Download Oral Hypoglycemic Update - Lafayette Medical Education Foundation

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.