Drugs for Diabetes Mellitus

Type I Diabetes Mellitus

- Must rely on exogenous insulin to control hyperglycaemia, avoid ketoacidosis & maintain acceptable levels of glycosylated haemoglobin (HbA1c)
- Goal of insulin therapy :
o to maintain blood glucose as close to normal as possible
o To avoid wide fluctuations in glucose Key Words :
Type II Diabetes Mellitus CV – Cardiovascular
- Influenced by genetic factors, aging, obesity & peripheral insulin resistance Pt / Pts – Patients
- Lifestyle changes : SC – Subcutaneous (injection)
o Weight reduction, exercise & dietary modification
o To decrease insulin resistance & correct hyperglycaemia
- Most patients require pharmacologic intervention with oral glucose-lowering agents
- As the disease progresses, beta cell function declines, & insulin therapy is often needed to achieve satisfactory glucose levels
- Goal of the treatment :
o To maintain blood glucose within normal limits
o To prevent the development of long-term complications

Insulin and Insulin Analogs

- Exogenous insulin
- To replace absent insulin secretion (Type I DM)
- To supplement insufficient insulin secretion (Type II DM)
- Human insulin : produced by recombinant DNA technology
o Using stains of Escherichia coli or yeast
o Genetically altered to contain the gene for human insulin
- Dose, injection site, blood supply, temperature & physical activity
– affect the onset & duration of various insulin preparations
- Degraded in GIT if taken orally
- Generally administered by subcutaneous injection
- In hyperglycaemic emergency – regular insulin is administered
intravenously (IV)
- Adverse Effects :
o Hypoglycaemia (most serious & common)
o Weight gain, local injection site reactions, lipodystrophy
o lIpodystrophy : minimised by rotation of injection sited
- Diabetics + renal insufficiency pt may require a decrease in insulin
dose
- Pt with asthma, chronic obstructive pulmonary disease & smokers
should not use inhalation formulation : potential of
bronchospasm
 1) Insulin Preparations and Treatment

Classification Actions Adverse Effects Others

Rapid-acting - To mimic the prandial release of insulins Hypoglycaemia : - Inhaled insulin also considered as rapid-acting insulin
- Insulin lispro - To control postprandial glucose - Headache - Peak levels 45 – 60 minutes
- Insulin aspart - Swift correction of elevated glucose - Anxiety - Administered 15 minutes preceding meal or within 15
- Insulin glulisine - Used in conjunction with a longer-acting - Tachycardia – 20 minutes after starting meal
basal insulin - Confusion - Suitable for IV administration
Short-acting - Vertigo - Peak levels of regular insulin : 50 – 120 minutes
- Regular insulin - Shakiness - Modification of amino acid sequence
- Weakness - Produces analogs (rapid-acting insulins)
- More rapid absorption, quicker onset, shorter
duration of action after SC injection
- Should be injected SC 30 minutes before meal
Intermediate-acting - Less soluble (due to combination with - Regular insulin + zinc + protamine -> insulin isophane
Neutral protamine protamine) - Usually given with rapid- or short- acting insulin for
Hagedorn (NPH) Insulin - Delayed absorption and longer duration mealtime control
of action - Should be given only SC
- Used for basal control in type 1 or type 2 - Should not be used when rapid glucose lowering is
diabetes needed (eg diabetic ketoacidosis)
Long-acting - Insulin glargine : - Insulin glargine :
- Insulin glargine - Isoelectric point lower than human - Slower onset than NPH insulin
- Insulin detemir insulin - Flat, prolonged hypoglycaemic effect with no peak
- Insulin degludec - Formation of a precipitate at the - Insulin detemir :
injection site - Long-acting properties similar to insulin glargine
- Releases insulin over an extended period - Insulin degludec :
- Insulin detemir : - Longest half-life
- Fatty side chain enhance association to
albumin - Should be administered SC only
- Insulin degludec : - Should not be mixed in the same syringe with other
- Remains in solution at physiologic pH insulins (may alter pharmacodynamic profile)
- Slow release over an extended period
Insulin Combinations
- To decreases the number of daily injections
- Difficult to adjust individual components of the insulin regimen

Standard Treatment vs Intensive Treatment

Standard Treatment Intensive Treatment

Involves twice daily injections Utilises 3 or more injections daily with frequent monitoring of blood glucose
levels
- To achieve ADA recommendation (target mean blood glucose level of 154 mg/dL
or less)
- Frequency of hypoglycaemic episodes, coma & seizures is higher
- Shows a significant reduction in microvascular complications – retinopathy and
nephropathy
- Should not recommended for patients with :
- Long standing diabetes
- Significant microvascular complications
- Advanced age
- Hypoglycaemic unawareness

Synthetic Amylin Analog

Amylin – a hormone – cosecreted with insulin from β cells following food intake
- Delays gastrc emptying
- Decreases postprandial glucagon secretion
- Improves satiety
1) Pramlintide – a synthetic amylin analog
a. Indicated as an adjunct to mealtime insulin therapy in pt type 1 and type 2 diabetes
b. Administered by SC injectionimmediately before meals
c. Pramlintide -> dose of mealtime insulin should be decreased 50% (to avoid risk of severe hypogycaemia)
- Adverse Effects : Nausea and vomiting
- May not be mixed in the same syringe with insulin
- Contraindications :
o Patients with diabetic gastroparesis (delayed stmach emptying), Cresol hypersensitivity or Hypoglycaemic unawareness
 2) Glucagon-like Peptide Receptor Agonists
- Oral intake of glucose -> higher secretion of insulin
- Incretin effect (markedly reduced in type 2 diabetes)
- Occurs because the gut releases incretin hormones [glucagon-like peptide-1 (GLP-1) & glucose-dependent insulinnotropic polypeptide (GIP)]
- In respone to meal
- Incretin hormones : responsible for 60% to 70% of postprandial insulin secretion

GLP-1 Receptor Agonists (injectable) Mechanism of Action Adverse Effects Others

- Albiglutide - Analogs of GLP-1 - Nausea - Liraglutide : also approved to reduce risk of
- Dulaglutide Long-acting GLP- - Exert their activity by : - Vomiting CV events & CV mortality in pts with type 2
- Liraglutide 1 receptor - Improving glucose- - Diarrhoea diabetes & CV diseases
- Semaglutide agonists dependent insulin - Constipation - 2 premixed preparations of long-acting
- Exenatide Short-acting GLP- secretion - Associated with insulin and GLP-1 receptor agonists
- Lixisenatide 1 receptor - Slowing gastric pancreatitis o Insuline glargine + lixisenatide
agonists emptying time - Longer-acting : o Insulin degludec + liraglutide
*Exenatide – both short-acting and - Reducing food intake associated with - To decrease daily insulin requirements &
extended-release (long-acting) (enhance satiety) thyroid C-cell tumours the number of daily injections
preparation - Decreasing postprandial in rodents Pharmacokinetics :
glucagon secretion Contraindications : - Administered SC (polypeptides)
- Promoting β cells - Pts with a history of - Abiglutide, semaglutide & dulaglutide are
proliferation medullary thyroid dosed once weekly
carcinoma or - Liraglutide is available as a once-daily
- Multiple endocrine injection
neoplasia type 2 - Lixisenatide is dosed once daily
- Exenatide – short-acting (dosed twice
daily) & extended-release preparation
(dosed once weekly)
- Exenatide should be avoided in pts with
severe renal impairment
 3) Oral Agents
- Useful treatment fo pts who have type 2 diabetes. That is not
controlled with diet
- Pts who developed diabetes after age 40 & have diabetes < 5 yrs –
most likely to respond well to oral glucose-lowering agents
- Pts with long-standin disease may require combination of oral agents
with / without insulin to control hyperglycaemia
Blockers of ATP sensitive K channels
*
1) Sulfonylureas in B cells in
pancreas .

a. Insulin secretagogues
b. They promote insulin release from β cells of the pancreas
c. Most used in clinical practice – second generation drugs
i. Glyburide
ii. Glipizide
iii. Glimepiride
d. MOA :
i. They block the ATP-sensitive K+ channels activation
maintain
ii. Resulting in depolarization ( Kt known to
"
B cells )
gradient across
iii. Ca2+ infux,
I insulin exocytosis
e. It may reduce hepatic glucose prouction & increase peripheral
insulin sensitivity
f. Given orally (drugs bind to serum proteins -> metabolized in
liver -> excreted in urine and faeces)
g. Duration of action ranges from 12 – 24 hrs
h. Adverse Efects :
i. Hypoglycaemia, hyperinsulinemia, weight gain
ii. Glyburide – renal impairment (increase the duration of
action & increase risk of hypoglycaemia significantly)
i. Should be used in caution in hepatic or renal insufficiency
(accumulation may cause hypoglycaemia)
j. Glipizide / limepiride (safer for renal dysfunction & in elderly
pts)
 are Lactate alanine
mourn substrate ,
glucose
in
which are converted to

glycerol
q
,
the
AMPK in
liver
activates
gluconeogenesis
blocks
liver ,

4) Glinides hepatic d. Metformin (the only one) – also useful in treatment of

* glucose
a. Insulin secretagogues polycystic ovary syndrome
b. Agents include : decreas e. MOA :
production
A. Repaglinide
B. Nateglinide y A. Reduction of hepatic gluconogenesis
B. Slows intestinal absorption of sugars glucose
-

c. MOA : C. Improves peripheral glucose uptake and

bind to similar A. Stimulate insulin secretion from β cells utilization
to sulfohyluveas
receptor
← B. Has rapid onset and short duration of action f. ADA – initial drug of choice for type 2 diabetic pts
C. Effective in early release of insulin that occurs g. Used alone or in combination with other oral agents /

÷ ÷ ÷ ÷ ÷: ÷*÷
soo
after meal & are categorized as postprandial insulin
's
glucose regulators iincrea
msn.ninpre.srenge.se
D. Should not be used in combination with
h. Well absorbed after oral administration -> not bound to
serum proteins -> not metabolized -> excretion via urine .

sulfonylureas (overlapping MOAs & increased i. Adverse Effects : blood

level in

risk of serious hypoglycaemia) ↳ decrease hepatic

A. Diarrhoea, nausea & vomiting (allevated by gluconeogenesis MOAI

d. Should be taken prior to meal titrating the dose of metformin slowly & T impairs
↳ metformin of,

e. Well absorbed after oral administration administered with meals) hepatic utilization
acid
lactic
f. Metabolized to inactive products by cyt P450 3A4 in the B. Long term used – vitamin B12 deficiency
liver -> excreted through bile j. Contraindications : metformin
✓ is not metabolize
g. Adverse Effects : A. Pts with renal dysfunction (risk of lactic in body excreted

A. Hypoglycaemia & weight gain (lower than with acidosis)

by
unchanged by kidneys)
for
used lower sulfonylureas) severe blood
lead to repair in
B. Discontinued – acute MI, exacerbation of heart
to
diet h. Contraindication : hypo (
level) failure, sepsis
fax - A. LGemfibrozil + repaglinide -> NO (Inhibit hepatic C. Caution – pts older than 80 yrs & pts with heart
)
I metabolism -> increase AE of repaglinide) failureor alcohol abuse
fibrates amount
B. Should be used in caution (pts with hepatic
-
decreaseproduced impairment)
fat
of river 6) Thiazolidinediones (TZDs)
my insulin
5) Biguanides increase a. Insulin sensitizers
✓ sensitivity
a. Insulin sensitizer b. Two agents :
b. Increases glucose uptake and useby target tissues -> A. Pioglitazone
decreasing insulin resistance B. Rosiglitazone
c. Does not promote insulin secretion (risk of C. TZDs do not promote insulin release from β
hypoglycaemia is far less) cells -> hyperinsulinemia is not a risk
 of receptor that we have in our

ligand nuclear
glucosidase is a natural enzyme
break carbohydrate into smaller units
and it helps to
for
body use that emerges that we use call glucose
the we can
d
pigglitahohl requires so
cea functions .

④ Drag *

/ pnieresmenoecogoitaiinsaii ontosr
its

bacton
c. MOA : B. Miglitol
PPAR y receptor
(
-

in nucleus A. Acting as agonists ) for the peroxisome b. MOA :

proliferator-activated receptor-γ (PPARγ), a A. (located in intestinal brush border) α-
£ muscle } adipose
related
nuclear hormone receptor ( mainly in liver glucosidase enzymes break down
⑨ regulates genes glucose
,
tissues decrease

to
glucose f. lipid
metabolism B. Leads to transcription of several insulin
responsive genes -> increased insulin sensitivity
metformin
carbohydrates -> glucose -> absorbed
B. Acarbose & Miglitol reversibly inhbit α- f.
availability
ft

sulfonyiuras
bn
:

" "
→ in adipose tissue, liver and skeletal muscle → primary
it'÷ SM AT glucosidase enzymes
"
the
glucose
d. Can be used as monoterapy / in combination with other fix
increase in i. her ,
,
power
sensitivity C. (Taken at the start of meal) drugs delay the that available
is

to mediated in bloodstream
increase
insulin
-

glucose-lowering agents / insulin digestion of carbohydrates -> lower ( effect insulin

no
uptake
glucose e. ADA – (pioglitazone) second or third line agents for type 2 postprandial glucose levels production )
pancreas
it will signal
diabetes D. Do not cause hypoglycaemia (monotherapy) ↳ do to
job its

f. Rosiglitazone – less utilized (concerns regarding CV AEs) c. Acarbose : poorly absorbed ↳ bcs pancreas still fx
{glucose of
those ups {
down

g. Both well absorbed after oral administration -> d. Adverse Effects : managing

extensively bound to serum albumin -> extensive A. + insulin secretagogues / insulin ->
metabolism by diff CYP450 isozymes hypoglycaemia may occur (must be treated
h. Pioglitazone -> renal elimination (negligible) – majority with glucose rather than sucrose – sucrase is
active metabolites -> excreted in bile -> eliminated in also inhibited by these drugs)
9
faeces B. Most common : flatulence, diarrhoea, → glucose osmotic
has water
i. Rosigitazone -> excreted in urine cholesterol abdominal cramping pull
of
HDL
j. Adverse Effects : increase a ) e. Contraindications :
rip ( activates PPAR
-

A. Liver toxicity ↳ decrease ride A. Pts with inflammatory bowel diseases, colonic
B. Weight gain (due to increased subcutaneus fat triglyceride } ulceration, intestinal obstruction
fatty acid
decrease and cause fluid retention) Plasma
level
at osteoblast ← C. Osteopenia & increases fracture risk in women
' 8) Dipeptidyl Peptidase-4 Inhibitors
formation D. Pioglitazone : increase the risk of bladder a. 4 agents :
cancer A. Alogliptin C. Saxaglitin
E. Rosiglitazone : potential increased risk of MI & B. Linaglitin D. Sitagliptin
angina
- Well absorbed after oral administration
k. Contraindications : Avoid in pts with severe heart failure
- Alogliptin & Sitagliptin mostly excreted unchanged in urine
- Saxagliptin -> metabolized via CYP450 3A4/5 -> active metabolite
to
on body 's ability
7) α-Glucosidase Inhibitors C it inhibits competitive inhibitors
the
use

glucosidase )as (primary route of elimination – renal)

a. Two agents : use
.

- Linagliptin primarily eliminated via enterohepatic system

A. Acarbose
 * insulin
sends signal glucose is actively normally glucose

/
intestines release ,
→
bad '" ago "
→
biggar & kidney
an
-
nephron
balance
•

incretion ( up l )
- to pancreas level ( filter { reabsorbed in the is filtered
inhibit fluid electrolytes proximal tube along
-12
passively into
"
y blood { wine )
:p melternaznysmmegmbrano the
'

* filtrate in
guy
-

between with wat

-
l

from cell membrane ( blood glomerulus {

# * not normal
under normal
310mmol IL )
these
glucose conditions call
inhibit glucose
in A tubule reabsorbed
Drugs proximal glucose
enough capacity
urine not
to no in urine )
go

b. MOA : b. MOA : reabsorb at

all it )

A. Inhibit enzyme DPP4, which responsible for the
inactivation of incretin hormones such as GLP-1
(increase incretin hormone production)
B. Prolonging the activity of incretin hormones ->
increases release of insulin in response to
meals -> reduces inappropriate secretion of
glucagon
c. May be used as monotherapy or in combination with
sulfonylureas, metformin, TZDs or insuln
d. DO NOT RECOMMEND the combination of DPP-4
inhibitors with GLP-1 receptor agonists (overlappin
mechanisms & toxicity) Lt GLPExenatide
mimetic I
-
A. SGLT2 responsible for reabsorbing filtered
glucose in tubular lumen of the kidney
B. Inhibit SGLT2 -> decreases reabsorption of
glucose -> increase urinary glucose excretion ->
lower blood glucose
C. Inhibit SGLT2 -> decreases reabsorption of
sodium -> osmotic diuresis -> reduce systolic
blood pressure
c. Hypertension : NO
d. Given once daily in the morning
e. Canagliflozin : taken before 1st meal of the day
f. All mainly metabolized by glucuronidation to inactive

e.
g :

all #
e. Do not cause satiety / fulness & are weight neutral metabolites
-
l
←
appetite
f. Adverse Effects : g. Contraindications :
A. General – well tolerated A. Should be avoided in pts with renal dysfunction
B. Nasopharyngitis & headache B. Used with caution in pts with ris factors that
C. Pancreatitis predispose to ketoacidosis (eg alcohol abuse)
D. Increase risk of severe, disabling joint pain h. Adverse Effects :
E. Alogliptin & Saxagliptn : increase the risk of A. Female genital mycotic infections (eg
heart failure hospitalizations vulvovaginal candidiasis) env for
urine great
g. Should be used withcaution in pts with or at risk for heart B. Urinary tract infections
=
in
T sugar to
bugs
-

failure C. Urinary frequency Candida ) UTI +

T risk -
ta ( thrush

D. Hypotension – in elderly or pts on diuretics

raised
9) Sodium-glucose Cotransporter 2 Inhibitors (SGLT2) E. Ketoacidosis only moderately→ blood glucose

rare
a. 4 agents : →

A. Canagliflozin SALT rebar

cell lining the

B. Dapagliflozin proximal tubule contains -18

transport glucose }
SULT
Molecule called of the
linked sodium out
C. Empagliflozin – also indicated to reducerisk of c sodium glucose
-

transporter ) reabsorbed
CV death in pts with type 2 diabetes & CV in the luminal
filtrate {
side to blood
diseases
D. Ertugliflozin reduce • to low
blood levels
sugar

→ to
. cause kidneys
into
excrete glucose
urine