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Managing Type 2 Diabetes: Review of Recent Guidelines
Gina Ryan, Pharm.D., BCPS, CDEClinical Associate Professor Mercer UniversityCollege of Pharmacy and Health Sciences
Program Disclosures
•This program has not been supported by any commercial interest.
•Gina Ryan has received a continuing educational grant from Ortho McNeil.
Educational ObjecivesAt the completion of this activity, the
participant should be able to:• Describe the agents that are recommended
by the American Diabetes Association (ADA);• Describe the mechanism of action of the
most commonly used diabetes drugs;• List the most common side effects observed
with diabetes drugs;• Describe the appropriate rationale for using
second-tier diabetes drugs; and• Provide quality patient counseling on
commonly used diabetes drugs.
Poll Question
•Your primary practice setting isa.Retail/community pharmacyb.Hospital pharmacyc.Long-term pharmacyd.Other
Two Problems = Two Targets
Type 2 Diabetes
Insulin Resistance DEMAND
Impaired InsulinSecretion SUPPLY
IGT IGT
Increases insulin supplySulfonylureas
Incretin MimeticsInsulin
Glinides
Decreases insulin demandMetforminGlitazone
Incretin Mimetics
α-glucosidase inhibitorLifestyle modification
Antihyperglycemic Therapy Insulin demand• Diet and Exercise• Metformin• Pioglitazone (TZD)• Incretin Mimetics
• GLP-1 agonists• DPP4 inhibitors
• Pramlintide• Alpha glucosidase
inhibitors
Insulin supply• Sulfonylureas• Insulins• Incretin mimetics
• GLP-1 agonists• DPP4 inhibitors
• Glinides
In ADA Algorithm
Management of Type 2 Diabetes ADA Consensus Statement
Nathan et al. Diabetes Care 2009: 32;1-11
FBG<250, if >250 use insulin
Metformin
Brand Generic DosingGlucophage® metformin 500 - 1000 mg
BID (max 2550 mg/day)
Glucophage XR® metformin 1000-2000 mg QAM
MetforminDecreases Insulin Demand• Decreases the hepatic production of
glucose• Increases insulin sensitivity• Reduces glucose absorption in GI
tract
Metformin
Advantages
• Well established• Weight loss • No hypoglycemia
(as monotherapy)• Decreases lipid
levels (LDL & TG) • QD dosing with ER• Inexpensive
Disadvantages
• GI upset (often transient)
• Lactic acidosis• Long list of
contraindications
Metformin
Efficacy•Lowers FBG by 60 to 70 mg/dL•Lowers A1c by 1.5 %•Benefits seen after first 2 - 3 weeks
Metformin
Patient Counseling•Take with food•May cause GI upset•Might cause weight loss•May take 2-3 weeks for full effect to be
observed•Report extreme fatigue to prescriber
Management of Type 2 Diabetes ADA Consensus Statement
Nathan et al. Diabetes Care 2009: 32;1-11
FBG<250, if >250 use insulin
SulfonylureasBrand Generic DosingFirst generationDiabinese® chlorpropamide 100 - 500 mg QDOrinase® tolbutamide 250 - 3000 mg BID Tolinase® tolazamide 100 - 750 mg QD -
BIDSecond generationGlucotrol® glipizide 2.5 - 20 mg QD -
BIDGlucotrol XL® glipizide 5 - 20 mg QDDiaBeta® glyburide 1.25 - 20 mg QD Micronase® glyburide 1.25 - 12 mg QDThird generationAmaryl® glimepiride 1 - 8 mg QD
Sulfonylureas•Increases Insulin Supply
▫basal and glucose-stimulated pancreatic insulin secretion
“pancreas”
Advantages Disadvantages
• Well established• Improves fasting and
postprandial glucose• Once-daily dosing• Inexpensive
▫ Hypoglycemia▫ Weight gain▫ Beta-cell burn out
Sulfonylureas
Poll Question
•How much weight gain is typically observed with sulfonylurea therapy?
a.2-3 lbsb.5-15 lbsc.16-25 lbsd.>25 lbs
Sulfonylureas
Efficacy•Lowers fasting blood glucose (FBG) by 60-
70 mg/dL•Lowers A1c by 1.5 - 2.0 %•Benefit seen after first 2 weeks
Sulfonlyureas
Patient Education•Don’t skip meals•Review signs and symptoms of
hypoglycemia•Warn of importance of weight
management•Review treatment of hypoglycemia
Poll Question
•Which of the following is a sign or symptom of hypoglycemia?
a. Tremorb. Thirstc. Polyuriad. Decreased heart rate
Management of Type 2 Diabetes ADA Consensus Statement
Nathan et al. Diabetes Care 2009: 32;1-11
FBG<250, if >250 use insulin
Poll Question
•Which of the following agents can be used for basal insulin?
a.NPHb.Regularc.Lisprod.Aspart
Insulin
Advantages Disadvantages
• Maximum effect on BG• Relatively inexpensive• Preserves beta-cell
function??• Well studied
• Weight gain• Hypoglycemia• Poor patient acceptance
Management of Type 2 Diabetes ADA Consensus Statement
Nathan et al. Diabetes Care 2009: 32;1-11
FBG<250, if >250 use insulin
Thiazolidinediones (TZD or Glitazones)
Brand Generic Dosing
Actos® pioglitazone 15 - 45 mg QD
Avandia® rosiglitazone 2 - 8 mg QD - BID
Poll Question
•Rosiglitazone is not in the ADA algorithm because it
a.Increases the risk of liver failureb.Increases blood pressurec.Increases the risk of heart attacksd.It’s not effective
Thiazolidinediones (TZD or Glitazones)
•Decreases Insulin Demand▫Improves peripheral insulin sensitivity
Instestine:glucose abs
Blood glucose
Pancreas:insulin secretion
TZD
Thiazolidinediones (TZD or Glitazones)
Advantages Disadvantages
• No hypoglycemia as monotherapy
• Improves insulin resistance
• Decreases TG levels• Possibly preserves beta
cell function• QD to BID dosing
• Weight gain• Edema• Slow onset of action• Expensive
Thiazolidinediones (TZD or Glitazones)
•Efficacy:▫Lowers FBG by 30 to 60 mg/dL▫Lowers A1c by 1.5 %▫3-4 month onset
Thiazolidinediones (TZD or Glitazones)•Patient Education
▫May cause edema▫May cause weight gain▫Takes 3-4 months for full
Management of Type 2 Diabetes ADA Consensus Statement
Nathan et al. Diabetes Care 2009: 32;1-11
FBG<250, if >250 use insulin
Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:492-498.
The Incretin Effect
0
50
100
150
200
-30 0 30 60 90 120 150 180 210
Time (min)
Glu
co
se
(m
g/d
L)
Insu
lin (
pm
ol/L
)
0
100
200
300
400
-30 0 30 60 90 120 150 180 210
Time (min)
Oral
IV
Incretin Effect
Insulin Secretion Is Greater in Response to Oral vs IV Glucose
α Cells:↓ Postprandial
glucagon secretion
GLP-1 Effects
Promotes satiety and reduces appetite
β Cells:Enhances glucose-dependent insulin
secretion
Adapted from Flint A, et al. J Clin Invest. 1998;101:515-520. Adapted from Larsson H, et al. Acta Physiol Scand. 1997;160:413-422.
Adapted from Nauck MA, et al. Diabetologia. 1996;39:1546-1553. Adapted from Drucker DJ. Diabetes. 1998;47:159-169.
Liver: ↓ Glucagon reduces
hepatic glucose output
Stomach: Helps regulate
gastric emptying
GLP-1 secreted upon the ingestion of food
↑ β-cell response
↓ β-cell workload
GLP-1 AgonistsAgents• Exenatide (Byetta®) 10 mcg sq bid• Liraglutide (Victoza®) 0.6-1.8 mcg sq qday
Decreases Insulin Demand and Increases Supply
• Glucagon-like peptide-1 analog• Decreases postprandial glucagon release• Slows GI emptying• Increases satiety• Increase first-phase insulin secretion
GLP-1 AgonistsAdvantages Disadvantages
• Weight loss• Decreases postprandial
BG• Preserves beta-cell
function??
• Nausea• Not for monotherapy• $$$• Subcutaneous• Requires temperature
controlled storage
GLP-1 AgonistsClinical Utility• FBG – ↓63 mg/dl• 2h Post prandial – ↓71 mg/dl• Exenatide - HbA1c ↓ 0.4- 0.8%• Liraglutide - HbA1c ↓ 1-1.5%
GLP-1 AgonistsPatient Education• Warn of nausea• Review sq administration technique• Must be kept in temperature controlled
environment▫ Exenatide <36- 77ºF▫ Liraglutide <36- 86ºF
Dipeptidyl Peptidase (DPP) IV Inhibitor
•Agents: Sitagliptin (Januvia®) 50-100 mg po qday Saxaglipitn (Onglyza ®) 2.5-5 mg po qday
• Decreases Insulin Demand and Increases Supply▫ DPP IV breaks down GLP-1
Decreases postprandial glucagon release Slows GI emptying Increases satiety Increase first-phase insulin secretion
Dipeptidyl Peptidase (DPP) IV InhibitorAdvantages Disadvantages
• No weight gain• Oral agent• Minimal adverse effects
• A1c ↓ 0.5-0.8%• Saxaglipitin – has more
drug interactions than sitagliptin
Glinides• Agents
▫nateglinide (Starlix®) 60-120 mg po tid ac▫repaglinide (Prandin ®) 0.4-4 mg po tid ac
• Increases insulin supply ▫Requires gluocose▫Works 1-4 hours▫Used for postprandial glucose control
“pancreas”
GlinidesAdvantages Disadvantages
• Targets postprandial glycemia
• Less hypoglycemia/ weight gain than sulfonylureas
• Lowers A1c 1-1.5%
• TID dosing• Hypoglycemia• Weight gain• Ineffective in
patients previously not controlled on sulfonylurea
Alpha-Glucosidase Inhibitors
•Agents▫acarbose (Precose ®)▫miglitol (Glyset ®)
•Decreases insulin demand▫Delays breakdown of complex carbohydrates
into glucose. ▫Slower and smaller increase in BG after meal
Alpha-Glucosidase InhibitorsAdvantages Disadvantages
• Targets postprandial glycemia
• No hypoglycemia• Nonsystemic
• TID dosing• Adverse GI side effects• Lowers A1C 0.5%
Multihormonal Regulation of Glucose
Brain
Plasma Glucose GLP-1
Tissues: Muscle, Fat
GlucoseDisposal
Rate ofGlucose
Appearance
Rate ofGlucose
Disappearance
↓ Food Intake
Gut
+ Satiety
Glucagon
LiverGlucose Production
Insulin
Pancreas
Amylin
GastricEmptying
Brain+ Satiety
Inhibits
Stimulates
Insulin Resistance
Visceral Fat
Increases
Stomach
Pramlintide (Symlin®)
•Indications – adjunctive treatment with mealtime insulin diabetes
• Dose ▫ Type 1 initial 15 mcg sq tid ac▫ Type 2 initial 60 mcg sq tid ac
•Decreases insulin demand▫ a synthetic amylin analog▫ ↓ postprandial glucagon▫ ↑satiety▫ slows gastric emptying
Pramlintide (Symlin®)Advantages Disadvantages
• Lowers A1c by 0.5-1%• Targets postprandial
glucose
• Sq administration may limit utility
• Transient nausea• Physically incompatible
with insulin• Requires refrigeration
▫ 36°F to 46°F