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

ADA Glycemic Goals

A1C<7.0%Preprandial BG– 70-130 mg/dL1-2 hr post prandial BG<180 mg/dL

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

Basal InsulinsNPH, determir, & glargine

Intensive InsulinTID & HS

Conventional Insulin BID

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

Agents not included in ADA Consensus Statement

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

QuestioQuestionsns