Download Oral Hypoglycemic Update

Oral Hypoglycemic
Agents
H.Rezvanian.MD
Objectives
1. List oral hypoglycemic agents currently on the market
2. Classify oral hypoglycemic agents based on their
mechanism, onset, duration, and place in therapy
3. Describe pros and cons of the different oral
hypoglycemic agents available
4. Summarize limitations and contraindications of oral
hypoglycemic agents
Classification and
Diagnosis
Diagnostic Criteria
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.
Prevention, Prevention, Prevention!
 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, thirdparty 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
Prevention, Prevention, Prevention!
 Medications shown to delay progression of IGT/IFG to T2DM
 Metformin (US DPP, NEJM 2002)
 Acarbose (STOP-NIDDM, Lancet 2002)
 Pioglitazone (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
A1c Monitoring
 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
ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S18.
A1C Correlation
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.
Easy A1c Correlation
 NOTE: This is an estimate only
 (A1C -2) x 30
 i.e. A1C= 7%; (7-2) x30 = 150mg/dL
Goals
Glycemic Recommendations
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.
Goals: A1c
 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.
Oral Hypoglycemic Treatment
Non-Insulin Hypoglycemic Agents
Oral
Biguanides
Sulfonylureas
Meglitinides
Thiazolidinediones
Alpha Glucosidase
inhibitors
Incretin Enhancers (DPP-IV
inhibitors)
Resin binder.
SGLT2 inhibitors
Parenteral
 Amylin analogs
 Incretin mimetics
Pharmacology - Biguanides
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
Pharmacology - Sulfonylureas
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.
Pharmacology – Meglitinides
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.
Pharmacology – Thiazolidinediones
(TZD)
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.
Pharmacology – Thiazolidinediones
(TZD)
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.
TZDs and the FDA
 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].
Pharmacology – Alpha-Glucosidase
Inhibitors
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.
Pharmacology – Incretin Mimetics
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.
Pharmacology – Incretin Enhancers
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.
Pharmacology – Amylin Analog
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].
Pharmacology – Bile Acid
Sequestrants
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.
The Role of SGLT-2 Inhibitors in
the
Management of Patients
with Type 2 Diabetes
The Kidneys Play an Important
Role in Glucose Control
Normal Renal Glucose Physiology
• 180 g of glucose is filtered each day
• Virtually all glucose reabsorbed in the proximal
tubules & reenters the circulation
• SGLT2 reabsorbs about 90% of the glucose
• SGLT1 reabsorbs about 10% of the glucose
• Virtually no glucose excreted in urine
Mather, A & Pollock, C. Kidney International. 2011;79:S1-S6.
Targeting the Kidney
Chao EC, et al. Nat Rev Drug Discovery. 2010;9:551-559.
Renal Glucose Transport
Chao, EC & Henry RR. Nature Reviews Drug Discovery. 2010;9:551-559.
Sodium- Glucose Cotransporters
SGLT1
SGLT2
Site
Mostly intestine with
some kidney
Almost exclusively kidney
Sugar Specificity
Glucose or galactose
Glucose
Affinity for glucose
High
Km= 0.4 Mm
Low
Km = 2 Mm
Capacity for glucose
transport
Low
High
Role
Dietary glucose
absorption
Renal glucose
reabsorption
Renal glucose
reabsorption
Lee YJ, at al. Kidney Int Suppl. 2007;72:S27-S35.
Familial Renal Glucosuria: A Genetic Model of SGLT2
Inhibition
Familial Renal Glucosuria
Presentation
• Glucosuria: 1-170 g/day
• Asymptomatic
Blood
• Normal glucose concentration
• No hypoglycemia or hypovolemia
Kidney / bladder
• No tubular dysfunction
• Normal histology and function
Complications
• No increased incidence of
– Chronic kidney disease
– Diabetes
– Urinary tract infection
Santer R, et al. J Am Soc Nephrol. 2003;14:2873-2882;
Wright EM, et al. J Intern Med. 2007;261:32-43.
Altered Renal Glucose Control in Diabetes
 Gluconeogenesis is increased in postprandial
and postabsorptive states in patients with Type
2 DM
 Renal contribution to hyperglycemia
 3-fold increase relative to patients without diabetes
 Glucose reabsorption
 Increased SGLT-2 expression and activity in renal
epithelial cells from patients with diabetes vs.
normoglycemic individuals
Marsenic O. Am J Kidney Dis. 2009;53:875-883.
Bakris GL, et al. Kidney Int. 2009;75(12):1272-1277.
Rahmoune H, et al. Diabetes. 2005;54(12):3427-3434.
SGLT2 Inhibitors in
Phase 3 Development
• Empagliflozin
• Canagliflozin
• Dapagliflozin
• Ipragliflozin
Typical A1c Reductions
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
Drug Pearls
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
Fasting vs. Postprandial Effect
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
Considerations When Selecting
Therapy
 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)?
QUESTIONS