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2003 CDA Clinical Practice Guidelines ORAL AGENTS

Options for Diabetes. 2003 CDA Clinical Practice Guidelines ORAL AGENTS. J. Robin Conway M.D. Diabetes Clinic - Smiths Falls, ON. Kingston April 17 2004. www.diabetesclinic.ca. Worldwide rates of diabetes mellitus: predictions. 80 70 60 50 40 30 20 10 0. Prevalence (millions).

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2003 CDA Clinical Practice Guidelines ORAL AGENTS

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  1. Options for Diabetes 2003 CDA Clinical Practice Guidelines ORAL AGENTS J. Robin Conway M.D. Diabetes Clinic - Smiths Falls, ON Kingston April 17 2004 www.diabetesclinic.ca www.diabetesclinic.ca

  2. Worldwide rates of diabetes mellitus: predictions 80 70 60 50 40 30 20 10 0 Prevalence (millions) Year 1995 2000 2025 North America Europe Southeast Asia World Health Organization.1997. Canadian Diabetes Association, 1998 website. www.diabetesclinic.ca

  3. 2 Million Canadians Have Diabetes Mellitus Frequency of diagnosed and undiagnosed diabetes and IGT, by age (U.S. data - Harris) Harris. Diabetes Care 1993;16:642-52. www.diabetesclinic.ca

  4. Cardiovascular Disease Risk is Increased 2 to 4 Times Framingham study: diabetes and CAD mortalityat 20-year follow-up Haffner Am J Cardiol 1999;84:11J-4J. www.diabetesclinic.ca

  5. The burden of Diabetes • 87% of Type 2 Diabetes is managed in Primary Care • Diascan Study: 23.5% of patients in our office have diabetes • Quebec screening >2 Risk Factors, 79% tested 7% Diabetes , 13% IGT or IFG 74% No Treatment Advice Leiter et al. Diabetes Care 2000 Strychar I et al. Cdn J Diab 2003(abs) www.diabetesclinic.ca

  6. T2DM in Family Practice • 84% of patients had A1c in past year • Average A1c 7.9% (goal<7%) • 88% had BP check • 48% had lipid profiles • 28% tested for microalbuminuria • 15% had foot exams Harris S et al. Cdn Fam Phys 2003 www.diabetesclinic.ca

  7. Organization and Delivery of Care • Diabetes should be organized using a DHC (Diabetes Healthcare) team approach • People with diabetes should be offered initial and ongoing needs-based diabetes education • The role of diabetes nurse educators and other DHC team members should be enhanced in cooperation with the physician www.diabetesclinic.ca

  8. Structured care • ACLS • ATLS • Seattle Defibrillator Experience • GREACE Study www.diabetesclinic.ca

  9. Structured CareVSUsual Care • Patients received atorvastatin 10 mg/d (titrated up to 80 mg/d) to reach the NCEP LDL-C goal • Specialist care unit with a strict protocol to achieve NCEP LDL-C target • Treatment from a physician of pt’s choice • All patients had access to any necessary medications, including statins • Included lifestyle modifications (diet and exercise) as well as lipid-lowering medications Structured Care: Usual Care: Αthyros VG et al. Curr Med Res Opin. 2002;18:220-228. www.diabetesclinic.ca

  10. Reduction in Relative Risk of Primary Endpoints % Reduction P=0.034 P=0.0021 P=0.0017 P=0.0001 P=0.0032 P=0.0011 P=0.021 Αthyros VG et al. Curr Med Res Opin. 2002;18:220-228. www.diabetesclinic.ca

  11. Recommended targets for glycemic control* FPG/preprandial PG (mmol/L) 2-hour postprandial PG (mmol/L) A1C** (%) Target for most patients 7.0 4.0-7.0 5.0-10.0 6.0 4.0-6.0 5.0-8.0 Normal range (considered for patients in whom it can be achieved safely) *Treatment goals and strategies must be tailored to the patient, with consideration given to individual risk factors. †Glycemic targets for children 12 years of age and pregnant women differ from these targets. Please refer to “Other Relevant Guidelines” for further details. **An A1C of 7.0% corresponds to a laboratory value of 0.070. Where possible, Canadian laboratories should standardize their A1C values to DCCT levels (reference range: 0.040 to 0.060). However, as many laboratories continue to use a different reference range, the target A1C value should be adjusted based on the specific reference range used by the laboratory that performed the test. As a useful guide: an A1C target of 7.0% refers to a threshold that is approximately 15% above the upper limit of normal. A1C = glycosylated hemoglobin DCCT = Diabetes Control and Complications Trial FPG = fasting plasma glucose PG = plasma glucose www.diabetesclinic.ca

  12. Physical Activity and Diabetes • For people who have not previously exercised regularly and are at risk of CVD, an ECG stress test should be considered prior to starting an exercise program Testing is particularly important before, during and for many hours after exercise. www.diabetesclinic.ca

  13. Nutrition Therapy People with diabetes should: • Receive nutrition counseling by a registered dietitian • Receive individualizedmeal planning • Follow Canada’s Guidelines for Healthy Eating • People on intensive insulin should also be taught to adjust the insulin for the amount of carbohydrate consumed www.diabetesclinic.ca

  14. Drugs in Type 2 www.diabetesclinic.ca

  15. 0 3 6 9 12 15 UKPDS:Long-term Glucose Control 9 Conventional 8 HbA1c (%) Intensive 7 ULN = 6.2% 6 0 Years of treatment UKPDS Study Group, Lancet, 1998;352:837-853. www.diabetesclinic.ca

  16. UKPDS demonstrated loss of glycemic control with all agents studied 9 8 (%) Conventional Glyburide Chlorpropamide Metformin Insulin A1C 7 Upper limit of normal = 6.2% 6 0 Overweight patientsCohort, median values 0 2 4 6 8 10 Years from randomization www.diabetesclinic.ca UK Prospective Diabetes Study Group. UKPDS 34. Lancet 1998; 352:854–865.

  17. 100 Non obese Obese 100 80 80 60 60 -cell function (%) 40 40 20 20 0 0 0 1 2 3 4 5 6 7 0 1 2 3 4 5 6 7 Years from randomization Progressive Loss of -cellFunction in UKPDS -cell function (%) Conventional Sulphonylurea Metformin www.diabetesclinic.ca Mean age at baseline 53 yrs. UKPDS 16: Diabetes 1995; 44:1249–1258

  18. Insulin Natural History of Type 2 Diabetes Lifestyle Metformin/Thiazolidinediones Secretagogues www.diabetesclinic.ca Henry. Am J Med 1998;105(1A):20S-6S.

  19. Sites of Action of Currently Available Therapeutic Options LIVER ADIPOSE TISSUE MUSCLE PANCREAS • GLUCOSE PRODUCTION • Biguanides • Thiazolidinediones • PERIPHERAL • GLUCOSE UPTAKE • Thiazolidinediones • (Biguanides) • INSULIN SECRETION • Sulfonylureas • Meglitinides • Insulin INTESTINE • GLUCOSE ABSORPTION Sonnenberg, Kotchen Curr Opin Nephrol Hypertens 1998;7:551-5. Alpha-glucosidase inhibitors www.diabetesclinic.ca

  20. Combination Antihyperglycemic Therapy Addition, rather than substitution recommended Agents from other classes should be added • Diff sites of action • Diff MOA www.diabetesclinic.ca

  21. Individualized Treatment • Metformin for overweight patients • If control not achieved add another agent • If A1c >9 start with 2 agents • Consider early insulin for hyperglycemia • Bedtime intermediate insulin (NPH) www.diabetesclinic.ca

  22. Clinical assessment and initiation of nutrition and physical activity Marked hyperglycemia (A1C 9.0%) Mild to moderate hyperglycemia (A1C <9.0%) Basal and/or preprandial insulin Non-overweight (BMI 25 kg/m2) Overweight (BMI 25 kg/m2) 2 antihyperglycemic agents from different classes † • biguanide • insulin sensitizer* • insulin secretagogue • insulin • alpha-glucosidase • inhibitor Biguanide alone or in combination with 1 of: 1 or 2† antihyperglycemic agents from different classes L I F E S T Y L E • insulin sensitizer* • insulin secretagogue • insulin • alpha-glucosidase • inhibitor • biguanide • insulin sensitizer* • insulin secretagogue • insulin • alpha-glucosidase • inhibitor If not at target If not at target If not at target If not at target Add an oral antihyperglycemic agent from a different class of insulin* Add a drug from a different class or Use insulin alone or in combination with: Intensify insulin regimen or add • biguanide • insulin secretagogue • insulin sensitizer* • alpha-glucosidase inhibitor • biguanide • insulin • secretagogue** • insulin sensitizer* • alpha-glucosidase • inhibitor Timely adjustments to and/or additions of oral antihyperglycemic agents and/or insulin should be made to attain target A1C within 6 to 12 months www.diabetesclinic.ca

  23. Clinical assessment and initiation of nutrition and physical activity Marked hyperglycemia (A1C 9.0%) Mild to moderate hyperglycemia (A1C <9.0%) Basal and/or preprandial insulin Non-overweight (BMI 25 kg/m2) Overweight (BMI 25 kg/m2) 2 antihyperglycemic agents from different classes † • biguanide • insulin sensitizer* • insulin secretagogue • insulin • alpha-glucosidase • inhibitor Biguanide alone or in combination with 1 of: 1 or 2† antihyperglycemic agents from different classes L I F E S T Y L E • insulin sensitizer* • insulin secretagogue • insulin • alpha-glucosidase • inhibitor • biguanide • insulin sensitizer* • insulin secretagogue • insulin • alpha-glucosidase • inhibitor If not at target If not at target If not at target If not at target Add an oral antihyperglycemic agent from a different class of insulin* Add a drug from a different class or Use insulin alone or in combination with: Intensify insulin regimen or add • biguanide • insulin • secretagogue** • insulin sensitizer* • alpha-glucosidase • inhibitor • biguanide • insulin secretagogue • insulin sensitizer* • alpha-glucosidase inhibitor Timely adjustments to and/or additions of oral antihyperglycemic agents and/or insulin should be made to attain target A1C within 6 to 12 months www.diabetesclinic.ca

  24. Mild to moderate hyperglycemia (A1C <9.0%) Add a drug from a different class or Use insulin alone or in combination with: • biguanide • insulin secretagogue • insulin sensitizer* • alpha-glucosidase inhibitor Timely adjustments to and/or additions of oral antihyperglycemic agents and/or insulin should be made to attain target A1C within 6 to 12 months Overweight (BMI 25 kg/m2) Biguanide alone or in combination with 1 of: • insulin sensitizer* • insulin secretagogue • insulin • alpha-glucosidase inhibitor L I F E S T Y L E If not at target • When used in combination with insulin, insulin sensitizers may increase the risk of edema or CHF. The combination • of an insulin sensitizer and insulin is currently not an approved indication in Canada. www.diabetesclinic.ca

  25. Pharmacotherapy • Metformin • Insulin Sensitizer (TZD) • Insulin Secretagogue • Insulin • Alpha-glucosidase inhibitor • Anorexiant* • If not at target • Add an agent from another class www.diabetesclinic.ca

  26. Pharmacotherapy • Treat the Predominant problem • Each Drug will lower A1c 1-1.5% (Acarbose & Orlistat 0-5%) • Start with Metformin in Obese or High FBS • Combination therapy if A1c >9% • Early Insulin if decompensated • Consider TZD www.diabetesclinic.ca

  27. HbA1C in Diet-Treated PatientsEffects of Various Medications (Difference from Placebo) HbA1C (%) Repaglinide Metformin Glyburide Glitazone Acarbose www.diabetesclinic.ca FDA approved Prescribing Information for various OADs

  28. Oral Agents for Type 2 Diabetes • Combination at less than maximal doses result in more rapid improvement of blood glucose • Counsel patients about hypoglycemia prevention and treatment SMBG is recommended at least once daily Canadian Diabetes Association 2003 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Cdn J Diabetes 2003; 27 (suppl 2) www.diabetesclinic.ca

  29. Pharmacologic Management of Type 2 Diabetes • Add anti-hyperglycemic agents if: Diet & exercise therapy do not achieve targets after 2-3 month trial or newly diagnosed and has an A1C of  9 Intensify to reach targets in 6-12 months www.diabetesclinic.ca

  30. Need for Combination Therapy in UKPDS % of Patients www.diabetesclinic.ca

  31. 2.0 (%) 1.5 1c 1.0 30 GI Distress Patients (%) Reduction vs. placebo, HbA 20 0.5 10 0 0 500 1000 1500 2000 2500 Dose Dose-Response Curve Metformin Dose-response curve showing GI related effects www.diabetesclinic.ca Riddle M. Combining sulfonylureasand other oral agents. Am J of Med2000; 108(6A):15S-22S .

  32. Mechanisms To Lower Glucose • Decrease glucose production: biguanides (or thiazolidinediones) • Increase muscle glucose uptake: thiazolidinediones (or biguanides) • Stimulate insulin secretion: repaglinide or sulfonylureas • Retard carbohydrate absorption: alpha-glucosidase inhibitors • Correct insulin deficiency: insulin or insulin analogues www.diabetesclinic.ca

  33. Biguanides: mechanism of action 1. Intestine:glucose absorption 2. Muscle and adipose tissue: glucose uptake Metformin  glucose utilization Blood glucose Insulin resistance 4.Liver: hepatic glucose output Metformin ¯HGO  Insulin resistance 3. Pancreas: insulin secretion www.diabetesclinic.ca

  34. Metformin – Advantages – • Corrects a primary pathophysiologic impairment: hepatic glucose production • High initial response rate • Long record of relative safety • No weight gain or modest weight loss • Advantageous lipid profile www.diabetesclinic.ca

  35. Metformin – Disadvantages – • GI side effects on initiation • Must be held prior to, and after, radiologic studies using intravascular iodinated contrast media • Risk of lactic acidosis: caution in • impaired renal function • impaired hepatic function • pharmacologically treated CHF • alcoholism www.diabetesclinic.ca

  36. Metformin Dosage • 500-2500 mg/day, no benefit over 2000 mg/day. Divide dose into twice daily. Tablets of 500 & 850 mg. 500 mg fully covered by ODB, 850 mg (Glucophage) not covered. • Start low and titrate up slowly to avoid GI side effects www.diabetesclinic.ca

  37. Thiazolidinediones: mechanism of actions Bloodglucose Muscle and adipose tissue insulin resistance glucose uptake Liver insulin resistance  hepatic glucose production Pancreas demand for insulin secretion ß-cell insulin content www.diabetesclinic.ca

  38. Thiazolidinediones – Advantages – • Corrects a primary pathophysiologic impairment: insulin resistance • Possible once-daily dosing • Improves Lipids, Lower serum triglyceride • May be used in renal insufficiency www.diabetesclinic.ca

  39. Thiazolidinediones – Disadvantages – • Delayed action (onset: 3 wks, full effect:10-12 wks) • Variable response in monotherapy • Weight gain • Increased LDL-cholesterol (short-term) • Few long-term studies www.diabetesclinic.ca

  40. Thiazolidenedione Dosage • Pioglitazone (Actos), dosage range 15-45 mg • Tablets of 15, 30 & 45 mg • Rosiglitazone (Avandia) dose range 2-8 mg Tablets of 2, 4, 8 mg • May take 3 weeks to 3 mo to see effect • ODB Section 8 with failure of max dose Metformin & Glyburide www.diabetesclinic.ca

  41. Sulfonylureas: mechanism of action 1. Intestine:glucose absorption 2. Muscle and adipose tissue: glucose uptake Insulin resistance Blood glucose  4. Liver: hepatic glucose output 3.Pancreas: Insulin secretionSulfonylureasinsulin secretion Insulin resistance www.diabetesclinic.ca

  42. Sulfonylureas – Advantages – • Improve a primary pathophysiologic impairment: insulin secretion • Physiologic route of insulin delivery • High initial response rate • No lag period before response www.diabetesclinic.ca

  43. Sulfonylureas – Disadvantages – • Hypoglycemia • may be prolonged or severe • Weight gain • Drug interactions (especially 1st generation) • Hyponatremia (with chlorpropamide) • Cannot use if allergic to sulfa compounds www.diabetesclinic.ca

  44. Sulphonylureas Dosage • Glyburide (Diabeta)dose range 2.5-20 mg, split into twice daily. Tablets of 2.5 and 5 mg Full ODB Coverage • Gliclazide (Diamicron) dose range 40-320 mg a day, divided into 2 doses. Diamicron MR 30 mg from 1-4 tablets, once daily ODB section 8 if hypoglycemia on Glyburide • Glimepiride (Amaryl) dose 0.5-4 mg OD Tabs 0.5, 1 , 2, 4 mg. No ODB coverage www.diabetesclinic.ca

  45. MEGLITINIDES New Class of Insulin Secretagogues Physiologic Reasons • Insulin secretion must be closely coupled to fluctuations in plasma glucose with little or no lag time • Prevents early postprandial hyperglycemia • Prevents late postprandial hypoglycemia • Insulin secretion should not be stimulated when plasma glucose is low www.diabetesclinic.ca

  46. Why is there a Need for New Classes of Insulin Secretagogues? Pharmacologic Reasons • Chronic sulfonylurea treatment causes desensitization of ß-cell insulin secretion • High “secondary failure” rate with sulfonylureas www.diabetesclinic.ca

  47. Therapeutic Need, 1988 “In general, older patients have more renal failure and cardiovascular and hepatic problems, as well as a tendency to skip meals and snacks. For this reason, it is best to choose an agent with relatively short duration of action, which is less likely to cause profound hypoglycemia.” Physician’s Guide to Non-Insulin-Dependent (Type II) Diabetes. Diagnosis and Treatment (Second Edition) p.39. ADA-CEP 1984,1988. www.diabetesclinic.ca

  48. Meglitinides Efficacy Summary • Rapid response • Decline in 24-hr mean BG ( 2.2-4.4 mmol/L) within 1 week • Good clinical response • Improves glucose control D HbA1C ~ 1.6-2.1% (vs placebo) • Glycemic control • Documented HbA1C reductions sustained over 1 year • Dose response • Reductions in mean glucose seen at 0.5-4 mg ac • Synergistic • Incremental improvements when used in combination with metformin www.diabetesclinic.ca

  49. MeglitinidesDosage • Repaglinide (Gluconorm) 0.5 to 4 mg with each meal. Tablets of 0.5, 1.0 and 2 mg ODB Section 8 requires hypoglyhcemia on Glyburide • Nateglinide (Starlix) 120 mg with each meal ODB No Coverage www.diabetesclinic.ca

  50. Insulin – Disadvantages – • Hypoglycemia • Weight gain • Need for injections • Non-physiologic route of administration (peripheral) • Patient and physician non-acceptance www.diabetesclinic.ca

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