Drug

MOA

Weig
ht
loss?

Metformin
(Biguinide)

insulin
sensitivity of
hepatic and
periph (muscle)
tissue
-Dominant
effect:
gluconeogen in
liver
-independent of
-cells
insulin
secretion by
reduced K+
channel
conductance

Meglitinides
(repaglin
= benzoic
acid derive
nateglin =
Dphenylalani
ne derive)

insulin
secretion by
reduced K+
channel
conductance

TZD
(Rosi =
LAST
LINE!!!)

insulin
sensitiv.
(indirect)
- CHO&lipid
metabolism
- Muscle/adipose

Sulfonylure
as

Effect on Insulin
Resistance

T2DM Medications
Advantages

BP (even in nondiabetics)
total cholesterol
LDL cholesterol
Triglycerides

In newly dxs obese

pts:
in macrovascular
events
mortality
diabetes-related
endpoints
No hypoglycemia

Both fasting and pp mortality and

insulin rls
macrovascular
complications
insulin sensitivity
insulin binding
hepatic glucose
production
stimulate glucose
utilization
No in fasting insulin
Faster onset that
levels => can dose
sulfonylurea
preprandial
Disadv: Shorter
less hypoglycemia than
duration of action
sulfonylureas (short dur)
May fasting insulin and
C-peptide
plasma insulin levels
after OGTT
glucose uptake in
muscle/fat
blood pressure
triglyc (pioglitazone)

No hypoglycemia

Dosing
Start
500mg/day
and titrate.
Max
2000mg/day

A/E and Safety

Major effect is NOT
hypoglycemia
GI**: metallic taste,
nausea, diarrhea,
abdo pain
Intestinal B12
absorption and serum
B12
lactic acidosis (rare)
Higher rates of
hypoglycemia with
glyburide
Weight gain
N/V, hypersensitivity
and disulfiram rxns,
alcohol intolerance

Prandial tx.
-Main AE is
Rapid
hypoglycemia
absorption
-Metabolized by
and
CYP2C8 and CYP3A4;
clearance,
caution with 2C8
take before
inhibitors (gemfibrozil)
each meal. If
and 3A4 inhibitors
miss a meal,
(itraconazole)
skip dose
6-12 weeks
Fluid retention
for maximal Periph edema
affect
CHF
Possible weight gain
BMD
MI risk (rosi)

Renal
Dosin
g

Yes
(Hepatic
also)

Yes
(hepa
tic
also)

No
mainl
y
hepati
cally
meta
bolize
d
No
mainl
y
hepa
ticall
y
meta

and HDL

tissue = 1
targets

Bladder cancer risk (pio)

glucosidase
inhibitors

- Slows intestinal
glucose
absorption

Improves postprandial
hyperglycemia

No hypoglycemia

2/3 have GI A/E!!!!!!!!

(flatulence, diarrhea,
abdo discomfort)
If hypoglycemic, pts
require glucose rather
than sucrose or
complexcarbs

DPP-4
Inhibitors
Sita/Linagli
p:
competitive
inhibitor
-Saxaglipin:
binds
covalently
to DPP4

GLP1, GIP by
prolonging their
t1/2
- Block release of
PP glucagon
- Improve insulin
response
-Improve
fasting and pp
glucose

Predominant
effect is PP BS

H/A, nasopharyngitis,
URTI
Associated w/
pancreatitis

GLP-1
Analogues
(all subcut)
ie
Exanatide

-promotes
insulin secretion
- glucagon
secreition
- Slow gastric
emptying
- resistant to
DPP4

SGLT2
Inhibitors
Canagliflozi

urinary
glucose
excretion
(glucosuria) due

Inhibits DPP4 for 24hrs

2-3x in GLP1/GIP
glucagon conc.
responsiveness of
insulin rls to glucose
plasma levels of insulin
and C-peptide
fasting glucose and
glucose excursion after
an oral glucose load or a
meal
delays stomach emptying
satiety/suppress
appetite
SBP
-cell survival, glucose
sensitivity

FBS, ppBS and A1C

BP
HDL
Osmotic diuresis

No risk of
hypoglycemia

Low incidence of AEs

boliz
ed

Only
for
Sita
and
saxa
glipti
n

CI if <18y/o
CI in liver diseasea

No risk of
hypoglycemia
Disadv:
Less effective when
glucose very high

Very low risk of

hypoglycemia
Disadv:
May LDL

Exanatide
CI in gastroparesis
often
Associated
administered
w/pancreatitis
with
Can absorption of
metformin
other drugs
May cause
hypoglycemia if
combined w/
sulfonylurea
dose of
risk of vaginal
insulin/insulin
thrush/UTI
secretogogue Thirst, nausea,
to avoid
constipation,

Yes
(Exan
atide
)

Yes

n
(Invokana)

to SGLT2
receptor
inhibition =>
renal threshold
for glucose

Pramlintidin
e (Amylin
analogue)

Slow gastric
emptying
-inhibits
glucagon
secretion

risk of
dehydration/elect
rolyte imbalance

No in fasting insulin
Improves postprandial
hyperglycemia, given
in conjunction with
insulin

hypoglycemia
urination
-dose if
Intravascular volume
taking UGT
depletion (electrolyte
inducers
imbalance, hypotens,
(rifamp, SJW,
syncope)
phenytoin,
Possible ketoacidosis??
etc)
Hypoglycemia
CI in gastroparesis

Metformin:
- If pt on metformin and have peripheral neuropathy, check B12 levels
- Metformin detailed MOA:
o hepatic gluconeogenesis via activation of AMP-activated protein kinase (AMPK)
o direct stimulation of glycolysis in tissues and increased glucose removal from the blood (i.e. increased
insulin action at muscle and fat)
o glucose absorption from the GI
o plasma glucagon levels
o glucose uptake in skeletal muscles
Thiazolidenediones Detailed MOA
- Bind to PPAR, a nuclear receptor
- Causes heterodimerization with retinoid X receptor
- This dimer interacts with PPAR response elements on specific genes, modulating gene expression
- Results:
o Adipocyte differentiation
o Uptake of circulating fatty acids into fat cells
o lipid storage in adipose tissue ( adipogenesis)
o insulin sensitivity / insulin resistance
glucose uptake in muscle and fat tissues
hepatic glucose output
Reserve rosiglitazone for last line (MI risk)
Meglitinides can plasma insulin/C-peptide
DPP-4 inhibitors can plasma insulin/C-peptide

Pancreatitis linked to GLP1 analogs

Agents that slow gastric emeptying: a-glucosidase inhibitors, GLP-1 agonists, and pramlintidine