1. Diabetes Management Guidelines: 2011 Diabetes Management Guidelines: 2011 USPHS Scientific and Training Symposium – Pharmacy Category June 21 st, 2011 CDR Ryan Schupbach, Pharm.D., BCPS, CACP, NCPS Clinical Pharmacy Director, PHS Claremore Indian Hospital Clinical Assistant Professor, University of Oklahoma College of Pharmacy

2. Objectives Generalize contemporary changes in guidelines relating to the diagnosis, treatment and medication management of diabetes Explore diabetes outcome measures where pharmacist practitioners can have significant impact Systematize preferred medications from evidence-based literature in the treatment of diabetes

3. Overview Impact of Diabetes Mellitus (DM) Diabetes Practice Guidelines – Focus: 2011 ADA Standards of Medical Care Treatment Algorithms for Glycemic Control – 2009 ADA/EASD guidelines for T2DM – AACE December 2009 Update T2DM= Type 2 Diabetes Mellitus

4. Diabetes Epidemiology - 2010 Diabetes affects 25.8 million in U.S. – 8.3% of population (>90% have T2DM) – 19 million diagnosed; 7 million undiagnosed 1.9 million adults diagnosed in 2010 79 million people have pre-diabetes in U.S. – 35% of adults aged 20 and older – 50% of adults aged 65 and older Center for Disease Control and Prevention. National Diabetes Fact Sheet, 2011.

5. Impact of Diabetes in the U.S. Diabetes is the leading cause of: – Kidney failure – Non-traumatic limb amputation – New cases of blindness Diabetes in the 7 th leading cause for death in U.S. Diabetes is a major cause of heart disease and stroke Center for Disease Control and Prevention. National Diabetes Fact Sheet, 2011.

8. Financial Impact of Diabetes (2007) Total (Indirect & Direct costs)$174 billion Direct medical costs$116 billion Indirect costs$58 billion (disability, work loss, premature mortality) “Medical expenses for patients with diabetes are more than two times higher than for people without diabetes” Center for Disease Control and Prevention. National Diabetes Fact Sheet, 2011. “Overall, the risk for death among people with diabetes is about twice that of people of similar age but without diabetes. “

9. 2 main sets of guidelines utilized in U.S. – American Diabetes Association (ADA) – American Association of Clinical Endocrinology (AACE) Lots of overlap, but AACE generally considered “more intense” Evidence based, well accepted, clinically relevant and can be easily incorporated into clinical practice Diabetes Guideline Management

10. ADA publishes guideline update every January in Diabetes Care journal – Clinical Practice Recommendations – http://professional.diabetes.org/CPR_Search.aspx AACE updates guidelines periodically in Endocrine Practice journal – April 2011 – Medical Guidelines for Clinical Practice for the Management of Diabetes Mellitus – www.aace.com/publications/guidelines Diabetes Guideline Management

11. STANDARDS OF MEDICAL CARE IN DIABETES—2011

12. Level of Evidence Description AClear or supportive evidence from adequately powered well- conducted, generalizable, randomized controlled trials Compelling nonexperimental evidence BSupportive evidence from well-conducted cohort studies or case-control study CSupportive evidence from poorly controlled or uncontrolled studies Conflicting evidence with the weight of evidence supporting the recommendation EExpert consensus or clinical experience ADA Evidence Grading System for Clinical Recommendations ADA. Diabetes Care 2011;34(suppl 1):S12. Table 1.

13. CLASSIFICATION AND DIAGNOSIS OF DIABETES

14. Type 1 diabetes – β-cell destruction Type 2 diabetes – Progressive insulin secretory defect Gestational diabetes mellitus Other specific types of diabetes – Genetic defects in β-cell function, insulin action – Diseases of the exocrine pancreas – Drug- or chemical-induced Classification of Diabetes ADA. I. Classification and Diagnosis. Diabetes Care 2011;34(suppl 1):S12.

15. Fasting plasma glucose (FPG) ≥126 mg/dl (7.0 mmol/l) OR Two-hour plasma glucose ≥200 mg/dl (11.1 mmol/l) during an OGTT OR A random plasma glucose ≥200 mg/dl (11.1 mmol/l) OR A1C ≥6.5% Criteria for the Diagnosis of Diabetes ADA. I. Classification and Diagnosis. Diabetes Care 2011;34(suppl 1):S13. Table 2.

16. A1C ≥6.5% The test should be performed in a laboratory using an NGSP-certified method standardized to the DCCT assay* Criteria for the Diagnosis of Diabetes *In the absence of unequivocal hyperglycemia, result should be confirmed by repeat testing. ADA. I. Classification and Diagnosis. Diabetes Care 2011;34(suppl 1):S13. Table 2.

17. Categories of increased risk for diabetes (Prediabetes)* IFG: FPG 100-125 mg/dl (5.6-6.9 mmol/l) or IGT: 2-h plasma glucose in the 75-g OGTT 140-199 mg/dl (7.8-11.0 mmol/l) or A1C 5.7-6.4% Prediabetes: IFG, IGT, Increased A1C *IFG = Impaired Fasting Glucose *IGT = Impaired Glucose Tolerance ADA. I. Classification and Diagnosis. Diabetes Care 2011;34(suppl 1):S13. Table 3.

18. TESTING FOR DIABETES IN ASYMPTOMATIC PATIENTS TESTING FOR DIABETES IN ASYMPTOMATIC PATIENTS

19. Consider testing overweight adults with one or more additional risk factors: In those without risk factors, begin testing at age 45 years If tests are normal: Repeat testing at 3-year intervals (E) Recommendations: Testing for Diabetes in Asymptomatic Patients ADA. II. Testing in Asymptomatic Patients. Diabetes Care 2011;34(suppl 1):S13-S14. Physical InactivityHDL 250mg/dL 1 st degree relative with DMPolycystic Ovarian Syndrome High risk race/ethnicity (e.g., African American, Native American) A1C ≥5.7%, IGT, or IFG on previous testing Women with baby >9 lbs or GDMConditions associated with insulin resistance (e.g., severe obesity, acanthosis nigricans) HTN or treatment for HTNHistory of CVD

20. DETECTION AND DIAGNOSIS OF GESTATIONAL DIABETES MELLITUS DETECTION AND DIAGNOSIS OF GESTATIONAL DIABETES MELLITUS

21. Screen for undiagnosed type 2 diabetes at the first prenatal visit in those with risk factors, using standard diagnostic criteria (B) In pregnant women not previously known to have diabetes, screen for GDM at 24-28 weeks gestation, using a 75-g OGTT and the diagnostic cutpoints below (B) GDM diagnosis: when any of the following plasma glucose values are exceeded: – Fasting ≥92 mg/dl – 1 h ≥180 mg/dl – 2 h ≥153 mg/dl Recommendations: Detection and Diagnosis of GDM ADA. III. Detection and Diagnosis of GDM. Diabetes Care 2011;34(suppl 1):S15.

22. PREVENTION AND/OR DELAY OF TYPE 2 DIABETES

23. Refer patients with IGT (A), IFG (E), or A1C 5.7-6.4% (E) to support program – Weight loss 7% of body weight – At least 150 min/week moderate activity Consider metformin if multiple risk factors, especially if hyperglycemia (e.g., A1C>6%) progresses despite lifestyle interventions (B) In those with prediabetes, monitor for development of diabetes annually (E) Recommendations: Prevention/Delay of Type 2 Diabetes ADA. IV. Prevention/Delay of Type 2 Diabetes. Diabetes Care 2011;34(suppl 1):S16.

24. DIABETES CARE

25. Initial Medical Evaluation Medical History Review of current treatment plan (if any) Physical Examination Laboratory Examination Referrals Components of the Comprehensive Diabetes Evaluation

26. A complete medical evaluation should be performed to: – Classify the diabetes – Detect presence of diabetes complications – Review previous treatment, glycemic control in patients with established diabetes – Assist in formulating a management plan – Provide a basis for continuing care Diabetes Care: Initial Evaluation ADA. V. Diabetes Care. Diabetes Care 2011;34(suppl 1):S16.

27. Physical examination Height, weight, BMI Blood pressure determination, including orthostatic measurements when indicated Fundoscopic examination* Thyroid palpation Skin examination (for acanthosis nigricans and insulin injection sites) Components of the Comprehensive Diabetes Evaluation ADA. V. Diabetes Care. Diabetes Care 2011;34(suppl 1):S17. Table 8. *See appropriate referrals for these categories.

28. Physical examination Comprehensive foot examination – Inspection – Palpation of dorsalis pedis and posterior tibial pulses – Presence/absence of patellar and Achilles reflexes – Determination of proprioception, vibration, and monofilament sensation Components of the Comprehensive Diabetes Evaluation ADA. V. Diabetes Care. Diabetes Care 2011;34(suppl 1):S17. Table 8.

30. Laboratory evaluation A1C, if results not available within past 2–3 months If not performed/available within past year: – Fasting lipid profile, including total, LDL, HDL and triglycerides – Liver function tests – Test for urine albumin excretion with spot urine albumin/creatinine ratio – Serum creatinine and calculated GFR – TSH in type 1 diabetes, dyslipidemia, or women >50 years of age Components of the Comprehensive Diabetes Evaluation ADA. V. Diabetes Care. Diabetes Care 2011;34(suppl 1):S17. Table 8.

31. Referrals Annual dilated eye exam Family planning for women of reproductive age Registered dietitian for MNT Diabetes self-management education Dental examination Mental health professional, if needed Components of the Comprehensive Diabetes Evaluation ADA. V. Diabetes Care. Diabetes Care 2011;34(suppl 1):S17. Table 8.

32. Self-monitoring of blood glucose should be carried out 3+ times daily for patients using multiple insulin injections or insulin pump therapy (A) For patients using less frequent insulin injections, noninsulin therapy, or medical nutrition therapy alone – SMBG may be useful as a guide to success of therapy (E) – However, several recent trials have called into question clinical utility, cost-effectiveness, of routine SMBG in non– insulin-treated patients Recommendations: Glucose Monitoring ADA. V. Diabetes Care. Diabetes Care 2011;34(suppl 1):S17.

33. Perform A1C test at least twice yearly in patients meeting treatment goals (and have stable glycemic control) (E) Perform A1C test quarterly in patients whose therapy has changed or who are not meeting glycemic goals (E) Use of point-of-care testing for A1C allows for timely decisions on therapy changes, when needed (E) Recommendations: A1C ADA. V. Diabetes Care. Diabetes Care 2011;34(suppl 1):S18.

34. Mean plasma glucose A1C (%)mg/dlmmol/l 61267.0 71548.6 818310.2 921211.8 1024013.4 1126914.9 1229816.5 Correlation of A1C with Estimated Average Glucose (eAG) ADA. V. Diabetes Care. Diabetes Care 2011;34(suppl 1):S18. Table 9. These estimates are based on ADAG data of ~2,700 glucose measurements over 3 months per A1C measurement in 507 adults with type 1, type 2, and no diabetes. The correlation between A1C and average glucose was 0.92. A calculator for converting A1C results into estimated average glucose (eAG) is available at http//professional.diabetes.org/GlucoseCalculator.aspx.

35. Recommendations: Glycemic Goals in Adults ADA. V. Diabetes Care. Diabetes Care 2011;34(suppl 1):S19. Lowering A1C to below or around 7% – Shown to reduce microvascular and neuropathic complications of diabetes – If implemented soon after diagnosis of diabetes, associated with long-term reduction in macrovascular disease Therefore, a reasonable A1C goal for many non-pregnant adults is <7% (B)

36. Recommendations: Glycemic Goals in Adults ADA. V. Diabetes Care. Diabetes Care 2011;34(suppl 1):S19. Conversely, less stringent A1C goals may be appropriate for patients with: – History of severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, extensive comorbid conditions – Those with longstanding diabetes in whom the general goal is difficult to attain despite diabetes self-management education, appropriate glucose monitoring, and effective doses of multiple glucose lowering agents including insulin (C)

37. Intensive Glycemic Control and Cardiovascular Outcomes: ACCORD Gerstein HC, et al, for the Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008;358:2545-2559. ©2008 New England Journal of Medicine. Used with permission. Primary Outcome: Nonfatal MI, nonfatal stroke, CVD death HR=0.90 (0.78-1.04)

38. A1C<7.0%* Preprandial capillary plasma glucose 70–130 mg/dl* Peak postprandial capillary plasma glucose† <180 mg/dl* Glycemic Recommendations for Non-Pregnant Adults with Diabetes *Postprandial glucose measurements should be made 1–2 h after the beginning of the meal, generally peak levels in patients with diabetes. ADA. V. Diabetes Care. Diabetes Care 2011;34(suppl 1):S21. Table 10.

39. Consider bariatric surgery for adults with BMI >35 kg/m 2 and type 2 diabetes (B) After surgery, life-long lifestyle support and medical monitoring is necessary (E) Insufficient evidence to recommend surgery in patients with BMI <35 kg/m 2 outside of a research protocol (E) Recommendations: Bariatric Surgery ADA. V. Diabetes Care. Diabetes Care 2011;34(suppl 1):S26.

40. Provide an influenza vaccine annually to all diabetic patients ≥6 months of age (C) Administer pneumococcal polysaccharide vaccine to all diabetic patients ≥2 years One-time revaccination recommended for those >64 years previously immunized at 5 years ago Recommendations: Immunization ADA. V. Diabetes Care. Diabetes Care 2011;34(suppl 1):S27.

41. PREVENTION AND MANAGEMENT OF DIABETES COMPLICATIONS

42. Measure blood pressure at every diabetes visit A goal systolic blood pressure <130 mmHg is appropriate for most patients with diabetes (C) Patients with diabetes should be treated to a diastolic blood pressure <80 mmHg (B) Patients with more severe hypertension (≥140/≥90 mmHg) at diagnosis or follow-up – Should receive pharmacologic therapy in addition to lifestyle therapy (A) Recommendations: Hypertension/ Blood Pressure Control ADA. VI. Prevention, Management of Complications. Diabetes Care 2011;34(suppl 1):S27.

43. Treatment Pharmacotherapy for DM patients with hypertension – Pair with a regimen that includes either an ACE inhibitor or angiotensin II receptor blocker – If one class is not tolerated, the other should be substituted If needed to achieve blood pressure targets – Thiazide diuretic should be added to those with estimated GFR ≥30 ml x min/1.73 m 2 – Loop diuretic for those with an estimated GFR <30 ml x min/1.73 m 2 (C) Recommendations: Hypertension/ Blood Pressure Control ADA. VI. Prevention, Management of Complications. Diabetes Care 2011;34(suppl 1):S27.

44. In most adult patients – Measure fasting lipid profile at least annually In adults with low-risk lipid values (LDL 50 mg/dl, and triglycerides <150 mg/dl) – Lipid assessments may be repeated every 2 years (E) To improve lipid profile in patients with diabetes, recommend lifestyle modification (A), focusing on – Reduction of saturated fat, trans fat, cholesterol intake – Increased n-3 fatty acids, viscous fiber, plant stanols/sterols – Weight loss (if indicated) – Increased physical activity Recommendations: Dyslipidemia/Lipid Management ADA. VI. Prevention, Management of Complications. Diabetes Care 2011;34(suppl 1):S29.

45. Statin therapy should be added to lifestyle therapy, regardless of baseline lipid levels, for diabetics: – with overt CVD (A) – without CVD who are >40 years of age and have one or more other CVD risk factors (A) In individuals without overt CVD – Primary goal is an LDL <100 mg/dl (2.6 mmol/l) (A) In individuals with overt CVD – Lower LDL goal of <70 mg/dl, using a high dose of a statin is an option (B) Recommendations: Dyslipidemia/Lipid Management ADA. VI. Prevention, Management of Complications. Diabetes Care 2011;34(suppl 1):S29.

46. A1C<7.0% * Blood pressure<130/80 mmHg † Lipids: LDL cholesterol<100 mg/dl ‡ Recommendations: Glycemic, Blood Pressure, Lipid Control in Adults *More or less stringent glycemic goals may be appropriate for individual patients. Goals should be individualized based on: duration of diabetes, age/life expectancy, comorbid conditions, known CVD or advanced microvascular complications, hypoglycemia unawareness, and individual patient considerations. †Based on patient characteristics and response to therapy, higher or lower systolic blood pressure targets may be appropriate. ‡In individuals with overt CVD, a lower LDL cholesterol goal of <70 mg/dl (1.8 mmol/l), using a high dose of statin, is an option. ADA. VI. Prevention, Management of Complications. Diabetes Care 2011;34(suppl 1):S31. Table 12.

47. Consider aspirin therapy (75–162 mg/day) (C) – As primary prevention in type 1 or type 2 diabetics at increased cardiovascular risk (10-year risk >10%) – Includes most men >50 years of age or women >60 years of age who have at least one additional major risk factor Family history of CVD, HTN, Smoking, Dyslipidemia, Albuminuria Aspirin should not be recommended for CVD prevention for diabetic adults at low CVD risk, since potential bleeding likely offset potential benefits (C) 10-year CVD risk <5%: men <50 and women <60 years of age with no major additional CVD risk factors Recommendations: Antiplatelet Agents ADA. VI. Prevention, Management of Complications. Diabetes Care 2011;34(suppl 1):S31.

48. Use aspirin therapy (75–162 mg/day) – Secondary prevention strategy in those with diabetes with a history of CVD (A) For patients with CVD, documented aspirin allergy – Clopidogrel (75 mg/day) should be used (B) Combination therapy with ASA (75–162 mg/day) and clopidogrel (75 mg/day) – Reasonable for up to 1 year after acute coronary syndrome (B) Recommendations: Antiplatelet Agents ADA. VI. Prevention, Management of Complications. Diabetes Care 2011;34(suppl 1):S31.

49. Recommendations: Smoking Cessation ADA. VI. Prevention, Management of Complications. Diabetes Care 2011;34(suppl 1):S32. *If not contraindicated. Advise all patients not to smoke (A) Include smoking cessation counseling and other forms of treatment as a routine component of diabetes care (B)

50. In patients with type 1 diabetes, hypertension, and any degree of albuminuria – ACE inhibitors shown to delay progression of nephropathy (A) In type 2 diabetes, hypertension, and microalbuminuria – Both ACE inhibitors and ARBs shown to delay progression to macroalbuminuria (A) In type 2 diabetes, hypertension, macroalbuminuria, and renal insufficiency (serum creatinine >1.5 mg/dl) – ARBs shown to delay progression of nephropathy (A) Recommendations: Nephropathy Treatment ADA. VI. Prevention, Management of Complications. Diabetes Care 2011;34(suppl 1):S33.

51. DIABETES CARE IN SPECIFIC SETTINGS

52. All patients with diabetes admitted to the hospital should have: – Their diabetes clearly identified in the medical record (E) An order for blood glucose monitoring, with results available to the health care team (E) Goals for blood glucose levels: – Critically ill patients: 140-180 mg/dl (A) – More stringent goals, such as 110-140 mg/dl may be appropriate for selected patients, if achievable without significant hypoglycemia (C) – Non-critically ill patients: base goals on glycemic control, severe comorbidities (E) Recommendations: Diabetes Care in the Hospital ADA. VIII. Diabetes Care in Specific Settings. Diabetes Care. 2011;34(suppl 1):S43.

53. A hypoglycemia management protocol should be adopted and implemented by each hospital or hospital system – Establish a plan for treating hypoglycemia for each patient; document episodes of hypoglycemia in medical record and track Obtain A1C for all patients if results within previous 2-3 months unavailable (E) Patients with hyperglycemia who do not have a diagnosis of diabetes should have appropriate plans for follow-up testing and care documented at discharge (E) Recommendations: Diabetes Care in the Hospital ADA. VIII. Diabetes Care in Specific Settings. Diabetes Care. 2011;34(suppl 1):S43.

54. STRATEGIES FOR IMPROVING DIABETES CARE

55. Facilitate timely and appropriate intensification of lifestyle and/or pharmaceutical therapy of patients who have not achieved beneficial levels of blood pressure, lipid, or glucose control Research on the comprehensive chronic care (CCM) model suggests additional strategies to improve diabetes care including: – Consistent, evidence-based care guidelines – Collaborative, multidisciplinary teams – Audit and feedback of process and outcome data to providers – Alterations in reimbursement Provider and Team Behavior Change ADA. IX. Strategies for Improving Diabetes Care. Diabetes Care. 2010;33(suppl 1):S47.

56. Diabetes Treatment Algorithms

57. At diagnosis: Lifestyle + metformin Lifestyle + metformin + Basal insulin Step 2Step 1Step 3 Lifestyle + metformin + sulfonylurea Lifestyle + metformin + pioglitazone No hypoglycemia Edema/CHF Bone loss Lifestyle + metformin + GLP-1 agonist No hypoglycemia Weight loss Nausea/vomiting Lifestyle + metformin + pioglitazone + sulfonylurea Lifestyle + metformin + basal insulin TIER 1: WELL-VALIDATED THERAPIES TIER 2: LESS WELL-VALIDATED THERAPIES Lifestyle + metformin + Intensive insulin Diabetes Care, Vol. 32, 2009, 193-203.

58. A1C 6.5 – 7.5% ** Monotherapy MET + GLP-1 or DPP4 1 TZD 2 Glinide or SU 5 TZD + GLP-1 or DPP4 1 MET + Colesevelam AGI 3 2 - 3 Mos. *** Dual Therapy MET + GLP-1 or DPP4 1 + TZD 2 Glinide or SU 4,7 A1C > 9.0% No Symptoms Drug Naive Under Treatment INSULIN ± Other Agent(s) 6 Symptoms INSULIN ± Other Agent(s) 6 INSULIN ± Other Agent(s) 6 Triple Therapy AACE/ACE Algorithm for Glycemic Control Committee Cochairpersons: Helena W. Rodbard, MD, FACP, MACE Paul S. Jellinger, MD, MACE Zachary T. Bloomgarden, MD, FACE Jaime A. Davidson, MD, FACP, MACE Daniel Einhorn, MD, FACP, FACE Alan J. Garber, MD, PhD, FACE James R. Gavin III, MD, PhD George Grunberger, MD, FACP, FACE Yehuda Handelsman, MD, FACP, FACE Edward S. Horton, MD, FACE Harold Lebovitz, MD, FACE Philip Levy, MD, MACE Etie S. Moghissi, MD, FACP, FACE Stanley S. Schwartz, MD, FACE * May not be appropriate for all patients ** For patients with diabetes and A1C < 6.5%, pharmacologic Rx may be considered *** If A1C goal not achieved safely †Preferred initial agent 1DPP4 if  PPG and  FPG or GLP-1 if  PPG 2TZD if metabolic syndrome and/or nonalcoholic fatty liver disease (NAFLD) 3AGI if  PPG 4Glinide if  PPG or SU if  FPG 5Low-dose secretagogue recommended 6a)Discontinue insulin secretagogue with multidose insulin b)Can use pramlintide with prandial insulin 7Decrease secretagogue by 50% when added to GLP- 1 or DPP-4 8If A1C < 8.5%, combination Rx with agents that cause hypoglycemia should be used with caution 9If A1C > 8.5%, in patients on Dual Therapy, insulin should be considered MET + GLP-1 or DPP4 1 ± SU 7 TZD 2 GLP-1 or DPP4 1 ± TZD 2 A1C 7.6 – 9.0% Dual Therapy 8 2 - 3 Mos. *** Triple Therapy 9 INSULIN ± Other Agent(s) 6 MET + GLP-1 or DPP4 1 or TZD 2 SU or Glinide 4,5 MET + GLP-1 or DPP4 1 + TZD 2 GLP-1 or DPP4 1 + SU 7 TZD 2 MET † DPP4 1 GLP-1TZD 2 AGI 3 Available at www.aace.com/pub © AACE December 2009 Update.

59. SUMMARY

60. Diabetes Management Guidelines: 2011 Diabetes Management Guidelines: 2011 USPHS Scientific and Training Symposium – Pharmacy Category June 21 st, 2011 CDR Ryan Schupbach, Pharm.D., BCPS, CACP, NCPS Clinical Pharmacy Director, PHS Claremore Indian Hospital Clinical Assistant Professor, University of Oklahoma College of Pharmacy ryan.schupbach@ihs.gov