Pharm D Program

Advanced Pharmacotherapy II
2024-2025

Prof Dr Manar A Nader

Endocrine wk-1 13
1
2
 Endocrine System
Endocrine glands are glands that excrete hormones
direct to the blood
We have 9 endocrine gland (hypothalmus, pituitary,
Thyroid, parathyroid, thymus, adrenal, pancrease and
ovary/testis)
Pancrease
Consists of 2 parts
Endocrine function Exocrine function
Islets of Langerhan secret from In the middle of the gland there is a
Alpha cell…..glucagon tube (pancreatic acini) which is
Beta cell……..insulin considered a part of the digestive
Both control blood glusoce system secreting amylase ( digest
carbohydrate), lipase (digest
carbohydrate) & protease (digest
protein) in the small intestine
4
 definition
Diabetes mellitus (DM) is a chronic metabolic disorders that are -
.characterized by hyperglycemia (raised blood glucose level)
DM is the commonest endocrine disorder encountered in clinical -
.practice
and It’s associated with long-term microvascular, macrovascular, -
.neuropathic complications
 Diabetes Mellitus (DM)
Released insulin from beta cells enter glucose to
muscle and adipose tissue while other cells
(kidney, eye, heart , nerve….) glucose enter with
no need to insulin leading to diabetic
complication in uncontrolled diabetes
Insulin decrease glucose thus decrease lipolysis
and increase protein production
If glucose did not enter cells (muscle and adipose
tissue) cell start to decompose lipid (lipolysis)
releasing ketone bodies causing diabetic
ketoacidosis
Types of Dm
► The most common types of DM are :
1- Type 1 DM (juvenile onset DM)
2- Type 2 DM (Adult onset DM)
3- Gestational diabetes (pregnancy diabetes)
 type 1 DM (juvenile onset Dm) -1
❖ 5 – 10 % of all diagnosed case of Dm.
❖ Major immunological features:
❖ Insulin-dependant DM (IDDM) 1- Human leukocyte antigen (HLA-DR3&
HLA-DR4) expression on the B-cells.
❖ Type 1 DM usually is diagnosed in
children and adults younger than 30
years of age, although the disease can 2- Presence of reactive autoimmune
present at any age. antibodies directed against B-cells.

❖ This form of the disease is characterized

by an absolute deficiency in insulin 3- Monocytes and T-lymphocytes
resulting from pancreatic B-cell infiltration of islets of Langerhans.
destruction by an autoimmune attack.

❖ Destruction of B-cells caused by :

- A stimulus of the environment ( such as
infection)
- An immune event(genetic determinant)
make B-cells recognized as non-self.
 Type 1 dm -1
symptoms Metabolic changes

❖ Symptoms appear ❖ Metabolic abnormalities occur due to insulin

when 80-90% of defficency.
B-cells destroyed. ❖ The hormonal level affect metabolism in :
Liver, muscle and adipose tissue.
❖ 4 main signs are 4T:
( toilet- thirsty-
tired-thinner) hyperglycemia :blood glucose due to ↑
- ↓ peripheral tissue uptake
❖ Symptoms:
- ↑ hepatic production of glucose
1- Polyuria, polydipsia,
ketoacidosis Very charactarestic for type 1 (not
poluphagia, glucosuria type 2)
2-weight loss hypertriacylglycer Xss fatty acid converted TAGs&
3- fatigue olemia secreted in form of VLDL
4- blurred vision
Type 1 dm-Honeymoon period
► At time of diagnosis, most patients have a 90% loss of β-cell
function.
► The remaining 10% of β-cell function at diagnosis creates a
“honeymoon period” during which blood glucose levels are
easier to control.
► Smaller amounts of insulin are required at this period.
► Once this remaining β-cell function is lost, patients become
completely insulin-deficient and require more exogenous
insulin.
type 2 Dm (adult onset Dm) -2
❖ More common than type 1
❖ Accounts for 90-95% of all
diabetecs.
❖ Occur mainly in adults (after 40
years)
❖ Non-insulin dependant DM
❖ Patient with type 2 DM have
combination of Insulin resistance
& Dysfunctional B-celles
❖ Metabolic alterations in type 2 are
milder than type 1 because the
presence of insulin although not
adequate but is sufficient to
prevent DKA.
❖ Occurrence is almost heridatry
not infection or autoimmune
antibodies.
 Type 2 dM pathophysiology
:a- insulin resistance
Cause of ❖ The most common cause is OBESITY:
insulin Accumlated fat in body cells distrupt their response to insulin
resistance →
hyperglycemia & Hyperinsluinemia (in early finding of type 2
DM)

Insulin ❖ Insulin resistance alone will not lead to type 2 DM, in absence
resistance & of defect in B-cell non-diabetic obese cases can compensate
type 2 DM for insulin resistance with increased level of insulin

❖ Insulin resistance and subsequent type 2 DM is commonly

observed in:
1- elderly
2- obese & physically inactive individuals
3- Pregnant women
❖ These patients are unable to sufficiently compensate for
insulin resistance with increased insulin level.
 Type 2 Dm Pathophysiology
B- Dysfunctional B-cells
❖ In early stages of type 2 DM, pancreas retain B-cells
capacity
❖ B-cells dysfunction occur because it fails to secrete
enough insulin to correct Hyperglycemia.
❖ The natural progression of the disease result in
declining ability to control Hyperglycemia with
endogenous secretion of insulin.
❖ Deterioration of B-cells function is accelerated by
the effect of :
1- Sustained Hyper glycemia
2- Elevated free fatty acids
 Type 2 DM
Risk factors Symptoms Metabolic changes

❖ Obesity (the chef ❖ Polyphagia ❖ Hyperglycemia :

risk factor) ❖ Polyuria Caused by diminished
❖ First-degree family ❖ Polydipsia peripheral uptake of
history of DM ❖ glucosuria glucose & increased
❖ Physical inactivity ❖ Weight gain hepatic production.
(sedentary life style) ❖ Slow-healing ❖ Hypertriacylglycerolemi
❖ Race or ethnicity sores a:
(Native American, ❖ Yeast infection Fatty acids are converted
Latino/Hispanic-Ame ❖ Blurred vision to TAG & secreted in form
rican,Asian-America of VLDL
n, African-American) ❖ N.B: No DKA due to
❖ Hypertension presence of insulin
❖ pregnancy
 Diagnosis of Diabetes Mellitus (DM)
Goal diabetic Pre-diab normal LAB ASSESSMENT
after s etics
treat
ment
80-10 126≤ 100-125 <100 Fasting blood glucose
0 level mg/dl
< 200≤ 140-200 140> Random blood glucose
180 level mg/dl
< 200≤ 140-200 140> OGTT mg/dl
180

<7 6.5≤ 5.7-6.5 <5.7 HBA1C%

Oral glucose tolerance test (OGTT): performed by giving 75 gm glucose then
measure blood glucose after 2 hrs
rate of formation of HbA1c is proportional to the average blood glucose
concentration over the previous 3 months; thus, HbA1c provides a measure of
how well treatment has normalized blood glucose in diabetics. Fragile patient
(A1C 7-8)
The elevated lab assessment most be accompanied with polyuria, Polydipsia &
polyphagia
 Goals of Diabetes Management in Non-pregnant Adults
Primary goal is to prevent the onset of acute or chronic complications.
Acute Hypoglycemia, diabetic ketoacidosis (DKA), hyperglycemic hyperosmolar non
complications: ketotic syndrome
Chronic ✔ Microvascular: Retinopathy, nephropathy, and neuropathy
complications ✔ Macrovascular: Cardiovascular, cerebrovascular, and peripheral vascular
diseases
Glycemic o A1C less than 7.0% (Note: The ACE/AACE guidelines recommend 6.5% or
therapy goals less.)
1. Obtain every 6 months in patients at goal A1C and every 3 months in those
over goal.
2. Less stringent A1C targets may be appropriate in those with a short life
expectancy (e.g., terminal cancer), advanced diabetic complications,
long-standing diabetes that is difficult to control (e.g., frail older adults
with a history of hypoglycemia at risk of falls), or extensive other
comorbidities. (In such situations, a higher A1C [e.g., less than 8%] may be
sufficient to limit the risk of acute complications of hyperglycemia such as
dehydration and electrolyte deficiencies.)
Non-glycemic Blood pressure less than 140/90 mm Hg
therapy goals No specific LDL goal is currently recommended
in lowering LDL by 30%–49% in patients with diabetes 40–75 years
Non-pregnant of age and by at least 50% if 10-year risk of cardiovascular
Adults event is at least 7.5%.
No specific TG or HDL goals are currently recommended.

Goals for✔ Primary goal is to prevent complications to mother and child.

✔ Glycemic therapy goals (more stringent): FPG of 95 mg/dL or
Gestational
less
Diabetes ✔ Potential complications of hyperglycemia during pregnancy
▪ Mother: Hypertension, preeclampsia, T2D after pregnancy
▪ Fetus/child: Macrosomia, hypoglycemia, jaundice, respiratory
distress syndrome
 Management Type 2 Diabetes
NONPHARMACOLOGIC THERAPY:
Medical Nutrition Therapy MNT:
►There is no standardized “diabetes diet” nor is there a single ideal
distribution of macronutrients; therefore, meal planning should be
individualized.
► An initial weight loss goal of at least 5% should be targeted in all patients
who are overweight or obese through calorie restriction.
► Carbohydrate intake from vegetables, fruits, legumes, whole grains, dairy
products, and those high in fiber is preferred.
Physical Activity
► Aerobic exercise improves insulin sensitivity, modestly improves
glycemic control in the majority of individuals, reduces CV risk,
contributes to weight loss or maintenance, and improves well-being.
► Physical activity goals include at least 150 minutes per week of
moderate intensity exercise spread over at least 3 days a week with no
more than 2 days between activities
Oral Medications
 ®Biguanide; Metformin- Glucophage
► ↓ hepatic glucose production, ↑ insulin sensitivity
► No hypoglycemia
► Reduction in cardiovascular events and mortality
► Contraindications- SCr ≥ 1.5mg/dL males, ≥ 1.4 mg/dL
females
► New FDA recommendations for metformin will include:
► eGFR < 30 mL/minute/1.73 m2
► eGFR between 30-45 mL/minute/1.73 m2 is not
recommended
► Best A1c benefit = 2,000mg/day
► data suggest that use of metformin decreases cancer
incidence due to AMP-activated protein kinase (AMPK) through LKB1. LKB1 is
a tumor suppressor, and activation of AMPK through LKB1 may play a role in
inhibiting cell growth.
 Metformin
► Disadvantages
► GI side effects
► Long-term use may interfere with vitamin B12
absorption
► Metformin is also contraindicated in
persons with hepatic dysfunction and/or
renal disease, acute myocardial infarction,
or diabetic ketoacidosis. [Note: Diabetics
being treated with heart-failure
medications should not be given metformin
because of an increased risk of lactic
acidosis]
 Metformin
For patients taking metformin, we measure:
► ●A1C every three to six months.
► ●Serum creatinine annually.
► ●Vitamin B12 annually
► Breastfeeding — Although data are
limited, metformin use by breastfeeding women with
PCOS does not appear to be associated with adverse
outcomes. Concentrations of metformin in breast milk
appear to be low, and the mean infant exposure to
metformin has been reported to be well below the
level of concern for breastfeeding; no adverse effects
on blood glucose of nursing infants have been
reported
Sulfonylureas
► Glyburide-Glynase®, Diabeta®
► Glipizide-Glucotrol®
► Glimepiride-Amaryl®
► ↑insulin secretion from pancreatic beta
cells
► ADE- hypoglycemia, weight gain
► Glyburide associated with most
hypoglycemia, avoid in patients with
renal insufficiency
► Elderly and/or hepatic or renal dysfunction
► Start with low dose and titrate
Sulfonylureas
► Advantages
► Inexpensive
► High initial response rate

► Disadvantages
► Hypoglycemia, especially in elderly
patients
► Weight gain
► Only effective when β cell function still
present
► Best used early in the disease process
Meglitinides
► Repaglinide- Prandin®
► Nateglinide- Starlix®
► ↑glucose-dependent insulin secretion from
pancreatic beta cells
► ↓post-prandial glucose excursions Thus,
are categorized as postprandial glucose
regulators.
► Given 30 minutes prior to meals
► ADEs- hypoglycemia (less than
sulfonylureas), weight gain
► Frequent dosing (meals)
Meglitinides
► Advantages
► Less hypoglycemia that sulfonylureas

► Disadvantages
► Hypoglycemia
► Weight gain
► Frequent dosing needed with each meal-
not convenient for patients
 Thiazolidinediones (TZDs)
► Pioglitazone- Actos®
► Rosiglitazone- Avandia®
► ↑ insulin sensitivity in muscle, liver, and fat
► No hypoglycemia
► ↑ HDL and LDL (rosi)-----bad
► ↑ HDL, ↓ TG (pio)----good ^^
► Generally, the clinical significance of lipid effects of
TZDs is unclear at this time
► Contraindicated in NYHA (New York Heart
Association) Class III/IV heart failure
► ADEs- fluid retention, weight gain, ↑ risk of bone
fractures
 α-Glucosidase Inhibitors
Acarbose- Precose® & Miglitol- Glycet®
► Inhibits intestinal α-glucosidase= slows intestinal complex carb
digestion and absorption
► Not well tolerated- flatulence, diarrhea
► Advantages: Weight neutral & Low hypoglycemia as monotherapy
► Adverse effects
• Flatulence, diarrhea, abdominal pain
• Increased liver enzymes with high doses of acarbose
• Contraindications in Inflammatory bowel disease, colonic ulcerations,
intestinal obstruction
► Efficacy: 0.5%–0.8% reduction in A1C, also shown to decrease body
weight
► Target postprandial glucose excursions
► Might not be as effective in patients using low-carbohydrate diets
Copyrights apply
Dipeptidyl Peptidase 4 (DPP-4) Inhibitors

► Sitagliptin- Januvia®
► Saxagliptin- Onglyza®
► Linagliptin- Tradjenta®
► Alogliptin- Nesina®
► Inhibits DPP-4 (increases postprandial incretins
GLP-1 and GIP)
► ↑ glucose-dependent insulin secretion
► ↓ glucose-dependent glucagon secretion
► Effect is primarily on PPBG levels
► Well tolerated, no hypoglycemia, weight neutral
► May be associated with pancreatitis
 Sodium-Glucose Cotransporter 2 (SGLT-2)
Inhibitors
► Canagliflozin- Invokana®, Dapagliflozin- Farxiga®
► Empagliflozin- Jardiance®, Ertugliflozin
► Inhibits SGLT-2 in the proximal nephron
► Blocks glucose reabsorption in the kidney, increasing glucosuria
► Once blood glucose concentrations exceed the renal threshold for
reabsorption (180mg/dL), glucose appears in the urine
► The kidney filters about 180 grams of glucose per day, and all of this
glucose is reabsorbed.
► 90% is reabsorbed by the SGLT-2 transporter
► 10% by the SGLT-1 transporter
► No glucose appears in the urine
► Patients on a SGLT-2 inhibitor will excrete between 70-100g of
glucose in urine per day
 SGLT-2 Inhibitors
► Low risk of hypoglycemia
► Some weight loss (4-7 lbs- stabilizes after 6-12 months)
► Reduced systolic blood pressure (3-5mmHg)
► ADEs- genitourinary fungal infections, urinary tract
infections, polyuria, volume depletion, Hypotension,
Class is linked with rare cases of euglycemic DKA and
Fournier gangrene. Possible increased bone fracture risk,
decreased bone mineral density, and foot or leg
amputation with canagliflozin
► Agent should be discontinued before any surgery to
reduce the risk of ketoacidosis
 SGLT-2 Inhibitors
Efficacy
► 0.3%–1.0% reduction in A1C
► Effect on both fasting and postprandial glucose
concentrations
► Mild weight loss
► Empagliflozin, dapagliflozin, and canagliflozin can reduce
cardiovascular morbidity in patients with T2D and
established cardiovascular disease and may improve renal
[Link] or dapagliflozin in patients with
significant urine albumin excretion and renal
insufficiency reduces the risk of end-stage renal disease,
doubling of SCr, or renal death.
2
36
Injectable Medications
 Glucagon Like Peptide-1 Agonists(GLP-1 Agonists)
► Exenatide- Byetta®, Exenatide extended release- Bydureon® (weekly)

► Liraglutide- Victoza®, Albiglutide- Tanzeum® (weekly)

► Dulaglutide- Trulicity® (weekly), injectable & Oral Simaglutide

► oral orforglipron (July 2023)

► Produce better reduction in Alc than DDP-4

► GԼР-1 exerts its main effect by stimulating glucose-dependent iոѕuliո release

from the pancreatic islets. GԼР-1 slow gastric emptying, inhibit inappropriate
post-meal glucagon release and reduce food intake. In patients with type 2
ԁiabеtеs, there is an impaired iոѕսliո response to GLΡ-1, possibly related to a
reduction in postprandial GLΡ-1 secretion
 Glucagon Like Peptide-1 Agonists(GLP-1 Agonists)
► GLP-1 receptor agonists provide lose and maintain weight
withachieving adequate glycaemic control.
► This difference between GLP-1 receptor agonists (weight loss)
and DPP-4 (weight neutral) therapies may stem from a
pharmacological perspective.
► Endogenous GLP-1 acts to reduce gastric emptying and inhibit
upper intestinal motility. This results in increased satiety and
decreased food intake. Although both incretin therapies cause
increased levels of GLP-1, DPP-4 inhibitors only achieve this
within physiological parameters. GLP-1 receptor agonists on the
other hand are administered at pharmacological doses potentially
resulting in far increased, longer lasting effects on satiety.
 Glucagon Like Peptide-1 Agonists(GLP-1 Agonists)
► ADEs- GI (nausea/vomiting)
► Possibly associated with pancreatitis
► associated with increased risk of gallbladder and biliary diseases
► Contraindication
► Patients with personal or family history of medullary thyroid cancer or
history of multiple endocrine tumors
► Shorter acting versus longer acting – In trials
comparing exenatide administered twice daily with
ехeոаtiԁе once weekly, liraglutide once daily,
or dulaglutide once weekly, the reduction in A1C with
the longer-acting (daily or weekly) GLР-1 receptor
agonists was significantly greater
Dual GLP-1/GIP Agonists

► A synthetic dual-acting GIP and GLP-1 receptor

agonist (tirzepatide, approved in 2022) is available
for the treatment of hyperglycemia in patients
with type 2 diabetes
Amylin Analog
► Pramlintide- Symlin ®
► Synthetic analog of human amylin
► Neuroendocrine peptide that is secreted
with insulin from pancreatic β cells in
response to food
► Delays gastric emptying, suppresses glucagon
secretion, and enhances satiety
► FDA-approved for T1DM and T2DM
► Reduces A1c about 0.5%
 Pramlintide
► ADE- hypoglycemia, nausea, vomiting
► To reduce risk of hypoglycemia, doses of
mealtime insulin should be reduced 30-50%
before pramlintide started
► Avoid in patients with gastroparesis (delayed
gastric emptying, is a disorder that slows or
stops the movement of food from the stomach
to the small intestine.
► Avoid in patients with A1c > 9%

Image from: [Link]

Insulin
► Most** insulins are 100 units/mL
► U-500 insulin is 500 units/mL
► Humalog®: 100unit/ml and 200unit/ml
concentrations
► Tresiba®: 100 units/mL and 200 units/mL
concentrations
► Toujeo®: 300 units/mL
► Basal insulin
► Bolus insulin
► ADE: hypoglycemia,
weight gain
► Decreases FBG (hepatic glucose production)
► Approximates ≈ 50% of daily insulin needs
► Physiological basal insulin; released during
sleep no carbohydrate it enter glucose to
muscle and adipose tissue during rest to keep
themBasal Insulin
Bolus Insulin
► alive
► Limits PPBG
► Each meal ≈ 15% of daily insulin
needs
 Insulin Preparations according to
onset and duration of action
1- Rapid-acting insulin analogues

✔ insulin lispro ( Humalog)

✔ insulin aspart (Novolog)
✔ insulin glulisine (Apidra)
► Generally the onset is 5 to 15 minutes after administration.
► They are administered to mimic the prandial (mealtime) release of insulin,
and they are usually not used alone but, rather, along with a longer-acting
insulin to assure proper glucose control
► It is usually administered 15 minutes prior to a meal or immediately
following a meal
► Are ideal for controlling the upward glycemic excursions that occur
immediately after meals in diabetics.
► All of the rapid-acting formulations are suitable for intravenous
administration, although regular insulin is most commonly used
 Short-acting insulin analogues -2
a) Regular insulins (Humulin R, Novolin R) a soluble,
crystalline zinc insulin.
► Regular insulin is usually given subcutaneously (or i.v in
emergencies e.g., diabetes ketoacidosis), and it rapidly
lowers blood glucose .
► take 30 minutes to begin to exert their effect , more gradual
onset of action ,but have a longer duration of action than
rapid- acting insulin.
► is designed to control postprandial hyperglycemia.
► used to supplement intermediate- and long-acting insulin
preparations.
► preparation of choice for glucose management during
surgery, trauma, shock, or diabetic ketoacidosis.
b) Prompt insulin zinc suspension (Semilente, amorphous
zinc is incorporated) it should be mixed only with Lente or
Ultralente insulin preparations.
► Rapid-acting and short-acting insulins are often administered
 Short-acting insulin analogues -2
c) Technosphere Insulin:
Technosphere insulin is a dry-powder
formulation of recombinant human
regular insulin that can be inhaled and
absorbed through pulmonary tissue. It
is a rapid acting powder insulin,
inhaled at mealtimes to improve blood
glucose control in type 1 and type 2
diabetic population
The patient should not use
technosphere as a substitute for
long-acting insulin and in diabetic
ketoacidosis.
It must be used along with long-acting
insulin in type 1 diabetes.
Technosphere insulin is a very small
whistle-like device, prepared as a
single-use color coded cartridge
providing 4, 8 or 12 units soon before
the meal.
 c) Technosphere Insulin:
It is not approved in:
1. Habitual smokers or who have recently
stopped smoking
2. Not proposed for use in children less
than 18 years of age.
3. It is contraindicated in asthmatic and
chronic obstructive pulmonary disease
patients. Requires spirometry testing at
baseline, at 6 months of therapy, and
annually thereafter
Technosphere should be inhaled at the
beginning of a meal as a single
inhalation per cartridge using inhaler.
Before putting the cartridge in the
inhaler, make sure it has been at room
temperature (~25οC) for at least 10 min.
Precautions should be taken like not
leaving cartridges in inhaler, not washing
inhaler and keeping mouthpiece cover
until the next dose.
Intermediate-acting preparations -3
A-Isophane insulin suspension (Neutral protamine Hagedorn, NPH) is a
suspension of crystalline zinc insulin combined at neutral pH with a positively
charged polypeptide, protamine, forming a less-soluble complex, to delayed
absorption of the insulin .
► NPH insulin should only be given subcutaneously (never I.V.)
► is useful in treating all forms of diabetes except diabetic ketoacidosis or
emergency hyperglycemia.
► given along with rapid- or short- acting insulin for mealtime control.
B-Neutral protamine lispro (NPL) insulin.
C-Lent insulin (Insulin zinc suspension) is a mixture of crystalline (ultralent) +
amorphous (semilent)
► Intermediate acting insulin preparations are usually given once or twice a day.
4. Long-acting insulin preparations
A- Insulin glargine: (Lantus)
► A molecule that is soluble at pH 4 but less soluble at neutral
(physiological) pH (in subcutaneous tissue) with enhanced stability at
physiological pH.
► Because it is necessary to maintain its acidic pH prior to injection,
insulin glargine must not be mixed with any other form of insulin
during injection.
it precipitated at the injection site, thereby extending its action.
It is slower in onset than NPH insulin and has a flat, prolonged
hypoglycemic effect that is, it has no peak
it must be given subcutaneously.
B- Insulin detemir: (Levemr)
Insulin detemir has a fatty-acid side chain.
The fatty-acid side chain enhances association to albumin.
Slow dissociation from albumin results in long-acting properties
similar to those of insulin glargine
Insulin Degludec:
✔ It is an ultra-long-acting (42 h) insulin analogue.
✔ The long duration of action is due to the
multihexamers depot formed at the injection site
and slow release of monomers.
✔ The mixture product is a combination of insulin
degludec and insulin aspart (70/30) for
subcutaneous injection.
✔ Another insulin degludec product is a fixed ratio
combination of insulin degludec and glucagon-like
peptide 1 agonist, liraglutide
5. Insulin combinations
Various premixed combinations of human insulins, such as
NPH insulin plus regular insulin (70%/ 30%) or (50%/ 50%)
75 % NPL insulin plus 25 % insulin lispro
► The mixture exert rapid onset and intermediate duration of action.
► They are accessible to diabetic patients having problem in mixing insulins.
► The fixed combinations are generally administered twice daily, with the morning
and evening meal. Dose is determined based on blood glucose values and precisely
individualized to attain optimum therapeutic effect.
► Premixed combinations are usually administered within 15 min before or after
having a meal.
► The fixed combination exhibits 2 phases of absorption. The initial phase represents
insulin lispro and its rapid onset of action; the ensuing phase demonstrates the
prolonged action of insulin protamine suspension.
Insulin Preparations

54
55
 Insulin preparations
features duration onset clear preparatio
ns
min prior meal 15 hr 3 15 Clear Aspart 1- Rapid
Bolus/post min IV or SC Lispro acting
prandial insulin Glulisine
Inhaled
min prior meal 30 hr 6 30 Clear Regular 2- Short
Bolus/post min IV or SC acting
prandial insulin
Basal insulin hr 12 hr 1 Cloudy Neutral 3-
SC protamine Intermediate
hagedron acting
Basal insulin hr 24 hr 2 Clear Detemir 4- Long
SC Glargine acting
degludec
Old strategy for management of T1DM is 2+ 3 (short + intermediate acting
insulin)
Recent strategy for management of T1DM is 1 + 4 (rapid + long acting
insulin)
General roles for Management of type 1DM
TOTAL DAILY INSULIN (TDI) requirement for
Individuals with T1DM is is 0.3 to 0.6 unit/kg/day
divided into multiple doses delivered according to
the regimen used (old or new strategy).
It is suggested that when insulin requirements
exceed 100 units/day, efforts to shrink insulin
resistance must be enforced, for example, exercise
and restricting dietary carbohydrate intake.
Suppose the patient weight is 100 kg thus the daily
requirement of insulin is 30, 40, 50, or 60 according
to patient status
Its preferred to start with the least dose 0.3
u/kg/day then titrate the dose according to patient
situation
 General roles for Management of type 1DM
Role for dosing of insulin in Old strategy for
management of T1DM (short + intermediate acting
insulin)
either premixed preparations or not with a ratio of 70%
NPH + 30% regular insulin or 75/25
divided into 2 doses; 2/3 the dose to be taken 30 min
before breakfast and 1/3 to be taken 30 min before
evening meal
eg; patient weight 100 kg need 30 U/day divided 20 U
before breakfast and 10 unit before dinner
After that we need to adjust the dose according to
patient requirement
Advantages: Daily insulin injection frequency two or
three times daily and less expensive than newer insulins
Disadvantages: Does not mimic natural insulin secretion
pattern; prone to hypoglycemic events
 General roles for Management of type 1DM
Role for dosing of insulin in Recent strategy for
management of T1DM (long + rapid acting insulin;
Basal/Bolus strategy; physiologic insulin therapy)
Preferred regimen as it simulate the physiological
insulin release
Use insulin analogs to better mimic natural insulin
secretion patterns
Use long-acting basal insulin to prevent ketosis and
control FPG
Use bolus insulin to control postprandial hyperglycemia
Advantages : More physiologic, less hypoglycemia, more
flexible to patient mealtimes
Disadvantages: Cost and increased frequency and
number of daily injections (rapid-acting and
basal insulin must be injected separately).
 General roles for Management of type 1DM
Basal/Bolus strategy
Bolus taken with each meal
Basal taken at rest (no feed, during rest and sleep)
Dose of insulin divided as 50% being delivered as
basal insulin, and the remaining 50% as bolus insulin
The basal insulin taken before sleep
The bolus insulin divided equally on the 3 meals
eg; patient weight 100 take 0.3 U/kg so total dose is 30U
15 U taken at bed time of insulin detemir
15 U taken as insulin lisipro taken 5 U 15 min before
each meal
After that we need to adjust the dose according to
patient requirement
 Insulin dose adjustment roles
Insulin titration algorithm
Bolus insulin Pre lunch Basal insulin Pre-breakfast
dose increment Pre dinner dose (pre-bed blood glucose
Pre lunch Pre bed blood dose) mg/dl
Pre dinner glucose mg/dl
Pre bed blood
glucose mg/dl

4 More than 180 8 More than 180

3 160-180 6 160-180
2 140-159 4 140-159
1 120-139 2 120-139
- 100-119 1 100-119
1- 80-99 - 80-99
2- 60-79 2- 60-79
3- Less than 60 4- Less than 60
 Insulin dose adjustment roles
comment on Insulin titration algorithm
► If the glucose reading is not as the goal of a meal
adjust insulin of the previous meal
► Morning fasting blood glucose if not adjusted so
change the basal insulin dose according to the Insulin
titration algorithm
► Before lunch blood glucose if not adjusted so change
the bolus insulin dose taken in the morning according
to the Insulin titration algorithm
► Before dinner blood glucose if not adjusted so
change the bolus insulin dose taken in the lunch
according to the Insulin titration algorithm
► Pre bed blood glucose if not adjusted so change the
bolus insulin dose taken in the dinner according to
the Insulin titration algorithm
► The honeymoon phase usually begins about 3 months after
you start treatment for type 1 diabetes. It can last anywhere
from 1 month to 13 years.
► The length of the honeymoon is different for each person.
► As time passes, and more beta cells die, your pancreas makes less
insulin.
► During the honeymoon phase, it may fall to 0.1 to 0.4 units/kg.
3
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 General roles for Management of T2DM
► Non Pharmacological therapy:
► Medical nutrition therapy — Medical nutrition therapy (MNT) is
the process by which a dietary plan is tailored for people with
diabetes, based on medical, lifestyle, and personal factors
► Weight management — For patients with type 2 diabetes, body
weight management should be considered as a therapeutic
target in addition to glycemia.
► Strategies for weight management include lifestyle change,
pharmacologic therapy, and metabolic surgery.
► Surgical therapy — Weight loss surgery in patients with obesity
and type 2 diabetes results in the largest degree of sustained
weight loss and, in parallel, improvements in blood glucose
management and the most frequent sustained remissions of
diabetes. Weight loss surgery is an option to treat poorly
managed type 2 diabetes when other modalities have failed.
 General roles for Management of T2DM
When to start
► For most patients presenting with A1C at or above target level
(ie, >7.5 to 8 percent), pharmacologic therapy should be
initiated at the time of type 2 diabetes diagnosis (with lifestyle
modification).
► For highly motivated patients with A1C near target (ie, <7.5
percent), a three- to six-month trial of lifestyle modification
before initiating pharmacologic therapy is reasonable.
 General roles for Management of T2DM
► Guideline for management of T2DM when A1C is more
than 7% and less than 10%
1. Metformin-preferred initial agent after excise and diet
control fail to control hyperglycemia unless contraindicated or
adverse effect preclude its use (severe renal, cardiac and hepatic
problems)
2. Adding 2nd medication if metformin mono therapy falls to
attain or maintain glycemic control (after 3 moths A1C is more
than 7%); add another agent based on several criteria and weighs
advantages and disadvantages of the various oral and injectable
agents:
A. Efficacy in lowering A1C
B. Risk of hypoglycemia, effect on weight, adverse effect & cost
profile
C. 2nd added agent many be SU, TZD, DPP-4 inhibitors, SGLT-2
inhibitor, GLP-1 agonist & basal insulin
 General roles for Management of T2DM
► Adding 2nd medication to metformin according to
1. CVD (HF, CAD, arrhysmia, heart valve disease & stroke)
; SGLT-2 inhibitor or GLP-1 agonist
2. Heart failure or CKD; SGLT-2 inhibitor(preferred) or
GLP-1 agonist
3. Compelling to minimize weight; SGLT-2 inhibitor or
GLP-1 agonist (preferred)
4. Compelling need to minimize hypoglycemia; SGLT-2
inhibitor or GLP-1 agonist, TZD & DPP-4 inhibitors
5. Cost; SU & TZD
 General roles for Management of T2DM
3. Adding 3rd medication to the dual oral DM agents
Reassessment of A1C
if A1C less than 7% continue the combined treatment
If A1C more than 7%:
1. add the other drug eg in Heart failure or CKD; SGLT-2
inhibitor plus GLP-1 agonist
2. Or add basal insulin
3. The basal insulin dose is 0.1-0.2u/kg/day
4. Increase the basal insulin dose according to morning
fasting glucose level as shown before
5. We can add bolus insulin dose to one or more meals if post
prandial glucose is of concern
 General roles for Management of T2DM
4-Changing from oral medication to insulin
Recommended because of adverse effect of
combined oral medication, lack of efficacy (A1C is
2% greater than the goal)
Before switching to insulin only treatment patient
must use GLP-1 agonist if failed start insulin only
therapy
We can use NPH/regular insulin or basal/bolus
approach after failure of GLP-1 agonist
TDI requirement in T2DM is much higher than TDI in
T1DM due to insulin resistance
 General roles for Management of T2DM
► Guideline for management of T2DM when A1C is
10% or more
► Start directly with basal/bolus insulin regimen or
basal insulin/GLP-1 agonist regimen
► GLP-1 agonist taken once or twice daily or once
weekly
► Adjust the dose according to insulin titration
algorithm
► Note that the same process of basal-bolus insulin
► therapy can apply to a patient with T2D who is
receiving intensive insulin therapy with or
► without oral DM medications.
 Hypoglycemia- BG < 70mg/dL
► Feeling shaky ► Blurred/impaired vision
► Being nervous or anxious ► Feeling sleepy
► Sweating, chills, clamminess ► Headaches
► Mood swings, irritability, ► Anger, sadness,
impatience stubbornness
► Confusion ► Coordination problems,
clumsiness
► Fast heartbeat
► Nightmares or crying out in
► Feeling light-headed or dizzy
sleep
► Hunger, nausea
► Bizarre behavior
► Color draining from skin (pallor)
► Seizures
► Tingling or numbness in lips,
► Being unconscious
tongue, cheeks
► Feeling weak, having no energy
Hypoglycemia- Rule of 15
► BG < 70mg/dL
Check BG

Treat with 15g glucose

Wait 15 min
Check BG again

Hypoglycemi BG normal
c 15g consume
glucose meal/snack

Wait 15 min
Check BG

BG normal,
consume
meal/snack
Hypoglycemia Treatments

► Sources of 15 grams of
carbohydrate:
► 4 glucose tablets
► 6 pieces of hard candy
(chewable)
► 4 ounces (1/2 cup) fruit juice or
regular soda
► 1 tube of glucose gel
 Hypoglycemia- Glucagon

Image from:
:Complications

► Microvascular complications are closely related to

glycemic control, and efforts to improve glycemia
significantly reduce the risk of developing these
complications and slow their progression.
►Microvascular complications take many forms but
most commonly manifest as damage to the kidneys,
eyes, and peripheral nerves.
 Nephropathy
►The kidneys contain millions of tiny blood vessel clusters (glomeruli) that
filter waste from your blood.
►Diabetes can damage this delicate filtering system.
►Severe damage can lead to kidney failure
or irreversible end-stage kidney
disease, which may require dialysis or
a kidney transplant.

Routine screening tests

► Urinary albumin test.
► Albumin/creatinine ratio.
► Glomerular filtration rate (GFR).
:Management
► 1st line therapy:
► Control multifactorial risk factor:
1. blood pressure control (tight control is advised)
2. Glycemic control
3. Lipid control (statin is recommended)
4. Lifestyle modification (diet, exercises, weight loss & smoking cessation)

► Does the patient have persisting kidney disease (confirmed by repeat

measuring every 3 month for one of the following): Urinary albumin test,
Albumin/creatinine ratio & Glomerular filtration rate

► ACEIs or ARDs delay the onset and slow the progression of DN in

people with diabetes independent of BP effects. They also slow the
progression of DN in people with diabetes who have poorly controlled
hyperglycemia. Use ACEIs & ARBs till max tolerated dose if needed
:Management
► If estimated GFR is more than 20 ml/min/1.73m2; SGLT-2 inhibitors with a
proven benefit of reducing CKD progression (empagliflozin, canagliflozin,
dapagliflozin) are recommended.
► Here SGLT-2 inhibitor have additional effects on the kidney, and, given their
weak glucose-lowering effect, these effects are likely independent of
glycemic control. By blocking the cotransporter, they reduce sodium
reabsorption, which is usually increased in patients with diabetes due to the
excess tubular glucose load.
► At this level GLP-1 is recommended to be added to achieve glycemic control
with metformin & SGLT-2
► However, unlike GLP-1 receptor agonists, DPP-4 inhibitors have not prevented
the development or progression of kidney disease in patients with diabetes,
nor do they have any cardiovascular benefits
:Management
► Finerenone, sold under the brand name Kerendia, is
a medication used to reduce the risk of kidney function
decline, kidney failure, cardiovascular death,
non-fatal heart attacks, and hospitalization for heart
failure in adults with chronic kidney disease associated
with type 2 diabetes. Finerenone is
a non-steroidal mineralocorticoid receptor
antagonist (MRA). It is taken orally.
► Finerenone was approved for medical use in the United States in July
2021, and in the European Union in February 2022.
► Among patients with type 2 diabetes who have measured or estimated
albuminuria ≥30 mg/day despite an ACE inhibitor (or ARB) and an SGLT2
inhibitor (or if an SGLT2 inhibitor is not tolerated), we suggest treatment with
a nonsteroidal selective MRA, specifically finerenone, where available,
provided the patient has a serum potassium ≤5 mEq/L and eGFR ≥25
mL/min/1.73 m2
 Retinopathy

►Diabetic retinopathy is caused by ischemia in the microcirculation in the eye coupled with
the inappropriate release of vascular growth factors.
► Patients with diabetes should have routine dilated eye examinations to fully evaluate the
retina.
►People with diabetes also have a higher rate of cataracts and open-angle glaucoma.
Prevention:
►Good glycemic control
►Good blood pressure control
►Good lipid profile control
Treatment
► Laser photocoagulation has markedly improved sight preservation
► Both bevacizumab and ranibizumab are anti-VEGF monoclonal antibodies.
 Neuropathy
►Excess sugar can injure the walls of the tiny blood vessels (capillaries) that
nourish your nerves, especially in your legs.
►This can cause tingling, numbness, burning or pain that usually begins at
the tips of the toes or fingers and gradually spreads upward.
►Left untreated, you could lose all sense of feeling in the affected limbs.
►For men, it may lead to erectile dysfunction.
►Prevention of complications by glycemic control, Foot care & avoid vitamin
b12 deficiency
 Neuropathy
Management:
pharmacotherapy options for painful diabetic neuropathy include several
antidepressants (eg, duloxetine, venlafaxine, amitriptyline and other tricyclic
drugs) and the gabapentinoid antiseizure medications
(pregabalin, gabapentin). Capsaicin can also be used but is generally poorly
tolerated.
Duloxetine, an SNRI, is a first-line treatment option for neuropathic pain in
patients with diabetic neuropathy
The recommended starting dose of duloxetine in patients with diabetic
neuropathy is 20 to 30 mg daily. The dose can be gradually titrated upwards
based on response and tolerability to a maximum of 60 to 120 mg daily. Pain
improvement may be seen as early as the first week of treatment
Alpha-lipoic acid (ALA) – For patients who are refractory to or intolerant of
first-line pharmacotherapies and interested in a nutritional supplement
approach, we suggest a trial of oral ALA (600 mg daily). ALA is an antioxidant
with the potential to diminish oxidative stress, improve the underlying
pathophysiology of neuropathy, and reduce pain.
Treatment algorithm for painful diabetic neuropathy. *FDA-approved treatment.
TENS transcutaneous electrical nerve stimulation, SNRI serotonin-norepinephrine
reuptake inhibitors, TCA tricyclic antidepressants, IV intravenous, SCS spinal cord
stimulation, DRG-SCS dorsal root ganglion spinal cord stimulation, PNS peripheral
nerve stimulation, IDDS intrathecal drug delivery system, IT intrathecal
:Macrovascular Complications
Cardiovascular disease (CVD)
►The risk for coronary heart disease (CHD) and ischemic stroke is
two to four times greater in patients with diabetes when
compared to individuals without diabetes.
► CV disease is the leading cause of mortality in patients with DM.
►The ADA recommends low-dose aspirin therapy (75–162 mg
daily) in all patients.
► If the patient is allergic to aspirin, clopidogrel may be used.
:Management

► liraglutide (GLP-1 RA) and empagliflozin (SGLT-2 inhibitor) demonstrated a reduction in

major adverse CV events and CV mortality and both have a label indication of
reducing CV events.
► if HF coexists, SGLT-2 inhibitors with a proven benefit of reducing HF progression
(empagliflozin, canagliflozin, dapagliflozin) are recommended.
► myocardial infarction, β-blocker therapy protects patients with diabetes from
recurrent CHD events, and the magnitude of benefit is greater than that seen in
patients without diabetes.
► While the adrenergic symptoms produced by hypoglycemia (eg, tachycardia, tremor)
can be masked by β blockers, sweating and neuroglycopenic symptoms are not.
► Therefore, βblockers should not be avoided in patients with diabetes if there is a
compelling indication to use them.
 Cerebrovascular Disease
►Diabetic cerebrovascular diseases are defined as cerebral vascular
diseases induced by diabetes with sugar, fat and a series of nutrient
substance metabolic disorders, resulting in intracranial large and small
vessel diseases.
► About 20%-40% patients with type 2 diabetes suffer from cerebral
blood vessel diseases.
►Diabetic cerebrovascular diseases are the main causes of death in
patients with diabetes mellitus.
►The major clinical manifestations are asymptomatic cerebral
atherosclerosis, stroke, cerebral small vessel disease and acute
cerebral vascular disease.
 Peripheral Artery Disease
►By definition, PVD is a circulatory condition associated with narrowed blood
vessels that reduce blood flow to limbs. Symptoms of PVD include leg pain or
numbness.

►Peripheral artery disease is characterized by occlusion of the lower-extremity

arteries, which can cause intermittent claudication and pain, especially upon
exercise and activity, and which can result in functional impairments and
disability.

►Severe PAD: foot ulceration and lower-extremity amputation.

 :Management
► Cilostazol (improves the flow of blood through the
blood vessels) may be useful in select patients to
reduce symptoms.
► Revascularization surgery can be considered;
however, small vessel disease that cannot be bypassed
is common in diabetes.
 Diabetic Ketoacidosis
► More common in T1D but can occur in T2D

► Usually occurs because of a precipitating factor that stresses the

body, resulting in increased counterregulatory hormones

► Inappropriate (including nonadherence) or inadequate insulin therapy

and infection are the two most common causes.

► Other causes: Myocardial infarction, pancreatitis, stroke, drugs (e.g.,

corticosteroids)

► Results in significant hyperglycemia, dehydration, and ketoacidosis

► Common signs and symptoms: Polyuria, polydipsia, vomiting,

dehydration, weakness, altered mental status, coma, abdominal pain,
Kussmaul respirations, tachycardia, hyponatremia, hyperkalemia
 Diabetic Ketoacidosis
Treatment
► Treat underlying cause, if known.
► Fluid replacement
► 0.45%–0.9% sodium chloride, depending on baseline serum sodium
concentrations
► Change to 5% dextrose with 0.45% sodium chloride when serum
glucose is less than 200 mg/dL.
 Diabetic Ketoacidosis
Treatment
► Insulin
i. Goal is to stop ketosis, not to normalize glucose concentrations.
ii. Intravenous bolus regular insulin: 0.1 unit/kg
iii. Intravenous infusion
(a) 0.1 unit/kg/hour regular insulin (increase if not a 50- to 75-mg/dL
decrease in serum glucose in the first hour)
(b) Alternatively, 0.14 unit/kg/hour if no insulin bolus is given
(c) If not at least a 10% decrease in serum glucose attained in first hour,
give 0.14-unit/kg intravenous bolus
(d) Reduce infusion rate to 0.02–0.05 unit/kg/hour when serum glucose
reaches 200 mg/dL, and keep glucose of 150–200 mg/dL until DKA
resolves.
iv. Interrupt insulin treatment if baseline serum potassium is less than 3.3
mEq/L and until corrected.
 Diabetic Ketoacidosis
Treatment
► Potassium
i. Potassium 20–30 mEq/L of intravenous fluid if baseline serum potassium
greater than 3.3 but less than 5.3 mEq/L
ii. Hold if 5.3 mEq/L or greater initially. Monitor and replace as needed.
iii. Potassium 20–30 mEq/hour if baseline less than 3.3 mEq/L
► e. Intravenous bicarbonate if serum pH less than 6.9
► f. DKA considered resolved and can be converted to subcutaneous
insulin when serum glucose is less than 200 mg/dL and at least two of
the following:
► i. Venous pH greater than 7.3
► ii. Serum bicarbonate of 15 mEq/L or greater
► iii. Calculated anion gap of 12 mEq/L or less
Gastroparesis therapy
► Autonomic neuropathy causes nausea and vomiting after meals
because of delayed gastric emptying.
► Nonpharmacologic strategies
i. More frequent but smaller meals
ii. Homogenize food
iii. Decrease fat and fiber in diet
iv. Gastric pacemaker
► Pharmacologic treatment
► Metoclopramide: 10 mg orally or 15 mg intranasally before meals;
risk of tardive dyskinesia or extrapyramidal reactions, chronic use
should assess the benefit-risk of continued therapy
► Erythromycin: 40–250 mg before meals for up to 1 month
► Itopride & mosapride