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Anita Schwartz, PharmD, BCPS August 8th, 2012 For Lafayette Medical Education Foundation, Inc. • This speaker has no conflict of interest with regard to this presentation. 1. Review diagnostic tests and treatment goals for diabetes 2. List oral hypoglycemic agents currently on the market 3. Classify oral hypoglycemic agents based on their mechanism, onset, duration, and place in therapy 4. Describe pros and cons of the different oral hypoglycemic agents available 5. Summarize limitations and contraindications of oral hypoglycemic agents 1. True or False: • A HgbA1C of 6.7% on two occasions is diagnostic of diabetes. 2. True or False: • Giving rapaglinide (Prandin®) with meals and glimepiride (Amaryl®) daily is a very good therapy option as it mimics basal bolus insulin. 3. True or False: • Rosiglitazone (Avandia®) can decrease LDL cholesterol and is a good option for patients with heart disease. ↑ Glucose Glycogenolysis Gluconeogenesis Postprandial metabolism Counterregulatory Hormones: Insulin Incretin Amylin Glucagon Epinephrine Cortisol Growth Hormone Turns On Glucose Glycogen AA Protein FFA TG Fasting metabolism ↓ Glucose Turns Off • Type 1 diabetes • β-cell destruction • Type 2 diabetes • Progressive insulin secretory defect • Other specific types of diabetes • Genetic defects in β-cell function, insulin action • Diseases of the exocrine pancreas • Drug- or chemical-induced • Gestational diabetes mellitus ADA. I. Classification and Diagnosis. Diabetes Care 2012;35(suppl 1):S11 • Consider testing overweight/obese adults (BMI ≥25 kg/m2) with one or more additional risk factors • In those without risk factors, begin testing at age 45 years • If tests are normal • Repeat testing at least at 3-year intervals • Use A1C, FPG, or 2-h 75-g OGTT • In those with increased risk for future diabetes • Identify and, if appropriate, treat other CVD risk factors ADA. II. Testing in Asymptomatic Patients. Diabetes Care 2012;35(suppl 1):S13. Normal Prediabetes Diabetes Fasting Glucose mg/dL 2-h OGTT mg/dL Random Glucose mg/dL A1c <100 <140 <200 <5.7% 100-125 (IFG) 140-199 (IGT) ≥ 126 ≥ 200 5.7-6.4% ≥ 200 ≥ 6.5% Note: In the absence of unequivocal hyperglycemia, result(s) should be confirmed by repeat testing. ADA. I. Classification and Diagnosis. Diabetes Care 2012;35(suppl 1):S12. Table 2. • Refer patients with IGT, IFG, or A1C 5.7–6.4% to ongoing support program • Target weight loss = 7% of total body weight • Minimum of 150 min/week of moderate physical activity • Follow-up counseling important for success • Based on cost-effectiveness of diabetes prevention, third-party payers should cover such programs • In those with pre-diabetes, monitor for development of diabetes annually ADA. IV. Prevention/Delay of Type 2 Diabetes. Diabetes Care 2012;35(suppl 1):S16 • Medications shown to delay progression of IGT/IFG to T2DM • Metformin (US DPP, NEJM 2002) • Acarbose (STOP-NIDDM, Lancet 2002) • Piaglitazone (ACT NOW, presentation 2008) • Consider metformin for prevention of type 2 diabetes if IGT, IFG, or A1C 5.7–6.4% • Especially for those with BMI >35 kg/m2, age <60 years, and women with prior GDM • None are FDA approved for Diabetes Prevention ADA. IV. Prevention/Delay of Type 2 Diabetes. Diabetes Care 2012;35(suppl 1):S16 • Twice Yearly in those who have stable glycemic control and no therapy changes • Quarterly in patients whose therapy has changed or who are not meeting glycemic goals • Use of point-of-care (POC) testing for A1c provides the opportunity for more timely treatment changes ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S18. Mean plasma glucose A1C (%) 6 7 mg/dL 126 154 mmol/L 7.0 8.6 8 9 10 11 12 183 212 240 269 298 10.2 11.8 13.4 14.9 16.5 ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S18. Table 8. • NOTE: This is an estimate only • (A1C -2) x 30 • i.e. A1C= 7%; (7-2) x30 = 150mg/dL Target Treatment Goal AACE/ACE 2011 ADA 2012 A1c ≤6.5% <7% Fasting Glucose FPG <110 mg/dl Preprandial PG 70130mg/dl Postprandial Glucose 2-hr postprandial <140mg/dl Peak <180mg/dl *Individualize goals based on these values. †Postprandial glucose measurements should be made 1–2 h after the beginning of the meal, generally peak levels in patients with diabetes ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S20. Table 9. • Goal: <7% • Lowering A1c <7% has been shown to reduce microvascular complications and, if implemented soon after the diagnosis of diabetes, is associated with long-term reduction in macrovascular disease • More stringent goals (i.e. 6.5%)are reasonable in patients if it can be achieved without significant hypoglycemia or side effect • New diagnosis of diabetes, long life expectancy and no significant CVD • Less stringent goals (i.e. 8%) may be reasonable for those who have experienced severe hypoglycemia, limited life expectancy, advanced complications, or extensive comorbidities. ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S18-19. ACCORD TRIAL Primary Outcomes: nonfatal MI, nonfatal stroke, CVD HR=0.90 (0.78-1.04) ADVANCE Primary Outcomes: Microvascular and Macrovascular Complications HR=0.90 (0.82-0.98) Gerstein HC, et al, for the Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008;358:2545-2559 Patel A, et al,. for the ADVANCE Collaborative Group. N Engl J Med 2008;358:2560-2572 Blood pressure Lipids LDL cholesterol <130/80 mmHg† <100 mg/dL (<2.6 mmol/L)‡ †Based on patient characteristics and response to therapy, higher or lower systolic blood pressure targets may be appropriate. ‡In individuals with overt CVD, a lower LDL cholesterol goal of <70 mg/dL (1.8 mmol/L), using a high dose of statin, is an option. ADA. VI. Prevention, Management of Complications. Diabetes Care 2012;35(suppl 1):S32. Table 11. • Metformin + lifestyle changes at diagnosis providing no contraindication • Medications are ALWAYS to be used in combination with healthy meal planning and regular physical activity (150 minutes per week) • If marked elevation of A1c /blood glucose and/or symptomatic consider insulin (+ or – other agents) from the outset • If noninsulin monotherapy at maximal tolerated dose does not achieve /maintain the A1c goal over 3–6 months, add a second oral agent, a GLP-1 receptor agonist, or insulin ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S21 Oral •Biguanides •Sulfonylureas •Meglitinides •Thiazolidinediones •Alpha Glucosidase inhibitors •Incretin Enhancers (DPP-IV inhibitors) •Resin binder Parenteral • Amylin analogs • Incretin mimetics Class Biguanides Compound Metformin Mechanism Activates AMP-kinase Action(s) • Hepatic glucose production • Intestinal glucose absorption • Insulin action Glucose Lowering Effect • Fasting • Post Prandial Advantages • No weight gain • No hypoglycemia • Reduction in cardiovascular events and mortality (UKPDS f/u) Disadvantages • • • • Cost Low – free at Marsh Gastrointestinal side effects (diarrhea, abdominal cramping) Lactic acidosis (rare) Vitamin B12 deficiency Contraindications: reduced kidney function ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S22. Adapted with permission from Silvio Inzucchi, Yale University Class Sulfonylureas (2nd generation) Compound • • • • Mechanism Closes KATP channels on β-cell plasma membranes Action(s) Insulin secretion Advantages • Generally well tolerated • Reduction in cardiovascular events and mortality (UKPDS f/u) Disadvantages • Relatively glucose-independent stimulation of insulin secretion: Hypoglycemia, including episodes necessitating hospital admission and causing death • Weight gain • Primary and secondary failure Cost Low – free at Marsh Glibenclamide/Glyburide Glipizide Gliclazide Glimepiride ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S22. Adapted with permission from Silvio Inzucchi, Yale University. Class Meglitinides Compound • Repaglinide (Prandin®) • Nateglinide (Starlix®) Mechanism Closes KATP channels on β-cell plasma membranes Action(s) Insulin secretion Advantages Accentuated effects around meal ingestion Disadvantages • Hypoglycemia, weight gain • Dosing frequency Cost Medium ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S22. Adapted with permission from Silvio Inzucchi, Yale University. Class Thiazolidinediones (Glitazones) Compound Pioglitazone (Actos®) Mechanism Activates the nuclear transcription factor PPAR- Action(s) Peripheral insulin sensitivity Advantages • No hypoglycemia • HDL cholesterol • Triglycerides Disadvantages • • • • Cost High Weight gain Edema Heart failure (CI with stage III and IV) Bone fractures ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S22. Adapted with permission from Silvio Inzucchi, Yale University. Class Thiazolidinediones (Glitazones) Compound Rosiglitazone (Avandia®) Mechanism Activates the nuclear transcription factor PPAR- Action(s) Peripheral insulin sensitivity Advantages No hypoglycemia Disadvantages • • • • • • • Cost High LDL cholesterol Weight gain Edema Heart failure (CI with stages III and IV) Bone fractures Increased cardiovascular events (mixed evidence) FDA warnings on cardiovascular safety ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S22. Adapted with permission from Silvio Inzucchi, Yale University. • Rosiglitazone • Restricted by FDA – can only be used by patients currently benefiting from therapy or do not get adequate DM treatment from other agents and not willing to use pioglitazone • 1-800-AVANDIA • Pioglitazone • FDA alert – ongoing analysis of risk of bladder cancer (with prolonged use >12 months) Lexi-Drugs Online [Internet]. Hudson (OH) : Lexi-Comp, Inc. 1978-2012[cited 2012 August 1]. Class α-Glucosidase inhibitors Compound • Acarbose • Miglitol Mechanism Inhibits intestinal α-glucosidase Action(s) Intestinal carbohydrate digestion and absorption slowed Advantages • Nonsystemic medication • Postprandial glucose Disadvantages • Gastrointestinal side effects (gas, flatulence, diarrhea) • Dosing frequency Cost Medium ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S22. Adapted with permission from Silvio Inzucchi, Yale University. Class DPP-4 inhibitors (incretin enhancers) Compound • • • • Mechanism Inhibits DPP-4 activity, prolongs survival of endogenously released incretin hormones Action(s) • Active GLP-1 concentration • Insulin secretion • Glucagon secretion Advantages • No hypoglycemia • Weight “neutrality” Disadvantages • Occasional reports of urticaria/angioedema • Cases of pancreatitis observed • Long-term safety unknown (cancer ?) Cost High Sitagliptin (Januvia®) Vildagliptin (available in Europe) Saxagliptin (Onglza®) Linagliptin (Tradjenta®) ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S23. Adapted with permission from Silvio Inzucchi, Yale University. Class GLP-1 receptor agonists (incretin mimetics) Compound • Exenatide (Byetta®) • Liraglutide (Victoza®) Mechanism Activates GLP-1 receptors (β-cells/endocrine pancreas; brain/autonomous nervous system Action(s) • • • • Advantages • Weight reduction • Potential for improved β-cell mass/function Disadvantages • • • • • Cost High Insulin secretion (glucose-dependent) Glucagon secretion (glucose-dependent) Slows gastric emptying Satiety Gastrointestinal side effects (nausea, vomiting, diarrhea) Cases of acute pancreatitis observed C-cell hyperplasia/medullary thyroid tumors in animals (liraglutide) Injectable Long-term safety unknown ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S23. Adapted with permission from Silvio Inzucchi, Yale University. Class Antihyperglycemic Synthetic Analog Compound • Pramlintide (Symilin®) Mechanism • Amylinomimetic Action(s) • Glucagon secretion (glucose-dependent) • Slows gastric emptying • Satiety Advantages • Potential weight loss Disadvantages • Meal time injections • Nausea • Hypoglycemia in combination with insulin Cost High Lexi-Drugs Online [Internet]. Hudson (OH) : Lexi-Comp, Inc. 1978-2012[cited 2012 August 1]. Class Bile acid sequestrants Compound Colesevelam (Welchol®) Mechanism Binds bile acids/cholesterol Action(s) Bile acids stimulate receptor on liver to produce glucose Results • Lowers fasting and post prandial glucose Advantages • No hypoglycemia • LDL cholesterol Disadvantages • Constipation • Triglycerides • May interfere with absorption of other medications Cost High ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S23. Adapted with permission from Silvio Inzucchi, Yale University. Monotherapy Route of Administration A1c (%) Reduction Sulfonylurea PO 1.5-2.0 Metformin PO 1.5 Glitazones PO 1.0-1.5 Meglitinides PO 0.5-2.0 α-glucosidase inhibitors PO 0.5-1.0 DPP-4 PO 0.5-0.7 GLP-1 agonists Injectable 0.8-1.5 Amylin analogs Injectable 0.6 Insulin Injectable Open to target Unger J et al. Postgrad Med 2010; 122: 145-57 Mostly targets FASTING hyperglycemia Mostly targets POSPRANDIAL hyperglycemia Insulin (long and intermediate action) Insulin (regular, rapid-action) Colesevelam α-glucosidase inhibitors Sulfonylureas Meglitinides TZD Pramlinitide Metformin DPP-4 inhibitors GLP-1 agonist AACE/ACE Consensus Panel for Type 2 Diabetes. Endocrine Practice 2009; 25: 540-559 • How long has the patient had diabetes (duration of disease – preservation of β-cell function)? • Which blood glucose level is not at target (fasting, postprandial, or both)? • Patient preference for route of administration (oral, injection)? • The degree of A1c lowering effect required to achieve goal? • Side effect profile and the patients tolerability? • Co – existing conditions ( CVD, osteoporosis, obesity, etc)? Medication PRO CON Metformin Low cost, A1c lowering, + CV effects, weight loss, PCOS Renal or hepatic impairment Sulfonylurea Low cost, A1c lowering Hypoglycemia, treatment failure Meglitinides Erratic meals, renal insufficiency Hypoglycemia, treatment failure Pioglitazone Insulin resistance, decrease in adipose tissue, TG reduction Edema, wt gain, CI with HF class III and IV α-glucosidase inhibitors Patients with constipation Long duration of T2DM, patients with GI problems DPP-4 Well tolerated ? long term safety GLP-1 agonists Obese patients GI side effects Amylin analogs Poor PPG control despite insulin therapy GI side effects Insulin Flexible treatment (basal, basal bolus, etc) Hypoglycemia, weight gain • ACEi or ARBs • If ACEi is not tolerated secondary to cough may try ARB • If ACEi is not tolerated secondary to angioedema DO NOT TRY ARB • Multiple medications are often needed to obtain blood pressure goals ADA. VI. Prevention, Management of Complications. Diabetes Care 2012;35(suppl 1):S29 • Statin therapy should be added to lifestyle therapy, regardless of baseline lipid levels • with overt CVD • without CVD >40 years who have one or more other CVD risk factors • For patients at lower risk (without overt CVD, <40 years, etc.) • Consider statin therapy in addition to lifestyle therapy if LDL cholesterol remains >100 mg/dL • In those with multiple CVD risk factors ADA. VI. Prevention, Management of Complications. Diabetes Care 2012;35(suppl 1):S30-31 • Consider aspirin therapy (75–162 mg/day) • In those with type 1 or type 2 diabetes at increased cardiovascular risk (10-year risk >10%) • Includes most men >50 years of age or women >60 years of age who have at least one additional major risk factor • Family history of CVD • Hypertension • Smoking • Dyslipidemia • Albuminuria ADA. VI. Prevention, Management of Complications. Diabetes Care 2012;35(suppl 1):S32. • Use aspirin therapy (75–162 mg/day) • Secondary prevention strategy in those with diabetes with a history of CVD • For patients with CVD and documented aspirin allergy • Clopidogrel (75 mg/day) should be used • Combination therapy with ASA (75–162 mg/day) and clopidogrel (75 mg/day) • Reasonable for up to a year after an acute coronary syndrome ADA. VI. Prevention, Management of Complications. Diabetes Care 2012;35(suppl 1):S32. • To reduce risk of cardiovascular events in patients with known CVD use the following if not contraindicated: • ACE inhibitor • Aspirin • Statin therapy • In patients with a prior MI • Beta-blockers should be continued for at least 2 years after the event ADA. VI. Prevention, Management of Complications. Diabetes Care 2012;35(suppl 1):S33.