Transcript Template #2

Oral diabetes Medications
P. Akhavan, M.D
Agenda
• Advantages and disadvantages of oral
antihyperglycemic agents
• Approaches to Glycemic Treatment (oral
agent)
• Noninsulin antihyperglycemic agent in GDM
Biguanides
 Activates AMP-kinase(? other)
• ↓ Hepatic glucose production increase
insulin-mediated peripheral glucose uptake
 Efficacy
:Reduce A1C 1.0-2.0%
 Advantages : Extensive experience
No hypoglycemia ,↓ CVD events (UKPDS)
No weight gain, with possible modest weight
loss
Biguanides
 Disadvantages
• Gastrointestinal side effects (diarrhea
abdominal cramping)
• Vitamin B12 deficiency
• Lactic acidosis risk (rare)
• Multiple contraindications: CKD, acidosis,
hypoxia, dehydration, etc
Sulfonylureas

Closes KATP channels on beta-cell
plasma membranes
• ↑ Insulin secretion
 Efficacy
– Decrease fasting plasma glucose 60-70 mg/dl
– Reduce A1C by 1.0-2.0%
 Advantages
• Extensive experiencec
• ↓ Microvascular risk(UKPDS)
Sulfonylureas
Disadvantages
• Hypoglycemia
Shorter acting sulfonylureas, such as
glipizide and gliclazide, are less likely to
cause hypoglycemia than the older, longacting sulfonylureas and therefore are the
preferred sulfonylureas, especially in older
patients.
• ? Blunts myocardial ischemic
Gliclazide are selective for the pancreatic
sulfonylurea receptors over the cardiac
receptors
• Do not appear to be associated with
increased cardiovascular mortality
compared with metformin or other
diabetes medications,
 although direct controlled clinical trials
have not been performed
j clin Endocrinol Metab 2010;95:4993
Hazard ratios (95% CI) for different endpoints in relation to monotherapies with different
glucose-lowering agents according to previous myocardial infarction.
Schramm T K et al. Eur Heart J 2011;32:1900-1908
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author
2011. For permissions please email: [email protected]
Meglitinides
• Closes KATP channels on beta-cell plasma
membranes
• ↑ Insulin secretion
 Efficacy
– Decreases peak postprandial glucose
– Decreases plasma glucose 60-70 mg/dl
– Reduce A1C 1.0-2.0%
Advantages
• Postprandial glucose excursions
• Dosing flexibility
Meglitinides
 Disadvantages
o Hypoglycemia (although may be less than with
sulfonylureas if patient has a variable eating
schedule)
o ↑ Weight
o Frequent dosing schedule
o ? Blunts myocardial ischemic
Thiazolidinediones
• Activates the nuclear transcription factor
PPAR-g
• ↑ Insulin sensitivity
Efficacy
– Decrease fasting plasma glucose ~35-40
mg/dl
– Reduce A1C ~0.5-1.4%
– 6 weeks for maximum effect
Thiazolidinediones
Advantages
•
•
•
•
•
No hypoglycemia
Durability
↑ HDL-C
↓ Triglycerides (pioglitazone)
? ↓ CVD events(PROactive,pioglitazone)
Thiazolidinediones
 Disadvantages
• ↑ Weight
• Edema/heart failure
• ↑ LDL-C (rosiglitazone) ?
• ↑ MI (meta-analyses, rosiglitazone
• Bone fractures
• Bone fracture
 In a large population-based study using
the UK-based General Practice Research
Database, both pioglitazone (OR 2.59, 95%
CI 0.96-7.01) and rosiglitazone (OR 2.38,
95% CI 1.39-4.09) were associated with
low-trauma fracture in men and women
intern Med 2008;168;8220
• bladder cancer
In the PROactive trial , there were more
cases of bladder cancer (14 versus 5) in
the pioglitazone than placebo group .
Drug saf 2009;32:187

In a10-year observational study of pioglitazone
use in patients with diabetes,
 there was not a significant association between
pioglitazone exposure and bladder cancer among
patients with median duration of therapy of two
years (HR for bladder cancer 1.2, 95% CI 0.9-1.5) .
 However, the risk of bladder cancer was
significantly increased in those with the longest
exposure to pioglitazone and to those exposed to
the highest cumulative dose.
Diabetes care 2011;34916
Thiazolidinediones
• In data from several double blind trials with
rrosiglitazon and pioglitazone involving over
5000 patients, fewer than 0.3 percent of
patients had alanine aminotransferase levels
more than three times the upper limit of
normal and no patients had values more than
10 times the upper limit of normal.
Thiazolidinediones
• US FDA currently recommends that patients
receiving pioglitazone or rosiglitazone undergo
baseline testing followed by periodic
monitoring of liver function based upon
clinical judgment.
Diabetes care 2002;25:815
Thiazolidinediones
Macular edema has been reported in patients
taking thiazolidinediones, though the
frequency of occurrence is unknown .
 Patients at greatest risk seem to be those
who are also at risk for peripheral edema
Alpha-glucosidase Inhibitors
• Inhibits intestinal a-glucosidase
• Slows intestinal carbohydrate
digestion/absorption
Efficacy : Decrease A1C 0.5-0.8%
 Advantages
• No hypoglycemia
• ↓Postprandial glucose excursions
• ? ↓ CVD events(STOP-NIDDM)
• Nonsystemic
Alpha-glucosidase Inhibitors
Disadvantages
• Generally modest A1C efficacy
• Gastrointestinal side effects (flatulence,
diarrhea)
• Frequent dosing schedule
DPP-4 inhibitors
• Inhibits DPP-4 activity, increasing
postprandial active incretin (GLP-1, GIP)
concentrations
• ↑ Insulin secretion(glucose-dependent)
• ↓ Glucagon secretion (glucose-dependent)
 efficacy :
Reduce A1C ~0.5-0.8%
the efficacy and safety of adding sitagliptin or glimepiride to the
metformin regimen
Diabetes, Obesity and Metabolism 13: 160–168, 2011.
DPP-4 inhibitors
 Advantages
• No hypoglycemia
• Well tolerate
DPP-4 inhibitors
 Disadvantages
• Angioedema/urticaria and other immunemediated dermatological effects
• ? ↑ Heart failure hospitalizations
• ? Acute pancreatitis
SGLT2 Inhibitor
• Inhibits SGLT2 in the
proximal nephron
• Blocks glucose
reabsorption by the
kidney, increasing
glucosuria
• Lowers A1C by 0.60.8%
SGLT2 inhibitors
Canagliflozin
Dapagliflozin
Empagliflozin
Advantages
• No hypoglycemia
• ↓ Weight ( 2-3% body weight loss)
• ↓ Blood pressure
SGLT2 inhibitors
Disadvantages
•
•
•
•
•
Genitourinary infections
Polyuria
Volume depletion/hypotension/ dizziness
↑ LDL-C
↑ Creatinine (transient)
Oral diabetes Medications in
type 1 diabetes
• Metformin
Adding metformin to insulin
therapy may reduce insulin
requirements and improve
metabolic control in
overweight/obese patients
with poorly controlled type 1
diabetes.
Incretin-Based Therapies
• Therapies approved for the treatment of
type 2 diabetes are currently being
evaluated in type 1 diabetes.
• GLP-1 agonists and DPP-4 inhibitors are
not currently FDA approved for those with
type 1 diabetes, but are being studied in
this population.
SGLT2 inhibitors
• There are insufficient data to recommend
clinical use in type 1diabetes at this time
Antihyperglycemic therapy in
type 2 diabetes
• A patient-centered
approach should be
used to guide choice of
pharmacological agents.
• Consider initiating combination insulin
injectable therapy when blood glucose
is>300–350 mg/dL and/or A1C is >10–12%.
• For all patients, consider initiating therapy
with a dual combination when A1C is >9%
to more expeditiously achieve the target
A1C level
• A comparative effectiveness metaanalysis suggests that overall each new
class of noninsulin agents added to initial
therapy lowers A1C around 0.9–1.1%.
Ann Intern Med 2011;154:602–613
• Rapid-acting secretagogues (meglitinides)
may be used instead of sulfonylureas in
patients with irregular meal schedules or
who develop late postprandial
hypoglycemia on a sulfonylurea effects.
• Other drugs not shown in the figure (e.g.,
a-glucosidase inhibitors, colesevelam,
bromocriptine, pramlintide) may be tried in
specific situations, but are generally not
favored due to modest efficacy, the
frequency of administration,and/or side
effects
Noninsulin antihyperglycemic agent in
GDM
• Randomized controlled trials support the
efficacy and short-term safety of glyburide
(11) (pregnancy category B) and metformin
(12,13) (pregnancy category B) for the
treatment of GDM.
• However, both agents cross the placenta, and
long-term safety data are not available (14).
Diabetes Care 2015;38
Insulin is the preferred agent for management
of diabetes in pregnancy because of the lack
of long-term safety data for noninsulin agents.
Diabetes Care 2015;38
 Metformin therapy can be used for glycemic
control only for those women with gestational
diabetes
 who do not have satisfactory glycemic control
despite medical nutrition therapy
 and who refuse or cannot use insulin
 and are not in the first trimester.
Endocrine Society, 2013
• Breastfeeding women with overt diabetes
successfully using metformin or glyburide
therapy during pregnancy should continue to
use these medications, when necessary,
during breastfeeding.
Endocrine Society, 2013
• Metformin use by the breastfeeding
woman vs. formula feeding appears to
have no adverse effects on infant growth,
motor-social development, and
intercurrent illness during the first 6
months of life .
• Glyburide was not detected in breast milk,
and hypoglycemia was not observed in
nursing infants of women using glyburide