PHAM 422 (Pharmacotherapy III)

Diabetes Mellitus

Dr. S. Mahmood Alqallaf

email: smalqallaf@uob.edu.bh
 Objectives
• 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 diabetec 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 plans for a patient with diabetes based on patient
specific factors.
Introduction
• “Diabetes mellitus describes a group of chronic
metabolic disorders characterized by hyperglycemia
that may result in long-term microvascular and
neuropathic complications”.

• 2 types of Chronic DM exist:

– Type 1 DM (IDDM)
– Type 2 DM (NIDDM)

• Type 1 DM is usually diagnosed before age 30 years

but can develop at any age.
• Type 2 DM is usually diagnosed after age 30 &
accounts for approximately 90% - 95% of all
diagnosed cases of DM
 Statistics
According to International Diabetes Federation:

• ˃ 425 million people have diabetes in the world

• ˃ 39 million people in the MENA (Middle East & North

Africa) Region have DM. By 2045 this is expected to
rise to 67 million.

• In Bahrain: there were 165,300 cases of diabetes in

2017. Total adult population: 1,022,000

• Prevalence of diabetes in adults :16.2%

Prevalence of DM in Bahrain
 Proportional mortality
(% of total deaths, all ages) in Bahrain
 Risk Factors
1. Lifestyle
– A sedentary lifestyle
– greater consumption of high-fat, high carbohydrate
foods
– larger portion sizes
– Obesity (might be attributed to the above changes)

2. Ethnicity: Certain ethnic groups are at a higher risk of

DM e.g. the risk of DM is 18% higher among Asian
Americans

3. Age: As the population ages, the incidence of T2DM

is expected to increase.
4. First-degree family history of DM

5. Hypertension & other cardiovascular disease

6. Low HDL cholesterol

7. History of gestational diabetes or delivery of a baby

weighing greater than 4 kg

9. History of polycystic ovarian syndrome

10. Other conditions associated with insulin resistance

Pathophysiology
Normal Carbohydrate Metabolism
• The main control of glucose in the body is via hormones
produced in the pancreas by cells in the islets of
Langerhans.
 • Produced by the β-cells (represent about 70% -
90% of the islets of Langerhans)
Insulin • Amylin is also produced by the same cells
• The main function of insulin is to decrease
blood glucose levels.

• Produced by the α-cells

Glucago • Glucagon & other counter-regulatory hormones
n (e.g. growth hormone, cortisol, and
epinephrine) increase blood glucose levels.

• Blood glucose levels may vary due to many factors, but

the opposing actions of insulin and glucagon (& the
counter-regulatory hormones) normally maintain fasting
BG between 79 - 99 mg/dL (4.4 – 5.5 mmol/L).
Normal Insulin Action
• After food is consumed, blood glucose levels rise, and
the insulin-secretion response occurs in two phases.
1st phase insulin 2nd phase of insulin
response: response:
• lasts approximately 5 • Characterized by a gradual
- 10 minutes and increase in insulin
causes suppression secretion, which lasts 60 -
of hepatic glucose 120 minutes and
production and stimulates glucose uptake
insulin-mediated by peripheral insulin-
glucose uptake by dependent tissues, namely
adipose tissue. muscle.
• This bolus of insulin • This Slow release of
minimizes insulin allows the body to
hyperglycemia during respond to the new
meals and during the glucose entering from
postprandial period. digestion while maintaining
• Amylin is a naturally occurring hormone that is co-
secreted with insulin from β cells.

• Diabetic patients have either a relative or complete

lack of amylin.
• Amylin has three major actions:
Regulation of the rate
Suppression of post- of gastric emptying
meal glucagon from the stomach to
secretion the small intestine,
which increases satiety

Regulation of blood
glucose concentrations
in the blood.
Impaired Insulin Secretion
• A pancreas with normal β-cell function is able to adjust
insulin production to maintain normal blood glucose levels.
• In T2DM, more insulin is secreted to maintain normal
blood glucose levels until eventually the pancreas can no
longer produce sufficient insulin.
• The resulting hyperglycemia is enhanced by:
– Extremely high insulin resistance and / or
– Pancreatic burnout (β cells lose functional capacity).
• Impaired β-cell function results in a reduced ability to
produce a first-phase insulin response sufficient to signal
the liver to stop producing glucose after a meal.
• Over time, patients with T2DM experience progressive β-
cell death and many require exogenous insulin to maintain
blood glucose control.
• In T1DM autoimmune destruction of the β cells causes
insulin deficiency. The autoimmune process is
mediated by macrophages & T lymphocytes with
autoantibodies to β-cell antigens (e.g. islet cell
antibody, insulin antibodies).
• T2DM is progressive in development, and is often
preceded by an increased risk for diabetes (previously
known as prediabetes).
• A combination of insulin deficiency, insulin resistance,
and other hormonal irregularities, primarily involving
glucagon, are key problems with T2DM.
• Insulin resistance is accompanied with increased
lipolysis and free fatty acid production, increased
hepatic glucose production, and decreased skeletal
muscle uptake of glucose.
Insulin Resistance
• Insulin resistance is the primary factor that
differentiates T2DM from other forms of diabetes.
• Insulin resistance may be present for several years
before the diagnosis of DM and can continue to
progress throughout the course of the disease.
• Resistance to insulin occurs in adipose tissue, skeletal
muscle and the liver.
• Insulin resistance in the liver
carries a double threat because:
• The liver becomes non- Elevated fasting
responsive to insulin for glucose leading and post-meal
to blood glucose
uptake
• Hepatic production of glucose levels.
after a meal does not stop
Natural history of T2DM
Incretin Effect
• When food enter the GIT, incretin hormones are released,
causing stimulation of insulin secretion.
• Incretin effect is mediated by two hormones:
– GLP-1 (glucagon-like peptide-1).
– GIP (glucose-dependent insulinotropic peptide)
• GLP-1 is secreted by the L cells of the ileum and colon
primarily, and GIP is secreted by the K cells.
• GLP-1 secretion is caused by endocrine and neural
signals starting when nutrients enter the GIT.
• Within minutes of food ingestion, GLP-1 levels rise
rapidly. A glucose-dependent release of insulin
occurs.
• Other glucose-lowering effects of GLP-1 include:
– Suppression of glucagon
– Slowing gastric emptying
– Increasing satiety.
• It is believed that a threshold glucose
concentration may be required for incretin activity
• After secretion, both incretins are rapidly degraded
by the enzyme DPP4 (Dipeptidyl-peptidase 4)
• Much of the research on glucose lowering products
involves prolonging the action of GLP-1.
Characteristics T1DM T2DM
Other names Previously, IDDM; juvenile-onset DM Previously, NIDDM; adult-onset
DM
Prevalence 5%–10% of diabetic population About 90%
Age at onset Usually <30 years; peaks at 12–14 Usually >40 years, but increasing
years; rare before 6 months; some prevalence among obese children
adults develop it during the 5th decade & young adults
Pancreatic function Non-functional pancreas usually Insulin present in low, normal, or
  high amounts
Pathogenesis Associated with certain HLA (Human Defect in insulin secretion; tissue
  Leukocyte Antigen) types; presence of resistance to insulin; ↑ hepatic
islet cell Ab suggests autoimmune dis. glucose output
Family history Generally not strong Strong
Obesity Uncommon Common (60%–90%)
History of Often present Rare, except in circumstances of
ketoacidosis unusual stress (e.g. infection)
Clinical presentation Moderate to severe symptoms that Mild polyuria, fatigue; often
  generally progress relatively rapidly diagnosed on routine physical or
(days to weeks): polyuria, polydipsia, dental examination
fatigue, weight loss, ketoacidosis
Non-pharmacological Medical Nutrition Therapy Medical Nutrition Therapy
Treatment Physical activity Physical activity
Latent autoimmune diabetes in adults

• Called also slow-onset type 1, or type 1.5 DM

• Is a form of autoimmune T1DM that occurs in

individuals older than the usual age of T1DM onset.

• Patients often are mistakenly thought to have T2DM

because the person is older and may respond initially
to oral antidiabetic agents.

• These patients do not have insulin resistance, but

antibodies that destroy pancreatic β cells are present
in the blood.
Clinical Presentation &
Diagnosis
 Clinical Presentation
T1DM
• The most common symptoms are Polyuria, Polydipsia, Polyphagia,
Weight Loss, and Lethargy accompanied with hyperglycemia.
• Patients are often slim and are prone to develop diabetic ketoacidosis
if insulin is withheld or under conditions of severe stress.
• Between 20% - 40% of patients present with diabetic ketoacidosis
after several days of polyuria, polydipsia, polyphagia, and weight loss.

T2DM
• Patients are often asymptomatic and may be diagnosed secondary to
unrelated blood testing.
• Polyuria, polydipsia, Lethargy, and nocturia can be present.
• Significant weight loss is less common. More often, patients are
overweight or obese.
 Criteria for Diagnosis of Diabetes
• Symptoms of diabetes + random plasma glucose level ≥ 200
mg/dL (11.1 mmol/L).
– Random is defined as any time of day without regard to time
since the last meal.
– The classic symptoms of diabetes include polyuria, polydipsia,
and unexplained weight loss. or
• FPG ≥ 126 mg/dL (7.0 mmol/L).
– Fasting is defined as no caloric intake for at least 8 hours. or
• Two-hour post-load glucose ≥ 200 mg/dL (11.1 mmol/L) during
an OGTT.
– The test should be performed as described by the WHO using a
glucose load containing the equivalent of 75 g of anhydrous
glucose dissolved in water. or
• HbA1c ≥ 6.5% (0.065; 48 mmol/mol Hgb).
• Normal FPG: ˂ 100 mg/dL (5.6 mmol/L).
• Impaired fasting glucose (IFG): FPG 100 - 125 mg/dL
(5.6–6.9 mmol/L).
• Impaired glucose tolerance (IGT): when the 2-hour post-
load sample of OGTT is 140 - 199 mg / dL (7.8–11.0
mmol/L).
• Pregnant women should undergo risk assessment for GDM
at first prenatal visit and have glucose testing if at high risk
(e.g. positive family history, personal history of GDM,
marked obesity, or member of a high-risk ethnic group).
• BP & other investigations (e.g. lipids) need to be done to
determine the health status of the patient and presence of
“Metabolic Syndrome”
• Metabolic Syndrome: combination of diabetes,
hypertension and obesity.
 DM complications
• over the years, DM carries risks of microvascular and macrovascular complications.
• Microvascular complications include retinopathy, neuropathy, and nephropathy.
• Macrovascular complications include CAD, stroke, & peripheral vascular disease.
• These complications make DM the leading cause of:
– New cases of blindness among adults
– End-stage renal disease
– Non-traumatic lower limb amputations
– Macrovascular complications (CAD, stroke, and peripheral vascular disease)
Non-pharmacological
treatment of DM
Medical nutrition therapy

• Recommended for all patients & preferably followed

by a dietitian.
• For T1DM, the focus is on physiologically regulating
insulin administration with a balanced diet to achieve
and maintain healthy body weight.
• The meal plan should be moderate in carbohydrates
and low in saturated fat, with a focus on balanced
meals.
• Since T2DM patients are often obese, they require
caloric restriction to promote weight loss.
Weight Management

• Moderate weight loss in patients with T2DM has been shown to reduce
CV risk, and delay or prevent the onset of DM in those with
prediabetes.
• The recommended primary approach to weight loss is therapeutic
lifestyle change, with the aim of 7% reduction in body weight and an
increase in physical activity.
• A slow but progressive weight loss of 0.45 - 0.91 kg per week is
preferred.
• A general rule for weight loss diets is that they should supply about
1000 - 1200 kcal/day for women and 1200 - 1600 kcal/day for men.
• Gastric reduction surgeries (gastric banding or procedures that bypass,
transpose, or resect portions of the small intestine), when used as a
part of a comprehensive approach to weight loss, are recommended
for consideration in patients with T2DM and a BMI that exceeds 35
kg/m2.
• Drug therapy options might be considered to aid weight loss in obese
patients
Physical Activity
• This has been shown to improve glucose control and reduce
CV risk factors such as hypertension & elevated serum lipids.
• Physical activity is also a primary factor associated with long-
term maintenance of weight loss and overall weight control. It
may prevent also the onset of T2DM in high-risk persons.
• Before initiating a physical activity program, patients should
undergo a detailed physical examination to assess health
status that may be worsened by a particular activity.
• Initiation of physical activities in individuals with history of a
sedentary lifestyle should begin with a modest increase in
activity e.g. walking, swimming, cycling. 150 minutes / wk over
at least 3 days of the week is recommended
• Gardening and usual housecleaning tasks are encouraged.
• Aerobic exercise can improve insulin sensitivity and glycemic
control and may reduce CV risk factors, contribute to weight
loss or maintenance, and improve well-being.
Vaccination

• Influenza and pneumonia are common preventable

infections that increase mortality & morbidity in
patients with chronic diseases, including DM.

Yearly influenza One-time pneumococcal

vaccinations, are vaccine is also
recommended for all recommended for
patients with DM 6 patients with DM who are
months of age or older. 2 years of age or older.

The hepatitis B vaccine

series should also be given
to patients with diabetes.
Dietary Supplements

• There is no sufficient evidence of efficacy for improved

BG control for any individual herb or supplement.
• Herbs and supplements commonly claimed to improve
glucose control include chromium, magnesium,
vitamin D, and cinnamon.

• Patients will inquire about and use dietary

supplements. It is important to respect the patient’s
health beliefs, address their questions and concerns
• Educate the patient on the differences between dietary
supplements and prescribed therapies (never stop
this).
Pharmacological Treatment
 Therapeutic goals of management of DM
1. Reducing, controlling, and managing long-term
microvascular, macrovascular, and neuropathic
complications
2. Preserving β-cells function
3. Preventing acute complications of the high blood
glucose levels (e.g. Diabetic ketoacidosis)
4. Minimizing hypoglycemic episodes
5. Maintaining the patient’s overall quality of life

• In addition to glycaemiac control, management of CV

risk factors (i.e. smoking cessation, treatment of
dyslipidemia, BP control, and antiplatelet therapy) is
needed to reduce macrovascular disease risk.
 Glycemia
HbA1C • < 7% (53 mmol/mol Hgb).
  • Evaluate every 3 months until in goal;
then every 6 months
Average Glucose < 154 mg/dL (8.6 mmol/L)
Preprandial plasma 80–130 mg/dL (4.4–7.2 mmol/L)
glucose
Peak postprandial < 180 mg/dL (10.0 mmol/L)
plasma glucose
Others
BP • < 140/80 mm Hg (Evaluate every visit)
Lipids • Evaluate at diagnosis and/or age 40,
then every 1-2 years thereafter
Monitoring for Complications
Eyes Dilated eye exam yearly
Feet Feet should be examined every visit
Urinary albumin Yearly
 Class & MOA Comments
Examples
Biguanides: Increases insulin 1957 (Europe), 1995 (FDA)
Metformin sensitivity, suppresses Gastrointestinal side effects,
glucose production in the lactic acidosis, C/I in renal
liver insufficiency

Sulfonylureas: Stimulation of insulin Glibenclamide (Glyburide):

Gliclazide, secretion by the pancreas 1969 (Europe), 1984 (FDA)
Glibenclamide Hypoglycemia risk, weight
(Glyburide) gain

Glinides: Stimulation of insulin Repaglinide: 1998 (EMA),

Repaglinide, secretion by the pancreas 1997 (FDA) Short half life –
Nateglinide pre-prandial administration;
hypoglycemia risk, weight
gain
 Class & Examples MOA Comments
Thiazolidinediones Reduction of insulin Rosiglitazone: 1999 (FDA),
Pioglitazone, resistance by activation 2000 (EMA) Increased risk for
Rosiglitazone of the Peroxisome HF, fluid retention, weight gain,
proliferator-activated bone fractures. CV concerns for
receptors (PPAR-gama) rosiglitazone only. Pioglitazone:
receptor Bladder cancer concerns.
Alpha-Glucosidase Reduction of glucose Acarbose: 1991 (Europe), 1995
inhibitors Acarbose, absorption in the gut (FDA) GI SE, no systemic
Miglitol, Vocarbose effects.
DPP4 inhibitors: Stimulation of glucose Sitagliptin: 2006 (FDA), 2007
Sitagliptin, dependent insulin (EMA); (Vildagliptin only
Vildagliptin, release and suppression approved by EMA, 2008).
Saxagliptin, of elevated glucagon Saxagliptin approved by FDA
Linagliptin levels by prolonging the and EMA, 2009. linagliptin 2011
half-life of endogenous (FDA).
GLP-1 (minor effects on
GI motility and satiety)
 Class & Examples MOA Comments
GLP-1 agonists: Stimulation of glucose Exenatide: 2005 (FDA), 2006
Exenatide, dependent insulin (EMA); Liraglutide 2010 (FDA),
Liraglutide, release, suppression of 2009 (EMA), Exenatide ER 2012
Albiglutide, elevated glucagon levels, (FDA), (Lixisenatide only
Dulaglutide reduction of GI motility, approved by EMA, 2013.)
stimulating satiety, weightalbiglutide 2014 (FDA and EMA).
loss Dulaglutide, 2014 (FDA)
SGLT2 inhibitors: Reducing renal Dapagliflozin: 2012 (EMA), 2014
Dapagliflozin, reabsorption of glucose, (FDA). canagliflozin 2013 (FDA),
Canagliflozin, resulting in increased empagliflozin 2014 (FDA and
Empagliflozin glucose excretion EMA). Genital infections,
possible diuretic effects, weight
reduction
Bile acid Possibly activation of the Colesevelam: 2008 (FDA); no
sequestrants: farnesoid X receptor / EMA approval for treatment of
Colesevelam bile acid receptor diabetes. Primarily a lipid
lowering drug with additional
glucose lowering effects
 Class & Examples MOA Comments

Dopamine agonists: Central modification of Bromocriptin: 2009 (FDA), no

Bromocriptine insulin resistance EMA approval for treatment of
diabetes.
Orthostatic hypotension,
nausea
Amylin analogue: Slowing of gastric Pramlintide: 2005 (FDA), no
Pramlintide emptying, suppression EMA approval.
of elevated glucagon, Approved for T1DM & T2DM.
stimulation of satiety Nausea, hypoglycemia when
combined with other drugs (e.g.
insulin)
Insulin: regular human Lowering of blood Regular insulin: 1982 (FDA);
insulin, NPH, insulin glucose 1984 (Europe); Bovine insulin:
aspart, insulin lispro, 1922.
insulin glargine, insulin Afrezza®: A new administration
detemir, insulin form of inhaled insulin has been
levemir recently approved (2014)
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.
• The usual approach attempts to 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.
• As a rule, the total daily dose 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.
• Following is an example of a regimen of 2 daily
injections that may roughly 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.
• Exact doses are individualized to the patient and the
amount of food consumed.
• Usual starting dose of insulin is about 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.
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
• 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
metformin
• 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 1.5%

- 2% decrease in HbA1c and a 60 - 70 mg/dL (3.3–3.9
mmol/L) reduction in FBG levels.
Biguanide: Only agent available is metformin.

• 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 (16.7
mmol/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 overweight patients with
T2DM compared with intensive therapy with sulfonylurea or
insulin. It also reduced diabetes-related death and MI
• In addition to lifestyle modification, metformin is considered
foundational therapy for T2DM because it is the only oral
antidiabetcic 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.
• 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.

• Patients should avoid consumption of excessive amounts of

alcohol while taking metformin, and use of the drug should
be avoided in patients with liver disease.
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.
• The most common route of
administration for insulin is SC.
• Patients should be educated to rotate
injection site to minimize local reactions
e.g. lipohypertrophy, which can decrease
or prevent proper insulin absorption
• 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 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.
 Promote a negative energetic balance and
consequent weight loss

 AACE (American association of Clinical

Endocrinologists) recommends SGLT2 inhibitors as
a monotherapy if metformin is contraindicated or
not tolerated

 Hypoglycemia is uncommon because they have no

effect on insulin release
Summary of effects of Parameter Response
HbA1c
SGLT2 inhibitors
FPG
PPG
 Reduction in BP is
Body weight
believed to be due to the
Blood pressure
diuretic and volume Lipids
depletion effects HDL-C
LDL-C
 Infections were primarily Triglycerides
fungal & more in females Infections
Genital
Urinary tract or
GLP-1 Receptor Agonists
e.g. Exenatide, Liraglutide, Albiglutide

 Among the most potent drugs for the treatment of

T2DM
 All currently available compounds are administered
parenterally
 They are protected against DPP4 degradation

 Oral & Inhalational GLP-1 agonists are in development

 Another innovative approach is continuous application

by using a subcutaneous device (will allow once yearly
administration)
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 used) –1.7

Sulfonylurea + α-glucosidase inhibitor –1.6

Metformin + meglitinide –1.4
Insulin + α-glucosidase inhibitor –1.2
Insulin + thiazolidinedione –1.2
Sulfonylurea + thiazolidinedione –1.1
GLP-1 Agonist + Metformin or Sulfonylurea –1.0
Metformin + thiazolidinedione –0.9
Metformin + α-glucosidase inhibitor –0.4
Gestational DM
• 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
– It can be difficult to exclude pre-existing T2DM presenting for the
first time in pregnancy.
• 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 SE
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
12/27/22 71
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
• 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 hypokalaemia, 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, pregnancy,
pancreatitis, trauma, hyperthyroidism, or MI)?
5. Can the patient measure and/or administer insulin
accurately?
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 to
eat and drink.
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 deficiency
exist.
– Hyperkalemia should prompt 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
• Bicarbonate use in DKA is controversial and may be
dangerous. It is rarely indicated because adequate fluid
and insulin therapy will resolve acidosis in DKA
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: Common causes of

1. Sweating hypoglycemia:
2. Tremors • Delayed or inadequate amounts of
food intake, esp. carbohydrates
3. Palpitation
• High doses of medications (e.g.
4. Fatigue sulfonylureas and insulin)
5. Confusion • Exercising when insulin doses are
6. Headache reaching peak effect
7. Dizziness • Inadequately adjusted drug
therapy in patients with impaired
8. Flushing
renal or hepatic function.
9. Coma
10. loss of consciousness
12/27/22 81
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’s 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 responsible for 90% of
the rise in blood glucose after a meal.
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
• BP
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 high after 2 or 3
supplemental doses of insulin, or your BG level
remains >240 mg/dL for >24 hours.
Thank You