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Management of the Patient with Type 2 Diabetes

Management of the Patient with Type 2 Diabetes. Gretchen M. Ray, Pharm.D. Cardiovascular Pharmacotherapy Resident University of New Mexico College of Pharmacy. Objectives. Provide diabetes screening criteria for adults

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Management of the Patient with Type 2 Diabetes

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  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 • Provide diabetes screening criteria for adults • Describe available pharmacologic treatment options for type 2 diabetes including advantages/disadvantages of therapy and contraindications • Given a patient case recommend appropriate lifestyle modifications and pharmacotherapy to achieve glycemic goals

  3. Objectives • Distinguish between microvascular and macrovascular complications • Provide screening criteria for nephropathy, neuropathy, and retinopathy • Provide treatment strategies for the prevention and treatment of micro and macrovascular complications

  4. Epidemiology of Type 2 DM • In 2005 20.8 million people (7% of the US population) had diabetes • 14.6 million diagnosed • 6.2 million undiagnosed • Type 2 diabetes accounts for 90-95% of patients with diabetes • In 2002 total indirect and direct medical costs for diabetes = $132 billion CDC. National diabetes fact sheet. 2005 available at www.cdc.gov/diabetes/pubs/pdf/ndfs_2005.pdf

  5. Risk factors for type 2 diabetes • Physically inactive • 1st degree relative with diabetes • Minority ethnic groups • Gestational diabetes or delivering a baby >9 lbs • Hypertension • HDL <35 mg/dL and/or triglycerides >250 mg/dL • Polycystic ovary syndrome • Previous impaired glucose tolerance (IGT) or impaired fasting glucose (IFG) • History of vascular disease • Psychiatric illness

  6. Diagnosis of diabetes • Symptoms of diabetes + casual plasma glucose ≥ 200 mg/dl • FPG ≥ 126 mg/dl • Oral glucose tolerance test (OGTT): 2-h postload glucose ≥ 200 mg/dl OR OR

  7. Definition of “pre-diabetes” • Impaired fasting glucose (IFG) = FPG 100-125 mg/dl • Impaired glucose tolerance (IGT) = 2-h post load glucose 140-199 mg/dl • IFG and IGT indicate a risk factor for diabetes and cardiovascular disease

  8. Diabetes Screening • Screening identifies asymptomatic patients who might have diabetes • Consider in patients ≥ 45 years especially if their BMI ≥ 25 kg/m2 • Screen patients < 45 years old if they are overweight + an additional risk factor • FPG should be done initially • Repeat screening every 3 years

  9. Oral Therapies

  10. Metformin •  hepatic glucose production,  intestinal glucose absorption,  insulin sensitivity • Efficacy:  A1C 1.5% • Adverse effects • Primarily GI (up to 50%) • Diarrhea, abdominal bloating, nausea • Titrate dose at weekly intervals to minimize AEs • Give with meals • Lactic acidosis- rare • Monitor SCr

  11. Contraindications to Metformin • Renal impairment SCr >1.5 for men, >1.4 for women • Radiocontrast studies • Age >80 unless normal GFR • Hypoxia • Liver dysfunction • Alcoholism • Heart Failure requiring pharmacologic therapy • According to package insert • Should heart failure be a contraindication to metformin?

  12. Improved Clinical Outcomes Associated with Metformin in Patients with Diabetes and Heart Failure • Investigate the association between metformin and clinical outcomes in patients with HF and diabetes • Retrospective study • Primary outcome: all-cause mortality at 1 year and end of follow-up • Secondary outcome: all-cause hospitalizations at 1 year and end of follow-up 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

  14. Improved Clinical Outcomes Associated with Metformin in Patients with Diabetes and Heart Failure • Lower all-cause mortality with metformin • No increase in hospitalizations associated with metformin • Observational study • Cannot prove that metformin is efficacious in this population Eurich DT, et al. Diabetes Care. 2005;28:2345-51

  15. Sulfonylureas • ↑ insulin secretion from pancreatic β-cells • Efficacy: ↓ A1C 1.5% • Glyburide • Not recommended if CrCl < 50 ml/min (use a different sulfonylurea) • Glipizide • Not recommended if CrCl < 10 ml/min • Glimepiride • Not recommended if CrCl < 22 ml/min • Response of sulfonylureas plateaus after half the max dose • Reduced GI absorption if blood glucose > 250 mg/dL

  16. Sulfonylureas Adverse Effects • Hypoglycemia • Elderly patients • Hepatic/renal impairment • Combination therapy • Weight gain

  17. Thiazolidenediones (TZDs) Insulin Sensitizers • TZDs are PPAR- gamma receptor activators • ↑ insulin sensitivity • Primarily in the peripheral tissue • Efficacy:  A1C 0.5-1.4% • Effect may not be seen for 4 weeks • Rosiglitazone (Avandia®) • Initial dose 4 mg/day, Max dose 8 mg/day • Pioglitazone (Actos®) • Initial dose 15-30 mg/day, Max dose 45 mg/day

  18. AE’s Fluid retention and peripheral edema Weight gain Fluid retention is a major contributor Redistribution of adipose tissue New-onset heart failure < 1% 2-3% when combined with insulin CI’s ALT > 2.5 x upper limit of normal Hepatic disease Alcohol Abuse HF NYHA class III or IV (see following slides) Adverse Effects/Contraindications of TZDs Granberry MC, et al. Am J Health-Syst Pharm. 2007;64:931-6

  19. TZD Use In Heart Failure • Use of TZDs in patients with NYHA class I or II HF • May be used with initiation of treatment at the lowest dosage (rosiglitazone 2 mg daily or pioglitazone 15 mg daily) • Observe for weight gain, edema, or exacerbation of HF • Do not use TZDs in patients with NYHA class III or IV HF Nesto RW, et al. Diabetes Care. 2004;27:256-63

  20. Meta-analysis of MI Risk With Rosiglitazone • 42 trials comparing rosiglitazone with placebo • 15,560 patients received rosiglitazone • 12,283 patients assigned to comparator groups • 24-52 week duration of trials • Mean baseline A1C 8.2% for both groups Nissen SE, et al. N Engl J Med. 2007;356:1-15

  21. Meta-analysis of MI Risk With Rosiglitazone Nissen SE, et al. N Engl J Med. 2007;356:1-15

  22. PROactive Trial • Primary objective: Determine if pioglitazone reduces CV morbidity and mortality in patients with diabetes • Pioglitazone vs. placebo • ↓ Triglycerides 11% vs. 1.8% ↑ • ↑ LDL 7.2% vs. 4.9% • ↓ LDL/HDL 9.5% vs. 4.2% • Non-significant reduction in the primary endpoint Dormandy JA, et al. Lancet. 2005;366:1279-89

  23. PROactive Sub-analysis • Evaluated same endpoints in patients with prior MI • Significant ↓ in fatal/nonfatal MI excluding silent MI with pioglitazone • 5.3% pioglitazone vs. 7.2% placebo p=0.0453 • Results for rosiglitazone and pioglitazone recently confirmed with two new meta-analyses Erdmann E, et al. J Am Coll Cardiol. 2007;49:1772-80

  24. HF in PROactive Dormandy JA, et al. Lancet. 2005;366:1279-89

  25. FDA Updates- August 14, 2007 • Rosiglitazone and pioglitazone received a “boxed warning” regarding CHF www.fda.gov Actos prescribing information. August 2007

  26. FDA Updates: November 19, 2007 • MI risk added to rosiglitazone boxed warning Avandia prescribing information. November 2007

  27. Sitagliptin (Januvia®) • DPP-4 inhibitor • Prevents the degradation of endogenous GLP-1 • Results in a rise in postprandial endogenous GLP-1 levels Sitagliptin Lauster CD et al. Am J Health Syst Pharm. 2007;64:1265-73

  28. Sitagliptin (Januvia®) • Efficacy: A1C 0.5-0.7% • 100 mg PO once daily • CrCl 30-50 ml/min 50 mg/day • CrCl <30 ml/min 25 mg/day • Approved for monotherapy or combination therapy • Weight neutral • Side effects similar to placebo • No contraindications identified yet

  29. Non-Oral Therapies

  30. Glucagon-like peptide 1 (GLP-1) agonists • Exenatide (Byetta®) • Glucagon-like-peptide-1 (GLP-1) analog • Incretin mimetic • Resistant to degradation by dipeptidyl peptidase-4 (DPP-4) • Suppresses high glucagon levels • Delays gastric emptying (can affect absorption of other medications) • Efficacy: ↓ A1C 0.5-1% • Dosing: • 5 mcg SC twice daily within 60 min of meals • Increase to 10 mcg bid after 4 weeks • FDA approved for type 2 diabetes in patients on metformin, sulfonylurea, TZD, or a combination who are not at goal • Not yet approved for use with basal insulin

  31. GLP-1 Physiology

  32. AE’s N/V, diarrhea (30-45%) Modest weight loss (a good side effect) Hypoglycemia especially in combination with sulfonylureas Anti-exenatide antibodies Monitoring Renal function A1C in 3 months CI’s Type 1 diabetes Precautions CrCl < 30 ml/min Gastroparesis Hypoglycemia Exenatide adverse effects/contraindications

  33. Pramlintide (Symlin®) • Synthetic analog of human amylin • Suppresses glucagon secretion • Suppression of endogenous glucose from liver • Slows gastric emptying • Less rapid glucose appearance in the circulation • Regulates food intake due to central modulation of appetite • Weight loss

  34. Pramlintide (Symlin®) • FDA approved for Type 1 or 2 diabetes in patients on optimal insulin therapy who are still not at goal • With or without metformin and/or sulfonylurea therapy • Efficacy: A1C ~0.1-0.4% in type1 and 0.3-0.7% in type 2 • 60 mcg (10 units) SC titrate to 120 mcg (20 units) before major meals (Type 2 dosing) • Dosed in mcg but drawn up in an insulin syringe • www.symlin.com/7522-Type-2-Dosing.aspx • Administered in conjunction with mealtime insulin

  35. Adverse Effects Insulin-Induced Severe Hypoglycemia: Hypoglycemia will occur within 3 hours of injection Must reduce pre-meal insulin by 50% at initiation to prevent serious reactions Further reduction in insulin may be needed as dosage of pramlintide is adjusted Contraindications Diagnosis of gastroparesis Hypoglycemia unawareness A1C > 9.0% Recurrent severe hypoglycemia requiring assistance during past 6 months Using other medications that stimulate gastrointestinal motility Pediatrics Pramlintide (Symlin®)

  36. Glycemic Goals

  37. ADA Guidelines A1C < 7.0% <6.5 may further reduce complications Fasting glucose 90-130 mg/dl Peak postprandial glucose <180 mg/dl 1-2 hours after the start of the meal AACE Guidelines A1C < 6.5% Fasting glucose < 110 mg/dl 2-h postprandial glucose <140 mg/dl Glycemic Control

  38. A1C and Meal Plasma Glucose Levels • A1C should be as close to normal for the individual patient • Use less intensive goals for patients with risk for hypoglycemia • Target postprandial glucose if A1C goals not met after reaching preprandial goals • Target fasting glucose first!

  39. Self-Monitoring of Blood Glucose (SMBG) • At least 3 times/day if on insulin injections • If on orals, just use SMBG to help them achieve their glycemic goals • Use the data to make decisions on what therapy to add

  40. Diabetes Care 2007;30(Suppl 1)

  41. Lifestyle + Metformin- Step 1 • Titrate metformin to max dose over 1-2 months • TZDs and sitagliptin are also approved for monotherapy • Consider adding other oral medications if there is persistent hyperglycemia

  42. Lifestyle Modifications

  43. Diet • Weight loss will reduce insulin resistance • Saturated fat < 7 % of total daily calories • Carbohydrates should be from fruits, vegetables, whole grains, legumes, low fat milk • Low carb diets < 130 g/day not recommended for weight loss • Recommend sugar alcohols and nonnutritive sweeteners • Limit alcohol to 1 drink/day for women 2 drinks/day for men • If on insulin or a secretagogue drink alcohol with food to avoid hypoglycemia

  44. Exercise • 150 min/week of moderate-intensity aerobic activity (50-70% of max heart rate) • 90 min/week of vigorous aerobic exercise (>70% of max heart rate) • Resistance exercise 3 times a week • Improves glycemia OR

  45. Diabetes Self-Management Education (DSME) • All patients with diabetes should receive DSME after diagnosis • Teaches patients about the disease and how to improve self care • Should be conducted by either a CDE or health care professional with recent experience in diabetes management

  46. Additional Medications - Step 2 • Add within 2-3 months of initiation of therapy • Sulfonylurea • Cheapest option • TZDs • More expensive • Cardiac risk with rosiglitazone • Insulin • Most effective option • Consider in patients with A1C >8.5% or symptoms of hyperglycemia • Initiate with basal insulin

  47. Step-2 Alternatives • Sitagliptin • Glinides • Exenatide

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