Anita Schwartz, PharmD, BCPS August 8 th, 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 Insulin Incretin Amylin Postprandial metabolism Turns On Glucose  Glycogen AA  Protein FFA  TG Turns Off ↓ Glucose Fasting metabolism Counterregulatory Hormones : Glucagon Epinephrine Cortisol Growth Hormone Glycogenolysis Gluconeogenesis

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/m 2 ) 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.

Fasting Glucose mg/dL 2-h OGTT mg/dL Random Glucose mg/dL A1c Normal<100<140<200<5.7% Prediabetes (IFG) (IGT) % Diabetes ≥ 126 ≥ 200 ≥ 6.5% ADA. I. Classification and Diagnosis. Diabetes Care 2012;35(suppl 1):S12. Table 2. Note: In the absence of unequivocal hyperglycemia, result(s) should be confirmed by repeat testing.

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/m 2, 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 (%)mg/dLmmol/L 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

ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S20. Table 9. *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 Target Treatment Goal AACE/ACE 2011ADA 2012 A1c ≤6.5%<7% Fasting Glucose FPG <110 mg/dlPreprandial PG mg/dl Postprandial Glucose 2-hr postprandial <140mg/dl Peak <180mg/dl

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 ADVANCE Primary Outcomes: Microvascular and Macrovascular Complications Gerstein HC, et al, for the Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008;358: Patel A, et al,. for the ADVANCE Collaborative Group. N Engl J Med 2008;358: HR=0.90 ( ) HR=0.90 ( )

ADA. VI. Prevention, Management of Complications. Diabetes Care 2012;35(suppl 1):S32. Table 11. Blood pressure<130/80 mmHg † Lipids LDL cholesterol<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.

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

ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S22. Adapted with permission from Silvio Inzucchi, Yale University ClassBiguanides CompoundMetformin MechanismActivates 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 Gastrointestinal side effects (diarrhea, abdominal cramping) Lactic acidosis (rare) Vitamin B 12 deficiency Contraindications: reduced kidney function CostLow – free at Marsh

ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S22. Adapted with permission from Silvio Inzucchi, Yale University. ClassSulfonylureas (2 nd generation) Compound Glibenclamide/Glyburide Glipizide Gliclazide Glimepiride Mechanism Closes K ATP 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 CostLow – free at Marsh

ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S22. Adapted with permission from Silvio Inzucchi, Yale University. ClassMeglitinides Compound Repaglinide (Prandin®) Nateglinide (Starlix®) Mechanism Closes K ATP channels on β -cell plasma membranes Action(s) Insulin secretion  AdvantagesAccentuated effects around meal ingestion Disadvantages Hypoglycemia, weight gain Dosing frequency CostMedium

ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S22. Adapted with permission from Silvio Inzucchi, Yale University. ClassThiazolidinediones (Glitazones) CompoundPioglitazone (Actos®) Mechanism Activates the nuclear transcription factor PPAR-  Action(s) Peripheral insulin sensitivity  Advantages No hypoglycemia HDL cholesterol  Triglycerides  Disadvantages Weight gain Edema Heart failure (CI with stage III and IV) Bone fractures CostHigh

ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S22. Adapted with permission from Silvio Inzucchi, Yale University. ClassThiazolidinediones (Glitazones) CompoundRosiglitazone (Avandia®) Mechanism Activates the nuclear transcription factor PPAR-  Action(s) Peripheral insulin sensitivity  AdvantagesNo hypoglycemia Disadvantages 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 CostHigh

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 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 [cited 2012 August 1].

ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S22. Adapted with permission from Silvio Inzucchi, Yale University. 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 CostMedium

ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S23. Adapted with permission from Silvio Inzucchi, Yale University. ClassDPP-4 inhibitors (incretin enhancers) Compound Sitagliptin (Januvia®) Vildagliptin (available in Europe) Saxagliptin (Onglza®) Linagliptin (Tradjenta®) MechanismInhibits 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 ?) CostHigh

ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S23. Adapted with permission from Silvio Inzucchi, Yale University. ClassGLP-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) Insulin secretion  (glucose-dependent) Glucagon secretion  (glucose-dependent) Slows gastric emptying Satiety  Advantages Weight reduction Potential for improved β -cell mass/function Disadvantages 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 CostHigh

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 CostHigh Lexi-Drugs Online [Internet]. Hudson (OH) : Lexi-Comp, Inc [cited 2012 August 1].

ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S23. Adapted with permission from Silvio Inzucchi, Yale University. ClassBile acid sequestrants CompoundColesevelam (Welchol®) MechanismBinds 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 CostHigh

MonotherapyRoute of AdministrationA1c (%) Reduction SulfonylureaPO MetforminPO1.5 GlitazonesPO MeglitinidesPO α -glucosidase inhibitors PO DPP-4PO GLP-1 agonistsInjectable Amylin analogsInjectable0.6 InsulinInjectableOpen to target Unger J et al. Postgrad Med 2010; 122:

Mostly targets FASTING hyperglycemia Mostly targets POSPRANDIAL hyperglycemia Insulin (long and intermediate action)Insulin (regular, rapid-action) Colesevelam α -glucosidase inhibitors SulfonylureasMeglitinides TZDPramlinitide MetforminDPP-4 inhibitors GLP-1 agonist

AACE/ACE Consensus Panel for Type 2 Diabetes. Endocrine Practice 2009; 25:

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)?

MedicationPROCON MetforminLow cost, A1c lowering, + CV effects, weight loss, PCOS Renal or hepatic impairment SulfonylureaLow cost, A1c loweringHypoglycemia, treatment failure MeglitinidesErratic meals, renal insufficiencyHypoglycemia, treatment failure PioglitazoneInsulin resistance, decrease in adipose tissue, TG reduction Edema, wt gain, CI with HF class III and IV α -glucosidase inhibitors Patients with constipationLong duration of T2DM, patients with GI problems DPP-4Well tolerated? long term safety GLP-1 agonistsObese patientsGI side effects Amylin analogsPoor PPG control despite insulin therapy GI side effects InsulinFlexible 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.