2003 CDA Clinical Practice Guidelines J Robin Conway

2003 CDA Clinical Practice Guidelines J. Robin Conway M. D. Diabetes Clinic Smiths Falls, ON www. diabetesclinic. ca

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

www. diabetesclinic. ca

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

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

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 Leiter et al. Diabetes Care 2000 • Que screening >2 Risk Factors 79% tested 7% Diabetes 13% IGT or IFG 74% No Treatment Advice Strychar I et al. Cdn J Diab 2003(abs) www. diabetesclinic. ca

T 2 DM in Family Practice • • • 84% of patients had A 1 c in past year Average A 1 c 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

Cardiovascular Risk • Statin • ACE • ASA Sask 19. 9% 48. 9% 23. 5% Smiths Falls 70% 91% 70% Brown L et al. Cdn J Diab 2003(abs) Nozek L et al. Cdn J Diab 2003(abs) Conway R et al. Cdn J Diab 2003(abs) www. diabetesclinic. ca

Burden of Poor Control - Cost www. diabetesclinic. ca

2003 CDA Guidelines • Early Aggressive Screening • FPG every 3 yrs over age 40 • High Risk Groups Relatives of Diabetics Aboriginals & Hispanics PCOS Schizophrenics Dyslipidemia www. diabetesclinic. ca

SCREENING & PREVENTION • All individuals should be evaluated annually for Diabetes risk on the basis of history, clinical and demographic criteria. • Screening for Diabetes using a fasting plasma glucose should be performed every 3 years for individuals over 40 years of age. • More frequent or earlier testing with either a fasting plasma glucose or OGTT in people with additional risk factors for Diabetes, www. diabetesclinic. ca

PREVENTION Pre diabetes • OGTT should be considered if BMI>25 and FPG between 5. 7 & 7 to identify IGT or Diabetes • With IGT a program of lifestyle mod that includes wt loss & exercise to prevent T 2 D • With IGT treatment with Metformin or Acarbose should be considered. www. diabetesclinic. ca

DIAGNOSIS • • • FBS >7 mmol/L + symptoms RBS >11 mmol/L + symptoms PREDIABETES IFG FBS 6. 1 -7 mmol/L IGT 2 hr PC glucose on OGTT 7. 8 -11 If FBS > 5. 7 mmol/L do OGTT www. diabetesclinic. ca

Recommended targets for glycemic control* A 1 C** (%) FPG/preprandial PG (mmol/L) 2 -hour postprandial PG (mmol/L) Target for most patients 7. 0 4. 0 -7. 0 5. 0 -10. 0 Normal range (considered for patients in whom it can be achieved safely) 6. 0 4. 0 -6. 0 5. 0 -8. 0 *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 A 1 C of 7. 0% corresponds to a laboratory value of 0. 070. Where possible, Canadian laboratories should standardize their A 1 C values to DCCT levels (reference range: 0. 040 to 0. 060). However, as many laboratories continue to use a different reference range, the target A 1 C value should be adjusted based on the specific reference range used by the laboratory that performed the test. As a useful guide: an A 1 C target of 7. 0% refers to a threshold that is approximately 15% above the upper limit of normal. A 1 C = glycosylated hemoglobin DCCT = Diabetes Control and Complications Trial FPG = fasting plasma glucose PG = plasma glucose www. diabetesclinic. ca

Monitoring • A 1 c every 3 months • Self Monitor Glucose, interpret results, alter food choices, physical activity, frequency of testing & medications • Type 1 should test at least 3 times a day • Type 2 should test at least daily • Type 1 in acute illness should test ketones if glucose >14 mmol/L www. diabetesclinic. ca

Exercise • 150 minutes of moderate intensity aerobic exercise over 3 nonconsecutive days of the week or if willing 4 hrs/week • Encourage resistance exercise 3 times/week www. diabetesclinic. ca

Nutrition • Nutrition Counselling • Canada Food Guide • For PPG control Amnt & source of CHO, Glycemic Index • Sucrose to 10% Cal • Discuss Alcohol • Intensive Insulin do CHO counting www. diabetesclinic. ca

Goals in Diabetes • • FBS<7, PC<11, A 1 c<7% BP <130/80 TC/HDL <4, LDL <2. 5, Trig <1. 5 ACR <2 Male, <2. 8 Female www. diabetesclinic. ca

Drugs in Type 2 www. diabetesclinic. ca

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

Pathophysiology of Type 2 Diabetes • Decreased insulin secretion • Loss of ‘first-phase’ insulin secretion • Increased insulin resistance, resulting in: – Decreased glucose and fat uptake – Increased free fatty acid release – Increased hepatic glucose output www. diabetesclinic. ca

UKPDS: Long-term Glucose Control Hb. A 1 c (%) 9 Conventional 8 Intensive 7 ULN = 6. 2% 6 0 0 3 6 9 12 Years of treatment www. diabetesclinic. ca UKPDS Study Group, Lancet, 1998; 352: 837 -853. 15

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

Type 2 Diabetes is Characterized by Insulin Resistance and Progressive ß-cell Failure Beta Cell Function (%) 100 Stages of Type 2 Diabetes in Relationship to ß-cell Function 75 50 25 Impaired glucose tolerance -12 -10 Postprandial hyperglycemia -6 -2 Type 2 diabetes phase I 0 Type 2 diabetes phase II 2 6 Type 2 diabetes phase III 10 14 Years from Diagnosis • 50% of ß-cell function is already lost at diagnosis • Elevated PPG occurs before diagnosis www. diabetesclinic. ca Lebovitz HE. Diabetes Review 1999; 7(3): 139 153.

Insulin secretion (pmol/min) Impaired Insulin Secretion in Type 2 Diabetes 800 healthy Type 2 diabetes 600 400 200 0 6 am 10 am 2 pm 6 pm Time www. diabetesclinic. ca Adapted from Polonsky KS et al. N Engl J Med 1996; 334: 777. 10 pm 2 am 6 am

Pathophysiology Type 2 Diabetes: Underlying Defects Beta-cell function Insulin resistance Type 2 diabetes Other defects: lipolysis release of NEFA hepatic glucose production Adapted from Matthaei et al. Endocrine Reviews 2000; 21: 585 -618. www. diabetesclinic. ca Adapted from Frayn. Br J Nutr 2000; 83(suppl 1): S 71 -S 77.

Type 2 Diabetes - Dual Impairment Insulin Secretion • Impaired insulin secretion from pancreatic ß-cells • A sluggish and inadequate response to the glucose load imposed by meals • Characteristic only of Type 2 diabetes • 100% of patients have impaired secretion at diagnosis Insulin Resistance • Approx. 84% have insulin resistance • Also associated with other metabolic conditions Lebovitz HE. Diabetes Review. 1999; www. diabetesclinic. ca 7(3): 139 -153. Polonsky KS, et al. NEJM 1988; 318: 1231 -9. Bonora E, et al. Diabetes 1998; 47: 1643 -49.

Issues to be Addressed when Selecting Agents • • Degree of -cell deficiency Magnitude of insulin resistance Extent of fasting hyperglycemia Magnitude of postprandial hyperglycemia www. diabetesclinic. ca

Epidemiological Evidence Linking PPG with Cardiovascular Disease www. diabetesclinic. ca

CHD Risk and Type 2 Diabetes Db- No diabetes; Db+ Diabetes; MI- No prior MI; MI+ prior MI Stroke CV death p<0. 001 for prior MI vs. no MI and diabetes vs. no diabetes calculated with Cox proportional-hazards models, adjusted for age and sex www. diabetesclinic. ca Haffner SM et al. N Engl J Med 339: 229 -234, 1998 MI

2 -hour PPG, Not FPG, Predicted All-cause Mortality 2. 0 1. 0 0. 5 P (m PG m , 7 ol 5 /L g ) OG ³ 11. 1 7. 8 – 11. 0 6. 1– 6. 9 7. 0 Fasting plasma glucose (mmol/L) Adjusted for age, centre, sex www. diabetesclinic. ca Adapted from DECODE Study Group. Lancet 1999; 354: 617. ho <6. 1 ur <7. 8 0. 0 TT 1. 5 2 - Hazard ratio 2. 5

Epidemiological Evidence Linking High * PPG with CVD Risk & Mortality 1 DECODE, 1999 High PPG is associated with increased risk of death, independent of FPG 2 Pacific and Indian Ocean, 1999 High PPG with normal FPG doubles the risk of mortality 3 Funagata Diabetes Study, 1999 IGT, but not IFG, is a risk factor for CVD 4 Whitehall, Paris, Helsinki Study 1998 Men in upper 2. 5% of PPG distribution had significantly higher CHD mortality 5 PPG more than doubles the risk of fatal CVD and heart disease in older adults 6 PPG (1 -hr post-breakfast), but not FPG, is associated with CHD The Rancho-Bernardo Study, 1998 Diabetes Intervention Study, 1996 *2 -hour PPG after 75 g OGTT, except where indicated www. diabetesclinic. ca 1 DECODE Study Group. Lancet 1999; 354: 617. 2 Shaw JE et al. Diabetologia 1999; 42: 1050.

Intervention Studies to Control PPG and its Effect on CV Disease Manzella 20051 Type 2 Repaglinide had greater PPG lowering and a significantly greater improvement in endothelial function and a decline in oxidative stress compared to glyburide Esposito 20042 Type 2 After 12 months, CIMT regression (decrease of > 0. 020 mm) was observed in 52% of the repaglinide group vs 18% in the glyburide group (p<0. 01). Hanefeld 20043 Type 2 Acarbose reduced relative risk of myocardial infarction by 64% (p=0. 012) and any CV event 35% (p=0. 0061) Chiasson 20034 IGT Acarbose reduced relative risk of CV events by 49% and new cases of hypertension by 34% compared to placebo www. diabetesclinic. ca 1. Chiasson et al. JAMA 2003; 290: 486. 2. Hanefeld M, et al. Eur Heart J 2004; 25(1): 10 -16. 3. Esposito K et al. Circulation 2004; 110. 4. Manzella D et al. Diabetes Care 2005; 28(2): 366.

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

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

Timeline for Therapy in Type 2 Diabetes Metformin/Thiazolidinediones Lifestyle Secretagogues Insulin Diabete s IGT Endogenous Insulin Normal Insulin Resistance Postprandial Blood Glucose Years Fasting Blood Glucose Normal Blood Glucose Avg www. diabetesclinic. ca Dx 6. 5 yrs Modified from graphic developed by the IDC

Canadian Diabetes Association 2003 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada www. diabetesclinic. ca

Individualized Treatment • • • Metformin for overweight patients If control not achieved add another agent If A 1 c >9 start with 2 agents Consider early insulin for hyperglycemia Bedtime intermediate insulin (NPH) www. diabetesclinic. ca

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

Clinical assessment and initiation of nutrition and physical activity Marked hyperglycemia (A 1 C 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 2 antihyperglycemic agents from different classes † Basal and/or preprandial insulin • biguanide • insulin sensitizer* • insulin secretagogue • insulin • alpha-glucosidase inhibitor I F E S T Y L E Mild to moderate hyperglycemia (A 1 C <9. 0%) If not at target L If not at target Add a drug from a different class or Use insulin alone or in combination with: • biguanide • insulin secretagogue • insulin sensitizer* • alpha-glucosidase inhibitor Add an oral antihyperglycemic agent from a different class of insulin* Timely adjustments to and/or additions of oral antihyperglycemic agents and/or insulin should be made to attain target A 1 C within 6 to 12 months www. diabetesclinic. ca Intensify insulin regimen or add • biguanide • insulin secretagogue** • insulin sensitizer* • alpha-glucosidase inhibitor

Mild to moderate hyperglycemia (A 1 C <9. 0%) Biguanide alone or in combination with 1 of: • insulin sensitizer* • insulin secretagogue • insulin • alpha-glucosidase inhibitor If not at target L I F E S T Y L E Overweight (BMI 25 kg/m 2) 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 A 1 C within 6 to 12 months www. diabetesclinic. ca * 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.

Expected A 1 C Lowering with Oral Monotherapy Metformin Repaglinide*# Sensitizers (pioglitazone, rosiglitazone) Sulfonylureas# (glyburide, gliclazide, glimepiride) Acarbose* Nateglinide*# Orlistat #oral 1 – 1. 5 % 0. 5 – 0. 8 % insulin secretagogue *targets PPG www. diabetesclinic. ca Adapted from Table 1. CDA 2003 Clinical Practice Guidelines, Can J Diabetes 2003; 27(Suppl 2): S 38.

Treatment Insulin Secretagogues: Mechanisms of Action 1. Intestine: glucose absorption Blood glucose 2. Muscle and adipose tissue: glucose uptake Insulin resistance 4. Liver: hepatic glucose output Insulin resistance www. diabetesclinic. ca Lebovitz HE. Joslin’s Diabetes Mellitus, Ch. 29, 508 -529. 3. Pancreas: Insulin secretion Sulfonylureas insulin secretion

glucose (mmol/l) Antihyperglycemic Agents Metformin Sulfonylureas TZD’s Acarbose Nateglinide Repaglinide Postprandial hyperglycemia Rapid-acting insulin 12. 5 analogues 10. 0 7. 5 5. 0 Basal hyperglycemia 0 0600 1200 1800 hours Basal insulin www. diabetesclinic. ca Adapted from Riddle et al. Diabetes Care. 1990; 13: 676 -686. 2400 0600

Attributes of Meglitinides Gluconorm (repaglinide) Starlix (nateglinide) • Increases early-phase insulin release • Physiologic response to meals (rapid onset and elimination) • Significant improvement in key blood glucose parameters (PPG, FPG, and Hb. A 1 c) • Low risk of hypoglycemia • Weight neutral www. diabetesclinic. ca

Hypoglycemia: Why is it Important? • Annually, about 5 - 20% of patients on oral agents have hypoglycemia • Under-recognized and under-reported • Substantial impact: – Social embarrassment – Emotional toll – “found dead in bed” – Work restrictions (e. g. operating machinery) – Devastating to elderly patients www. diabetesclinic. ca

Adding Repaglinide to Restore Mealtime Insulin Secretion If A 1 C ≥ 8% 1 mg or 2 mg with meals • If repaglinide is 1 st line or A 1 C <8%, start 0. 5 mg with meals • Double the dose every week until target achieved • Maximum mealtime dose (4 mg); Maximum daily dose (16 mg) PPG Control Gluco. Norm® Product Monograph, Novo Nordisk Canada Inc. , 2005. 47

Basal/Bolus Treatment Program with Rapid-acting and Long-acting Analogs Breakfast Lunch Plasma insulin Aspart or Lispro Dinner Aspart or Lispro Glargine or Detemir 4: 00 8: 00 12: 00 16: 00 Time 20: 00 www. diabetesclinic. ca 24: 00 8: 00