ul><ul><li>Dosed in mcg but drawn up in an insulin syringe </li></ul></ul><ul><ul><li>www.symlin.com/7522-Type-2-Dosing.aspx </li></ul></ul><ul><li>Administered in conjunction with mealtime insulin </li></ul>
    35. 37. Pramlintide (Symlin ® ) <ul><li>Adverse Effects </li></ul><ul><li>Insulin-Induced Severe Hypoglycemia: </li></ul><ul><li>Hypoglycemia will occur within 3 hours of injection </li></ul><ul><li>Must reduce pre-meal insulin by 50% at initiation to prevent serious reactions </li></ul><ul><li>Further reduction in insulin may be needed as dosage of pramlintide is adjusted </li></ul><ul><li>Contraindications </li></ul><ul><li>Diagnosis of gastroparesis </li></ul><ul><li>Hypoglycemia unawareness </li></ul><ul><li>A1C > 9.0% </li></ul><ul><li>Recurrent severe hypoglycemia requiring assistance during past 6 months </li></ul><ul><li>Using other medications that stimulate gastrointestinal motility </li></ul><ul><li>Pediatrics </li></ul>
    36. 38. Glycemic Goals
    37. 39. Glycemic Control <ul><li>ADA Guidelines </li></ul><ul><li>A1C < 7.0% </li></ul><ul><ul><li><6.5 may further reduce complications </li></ul></ul><ul><li>Fasting glucose 90-130 mg/dl </li></ul><ul><li>Peak postprandial glucose <180 mg/dl </li></ul><ul><ul><li>1-2 hours after the start of the meal </li></ul></ul><ul><li>AACE Guidelines </li></ul><ul><li>A1C < 6.5% </li></ul><ul><li>Fasting glucose < 110 mg/dl </li></ul><ul><li>2-h postprandial glucose <140 mg/dl </li></ul>
    38. 40. A1C and Meal Plasma Glucose Levels <ul><li>A1C should be as close to normal for the individual patient </li></ul><ul><li>Use less intensive goals for patients with risk for hypoglycemia </li></ul><ul><li>Target postprandial glucose if A1C goals not met after reaching preprandial goals </li></ul><ul><ul><li>Target fasting glucose first! </li></ul></ul>345 12 310 11 275 10 240 9 205 8 170 7 135 6 Mean Plasma glucose mg/dl A1C
    39. 41. Self-Monitoring of Blood Glucose (SMBG) <ul><li>At least 3 times/day if on insulin injections </li></ul><ul><li>If on orals, just use SMBG to help them achieve their glycemic goals </li></ul><ul><li>Use the data to make decisions on what therapy to add </li></ul>
    40. 42. <ul><ul><li>Diabetes Care 2007;30(Suppl 1) </li></ul></ul>
    41. 43. Lifestyle + Metformin- Step 1 <ul><li>Titrate metformin to max dose over 1-2 months </li></ul><ul><li>TZDs and sitagliptin are also approved for monotherapy </li></ul><ul><li>Consider adding other oral medications if there is persistent hyperglycemia </li></ul>
    42. 44. Lifestyle Modifications
    43. 45. Diet <ul><li>Weight loss will reduce insulin resistance </li></ul><ul><li>Saturated fat < 7 % of total daily calories </li></ul><ul><li>Carbohydrates should be from fruits, vegetables, whole grains, legumes, low fat milk </li></ul><ul><ul><li>Low carb diets < 130 g/day not recommended for weight loss </li></ul></ul><ul><li>Recommend sugar alcohols and nonnutritive sweeteners </li></ul><ul><li>Limit alcohol to 1 drink/day for women 2 drinks/day for men </li></ul><ul><ul><li>If on insulin or a secretagogue drink alcohol with food to avoid hypoglycemia </li></ul></ul>
    44. 46. Exercise <ul><li>150 min/week of moderate-intensity aerobic activity (50-70% of max heart rate) </li></ul><ul><li>90 min/week of vigorous aerobic exercise (>70% of max heart rate) </li></ul><ul><li>Resistance exercise 3 times a week </li></ul><ul><li>Improves glycemia </li></ul>OR
    45. 47. Diabetes Self-Management Education (DSME) <ul><li>All patients with diabetes should receive DSME after diagnosis </li></ul><ul><li>Teaches patients about the disease and how to improve self care </li></ul><ul><li>Should be conducted by either a CDE or health care professional with recent experience in diabetes management </li></ul>
    46. 49. Additional Medications - Step 2 <ul><li>Add within 2-3 months of initiation of therapy </li></ul><ul><li>Sulfonylurea </li></ul><ul><ul><li>Cheapest option </li></ul></ul><ul><li>TZDs </li></ul><ul><ul><li>More expensive </li></ul></ul><ul><ul><li>Cardiac risk with rosiglitazone </li></ul></ul><ul><li>Insulin </li></ul><ul><ul><li>Most effective option </li></ul></ul><ul><ul><li>Consider in patients with A1C >8.5% or symptoms of hyperglycemia </li></ul></ul><ul><ul><li>Initiate with basal insulin </li></ul></ul>
    47. 50. Step-2 Alternatives <ul><li>Sitagliptin </li></ul><ul><li>Glinides </li></ul><ul><li>Exenatide </li></ul>
    48. 52. Step-3 Initiate or intensify insulin therapy <ul><li>Start or intensify insulin if lifestyle + metformin + a 2 nd medication have not attained goal A1C </li></ul><ul><li>Third oral medication can be considered if A1C is close to goal <8.0% </li></ul><ul><ul><li>Expensive, not as effective as insulin </li></ul></ul><ul><ul><li>Exenatide could be used at this step </li></ul></ul><ul><li>D/C insulin secretagogues (sulfonylurea or glinides) when pre-prandial rapid insulin is started </li></ul>
    49. 53. Long Acting Insulin 10 units or 0.2 units/kg Increase dose 2 units q 3 days until fasting levels 70-130 mg/dl A1C ≥ 7% after 2-3 months? No Continue regimen Check A1C q 3 months Check pre-meal BG & add 2 nd injection ~4 units before meal Yes Pre-Lunch BG high: Add rapid acting at breakfast Pre-Dinner high: Add rapid acting at lunch Pre-Bed high: Add rapid acting at dinner A1C ≥ 7% after 2-3 months? Nathan DM, et al. Diabetes Care 2006;29
    50. 54. A1C ≥ 7% after 2-3 months? Yes Recheck pre-meal BG and add another injection. Check 2-h postprandial BG and adjust pre-prandial insulin dose No Continue regimen and check A1C q 3 months Nathan DM, et al. Diabetes Care 2006;29
    51. 55. Pramlintide Exenatide Sitagliptin TZD Exenatide
    52. 56. CASE 1 <ul><li>JK is a 59 year old male presenting for a follow-up visit to the diabetes clinic. </li></ul><ul><li>Past Medical History </li></ul><ul><ul><li>Type 2 diabetes </li></ul></ul><ul><ul><li>Hypertension </li></ul></ul><ul><ul><li>Coronary artery disease </li></ul></ul><ul><ul><li>Chronic renal insufficiency </li></ul></ul>
    53. 57. CASE 1 <ul><li>Medications </li></ul><ul><li>Metformin 1000 mg BID </li></ul><ul><li>Glyburide 10 mg BID </li></ul><ul><li>Pioglitazone 45 mg once daily </li></ul><ul><li>Metoprolol XL 50 mg once daily </li></ul><ul><li>Fosinopril 20 mg once daily </li></ul><ul><li>Aspirin 81 mg once daily </li></ul><ul><li>Labs (fasting) </li></ul><ul><li>Glucose 170 mg/dL </li></ul><ul><li>A1C 9.0% </li></ul><ul><li>SCr 1.7 mg/dL </li></ul><ul><li>CrCl 70 ml/min </li></ul>
    54. 58. CASE 1 <ul><li>Which diabetes medication on his profile is contraindicated and should be discontinued? </li></ul><ul><li>A . Metformin </li></ul><ul><li>B . Glyburide </li></ul><ul><li>C . Pioglitazone </li></ul>
    55. 59. CASE 1 <ul><li>Why? </li></ul><ul><li>A . Coronary artery disease </li></ul><ul><li>B . Renal insufficiency </li></ul><ul><li>C . Drug Interaction </li></ul><ul><li>D . Non-adherence </li></ul>
    56. 60. CASE 1 <ul><li>Which one of the following would be most appropriate to replace the discontinued medication? </li></ul><ul><li>A . Glipizide XL 20 mg PO once daily </li></ul><ul><li>B . Insulin aspart 4 units SC before breakfast </li></ul><ul><li>C . Insulin glargine 10 units SC at bedtime </li></ul><ul><li>D . Pramlintide 60 mcg SC before meals </li></ul>
    57. 61. Complications of Diabetes
    58. 62. Complications of Uncontrolled Diabetes Hanefeld M, et al. Diabet Med. 1997;14(suppl 3):S6 HbA 1C PPG Hyperglycemia Spike Continuous Chronic Toxicity Acute Toxicity Tissue Lesions Diabetic Complications Microvascular Macrovascular Nephropathy Neuropathy Retinopathy PVD MI Stroke
    59. 63. Relative Risk of Progression of Diabetic Complications by Mean HbA 1c * Updated Mean HbA 1c (%) Stratton IM, et al. BMJ. 2000;321:405-12. Adjusted Incidence per 1000 person years 6 7 8 9 10 11 *Based on UKPDS 35 data
    60. 64. Macrovascular Complications
    61. 65. Macrovascular Complication Statistics <ul><li>CVD and Stroke </li></ul><ul><ul><li>Adults with DM have heart disease death rates 2-4x higher than non-diabetics </li></ul></ul><ul><ul><li>Risk for stroke is 2 to 4x higher and risk of death from stroke is 2.8x higher than in non-diabetics </li></ul></ul>U.S. Department of Health and Human Services, National Institute of Health, 2005.
    62. 66. Macrovascular Complications <ul><li>~ 80% of all diabetic mortality </li></ul><ul><ul><li>75% from coronary atherosclerosis </li></ul></ul><ul><ul><li>25% from cerebral or peripheral vascular disease </li></ul></ul><ul><li>> 75% of all hospitalizations for diabetic complications </li></ul><ul><li>> 50% of patients with newly diagnosed type 2 diabetes have CHD </li></ul>National Diabetes Data Group. Diabetes in America. 2 nd . Ed. NIH; 1995.
    63. 67. Insulin Resistance and Atherosclerosis Accelerated atherosclerosis Clinical diabetes Hyperinsulinemia Impaired glucose tolerance Hypertriglyceridemia Decreased HDL-C Essential hypertension Insulin resistance
    64. 68. Heart Disease and Diabetes <ul><li>Intensive treatment of hyperglycemia </li></ul><ul><li>Therapy for insulin resistance </li></ul><ul><li>Appropriate lipid management </li></ul><ul><li>Aggressive blood pressure control </li></ul>Treatment of CVD in diabetes is similar to therapy for non-diabetic individuals, the risk of CVD is much higher and the benefits of therapy are greater
    65. 69. Hypertension <ul><li>Defined as BP ≥ 140/90 mmHg </li></ul><ul><ul><li>GOAL BP: < 130/80 mmHg </li></ul></ul><ul><li>20 – 60% of Diabetics have HTN </li></ul><ul><li>Epidemiologic evidence from the UKPDS indicate that each 10 mmHg decrease in mean SBP results in: </li></ul><ul><ul><li> 12% any DM complication </li></ul></ul><ul><ul><li> 15% any DM-related death </li></ul></ul><ul><ul><li> 11% MI </li></ul></ul><ul><ul><li> 13% microvascular complications </li></ul></ul>American Diabetes Association. Diabetes Care. 2007;30:S4-S41.
    66. 70. Hypertension <ul><li>Weight loss </li></ul><ul><ul><li> 1 kg results in  of MAP ~ 1 mmHg </li></ul></ul><ul><li>Sodium restriction </li></ul><ul><ul><li>In non-diabetic patients reduces SBP ~ 5 mmHg and DBP ~2 - 3 mmHg </li></ul></ul><ul><li>Drug Therapy (If SBP ≥ 140 mmHg or DBP ≥ 90 mmHg or lifestyle modification failure) </li></ul><ul><ul><li>1 st choice: ACE-I or ARB </li></ul></ul><ul><ul><li>2 nd choice: Thiazide, β -Blocker, or Non-DCCB </li></ul></ul>JNC 7 report. JAMA 2003;289:2560-72.
    67. 71. Cholesterol Management <ul><li>Screening: </li></ul><ul><ul><li>Fasting lipid panel at least annually </li></ul></ul><ul><ul><li>More often if needed to achieve goals </li></ul></ul><ul><ul><li>In adults with low-risk lipid values, may obtain fasting lipid panel every 2 years </li></ul></ul><ul><li>Goals: </li></ul><ul><ul><li>LDL < 100 mg/dL </li></ul></ul><ul><ul><ul><li>Optional: LDL <70 mg/dL </li></ul></ul></ul><ul><ul><li>TG < 150 mg/dL </li></ul></ul><ul><ul><li>HDL: </li></ul></ul><ul><ul><ul><li>> 40 mg/dL for males </li></ul></ul></ul><ul><ul><ul><li>> 50 mg/dL for females </li></ul></ul></ul>American Diabetes Association. Diabetes Care .2007;30:S4-S41.
    68. 72. Macrovascular Complications <ul><li>Aspirin Therapy: 75 – 162 mg/day </li></ul><ul><li>Primary prevention in those with ↑ CVD risk : </li></ul><ul><ul><li>Family Hx of CVD </li></ul></ul><ul><ul><li>Tobacco use </li></ul></ul><ul><ul><li>HTN </li></ul></ul><ul><ul><li>Albuminuria </li></ul></ul><ul><ul><li>Lipids: TC >200; LDL >100; HDL < 45 (or 55) & TG >200 </li></ul></ul><ul><ul><li>Age ≥ 40 years </li></ul></ul><ul><li>Secondary prevention in those with DM + CVD </li></ul><ul><li>Not recommended for patients < 30 years-old </li></ul>American Diabetes Association. Diabetes Care .2007;30:S4-S41.
    69. 73. Macrovascular Complications <ul><li>Smoking cessation </li></ul><ul><ul><li>Advise all patients not to smoke </li></ul></ul><ul><ul><li>Provide smoking cessation counseling and other forms of treatment if needed </li></ul></ul>American Diabetes Association. Diabetes Care .2007;30:S4-S41.
    70. 74. Management Summary for Macrovascular Complications American Diabetes Association. Diabetes Care .2007;30:S4-S41. Macrovascular Complications Goals Hypertension Dyslipidemia <ul><li>LDL < 100 mg/dL </li></ul><ul><ul><li>Optimal < 70 mg/dL </li></ul></ul><ul><li>TG < 150 mg/dL </li></ul><ul><li>HDL: </li></ul><ul><ul><li>> 40 mg/dL – Male </li></ul></ul><ul><ul><li>> 50 mg/dL - Female </li></ul></ul><ul><li>Blood Pressure: </li></ul><ul><li>< 130/80 mmHg </li></ul>Treatment <ul><li>Weight loss </li></ul><ul><li>Sodium restriction </li></ul><ul><li>ACE-I / ARB </li></ul><ul><li>Everyone needs: </li></ul><ul><li>Aspirin </li></ul><ul><li>Lifestyle modifications </li></ul><ul><li>Smoking Cessation </li></ul><ul><li>Statin </li></ul>
    71. 75. Microvascular Complications
    72. 76. Relative Risk of Progression of Diabetic Complications by Mean HbA 1c * Skyler JS ,et al. Endocrinol Metab Clin North Am . 1996;25:243-54. Relative risk 6 7 8 9 10 11 12 15 13 11 9 7 5 3 1 HbA 1c (%) Diabetic retinopathy Nephropathy Neuropathy Microalbuminuria *Based on DCCT data
    73. 77. Diabetic Nephropathy <ul><li>Occurs in 20 to 40% of diabetics </li></ul><ul><li>Most common cause of ESRD </li></ul><ul><li>ESRD develops in 50% of type 1 patients with overt nephropathy within 10 years </li></ul><ul><li>ESRD develops in about 20% of type 2 patients with overt nephropathy within 20 years </li></ul>American Diabetes Association. Diabetes Care. 2007;30:S4-S41.
    74. 78. Nephropathy: Diagnosis Category Spot Collection (albumin-to-creatinine) (mcg/mg) Normal < 30 Microalbuminuria 30 - 299 Clinical albuminuria > 300 Two of three specimens collected within a 3-6 month period should be abnormal before diagnosing . Exercise within 24 hr, infection, fever, CHF, marked hyperglycemia or HTN, pyuria, & hematuria may elevate urinary albumin excretion over baseline values American Diabetes Association. Diabetes Care. 2007;30:S4-S41.
    75. 79. Nephropathy: Screening <ul><li>Screening </li></ul><ul><ul><li>DM 1: Within 5 years of diagnosis </li></ul></ul><ul><ul><li>DM 2: Upon diagnosis </li></ul></ul><ul><ul><li>DM 1 and 2: Follow-up exams annually </li></ul></ul><ul><li>If (+) for microalbuminuria, test twice more over next 3 to 6 months </li></ul><ul><ul><li>If 2 of 3 tests are positive, they have microalbuminuria and should have treatment started </li></ul></ul><ul><li>Serum creatinine should be measured at least annually for estimation of GFR </li></ul>American Diabetes Association. Diabetes Care. 2007;30:S4-S41
    76. 80. Nephropathy: Treatment <ul><li>Glycemic control: HbA 1c < 7% </li></ul><ul><li>Blood pressure control: BP < 130/80 mmHg </li></ul><ul><ul><li>ACE-I / ARBs </li></ul></ul><ul><ul><ul><li>Decrease progression of microalbuminuria and slow rate of decline in GFR in patients with proteinuria </li></ul></ul></ul><ul><ul><ul><li>Non-DCCBs, BB’s, or thiazide acceptable if intolerant to ACEI/ARB </li></ul></ul></ul><ul><ul><ul><li>If ACE-I, ARBs, or thiazide used, monitor K + </li></ul></ul></ul><ul><li>Protein restriction </li></ul><ul><ul><li>With presence of nephropathy </li></ul></ul><ul><ul><ul><li>≤ 0.8 g/kg per day ( ~ 10% of daily calories) </li></ul></ul></ul>American Diabetes Association. Diabetes Care. 2007;30:S4-S41
    77. 81. Diabetic Neuropathy <ul><li>Sensorimotor </li></ul><ul><li>Muscular </li></ul><ul><ul><li>Muscle weakeness </li></ul></ul><ul><ul><li>Balance difficulties </li></ul></ul><ul><li>Sensory </li></ul><ul><ul><li>Pain </li></ul></ul><ul><ul><li>Parathesias </li></ul></ul><ul><ul><li>Numbness </li></ul></ul><ul><ul><li>Cramping </li></ul></ul><ul><ul><li>Nighttime falls </li></ul></ul><ul><li>Autonomic </li></ul><ul><li>Cardiovascular </li></ul><ul><ul><li>Syncope, fatigue, sustained heart rate </li></ul></ul><ul><li>GI </li></ul><ul><ul><li>Dysphagia, N/V, constipation, diarrhea </li></ul></ul><ul><li>Genitourinary </li></ul><ul><ul><li>↓ bladder control, UTIs, ED, Dyspareunia </li></ul></ul><ul><li>Sudomotor </li></ul><ul><ul><li>Dry skin, calluses, limb hair loss </li></ul></ul><ul><li>Endocrine </li></ul><ul><ul><li>Hypoglycemic unawareness </li></ul></ul><ul><li>Other </li></ul><ul><ul><li>Depression, anxiety, sleep disorders </li></ul></ul>
    78. 82. Diabetic Neuropathy Screening <ul><li>Annual foot exam: </li></ul><ul><ul><li>Assessment for protective sensation, foot structure and biomechanics, vascular status, and skin integrity. </li></ul></ul><ul><ul><ul><li>Neurologic status assessed with 5.07 (10-g) monofilament </li></ul></ul></ul><ul><ul><ul><li>Also consider: pin-prick sensation, temperature and vibration perception (using tuning fork) </li></ul></ul></ul><ul><ul><ul><li>Assess for history of claudication, and assess pedal pulses </li></ul></ul></ul><ul><ul><ul><li>Assess skin integrity especially b/w toes and under metatarsal heads. Look for erythema, warmth, or callus formation (increased plantar pressure) </li></ul></ul></ul><ul><ul><ul><li>Bony deformities, limitation in joint mobility, and gait and balance should be assessed </li></ul></ul></ul>
    79. 83. Diabetic Neuropathy Treatment <ul><li>Glycemic control: HbA 1c < 7% </li></ul><ul><li>Foot care </li></ul><ul><ul><li>Proper footwear </li></ul></ul><ul><ul><li>Daily patient assessment </li></ul></ul><ul><ul><li>Moisturizing </li></ul></ul><ul><ul><ul><li>Not between toes </li></ul></ul></ul><ul><ul><li>NO bare feet! </li></ul></ul>
    80. 84. Peripheral Neuropathy Treatment <ul><li>Optimal glycemic control: GOAL HbA 1c < 7% </li></ul>Wong M, et al. BMJ. 2007; 335; 1-10.
    81. 85. Diabetic Retinopathy <ul><li>Leading cause of new cases of blindness among adults (20 to 74 years of age). </li></ul><ul><li>Prevalence is strongly related to duration of diabetes. </li></ul>Normal Vision Diabetic Retinopathy
    82. 86. Diabetic Retinopathy Screening <ul><li>Comprehensive dilated eye exam: </li></ul><ul><ul><li>DM 1: Within 3 to 5 years of diagnosis </li></ul></ul><ul><ul><li>DM 2: Upon diagnosis </li></ul></ul><ul><ul><li>DM 1 and 2: Follow-up exams annually </li></ul></ul>American Diabetes Association. Diabetes Care. 2007;30:S4-S41.
    83. 87. Diabetic Retinopathy Management <ul><li>Tight glycemic control HbA 1C < 7% </li></ul><ul><li>Tight blood pressure control <130/80 mmHg </li></ul><ul><ul><li>Both shown to delay or prevent onset of retinopathy </li></ul></ul>
    84. 88. Management Summary for Microvascular Complications Microvascular Complications Screening Nephropathy Neuropathy Retinopathy <ul><li>Annual Exam: </li></ul><ul><li>Dilated Eye </li></ul><ul><li>Retinal vessels </li></ul><ul><li>Cataract </li></ul><ul><li>Intraocular Pressure </li></ul><ul><li>Annual Microalbumin: </li></ul><ul><li>Screen Albumin: </li></ul><ul><ul><li>Creatinine ratio </li></ul></ul><ul><ul><li>Repeat to confirm </li></ul></ul><ul><li>Comprehensive foot exam: </li></ul><ul><li>Inspection </li></ul><ul><li>Vascular </li></ul><ul><li>Vibratory perception </li></ul><ul><li>Monofilament </li></ul>Treatment <ul><li>Glycemic Control </li></ul><ul><li>ACE-I / ARB </li></ul><ul><li>Glycemic Control </li></ul><ul><li>Foot care/ footwear </li></ul><ul><li>Medication Management </li></ul><ul><li>Glycemic Control </li></ul><ul><li>BP Control </li></ul><ul><li>Photocoagulation </li></ul>Everyone needs lifestyle modifications
    85. 89. Standards of Care in Diabetes Diabetes Care. 2007;30(suppl 1):S4-S41
    86. 90. Medical history during the 1 st evaluation <ul><li>Age and characteristics of onset of diabetes </li></ul><ul><li>Eating patterns </li></ul><ul><li>History of diabetes education </li></ul><ul><li>Previous and current treatments </li></ul><ul><li>Exercise history </li></ul><ul><li>Hypoglycemic episodes </li></ul><ul><li>History of DKA? </li></ul><ul><li>History of diabetes related complications </li></ul>
    87. 91. Physical Exam/Labs <ul><li>Physical Exam </li></ul><ul><li>BP </li></ul><ul><li>Fundoscopic exam </li></ul><ul><li>Thyroid palpation </li></ul><ul><li>Skin exam </li></ul><ul><li>Peripheral pulses </li></ul><ul><li>Patellar and achilles reflexes </li></ul><ul><li>Peripheral sensation </li></ul><ul><li>Labs to order </li></ul><ul><li>A1C </li></ul><ul><li>Fasting lipids </li></ul><ul><li>LFTs </li></ul><ul><li>Microalbuminuria </li></ul><ul><li>SCr and GFR </li></ul><ul><li>TSH </li></ul>
    88. 92. Health Maintenance/Prevention of Complications <ul><li>Influenza vaccine annually </li></ul><ul><li>Pneumococcal vaccine for all adults </li></ul><ul><li>Smoking cessation! </li></ul><ul><li>BP at every visit, goal < 130/80 mmHg </li></ul><ul><li>Check lipids annually: Goal LDL <100 mg/dL, TG <150 mg/dL, HDL >40 for men >50 for women </li></ul><ul><li>Annual test for microalbuminuria </li></ul><ul><li>Annual eye exam to screen for retinopathy </li></ul><ul><li>Annual screening for peripheral and autonomic neuropathy </li></ul><ul><li>Foot care </li></ul>
    89. 93. CASE 2 <ul><li>JT is a 58 year old male newly diagnosed with Type 2 diabetes </li></ul><ul><li>PMH </li></ul><ul><ul><li>Dyslipidemia </li></ul></ul><ul><li>SH: Tobacco 1 pack/day x 30 years; Rare ETOH use; denies illicit drug use; diet is high in carbohydrates and sugars and low in vegetables; physical activity “little to none” </li></ul>
    90. 94. CASE 2 <ul><li>How much exercise should you recommend for JT? </li></ul><ul><li>A . 90 minutes/week </li></ul><ul><li>B . 60 minutes/week </li></ul><ul><li>C . 150 minutes/week </li></ul><ul><li>D . 300 minutes/week </li></ul>
    91. 95. CASE 2 <ul><li>Which of the following should be done at diagnosis? </li></ul><ul><li>A . Eye exam </li></ul><ul><li>B . Test for microalbuminuria </li></ul><ul><li>C . Blood pressure </li></ul><ul><li>D . Fasting lipids </li></ul><ul><li>E . All of the above </li></ul>
    92. 96. CASE 2 <ul><li>JT’s blood pressure is 150/90, what would be your recommendation for initial therapy? </li></ul><ul><li>A . Fosinopril </li></ul><ul><li>B . HCTZ </li></ul><ul><li>C . Diltiazem </li></ul><ul><li>D . Metoprolol </li></ul>