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2003 CDA Clinical Practice Guidelines ORAL AGENTS Options for Diabetes Kingston April 17 2004 J. Robin Conway M.D. Diabetes Clinic - Smiths Falls, ON www.diabetesclinic.ca www.diabetesclinic.ca Worldwide rates of diabetes mellitus: predictions 80 70 60 50 Prevalence (millions) 40 30 20 Year 1995 2000 2025 10 0 North America Europe Southeast Asia World Health Organization. 1997. www.diabetesclinic.ca Canadian Diabetes Association, 1998 website. 2 Million Canadians Have Diabetes Mellitus Frequency of diagnosed and undiagnosed diabetes and IGT, by age (U.S. data - Harris) 40 35 30 % of population IGT Undiagnosed diabetes Diagnosed diabetes 25 20 15 10 5 0 20-34 35-44 45-54 Harris. Diabetes Carewww.diabetesclinic.ca 1993;16:642-52. 55-64 65-74 Cardiovascular Disease Risk is Increased 2 to 4 Times Framingham study: diabetes and CAD mortality at 20-year follow-up Haffner Am J Cardiolwww.diabetesclinic.ca 1999;84:11J-4J. The burden of Diabetes • 87% of Type 2 Diabetes is managed in Primary Care • Diascan Study: 23.5% of patients in our office Leiter et al. Diabetes Care 2000 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) www.diabetesclinic.ca 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 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 Structured care • • • • ACLS ATLS Seattle Defibrillator Experience GREACE Study www.diabetesclinic.ca Structured Care VS Usual 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 www.diabetesclinic.ca Αthyros VG et al. Curr Med Res Opin. 2002;18:220-228. Reduction in Relative Risk of Primary Endpoints Total Mortality Coronary Mortality Nonfatal MI Unstable Angina PTCA/CABG CHF -51 -50 Stroke 0 -10 -20 -30 -40 -50 -43 -47 -52 -60 -47 -59 P=0.0021 P=0.0017 P=0.0001 P=0.0032 Αthyros VG et al. Curr Med Reswww.diabetesclinic.ca Opin. 2002;18:220-228. P=0.0011 P=0.021 P=0.034 Recommended targets for glycemic control* A1C** (%) 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. 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. †Glycemic A1C = glycosylated hemoglobin DCCT = Diabetes Control and Complications Trial FPG = fasting plasma glucose PG = plasma glucose www.diabetesclinic.ca Physical Activity and Diabetes Type Recommendation Aerobic – especially type 2 Brisk walking 150 minutes of moderate-intensity Biking exercise each week Raking leaves spread out over at least 3 nonContinuous swimming consecutive days gradually increase to 4 hours or more a Dancing Water aerobics week sessions should be at least 10 minutes at a time Weight lifting 3 times a week Exercise with weight start with 1 set of 10-15 repetitions machines progress to 2 sets of 10-15 then 3 sets of 8 Resistance – all persons with diabetes, including elderly Example • 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 www.diabetesclinic.ca 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 www.diabetesclinic.ca Drugs in Type 2 www.diabetesclinic.ca UKPDS: Long-term Glucose Control 9 HbA1c (%) 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 A1C (%) UKPDS demonstrated loss of glycemic control with all agents studied 9 8 Conventional Glyburide Chlorpropamide Metformin Insulin 7 6 0 Upper limit of normal = 6.2% 0 2 4 6 8 Years www.diabetesclinic.ca from randomization UK Prospective Diabetes Study Group. UKPDS 34. Lancet 1998; 352:854–865. 10 Overweight patients Cohort, median values Progressive Loss of -cell Function in UKPDS Non obese Obese 100 80 80 60 60 40 40 20 20 0 0 0 1 2 3 4 5 6 7 0 1 2 Years from randomization Conventional Sulphonylurea www.diabetesclinic.ca UKPDS 16: Diabetes 1995; 44:1249–1258 Mean 3 4 5 6 7 Metformin age at baseline 53 yrs. -cell function (%) -cell function (%) 100 Natural History of Type 2 Diabetes Lifestyle Metformin/Thiazolidinediones Insulin Insulin resistance Secretagogues Glucose level -cell dysfunction Insulin production Time Normal Impaired glucose tolerance 10 yrs Type 2 diabetes 12-15 yrs www.diabetesclinic.ca Henry. Am J Med 1998;105(1A):20S-6S. Sites of Action of Currently Available Therapeutic Options LIVER ADIPOSE TISSUE PANCREAS GLUCOSE PRODUCTION Biguanides Thiazolidinediones MUSCLE PERIPHERAL INSULIN SECRETION Sulfonylureas Meglitinides Insulin INTESTINE GLUCOSE ABSORPTION Alpha-glucosidase inhibitors GLUCOSE UPTAKE Thiazolidinediones (Biguanides) Sonnenberg, Kotchen Curr Opin Nephrol Hypertens 1998;7:551-5. www.diabetesclinic.ca Combination Antihyperglycemic Therapy Addition, rather than substitution recommended Agents from other classes should be added – Diff sites of action – Diff MOA www.diabetesclinic.ca 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 Mild to moderate hyperglycemia (A1C <9.0%) Non-overweight (BMI 25 kg/m2) Overweight (BMI 25 kg/m2) Biguanide alone or in combination with 1 of: • insulin sensitizer* • insulin secretagogue • insulin • alpha-glucosidase inhibitor 1 or 2† antihyperglycemic agents from different classes Marked hyperglycemia (A1C 9.0%) 2 antihyperglycemic agents from different classes † Basal and/or preprandial insulin • biguanide • insulin sensitizer* • insulin secretagogue • insulin • alpha-glucosidase inhibitor • biguanide • insulin sensitizer* • insulin secretagogue • insulin • alpha-glucosidase inhibitor F E S T Y L E Clinical assessment and initiation of nutrition and physical activity If not at target If not at target If not at target L I 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 www.diabetesclinic.ca and/or insulin should be made to attain target A1C within 6 to 12 months Intensify insulin regimen or add • biguanide • insulin secretagogue** • insulin sensitizer* • alpha-glucosidase inhibitor Clinical assessment and initiation of nutrition and physical activity Overweight (BMI 25 kg/m2) Biguanide alone or in combination with 1 of: • insulin sensitizer* • insulin secretagogue • insulin • alpha-glucosidase inhibitor Non-overweight (BMI 25 kg/m2) 1 or 2† antihyperglycemic agents from different classes Marked hyperglycemia (A1C 9.0%) 2 antihyperglycemic agents from different classes † Basal and/or preprandial insulin • biguanide • 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 L I F E S T Y L E 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 Add an oral antihyperglycemic agent from a different class of insulin* Timely adjustments to www.diabetesclinic.ca and/or additions of oral antihyperglycemic agents and/or insulin should be made to attain target A1C within 6 to 12 months Intensify insulin regimen or add • biguanide • insulin secretagogue** • insulin sensitizer* • alpha-glucosidase inhibitor Mild to moderate hyperglycemia (A1C <9.0%) Overweight (BMI 25 kg/m2) • insulin sensitizer* • insulin secretagogue • insulin • alpha-glucosidase inhibitor Y L E Biguanide alone or in combination with 1 of: Add a drug from a different class or Use insulin alone or in combination with: • biguanide • insulin secretagogue • insulin sensitizer* • alpha-glucosidase inhibitor L I F E S T 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 •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 notwww.diabetesclinic.ca an approved indication in Canada. 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 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 HbA1C in Diet-Treated Patients Effects of Various Medications (Difference from Placebo) 0 HbA1C (%) -0.5 -1 -1.5 -2 -2.5 Repaglinide Metformin Glyburide Glitazone Acarbose www.diabetesclinic.ca FDA approved Prescribing Information for various OADs Oral Agents for Type 2 Diabetes Αlpha-glucosidase inhibitor Expected decrease in A1C with monotherapy 0.5 – 0.8 Biguanide 1.0 – 1.5 Insulin Depends on regimen Insulin secretagogues Insulin sensitizers (TZDs) 1.0 – 1.5 0.5 for nateglinide 1.0 – 1.5 Combined rosiglitazone and metformin 1.0 – 1.5 Antiobesity agent (orlistat) 0.5 Class • 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 www.diabetesclinic.ca 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 A1C & BMI Suggested starting agent BMI 25 Biguanide alone or in combination < 9% 9% BMI < 25 1 or 2 agents from different classes -- 2 agents from different classes or insulin basal and/or preprandial Intensify to reach targets in 6-12 months www.diabetesclinic.ca Need for Combination Therapy in UKPDS % of Patients 80% 70% 60% 75% 50% 40% 30% 50% 20% 10% 0% 3 years 9 years www.diabetesclinic.ca Dose-Response Curve 1.5 1.0 30 20 0.5 GI Distress Patients (%) Reduction vs. placebo, HbA1c (%) 2.0 10 0 0 500 1000 1500 2000 2500 Dose Metformin Dose-response curve showing GI related effects Riddle M. Combining sulfonylureasand other oral agents. Am J of Med2000; www.diabetesclinic.ca 108(6A):15S-22S . 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 Biguanides: mechanism of action 1. Intestine: glucose absorption 4. Liver: hepatic Blood glucose 2. Muscle and adipose tissue: glucose uptake Metformin glucose utilization Insulin resistance glucose output Metformin HGO Insulin resistance www.diabetesclinic.ca 3. Pancreas: insulin secretion 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 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 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 Thiazolidinediones: mechanism of actions Blood glucose Liver insulin resistance hepatic glucose production Muscle and adipose tissue insulin resistance glucose uptake Pancreas demand for insulin secretion ß-cell insulin content www.diabetesclinic.ca 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 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 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 Sulfonylureas: mechanism of action 2. 1. Intestine: glucose absorption Insulin resistance Blood glucose 4. Liver: hepatic glucose output Muscle and adipose tissue: glucose uptake 3. Pancreas: Insulin secretion Sulfonylureas insulin secretion Insulin resistance www.diabetesclinic.ca 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 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 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 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 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 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 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 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 www.diabetesclinic.ca Insulin – Disadvantages – • • • • Hypoglycemia Weight gain Need for injections Non-physiologic route of administration (peripheral) • Patient and physician non-acceptance www.diabetesclinic.ca Alpha-Glucosidase inhibitors mechanism of action 2. Muscle and adipose tissue: glucose uptake Insulin resistance 1. Intestine: glucose absorption Blood glucose 4. Liver: hepatic glucose output Insulin resistance 3. Pancreas: insulin secretion Amatruda, Diabetes Mellitus, 1996. www.diabetesclinic.ca Alpha-Glucosidase Inhibitors – Advantages – • Good safety profile • No weight gain or modest weight loss • Dose coupled to meals www.diabetesclinic.ca Alpha-Glucosidase Inhibitors - Disadvantages • Modest effect on fasting plasma glucose and HbA1C • Flatulence, gastrointestinal side effects • Cannot treat hypoglycemia with sucrose, maltose, or starch – use glucose, fructose, or lactose www.diabetesclinic.ca Acarbose Dosage • Acarbose (Prandase) dose 50-100 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 www.diabetesclinic.ca 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 www.diabetesclinic.ca 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 www.diabetesclinic.ca 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 (HbA1c <6%) www.diabetesclinic.ca 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 www.diabetesclinic.ca QUESTIONS? www.diabetesclinic.ca www.diabetesclinic.ca