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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
  • Transcript

    • 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. 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. 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. 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. 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. 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. 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. 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. Oral Therapies
    • 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. 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. 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. 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. 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. 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. 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. 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. 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. 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 27. FDA Updates: November 19, 2007 <ul><li>MI risk added to rosiglitazone boxed warning </li></ul>Avandia prescribing information. November 2007
    • 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
    • 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>
    • 30. Non-Oral Therapies
    • 31.  
    • 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>
    • 33. GLP-1 Physiology
    • 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>
    • 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>
    • 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>
    • 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>
    • 38. Glycemic Goals
    • 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>
    • 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
    • 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>
    • 42. <ul><ul><li>Diabetes Care 2007;30(Suppl 1) </li></ul></ul>
    • 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>
    • 44. Lifestyle Modifications
    • 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>
    • 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
    • 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>
    • 48.  
    • 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>
    • 50. Step-2 Alternatives <ul><li>Sitagliptin </li></ul><ul><li>Glinides </li></ul><ul><li>Exenatide </li></ul>
    • 51.  
    • 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>
    • 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
    • 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
    • 55. Pramlintide Exenatide Sitagliptin TZD Exenatide
    • 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>
    • 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>
    • 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>
    • 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>
    • 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>
    • 61. Complications of Diabetes
    • 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
    • 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
    • 64. Macrovascular Complications
    • 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.
    • 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.
    • 67. Insulin Resistance and Atherosclerosis Accelerated atherosclerosis Clinical diabetes Hyperinsulinemia Impaired glucose tolerance Hypertriglyceridemia Decreased HDL-C Essential hypertension Insulin resistance
    • 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
    • 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.
    • 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.
    • 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.
    • 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.
    • 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.
    • 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>
    • 75. Microvascular Complications
    • 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
    • 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.
    • 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.
    • 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
    • 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
    • 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>
    • 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>
    • 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>
    • 84. Peripheral Neuropathy Treatment <ul><li>Optimal glycemic control: GOAL HbA 1c < 7% </li></ul>Wong M, et al. BMJ. 2007; 335; 1-10.
    • 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
    • 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.
    • 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>
    • 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
    • 89. Standards of Care in Diabetes Diabetes Care. 2007;30(suppl 1):S4-S41
    • 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>
    • 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>
    • 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>
    • 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>
    • 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>
    • 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>
    • 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>

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