Anita Schwartz, PharmD, BCPS August 8 th, 2012 For Lafayette Medical Education Foundation, Inc

Anita Schwartz, PharmD, BCPSAugust 8th, 2012For 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

InsulinIncretinAmylin

Postprandial metabolism

Turns On

Glucose GlycogenAA Protein

FFA TG

Turns Off↓ Glucose

Fasting metabolism

Counterregulatory Hormones:Glucagon

EpinephrineCortisol

Growth Hormone

GlycogenolysisGluconeogenesis

• 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.

Fasting Glucose mg/dL

2-h OGTT mg/dL

Random Glucosemg/dL

A1c

Normal <100 <140 <200 <5.7%

Prediabetes 100-125(IFG)

140-199(IGT)

5.7-6.4%

Diabetes ≥ 126 ≥ 200 ≥ 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/m2, age <60 years,

and women with prior GDM

• None are FDA approved for Diabetes PreventionADA. 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/dL mmol/L

6 126 7.0

7 154 8.6

8 183 10.2

9 212 11.8

10 240 13.4

11 269 14.9

12 298 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

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 2011

ADA 2012

A1c ≤6.5% <7%

Fasting Glucose FPG <110 mg/dl Preprandial PG 70-130mg/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 TRIALPrimary Outcomes: nonfatal

MI, nonfatal stroke, CVD

ADVANCEPrimary 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;358:2545-2559

Patel A, et al,. for the ADVANCE Collaborative Group. N Engl J Med 2008;358:2560-2572

HR=0.90 (0.78-1.04)

HR=0.90 (0.82-0.98)

ADA. VI. Prevention, Management of Complications. Diabetes Care 2012;35(suppl 1):S32. Table 11.

Blood pressure <130/80 mmHg†

LipidsLDL 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

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 • Gastrointestinal side effects (diarrhea, abdominal cramping)

• Lactic acidosis (rare)• Vitamin B12 deficiency• Contraindications: reduced kidney function

Cost Low – free at Marsh

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

Class Sulfonylureas (2nd generation)

Compound • Glibenclamide/Glyburide• Glipizide• Gliclazide• Glimepiride

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


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


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 • Weight gain• Edema• Heart failure (CI with stage III and IV)• Bone fractures

Cost High


Class Thiazolidinediones (Glitazones)

Compound Rosiglitazone (Avandia®)

Mechanism Activates the nuclear transcription factor PPAR-

Action(s) Peripheral insulin sensitivity

Advantages No 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

Cost High

• 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


Class DPP-4 inhibitors (incretin enhancers)

Compound • Sitagliptin (Januvia®)• Vildagliptin (available in Europe)• Saxagliptin (Onglza®)• Linagliptin (Tradjenta®)

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


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) • 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

Cost High

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

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 CONMetformin 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


• 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


Documents

Anita Schwartz, PharmD, BCPS August 8 th, 2012 For Lafayette Medical Education Foundation, Inc