This document summarizes the pharmacotherapy of diabetes mellitus. It describes the types of diabetes, diagnostic criteria, goals of treatment, and various classes of medications used to treat diabetes. The main drug classes discussed include insulin, sulfonylureas, meglitinides, incretin mimetics, DPP-4 inhibitors, metformin, thiazolidinediones, and SGLT-2 inhibitors. For each class, the mechanisms of action, pharmacokinetics, indications, and side effects are summarized. The document provides an overview of current best practices for treatment and medication management of both type 1 and type 2 diabetes.

1. Pharmacotherapy of
diabetes mellitus (DM)
By Nehal M. Ramadan. M.B.B.CH, MSc, PhD
Lecturer of Clinical Pharmacology
Clinical Pharmacology department, Faculty of Medicine, Mansoura University,
Egypt

2. Diabetes mellitus
Def → a group of disorders that
develop due to
● Insulin deficiency → T1DM
● Insulin resistance → inadequate
actions of insulin in stimulating
the uptake of glucose by
peripheral tissues → T2DM
→ hyperglycemia + disturbances in
metabolism of CHO, fat, and protein.

3. Diagnostic criteria
Clinical symptoms +
● Fasting blood glucose > 126 mg/dL
● Random blood glucose > 200 mg/dL
● 2-hour post-prandial glucose level > 200 mg/dL
● Hemoglobin A1c (HbA1c ) level >= 6.5%
HbA1c → the percentage of hemoglobin in circulating erythrocytes that is
glycosylated → an index of the average blood glucose level over the preceding 2 to 3
months.

4. Treatment of
T1DM
→ Patients with T1DM have an
absolute requirement for exogenous
insulin.
→ Most generally accepted target
goal for HbA1c in T1DM is 7.0%
Improved glycemic control in
patients with T1DM ↓ long-term
microvascular & macrovascular
complications

5. Insulin -> MOA
● When blood glucose ↑ → more glucose
enters pancreatic β cell via GLUT2 →
glycolysis → ↑ the ATP/ADP ratio →
inhibition of the ATP-sensitive K+ channel
(KATP) → membrane depolarization →
activation of voltage-gated Ca++ channels
→ ↑ intracellular Ca++ → insulin
secretion.
● Released insulin rapidly reaches liver,
muscles, and adipose tissue → binds to
and activates insulin receptor (a tyrosine
kinase receptor) → promote translocation
of glucose transporters (GLUT4) from
intracellular vesicles to the plasma
membrane → ↑ glucose uptake into the
cell.

6. Pharmacokinetics
of insulin
Route of administration →
● SC → most common for maintenance,
● IV → emergency treatment of diabetic
ketoacidosis → (regular insulin only)
● Recently → insulin SC infusion pumps &
inhaled insulin formulations
● Proteolytic destruction in the GI tract
prevents oral administration
Insulin preparations →
with different pharmacokinetics to meet different
physiological functions of insulin →
● Maintenance of constant low plasma glucose
levels during fasting
● Lowering blood glucose peaks after meals.

7. Insulin
Preparations
Insulin Type Onset Preprandial Injection Timing Peak Duration
Rapid-acting
● Lispro
● Aspart
● Glulisine
10-15 min At start of meal 1-2 h 3-5 h
Short-acting
Regular
30 min 30 min before meal 2-4 h 6-8 h
Intermediate-acting
NPH
1 h 30 min before meal 6 h Up to 18 h
Long-acting
● Glargine
● Detemir
● Degludec
2 h Once daily Peakless Up to 24 h
Peak insulin level
For
control
of
postprandial
hyperglycemia
To
maintain
baseline
glucose
levels

8. Premixed insulin
preparations (biphasic)
→ A premixed preparations of intermediate-acting
insulin (NPH) + short- or rapid-acting insulin, are
available as vials for injection with syringes or as
insulin pens.
→ Faster onset & longer duration of action
→ Greater ease of use → but are less likely to
achieve good glycemic control.
→ NPH/regular 70/30, NPH/regular 50/50,
NP/lispro 75/25, NP/lispro 50/50, NP/aspart 70/30

9. Insulin regimens
● Basal-bolus insulin therapy → intensive insulin regimen
→ MULTIPLE daily SC injections → injection of a long-
acting insulin analogue (e.g, glargine) once daily to
establish a stable basal insulin level + injection of rapid-
acting insulin analogue three or more times daily
(before each meal) to provide appropriate post-meal
peaks in insulin levels.
● Continuous SC insulin infusion → insulin pump
● Conventional insulin therapy → split-mixed regimen →
TWO daily injections of a premixed preparation
NPH/regular (or NPH/lispro) → ⅔ of the total daily
dose is given before breakfast and ⅓ before dinner

10. Let’s calculate
→ Total daily insulin requirements =
Body weight x starting dose =
0.2 x 45 = 9 U/day
● For a basal bolus regimen →
Divide the total daily insulin
requirements into ⅓ and ⅔ →
➔ Long-acting insulin → ⅓ of total
daily dose → 3U at bed time
➔ Rapid-acting insulin → ⅔ → 6U,
divided on 3 injections just before
each meal → 2U each
● For split-mixed regimen →
Divide the total daily insulin
requirements into ⅓ and ⅔ →
➔ Premixed NPH/regular 70/30 → ⅔
of total daily dose before
breakfast→ 6U
➔ Premixed NPH/regular 70/30 → ⅓
before dinner→ 3U
An adolescent girl is recently diagnosed
with T1DM → her body weight is 45 kg.
1. Given the information that the
typical starting insulin dose is 0.2
U/kg/day → calculate the total daily
insulin requirements for this girl?
2. Explain how can you formulate
these daily insulin requirements
into →
a. Basal bolus regimen
b. Split-mixed regimen
(conventional)

11. Insulin SEs
2. Diabetic ketoacidosis →
● Develops over hours or days.
● Opposite causes → low insulin dose,
skipped dose
● Hyperglycemia, ketoacidosis, electrolyte
imbalance, and dehydration
Other SE →
3. General weight gain
4. Temporary visual disturbances → changes in
the refractile properties of the lens
5. Localized fat accumulation/atrophy → if insulin
is repeatedly administered at the same site
→ disturbance in local adipocyte lipogenesis
functions → prevented by rotating injection
sites.
6. Local allergic reactions
7. Systemic allergic reactions → rare
1. Hypoglycemia→
○ The most serious complication
○ Rapid onset
○ Usually occurs due to → insulin overdoses,
changes in timing of injections or in eating
patterns (skipped meal), or high levels of
exercise.
○ Severe hypoglycemia can cause
unconsciousness, convulsions, brain
damage, and death.
○ Management → rapid restoration of blood
glucose → by iv concentrated dextrose
solutions

12. Insulin indications
1. Absolutely indicated in all cases of T1DM
2. T2DM patients if →
● Not controlled on antidiabetic
drugs
● In pregnancy
● In complications like diabetic
ketoacidosis → regular insulin i.v. is
preferred
● Stressful conditions like infections
and surgery etc.
3. Acute hyperkalemia

13. Diabetic
ketoacidosis
1. IV fluids → to correct fluid depletion
2. Continuous iv infusion of regular insulin
→ to slowly ↓ plasma glucose levels at
a rate of 50 to 100 mg/dL/hr.
3. IV administration of KCl → to
counteract hypokalemia
4. Glucose should be added to the iv insulin
infusion when glucose levels fall <
250 mg/dL → why? → Insulin infusion
are usually sufficient to treat acidosis &
should be continued until plasma
bicarbonate level is above 15 mEq/L.
However, hyperglycemia is usually
corrected more rapidly than acidosis →
added glucose will guard against
development of hypoglycemia
1
2
3
4
5
6

14. Treatment of
T2DM
→ treated mainly with anti-diabetic drugs
→ starting with one or two antidiabetic
drugs (acc. to the degree of hyperglycemia)
→ there is a progressive loss of beta-cell
function in T2DM over years → need for
adding a 3rd antidiabetic drug and →
ultimately, use of insulin
→ for younger T2DM patients → a target
goal for HbA1c in T1DM is 7.0%
→ for older T2DM patients with
complicating medical conditions → HbA1c
8% may be an acceptable and safer target
Improved glycemic control in
patients with T2DM ↓ long-term
microvascular complications

15. Antidiabetic
drugs
● Insulin secretagogues →
○ Sulfonylureas
○ Meglitinides
○ GLP-1 (glucagon-like peptide-1)
analogues
○ DDP4 (dipeptidyl peptidase-4)
inhibitors → gliptins
● Insulin sensitizers →
○ Thiazolidinediones → pioglitazone
○ Biguanides → metformin
● Drugs ↓ intestinal glucose absorption →
○ α-glucosidase inhibitors → acarbose
● Drugs ↑ urinary glucose excretion →
○ Sodium-glucose cotransporter-2
(SGLT-2) inhibitors → gliflozins

16. Insulin secretagogues
● Sulfonylureas
● Meglitinides
● GLP-1 analogues
● DDP4 inhibitors → gliptins

17. s
Meglitinides
SUs & meglitinides → common MOA → bind to SU
receptors on the KATP channels → channel closure
→ membrane depolarization & Ca++ entry → ↑
insulin release.
➔ Sulphonylureas
◆ 1st generation → Tolbutamide and
chlorpropamide → less potent & higher
risk of SE
◆ 2nd generations → glyburide, glipizide,
and glimepiride → 100 times more
potent, longer duration of action &
;ower risk of SE
➔ Meglitinides
◆ Repaglinide and nateglinide → rapid
onset of action & short-duration
Sulphonylureas
Meglitinides
GLP-1 analogues

18. Pharmacokinetics
& SEs
● Hypoglycemia →
○ the most common
○ result from overdose, skipped meals,
inadequate ingestion of carbohydrate,
renal or hepatic disease.
● Weight gain →
○ Common
○ Released insulin → ↑ lipogenesis
● Skin rashes
● GIT disturbances → nausea, vomiting, and
cholestasis.
● Hematologic reactions → leukopenia,
thrombocytopenia, and hemolytic anemia.
SUs (2nd gen) Meglitinides
MOA Common ????
Route Oral
Onset Faster than SUs
Duration of action Long → 24 h Short → 2-3 h
Administration Once daily, shortly
before/with
breakfast
Multiple, shortly
before/with each
meal
Effect on FBG ↓ →
Effect on PBG ↓ ↓
HA1c % ↓ 2% 1%
Plasma protein
binding
> 90%
Elimination Hepatic metabolism → renal/biliary
excretion
Hypoglycemia &
weight gain
less than SUs

19. Incretins
➔ Incretins → hormones released
from endocrine cells in small
intestine in response to food →
act on specific Rs pancreatic β
cells → ↑ insulin secretion
(glucose-dependant insulin
secretion)
➔ Two incretin hormones in
humans → glucose-dependent
inosulintropic polypeptide (GIP)
and glucagon-like peptide-1
(GLP-1).
➔ Incretins are rapidly catabolized
by dipeptidyl peptidase-IV
(DPP-IV)
Other effects of incretins:
➔ ↑ proliferation of β cells.
➔ ↓ glucagon secretion
➔ GLP-1 →
◆ Delays gastric emptying
◆ ↓ appetite
◆ ↓ blood pressure
◆ ↑ lipolysis in adipose tissue

20. Incretin mimetics
(GLP-1 analogues)
MOA →
➔ Liraglutide & exenatide → synthetic analogues
of human GLP-1 + resistant to degradation by
DPP-IV → prolonged duration of action
➔ GLP-1 analogues → bind to GLP-1 receptors
on beta cell → ↑ intracellular cAMP →
● cAMP-mediated activation of calcium
channel → glucose-dependent insulin release
● ↓ glucagon secretion
➔ Delays gastric emptying
➔ ↓ appetite
➔ ↓ blood pressure
Sulphonylureas
Meglitinides
GLP-1 analogues
Administered SC , once or
twice daily
Newer GLP-1 analogues → Dulaglutide
→ has been linked to human Ig or
albumin → very slowly eliminated →
half-life of a week → administered
once weekly

21. Incretin mimetics
(DPP-4 inhibitors)
MOA →
➔ Gliptins → sitagliptin, saxagliptin,
linagliptin
➔ Competitive inhibitors of DPP-IV (enzyme
that inactivates endogenous incretins) →
2x to 3x ↑ in incretin levels → glucose-
dependant insulin release ↑
Administered orally, once daily

22. DPP-4 inhibitors
● GIT SEs → low risk
● Hypoglycemia → rare
● Weight → neutral
● Pancreatitis → no
● Thyroid C-cell tumors → no
● ↑ in upper resp. tract infections & UTIs
● Arthralgia and hypersensitivity
reactions
● GIT SEs → mild-moderate nausea,
vomiting, diarrhea → ↓ over time →
start with low dose
● Hypoglycemia → rare, unless
combined with insulin, sulfonylureas,
or meglitinides → ↓ dose of insulin, etc
● Weight → ↓
● Pancreatitis → slight ↑ → require further
investigations
● Thyroid C-cell tumors → only in rodents
● Antibody formation → GLP-1 analogues →
synthetic peptides → could be recognized as
antigens → incidence is high with exenatide
GLP-1 analogues

23. Insulin sensitizers
● Thiazolidinediones → pioglitazone
● Biguanides → metformin
Low risk of hypoglycemia

24. Metformin
MOA →
➔ 1st-line drug for ttt of T2DM → esp.
for obese ptns with insulin resistance
➔ 1ry & most imp. effects → in the liver
→ inhibition of gluconeogenesis → ↓
hepatic glucose output
◆ Maybe due to inhibition of the
mitochondrial electron complex 1 →
activation of 5′adenosine
monophosphate-activated kinase
(AMPK) → ↓ transcription of genes
for gluconeogenesis
➔ ↑ insulin sensitivity & ↑ glucose uptake
in skeletal muscle and adipose tissue
➔ ↓ glucose absorption from the
intestines

25. Metformin
● GIT SEs →
○ the most common SEs
○ Diarrhea (30% of ptns), nausea,
vomiting, and flatulence.
○ Usually subsides over time.
● Lactic acidosis →
○ Very rare (only 3 cases per
100,000 ptn)
○ Due to interference with hepatic
mitochondrial glucose oxidation
○ CI in ptns with renal or hepatic
disease, or alcoholics → higher risk
of lactic acidosis

26. Thiazolidinediones
MOA →
➔ Pioglitazone & rosiglitazone
➔ 1ry & most imp. effects → on skeletal
muscle and adipose tissue
◆ A lesser effect → on the liver.
➔ Agonists at the peroxisome proliferator–
activated receptor-γ (PPAR-γ) → ↑
transcription of insulin-responsive
genes → ↑ peripheral insulin sensitivity
(60%) in ptns with T2DM.
◆ ↑ number of GLUT4 glucose
transporters in cell membranes of
muscle and adipose tissue → ↑
peripheral uptake of glucose

27. Metformin
● Body weight → ↓
● CV SEs → ↑ plasma volume, edema,
and ↑ risk of developing heart failure →
not used as 1st-line therapy in T2DM
& CI in ptns with/at risk of heart failure.
● Body weight→ ↑
● Risk of bladder cancer → slight ↑ →
pioglitazone
● Osteoporosis & fractures → ↑ → as it ↓
bone mineral density
Pioglitazone

28. Drugs that ↓ glucose reabsorption
● SGLT-2 inhibitors
Low risk of hypoglycemia

29. SGLT-2 inhibitors
MOA →
➔ The newest oral drugs for T2DM →
canagliflozin, dapagliflozin, and
empagliflozin.
➔ SGLT-2 → responsible for reabsorption
of 90% of filtered glucose in PCT
➔ SGLT2 inhibitors → selectively inhibit
SGLT2 → ↓ renal glucose reabsorption →
↑ urinary glucose excretion → ↓ blood
glucose levels
➔ High glucose in renal tubules → osmotic
diuresis → ↑ urine volume → ↓ blood
pressure
➔ Loss of calories in urine → ↓ weight
Based on the fact that → efficacy of SGLT-2
inhibitors is dependent on renal glomerular
filtration of glucose → SGLT-2 inhibitors are CI
in ptns with glomerular filtration rates <
50 mL/min.

30. ● ↑ incidence of UTIs and genital
yeast infections → as they ↑
urinary glucose levels & facilitate
microbial growth.
● Volume depletion → as they cause
osmotic diuresis → cases of acute
renal injury; in susceptible ptns
(dehydrated, heart failure or low
blood pressure, or are taking other
drugs affecting the kidneys as
diuretics and angiotensin-
converting enzyme (ACE) inhibitors)
→ reversible.
SGLT-2 inhibitors ● Rarely diabetic ketoacidosis →
euglycemic
● ↑ risk of osteoporosis and bone
fractures,

31. Drugs that ↓ glucose absorption
● α-glucosidase inhibitors
Low risk of hypoglycemia

32. MOA →
● Acarbose → a competitive
inhibitor of α- glucosidase enzyme
→ an intestinal enzyme that
converts oligosaccharides and
disaccharides to glucose → ↓
digestion & absorption of dietary
starch and disaccharides → ↓
postprandial blood glucose.
Acarbose SEs →
● Flatulence and abdominal bloating →
most common → result from delivery of
greater amounts of carbohydrate to
colon → exert an osmotic attraction for
water and are metabolized by bacteria.
● ↓ iron absorption.
N/B.. If ptns is on concurrent ttt with insulin
and acarbose, then he develops
hypoglycemia → should be treated with oral
glucose (dextrose) NOT sucrose → as sucrose
requires α-glucosidase activity for digestion

33. For T2DM→
● Metformin →
generally preferred as
first-line therapy
● For patients with CV
disease or chronic
kidney disease (CKD)
→ SGLT-2 inhibitors or
GLP-1 agonists →
recommended as first
line → proved to ↓ in
diabetes-related CV
complications
● Ptns requiring dual
therapy →
METformin +
1. GLP-1 analogues
2. SGLT inhibitors
3. DPP-4 inhibitors
4. TZD
5. SU

34. A 44-year-old man with a body mass
index of 34 kg/m2 was found to have
type-2 diabetes mellitus on routine
testing 3 months ago. He was advised
a low-energy, weight-reducing diet
and exercise. He has been unable to
comply with this, and recent
investigations show postprandial
blood glucose concentration is 250
mg/dl.
What would be the best drug to initiate
as first-line therapy for type-2
diabetes in this patient?
A. Gliclazide
B. Insulin
C. Metformin
D. Pioglitazone
E. Sitagliptin

35. A 34-year-old male patient has a past
medical history of Type 2 diabetes
and hypertension he has been
experiencing profound swelling in his
feet and lower legs for the past two
weeks
Medications:
● Metformin 850 mg tablet 1 po three times
daily;
● Gliclazide tablet two po twice daily;
● Pioglitazone 45 mg tablet 1 po once daily;
● insulin glargine inject 20 units
subcutaneously every evening;
● lisinopril 10 mg tablet 1 po once daily
Which diabetes medication is most
likely responsible for his new edema?
A. Gliclazide
B. Insulin
C. Metformin
D. Pioglitazone

36. A 52-year-old man presents to his
PCP’s office for a routine follow-up
visit on diabetes. His diabetes was
diagnosed one year ago and he has
only been prescribed metformin for
treatment. His metformin dose was
maximized last month, but his blood
glucose levels are still not at goal.
You need to add an oral agent that is
safe, and effective enough to
potentially attain a goal A1c of <7
percent.
What drug class do you recommend?

37. Which of the following
statements is correct
regarding insulin glargine?
A. It is primarily used to control
postprandial hyperglycemia.
B. It is a “peakless” insulin.
C. The prolonged duration of
activity is due to slow
dissociation from albumin.
D. It should not be used in a
regimen with insulin lispro or
glulisine.
E. It may be administered
intravenously in emergency
cases

38. A 78-year-old nursing home resident is
admitted to the acute medical unit after being
found collapsed in his room. A carer from the
nursing home is present and reports that he has
had regular 'hypos' recently. On admission he
was drowsy and the blood glucose was 45 mg/dl.
Following intravenous dextrose the patient's
condition significantly improved.
His medication on admission is as follows:
Metformin 1g bd
Glipizide 160mg od
Pioglitazone 45mg od
Aspirin 75mg od
Simvastatin 40mg od
What is the most appropriate initial
action?
A. Stop metformin
B. Stop pioglitazone
C. Stop gliclazide
D. Make no changes to the
medication
E. Stop all oral antidiabetic
medications

39. Thank you..