Transcript Oral Agents*The Old and New in the Management of T2DM

ORAL AGENTS— OLD &
NEW FOR THE
MANAGEMENT OF T2DM
VERONICA BRADY, PHD, FNP-BC, BC- ADM, CDE
ECHO-Diabetes
July 21 , 2016
OBJECTIVES
 Overview of Diabetes
 Oral hypoglycemic agents
 Define various classes of medications
 Describe mechanisms of action
 Define indications/contraindications for use
Q&A
DIABETES – THE FACTS
 29.1 million in US ( 9.3% of population)
 Nearly 1/3 (27.8%) unaware that they have diabetes
 7 th leading cause of death in the US in 2010
 More than 234,051 death certificates list diabetes as
underlying cause in 2010
 Cost of care $245 billion—2.3 x higher medical
expenditures for people with DM
 Increasing prevalence in children and adults
CDC.gov/diabetes, 2014
As many as 1 in 3 US adults
could have diabetes by 2050
 CDC.gov/diabetes
TYPE 2 DM
 Formerly Non-insulin Dependant Diabetes (NIDDM)
 Heterogeneous disorder
 Variable plasma insulin levels-low or high
 Peripheral insulin resistance
 Associated with increased CV risk
PATHOPHYSIOLOGIC DEFECTS IN T2DM

Diagram used in talk in 2008
PATHOPHYSIOLOGIC DEFECTS IN T2DM
Pancreas
Adipose
Tissue
Intestine
Kidney
Liver
DeFronzo,R. 2009 Diabetes
Brain
Muscle
Kendall. GLP-1 based therapies, Medscape. Accessed 9-7-14
TARGETS FOR THERAPY IN DIABETES
Evans, J.L & Rushakoff, R.J, 2010, Endotext.org
Medication Class
Year
HbA1c %
reduced
PO
1946
1.5
PO
1995
0.5-0.8
PO
PO
PO
The NEW
PO
PO
PO
The NOVEL
PO
1995
1997
1999
1.5
1-1.5
0.8-1.0
2006
2008
2009
0.5-0.8
0.5 with metformin
0.5-0.9
2013
0.91-1.16
Route
The OLD
Sulfonylurea
Alpha-glucosidase
inhibitor
Biguanide
Meglitinides
Thiazolidinedione
DPP-4 inhibitors
Bile acid sequestrin
Dopamine agonist
SGLT2 inhibitor
ORAL HYPOGLYEMIC
AGENTS (OHA)
SULFONYLUREAS
Increases insulin secretion in people with
capacity to produce insulin, may also decrease
the rate of hepatic glucose production, and
increase insulin receptor sensitivity and increase
the number of insulin receptors
SULFONYLUREAS
Lowers HbA1c
1.5%
Main Benefits
Can be used as monotherapy or in combination with other
oral agents (with the exception of glinides) or with insulin
Common adverse Hypoglycemia, weight gain
effects
Cautious Use
Impaired renal and hepatic function, adrenal or pituitary
insufficiency, elderly, malnourished
Contraindications Ketoacidosis
SULFONYLUREAS
 Considerations:
 Lead to progressive decline in β-cell function
 No protective effect against atherosclerotic cardiovascular
complications
 Within 3 years most patients require 2 nd anti-diabetic
medication
Defronzo, 2009. Diabetes
SULFONYLUREAS
Name
Dose Available mg
Usual Start Dose mg Max Dose mg
Glimepiride
(Amaryl)
1, 2, 4
1–2 qd
Max Dose: 8
Glipizide
(Glucotrol)
5, 10
5 qd
Max Dose: 20 qd
Glipizide ext-rel
(Glucotrol XL)
5, 10
5 qd
Max Dose: 20 qd
Glyburide
(Diabeta)
1.25, 2.5, 5
2.5 – 5; 1.25 for
elderly
Max Dose: 20 qd
2.5 – 5; 1.25 for
elderly
Max Dose: 20 qd
Glyburide
1.5, 3, 6
(Glynase Pres Tab)
ALPHA-GLUCOSIDASE INHIBITORS
Inhibits enzyme that facilitates
breakdown of complex sugars to glucose
in the small intestine, causes
malabsorption of carbohydrates
ALPHA-GLUCOSIDASE INHIBITORS
Lowers HbA1c
0.5-0.8%
Improves postprandial blood glucose. Does not cause
hypoglycemia or weight gain
Common adverse Abdominal pain, diarrhea, elevated serum transaminases,
effects
flatulence
Main Benefits
Concurrent use with sulfonylureas, If hypoglycemia occurs,
treat with oral dextrose not sucrose
Contraindications Hypersensitivity, diabetic ketoacidosis, cirrhosis,
inflammatory bowel disease, colonic ulceration, partial
intestinal obstruction
Cautious Use
ALPHA-GLUCOSIDASE INHIBITORS
Name
Dose Available mg
Usual Start Dose
mg
Max Dose mg
Acarbose
(Precose)
25, 50, 100
25 tid
Max Dose: Adult:
150/d < 60 kg,
300/d > 60 kg
Miglitol
(Glyset)
25, 50, 100
25 tid
Max Dose: 300
BIGUANIDES
Decreases hepatic glucose production, decreases
GI glucose absorption, increase target cell insulin
sensitivity,reduces appetite, improves glucose
uptake by fat/muscles
BIGUANIDES
Lowers HbA1c
1.5%
Main Benefits
Decreases blood glucose without causing hypoglycemia or weight
gain, low cost
Nausea, vomiting, diarrhea, flatulence, low serum B12. May cause
ovulation in anovulatory and premenopausal PCOS patients
Common adverse
effects
Cautious Use
Contraindications
Malnourished, debilitation, infection-induced stress, fever, trauma,
elderly
BLACK BOX WARNING: lactic acidosis is rare but potentially severe
Do not use /discontinue in unstable, acute CHF if risk of
hypoperfusion and hypoxemia, renal dysfunction (creatinine > 1.4 in
women, and > 1.5 in men, dehydration, sepsis, surgery, tests
involving the injection of dye, hepatic disease, excessive or chronic
alcohol consumption, hypersensitivity, DKA metabolic acidosis
BIGUANIDES
Name
Dose Available mg
Usual Start Dose
mg
Metformin
(Glucophage)
500, 850, 1000
500 bid or 850 qd
Metformin Ext-rel
(Glucophage XR,
Fortamet
500, 750
500 bid or 850 qd
Metformin Oral
Solution
(Riomet)
100/ml
500 bid or 850 qd
Max Dose mg
Max Dose: 2550
qd; Contra:
renal/hepatic
disease
Max dose: 2500;
Contra in
renal/hepatic
disease
Max Dose: 2550
qd; Contra in
renal/hepatic
disease
BIGUANIDES
 Considerations:
 May be safe for use in patients with slightly elevated
Cr—if it has been stable (1.4-1.7mg/dL), patient does
not drink alcohol and dose not have large areas of
tissue damage
 May be used in patients with IFG/IGT
 Metformin is not metabolized and most of drug is
excreted in the urine (Barieri, et al. 2014. Uptodate)
MEGLITINIDES
 Increases insulin secretion by binding to K+ channels
on beta islet cells. Repaglinide is metabolized by the
liver enzymes CYP3A4 & CYP2C8. Nateglinide is
metabolized by hepatic cytochrome P450 CYP2Cp
(70%) and CYP34A (30%)
MEGLITINIDES
Lowers HbA1c
1-1.5%
Main Benefits
Increases insulin levels for a short period of time compared to
sulfonylurea agents. Meglitinides have a lower risk of
hypoglycemia compared to sulfonylureas. Good for those who skip
meals.
Common adverse
effects
Hypoglycemia (less risk compared to sulfonylureas)
Cautious Use
Renal insufficiency, liver disease, use with insulin, adrenal
insufficiency, surgery, trauma, elderly, pituitary insufficiency,
malnourished
Contraindications
Ketoacidosis, allergy to medication, Type 1 diabetes, used with
gemfibrozil results in increased repaglinide plasma concentrations
8-fold and may result in severe hypoglycemia
MEGLINITIDES
Name
Dose Available mg
Usual Start Dose
mg
Nateglinide
(Starlix)
60, 120
120 tid;
Max Dose: 360 qd;
Can start at 60 tid if
A1c near target
Caution:
hepatic/renal
impairment
Repaglinide
(Prandin)
0.5, 1, 2
0.5 ac if A1c < 8
Max Dose: 16 qd;
Caution :hepatic
impairment
Max Dose mg
THIAZOLIDINEDIONES
 Improves target cell response to insulin, Increases
glucose uptake by muscle and fat and decreases
hepatic gluconeogenesis. Metabolized to active
metabolites by hepatic CYP2C8 & CYP34A
THIAZOLIDINEDIONES
Lowers HbA1c
0.8-1%
Main Benefits
Improves blood glucose control without hypoglycemia
Common adverse
effects
Bladder cancer risk (not significant), increased risk of fracture in
females, may causes ovulation in females in some premenopausal
anovulatory women, weight gain, edema
If ALT increases to 3 x UNL, stop treatment, if 1.5-3 x ULN retest
weekly until normal or until 3 x UNL and need to discontinue,
dyspnea, rapid weight gain, combination with used with insulin or
other oral diabetes agents
Cautious Use
Contraindications
BLACK BOX WARNING: Active bladder cancer. Do not use if NYHA
class III or IV heart failure, diabetic ketoacidosis, hypersensitivity,
type 1 diabetes, moderate-severe hepatic impairment (ALT > 2.5
UNL)
THIAZOLIDINEDIONES
Name
Dose Available mg
Usual Start Dose mg Max Dose mg
Pioglitizone
(Actos)
15, 30, 45
15 or 30 qd
Max Dose: 45 qd;
Contra in Class III or
IV HF
Rosiglitizone
(Avandia)
2, 4, 8
4 qd or 2 bid
Max dose: 8 qd
DIPEPTIDYL PEPTIDASE 4 INHIBITOR
 Increases and prolongs incretin hormone activity that
is inactivated by DPP-4 activity; metabolism limited,
primarily by CYP3A4
 Reduces fasting and post prandial glucose
concentrations by increasing insulin release and
decreasing glucagon concentration.
DIPEPTIDYL PEPTIDASE 4 INHIBITOR
Lowers HbA1c
0.5-0.8%
Main Benefits
Improves blood glucose control without risk of hypoglycemia or
weight gain, can be use with SU, Biguanides, TZDs, & insulin
Common adverse
effects
Few, comparable to placebo, abdominal pain, diarrhea,
nasopharyngitis, nausea headache, URI (sciatic nerve pain)
Cautious Use
Renal impairment, acute pancreatitis, use with insulin or
sulfonylureas
Contraindications
Type 1 diabetes, diabetic ketoacidosis; do not use with GLP-1
analog
DIPEPTIDYL PEPTIDASE 4 INHIBITOR
Dose Available
mg
25, 50, 100
Usual Start Dose mg
Max Dose mg
100 qd
Max Dose 100; Cr Cl
30-50: 50 qd, Cr Cl <
30: 25 qd
Saxagliptin
(Onglyza)
2.5, 5
Linagliptin
(Tradjenta)
5
Alogliptin
(Nesina)
6.25, 12.5, 25
2.5-5 qd
5
Reduce to 2.5 if CrCl <
50
1 dose for all. No
5
adjustments for renal
failure
25
25
CrCl 30-59; 12.5
CrCl <30:6.25
Name
Sitagliptin
Phosphate
(Januvia)
BILE ACID SEQUESTRANT
Binds with bile acids in the intestine thereby impeding their
reabsorption. As the bile acid pool is depleted, the hepatic
enzyme, cholesterol 7-alpha-hydroxylase is upregulated, which
increases the conversion of cholesterol to bile acids. The
mechanism of action for reducing blood glucose is unknown.
BILE ACID SEQUESTRANT
Lowers HbA1c
0.5-0.6%
Main Benefits
Lowers both HbA1c and LDL
Common adverse Constipation, dyspepsia, nausea, dysphagia
effects
Biliary obstruction, breast-feeding, children, cholelithiasis,
coagulopathy, constipation, dysphagia, gastroparesis,
hemorrhoids, ileus, phenylketonuria, pregnancy, surgery,
vitamin K deficiency
Contraindications Ketoacidosis, GI obstruction, hypertriglyceridemia,
pancreatitis
Cautious Use
BILE ACID SEQUESTRANT
Name
Dose Available mg
Usual Start Dose
Max Dose
Colesevelam
(Welchol)
625
3 tab bid, or 6 tab
qd
Max Dose: 7 tab/day
DOPAMINE AGONIST
 Synthetic dopamine agonist. The mechanism of
action is not understood but thought that stimulating
dopamine receptors in the brain at certain times of
the day “resets” the biological clock and improves
metabolism.
DOPAMINE AGONIST
Lowers HbA1c
0.3-0.5%
Main Benefits
Postprandial glucose concentrations were improved without
increasing plasma insulin concentrations
Common adverse
effects
GI upset, fatigue, dizziness, headache, hypotension, syncope,
somnolence, hypoglycemia
Cautious Use
Abrupt discontinuation, acute MI, angina, bipolar disorder, cardiac arrhythmias,
cardiac disease, children coronary artery disease, dementia, depression, driving or
operating machinery, geriatric, GI bleed, hepatic disease, hypotension, peptic ulcer
disease, peripheral vascular disease, pregnancy, pulmonary fibrosis, renal disease,
renal impairment, retroperitoneal fibrosis, schizophrenia, surgery
Contraindications
Ketoacidosis, type 1 diabetes, basilar/hemiplegic migraine, breast-feeding,
eclampsia, ergot alkaloid hypersensitivity, hypertension, preeclampsia
DOPAMINE AGONIST
Name
Dose Available mg
Usual Start Dose
mg
Max Dose mg
Bromocriptine
(Cycloset)
0.8
0.8 qd in the
morning within 2
hours of waking,
increase the dose
by 0.8/d no more
frequently than
every 1 week
Max Dose: 1.6-4.8
qd
SODIUM-GLUCOSE CO-TRANSPORTER 2
(SGLT2)
 Blocks the reabsorption of glucose by the kidneys
which results in increased glucose excretion and
lower blood glucose concentrations in patients with
type 2 diabetes
SODIUM-GLUCOSE CO-TRANSPORTER 2
(SGLT2)
Lowers HbA1c
0.8% with the 100 dose
1.03% with the 300 dose
Main Benefits
Weight loss, low risk of hypoglycemia
Common adverse
effects
Female genital mycotic infections, urinary tract infection,
increased urination (bone fractures 6% @ 104 weeks)
Cautious Use
Adrenal insufficiency, balanitis, breast-feeding, children,
dehydration, diabetic ketoacidosis, fever, geriatric, hepatic
disease, hypercholesterolemia, hypercortisolism, hyperglycemia,
hyperkalemia, hyperthyroidism, hypoglycemia, vaginitis, renal
impairment, pregnancy, pituitary insufficiency, neonates,
malnutrition, infants
Contraindications
Ketoacidosis, dialysis, renal failure, type 1 diabetes
SODIUM-GLUCOSE CO-TRANSPORTER 2
(SGLT2)
Name
Dose Available mg
Usual Start Dose
mg
Max Dose mg
Canaglidlozin
(Invokana)
100, 300
Max Dose: 300 qd
Dapagliflozin
(Farxiga)
5,10
100 qd taken
before 1st meal of
the day
5
Empagliflozin
(Jardiance)
10,25
10
25
10
Do not use if
CrCl<60
COMBINATION ORAL AGENTS
Name
Dose Available mg
Usual Start Dose mg Max Dose
Glipizide +
metformin
(Metaglip)
2.5/250; 2.5/500;
5/500
2.5/250 qd If BG
280-320 mg /dL
start 2.5/500 bid
Max Dose: 20/2000
Glyburide +
metformin
(Glucovance)
1.25/250; 2.5/500;
5/500
1.25/250 qd or bid
Max Dose: 20/2500
Linagliptin +
metformin
(Jentadueto)
2.5/500; 2.5 850;
2.5/1000
If new to metformin: Max Dose: 2.5/1000
2.5/500 bid;
bid
previously on
metformin:
2.5/current dose of
metformin bid
COMBINATION ORAL AGENTS
Pioglitizone +
glimepiride
(Duetact)
30/2; 30/4
If on previously
start with usual
dose. If not, start
30/2 or 30/4 daily
Max dose: 30/4
Pioglitizone +
metformin
(Actoplus Met)
15/500, 15/850
15/500 qd or bid;
15/850 qd or bid
Max Dose: 45/2550
Pioglitizone +
metformin XR
(Actoplus Met XR)
15/500, 15/ 850
15/500 qd or bid;
15/850 qd or bid
Max Dose: 45/2550
COMBINATION ORAL AGENTS
Repaglinide +
metformin
(PrandiMet)
1/500; 2/500
1/500 with meals Max Dose:
10/2500
Rosiglitizone +
glimepiride
(Avandaryl)
4/1; 4/2; 4/4
4/1 qd
Max Dose: 4 /4
Rosiglitizone +
metformin
(Avandamet)
1/500; 2/500;
4/500;
2/1000; 4/1000
2/500 qd or bid
Max Dose:
8/2000; Conta in
Class III or IV HF
COMBINATION ORAL AGENTS
Sitagliptin
phosphate +
metformin
(Janumet)
50/500; 50/1000
50/500 bid
Max Dose:
100/2000
Sitagliptin
phosphate +
metformin XR
(Janumet XR)
50/500; 50/1000;
100/1000
50/500 bid
Max Dose:
100/2000
Sitagliptin +
simvastatin
(Juvisync)
50/10; 50/20;
50/40; 100/10;
100/20; 100/40
100/40 qd. If
already on
simvastatin:
100/current
simvastatin dose
100/40
COMBINATION ORAL AGENTS
Saxagliptin +
metformin XR
(Kombiglyze XR)
5/500; 5/1000;
2.5/1000
Take daily in the
evening
Max: 5/2000
KEY POINTS (ADA-EASD)
D I A B E T E S C A R E , D I A B E T O LO G I A . 1 9 A P R I L 2 01 2
 Glycemic targets & BG-lowering therapies must be
individualized.

 Diet, exercise, & education: foundation of any T2DM therapy
program
 Unless contraindicated, metformin = optimal 1st -line drug.
 After metformin, data are limited. Combination therapy
with 1-2 other oral / injectable agents is reasonable;
minimize side ef fects.
KEY POINTS (CONT)
 Ultimately, many patients will require insulin therapy alone /
in combination with other agents to maintain BG control .
 All treatment decisions should be made in conjunction with
the patient (focus on preferences, needs & values .)
 Comprehensive CV risk reduction - a major focus of therapy.
QUESTIONS?