1. TYPE 2 DIABETES MELLITUS REVIEW OF Clinical Practice Guidelines WEEK 2: Therapy UHN AIMGP CLINIC SEMINAR SERIES 2007 Updates Dr. K. Tzanetos WEEK 2: Therapy UHN AIMGP CLINIC SEMINAR SERIES 2007 Updates Dr. K. Tzanetos

2. T2DM: References Canadian Diabetes Association (CDA): 2003 Clinical Practice Guidelines for the Prevention and Management of diabetes in Canada. Can J Diabetes 2003; 27 (Suppl 2). Can J Diabetes 2003; 27 (Suppl 2). http://www.diabetes.ca/cpg2003 http://www.diabetes.ca/cpg2003 American Diabetes Association (ADA): Clinical Practice Recommendations 2006. Diabetes Care 2006; 29 (Suppl 1). Diabetes Care 2006; 29 (Suppl 1). Canadian Diabetes Association (CDA): 2003 Clinical Practice Guidelines for the Prevention and Management of diabetes in Canada. Can J Diabetes 2003; 27 (Suppl 2). Can J Diabetes 2003; 27 (Suppl 2). http://www.diabetes.ca/cpg2003 http://www.diabetes.ca/cpg2003 American Diabetes Association (ADA): Clinical Practice Recommendations 2006. Diabetes Care 2006; 29 (Suppl 1). Diabetes Care 2006; 29 (Suppl 1).

3. T2DM: Therapy WEEK 2 OBJECTIVES: Develop familiarity with the indications, goals and therapy progression of treatment: 1) Non-pharmacologic therapy 2) Pharmacologic therapy for glycemia - Oral agents: monotherapy and combination - Oral agents: monotherapy and combination - Insulin: monotherapy and in combination with OHAs - Insulin: monotherapy and in combination with OHAs 3) Therapy for nephropathy (if time permits) 4) Therapy for neuropathy (if time permits) Note: HTN, CAD, and Dyslipidemia will be discussed in future seminars… WEEK 2 OBJECTIVES: Develop familiarity with the indications, goals and therapy progression of treatment: 1) Non-pharmacologic therapy 2) Pharmacologic therapy for glycemia - Oral agents: monotherapy and combination - Oral agents: monotherapy and combination - Insulin: monotherapy and in combination with OHAs - Insulin: monotherapy and in combination with OHAs 3) Therapy for nephropathy (if time permits) 4) Therapy for neuropathy (if time permits) Note: HTN, CAD, and Dyslipidemia will be discussed in future seminars…

4. T2DM: Therapy – Take a minute to discuss… CASE: Recall Mrs. X, our 58 yo woman with recently diagnosed Type 2 DM Recall Mrs. X, our 58 yo woman with recently diagnosed Type 2 DM She has completed her diabetes education course and has learned how to self-monitor her blood glucose She has completed her diabetes education course and has learned how to self-monitor her blood glucose She has returned to clinic in follow-up… She has returned to clinic in follow-up… ‘You explain that overall metabolic control (of both glycemia and lipids) will be important to her future health’ How can glycemic control be measured, and what are the CDA recommended target values for each test? How can glycemic control be measured, and what are the CDA recommended target values for each test?CASE: Recall Mrs. X, our 58 yo woman with recently diagnosed Type 2 DM Recall Mrs. X, our 58 yo woman with recently diagnosed Type 2 DM She has completed her diabetes education course and has learned how to self-monitor her blood glucose She has completed her diabetes education course and has learned how to self-monitor her blood glucose She has returned to clinic in follow-up… She has returned to clinic in follow-up… ‘You explain that overall metabolic control (of both glycemia and lipids) will be important to her future health’ How can glycemic control be measured, and what are the CDA recommended target values for each test? How can glycemic control be measured, and what are the CDA recommended target values for each test?

5. RCTs have provided compelling evidence that long-term complications of DM can be reduced with tight glycemic control (DM1: DCCT, DM2: UKPDS) RCTs have provided compelling evidence that long-term complications of DM can be reduced with tight glycemic control (DM1: DCCT, DM2: UKPDS) HbA1c levels >7% are associated with markedly increased risk of both micro and macrovascular complications (regardless of underlying therapy) HbA1c levels >7% are associated with markedly increased risk of both micro and macrovascular complications (regardless of underlying therapy) RCTs have provided compelling evidence that long-term complications of DM can be reduced with tight glycemic control (DM1: DCCT, DM2: UKPDS) RCTs have provided compelling evidence that long-term complications of DM can be reduced with tight glycemic control (DM1: DCCT, DM2: UKPDS) HbA1c levels >7% are associated with markedly increased risk of both micro and macrovascular complications (regardless of underlying therapy) HbA1c levels >7% are associated with markedly increased risk of both micro and macrovascular complications (regardless of underlying therapy) T2DM: Therapy

6. TYPE 2 DIABETES MELLITUS: Therapy Table 1. Targets for Glucose control in DM (CDA) Ideal = Normal, nondiabetic Optimal = Minimal long-term complications, difficult to achieve Suboptimal = May not prevent complications, but is attainable for the majority of patients Inadequate = Markedly ­ risk of long-term complications Table 1. Targets for Glucose control in DM (CDA) Ideal = Normal, nondiabetic Optimal = Minimal long-term complications, difficult to achieve Suboptimal = May not prevent complications, but is attainable for the majority of patients Inadequate = Markedly ­ risk of long-term complications IdealOptimalSub- optimal Inadequate HbA1C (%)< 0.06<0.070.07-0.084>0.084 FPG or pre-P (mmol/L) 4-64-77.1-10>10 2-hr post-P (mmol/L) 5-85-1010.1-14>14

7. T2DM: Therapy CASE: Mrs. X. has an HbA1c of 0.95!! Mrs. X. has an HbA1c of 0.95!! Here are the BG levels from her record book for the last few days: Here are the BG levels from her record book for the last few days:CASE: Mrs. X. has an HbA1c of 0.95!! Mrs. X. has an HbA1c of 0.95!! Here are the BG levels from her record book for the last few days: Here are the BG levels from her record book for the last few days: FBGLunchDinner M101416 T9.51415.2 W121218

8. T2DM: Therapy – Take a minute to discuss… Given the CDA goals, how would you characterize her glycemic control ? Given the CDA goals, how would you characterize her glycemic control ? How would you begin to lower her blood glucose levels ? How would you begin to lower her blood glucose levels ? Given the CDA goals, how would you characterize her glycemic control ? Given the CDA goals, how would you characterize her glycemic control ? How would you begin to lower her blood glucose levels ? How would you begin to lower her blood glucose levels ?

9. T2DM: Therapy Mrs. X.’s glycemic control is INADEQUATE according to the CDA guidelines for both HbA1c and FBG (or post-prandial) Mrs. X.’s glycemic control is INADEQUATE according to the CDA guidelines for both HbA1c and FBG (or post-prandial) The first step in improved glycemic control is to initiate non-pharmacologic therapy The first step in improved glycemic control is to initiate non-pharmacologic therapy Mrs. X.’s glycemic control is INADEQUATE according to the CDA guidelines for both HbA1c and FBG (or post-prandial) Mrs. X.’s glycemic control is INADEQUATE according to the CDA guidelines for both HbA1c and FBG (or post-prandial) The first step in improved glycemic control is to initiate non-pharmacologic therapy The first step in improved glycemic control is to initiate non-pharmacologic therapy

10. T2DM: Therapy – Take a minute to discuss… What are the major components of non- pharmacologic therapy? What are the major components of non- pharmacologic therapy? Diet Weight loss Exercise

11. T2DM: Nutritional approaches (CDA) Individualized counseling by registered dietician Individualized counseling by registered dietician Weight reduction to target (0.25-1 kg/week) Weight reduction to target (0.25-1 kg/week) for all patients with BMI > 25 for all patients with BMI > 25 loss of 5% body weight can have significant health benefits loss of 5% body weight can have significant health benefits Individualized counseling by registered dietician Individualized counseling by registered dietician Weight reduction to target (0.25-1 kg/week) Weight reduction to target (0.25-1 kg/week) for all patients with BMI > 25 for all patients with BMI > 25 loss of 5% body weight can have significant health benefits loss of 5% body weight can have significant health benefits

12. Balanced diet from the 4 food groups with: Balanced diet from the 4 food groups with: fat <30% of caloric intake (saturated fats <10%) fat <30% of caloric intake (saturated fats <10%) carbohydrates 50-55% carbohydrates 50-55% protein 15-20% protein 15-20% sucrose containing foods up to a maximum of 10% of calories (< 10 g/d of sugar alcohols) sucrose containing foods up to a maximum of 10% of calories (< 10 g/d of sugar alcohols) Balanced diet from the 4 food groups with: Balanced diet from the 4 food groups with: fat <30% of caloric intake (saturated fats <10%) fat <30% of caloric intake (saturated fats <10%) carbohydrates 50-55% carbohydrates 50-55% protein 15-20% protein 15-20% sucrose containing foods up to a maximum of 10% of calories (< 10 g/d of sugar alcohols) sucrose containing foods up to a maximum of 10% of calories (< 10 g/d of sugar alcohols) T2DM: Nutritional approaches (CDA)

13. T2DM: Physical activity and Diabetes (CDA) Accumulate at least 150 minutes (up to > 4 hrs) of moderate intensity aerobic exercise each week (spread over at least 3 non-consecutive days) Accumulate at least 150 minutes (up to > 4 hrs) of moderate intensity aerobic exercise each week (spread over at least 3 non-consecutive days) Encourage to perform resistance exercise training 3x/wk Encourage to perform resistance exercise training 3x/wk Accumulate at least 150 minutes (up to > 4 hrs) of moderate intensity aerobic exercise each week (spread over at least 3 non-consecutive days) Accumulate at least 150 minutes (up to > 4 hrs) of moderate intensity aerobic exercise each week (spread over at least 3 non-consecutive days) Encourage to perform resistance exercise training 3x/wk Encourage to perform resistance exercise training 3x/wk

14. T2DM: Physical Activity And Exercise (CDA) Consider the need for a pre-emptive EST in patients at high risk of occlusive vascular disease, neuropathy or microvascular disease (or previously sedentary) Consider the need for a pre-emptive EST in patients at high risk of occlusive vascular disease, neuropathy or microvascular disease (or previously sedentary) NB: Exercise may induce short-term hypoglycemia NB: Exercise may induce short-term hypoglycemia Emphasize: Emphasize: Proper foot care Proper foot care Avoidance of exercise at times of poor metabolic control or extreme heat or cold Avoidance of exercise at times of poor metabolic control or extreme heat or cold The need to take rapid-acting CHO if pre-exercise BG <5 The need to take rapid-acting CHO if pre-exercise BG <5 Insulin injections at a site remote from the exercising limb Insulin injections at a site remote from the exercising limb Consider the need for a pre-emptive EST in patients at high risk of occlusive vascular disease, neuropathy or microvascular disease (or previously sedentary) Consider the need for a pre-emptive EST in patients at high risk of occlusive vascular disease, neuropathy or microvascular disease (or previously sedentary) NB: Exercise may induce short-term hypoglycemia NB: Exercise may induce short-term hypoglycemia Emphasize: Emphasize: Proper foot care Proper foot care Avoidance of exercise at times of poor metabolic control or extreme heat or cold Avoidance of exercise at times of poor metabolic control or extreme heat or cold The need to take rapid-acting CHO if pre-exercise BG <5 The need to take rapid-acting CHO if pre-exercise BG <5 Insulin injections at a site remote from the exercising limb Insulin injections at a site remote from the exercising limb

15. T2DM: Therapy CASE: Mrs. X. has followed your advice Mrs. X. has followed your advice She has improved her diet and now walks 1.5 kms/d (She has lost 4 kg) She has improved her diet and now walks 1.5 kms/d (She has lost 4 kg) However, her SMBG levels have not markedly improved and she has developed symptoms of sensory peripheral neuropathy However, her SMBG levels have not markedly improved and she has developed symptoms of sensory peripheral neuropathy Her electrolytes, creatinine and liver function tests and enzymes are normal Her electrolytes, creatinine and liver function tests and enzymes are normalCASE: Mrs. X. has followed your advice Mrs. X. has followed your advice She has improved her diet and now walks 1.5 kms/d (She has lost 4 kg) She has improved her diet and now walks 1.5 kms/d (She has lost 4 kg) However, her SMBG levels have not markedly improved and she has developed symptoms of sensory peripheral neuropathy However, her SMBG levels have not markedly improved and she has developed symptoms of sensory peripheral neuropathy Her electrolytes, creatinine and liver function tests and enzymes are normal Her electrolytes, creatinine and liver function tests and enzymes are normal

16. T2DM: Therapy – Take a minute to discuss… How can we further improve Mrs. X.’s glycemic control ? How can we further improve Mrs. X.’s glycemic control ? What agents are available and how would you choose one from among them? What agents are available and how would you choose one from among them? How can we further improve Mrs. X.’s glycemic control ? How can we further improve Mrs. X.’s glycemic control ? What agents are available and how would you choose one from among them? What agents are available and how would you choose one from among them?

17. T2DM: Therapy Oral Hypoglycemic Agents (OHAs) are the next step in management Oral Hypoglycemic Agents (OHAs) are the next step in management The 5 main classes of OHAs are: The 5 main classes of OHAs are: Alpha-glucosidase inhibitors (acarbose) Alpha-glucosidase inhibitors (acarbose) Biguanides (metformin) Biguanides (metformin) Sulfonylureas (glyburide) Sulfonylureas (glyburide) Meglitinides (repaglinide) Meglitinides (repaglinide) Thiazolidinediones (rosiglitazone) Thiazolidinediones (rosiglitazone) Each has a unique mechanism of action Each has a unique mechanism of action Oral Hypoglycemic Agents (OHAs) are the next step in management Oral Hypoglycemic Agents (OHAs) are the next step in management The 5 main classes of OHAs are: The 5 main classes of OHAs are: Alpha-glucosidase inhibitors (acarbose) Alpha-glucosidase inhibitors (acarbose) Biguanides (metformin) Biguanides (metformin) Sulfonylureas (glyburide) Sulfonylureas (glyburide) Meglitinides (repaglinide) Meglitinides (repaglinide) Thiazolidinediones (rosiglitazone) Thiazolidinediones (rosiglitazone) Each has a unique mechanism of action Each has a unique mechanism of action

18. T2DM: Therapy Secretagogues: Secretagogues: Sulfonylureas and meglitinides stimulate pancreatic insulin release Sulfonylureas and meglitinides stimulate pancreatic insulin release Insulin Sensitizers: Insulin Sensitizers: Biguanides decrease hepatic glucose production and enhance insulin-mediated glucose uptake Biguanides decrease hepatic glucose production and enhance insulin-mediated glucose uptake Thiazolidinediones decrease insulin resistance Thiazolidinediones decrease insulin resistance Absorption Inhibitors: Absorption Inhibitors: Alpha-glucosidase inhibitors slow absorption of starch and sucrose in the gut Alpha-glucosidase inhibitors slow absorption of starch and sucrose in the gut Secretagogues: Secretagogues: Sulfonylureas and meglitinides stimulate pancreatic insulin release Sulfonylureas and meglitinides stimulate pancreatic insulin release Insulin Sensitizers: Insulin Sensitizers: Biguanides decrease hepatic glucose production and enhance insulin-mediated glucose uptake Biguanides decrease hepatic glucose production and enhance insulin-mediated glucose uptake Thiazolidinediones decrease insulin resistance Thiazolidinediones decrease insulin resistance Absorption Inhibitors: Absorption Inhibitors: Alpha-glucosidase inhibitors slow absorption of starch and sucrose in the gut Alpha-glucosidase inhibitors slow absorption of starch and sucrose in the gut

19. T2DM: Therapy – Take a minute to discuss… How would you choose one medication from among the OHAs? How would you choose one medication from among the OHAs? Vary your choice according to your patient’s individual characteristics Vary your choice according to your patient’s individual characteristics How would you choose one medication from among the OHAs? How would you choose one medication from among the OHAs? Vary your choice according to your patient’s individual characteristics Vary your choice according to your patient’s individual characteristics

21. T2DM: Pharmacologic Therapy With significant hyperglycemia (FPG > 10) → initiation of metformin and/or a sulfonylurea should be considered With significant hyperglycemia (FPG > 10) → initiation of metformin and/or a sulfonylurea should be considered Metformin is associated with both decreased weight gain and hypoglycemic events Metformin is associated with both decreased weight gain and hypoglycemic events Metformin is contraindicated however in the presence of significant renal or hepatic insufficiency Metformin is contraindicated however in the presence of significant renal or hepatic insufficiency With significant hyperglycemia (FPG > 10) → initiation of metformin and/or a sulfonylurea should be considered With significant hyperglycemia (FPG > 10) → initiation of metformin and/or a sulfonylurea should be considered Metformin is associated with both decreased weight gain and hypoglycemic events Metformin is associated with both decreased weight gain and hypoglycemic events Metformin is contraindicated however in the presence of significant renal or hepatic insufficiency Metformin is contraindicated however in the presence of significant renal or hepatic insufficiency

22. typically used in combination GI SEs contraindicated in hepatic dysfunction used in combination with insulin – may increase edema and CHF contraindicated in persons with renal or hepatic dysfunction less weight gain GI SEs risks of hypoglycemia and weight gain use with caution in the elderly

23. T2DM: Therapy – Take a minute to discuss… CASE: You choose metformin for Mrs. X. and maximize the dose to 1 g po bid You choose metformin for Mrs. X. and maximize the dose to 1 g po bid Unfortunately, she still has not achieved her target glucose goals Unfortunately, she still has not achieved her target glucose goals What is the next step? What is the next step?CASE: You choose metformin for Mrs. X. and maximize the dose to 1 g po bid You choose metformin for Mrs. X. and maximize the dose to 1 g po bid Unfortunately, she still has not achieved her target glucose goals Unfortunately, she still has not achieved her target glucose goals What is the next step? What is the next step?

24. T2DM: Pharmacologic Therapy 1. 1. Add agents from different classes and maximize the doses (glyburide, acarbose and/or rosiglitazone) 2. 2. Consider adding an insulin HS dose to the OHAs 3. 3. Switch to multi-injection insulin therapy alone or with concomitant oral acarbose, biguanide or thiazolidinedione therapy 1. 1. Add agents from different classes and maximize the doses (glyburide, acarbose and/or rosiglitazone) 2. 2. Consider adding an insulin HS dose to the OHAs 3. 3. Switch to multi-injection insulin therapy alone or with concomitant oral acarbose, biguanide or thiazolidinedione therapy

25. T2DM: Insulin Therapy

26. T2DM Complications: Nephropathy CASE: Mrs. X. was noted to have trace proteinuria on dipstick by the family MD (You obtain a subsequent albumin:creatinine ratio of 3.0 on a random daytime urine) Over the next 3 months two further ACRs of 2.8 and 2.7 are obtained (a 24-hr urine collection confirms microalbuminuria at 225 mg/d) CASE: Mrs. X. was noted to have trace proteinuria on dipstick by the family MD (You obtain a subsequent albumin:creatinine ratio of 3.0 on a random daytime urine) Over the next 3 months two further ACRs of 2.8 and 2.7 are obtained (a 24-hr urine collection confirms microalbuminuria at 225 mg/d)

27. T2DM Complications: Nephropathy – Take a minute to discuss… How would you minimize any further progression of Mrs. X.’s nephropathy? How would you minimize any further progression of Mrs. X.’s nephropathy?

28. T2DM Complications: Nephropathy

29. 1) ACE-I/ARB adjust dose to obtain target BP if the patient is hypertensive 2) Intensify glucose control 3) Consider dietary protein restriction controversial mentioned in CDA guidelines ADA guidelines suggest 10% of calories should be protein with overt nephropathy [0.8 g/kg/d] with a reduction to 0.6 g/kg/d with further decline in creatinine clearance 4) Referral to nephrology with greater than 50% decrease in creatinine clearance 1) ACE-I/ARB adjust dose to obtain target BP if the patient is hypertensive 2) Intensify glucose control 3) Consider dietary protein restriction controversial mentioned in CDA guidelines ADA guidelines suggest 10% of calories should be protein with overt nephropathy [0.8 g/kg/d] with a reduction to 0.6 g/kg/d with further decline in creatinine clearance 4) Referral to nephrology with greater than 50% decrease in creatinine clearance

30. T2DM Complications: Neuropathy CASE: During follow-up, you confirm that Mrs. X. has mild to moderate stocking-glove sensory neuropathy with decreased vibration at the great toes and midfoot, and a loss of sensitivity to 10 gm monofilament at the great toes During follow-up, you confirm that Mrs. X. has mild to moderate stocking-glove sensory neuropathy with decreased vibration at the great toes and midfoot, and a loss of sensitivity to 10 gm monofilament at the great toes She also complains of a constant prickly, painful sensation over the same distribution which keeps her awake at night She also complains of a constant prickly, painful sensation over the same distribution which keeps her awake at nightCASE: During follow-up, you confirm that Mrs. X. has mild to moderate stocking-glove sensory neuropathy with decreased vibration at the great toes and midfoot, and a loss of sensitivity to 10 gm monofilament at the great toes During follow-up, you confirm that Mrs. X. has mild to moderate stocking-glove sensory neuropathy with decreased vibration at the great toes and midfoot, and a loss of sensitivity to 10 gm monofilament at the great toes She also complains of a constant prickly, painful sensation over the same distribution which keeps her awake at night She also complains of a constant prickly, painful sensation over the same distribution which keeps her awake at night

31. T2DM Complications: Neuropathy – Take a minute to discuss… What are the therapeutic options for her neuropathy ? What are the therapeutic options for her neuropathy ?

32. T2DM: Complications: Neuropathy Treatment 1) Intensify glucose control 2) Low dose tricyclic antidepressant or carbamazepine 3) Topical capsaicin ointment Treatment 1) Intensify glucose control 2) Low dose tricyclic antidepressant or carbamazepine 3) Topical capsaicin ointment

33. T2DM: Week Two Objectives We have reviewed: 1) Non-pharmacologic therapy 2) Pharmacologic therapy for glycemia - Oral agents: monotherapy and combination - Insulin: monotherapy and in combination with OHAs 3) Therapy for nephropathy 4) Therapy for neuropathy We have reviewed: 1) Non-pharmacologic therapy 2) Pharmacologic therapy for glycemia - Oral agents: monotherapy and combination - Insulin: monotherapy and in combination with OHAs 3) Therapy for nephropathy 4) Therapy for neuropathy