1. Canadian Diabetes Association 2003 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada Canadian Diabetes Association 2003 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada This material has been reviewed by the Canadian Diabetes Association for its medical and scientific accuracy. Presence of the Canadian Diabetes Association Partners in Progress mark does not constitute an endorsement of the products or services of GlaxoSmithKline Inc. Getting to Goal in Type 2 Diabetes Getting to Goal in Type 2 Diabetes

2. 1 Harris S, et al, The Diabetes in Canada Evaluation (DICE) Study, ADA 2003, 2162-PO 2 Harris MI, et al. Diabetes Care 1999; 22:403–408. Percentage of subjects 0 20 40 60 80 100 <7% > 7% A1C (%) US (1988-1994) 2 Many patients have inadequate glycemic control 38% 62% Percentage of subjects 0 20 40 60 80 100 < 7%  7% A1C (%) CAN (2003) 1 50%

3. Years T2DM Proportion of patients with A1C > 7.0 increases with duration of type 2 diabetes Proportion of patients with A1C > 7.0 increases with duration of type 2 diabetes <=2 3-5 6-9 10-14 15+ 31% 42% 53% 67% 62% Harris,S et al. CDA 2003; Type 2 Diabetes and Associated Complications in Primary Care in Canada: The Impact of Duration of Disease on Morbidity Load.

4. Proportion of patients with hypertension increases with duration of type 2 diabetes Years T2DM <=2 3-5 6-9 10-14 15+ 53% 57% 64% 71% 72% Harris,S et al. CDA 2003; Type 2 Diabetes and Associated Complications in Primary Care in Canada: The Impact of Duration of Disease on Morbidity Load.

5. Proportion of patients with dyslipidemia increases with duration of type 2 diabetes Years T2DM <=2 3-5 6-9 10-14 15+ 55% 57% 58% 59% 66% Harris,S et al. CDA 2003; Type 2 Diabetes and Associated Complications in Primary Care in Canada: The Impact of Duration of Disease on Morbidity Load.

6. Proportion of patients with cardiovascular disease increases with duration of type 2 diabetes Years T2DM <=2 3-5 6-9 10-14 15+ 15% 21% 24% 29% 48% Harris,S et al. CDA 2003; Type 2 Diabetes and Associated Complications in Primary Care in Canada: The Impact of Duration of Disease on Morbidity Load.

7. Proportion of patients with microvascular disease increases with duration of type 2 diabetes Years T2DM <=2 3-5 6-9 10-14 15+ 21% 32% 42% 44% 62% Harris,S et al. CDA 2003; Type 2 Diabetes and Associated Complications in Primary Care in Canada: The Impact of Duration of Disease on Morbidity Load.

8. The evolution of management guidelines  Studies including UKPDS have highlighted the importance of glycemic control in reducing complications  New guidelines include tighter targets for glycemic control  Guidelines recognize importance of treating all aspects of the condition  Current guidelines therefore include targets for glycemic control lipid levels blood pressure  Studies including UKPDS have highlighted the importance of glycemic control in reducing complications  New guidelines include tighter targets for glycemic control  Guidelines recognize importance of treating all aspects of the condition  Current guidelines therefore include targets for glycemic control lipid levels blood pressure

9. Adapted from Stratton IM, et al. UKPDS 35. BMJ 2000; 321:405–412. UKPDS: decreased risk of diabetes-related complications associated with a 1% decrease in A1C Percentage decrease in relative risk corresponding to a 1% decrease in HbA1C ** Any diabetes- related endpoint 21% ** Diabetes- related death 21%** All cause mortality 14% * Stroke 12% ** Peripheral vascular disease † 43% ** Myocardial infarction 14% ** Micro- vascular disease 37% ** Cataract extraction 19% Observational analysis from UKPDS study data † Lower extremity amputation or fatal peripheral vascular disease *P = 0.035; **P < 0.0001

10. Stratton IM, et al. UKPDS 35. BMJ 2000; 321:405–412. UKPDS: the benefits of improved glycemic control  Improved glycemic control significantly reduces risk of diabetes-related complications  UKPDS results indicated that a 1% reduction in A1C would reduce the risk of microvascular complications by 37%, but have less effect (16%) on macrovascular complications  Further improvement in sustained glycemic control and reduction in the burden of cardiovascular disease are needed  Improved glycemic control significantly reduces risk of diabetes-related complications  UKPDS results indicated that a 1% reduction in A1C would reduce the risk of microvascular complications by 37%, but have less effect (16%) on macrovascular complications  Further improvement in sustained glycemic control and reduction in the burden of cardiovascular disease are needed

11. 0 6 7 8 9 246810 A1C (%) Years from randomization Upper limit of of normal = 6.2% Conventional Glyburide Chlorpropamide Metformin Insulin 0 UKPDS demonstrated loss of glycemic control with all agents studied UK Prospective Diabetes Study Group. UKPDS 34. Lancet 1998; 352:854–865. Overweight patients Cohort, median values

12. Turner RC, et al. UKPDS 49. JAMA 1999; 281:2005–2012. 100 Years from randomization 369 0 20 40 60 80 369 369369 Diet Insulin MetforminSulfonylurea Overweight patients Proportion of patients (%) 50% Proportion of patients with A1C < 7.0% on monotherapy at 3, 6 and 9 years Error bars = 95% CI

13. The UKPDS demonstrated progressive decline of  -cell function over time 100 80 60 40 P < 0.0001 HOMA model, diet-treated n = 376 Time from diagnosis (years) 100  -cell function (%) 80 60 40 20 0 Start of treatment Adapted from Holman RR. Diabetes Res Clin Pract 1998; 40 (Suppl.):S21–S25. –10–9–8–7–6–5–4–3–2–1123456

14. Canadian Diabetes Association 2003 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada Canadian Diabetes Association 2003 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada Glycemic Targets

15. CMAJ 1998; 159 (8 Suppl):S1-29 1998 CDA Treatment Targets Level Ideal (normal nondiabetic) Optimal * (target goal) Suboptimal † (action may be required) Inadequate ‡ (action required) GlycatedHb (% of upper limit) e.g., HbA1c assay <100 (.04-.06) <115 (<0.07) 116-140 (.07-8.4) >140 (>0.084) Fasting or premeal glucose level (mmol/L) 3.8-6.14-77.1-10>10 Glucose level 1-2 h after meal (mmol/L) 4.4-75.0-1111.1-14>14 Hb = hemoglobin *These levels are likely related to minimal long-term complications but may be impossible to achieve in most paients with type 1 diabetes with current therapies † Attainable in the majority of people with diabetes but may not be adequate to prevent compications ‡ These levels are related to a markedly increased risk of long-term complications, requiring a reassessment and readjustment of therapy

16. A1C** (%) FPG/preprandial PG (mmol/L) 2-hour postprandial PG (mmol/L) Target for most patients  7.0 4.0-7.05.0-10.0 Normal range (considered for patients in whom it can be achieved safely)  6.0 4.0-6.05.0-8.0 A1C = glycosylated hemoglobin DCCT = Diabetes Control and Complications Trial FPG = fasting plasma glucose PG = plasma glucose 2003 CDA Recommended Targets for Glycemic Control

17. Components of Glycemic Control 2 h. Postprandial Plasma Glucose 5-10 mmol/L 5-8 mmol/L* 2 h. Postprandial Plasma Glucose 5-10 mmol/L 5-8 mmol/L* Fasting/Preprandial Plasma Glucose 4-7 mmol/L 4-6 mmol/L* Fasting/Preprandial Plasma Glucose 4-7 mmol/L 4-6 mmol/L* A1C <7%, <6%* A1C <7%, <6%* *If can be achieved safely

18. Canadian Diabetes Association 2003 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada Canadian Diabetes Association 2003 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada Management of Hyperglycemia in Type 2 Diabetes Management of Hyperglycemia in Type 2 Diabetes

19. Lifestyle Intervention  The first step in treating type 2 diabetes  Nutrition therapy and exercise can improve glycemic control  Success of lifestyle intervention related to:  patient’s initial fasting plasma glucose level  amount of weight loss achieved by patient  Only a minority of patients are able to attain treatment targets using lifestyle intervention alone.  The first step in treating type 2 diabetes  Nutrition therapy and exercise can improve glycemic control  Success of lifestyle intervention related to:  patient’s initial fasting plasma glucose level  amount of weight loss achieved by patient  Only a minority of patients are able to attain treatment targets using lifestyle intervention alone.

20. UKPDS 7: Response of FPG to Diet Therapy in Newly Diagnosed Patients  N= 3044, newly diagnosed patients  FPG at diagnosis 12.1+/- 3.7 mmol/L  Diet counseling  Patients with FPG 10-12 mmol/L needed reduction of 28% ideal body weight; to attain FPG <6 mmol/L  16% achieved FPG <6 after 3 months:  in the group presenting with FPGs of 6-8 mmol/L 50% met this target  in the group presenting with FPGs of 16-22 mmol/L only 10% were successful  N= 3044, newly diagnosed patients  FPG at diagnosis 12.1+/- 3.7 mmol/L  Diet counseling  Patients with FPG 10-12 mmol/L needed reduction of 28% ideal body weight; to attain FPG <6 mmol/L  16% achieved FPG <6 after 3 months:  in the group presenting with FPGs of 6-8 mmol/L 50% met this target  in the group presenting with FPGs of 16-22 mmol/L only 10% were successful Metabolism, 1990; 39(3): 905-912

21. Antihyperglycemic Agents

22. Glucose (G) Insulin I I I I I I I I G G G G G G G G I G G G Adipose tissue Liver Pancreas Muscle Gut I G Carbohydrate Stomach  -glucosidase inhibitors Insulin secretagogues Biguanides Thiazolidinediones Primary Sites of Action of Oral Antihyperglycemic Agents Adapted from Kobayashi M. Diabetes Obes Metab 1999; 1 (Suppl. 1):S32–S40. Nattrass M & Bailey CJ. Baillieres Best Pract Res Clin Endocrinol Metab 1999; 13:309–329.

23. Key Recommendations Antihyperglycemic agents should be initiated if glycemic targets not met after 2-3 months of lifestyle intervention Antihyperglycemic agents should be started concomitantly with lifestyle if A1C levels are greater than 9% The lag period before adding other agent(s) should be kept to a minimum to achieve glycemic targets within 6-12 months Unless contraindicated, metformin should be used first line; other agents should be considered in the order they appear in the treatment algorithm Insulin therapy should be initiated if targets cannot be achieved with lifestyle changes and oral therapy Antihyperglycemic agents should be initiated if glycemic targets not met after 2-3 months of lifestyle intervention Antihyperglycemic agents should be started concomitantly with lifestyle if A1C levels are greater than 9% The lag period before adding other agent(s) should be kept to a minimum to achieve glycemic targets within 6-12 months Unless contraindicated, metformin should be used first line; other agents should be considered in the order they appear in the treatment algorithm Insulin therapy should be initiated if targets cannot be achieved with lifestyle changes and oral therapy

24. Diet/ exercise Oral monotherapy Oral combination Insulin Early aggressive combination therapy as required Stepwise treatment Oral +/- insulin New Treatment Options for Type 2 Diabetes

25. Management of Hyperglycemia in Type 2 Diabetes Clinical assessment and initiation of nutrition and physical activity Overweight (BMI  25 kg/m 2 ) Non-overweight (BMI  25 kg/m 2 ) Mild to moderate hyperglycemia (A1C <9.0%) Marked hyperglycemia (A1C  9.0%)

26. 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 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. Overweight (BMI  25 kg/m 2 ) Mild to moderate hyperglycemia (A1C <9.0%) 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

27. Dose-Effect Relationship Riddle M. Combining sulfonylureas and other oral agents.Am J of Med. 2000; 108(6A):15S-22S. Graph of theoretical dose-effect relationship for many drugs, showing that half-maximal dosages yield far more than 50% of the therapeutic effects and that side effects can increase as the dosage nears maximal levels. Maximal Half-maximal Maximal Therapeutic effect Side effect Effect Dose

28. Dose-Response Curve Riddle M. Combining sulfonylureas and other oral agents.Am J of Med. 2000; 108(6A):15S-22S. Dose-response curve showing GI related effects 30 20 10 05001000150020002500 0 0.5 1.0 1.5 2.0 Dose GI Distress Patients (%) Reduction vs. placebo, HbA 1c (%)

29. Non-overweight (BMI  25 kg/m 2 ) Mild to moderate hyperglycemia (A1C <9.0%) 1 or 2 † antihyperglycemic agents from different classes biguanide insulin sensitizer* insulin secretagogue insulin 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 Add a drug from a different class or Use insulin alone or in combination with: biguanide insulin secretagogue insulin sensitizer* alpha-glucosidase inhibitor 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. † May be given as a combined formulation: rosiglitazone and metformin (Avandamet TM ) L I F E S T Y L E

30. Marked hyperglycemia (A1C  9.0%) 2 antihyperglycemic agents from different classes † biguanide insulin sensitizer* insulin secretagogue insulin alpha-glucosidase inhibitor Add an oral antihyperglycemic agent from a different class or insulin* 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 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. † May be given as a combined formulation: rosiglitazone and metformin (Avandamet TM ) L I F E S T Y L E

31. Marked hyperglycemia (A1C  9.0%) Basal and/or preprandial insulin * 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. * * If using preprandial insulin, do not add an insulin secretagogue. L I F E S T Y L E Intensify insulin regimen or add 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 If not at target

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

33. A1C <7% (< 6% if can be achieved safely) Aim to achieve targets within 6-12 months Start with combination therapy or insulin for patients with A1C > 9% Consider insulin at any stage of treatment Vascular protection to further reduce cardiovascular risk A1C <7% (< 6% if can be achieved safely) Aim to achieve targets within 6-12 months Start with combination therapy or insulin for patients with A1C > 9% Consider insulin at any stage of treatment Vascular protection to further reduce cardiovascular risk Key Changes

34. Canadian Diabetes Association 2003 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada Canadian Diabetes Association 2003 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada This material has been reviewed by the Canadian Diabetes Association for its medical and scientific accuracy. Presence of the Canadian Diabetes Association Partners in Progress mark does not constitute an endorsement of the products or services of GlaxoSmithKline Inc. Getting to Goal in Type 2 Diabetes Getting to Goal in Type 2 Diabetes

35. Supplementary Slides: Key Recommendations Supplementary Slides: Key Recommendations

36. In people with type 2 diabetes, if glycemic targets are not achieved using lifestyle management within 2 to 3 months, antihyperglycemic agents should be initiated [Grade A, Level 1A ]. In the presence of marked hyperglycemia (A1C > 9.0%), antihyperglycemic agents should be initiated concomitant with lifestyle counselling [Grade D, Consensus]. In people with type 2 diabetes, if glycemic targets are not achieved using lifestyle management within 2 to 3 months, antihyperglycemic agents should be initiated [Grade A, Level 1A ]. In the presence of marked hyperglycemia (A1C > 9.0%), antihyperglycemic agents should be initiated concomitant with lifestyle counselling [Grade D, Consensus]. Recommendation 1

37. If glycemic targets are not attained when a single antihyperglycemic agent is used initially, an antihyperglycemic agent or agents from other classes should be added. The lag period before adding other agent(s) should be kept to a minimum, taking into account the pharmacokinetics of the different agents. Timely adjustments to and/or additions of antihyperglycemic agents should be made in order to attain target A1C within 6 to 12 months [Grade D, Consensus]. Recommendation 2

38. Recommendation 3 This choice of antihyperglycemic agent(s) should take into account the individual and the following factors: Unless contraindicated, a biguanide (metformin) should be the primary drug used in overweight patients [Grade A, Level 1A]; and Other classes of antihyperglycemic agents may be used either alone or in combination to attain glycemic targets, with consideration given to the information in Table 1 and Figure 1 [Grade D, Consensus for the order of antihyperglycemic agents listed in Figure 1]. This choice of antihyperglycemic agent(s) should take into account the individual and the following factors: Unless contraindicated, a biguanide (metformin) should be the primary drug used in overweight patients [Grade A, Level 1A]; and Other classes of antihyperglycemic agents may be used either alone or in combination to attain glycemic targets, with consideration given to the information in Table 1 and Figure 1 [Grade D, Consensus for the order of antihyperglycemic agents listed in Figure 1].

39. Recommendation 4 In people with type 2 diabetes, if individual treatment goals have not been reached with a regimen of nutrition therapy, physical activity and sulfonylurea [Grade A, Level 1A], sulfonylurea plus metformin [Grade A, Level 1A] or other oral antihyperglycemic agents [Grade D, Consensus], insulin therapy should be initiated to improve glycemic control.

40. Recommendation 5 Combining insulin and the following oral antihyperglycemic agents (listed in alphabetical order) has been shown to be effective in people with type 2 diabetes: alpha-glucosidase inhibitors (acarbose) [Grade A, Level 1A] biguanide (metformin) [Grade A, Level 1A] Insulin secretagogues (sulfonylureas) [Grade A, Level 1A] Insulin sensitizers (thiazolidinediones) [Grade A, Level 1A] (The combination of an insulin sensitizer plus insulin is currently not an approved indication in Canada.) Combining insulin and the following oral antihyperglycemic agents (listed in alphabetical order) has been shown to be effective in people with type 2 diabetes: alpha-glucosidase inhibitors (acarbose) [Grade A, Level 1A] biguanide (metformin) [Grade A, Level 1A] Insulin secretagogues (sulfonylureas) [Grade A, Level 1A] Insulin sensitizers (thiazolidinediones) [Grade A, Level 1A] (The combination of an insulin sensitizer plus insulin is currently not an approved indication in Canada.)

41. Recommendation 6 Insulin may be used as initial therapy in type 2 diabetes [Grade A, Level 1A], especially in cases of marked hyperglycemia (A1C > 9.0%) [Grade D, Consensus].

42. Recommendation 7 To safely achieve optimal postprandial glycemic control, mealtime insulin lispro or insulin aspart is preferred over regular insulin [Grade B, Level 2]. To safely achieve optimal postprandial glycemic control, mealtime insulin lispro or insulin aspart is preferred over regular insulin [Grade B, Level 2].

43. Recommendation 8 When insulin given at night is added to oral antihyperglycemic agents, insulin glargine may be preferred over NPH to reduce overnight hypoglycemia [Grade B, Level 2] and weight gain [Grade B, Level 2 ]. When insulin given at night is added to oral antihyperglycemic agents, insulin glargine may be preferred over NPH to reduce overnight hypoglycemia [Grade B, Level 2] and weight gain [Grade B, Level 2 ].

44. Recommendation 9 All individuals with type 2 diabetes currently using or starting therapy with insulin or insulin secretagogues should be counselled about the recognition and prevention of drug-induced hypoglycemia [Grade D, Consensus]. All individuals with type 2 diabetes currently using or starting therapy with insulin or insulin secretagogues should be counselled about the recognition and prevention of drug-induced hypoglycemia [Grade D, Consensus].

45. Supplementary Slides: Alternate Animation for Treatment Algorithm Supplementary Slides: Alternate Animation for Treatment Algorithm

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

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

48. Add a drug from a different class or Use insulin alone or in combination with: biguanide insulin secretagogue insulin sensitizer* alpha-glucosidase inhibitor Overweight (BMI  25 kg/m 2 ) Mild to moderate hyperglycemia (A1C <9.0%) 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 Biguanide alone or in combination with 1 of: insulin sensitizer* insulin secretagogue insulin alpha-glucosidase inhibitor 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. L I F E S T Y L E

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

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

51. Add a drug from a different class or Use insulin alone or in combination with: biguanide insulin secretagogue insulin sensitizer* alpha-glucosidase inhibitor Non-overweight (BMI  25 kg/m 2 ) Mild to moderate hyperglycemia (A1C <9.0%) 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 1 or 2 † antihyperglycemic agents from different classes biguanide insulin sensitizer* insulin secretagogue insulin alpha-glucosidase inhibitor 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. † May be given as a combined formulation: rosiglitazone and metformin (Avandamet TM ) L I F E S T Y L E

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

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

54. Add an oral antihyperglycemic agent from a different class or insulin* Marked hyperglycemia (A1C  9.0%) 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 2 antihyperglycemic agents from different classes † biguanide insulin sensitizer* insulin secretagogue insulin alpha-glucosidase inhibitor 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. † May be given as a combined formulation: rosiglitazone and metformin (Avandamet TM ) L I F E S T Y L E

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

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

57. Marked hyperglycemia (A1C  9.0%) 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 Basal and/or preprandial insulin If not at target Intensify insulin regimen or add biguanide insulin secretagogue** insulin sensitizer* alpha-glucosidase inhibitor * 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. * * If using preprandial insulin, do not add an insulin secretagogue. L I F E S T Y L E