CDA Clinical Practice Guidelines ORAL AGENTS J. Robin Conway M.D. Diabetes Clinic - Smiths Falls, ON Options for Diabetes Kingston April

Prevalence (millions) North America Europe Southeast Asia Year World Health Organization Canadian Diabetes Association, 1998 website. Worldwide rates of diabetes mellitus: predictions

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

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

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 Strychar I et al. Cdn J Diab 2003(abs) Leiter et al. Diabetes Care 2000

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

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

Structured care ACLS ATLS Seattle Defibrillator Experience GREACE Study

Structured Care VS Usual Care Αthyros VG et al. Curr Med Res Opin. 2002;18: 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:

Reduction in Relative Risk of Primary Endpoints Αthyros VG et al. Curr Med Res Opin. 2002;18: % Reduction P= P= P= P=0.034 P= P= P=0.021

Recommended targets for glycemic control* A1C** (%) FPG/preprandial PG (mmol/L) 2-hour postprandial PG (mmol/L) Target for most patients  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 Where possible, Canadian laboratories should standardize their A1C values to DCCT levels (reference range: 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

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.

Nutrition Therapy People with diabetes should: Receive nutrition counseling by a registered dietitian Receive individualized meal 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

Drugs in Type 2

9 HbA 1c (%) UKPDS: Long-term Glucose Control Years of treatment Conventional Intensive ULN = 6.2% UKPDS Study Group, Lancet, 1998;352:

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

 -cell function (%) ConventionalSulphonylureaMetformin UKPDS 16: Diabetes 1995; 44:1249–1258 Progressive Loss of  -cell Function in UKPDS Mean age at baseline 53 yrs.

Natural History of Type 2 Diabetes Henry. Am J Med 1998;105(1A):20S-6S. LifestyleMetformin/Thiazolidinediones Secretagogues Insulin

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

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

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)

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 of insulin* Intensify insulin regimen or add biguanide insulin secretagogue** insulin sensitizer* alpha-glucosidase inhibitor L I F E S T Y L E 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

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 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 of 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 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 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 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 not at target Biguanide alone or in combination with 1 of: insulin sensitizer* insulin secretagogue insulin alpha-glucosidase inhibitor Overweight (BMI  25 kg/m 2 )   L I F E S T Y L E

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

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

Glyburide HbA 1C (%) Metformin AcarboseGlitazone Repaglinide HbA 1C in Diet-Treated Patients Effects of Various Medications (Difference from Placebo) FDA approved Prescribing Information for various OADs

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

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 A1C& BMISuggested starting agent < 9% BMI  25 Biguanide alone or in combination BMI < 251 or 2 agents from different classes  9% -- 2 agents from different classes or insulin basal and/or preprandial

Need for Combination Therapy in UKPDS % of Patients

Dose-Response Curve Riddle M. Combining sulfonylureasand other oral agents. Am J of Med2000; 108(6A):15S-22S. Dose-response curve showing GI related effects Dose GI Distress Patients (%) Reduction vs. placebo, HbA 1c (%) Metformin

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

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

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

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

Metformin Dosage 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

Thiazolidinediones: mechanism of actions Muscle and adipose tissue  insulin resistance  glucose uptake Liver  insulin resistance  hepatic glucose production Blood glucose Pancreas  demand for insulin secretion  ß- cell insulin content

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

Thiazolidinediones – Disadvantages – Delayed action (onset: 3 wks, full effect: wks) Variable response in monotherapy Weight gain Increased LDL-cholesterol (short-term) Few long-term studies

Thiazolidenedione Dosage Pioglitazone (Actos), dosage range 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

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

Sulfonylureas – Advantages – Improve a primary pathophysiologic impairment: insulin secretion Physiologic route of insulin delivery High initial response rate No lag period before response

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

Sulphonylureas Dosage Glyburide (Diabeta)dose range mg, split into twice daily. Tablets of 2.5 and 5 mg Full ODB Coverage Gliclazide (Diamicron) dose range 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 mg OD Tabs 0.5, 1, 2, 4 mg. No ODB coverage

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

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

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.

Meglitinides Efficacy Summary Rapid response –Decline in 24-hr mean BG (  mmol/L) within 1 week Good clinical response –Improves glucose control  HbA 1C ~ % (vs placebo) Glycemic control –Documented HbA 1C reductions sustained over 1 year Dose response – Reductions in mean glucose seen at mg ac Synergistic –Incremental improvements when used in combination with metformin

Meglitinides Dosage 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

Insulin – Disadvantages – Hypoglycemia Weight gain Need for injections Non-physiologic route of administration (peripheral) Patient and physician non-acceptance

Alpha-Glucosidase inhibitors mechanism of action Amatruda, Diabetes Mellitus, Insulin resistance 1. Intestine: glucose absorption 2. Muscle and adipose tissue: glucose uptake 3. Pancreas: insulin secretion 4. Liver: hepatic glucose output Insulin resistance Blood glucose 

Alpha-Glucosidase Inhibitors – Advantages – Good safety profile No weight gain or modest weight loss Dose coupled to meals

Alpha-Glucosidase Inhibitors - Disadvantages - Modest effect on fasting plasma glucose and HbA 1C Flatulence, gastrointestinal side effects Cannot treat hypoglycemia with sucrose, maltose, or starch –use glucose, fructose, or lactose

Acarbose Dosage Acarbose (Prandase) dose mg with the first bite of each meal. High index of side effects, start low (25 mg OD) and titrate up gradually. Not very effective for hyperglycemia 0.5% A1c reduction. ODB Coverage on LU

Anorexiants Dosage Orlistat (Xenical) 120 mg tabs, one with the first bite of each meal. Inhibits 30% of dietaryt fat absorpton needs to be used with a low fat diet. Lifestyle counseling essential. Prevented Diabetes in XENDOS study. ODB Section 8 with failure of Metformin & SU in the obese patient Sibutramine (Meridia) dose 10 or 15 mg caps OD. No ODB Coverage

Type 2 Diabetes Key Concepts Dual impairment: –ß-cell function: insulin secretion –insulin action: insulin resistance “Glucose toxicity” aggravates both impairments Multiple mechanisms to correct hyperglycemia Most patients require combination therapy

Combination Therapy Summary The magnitude of the diabetic epidemic dictates more aggressive approaches to treatment Evidence clearly suggest that early intensive treatment results in significant decrease in complications To reduce macrovascular disease more strict glucose control might be needed (HbA 1c <6%)

In Conclusion Prevalence of type 2 diabetes is increasing dramatically Majority of patients are diagnosed and treated by the family physician New paradigm: need to be much more aggressive early in the treatment of these patients utilizing dual therapies Hypoglycemia can be managed through proper treatment choices and lifestyle management Glucose is a continuous progressive risk factor for cardiovascular disease

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