DM Pharmacotherapy

Edy Junaidi

Diabetes Mellitus
A group

of chronic metabolic disorders

characterized by hyperglycemia that may result
in long-term microvascular, macrovascular, and
neuropathic complications
DM is the leading cause of

New cases of blindness among adults

End-stage renal disease
Non-traumatic lower limb amputations

Contribution on increasing cardiovascular risk

DM

Type 1 (previously known as IDDM, juvenile-onset

DM)

Usually diagnosed in children and adults younger than 30

years of age although the disease can present at any age
Characterized by absolute insulin deficiency
LADA (latent autoimmune diabetes in adult) slow onset
type 1 or Type 1.5 DM occur at older age than the usual
age of onset; Often mistakenly diagnosed as Type 2

Type 2 (previously known as NIDDM, adult-onset DM)

90 95% of all diagnosed cases

Usually preceded by pre-diabetes
Insulin resistance or relative insulin deficiency
Other specific types (WHO/NCD/NCS/99.2)

The easiest way of differentiating Type 1 and Type 2 is by measuring Cpeptide level : < 1 ng/ml (type 1); Type 2 > 1 ng/ml

Disorder of glycaemia: Etiological type &

clinical stages

Clinical presentation of DM

Criteria for Diagnosis of DM

Cook et al., 2008, pp.684 - 707

Uncontrolled DM

Pharmacotherapy
Insulin
OAD :

Sulfonylurea secretagogues

1st generation : acetohexamide, tolazamide, tolbutamide,

chlorpropamide
2nd generation : glipizide, glimepiride, glyburide

Non-sulfonylurea secretagogous (nateglinide,

repaglinide)
Biguanide (Metformin)
-glucosidase inhibitor (acarbose, miglitol)
PPAR agonist Thiazolidinediones insulin
sensitizer (pioglitazone, rosiglitazone)
Dipeptydil peptidase-4 inhibitors (DPP-IV inhibitors:
sitegliptin)

Regulation of blood glucose

Insulin
Key

tissue target of insulin in regulating of

glucose : Liver, muscle and fat

Regulation of insulin secretion

Involve interplay of : GI hormones, pancreatic
hormones, & autonomic neurotransmitter

In general, any conditions that activate sympathetic nervous

system (hypoxia, hypoglycemia, exercise, severe burns,
surgery, etc) suppresses insulin release by stimulation of adrenergic receptor.
Oral glucose provoke insulin release better than if its
administered intravenously; Oral route stimulate GI hormones
& vagal activity, the most potent of which are Glucagondependent insulinotropic peptide (GIP) & glucagon-like
peptide 1 (GLP-1)

ATP-dependent

Voltage-gated

Insulin signaling pathway

Physiological Effects of Insulin

Increases the number of glucose transporters in the membrane;

it may also increase the rate at each transporter.
Alters the concentration of fructose 2,6-bisphosphate, which in
turn dramatically alters the activity of phosphofructokinase and
fructose 1,6-bisphosphatase.
Increases the activity of pyruvate kinase but inhibits the
activity and the synthesis of phosphoenolpyruvate
carboxykinase.
Iincreases the activity of pyruvate dehydrogenase, probably
through the insulin mediator
Promotes lipogenesis and forms fats for storage from glucose
through acetyl CoA.
Promotes the synthesis of glycogen by increasing the activity
of glycogen synthase (independent form).
Inhibits the breakdown of glycogen by inhibiting glycogen
phosphorylase.

Goodmann & Gillman, 2008

Classification of Insulin
Short- and Rapid-acting Insulin

Short acting insulin before or after meal

All rapid acting insulin may be administered
postprandially to provide smoother glycemic control
and to prevent hypoglycemia

Intermediate acting insulin

Usually given once a day before breakfast or twice

a day
In T2DM patients, intermediate acting insulin given
at bedtime may normalize fasting blood glucose

Long acting insulin

Provide low basal concentration of insulin

throughout the day

Indication
Management of type 1 DM
Management of type 2 DM which is not
controlled by diet &/ OAD alone,
Post pancreatectomy diabetes
Gestational diabetes
Diabetic ketoacidosis
Non ketotic coma
Perioperative management of patient with
type 1 & type 2 DM

Adverse Effects
Hypoglycemia
Insulin allergy & resistance
Lipoatrophy & lipohypertrophy

Atrophy probably is immune response to

insulin
Hypertrophy is considered as lipogenic
action of high local insulin at the site of
injection

Both problems are rare with more purified

preprarations

Insulin edema

ORAL ANTIDIABETICs (OADs)

Sulfonylurea
Insulin

secretion enhancer

SUR = specific sulfonylurea receptor

 Classification of sulfonylurea based on :

Difference in relative potency

Relative potential side effects

Different protein binding properties

All sulfonylurea are equally effective at

equipotent doses
All

sulfonylurea are metabolized in liver

(CYP450 2C9); metabolites status : active (less
potent, equally potent), inactive
Half-life directly relate to the risk of
hypoglycemia cautious use in patient with
hepatic or renal impairment

 Adverse effects :

Hypoglycemia

Hyponatremia

Weight gain

Skin rash

Hemolytic anemia

GI upset

Cholestasis
Drug

interactions :
Close monitoring concomitant use of CYP450 2C9
inducer /inhibitor with sulfonylurea

Glinides
Short-acting insulin secretagogues

(repaglinide,

nateglinide)
Mechanism of action :

Repaglinide closes ATP-dependent potassium channels in the

-cell membrane by binding at characterizable sites
potassium channel blockade depolarizes the -cell, which
leads to an opening of calcium channels increased calcium
influx induces insulin secretion.
The ion channel mechanism is highly tissue selective with low
affinity for heart and skeletal muscle

Kinetics:

Rapidly absorbed, short half-life (1 1.5 hours)

Nateglinide predominantly metabolized by CYP450 2C9
(70%) and CYP3A4 (30%), renal elimination; repaglinide
predominantly metabolized by CYP3A4, excreted in bile

Efficacy

Both (monotherapy) significantly reduce postprandial

glucose and HbA1c level
Lower efficacy of glinides vs sulfonylureas should be
considered when patients are >1% above their HbA1c goal

Adverse effects
Hypoglycemia (less than sulfonylurea)

Rates of hypoglycemia : 3% with nateglinide, 15% repaglinide

vs glyburide (15%) & glipizide (19%)

Weight gain : 2 3 kg with repaglinide, < 1 kg with

nateglinide

Drug interaction

No significant drug interaction have been reported

Biguanide
Metformin : the only biguanide available in use
(Phenformin & Buformin withdrawn from market due to toxic
effects)
Enhance insulin sensitivity in liver and

peripheral (muscle) tissues

No direct effect on -cells
Mechanisms:

AMP-activated protein kinase activity, tyrosine kinase activity

enhancement, glucose transporter 4 are all contributes on the
activity of metformin

Kinetics :

50 60 % oral bioavailability
Low lipid solubility; Vd approximate body water
Metformin is not metabolized & does not bind to plasma
protein
Eliminated by renal tubular secretion & glomerular
filtration
Average half-life 6 hours

Efficacy

Consistently reduce HbA1c level by 1.5 2 %

Reduce fasting plasma glucose 60 80 mg/dl
Retain its glucose-reducing ability at extremely high
glucose level (>300 mg/dl)
Reduce plasma triglycerides & LDL-C by 8 - 15%

Adverse effects:

GI side effects :

Abdominal discomfort, stomach upset, &/ diarrhea in

approximately 30% of patients
Anorexia & stomach fullness contribute on weight loss effect
of metformin
GI side effect tend to be transiet, lessening within several weeks

Lactic acidosis (rare)

Metformin is contraindicated in renal insufficiency (renal
elimination)

Drug interaction:

Cationic drugs may compete on renal tubular secretion

:cimetidine, procainamide, digoxin, quinidine,
trimethoprim, vancomicin

Peroxisome Proliferator Activator

Receptor - agonists (PPAR)
Glitazones
PPAR primarily located on fat cells & vascular
cells
Glitazones PPAR receptor interaction
maturation of preadipocytes (small fat cells are
more sensitive to insulin & more able to store
FFA) influx FFA out of plasma, fat, & liver
into subcutaneous fat less insulin-resistant
storage- tissue
Muscle intracellular fat products, which
contribute to insulin-resistant, also decline

Kinetics:

Well absorbed & highly bound to protein plasma

Half-life: pioglitazone:3 7 hours, rosiglitazone 3 4
hours
Active metabolites with longer half-life deliver the
majority of activity at steady state
Both have 24 hours duration of antihyperglycemic activity

Efficacy

Reduce HbA1c 1.5%, lower glucose (FPG) level 60 70

mg/dl at maximal doses
Glycemic lowering onset is slow, maximal effect may not
observed until 3 4 months therapy
The efficacy of both drugs is dependent on sufficient
insulinemia

Adverse effects:

Troglitazone, the first thiazolidinedione, were removed

from market in March 2000 because of idiosyncratic
hepatotoxicity resulting in 28 deaths

No evidence of hepatotoxicity in more than 5.000 patients

given pioglitazone & rosiglitazone
It is recommended to check ALT periodically (every 2
months on the 1st year of therapy)
Patients withALT level >2.5 times of upper limit of normal
should not start either medication
Patient on medication with ALT level > 3 times of upper
limit of normal, medication should be STOP

Fluid retention edema, dose related

Reduction of plasma Hb
Weight gain

Drug interaction:

No significant drug interaction have been noted with either

medication

-glucosidase Inhibitor
Competitively

inhibit enzymes (maltase,

isomaltase, sucrase, & glucoamylase) in the small
intestine, delaying breakdown of sucrose and
complex carbohydrate

They do not cause any malabsorption of these nutrients

Kinetics:

Mechanism of -glucosidase inhibitor is limited to

luminal site of intestine
Some acarbose are absorbed sistemically & renally
excreted, while majority of miglitol is absorbed &
renally excreted unchanged

Efficacy:

Reduce postprandial glucose (40 50 mg/dl), fasting

glucose level relatively unchanged
Efficacy on glycemic control is modest (reduction in
HbA1c 0.3 1%)

Adverse effects:

Flatulence, bloating, abdominal discomfort, and diarrhea

are very common greatly limit the use of -glucosidase
inhibitors

Distal intestinal degradation of undigested carbohydrate by

microflora CO2 & methane production

Elevated ALT level in high doses of acarbose

Dipeptidyl peptidase-4 Inhibitor

The

newest therapeutic class of oral agents for

Diabetes
Sitagliptin is the only FDA approved
(vildagliptin, saxagliptin are in clinical trial
www.clinicaltrial.gov)
DPP-IV inhibitors slow inactivation of incretin
hormones within the gut
Incretin hormones are release throughout the day
and increase level with meal
Drug activity glucose dependent

reduce HbA1c 0.7 0.8 % compared to placebo

Renal function monitoring recommended prior to
initiation and during treatment

Adverse effects:

Nasopharyngitis (5.2%)
Upper respiratory infection (6.3%)
Headache (5.1%)

No

current drug interaction data available