Diabetes Mellitus

By: Bedilu L.
 Introduction
• Is a group of metabolic disorders characterized by
hyperglycemia.

• Is associated with abnormalities in

• Carbohydrate ,

• Fat, and

• Protein metabolism

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 Classification

• DM is classified on the basis of the pathogenic process that

leads to hyperglycemia.

• The two broad categories of DM are designated:

 type 1 and type 2

• Both types of diabetes are preceded by a phase of abnormal

glucose homeostasis as the pathogenic processes progresses.

 GDM

• Diabetes diagnosed during pregnancy

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 Others
Drug induced: Endocrinopathies:
 Pentamidine  Acromegaly
 Glucocorticoids
 Nicotinic acid  Cushing syndrome
 Interferon alfa,  Pheochromocytoma
 Diazoxide,
 Hydrochlorothiazide,
 Atypical
 antipsychotics,
 Protease inhibitors
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 Pancreatic exocrine
Genetic defects
disease
 Defects of beta-cell function  Pancreatitis
or insulin function  Trauma
 Ex: Maturity-onset diabetes  Infection
of the young  Cystic fibrosis

 Hemochromatosis

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 Type 1 Diabetes
• The result of complete or near-total insulin deficiency
– Results from autoimmune destruction of the β cells of the
pancreas
– Can be also idiopathic
• Usually occurs in children and adolescents, it can occur at any age

• Younger individuals typically have a rapid rate of β-cell destruction

and present with ketoacidosis

• Mean age of onset: 8-12 years

– 5-10% of all diabetes cases

– Generally develops in early childhood or early adulthood

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BLE
 Type 2 Diabetes
• It is a heterogeneous group of disorders characterized by variable
degrees of insulin resistance, impaired insulin secretion, and
increased glucose production.
• Most individuals exhibit abdominal obesity, which itself causes
insulin resistance.
The insulin resistance syndrome or the metabolic syndrome.
• It is preceded by a period of abnormal glucose homeostasis
classified as impaired fasting glucose (IFG) or impaired glucose
tolerance (IGT).
– 90-95% of all diabetes
– Common in a life-style of excessive calories, inadequate
exercise, and obesity is superimposed upon a susceptible
genotype
– Typically occurs after age 40BLE
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 Metabolic syndrome

• The association of insulin resistance with a clustering of

cardiovascular risk factors including hyperinsulinemia,

hypertension, abdominal obesity, dyslipidemia, and coagulation

abnormalities

• Abdominal obesity more highly correlated with metabolic risk

factors than elevated BMI

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 Epidemiology
• Prevalence of both type 1 and type 2 DM is increasing worldwide
• The prevalence of type 2 DM is rising because of increasing
obesity and reduced activity levels
• The prevalence is similar in men and women but is slightly greater in
men >60 years
• Medical management of persons with diabetes is costly
– 2007 , US data - total cost of diabetes was ≈ $174 billion
– The leading cause of blindness in adults
– Approximately 2/3 of deaths are caused by a cardiovascular
event in DM pts
• Non communicable diseases are an emerging challenge – Ethiopia
– A population study at Gilgel Gibe filed research - 0.5%

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 11
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 Pathogenesis: Type 1 DM
 Loss of insulin secretion results from autoimmune destruction of the
insulin-producing β-cells in the pancreas
 triggered by environmental factors, such as viruses or toxins, in
genetically susceptible individuals

 65% to 85% -- have circulating antibodies against islet cells

 20% to 60% - have measurable antibodies directed against

insulin

 ~90% pts----- have markers of immune β-cell destruction at Dx

 Children, adolescent--- rapid beta cell destruction

 LADA….late age presentation [ slow onset type 1 DM]

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Proposed Scheme of Natural History of Beta -Cell Defect

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 Pathogenesis: Type 2 Diabetes

 The exact pathogenesis of type 2 is the least understood

 Characterized by impaired insulin secretion and resistance to
insulin action
 Hyperglycemia: due
 glucose utilization by tissues is impaired, hepatic glucose
production is increased, and excess glucose accumulates in the
circulation
 Pancreas to produce more insulin in an attempt to overcome
insulin resistance
 Genetic predisposition may play a role
• People with type 2 diabetes have a stronger family history
of diabetes than those with type 1
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 Risk Factors: Type 2 DM
 First-degree family history of DM
(i.e., parents or siblings)
 Overweight or obese
 Habitual physical inactivity
 Race or ethnicity (Native American,
Latino or Hispanic American, Asian
American, African American, and
Pacific Islanders)
 History of cardiovascular disease
 History of polycystic ovarian
syndrome
 Other conditions associated with
insulin resistance (e.g., acanthosis
nigricans
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 Previously identified IFG, IGT, or
A1c between 5.7% and 6.4%
 Hypertension (greater than or
equal to 140/90 mm Hg or on
therapy for hypertension)
 High-density lipoprotein (HDL)
less than 35 mg/dL and/or a
triglyceride level greater than
250 mg/dL
 History of gestational diabetes
or delivery of a baby weighing
greater than 4 kg (9 lb)
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 Classical Clinical Presentation of Diabetes
Mellitus

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 Diagnosis
Clinical Pearls:
1. DM symptoms + 1 confirmed abnormal test
2. Without DM symptoms,1 abnormal test confirmed again
preferably by the same test on 2 different days
3. If two different tests are available for an individual and the
results are discordant, the test whose result is abnormal should be
repeated to confirm the diagnosis
• Symptoms of DM
– Polyuria Polydipsia
– Weight loss
– Polyphagia
– blurred vision

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 TESTS
• Tests
 FBS
 HgA1C
 RBS
 OGTT
• A1C is not accurate sickle cell disease, pregnancy (2nd and 3rd
trimesters), hemodialysis, blood loss or transfusion, or
erythropoietin therapy

– Plasma BG criteria should be used to diagnose DM.

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• The ADA recommends using the fasting glucose test as the
principal tool for the diagnosis of DM in non pregnant adults.

• Criteria for the Diagnosis of Diabetes Mellitus

o Symptoms of diabetes plus random blood glucose

concentration ≥ 11.1 mmol/L (200 mg/dL) or

o Fasting plasma glucose≥ 7.0 mmol/L (126 mg/dL) or

o Two-hour plasma glucose ≥ 11.1 mmol/L (200 mg/dL)

during an oral glucose tolerance test

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 Screening
• A large number of individuals who meet the current criteria for
DM are asymptomatic and unaware that they have the disorder

• Epidemiologic studies suggest that type 2 DM may be present for

up to a decade before diagnosis

• As many as 50% of individuals with type 2 DM have one or

more diabetes-specific complications at the time of their
diagnosis

• Treatment of type 2 DM may favorably alter the natural history

of DM
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 Screening

Screening for Type 1 DM

 Only if symptomatic
 Screening for monitoring purposes may be considered if the
patient has a first-degree relative with T1DM

Which tests are used for screening?

1-islet cell antibodies **

2-insulin antibodies

3-glutamic aciddecarboxylase antibodies

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• Screening for Type 2 DM
1. Every 3 years starting at 45 years old.
2. Overweight (BMI ≥25 or≥23 if Asian American)+≥1 Risk
Factor:
 First-degree relative withT2DM
 High-risk ethnicity: African American, Asian American, Native
American, Latino, Pacific Islander
 Physical inactivity
 History of: HTN ≥140/90 or High TG (>250) or
– Low HDL (<35) or PCOS or CVD
3. Prediabetes (A1C ≥5.7)
4. History of GDM (Screen every 3 yrs)
– If tests are normal, repeat testing carried out at a minimum of
3-year intervals is reasonable.
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 Gestational DM
 Screen between weeks 24-28 of gestation if patient has no
diabetes risk factors

 Screen at 1st prenatal visit for a patient with even one diabetes
risk factor and if normal finding, repeat between weeks 24 & 28.

 Women with a history of GDM should be screened for diabetes

6–12 weeks postpartum by using non-pregnant OGTT criteria (and
lifelong screening, at least every 3 year
 Screen with a 75-g 2-hour OGTT
 One abnormal BG result makes the diagnosis.

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 Prevention
• Type 2 DM is preceded by a period of IGT, and a number of lifestyle
modifications and pharmacologic agents prevent or delay the onset of
DM.

• Intensive changes in lifestyle (diet and exercise for 30 min/day five

times/week) in individuals with IGT prevented or delayed the
development of type 2 DM by 58% compared to placebo

• Metformin prevented or delayed diabetes by 31% compared to

placebo

 prediabetes, especially for those with BMI$35 kg/m2 ,those

aged ,60 years, and women with prior gestational diabetes
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 Case study
A 64-year-old African American woman has had a 12-kg (27 lb) weight
increase during the past year, primarily because of inactivity and a poor
diet. Her BMI is 44 kg/m2. Her mother and sister both have T2D. Her
fasting glucose concentration today is 212 mg/dL. Which is the best
course of action?

– A. Diagnose T2D and begin treatment.

– B. Diagnose T1D and begin treatment.

– C. Obtain another glucose concentration today.

– D. Obtain an A1C today in addition to the glucose concentration.

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Answer: D
 Historically, the ADA has recommended a subsequent test of
hyperglycemia to be performed at another date.

 Updated recommendations state that two different tests of

hyperglycemia can be obtained on the same day and sample.

 In this case, Answer D is correct; an A1C in addition to the obtained

glucose concentration can be obtained.

 Answers A and B would only be correct if the patient had signs or

symptoms of hyperglycemia.
 Answer C is not recommended because the concentration has
already been obtained.
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TREATMENT APPROACH
 Treatment
• The goals of therapy for type 1 or type 2 DM

– (1) Eliminate symptoms related to hyperglycemia,

– (2) Reduce or eliminate the long-term microvascular and

macrovascular complications of DM, and

– (3) Allow the patient to achieve as normal a lifestyle as

possible.

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 Glycemic Goals

1. A1C of ≤7% (ADA)

2. Pre-prandial BG concentration: 80–130 mg/dL (ADA);

<95 mg/dL for patients with GDM

3. Post-prandial BG concentration (2 hours after initiation of

meal): <180 mg/dL (ADA); <120 mg/dL for patients with

GDM

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 When used properly, continuous glucose monitoring in conjunction
with intensive insulin regimens is a useful tool to lower A1C in
adults with type 1 diabetes who are not meeting glycemic targets.

 Less stringent A1C goals (such as,8% [64mmol/mol])may be

appropriate for patients with
 History of severe hypoglycemia
 Limited life expectancy
 Advanced microvascular or macrovascular complications,
extensive comorbid conditions, or
 Long-standing diabetes in whom the goal is difficult to achieve
with maximum treatment

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 Nonpharmacologic Therapy

o Diet: medical nutrition therapy w/c includes meals moderate in

carbohydrates and low in saturated fat, with a focus on balanced
meals is recommended.

o Exercise

– 150 min/week (distributed over at least 3 days) of aerobic

physical activity.

– Cardiovascular risk reduction, reduced blood pressure,

maintenance of muscle mass, reduction in body fat, and weight
loss.

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PHARMACOTHERAPY of Type 1 DM
 Most individuals with type 1 diabetes should be treated with
multiple daily injections of prandial and basal insulin, or continuous
subcutaneous insulin infusion

 Most individuals with type 1 diabetes should use rapid-acting

insulin analogs to reduce hypoglycemia risk

 Individuals with type 1 diabetes should receive education on how

to match mealtime insulin doses to carbohydrate intake, fat and
protein content, and anticipated physical activity
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 Insulin
• Insulin is an anabolic and anti catabolic hormone.

• Characteristics that are commonly used to categorize insulins

include source, strength, onset, and duration of action.

• Regular or neutral protamine Hagedorn (NPH) insulin is commonly

injected in (from most rapid to slowest absorption)

• Abdominal fat,

• Posterior upper arms

• Lateral thigh area

• Superior buttocks area

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• Insulin replacement regimens typically consist of

Basal insulin,

Mealtime insulin

 Correction insulin

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A. Basal insulin (detemir, glargine, degludec, NPH)

– ↓FBG

– Approximates 50% of daily insulin needs

– Equivalent doses:
• (a) 60U NPH once daily = 60 U Glargine once daily= 60 U
Detemir once daily.
• (b) 30 U NPH twice daily = 48 U Glargine once daily = 60
U Detemir once daily.
B. Bolus insulin (regular, aspart, glulisine, lispro)
↓Postprandial BG
 Immediate insulin peak and onset of activity
 Each meal requires 10%–20% of daily insulin requirements
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C. Mixed insulin: Typically reserved for patients who will not or
cannot be treated with dosing regimens that are more complex and
given before the morning and evening meals

 Humulin 70/30: 70% NPH, 30% regular

 Humalog Mix 75/25: 75% lispro protamine, 25% lispro

 Humalog Mix 50/50: 50% lispro protamine, 50% lispro

 Novolin 70/30: 70% NPH, 30% regular

 NovoLog Mix 70/30: 70% aspart protamine, 30% aspart

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(a) Advantages of mixed insulin

 Less frequent injections

 No mixing of insulins required

 Provides basal insulin supplementation and short-term mealtime

coverage with one injection

(b) Disadvantages of mixed insulin

 Less dosing flexibility
 Not as suitable as single-insulin formulations for adjusting daily
doses to account for changes in activity levels and meal regimens
 Causes more hypoglycemia and allows less glycemic control than
use of individual basal/bolus insulins
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 Initial Dosing of Insulin in T1DM
 Total daily insulin requirements can be estimated based on weight,
with typical doses ranging from 0.4 to 1.0 units/kg/day

– Higher amounts are required during puberty, pregnancy, and

medical illness

 0.5 units/kg/day as a typical starting dose in individuals with

type 1 diabetes who are metabolically stable

 Half administered as prandial insulin given to control blood

glucose after meals and the other half as basal insulin to control
glycemia in the periods between meal absorption

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• Multidose regimens for individuals with type 1 diabetes combine
premeal use of shorter-acting insulins with a longer-acting
formulation.

• The long-acting basal dose is titrated to regulate overnight, fasting

glucose.

• Postprandial glucose excursions are best controlled by a well-timed

injection of prandial insulin.

• The optimal time to administer prandial insulin varies, based on the

pharmacokinetics of the formulation (regular, RAA, inhaled), the
premeal blood glucose level, and carbohydrate consumption.
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 Regimens that more closely mimic normal insulin secretion

Injected insulin regimens Flexibility Lower risk of Higher

hypoglycemia costs

MDI with LAA + RAA or URAA +++ +++ +++

Less-preferred, alternative injected insulin regimens

MDI with NPH + RAA or URAA ++ ++ ++

MDI with NPH + short-acting (regular) ++ + +

insulin

Two daily injections with NPH + + + +

short-acting (regular) insulin or
premixed
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Continuous insulin Flexibility Lower risk of Higher costs
infusion regimens hypoglycemia

Hybrid closed loop +++++ ++++++ +++++++

technology

Insulin pump with ++++ ++++ +++++

threshold

Insulin pump +++ +++ ++++

therapy without
automation
The number of plus signs (+) is an estimate of relative association of the regimen with
increased flexibility, lower risk of hypoglycemia, and higher costs between the
considered regimens. LAA, long-acting insulin analog; MDI, multiple daily injections;
RAA, rapid-acting insulin analog;URAA, ultra-rapid-acting insulin analog
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 Initiate with multiple daily insulin injection therapy:
• (a) Calculate daily dose (0.5 unit of insulin per kilogram per
day).
• (b) Give 50% as basal insulin. Perform dose titration to FBG
values.
• (c) Give 50% as bolus insulin. Split into three mealtime doses.
• Example: 80-kg patient starting multiday injection therapy: 0.5 unit/kg
= 40 units of insulin/day; half as basal, half as bolus, with the
following:
– (1) Glargine or detemir 20 units every day
– (2) Aspart or glulisine, lispro 6 units prebreakfast
– (3) Aspart or glulisine, lispro 7 units prelunch
– (4) Aspart or glulisine, lispro 7 units predinner
– (5) Titrate insulin doses to BG values.
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• Correctional insulin dosing – Meant to correct for premeal

glycemic excursions:

– (1) Rapid-acting insulin (the rule of 1800): 1800/current

total daily insulin dose = mg/ dL change/1 unit (e.g., 40

units/day: 1800/40 = 45 mg/dL [insulin sensitivity]).

– (2) Regular insulin (the rule of 1500): 1500/current total

daily insulin dose = mg/dL change/1 unit (e.g., 50)

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Example
• TDD= 50 units insulin
• ISF=1800 /50 = 36mg/dL
• The current premeal blood sugar is 200 mg/dL
• The target premeal blood sugar is 80-130 mg/dL
Correction dose =
– (Current blood sugar -Target blood sugar) / ISF = (200-
130)/ 36 = 1.95 units

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 Approach to use older insulin formulations: NPH & regular insulin
Two daily injections
A. 2/3rd of TDI given before morning meal

 Two-thirds of this given as NPH and one-third as regular insulin

B. 1/3rd of TDI given before the evening meal (or regular given
before a meal & NPH at bedtime)

 Again, 2/3rd of this given as NPH & 1/3rd as regular insulin

 Advantages: daily insulin injection frequency is only two or three

times daily & inexpensive
 Disadvantages: does not mimic natural insulin secretion pattern;
prone to hypoglycemic events
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 Noninsulin Treatments for Type 1
Diabetes

• Pramlintide is based on the naturally occurring b-cell peptide

amylin and is approved for use in adults with type 1 diabetes.

– Clinical trials have demonstrated a modest reduction in A1C

(0.3–0.4%) and modest weight loss (1 kg) with pramlintide

– only pramlintide is approved for treatment of type 1

diabetes.

• Pancreas and Islet Transplantation

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 Case study
A 21-year-old patient (weight 80 kg) is given a diagnosis of T1D
after the discovery of elevated glucose concentrations (average 326
mg/dL), and the patient has signs and symptoms of hyperglycemia.
Which is the most appropriate initial dose of rapid-acting insulin
before breakfast for this patient? (Assume a TDI regimen of 0.5
unit/kg/day.)

A. 2 units. B. 4 units. C. 7 units. D. 14 units

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Answer: C

• This patient’s TDI requirement is 40 units (80 kg ×0.5

unit/kg/day).

• Half of this is initially used for basal insulin requirements and half
for bolus insulin requirements before meals.

• The 20 units for bolus requirements should initially be divided

equally between three meals (i.e., 6–7 units), making Answer C
correct.

• The other three answers would provide either too much (Answer D
is incorrect) or too little (Answers A and B are incorrect) estimated
insulin at each meal.
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TREATMENT APPROACH for TYPE 2
DM
 Anti hyperglycemic Agents
Sulfonylureas
• Stimulate insulin secretion.

• First-generation and second-generation agents.

• Based on:

– Differences in relative potency

– Relative potential for selective side effects, and

– Differences in binding to serum proteins (i.e., risk for protein-

binding displacement drug interactions).

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 Sulfonylureas cont…
• First generation agents consist of acetohexamide, chlorpropamide,
tolazamide, and tolbutamide.

• Second-generation drugs: glimepiride, glipizide, and glyburide

• All sulfonylureas are equally effective at lowering blood glucose

when administered in equipotent doses.

• Individuals at high risk for hypoglycemia (e.g., elderly individuals

and those with renal insufficiency or advanced liver disease) should
be started at a very low dose of a sulfonylurea with a short half-
life

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 Sulfonylureas cont….
• On average, HbA1c will decrease 1.5% to 2%, with FPG reductions
of 60 to 70 mg/dL.

• Glipizide is DOC in renal impairment

• Patients who fail sulfonylurea usually fall into two groups: Those with
low C-peptide levels and high (>250 mg/dL) FPG levels.
• Factors that facilitate a positive response include;
– Newly diagnosed patients with no indicators of type 1 DM,
– High fasting C-peptide levels, and
– Moderate fasting hyperglycemia (<250 mg/dL).

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Sulfonylureas cont….
• Adverse Effects.
– hypoglycemia
– Hyponatremia (serum sodium <129 mEq/L) is reportedly
associated with tolbutamide
– Weight gain
– Rash – Sulphur content
• Contraindication
– T1DM
– Severe liver or kidney disease
– Hypoglycemia unawareness

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 Short-Acting Insulin Secretagogues
Meglitinides
• Nateglinide and repaglinide stimulate insulin secretion from the β
cells of the pancreas
• Both require the presence of glucose to stimulate insulin secretion.
• Rapid acting insulin secretagogues that are rapidly absorbed
(~0.5 to 1 hour) and have a short half-life (1 to 1.5 hours).
• Need for multiple dosing - TID
• Not used with repaglinide use with gemfibrozil
Adverse Effects. Weight gain of 2 to 3 kg with repaglinide and with
nateglinide appears to be <1 kg

• Hypoglycemia
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 Biguanides
• Metformin is the only biguanide
• Enhances insulin sensitivity of both hepatic and peripheral
(muscle) tissues
• Has approximately 50% to 60% oral bioavailability, low lipid
solubility, and a volume of distribution that approximates body
water

• Is not metabolized and does not bind to plasma proteins

• Metformin is eliminated by renal tubular secretion and glomerular
filtration

• The average half-life of metformin is 6 hours, although

pharmacodynamically, metformin’s antihyperglycemic effects last
>24 hours.
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 Metformin cont…
• Consistently reduces HbA1c levels by 1.5% to 2.0%, FPG levels by
60 to 80 mg/dL, and retains the ability to reduce FPG levels when
they are extremely high (>300 mg/dL)

• Decreases plasma triglycerides and LDL-C by approximately 8%

to 15%, as well increasing HDL-C very modestly (2%).

• Metformin should be included in the therapy for all type 2 DM

patients, if tolerated and not contraindicated

• it is the only oral antihyperglycemic medication proven to reduce

the risk of total mortality
• First-line drug unless contraindicated
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No hypoglycemia , Weight LossBLE 62
 Metformin cont….
• If CrCl (30-45): Reduce dose by 50% If CrCl (45–60) : continue
regular dose and monitor renal function every 3–6 months

• Discontinue if eGFR is < 30 mL

• DON’T initiate if eGFR is (30–45)

• Severe hepatic or ADHF, COPD & Age 80 yrs old

• Serum creatinine of 1.4 mg/dL in women and 1.5 mg/dL in men or

greater, is contraindication, as it is renally eliminated

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Metformin cont…
• Adverse Effects.

 N,V,D (especially early)

 Uncommon: Macrocytic anemia (caused by vitamin B12

deficiency); lactic acidosis

 B12 supplementation in those taking metformin: A

recommendation has been added to consider periodic
measurement of B12 levels and supplementation prn

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 Thiazolidinediones (TZDs or glitazones)
• Pioglitazone and rosiglitazone
• enhance insulin sensitivity at muscle, liver, and fat tissues indirectly
• Pioglitazone and rosiglitazone are well absorbed with or without
food.
• Both are highly (>99%) protein bound to albumin
• The half-life of pioglitazone and rosiglitazone is 3 to 7 hours and
3 to 4 hours, respectively
• Both medications have a duration of antihyperglycemic action of
more than 24 hours
• Glycemic-lowering onset is slow, and maximal glycemic-lowering
effects may not be seen until 3 to 4 months of therapy

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 Thiazolidinediones cont….

 ↑HDL-C values (pioglitazone, rosiglitazone) ↓TG values

(pioglitazone)

 Can induce ovulation in PCOS patients

 No hypoglycemia as monotherapy.

 FDA restricted access program - CVS risks

• Rosiglitazone access was restricted to those:

 (1) Already taking rosiglitazone and

 (2) unable to achieve glycemic control with other medications

who couldn't take pioglitazone
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Thiazolidinediones cont….
PRECUATION
 History of or risk for bladder cancer
 Elevated liver enzymes Patients with ALT levels >2.5 times the
upper limit of normal should not start either medication,
 if the ALT is >3 times the upper limit of normal the medication
should be discontinued
Adverse Effects.
 Fluid retention- edema, dilutional anemia,
 Weight gain , increase fracture rate in women (upper limb),
resume ovulation
Contraindications
 stage III and IV HF

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 Incretin mimetics
– Exenatide

– Liraglutide

– Exenatide XR

– Albiglutide

– Dulaglutide

– Lixisenatide (pen)

• Shares amino acid sequence with human glucagon-like peptide

(GLP-1).

• Subcutaneously adminstered
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Incretin cont….
• Enhances glucose dependent insulin secretion while suppressing
inappropriately high postprandial glucagon secretion in the
presence of elevated glucose concentrations,

• resulting in a reduction in hepatic glucose production

• Exenatide significantly decreases postprandial glucose excursions

but has only a modest effect on FPG values.

• The average HbA1c reduction is approximately 0.9% with

exenatide

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 Incretin cont…..
• All of them are independent of meals except Exenatide: 60 min.
before morning & evening meals

• Exenatide XR inject immediately after the powder is suspended in

the diluent and transferred to the syringe

• Albiglutide: inject 15 minutes after the lyophilized powder is

reconstituted within the delivery pen

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 Incretin cont…..
S/ES: N,V,D ; Injection-site nodule (Exenatide)

Contraindication

 Gastroparesis

 Pancreatitis history

 Exenatide: CrCl <30

 All of them except Exenatide are contraindicated in Personal or

family history of medullary thyroid carcinoma; in patients with
MEN 2 (multiple endocrine neoplasia syndrome type 2)

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 Dipeptidyl peptidase IV enzyme (DPP-IV)
inhibitors
Sitagliptin, Saxagliptin, Linagliptin, Alogliptin

• prolong the half-life of an endogenously produced glucagon-like

peptide-1 (GLP-1).

• The average reduction in HbA1c is approximately 0.7% to 1% at a

dose of 100 mg a day

 No hypoglycemia as monotherapy

 All need renal and hepatic adjustment except Linagliptin

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S/ES

 URTI, Pancreatitis, GIT S.E

 FDA recommended added warnings to package labeling of both

saxagliptin and alogliptin (↑HF Hospitalization Risk)

Contraindication

 Pancreatitis history

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 α-Glucosidase Inhibitors
 Acarbose and miglitol
 Competitively inhibit enzymes (maltase, isomaltase, sucrase, and
glucoamylase) in the small intestine, delaying the breakdown of
sucrose and complex carbohydrates
 Reduce the postprandial blood glucose rise
 No hypoglycemia as monotherapy.
 GIT Disturbances may diminish after 4–8 weeks of therapy
 Need for multiple dosing - TID
 ↑LFTs (rare)
 Contraindications

 IBD , Intestinal obstruction , Malabsorption, Cirrhosis

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 Bile acid sequestrant
• Colesevelam

• No hypoglycemia as monotherapy

• ↓LDL

• Can be Combined with Metformin

S/ES

• Constipation/dyspepsia , ↑TGHF

Contraindication

• Bowel obstruction

• TG > 500 mg/dL

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 Dopamine agonist

 Bromocriptine
S/ES
 GIT Disturbances
Contraindication
• Ergot Hypersensitivity
• Lactation, migraines
• Uncontrolled HTN
• Postpartum period in patients with CAD

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 Sodium-dependent glucose transporter-2
(SGLT-2) inhibitor
 Canagliflozin

 Dapagliflozin

 Empagliflozin

 Canagliflozin not recommended at CrCl < 45 Contraindicated at

CrCl<30

• Dapagliflozin Contraindicated at CrCl<60

• Empagliflozin Contraindicated at CrCl<45

• No hypoglycemia with monotherapy

BLE 77
S/ES

Weight Lose

Hyperkalemia,

Hypotension,

Genital infections (More common in females) & UTI

(Strengthen Warning)

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 Amylin analog
Pramlintide
 Subcutaneously with meals daily (mealtime insulin dose must be
reduced by 50% on initiation of pramlintide)
 Hypoglycemia with insulin
 Precaution if A1C >9%
 Requires three additional injections per day (cannot be mixed
with insulin)
 May reduce the rate and extent of absorption of drugs that
require rapid absorption (e.g., pain relievers, antibiotics, oral
contraceptives); separate administration by at least 1 hour

C/IS
– Gastroparesis
– Hypoglycemia unawareness
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Treatment Approach in Type 2 Diabetes

• Patients with HbAlc ~7% or less are usually treated with

therapeutic lifestyle measures and single agent

• Patients with higher initial HbAlc can benefit from initial

therapy with two oral agents, or even insulin.

• Obese patients (>120% ideal body weight) should be started

on metformin titrated to ~2,000 mg/day.

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• Failure of initial therapy should result in addition rather than
substitution of another class of drug

• TZDs, exenatide, vildagliptin, and sitagliptin can potentially

preserve β-cell function

• Sulfonylureas are often stopped when insulin is added, but

continuing the sulfonylurea is permissible until multiple daily
injections are started, at which time it should definitely be
discontinued

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 82
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4/21/2024 BLE 83
4/21/2024 BLE 84
 Combination Injectable Therapy for Type 2 DM

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4/21/2024 BLE 86
COMPLICATIONS of DM
• Leads to many complications

• DM is the leading cause of

–End-stage renal disease (ESRD),

–Nontraumatic lower extremity

amputations,

–Adult blindness

• Acute and chronic complications

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 Acute Complications of DM

• Diabetic ketoacidosis (DKA), hypoglycemia and hyperglycemic

hyperosmolar state (HHS) are acute complications of diabetes.

• Both disorders are associated with – DKA, HHS

– Absolute or relative insulin deficiency,

– Volume depletion, and

– Acid-base abnormalities.

• DKA and HHS exist along a continuum of hyperglycemia, with or

without ketosis.
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 Hypoglycemia
• BG (less than 70 mg/dL)

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 Treatment of Hypoglycemia
 If patient is conscious, (10 to 15 g) rapid-acting carbohydrates
orally (four Life Savers or other hard candy [chew], 4 teaspoons of
sugar, ½ cup of soda or juice, 1 cup of skim milk). Recheck BG
concentration in 15 minutes

 If BG reading is above 70 mg/dL and it is more than 1 hour until

the next scheduled meal a long-acting source of carbohydrates

 Dextrose

 IV may be required in individuals who have lost consciousness.

 Glucagon
 1 g intramuscular, is the treatment of choice in unconscious
patients when IV access cannot
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be established 91
 Diabetic Ketoacidosis and Hyperglycemic
Hyperosmolar State

• May be the initial symptom complex that leads to a diagnosis

of type 1 DM.
• But more frequently it occurs in individuals with established
diabetes.
• The prototypical patient with HHS is an elderly individual with
type 2 DM, with a several week history of polyuria, weight
loss, and diminished oral intake that culminates in mental
confusion, lethargy, or coma
• The physical examination reflects profound dehydration and
hyperosmolality and reveals hypotension, tachycardia, and
altered mental status.

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Pathophysiology
DKA
• DKA results from relative or absolute insulin deficiency combined
with counterregulatory hormone excess (glucagon,
catecholamines, cortisol, and growth hormone).

• Both insulin deficiency and glucagon excess, in particular, are

necessary for DKA to develop.
• Hyperglycemia develops as a result of three processes:
– increased gluconeogenesis, accelerated glycogenolysis, and
impaired glucose utilization by peripheral tissues
• Ketosis results from a marked increase in free fatty acid release
from adipocytes, with a resulting shift toward ketone body
synthesis in the liver.
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 Pathophysiology
HHS

• The pathogenesis of HHS is not as well understood as that of DKA

– Greater degree of dehydration (due to osmotic diuresis)

– Endogenous insulin secretion appears to be greater than in

DKA,

negligible Insulin levels in HHS are inadequate to facilitate

glucose utilization by insulin sensitive tissues but adequate to
prevent lipolysis and subsequent ketogenesis

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4/21/2024 BLE 95
 Precipitating Factors

 Infection - most common

 Discontinuation of or inadequate insulin therapy

 pancreatitis, myocardial infarction, cerebrovascular accident,

 drugs

 New-onset type 1 diabetes

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 Diagnostic criteria for DKA and HHS

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 Diagnostic….
– DKA is characterized by hyperglycemia, ketosis, and metabolic
acidosis (increased anion gap)

– Despite a total-body K deficit, the serum potassium at K may

be mildly elevated, secondary to the acidosis.

– Total-body stores of sodium, chloride, phosphorous, and

magnesium are also reduced in DKA but are not accurately
reflected by their levels in the serum because of dehydration
and hyperglycemia.

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Treatment

• Successful treatment of DKA and HHS requires

– Correction of dehydration, hyperglycemia, and electrolyte

imbalances;

– Identification of comorbid precipitating events,

– Frequent patient monitoring.

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Fluid therapy
• Initial fluid therapy is directed toward expansion of the
intravascular, interstitial, and intracellular volume,
– reduced in hyperglycemic crises and restoration of renal
perfusion
• Fluid replacement should initially stabilize the hemodynamic status
of the patient (1–3 L of 0.9% normal saline over the first 2–3 h).
• Choice for fluid replacement depends on
– Hemodynamics state, the state of hydration, serum electrolyte levels, and
urinary output.
• 0.45% NaCl infused at 250 –500 ml/h is appropriate if the
corrected serum sodium is normal or elevated;
• 0.9% NaCl at a similar rate is appropriate if corrected serum
sodium is low
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 • Fluid replacement should correct estimated deficits within the first
24 hr

• In patients with renal or cardiac compromise, monitoring of serum

osmolality and frequent assessment of cardiac, renal, and mental
status must be performed during fluid resuscitation to avoid
iatrogenic fluid overload

• Aggressive rehydration with subsequent correction of the HHS

has been shown in a more robust response to low-dose insulin
therapy
• Once the plasma glucose is 200 mg/dl, 5% dextrose should be
added to replacement fluids
101
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 Treatment cont…
Insulin therapy
• A reasonable regimen for HHS and DKA begins with an IV insulin
bolus of 0.1 units/kg followed by IV insulin at a constant infusion
rate of 0.1 units/kg per hour.

• If the serum glucose does not fall, increase the insulin infusion rate
by twofold.

• The insulin infusion should be continued until the patient has resumed
eating and can be transferred to a SC insulin regimen.

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 • Continuous IV infusion of regular insulin is preferred.

• Use IM route only if infusion is not available

• Bolus dose: 0.1 unit/kg IV

• Maintenance dose: 0.1 unit/kg/hr IV

• If blood glucose level has not decreased by 50–75 mg/dL after

1 hr, double infusion rate
• Once blood glucose reaches 200 mg/dL, reduce infusion rate to
0.05–0.1 unit/kg/hr and change fluid to 5% dextrose with
0.45% NaCl (do not stop insulin infusion).
• When SC insulin can be initiated, administer dose 1–2 hr before

discontinuing IV infusion.
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• Potassium

– Establish adequate renal function (urine output ∼50 mL/hr).

– If K is <3.3mEq/L, hold insulin and give 20–40 mEq/hr until

K >3.3 mEq/L

– If K is >5.5mEq/L, do not give K and check serum K Q 2 hr.

If K is >3.3 but <5.3 mEq/L, give 20–30 mEq in each liter

IV fluid to maintain K between 4–5 mEq/L.

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Protocol for management of adult patients with DKA or HHS

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Chronic Complications of DM
• Are responsible for the majority of morbidity and mortality
associated with the disease
• They can be divided into vascular and nonvascular
complications.
• The vascular complications
– Microvascular (retinopathy, neuropathy, nephropathy)
– Macrovascular complications [(CAD), (PAD), cerebrovascular
disease].
• Nonvascular complications
– gastroparesis, infections, and skin changes.
• Long-standing diabetes may be associated with hearing loss.

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• Retinopathy: Eye Examination Annually

• Nephropathy: Measure SCr and albuminuria at least annually.

– Treat with ACEI or ARB therapy.

– Microalbuminuria (albuminuria 30 to <300 mg/24 hours or

creatinine 30 to <300 mcg/mg)

– Macroalbuminuria (albuminuria ≥300 mg/24 hours or

creatinine ≥300)

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Macrovascular Complication
CAD,PAD ,Stroke
Tighter glycemic control early after DM diagnosis decreases
macrovascular complications
Neurologic:
– Peripheral neuropathy - screened annually
– Autonomic neuropathies
– (a) Gastroparesis
– (b) Erectile dysfunction
– (c) Urinary retention
– (d) Diabetic diarrhea
– (e) CV autonomic neuropathy (e.g., orthostatic hypotension,
resting tachycardia)
– (f) Hypoglycemia unawareness
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• Neuropathic pain treatment
TCAs (amitriptyline, desipramine):
Anticonvulsants (gabapentin, lamotrigine, pregabalin):
– Pregabalin is the only anticonvulsant approved for use in DM
neuropathic pain
SSRIs/SNRIs (duloxetine, paroxetine, citalopram)
– Duloxetine is the only approved agent
• Opioids: Tapentadol extended release
– The only approved agent in this class; no head-to-head efficacy
studies
• Gastroparesis Treatment:
– Metoclopramide: 10 mg before meals.
• Risk of tardive dyskinesia or EPS
. Erythromycin: 40–250 mg before meals
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• READING ASSIGNMENT
– DIABETIC FOOT ULCER

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 Diabetes Insipidus
• Diabetes insipidus (DI) is usually a result of decreased production
of antidiuretic hormone,

– vasopressin, in central DI, or a lack of antidiuretic hormone

effect in the kidneys (nephrogenic DI)

• Diabetes insipidus is a rare disorder that causes the body to make

too much urine.

• While most people make 1 to 3 lit. of urine a day, people with

diabetes insipidus can make up to 20 lit. of urine a day

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• Classification

1. Central or neurogenic

– a. Idiopathic

– b. Trauma (brain injury)

– c. Neoplasm d. Hypodipsia e. Genetic abnormality

2. Nephrogenic

– a. Genetic abnormality

– b. Acquired (more common) i. Drug induced (e.g., lithium,

amphotericin B, foscarnet, cidofovir) ii. Kidney disease (e.g.,
polycystic kidney disease, obstruction) iii. Electrolyte disorder
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(hypercalcemia, hypokalemia
BLE 112
Signs and Symptoms

 Polydipsia

 Polyuria or nocturia

 Weakness or lethargy

 Confusion or delirium (if severe

Diagnosis

 Elevated urine volume (greater than 3 L/day)

 Decreased urine osmolarity (less than 200 mOsm/kg)

 Response to water deprivation (may help differentiate between

nephrogenic and central etiology in non–critically ill patients
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• Treatment

Treat underlying cause, if known.

2. Central DI

a. Desmopressin: 5–20 mcg intranasally once or twice daily

b. Adjunctive therapies: Chlorpropamide, carbamazepine

3. Nephrogenic DI

a. Thiazide diuretic

b. Dietary sodium restriction

c. Indomethacin
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 Thank you!!!

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