Update in Diabetes Management Oral Therapies

1
Update in Diabetes Management Oral Therapies

• Amy M. Lugo, PharmD, BCPS, CDM
• Clinical Coordinator
• Department of Pharmacy
• National Naval Medical Center
• Bethesda, Maryland

2
Objectives

• Review the epidemiology of diabetes
• Define IFG and IGT
• Discuss screening for DM
• Identify the goals of therapy for diabetes
• Describe the major metabolic defects in Type 2
  Diabetes
• Review the MOA, pertinent kinetics, SE, and CI of
  each class
• Discuss new oral therapies available and in the
  pipeline

3
Epidemiology

• 21 million people with diabetes in the US
• 5.2 million people dont even know they have the
  disease
• 41 million people in the US have
  pre-diabetes

http//www.diabetes.org/uedocuments/Forefront.Summ
er.Fall.2005.pdf
4
Pre-Diabetes

• Patients with IFG and/or IGT are now referred to
  as having "pre-diabetes"
• Impaired Fasting Glucose (IFG)
• 100 mg/dL to lt 126 mg/dL
• Impaired Glucose Tolerance (IGT)
• 2-hr PG 140 and lt 200 mg/dL

www.diabetes.org
5
Screening for DM

• Should be considered by health care providers at
  3-year intervals beginning at age 45
• Particularly in those with BMI gt 25 kg/m2
• Testing should be considered at a younger age or
  be carried out more frequently in individuals who
  are overweight and have one or more other risk
  factors

www.diabetes.org
6
Risk Factors for Type 2 DM

• Age gt 45 years
• Overweight (BMI gt 25 kg/m2)
• Family history of diabetes (i.e., parents or
  siblings with diabetes)
• Habitual physical inactivity
• Race/ethnicity (e.g., African-Americans,
  Hispanic-Americans, Native Americans,
  Asian-Americans, and Pacific Islanders)
• Previously identified IFG or IGT
• History of GDM or delivery of a baby weighing gt9
  lbs
• Hypertension (140/90 mmHg in adults)
• HDL cholesterol lt 35 mg/dl and/or a triglyceride
  level gt 250 mg/dl
• Polycystic ovary syndrome
• History of cardiovascular disease

www.diabetes.org
7
Treatment Goals for the Whole Patient

• FPG 70-110 mg/dL
• HbA1c lt 7
• AACE lt 6.5
• BP lt 130/80 mmHg
• LDL lt 100 mg/dL
• HDL gt 40 mg/dL (men)
• HDL gt 50 mg/dL (women)
• TG lt 150 mg/dL

Diabetes Care 2005 (suppl)28S4-S36.
8
Therapies for Diabetes

• Approximately 90 of persons with diabetes
  require oral medications, insulin injections, or
  both
• Monotherapy with any of these agents is
  associated with a 0.5-2.0 reduction in HbA1C

9
Major Metabolic Defectsin Type 2 Diabetes

• Peripheral insulin resistance in muscle and
  fat
• Decreased pancreatic insulin secretion
• Increased hepatic glucose output

Haffner SM, et al. Diabetes Care, 1999
10
Oral Agents

• Sulfonylureas
• Meglitinides
• Biguanides
• Thiazolidinediones
• Alpha-glucosidase inhibitors

11
Sulfonylureas

• First Generation
• Tolbutamide (Orinase)
• Acetohexamide (Dymelor)
• Tolazamide (Tolinase)
• Chlorpropamide (Diabinese)

• Second Generation
• Glyburide (Diabeta, Micronase)
• Micronized glyburide (Glynase)
• Glipizide (Glucotrol, Glucotrol XL)
• Glimepiride (Amaryl)

12
Sulfonylureas

• Insulin secretagogues
• MOA Increases insulin release from the pancreas
• Maximum hypoglycemic effect between agents is
  similar
• Initial dosage may need to be adjusted for
  patients with hepatic or renal dysfunction
• Kinetics absorption is rapid, fairly complete,
  and unaffected by food, except for glipizide,
  which is most effective when taken on an empty
  stomach

13
Antihyperglycemic Agents
Major Sites of Action
Plasma glucose
? Glucosidase Inhibitors
(-)
Glucose Uptake
Glucose Production
Carbohydrate Absorption
Muscle/Fat
GI tract
Injected Insulin
(-)
Liver
()
Metformin Glitazones
Insulin Secretion
Insulin Secretion
Sulfonylureas Meglitinides
Pancreas
()
Hines SE. Intensive management of type 2
diabetes. Patient Care.April 30,
200091-107. Kelley DB, ed. Medical Management of
Type 2 Diabetes. 4th ed. Alexandria, Va American
Diabetes Association 199856-72.
14
Sulfonylureas

• Side Effects
• Hypoglycemia
• Weight gain
• GI (nausea, vomiting, heartburn)
• Skin reactions
• Hematologic reactions

15
Sulfonylureas

• Contraindications
• Not recommended during pregnancy, breastfeeding
  or for children
• Sulfonylurea hypersensitivity
• Diabetic ketoacidosis
• Severe infection
• Surgery, trauma, or other severe metabolic
  stressor

16
Meglitinides

• Repaglinide (Prandin)
• Benzoic acid derivative
• 0.5mg, 1mg, 2mg tablets
• Nateglinide (Starlix)
• D-Phenylalanine derivative
• 60mg and 120mg tablets

17
Meglitinides

• Insulin secretagogues
• MOA Increases insulin release from the pancreas
• Kinetics
• Absorption is rapid and complete from the GI
  tract slightly decreased by food
• Rapid hepatic metabolism

18
Antihyperglycemic Agents
Major Sites of Action
Plasma glucose
? Glucosidase Inhibitors
(-)
Glucose Uptake
Glucose Production
Carbohydrate Absorption
Muscle/Fat
GI tract
Injected Insulin
(-)
Liver
()
Metformin Glitazones
Insulin Secretion
Insulin Secretion
Sulfonylureas Meglitinides
Pancreas
()
Hines SE. Intensive management of type 2
diabetes. Patient Care.April 30,
200091-107. Kelley DB, ed. Medical Management of
Type 2 Diabetes. 4th ed. Alexandria, Va American
Diabetes Association 199856-72.
19
Meglitinides

• Side Effects
• Repaglinide (Prandin)
• GI disturbances
• URI
• Arthralgias
• Headache
• Hypoglycemia

• Nateglinide (Starlix)
• Mild hypoglycemia
• Dizziness
• Weight gain

20
Meglitinides

• Contraindications
• Not recommended during pregnancy, breastfeeding,
  or for children
• Diabetic ketoacidosis
• Severe infection
• Surgery, trauma, or other metabolic stressor
• Impaired hepatic function

21
Biguanides

• Agents
• Metformin (Glucophage)
• 500mg, 850mg, and 1000mg tablets
• Metformin (Glucophage XR)
• 500mg extended-release tablets
• Glyburide/Metformin (Glucovance)
• 1.25/250mg, 2.5/500mg, 5/500mg tablets
• Glipizide/Metformin (MetaglipTM)
• 2.5/250mg, 2.5/500mg, 5/500mg

22
Metformin (Glucophage)

• MOA
• Primary effect
• Reduces hepatic glucose production by inhibiting
  glycogenolysis
• Increases insulin sensitivity in adipose tissue
  and skeletal muscle
• Secondary effect (minor)
• Decreases intestinal absorption of glucose
• Kinetics
• Food decreases the extent of bioavailability and
  slightly delays the absorption of metformin
• Major excretion via kidneys

23
Antihyperglycemic Agents
Major Sites of Action
Plasma glucose
? Glucosidase Inhibitors
(-)
Glucose Uptake
Glucose Production
Carbohydrate Absorption
Muscle/Fat
GI tract
Injected Insulin
(-)
Liver
()
Metformin Glitazones
Insulin Secretion
Insulin Secretion
Sulfonylureas Meglitinides
Pancreas
()
Hines SE. Intensive management of type 2
diabetes. Patient Care.April 30,
200091-107. Kelley DB, ed. Medical Management of
Type 2 Diabetes. 4th ed. Alexandria, Va American
Diabetes Association 199856-72.
24
Metformin (Glucophage)

• Side Effects
• Gastrointestinal effects (30 of patients)
• Diarrhea
• Abdominal bloating
• Nausea
• Cramping
• Feeling of fullness
• Miscellaneous agitation, sweating, headache, and
  metallic taste

25
Metformin (Glucophage)

• Contraindications and Precautions
• Generally not indicated during pregnancy,
  breastfeeding, or for children
• Renal dysfunction SrCr gt 1.5 in males or gt 1.4
  in females
• Hepatic dysfunction
• Acute or chronic lactic acidosis

26
Alpha-Glucosidase Inhibitors

• Agents
• Acarbose (Precose)
• 25mg, 50mg, 100mg tablets
• Miglitol (Glyset)
• 25mg, 50mg, 100mg tablets

27
Alpha-Glucosidase Inhibitors

• Not hypoglycemic agents
• MOA
• Inhibit intestinal absorption of starches and
  sucrose, thereby decreasing CHO-mediated
  postprandial blood glucose elevation
• Kinetics
• Miglitol is almost completely absorbed
• Acarbose is negligibly absorbed

28
Alpha-Glucosidase Inhibitors

• Side Effects
• Monotherapy is not associated with hypoglycemia
• GI effects
• Diarrhea
• Abdominal pain
• Flatulence
• Increased LFTs

29
Thiazolidinediones

• Agents
• Pioglitazone (Actos)
• 15mg, 30mg, 45mg tablets
• Rosiglitazone (Avandia)
• 2mg, 4mg, 8mg tablets
• Rosiglitazone/Glimepiride (Avandaryl)
• tablets
• Troglitazone (Rezulin)
• Recalled by FDA
• Rosiglitazone/Metformin (Avandamet)
• 2mg/500mg, 4mg/500mg

30
Thiazolidinediones

• Not hypoglycemic agents
• MOA
• Insulin sensitizers
• Act at the peroxisome-proliferator-activated
  receptor-gamma (PPAR-?) to reduce insulin
  resistance and improve blood glucose levels
• Kinetics
• Both well absorbed without regard to meals
• Extensively bound to albumin (gt99)
• Both extensively metabolized in the liver

31
Antihyperglycemic Agents
Major Sites of Action
Plasma glucose
? Glucosidase Inhibitors
(-)
Glucose Uptake
Glucose Production
Carbohydrate Absorption
Muscle/Fat
GI tract
Injected Insulin
(-)
Liver
()
Metformin Glitazones
Insulin Secretion
Insulin Secretion
Sulfonylureas Meglitinides
Pancreas
()
Hines SE. Intensive management of type 2
diabetes. Patient Care.April 30,
200091-107. Kelley DB, ed. Medical Management of
Type 2 Diabetes. 4th ed. Alexandria, Va American
Diabetes Association 199856-72.
32
Thiazolidinediones

• Side Effects
• Increased LFTs
• Plasma volume expansion, causing a decrease
  in Hgb, Hct, and neutrophil counts
• Weight gain
• Mild to moderate edema
• GI discomfort, headache,
  pharyngitis

33
Thiazolidinediones

• Contraindications and Precautions
• Not indicated during pregnancy, breastfeeding, or
  for children
• Use with caution in hepatic dysfunction
• Use in premenopausal anovulatory women may cause
  resumption of ovulation
• Contraindicated in NYHA class III and IV failure

34
Thiazolidinediones

• Drug interactions
• Rosiglitazone is metabolized by CYP2C9 and
  CYP2C8 usually not clinically significant
• Pioglitazone is partially metabolized by CYP3A4

35
Oral Agents and Effects on Lipids
JAMA, Jan 16, 2002 287360-372.
36
New Oral Generics/Combinations

• Glimepiride
• 1mg, 2mg, 4mg
• Rosiglitazone
• 2mg, 4mg, 8mg
• Glimepiride/Rosiglitazone (Avandaryl)
• 1mg/4mg, 2mg/4mg, 4mg/4mg
• Pioglitazone
• 15mg, 30mg, 45mg
• Pioglitazone/Metformin (Actoplus MetTM)
• 15mg/500mg, 15mg/850mg

37
Peroxisome Proliferator-Activated Receptors
(PPARs)

• PPAR Receptors
• Located in the cell nucleus
• PPAR? (fat)
• ? FFA, ? insulin sensitivity, ? glucose uptake
• ? plasma glucose
• PPAR? (liver, muscle)
• ? FA oxidation, ? apo CIII, ? apo A1
• ? plasma TG, ? HDL-C

38
Muraglitazar (PargluvaTM)

• Glitazars
• Dual alpha/gamma PPAR activators
• PPAR gamma activation
• Lowers plasma glucose and free fatty acid
  concentrations
• PPAR alpha activation
• Lowers plasma triglyceride concentrations and
  increases HDL cholesterol

JAMA. 2005 Nov 23294(20)2581-6
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Muraglitazar (PargluvaTM)

• NDA submitted to the FDA in Dec 2004
• Concerns
• FDA requested additional cardiovascular safety
  information from ongoing trials
• Considering conducting additional studies or
  terminating further development
• Additional studies could take approximately five
  years to complete

40
The Incretin System

• Incretin hormones
• Glucose-dependent insulinotropic polypeptide
  (GIP)
• Glucagon-like peptide-1 (GLP-1)
• Eating causes secretion of hormones from
  the GI tract
• Enzyme
• Dipeptidyl peptidase-4 (DPP-4) inactivates GLP-1
• G-protein-coupled receptors (GPCRs)

Lancet 20063681696-705.
41
The Incretin System

• Actions of GLP-1
• Inhibits glucagon secretion
• Inhibits gastric emptying
• Inhibits food ingestion
• Promotes glucose disposal
• GLP-1 receptors (GLP-1R) are expressed in islet ?
  and ? cells and in peripheral tissues

Lancet 20063681696-705.
42
Exenatide (ByettaTM)

• Class
• Incretin mimetics
• GLP-1R agonists
• Indication
• Adjunctive therapy in patients with Type 2
  diabetes uncontrolled on metformin, a
  sulfonylurea, or their combination
• Do not need to be on insulin therapy

43
Exenatide (ByettaTM)

• MOA
• Mimics the effects of the incretin glucagon-like
  peptide 1 (GLP-1)
• Enhances glucose-dependent insulin secretion by
  pancreatic beta-cells
• Suppresses inappropriately elevated glucagon
  secretion
• Slows gastric emptying
• Administration
• SQ injections in pre-filled pens
• Major adverse effect nausea

44
Sitagliptin (Januvia)

• Class
• Dipeptidyl peptidase-4 inhibitor (DPP-4)
• Indication
• Treatment of DM2
• Monotherapy and as add-on therapy to metformin
  or thiazolidinediones (TZDs)
• NOT approved with insulin or sulfonylureas
• Dose 100 mg once daily

45
Sitagliptin (Januvia)

• MOA
• Enhances the incretin system by inhibiting DPP-4,
  which breaks down GLP-1
• Helps to regulate glucose by affecting beta cells
  and alpha cells
• Adverse effects
• ( 5) stuffy or runny nose, sore throat, URI,
  and headache

46
Sitagliptin (Januvia)

• Advantages
• Does not cause weight gain
• Less GI side effects
• Safety concerns
• May effect other endogenous hormones
• No long-term studies published
• 52 week ongoing study of patients inadequately
  controlled on metformin monotherapy
• Pts randomized to either sitagliptin 100mg qd
  plus metformin or glipizide plus metformin
• Abstract suggested only HbA1c 0.67 decrease

Diabetes Care 2006. 29(12)2632-2637.
47
Cost Comparison
48
On the Horizon

• GLP-1R Agonists
• Liraglutide Novo Nordisk
• DPP-4 inhibitors
• Vildagliptin (Galvus) Novartis
• Saxagliptin
• Denagliptin

Lancet 20063681696-705.
49
Summary of Changesin 2007 Guidelines

• Revisions
• Components of the comprehensive diabetes
  evaluation revised
• Lowering A1C has been associated with a reduction
  of microvascular and neuropathic complications of
  diabetes and possibly macrovascular
• Medical nutrition therapy extensively revised
• Nephropathy
• Reduction of protein intake to 0.8-1.0 g/kg/day
  may improve measures of renal function

Diabetes Care 29S3, 2006
50
Summary of Changesin 2007 Guidelines

• Revisions
• Celiac disease
• Children with positive antibodies should be
  referred to a gastroenterologist for evaluation
• Children with confirmed celiac dz should have
  consultation with a dietitian and placed on a
  gluten-free diet

51
Summary of Changesin 2007 Guidelines

• Diabetes care in the hospital
• Using correction dose or supplemental insulin
  to correct premeal hyperglycemia in addition to
  scheduled prandial and basal insulin is
  recommended
• Preconception care
• Based on recent research, ACE inhibitors should
  also be D/Cd before conception

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Questions