PHAM 422 (Pharmacotherapy III)

Diabetes Mellitus

Dr. S. Mahmood Alqallaf

 Objectives
By the end of this session you should be able to:
• Discuss the incidence and economic impact of diabetes.
• Describe the clinical features of type 1, type 2, and gestational
diabetes.
• Mention diagnostic and monitoring criteria for diabetes.
• Discuss therapeutic goals of management of diabetic patients.
• Recommend non-drug treatment of diabetes mellitus.
• Discuss pharmacotherapy of T1DM, T2DM and GDM.
• Select suitable insulin treatment based on onset, peak, and duration
of action.
• Discuss the clinical manifestations and management of
hypoglycemia.
• Define diabetic ketoacidosis and discuss its management.
• Develop an educational and a comprehensive therapeutic
monitoring plan for a patient with diabetes based on patient specific
Treatment of T1DM
 Treatment of T1DM
• Treatment of T1DM requires EXOGENOUS INSULIN to
compensate for the deficient endogenous insulin from
the non-functional pancreas.

• Ideally, insulin therapy mimics normal insulin

physiology:

– Reproduce basal insulin response using intermediate-

or long-acting insulin
– Short- or rapid-acting insulin replicates bolus release
of insulin physiologically seen around a meal in non-
diabetics

• A number of different regimens have been used to more

closely follow natural insulin patterns.
 Treatment of T1DM
• As a rule, the total daily dose (TDD) should be
provided by:
– Basal insulin (intermediate- or long-acting) makes
up approximately 50%.
– The remaining half is provided with bolus (Short-
or rapid-acting insulin) doses around three daily
meals.

• Exact doses are individualized to the patient and the

amount of food consumed.
 Treatment of T1DM
• Usual starting dose of insulin is about 0.3-0.6
unit/kg/day, and then doses are titrated until
glycemic goals are reached.

• Most people with T1DM need 0.6 - 1 unit/kg/day.

Action Profiles of Injectable Insulins
Action Profiles of Injectable Insulins

30% Insulin Aspart and 70%

protamine co-crystallised Insulin
Aspart
25% Insulin Lispro and 75% Insulin Lispro
Protamine Suspension
30% soluble insulin and 70% isophane
insulin
 Examples of Regimens
• Example of a regimen of 2 daily injections that
may approximate physiologic insulin secretion is:
 Mixed injections of intermediate-duration insulin (e.g.
NPH) + regular insulin before breakfast & before the
evening meal
 This assumes that the morning intermediate-acting insulin
provides basal insulin for the day and covers the midday
meal, the morning regular insulin covers breakfast
 The evening intermediate-acting insulin gives basal
insulin for the rest of the day & evening regular insulin
covers the evening meal.
NB: 70/30 mix: 70% NPH + 30% Regular insulin
75/25 mix: 75% Insulin Lispro protamine suspension + 30% Insulin lispro
Guide to adjusting insulin dosage
according to blood glucose test
results:
 Insulin Pump
• Also called “continuous subcutaneous insulin
infusion”
• Currently, this is the most advanced form of insulin
delivery
• Using rapid-acting insulin only, these pumps are
programmed to provide a slow release of small amounts
of insulin as the basal portion of therapy
• Larger boluses of insulin are injected by the patient to
account for the consumption of food.
 Pramlintide
• A synthetic analog of the naturally occurring
hormone amylin

• This is another injectable blood glucose–lowering

medication that can be used in T1DM patients

• Also can be used for T2DM patients using insulin.

• It is not widely used because of required multiple

injections and limited efficacy in lowering HbA1c.
Treatment of T2DM
 Treatment of T2DM
• In T2DM begin with lifestyle changes: healthy
eating, weight control, increased physical
activity

• Add METFORMIN monotherapy at, or soon

after diagnosis based on the HbA1C. Other
drugs might be considered depending on the
patient's condition.

• If HbA1c target is not achieved after 3

months (of starting metformin), consider
other treatment options in addition to
 Treatment of T2DM
• Because T2DM generally tends to be a progressive
disease, blood glucose levels will eventually
increase, making insulin therapy the eventual
required therapy in many patients.

• Starting insulin is done when several oral agents

have been used with inadequate glucose-lowering
results.

• Symptomatic patients may initially require insulin or

combination oral therapy to reduce glucose toxicity
(extremely high glucose levels which may reduce β-
cell insulin secretion and worsen insulin resistance).
 Sulfonylureas
E.g. Gliclazide, Glibenclamide

• One limitation of sulfonylureas is their inability to

stimulate insulin release from β cells during glucose
toxicity (a phenomenon characterized by extremely
high glucose levels)

• All sulfonylureas (except tolbutamide) require dose

adjustment or not recommended in renal
impairment.

• In elderly patients or those with compromised renal

or hepatic function, lower starting dosage is
necessary.

• Sulfonylureas monotherapy generally produces a

 Biguanides
• The only agent available is metformin.

• Has been shown to reduce HbA1c levels by 1.5% - 2% &

FPG levels by 60 - 80 mg/dL (3.3–4.4 mmol/L) when
used as monotherapy.
• Unlike sulfonylureas, metformin retains the ability to
reduce fasting glucose levels when they are over 300
mg/dL (16.7mmol/L).
• Metformin has synergistic effect when used in
combination with other antidiabetics
• Metformin does not affect insulin release from β cells of
the pancreas, so HYPOGLYCEMIA IS NOT COMMON.
• Studies have shown that metformin significantly
reduces all-cause mortality and the risk of stroke in
 Biguanides
• In addition to lifestyle modification, metformin is
considered foundational therapy for T2DM because it
is the only oral antidiabetic medication proven
to reduce mortality and is available generically

• Metformin is contraindicated in patients with

abnormal creatinine clearance.

• Metformin should be withheld in patients undergoing

surgery or radiographic procedures in which a
nephrotoxic contrast media is used.

• Therapy should be withheld on the day of the

radiographic procedure, and renal function should be
assessed 48 hours after the procedure and if renal
function is normal, therapy may be resumed.
 Biguanides
• Primary SEs of metformin are GI in nature: decreased
appetite, nausea, and diarrhea, but can be minimized
by slow titration of the dose and often subside within 2
wks.

• Interference with vitamin B12 absorption has also been

reported.

• Metformin is thought to inhibit mitochondrial oxidation

of lactic acid, thereby increasing the risk of lactic
acidosis.
• Although lactic acidosis is rare, but risk increases with
renal impairment & in patients of advanced age.
• Metformin should be withheld promptly in cases of
hypoxemia, sepsis, or dehydration.
 Insulin
• Insulin is the only antidiabetic that can be used
in all types of DM and has no specific
maximum dose (i.e. can be titrated to suit each
individual patient’s needs)

• Insulin can be divided into two main classes:

basal and bolus, based on their length of action
to mimic endogenous insulin physiology.

• Most insulin formulations are available as U-

100, indicating a concentration of 100 unit/mL.

• Insulin is typically refrigerated, though most

vials are good for 28 days at RT after 1st open.
 Insulin
• Most common route of
administration for insulin
is SC.

• Additionally, patients
should understand that
the absorption rate may
vary among injection
sites (abdomen, thigh,
arm, and buttocks)
because of differences in
blood flow, with
absorption occurring
fastest in the abdomen
and slowest in the
buttocks.
 Insulin
• Patients should be educated to rotate
injection site to minimize local reactions e.g.
lipohypertrophy, which can decrease or
prevent proper insulin absorption
 Insulin
• Insulin is administered by
syringes and pens and both
are now available with
shorter needles which do not
require the patient to pinch
up their skin before injecting.

• With the no pinch technique,

the needle is injected
straight in at a 90-degree
angle until flush with the
skin.

• These products require a 10

second count to allow
enough time for the insulin
to be injected.
 Sodium glucose co-transporter 2 (SGLT2)
inhibitor (gliflozins)
E.g. Dapagliflozin, Canagliflozin, Empagliflozin
• Novel class that offer a unique treatment option for
T2DM that is independent of the secretion or action
of insulin
• Can work even in states of pancreatic beta-cell
failure or insulin resistance.
• There is great potential for its use in T1DM, and
several clinical trials are being conducted to
examine this.
• Promotes negative energetic balance and weight
loss
• AACE (American association of Clinical
Endocrinologists) recommends SGLT2 inhibitors as a
 Parameter Response
Summary of effects
HbA1c
of SGLT2 inhibitors
FPG
PPG
 Reduction in BP is
Body weight
believed to be due to Blood pressure
the diuretic and Lipids
volume depletion HDL-C
effects LDL-C
Triglycerides
 Infections were Infections
primarily fungal & Genital
more in females Urinary tract or
 GLP-1 Receptor Agonists
E.g. Exenatide, Liraglutide, Albiglutide

• Among the most potent drugs for the treatment of

T2DM
• Licensed in some countries for weight
management.

• They are protected against DPP4 degradation

• Some agents from this class are available for oral
administration.
• Inhalational GLP-1 agonists are in development

• Another innovative approach is continuous

application by using a subcutaneous device (will
 DPP-4 Inhibitors (Gliptins)
E.g. Sitagliptin, Vildagliptin, Saxagliptin

• Can inhibit > 80% of DPP4 activity

• Increasing levels of active GLP-1 and GIP by 2-3 x

• Thereby increase insulin secretion, reduce glucagon

secretion and improve glycaemic control

• Available in oral dosage form

• Once weekly agents are under clinical trials

 Both GLP-1 agonists & DPP-4 inhibitors carry similar
risk of hypoglycaemia to placebo or slightly higher
(GLP-1 agonists)

 Concerns were raised about risk for medullary thyroid

cancer, pancreatitis or pancreatic cancer – not
confirmed in clinical trials and by FDA and EMA.
Combination Therapy (Average HbA1c
Reductions(
Drug Combination Change in
HbA1c (%)
Sulfonylurea + metformin –2.2

Sulfonylurea + insulin –1.9

Meglitinide + thiazolidinedione –1.7

Metformin + insulin (1st combination –1.7

used)
Sulfonylurea + α-glucosidase inhibitor –1.6

Metformin + meglitinide –1.4

Insulin + α-glucosidase inhibitor –1.2

 Activity
• Explore the given publication:
“CONSENSUS STATEMENT BY THE AMERICAN ASSOCIATION
OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE
OF ENDOCRINOLOGY ON THE COMPREHENSIVE TYPE 2
DIABETES MANAGEMENT ALGORITHM – 2020 EXECUTIVE
SUMMARY”

• Read pgs 116 – 119 T2D Pharmacotherapy – highlight the

essential elements of the algorithm for management of
T2D and relate them to the algorithm in the next slide
Gestational DM
 Gestational Diabetes
• Glucose intolerance may develop during pregnancy
due, in part, to increases in maternal insulin
resistance resulting from circulating placental
hormones.
• GDM is a predictor of diabetes in later life and
regular follow-up is required.
• Individualized meal plan consisting of 3 meals & 3
snacks / day is commonly recommended in GDM.
• An abundance of glucose causes excessive insulin
production by the fetus, which if left uncontrolled,
can lead to the development of complications e.g.
preterm birth, neonatal respiratory distress &
hypoglycemia.
• Diagnosis of GDM:
– Same as DM
 Gestational Diabetes
• Complications of GDM:
– Development of abnormally large fetus &
complications associated with this.
– Infant hypoglycemia at delivery
– Hyperbilirubinemia

• Therapeutic goals of GDM:

– Preventing ketosis
– Promoting adequate growth of the fetus
– Maintaining satisfactory blood glucose
levels
– Preventing nausea and other undesired GI
 Gestational Diabetes
Treatment of GDM:
• Insulin should be used when blood glucose levels are
not maintained adequately by diet and physical
activity.
• Insulin analogs (e.g. detemir, aspart, lispro), and
regular insulin carry Category B safety ratings.
•Studies were done on Glibenclamide in GDM & found:
 Adequate control of blood glucose compared to
insulin in majority of patients
 Birth weight and incidence of hypoglycemia were
higher with glibenclamide
 No conclusion regarding teratogenicity could be
made
 Conclusion: further studies are needed to
establish its safety
Oct 3, 2023 41
Diabetes Care in the Hospital
 Diabetes Care in the Hospital
• In most instances in the hospital setting, insulin is the
preferred treatment for glycemic control.
• Initiate insulin therapy is indicated for hyperglycemia
greater than 180 mg/dL (10.0 mmol/L).
• Once insulin therapy is initiated, a glucose target of
140–180mg/dL (7.8–10.0 mmol/L) is recommended for
most patients
• In certain circumstances, it may be appropriate to
continue previous regimens including oral antidiabetic
drugs
• In ICU, IV insulin infusion has been shown to be the
best method for achieving glycemic targets.
• Outside ICU, regular SC insulin injections should align
with meals and bedtime or every 4–6 h if no meals or
if continuous enteral / parenteral therapy is used
Diabetic Ketoacidosis
 Diabetic Ketoacidosis (DKA)
• DKA is a potentially life-threatening, complex
metabolic disorder characterized by ketonaemia,
hyperglycemia and acidemia.
• It usually occurs in patients with T1DM
• T2DM patients can also develop DKA if sufficiently
stressed (e.g. by surgery, severe infection or MI)
• Mortality in case of DKA remains high among non-
hospitalized patients.
• Most common cause of death in children and
adolescents is cerebral oedema
• Main causes of mortality in adults: severe
hypokalemia, adult respiratory distress syndrome
and comorbid states, e.g. Pneumonia, MI and sepsis
Diagnosis of DKA:
– Blood ketones ≥3mmol/L or significant ketonuria
– Blood glucose ˃11mmol/L or known DM
– Serum venous bicarbonate < 15mmol/L and/or
venous pH <7.3.
Questions to Ask patient regarding DKA
1. Has insulin use been discontinued or a dose
skipped for any reason?
2. If an insulin pump is being used, is the tubing
blocked or twisted? Has the catheter become
dislocated?
3. Has the insulin being used lost its normal
activity? Is the bottle of rapid-acting / regular
or basal insulin cloudy? Does the bottle of
NPH look frosty?
4. Have insulin requirements increased due to
illness or other forms of stress (infection,
What to Look For in case of DKA
1. S & S of hyperglycemia: thirst, excessive urination,
fatigue, blurred vision, consistently elevated BG (>300
mg/dL)
2. Signs of acidosis: fruity breath odor, deep and difficult
breathing
3. Signs of dehydration: dry mouth; warm, dry skin; fatigue
4. Others: stomach pain, nausea, vomiting, loss of appetite

What the patient shall do if DKA occurred:

5. Review “sick day management”
6. Test blood glucose at least 4 times daily
7. Test urine for ketones when BG is >300 mg/dL
8. Drink plenty of fluids (water, clear soups)
9. Continue taking insulin dose
10.Contact physician or other healthcare provider
immediately
Management of DKA

1.Fluids
– Fluid and electrolyte deficits may be significant
because of osmotic diuresis and vomiting,
therefore fluid replacement must be initiated
promptly.
– NaCl 0.9% (NS) is the fluid of choice
– Later, if sodium is normal or elevated, use ½ NS
(0.45% NaCl)

2. Insulin
• Continuous IV infusion of regular insulin is preferred.
• IM route can be used only if infusion is not available.
• SC insulin should be introduced or restarted as soon
as the patient is biochemically stable and feels able
3. Potassium (K+)
DKA is usually associated with hyperkalaemia because of
insulin deficiency. This represents a shift of K + from the
intracellular to the extracellular fluid, although a total
body potassium
 Hyperkalemia deficiency
should promptexist.
cardiac monitoring until levels
return back to normal.
 Once insulin is given,
potassium levels can change
rapidly (as it transfer K+
intracellularly)

 Patients require serum K+ measurement on admission

and at least every 2 hours throughout treatment to
assess requirements.
 K+ is not usually added to the first litre of NS, but if
needed should be provided in subsequent bags to
maintain normal serum potassium levels
Hypoglycemia
•
Hypoglycemia
Hypoglycemia can be defined clinically as a blood
glucose level of less than or equal to 70 mg/dL (3.9
mmol/L).
• It’s the most serious S.E. of insulin & sulfonylureas.
S & S:
1. Sweating
2. Tremors
3. Palpitation
4. Fatigue Common causes of hypoglycemia:
5. Confusion • Delayed or inadequate amounts of
food intake, esp. carbohydrates
6. Headache
• High doses of medications (e.g.
7. Dizziness sulfonylureas and insulin)
8. Flushing • Exercising when insulin doses are
9. Coma reaching peak effect
10. loss of • Inadequately adjusted drug therapy in
patients with impaired renal or hepatic
consciousness
function.
Oct 3, 2023 51
Management of Hypoglycemia:
• Patients experiencing symptoms of hypoglycemia
should check their BG level, take 15 g of CHO, wait 15
minutes for symptom resolution, and retest.
• Examples of acceptable treatments (15 g CHO) include:
• Orange, grapefruit, or apple juice; regular, non-diet
soda: 1/2 cup
• Fat-free milk: 1 cup
• Grape juice, cranberry juice cocktail: 1/3 cup
• Sugar: 1 tbsp or 3 cubes
• For patients with hypoglycemia experiencing a loss of
consciousness: a glucagon emergency kit should be
administered by IM or SC route.
• The patient should be rolled onto his or her side to
prevent aspiration because many patients receiving the
glucagon injection vomit.
• Glucose IV can be given as alternative to glucagon
Patient Education
1. Diabetes: Pathogenesis and the
complications

2. Hyperglycemia: S & S and what to do

3. Ketoacidosis: S & S and what to do

4. Hypoglycemia: S & S and appropriate

treatment

5. Exercise: Effect on BG level and insulin

dose

6. Diet: Emphasis placed on carbohydrate

counting because the carbohydrate is
7. Insulins:
• Injection technique
• Types of insulin
• Time action profiles (onset, peak, and
duration)
• Storage and expiration once in use
• Stability (look for crystallization and
precipitation with NPH insulin)

8. Therapeutic goals:
• HbA1C
• Fasting, preprandial and postprandial BG
levels
• Cholesterol
• Triglyceride
9. Self Monitoring BG & Interpretation of
results

10. Foot care:

• Inspect feet daily
• Wear well-fitted shoes
• Avoid self-care of ingrown toenails, corns, or
athlete’s foot; see a podiatrist

11. Sick day management

12. Cardiovascular risk factors:
• Tobacco use
• High BP
• Obesity
• Elevated cholesterol

13. Importance of annual ophthalmologic

examinations

14. Tests for microalbuminuria

15. Immunization
 Factors that can alter BG Control

• Diet
– Insufficient calories (e.g. alcoholism, eating
disorders, anorexia, nausea, and vomiting)
– Over-eating (e.g. during the holidays)
– Irregularly spaced, skipped, or delayed meals
– Dietary content (e.g. fiber, carbohydrate content)

• Physical Activity
• Stress
– Infection
– Surgery/trauma
– Psychological
• Drugs: Certain medications can increase or decrease blood
glucose levels. It is important to assess for potential effects
on the blood glucose when starting new medications.

• Hormonal Changes
– Menstruation: Glucose concentrations may increase pre-
menstrually and return to normal after menses.
– Pregnancy
– Puberty: hyperglycemia probably related to high growth hormone
levels
• Altered Insulin Pharmacokinetics
• Insulin Injection Technique
– Measuring
– Timing
– Technique
• Inactive Insulin
– Outdated insulin
– Improperly stored insulin (heat or cold)
– Crystallized insulin
 Sick Day Management

1. Continue taking your insulin even if you are

not eating well or have nausea or vomiting.
2. Test your BG more frequently: every 3–4
hours.
3. Apply self-management protocol if indicated
4. Begin testing your ketones (urine or blood)
if you have T1DM. If you have T2DM, begin
testing especially when glucose readings
exceed 300 mg/dL.
5. Try to drink plenty of fluids (1/2 cup/hour for
adults)
6. Call a physician if your BG level remains
>300 mg/dL, or your urine ketones remain
Thank You