Transcript 9 MB 2016 Book of Potions

BOOK OF POTIONS
UPDATE ON TYPE 2 DIABETES MEDICATIONS
CHRISTINE SUCHAN, APRN
APRIL 29, 2016
DISCLOSURES
NONE
OBJECTIVES
Identify insulin resistance versus insulin deficiency.
Identify AACE and ADA guidelines in Diabetes treatment.
Identify new classes of diabetes medications and their
mechanism of action.
TRIUMVIRATE
MUSCLE
LIVER
BETA CELL
PRIOR TO 2009
INSULIN RESISTANCE IN THE MUSCLE AND LIVER PLUS
BETA CELL FAILURE REPRESENTED THE CORE DEFECTS IN
TYPE 2 DIABETES
NOW
THE OMINOUS OCTECT
OMINOUS OCTET
MUSCLE
LIVER
BETA CELL
FAT CELL
GI TRACT
ALPHA CELL
KIDNEY
BRAIN
MUSCLE CELL
IMPAIRED GLUCOSE TRANSPORT ON THE SURFACE OF THE MUSCLE
CELL RESULT IN DECREASED GLUCOSE UPTAKE
LIVER
Liver is responsible for 50% of serum glucose in a fasting state
(Gluconeogenesis)
Liver has inappropriate response
Releases glucose inappropriately = increased glucose release in a
fasting and fed state.
BETA CELL
Aware of body’s sensitivity
Adjusts it’s insulin secretion to maintain normoglycemia.
Failure occurs earlier and more severe than previously
thought.
First = loss of beta cell mass
Second = decrease in cell function
BETA CELL
At Diagnosis: 80% beta cell loss
Cause:
1) aging
2) genetic
INSULIN RESISTANCE IS THE INVERSE OF INSULIN SENSITVITY
FAT CELL
Has 3 friends: muscle, liver and beta cell.
Dysfunctional fat cell results in:
Increased free fatty acid concentration
Increased gluconeogenesis
Inflammatory response = decrease adiponectin
Lipid overflow to muscle, liver and beta cell
GI TISSUE
Secretes 2 Hormones : GLP-1, GIP
GLP-1 Glucose Like Peptide 1
GIP – Gastrin Inhibitory Polypeptide
GLP-1
Secreted by the L cells of the distal small intestine.
Known to be deficient in Type 2 Diabetes.
It is a potent INHIBITOR of glucagon secretion.
GIP
Secreted by the K cells of the proximal small intestine.
Elevated GIP results in decreased insulin levels = beta cell
resistance.
PANCREATIC ALPHA CELL
Responsible for glucagon secretion.
Defective in Type 2 diabetes resulting in:
increased glucagon concentration
results in liver hypersensitivity = fasting hyperglycemia
KIDNEY
Kidney filters around 162 grams of glucose daily.
90% of glucose is reabsorbed by the SGLT -2 in the proximal tubule
and 10% reabsorbed by the SGLT-1 transporter in proximal tubule.
RESULT- NO GLUCOSE IN THE URINE.
Diabetic kidney is maladaptive so instead of dumping glucose into
the urine it reabsorbs more.
BRAIN
Now believed that insulin resistance in the liver, and muscle also
extends to the brain tissue.
Insulin is known to be appetite suppressant
This dysfunction contributes to increased food uptake and increases
obesity. (Leading to increased insulin resistance).
IMPLICATIONS FOR TREATMENT
ADA GUIDELINES
AACE GUIDELINES
BOTTOM LINE- MAKE A1C GOAL INDIVIDUALIZED TO PATIENT
TREATMENTS FOR HYPERGLYCEMIA
Medications that act on Sulfonylurea Receptor Complex
Medications that act on Insulin Target Cells
Medications that effect Glucose Absorption
Medications that act on the Beta Cell
Medications that block Glucose Reabsorption
Drugs that Replace Insulin
MEDICATIONS THAT ACT ON SULFONYLUREA
RECEPTOR COMPLEX
Sulfonylureas
Meglitinide Analogs
Phenylalanine Derivatives
SULFONYLUREAS
Stimulate the Beta Cell to produce more insulin.
Metabolized in the liver, excreted by the kidney and in the bile.
Contraindicated in liver disease and severe kidney disease.
Side Effects: Weight Gain, Hypoglycemia
SULFONYLUREAS
Glyburide – 1.25, 2.5, 5mg tablets
Maximum Dose: 10 mg as single dose
Half Life – 1-2 hours but biologic effect up to 24 hours as it
enters the beta cell as well as binds to the receptor.
Use cautiously in elderly patient because of beta cell binding
SULFONYLUREAS
Glipizide- 5mg and 10 mg tablets Also available ER.
Maintenance Dose: 20-40mg daily
Half Life: 1 hour
Preferable in elderly because of shorter half life.
SULFONYLUREAS
Glimepiride – 1, 2 and 4mg scored tablets.
Maintenance Dose: 8 mg – can be dosed 4mg twice daily or
8mg daily.
Half –Life : 5 hours
MEGLITINIDE ANALOGS
Binds to the sulfonylurea receptor =beta cell secretes more insulin
for short period of time.
Metabolized in the liver, excreted in urine.
Side effects: Weight gain, hypoglycemia
Useful in patients with kidney disease or sulfa allergy.
MEGLITINIDE ANALOGS
Repaglinide (Prandin) 0.5, 1 and 2mg tablets.
Half-Life: 1 hour
Administer 15 minutes prior to meal or snack.
Maximum Dose: 16 mg day
Better to use in patients with kidney impairment because of half-life.
MEGLITINIDE ANALOG-PHENYLALANINE DERIVATIVE
Nateglinide (Starlix): 60 and 120 mg tablet.
Half-Life: 1-1/2 hours.
Maximum Dose: 120 mg three times a day
Better to use in patients with kidney impairment.
MEDICATIONS THAT ACT ON INSULIN TARGET CELLS
Biguinides
Thalizolidinediones
BIGUINIDES
Metformin: IR 500, 850, 1000mg tablets;
ER 500 and 750 mg tablets
Maximum Dose: IR – 2500 mg in divided doses (2000 usually)
ER 2000mg once a day.
Half-Life: 1.5-3 hours
Tip: Give with food to increase absorption and decrease GI SE
Side Effects: Anorexia, nausea, flatulence, bloating, diarrhea, LACTIC
ACIDOSIS, macrocytic anemia secondary to decreased B12 absorption.
Use cautiously in history of CHF, alcohol abuse.
THALIZOLIDINEDIONES (TZD)
Activates nuclear receptor(PPARy):
increases glucose transport into the cell,
decreases fatty acid levels,
decreases hepatic glucose output
decreases resistin release from adipocytes.
Metabolized in Liver, excreted in urine and feces.
Side Effects: Edema, weight gain (central).
Contraindicated in Liver Disease, Class III and IV Heart Failure.
TZD
Rosiglitazone (Avandia): 4 and 8mg tablets.
Half-Life: 3-4 hours.
Maximum Dose: 8 mg.
Pioglitazone (Actos): 15, 30, 45 mg tablets.
Half-Life: 3-7 hours – Metabolite 24 hours
Maximum Dose: 45 mg.
MEDICATIONS THAT AFFECT GLUCOSE ABSORPTION
Inhibits glucose absorption at brush border in the intestine.
Metabolized: GI tract.
Excreted: Excreted Feces and Urine.
SE: Flatulence, diarrhea, abdominal pain, increased LFT’s, ileus
Contraindicated: GI disease, Malabsorption Syndromes, Cirrhosis
and Creatinine >2.0.
ALPHA GLUCOSIDASE INHIBITORS
Acarbose (Precose): 50 and 100 mg tablets.
Given start of each meal.
Maximum Dose: 100 mg three times daily.
Miglitol (Glycet): 25, 50, 100 mg tablets.
Start 25mg three times daily for 4-8 weeks
Maximum Dose: 100 mg three times daily.
INCRETINS
Increases gut hormone = increases post meal insulin secretion
Need a functioning beta cell.
Natural occurring GLP-1 half-life is only 1-2 minutes.
2 Classes of medications: GLP-1 Receptor Analogs and DDP4
Inhibitors.
DPP-4 INHIBITORS
DPP-4 = Dipeptidyl Peptidase IV
Inhibits the enzyme which breaks down GLP-1.
Increases longer action of natural GLP-1 and GIP.
Increases insulin synthesis.
Metabolized: Liver, Excreted Urine.
Side Effects: Nasopharyngitis, URI, Pancreatitis.
Contraindicated: Type 1 Diabetes, DKA, Pancreatitis, or History of
Pancreatitis.
DPP-4 INHIBITORS
Sitagliptin(Januvia): 25, 50, 100mg tablets.
Maintenance: 100 mg, decrease to 50 if Cr Cl 30-50; 25 if <30.
Half-Life: 12.4 hours
Saxagliptin(Onglyza): 2.5, 5 mg tablet.
Maintenance: 2.5 or 5mg, decrease to 2.5mg if Cr Cl <50.
Half-Life: 2.5 hr, Metabolite 3.1hr.
DPP-4 INHIBITORS
Linagliptin(Tradjenta): 5mg tablets.
Half-Life: 12 hours. Safe for Cr Cl <50.
Alogliptin (Nesina): 6.25, 12.5, 25 mg tablets.
Half-Life: 21 hours
Maintenance: 25 mg daily, 12.5 mg CrCl 30-59; 6.25mg CrCl <30.
GLP-1 ANALOGS
Injectable only.
Increases GLP-1 to super-physiologic levels.
Reduces hepatic glucose production.
Augment beta cell function.
Stimulates brain to reduce appetite.
GLP-1 ANALOGS
Exenetide (Byetta)
5mg or 10 mg pen, twice daily 60 minutes before the meal.
Half-Life: 2.4 hours
SE: Nausea, vomiting, diarrhea, headache, nephrotoxicity,
pancreatitis, weight loss
Contraindicated: GI disease, Gastroparesis, history of pancreatitis,
Cr Cl <30, Type 1 Diabetes
GLP-1 ANALOGS
Exendrin 4 (Bydureon): 2mg Reconsituted Pen.
Once weekly – same day
Half-Life: ~2 weeks
SE:: same as Byetta, also “bumps” at injection site.
Takes 6-8 weeks to get to steady state.
GLP1 ANALOGS
Liraglutide(Victoza): 1.8mg pen
Given SQ daily, begin at 0.6mg titrate weekly.
Half-Life: 11 hours
Excreted in urine.
Contraindications: same as GLP-1 class , history of medullary thyroid
cancer, family history of medullary thyroid cancer or MEN2
GLP-1 ANALOG
Abiglutide (Tanzeum): 30mg; 50mg pen – needs reconstitution.
Once weekly injection.
Half-Life 5 days.
Contraindications: Same as Liraglutide.
GLP-1 ANALOGS
Dulaglutide (Trulicity): 0.75 and 1.5mg pen SQ weekly.
Half-Life: 5 days
Contraindications: Same as Liraglutide.
MEDICATIONS THAT BLOCK GLUCOSE REABSORPTION
Inhibits the sodium-glucose cotransporter 2 (SGLT2) =
1) reduction in the amount of glucose reabsorption
2) increases urinary excretion of glucose
Canafliflozin (Invokana) ; Dapagliflozin(Farxiga); Empagliflozin
(Jardiance)
SGLT-2
Canagliflozin (Invokana): 100 and 300mg tablets.
Administer before first meal.
Half-Life: 10.6-13.1 hours
Metabolized in the liver, excreted urine and feces.
SE: Hyperkalemia, genital mycotic infections, hypoglycemia,
UTI, hypotension, pancreatitis, elevated creatinine,
possible DKA.
Contraindications: Type 1 Diabetes, Volume Depletion, GFR <45
SGLT-2
Dapagliflozin (Farxiga): 5 and 10 mg tablet.
Half-Life: 12.9 hours.
Do not use if GFR less than 60.
Contraindications: Same as Canagliflozin.
SGLT-2
Empagliflozin (Jardiance): 10 and 25 mg tablet.
Half-Life: 12 hours.
Discontinue if GFR <45.
Contraindications: Same as Canagliflozin.
OTHER MEDICATIONS
Pramlintide
Bromocriptine
Colesevelam
Insulin
PRAMLINTIDE
TRADE NAME: SYMLIN - Type 1 and Type 2 Diabetes
An amylin mimetic:
1) suppresses plasma glucagon secretion from the liver,
2) slows gastric emptying
3) promotes satiety (similar to GLP-1)
Half-Life: 48 minutes
Administer SQ before meals. T1- 60 mg tid, T2 120 mg tid.
Contraindications: Gastroparesis, A1c >9.0% hypoglycemia unawareness
SE: nausea, headache, anorexia, arthralgias, hypoglycemia, dizziness.
BROMOCRIPTINE
Trade Name: Cyclocet
Mechanism of Action:
1) stimulates Dopamine receptorsin brain
2) inhibits anterior pituitary prolactin,
3) BUT precise mechanism of action in Diabetes is unknown.
Supplied: 8 mg tablet given with food within 2 hours of awakening.
Max Dose: 4.8 mg daily
Half-Life: 4-4.5 hours, Metabolite 15 hours.
SE: Hypotension, syncope, hypoglycemia, nausea, rhinitis, dyspepsia, somnolence.
Contraindications: Migraines, syncope, breastfeeding, psychosis, renal impairment.
COLESVELAM
Trade Name: Welchol
Mechanism of Action: Binds intestinal bile acids, in DM unknown.
Supplied: 625mg tablets, 1875 or 3750 mg powder packets.
Administer: 4 hours after all medications, either BID or 3750 QD.
No systemic absorption.
SE: Rash, oral blisters, intestinal obstruction, fecal impaction, pancreatitis.
Contraindications: GI obstruction, GI motility disorders
Case Studies
Martina is a 38 yo Latino female
Diagnosed 2 years ago
History of gestational 4 years ago, diet controlled (baby 8# 3oz)
Ht: 66 inches, Wt: 179#; BMI 29 kg/m2
PMH: Irritable bowel with diarrhea dominant (no treatment)
FMH: DM2 (F, S, S)
Non-Smoker
Works Full Time as Dentist (50 hrs weekly)
Today: A1c is 7.1%.
BP: 132/70 ; P76
THOUGHTS FOR TREATMENT
CASE STUDY
James is a 69 yo AA male
Diabetes for 15 years
Complications of retinopathy, polyneuropathy
History CAD (MI 11 Years ago)
Current Meds: Metformin 1000mg twice daily; Pioglitazone 30 mg daily, Glimepiride 4mg Daily
A1c today is 7.9%. GFR 63 ml/min; Cr. 1.2
THOUGHTS
SOURCES
AACE Comprehensive Diabetes Management Algorithm 2015
ADA Standard of Medical Care in Diabetes 2015, Diabetes Care, 2015
Diabetes Best Clinical Practice and Research Compendium, 2006 Elsevier
From the Triumvirate to the Ominous Octet; Ralph DeFronzo, Diabetes, April 2009, Vol 54
Greenspan’s Basic & Clinical Endocrinology, 9th Edition; 9th Edition, David Gardner, Dolores
Shoback