Managing Type 2 Diabetes: Review of Recent Guidelines Gina Ryan, Pharm.D., BCPS, CDE Clinical Associate Professor Mercer University College 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 Objecives At 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 is a.Retail/community pharmacy b.Hospital pharmacy c.Long-term pharmacy d.Other

Two Problems = Two Targets Type 2 Diabetes Insulin Resistance  DEMAND Impaired Insulin Secretion  SUPPLY IGT Increases insulin supply Sulfonylureas Incretin Mimetics Insulin Glinides Decreases insulin demand Metformin Glitazone Incretin Mimetics α-glucosidase inhibitor Lifestyle 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– mg/dL 1-2 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 use insulin

Metformin BrandGenericDosing Glucophage ® metformin mg BID (max 2550 mg/day) Glucophage XR ® metformin mg QAM

Metformin Decreases 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 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 use insulin

Sulfonylureas BrandGenericDosing First generation Diabinese ® chlorpropamide mg QD Orinase ® tolbutamide mg BID Tolinase ® tolazamide mg QD - BID Second generation Glucotrol ® glipizide mg QD - BID Glucotrol XL ® glipizide mg QD DiaBeta ® glyburide mg QD Micronase ® glyburide mg QD Third generation Amaryl ® glimepiride 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 lbs b.5-15 lbs c lbs d.>25 lbs

Sulfonylureas Efficacy Lowers fasting blood glucose (FBG) by mg/dL Lowers A1c by % 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. Tremor b. Thirst c. Polyuria d. Decreased heart rate

Management of Type 2 Diabetes ADA Consensus Statement Nathan et al. Diabetes Care 2009: 32;1-11 FBG 250 use insulin

Poll Question Which of the following agents can be used for basal insulin? a.NPH b.Regular c.Lispro d.Aspart

Basal Insulins NPH, determir, & glargine

Intensive Insulin TID & 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 use insulin

Thiazolidinediones (TZD or Glitazones) BrandGenericDosing Actos ® pioglitazone mg QD Avandia ® rosiglitazone2 - 8 mg QD - BID

Poll Question Rosiglitazone is not in the ADA algorithm because it a.Increases the risk of liver failure b.Increases blood pressure c.Increases the risk of heart attacks d.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 use insulin

Nauck MA, et al. J Clin Endocrinol Metab. 1986;63: The Incretin Effect Time (min) Glucose (mg/dL) Insulin (pmol/L) 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: Adapted from Larsson H, et al. Acta Physiol Scand. 1997;160: Adapted from Nauck MA, et al. Diabetologia. 1996;39: Adapted from Drucker DJ. Diabetes. 1998;47: Liver: ↓ Glucagon reduces hepatic glucose output Stomach: Helps regulate gastric emptying ↑ β-cell response ↓ β-cell workload

GLP-1 Agonists Agents Exenatide (Byetta ® ) 10 mcg sq bid Liraglutide (Victoza ® ) 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 Agonists Advantages Disadvantages Weight loss Decreases postprandial BG Preserves beta-cell function?? Nausea Not for monotherapy $$$ Subcutaneous Requires temperature controlled storage

GLP-1 Agonists Clinical Utility FBG – ↓ 63 mg/dl 2h Post prandial – ↓ 71 mg/dl Exenatide - HbA1c ↓ % Liraglutide - HbA1c ↓ 1-1.5%

GLP-1 Agonists Patient 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 ® ) mg po qday  Saxaglipitn (Onglyza ® ) 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 Inhibitor Advantages Disadvantages No weight gain Oral agent Minimal adverse effects A1c ↓ % Saxaglipitin – has more drug interactions than sitagliptin

Glinides Agents ▫nateglinide (Starlix ® ) mg po tid ac ▫repaglinide (Prandin ® ) mg po tid ac Increases insulin supply ▫Requires gluocose ▫Works 1-4 hours ▫Used for postprandial glucose control “pancreas”

Glinides Advantages 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 Inhibitors Advantages 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 Glucose Disposal Rate of Glucose Appearance Rate of Glucose Disappearance ↓ Food Intake Gut + Satiety Glucagon Liver Glucose Production Insulin Pancreas Amylin Gastric Emptying 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

Questions