Diabetes Mellitus

By:
Zenebe N.(B Pharm, M Pharm)
May, 2022

1
 Learning objectives
Upon completion of this chapter, students will
be able to:
Distinguish the clinical differences b/n type 1, type 2, and GDM

Discuss therapeutic goals for BGL, BP, and lipids for a pts with DM

Compare oral agents used in treating DM by their mechanisms of action,

time of action, SEs, CIs, and effectiveness.

 Select appropriate insulin therapy based on onset, peak, and DOA.

Discuss signs, symptoms, and treatment of hypoglycaemia.

You will understand the different complications and its treatments.

Monitoring parameters 2
Myths and misconception

3
 Introduction
• DM a group of chronic metabolic disorder or as well as altered
carbohydrate, fat and protein metabolism characterized by
hyperglycaemia that results from defects in insulin secretion, insulin
resistance (sensitivity) or both, and result in long-term
microvascular, and microvascular complications
• These complications contribute to DM being the leading cause of:
 New cases of blindness among adults
End-stage renal disease, non-traumatic lower limb
amputations
• DM complications can be delayed or prevented through proper
BGL management 4
 Epidemiology of DM
• In 2017, it was estimated that 425 million people (20–79
years of age) suffered from DM, and the number is expected
to rise to 629 million by 2045.

• In 2016, an estimated 1.6 million deaths were directly caused

by diabetes.

• Diabetes is a major cause of blindness, kidney failure, heart

attacks, stroke and lower limb amputation

• There were 2,567,900 cases of diabetes in Ethiopia in 2015

and prevalence is 5.2%
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 Pathophysiology
• Type 1 DM
 Caused by an absolute deficiency of insulin

 Accounts for 5% to 10% of all diabetes cases.

 It generally develops in childhood or early adulthood
 It can occur at any age and results from autoimmune
destruction of pancreatic β-cells, resulting in an absolute
deficiency of insulin.
 The factors that initiate autoimmune process are
unknown, but the process is mediated by macrophages
and T lymphocytes with circulating autoantibodies to various
β-cell antigens (e.g., islet cell antibody, insulin antibodies).
6
 There is a long preclinical period (up to 9 to 13
yrs) marked by the presence of immune markers
when β-cell destruction is thought to occur
 Hyperglycemia occurs when 80% to 90% of β-
cells are destroyed.
 There is a transient remission (“honeymoon”
phase) followed by established dx with
associated risks for complications and death.
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8
 Type 2 DM
 Accounts for as many as 90% of DM cases
 Is usually characterized by presence of both insulin
resistance (is considered as a pathological condition in
which cells fail to respond normally to hormone insulin)
 Relative insulin deficiency that is insufficient to normalize
plasma glucose levels, with a progressive loss of β-cell
over time (People with type 2 DM lose approximately 5% to
7% of β-cell function per year)
 Insulin resistance is manifested by:
 Increased lipolysis and free fatty acid production,
 Increased hepatic glucose production, and
 Decreased skeletal muscle uptake of glucose 9
 Cont.……
 β-Cell dysfunction is progressive and contributes to worsening
blood glucose control over time.
 Type 2 DM occurs when a diabetogenic lifestyle is superimposed
upon a susceptible genotype, such as:

 Excessive calories,
 Inadequate exercise (sedentary life), and
 Obesity
 Most individuals with type 2 diabetes exhibit abdominal
obesity, which is the major contributor to insulin resistance
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11
 Gestational Diabetes Mellitus (GDM)
• GDM is defined as Impaired glucose intolerance
which is first recognized during pregnancy
• Hormone changes during pregnancy result in
increased insulin resistance
• In most, glucose intolerance first appears near the
beginning of the third trimester.
• Most women become normoglycemic after pregnancy;
however, 30% to 50% of these women develop type 2
DM later in life

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Other Specific Types of Diabetes (Less Than 5% of
Diabetes)
 Endocrine disorders (e.g., acromegaly, Cushing’s
syndrome),

 Dx of the exocrine pancreas (e.g., pancreatitis),

 Medications (e.g., glucocorticoids, niacin, and α-
interferon).

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 Clinical presentation
• TYPE 1 DIABETES MELLITUS
• Individuals with type 1 DM are often thin and are
prone to develop diabetic ketoacidosis (DKA) if
insulin is withheld or under conditions of severe
stress with an excess of insulin counterregulatory
hormones.
• Between 20% and 40% of pts present with DKA
after several days of polyuria, glucosuria,
polydipsia, polyphagia, and weight loss.
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 TYPE 2 DIABETES MELLITUS

• Pts with T2DM are often asymptomatic and may be

diagnosed 20 to unrelated blood testing.

• However, the presence of complications may

indicate that they have had DM for several yrs.

 Lethargy, polyuria, nocturia, and polydipsia can

be present on diagnosis; significant weight loss
is less common.
15
Classical Clinical Presentation of DM

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 Screening
• Screening for type 2 DM should be performed every 3
yrs in all adults beginning at the age of 45.

• Testing should be considered at an earlier age and

more frequently in individuals with risk factors (e.g.,
family hx of DM, obesity, signs of insulin resistance).

• The recommended screening test is a fasting

plasma glucose (FPG).

• Normal FPG: is less than 99 mg/dL (5.6 mmol/L). 17

 Diagnostic test of DM
Normal Prediabetes Diabetes

RBS <115 mg/dl - >200 mg/dl

FBS 70-99 mg/dl 100-125 mg/dl ≥126 mg/dl

2hr OGTT <140 mg/dl 140-199 mg/dl ≥200 mg/dl

HgbA1c 4-5.7 % 5.7 -6.4 % ≥ 6.5%

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• The hemoglobin A1c test tells the average level
of blood sugar over the past 2 to 3 months
• An HbA1c of 6.5% is recommended as the cut point for
diagnosing diabetes.

• Fasting is defined as no caloric intake for at least 8 hrs.

• OGTT: The test should be performed as described by the
WHO, using a glucose load containing the equivalent of
75 g anhydrous glucose dissolved in water.

• OGTT is not recommended for routine clinical use.

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Screening for and Diagnosis of Gestation
al Diabetes Mellitus (GDM)

1. One-step method (fasting 75-g OGTT)

One abnormal value is diagnostic of GDM

Time Plasma Glucose

Fasting ≥92 mg/dL (5.1 mmol/L)
1 hour ≥180 mg/dL (10.0 mmol/L)
2 hours ≥153 mg/dL (8.5 mmol/L)
5/19/2022 20
2. Two-step method

Step 1: Perform a 50-g OGTT (nonfasting) at 24-28 weeks of gestation in

women not previously diagnosed with diabetes.

1 hour value ≥140 mg/dL (7.8 mmol/L)

Step 2: If screening test is positive, perform 100-g OGTT (fasting).

Two or more abnormal values are diagnostic for GDM

Time Carpenter/Coustan National Diabetes Data Group

Fasting 95 mg/dL (5.3 mmol/L) 105 mg/dL (5.8 mmol/L)
1 hour 180 mg/dL (10.0 mmol/L) 190 mg/dL (10.5 mmol/L)
2 hours 155 mg/dL (8.6 mmol/L) 165 mg/dL (9.2 mmol/L
3 hours 140 mg/dL (7.8 mmol/L) 145 mg/dL (8.0 mmol/L)
American Diabetes Association. Classification and Diagnosis of Diabetes. Diabetes Care. 2015;38(Suppl 1):S8-S16.
5/19/2022 21
Case
GH is a 56-year-old African American man who
presents to his physician for a follow-up appointment
for HTN. Upon questioning, GH states that he has
noticed more frequent trips to the bathroom than
usual and his appetite has substantially increased. He
denies much physical activity, although he has lost
approximately 6.8 kg since his last visit 6 months ago.
He is concerned about developing diabetes and heart
disease like both of his parents.
PMH: hypercholesterolemia, hypertension
FH: Father has diabetes, hypertension, and a hx of MI
at age 54 years; mother has diabetes and a history of
stroke at age 70 years. 22
SH: Smokes ½ pack per day for 20 years; denies alcohol or
illicit drug use
Meds: HCT 25 mg/d, Simvastatin 20 mg/
VS: BP 134/85 mm Hg, P 82 beats/min, RR 20, T 38°C
(100°F)
height: 190.5 cm Weight:129.5 kg
ROS: (+) Fatigue, (-) N/V/D, HA, SOB, chest pain
What risk factors does this patient have for diabetes?
Which type of diabetes does his characteristics suggest?
What additional information is needed to diagnose this patient
with diabetes?

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• GH returns in 3 days with results of his fasting blood work requested
by his physician. The physician also requests that his blood glucose
level A1c, and vital signs be obtained again today. The results are listed
below.
VS: BP 122/76 mm Hg, P 70 beats/min, RR 19, A1c (today): 7.9%
(0.079; 63 mmol/mol Hb) FpG (today): 189 mg/dL (10.5 mmol/L)
Labs (2 days ago)
• Na: 136 mEq/L (136 mmol/L)

• K: 3.6 mEq/L (3.6 mmol/L)

• BUN: 15 mg/dL (5.4 mmol/L)

• SCr: 1.3 mg/dL (115 µmol/L)

• Glu: 172 mg/dL (9.5 mmol/L)

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• GH is diagnosed with T2DM. Identify the goals of treatment
for this patient.

• What non-pharmacologic and pharmacologic alternatives

are available for this patient for his diabetes?

• What is the most appropriate initial therapy for this patient in

regards to his diabetes?

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 Treatment
DESIRED OUTCOME

 To ameliorate symptoms of hyperglycaemia,

 Reduce the onset and progression of
microvascular and macrovascular complications,

 Reduce mortality, and Improve quality of life.

 Minimizing weight gain and hypoglycaemia

especially severe hypoglycemia
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 GENERAL APPROACH

• Near-normoglycemia reduces the risk of

microvascular dx complications
• Aggressive mgt of traditional cardiovascular risk
factors (i.e., smoking cessation, treatment of
dyslipidemia, intensive BP control, antiplatelet
therapy) is needed to reduce macrovascular
disease risk.
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 Non-pharmacologic Therapy
 Medical nutrition therapy is a cornerstone of
treatment for all patients with DM
 A meal plan that is moderate in carbohydrates and low in
saturated fat, with a focus on balanced meals is
recommended.
 Physical activity
 For individuals with type 1 DM, the focus is on
regulating insulin administration with a balanced diet
to achieve and maintain a healthy body weight.
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 Non-pharmacologic Therapy…….

• Aerobic exercise can improve insulin resistance and

glycemic control in most pts and may reduce cardiovascular
risk factors

• Exercise should be started slowly in previously sedentary

pts.

• Older pts and those with atherosclerotic dx should have a

cardiovascular evaluation prior to beginning a substantial
exercise program
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 PHARMACOTHERAPY OF TYPE 1 DM
 All pts with type I DM require insulin, but the type
and manner of delivery differ considerably among
individual pts and clinicians.
 Therapeutic strategies should attempt to match
carbohydrate intake with glucose-lowering processes
(usually insulin) and exercise.
 Dietary intervention should allow the pt to live as
normal a life as possible.
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• The timing of insulin onset, peak, and duration of effect
must match meal patterns and exercise schedules to
achieve near-normal blood glucose values throughout the
day.

• A regimen of two daily injections that may roughly

approximate physiologic insulin secretion is split-mixed
injections of a morning dose of NPH insulin and regular
insulin before breakfast and again before the evening
meal.

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32
 This assumes that morning NPH insulin provides basal
insulin for the day and covers the midday meal, the morning
regular insulin covers breakfast, the evening NPH insulin
gives basal insulin for the rest of the day, and evening
regular insulin covers the evening meal.

 Most pts require total daily doses of 0.5-1 units/kg/day.

 Pts may be started on 0.6 units/kg/day, with two-thirds
given in the morning and one-third in the evening.
 NPH should comprise two-thirds of the morning dose and
one-half of the evening dose.

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 Cont.….
• The basal-bolus injection concept attempts to
replicate normal insulin physiology by giving
intermediate or long-acting insulin as the basal
component and short-acting insulin as the bolus
portion.

 The basal insulin component may be provided by twice-

NPH, once daily detemir and glargine

 The bolus insulin component is given before meals with

regular insulin, insulin lispro, insulin aspart, or insulin
glulisine. 34
 Cont…

• This permits more convenient dosing within 10 min of

meals (rather than 30 min prior), produces better
efficacy in lowering postprandial blood glucose than
regular insulin in type 1 DM,

• Regular insulin has a relatively slow onset of action

when given SC, requiring injection 30 min prior to
meals to achieve optimal postprandial glucose control
and to prevent delayed postmeal hypoglycemia
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Pharmacokinetics of Various Types of Insulins
Administered Subcutaneously

5/19/2022 36
SEs of Insulin
 Hypoglycemia
 Weight gain
 Lipodystrophy: is an abnormal distribution of fat in
the body

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 Hypoglycemia(<70 mg/dl):
is a condition
characterized by abnormally low blood glucose, which in
extreme cases can lead to unconsciousness and death
 Signs include hunger, nervousness, shakiness,
perspiration, dizziness or light-headedness, sleepiness and
confusion.

Treatment of hypoglycemia is as follows:

✓ Glucose (10 to 15 g) given po is the recommended
treatment in conscious pts.
✓ Dextrose IV may be required in individuals who have lost
consciousness.
✓ Glucagon, 1 g im, is the treatment of choice in
unconscious pts when IV access cannot be established.
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 Quiz

1. What are the difference between type 1 and type 2

DM(at least 5 difference)

2. What are the four cut of points for diagnosis of

DM?

3. List at least 4 risk factors for T2DM?

4. What is basal-bolus injection concept ?

5. What are the goal of therapy in T2DM patients?

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 PHARMACOTHERAPY OF TYPE 2
DM
• Symptomatic pts may initially require insulin or combination
oral therapy to reduce glucose toxicity (which may reduce β-
cell insulin secretion and worsen insulin resistance)
• Pts with A1C of about 7% or less are usually treated with
therapeutic lifestyle measures with or without an insulin
sensitizer.
• Those with A1C >7% but <8.5 % are initially treated with a
single oral agent or combination therapy
• Patients with higher initial A1C values may benefit from initial
therapy with two oral agents or insulin

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• Near-normal-weight pts may be treated with insulin
secretagogues, increase insulin secretion.

• Failure of initial therapy should result in addition of another

class of drug.

• Substitution of a drug reserved for drug intolerance.

• Metformin and an insulin secretagogue are often first and
second-line therapy.

• Virtually all pts ultimately become insulinopenic, that

require insulin therapy. 41
• Insulin sensitizers are commonly used with insulin
because most pts are insulin resistant.

• When combination of bedtime insulin plus daytime oral

medications fails, a conventional multiple daily dose
insulin regimen with an insulin sensitizer can be tried.

• Because of the variability of insulin resistance, insulin

doses may range from 0.7 to 2.5 units/kg/day or more.

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 Considerations When Selecting Pharmacotherapy for Type 2 Diabetes
A1C Hypoglyc
Medication Primary Physiologic Effect ASCVD Oral Adverse Effects
Reduction emia Cost
class Action on Wt Effects /SC and Safety
Efficacy Riska
↓ hepatic glucose Potential GI (diarrhea), B12
Metformin High No Neutral Low Oral
production benefit deficiency
Hypoglycemia,
SUs ↑ insulin secretion High Yes Gain Neutral Low Oral
weight gain
Potential Edema, weight gain, risk of heart
TZDs ↑ insulin sensitivity High No Gain benefit Low Oral failure, bone
(pioglitazone) fractures, bladder cancer
↑ insulin secretion
Risk of heart
DPP-4 (glucose dependent); Intermedi
No Neutral Neutral High Oral failure, pancreatitis,
inhibitors ↓ glucagon secretion ate
joint pain
(glucose dependent)
Blocks glucose Benefitb GU infections, risk of volume
SGLT-2 reabsorption by the Intermedi (empagliflozin depletion, hypotension, risk of
No Loss High Oral
inhibitors kidney, increasing ate , amputations, bone fractures
glucosuria canagliflozin) (canagliflozin), risk of DKA
↑ insulin secretion
(glucose dependent);
Benefitb GI (nausea, vomiting), injection
↓ glucagon secretion
(liraglutide, SC/ site reactions, risk of thyroid C-
GLP-1 RAs (glucose dependent); High No Loss High
semaglutide Oral cell tumors, pancreatitis,
slows gastric
dulaglutide) cholelithiasis
emptying;
↑ satiety

↑ glucose disposal;
Hypoglycemia,
↓ hepatic glucose
Basal weight gain,
production; High Yes Gain Neutral High SC
Insulin injection site
suppresses
reactions
ketogenesis
5/19/2022 43
 Sulfonylureas
• Sulfonylureas exert a hypoglycemic action by
• stimulating pancreatic secretion of insulin.
• All sulfonylureas are equally effective in lowering
blood glucose when administered in equipotent
doses.

• On average, the A1C will fall by 1.5% to 2% with

FPG reductions of 60 to 70 mg/dL .

44
Sulfonylureas for the Treatment of
Type 2 DM

45
 Cont.………..
• Most common side effect is hypoglycemia,

• Individuals at high risk include:

 Elderly
 Those with renal insufficiency or advanced liver
disease and

 Those who skip meals, exercise vigorously,

or lose a substantial amount of weight.
46
Side Effects

• Weight gain is common SE of

sulfonylurea
• less common adverse effects include skin rash,
hemolytic anemia, GI upset, and cholestasis.

• The recommended starting doses should be

reduced in elderly pts who may have
compromised renal or hepatic function.

• Dosage can be titrated every 1 to 2 wks 47

 Biguanides
• Metformin is the only biguanide currently available.

• It enhances insulin sensitivity of both hepatic and

peripheral (muscle) tissues.
• This allows for increased uptake of glucose into these
insulin sensitive tissues.

• Metformin consistently reduces A1C levels by 1.5% to 2%,

FPG levels by 60 to 80 mg/dL, and retains the ability to
reduce FPG levels when they are very high (>300 mg/dL).

48
• It reduces plasma triglycerides and LDL by 8% to
15% and modestly increases HDL 2%.

• It does not induce hypoglycemia when used alone.

• Metformin should be included in the therapy for all

type 2 DM pts (if tolerated and not contraindicated)
because it is the only oral antihyperglycemic
medication proven to reduce the risk of total mortality
and cardiovascular death. 49
• Most patients with type 2 DM are initially treated
with metformin due its long track record of use in
clinical practice, efficacy, weight neutrality, low risk
of hypoglycemia, and low cost
• The most common adverse effects:
• Abdominal discomfort, stomach upset, diarrhea,
anorexia, and a metallic taste.
 These effects can be minimized by titrating the dose
slowly and taking it with food.
 Extended release metformin (Glucophage XR) may
reduce some of the GI side effects.
50
 Lactic acidosis occurs rarely and can be minimized by
avoiding its use in pts with renal insufficiency (eGFR
< 30 mL/min/1.73 m2), congestive heart failure, or
conditions predisposing to hypoxemia or inherent lactic
acidosis.
 Due to the risk of acute renal failure when IV contrast
dye is used during imaging procedures,
 metformin therapy should be withheld starting the day of
the procedure and resumed 2 to 3 days later, if normal
renal function has been documented.

 It need not be withheld for days prior to the procedure.

51
Metformin is renally excreted and accumulates in patients
with renal insufficiency;
Therefore, metformin is contraindicated in patients with
an eGFR < 30 mL/min/1.73 m2 and should be used with
caution in patients with milder renal insufficiency.

 Initiation of metformin is not recommended in patients

with an eGFR 30-45 mL/min/1.73 m2 but can be continued
with increased renal function monitoring; a dose reduction
of 50% of maximal dose may be warranted.

5/19/2022 52
• Metformin immediate-release is usually initiated at
500 mg bid with the largest meals and increased by
500 mg wkly until glycemic goals or 2,000
mg/day is achieved.

• Metformin 850 mg can be dosed once daily and

then increased every 1 to 2 wks to a maximum of
850 mg three times daily (2,550 mg/day).
53
 Thiazolidinediones (Glitazones)

• These agents activate PPAR-γ, a nuclear

transcription factor important in fat cell
differentiation and fatty acid metabolism.

• PPAR-γ agonists enhance insulin sensitivity in

muscle, liver, and fat tissues indirectly.

• Insulin must be present in significant quantities

for these actions to occur.
54
• When given for about 6 months, pioglitazone and
rosiglitazone reduce A1C values by about 1.5% and FPG
levels by about 60 to 70 mg/dL at maximal doses.
• Maximal glycemic-lowering effects may not be seen until
3 to 4 mths of therapy.
• Monotherapy is often ineffective unless the drugs are given
early in the disease course when sufficient β-cell function
and hyperinsulinemia are present.

55
 Pioglitazone decreases plasma triglycerides by 10% to
20%, whereas rosiglitazone tends to have no effect.

 Side effects

• Fluid retention may occur

• Weight gain (1.5 - 4 Kg) is dose related:

 Rarely, rapid gain of a large amount of weight may
necessitate discontinuation of therapy.

 Weight gain positively predicts a larger A1C reduction

• but must be balanced with long term weight gain.
56
• Hepatotoxicity
 The drugs should be discontinued if the ALT is more
than 3 times the upper limit of normal.
• Pioglitazone (Actos) is started at 15 mg once daily. The
maximum dose is 45 mg/day.
• Rosiglitazone (Avandia) is initiated with 2 to 4 mg once
daily. The maximum dose is 8 mg/day.
• A dose of 4 mg twice daily can reduce A1C by 0.2% to
0.3% more than a dose of 8 mg taken once daily.
57
Glucagonlike Peptide 1 Receptor Agonists (GLP1RAs)

 Dulaglutide, exenatide, exenatide XR, lixisenatide,

liraglutide, and semaglutide
Stimulate insulin secretion and suppress inappropriately
high postprandial glucagon secretion, decreasing hepatic
glucose output.
Also slow gastric emptying, increase satiety, and cause
weight loss (ave 1–3 kg).
 2nd line agents for patients with established ASCVD or CKD
 Used in combination with metformin, TZDs, SUs, SGLT2
inhibitors, and basal insulin.
 The most common adverse effects of GLP1RAs are nausea,
vomiting, and diarrhea.

5/19/2022 58
 Dipeptidyl Peptidase-4 (DPP4) Inhibitors

Alogliptin, Linagliptin, Saxagliptin, Sitagliptin and

Vildagliptin
Prolong the half-life of endogenously produced GLP1 and
GIP, thereby
Increasing glucose dependent insulin secretion from the
pancreas and
Reducing inappropriate postprandial glucagon secretion,
Resulting in lower glucose levels without an increase in
hypoglycemia when used as monotherapy.
They do not alter gastric emptying, cause nausea, have
significant effects on satiety, or cause weight gain/loss.
Produce average A1C reductions of 0.5%–0.9% when used at
max doses.

5/19/2022 59
 DPP-4 Inhibitors……….
• DPP4 inhibitors are considered 2nd or 3rd therapy.
• Advantages include once daily dosing, oral administration,
weight neutrality, low risk of hypoglycemia, and good
tolerability.
• Adverse effects are uncommon and include stuffy, runny
nose; headache; and upper respiratory tract infections.
• The labeling of saxagliptin and alogliptin includes
information about increased risk of hospitalizations for HF.
• The FDA has also issued a warning on the risk of severe
joint pain with DPP4 inhibitors.
• Pancreatitis appears to be an established but rare safety
concern.

5/19/2022 60
 Sodium-Glucose Co-transporter-2 Inhibitors

Canagliflozin, Dapagliflozin, Empagliflozin, and Ertugliflozin

Reduce plasma glucose by preventing the kidneys from
reabsorbing glucose back into the bloodstream, leading to
increased glucose excretion in the urine.
Lower both FPG and PPG and are effective even in the
absolute absence of insulin.
Reduce a1c by 0.5%–1% and appear to be more effective
in patients with higher baseline A1C levels.
Renal impairment decreases the efficacy of SGLT2
inhibitors

5/19/2022 61
 SGLT2 inhibitors……
2nd line agents that can be added to metformin or other 2nd
line agents.
Recommended for patients with established ASCVD or CKD
and those with a need to avoid hypoglycemia or weight gain
or loss.
The most common adverse effect is genital mycotic
infections, which are more common in women and
uncircumcised men.
Polyuria, dehydration, dizziness, or hypotension may occur
because of the osmotic diuresis effects.
Older adults and patients with stage 4 or 5 CKD are not
optimal treatment candidates.
should be started at a low dose with assessment of volume
status, adverse effects, and renal function.
5/19/2022 62
 Dosing Recommendations for Oral
Medications Used to Treat Type 2 DM
Generic (Brand) Starting Dose Usual Maximal Dosing/Use in Renal
a
Name Recommended dose Insufficiency
Dose (mg/day)
Biguanides
Metformin 500 mg QD or BID or 850 1000 mg 2550 Do not initiate if eGFR 30–45;
(Glucophage) mg QD, titrate to target BID Do not use if eGFR <30
dose as tolerated
Metformin XR 500–1000 mg QD, titrate 2000 mg 2500 Do not initiate if eGFR 30–45;
to target dose as QD Do not use if eGFR <30
tolerated
Sulfonylureas (first generation)
Chlorpropamide 250 mg QD (100 100–500 mg 750 Consider alternative agent or initiate
mg QD in older QD conservatively at 100 mg in renal
adults) insufficiency to avoid hypoglycemia
Tolazamide 250 mg QD(100 mg 250–500 mg 1000 Consider alternative agent or initiate
QD in older adults QD conservatively at 100 mg in renal
or if FPG <200 insufficiency to avoid hypoglycemia
mg/dL)
Tolbutamide 1000–2000 mg 1000–2000 3000 Consider alternative agent or initiate
QD(250–500 mg QD mg QD conservatively in renal insufficiency
5/19/2022 in older adults) to avoid hypoglycemia 63
Sulfonylureas (second generation)
Glimepiride 1–2 mg QD(1 mg QD in 4 mg 8 Initiate conservatively at 1 mg in renal
(Amaryl) older adults) QD insufficiency to avoid hypoglycemia
Glipizide 5 mg QD(2.5 mg daily in 5–10 40 Initiate conservatively at 2.5 mg in renal
(Glucotrol) older adults) mg QD insufficiency to avoid hypoglycemia
Glipizide XL 5 mg QD(2.5 mg QD in 5–10 20 Initiate conservatively at 2.5 mg in renal
(Glucotrol XL) older adults) mg QD insufficiency to avoid hypoglycemia
Glyburide 2.5–5 mg QD(1.25 mg 5–10 20 Consider alternative agent or initiate
(Diabeta) QD in older adults) mg QD conservatively at 1.25 mg in renal
insufficiency to avoid hypoglycemia
Glyburide 1.5–3 mg QD(0.75 mg 3–6 mg 12 Consider alternative agent or initiate
micronized QD in older adults) QD conservatively at 0.75 mg in renal
(Glynase) insufficiency to avoid hypoglycemia
Meglitinides
Nateglinide 120 mg TID before 120 mg TID 360 No adjustment required
(Starlix) meals before meals
Repaglinide 1–2 mg TID before 2–4 mg ITD 16 Initiate conservatively at 0.5
(Prandin) meals (0.5 mg before before meals mg before meals if CrCl 20–
meals if A1C <8%) 40 mL/min)
Thiazolidinediones
Pioglitazone (Actos) 15 mg QD 30 mg QD 45 No dose adjustment required
Rosiglitazone 4 mg QD or in 4 mg QD or in 8 No dose adjustment required
(Avandia)
5/19/2022
two divided doses two divided doses 64
α-Glucosidase inhibitors
Acarbose (Precose) 25 mg QD to TID with the first 50 mg QD to TID with 300 Avoid if CrCl <25 mL/min
bite of a meal meals
Miglitol (Glyset) 25 mg QD to TID with the first 50 mg QD to TID with 300 Avoid if CrCl <25 mL/min
bite of a meal meals
Sodium-glucose transporter (SGLT)-2 inhibitors
Canagliflozin (Invokana) 100 mg QD, taken before 100–300 mg QD 300 100 mg QD if eGFR 45–60;
the first meal of the day Avoid if eGFR <45
Dapagliflozin (Farxiga) 5 mg QD in the morning 5–10 mg QD 10 Avoid if eGFR <60
Empagliflozin (Jardiance) 10 mg QD in the morning 10–25 mg QD 25 Avoid if eGFR <30
Ertugliflozin (Steglatro) 5 mg QD in the morning 5–15 mg QD 15 Avoid if eGFR<60
Dipeptidyl peptidase (DPP)-4 inhibitors
Alogliptin (Nesina) 25 mg QD 25 mg QD 25 12.5 mg QD if CrCl 30–60 mL/min; 6.25
mg QD if CrCl <30 mL/min
Linagliptin (Tradjenta) 5 mg QD 5 mg QD 5 No dose adjustment needed
Saxagliptin (Onglyza) 2.5–5 mg QD 5 mg QD 5 2.5 mg QD if eGFR ≤50
Sitagliptin (Januvia) 100 mg QD 100 mg QD 100 50 mg QD if eGFR 30–50;
25 mg QD if eGFR <30
Vildagliptin(Galvus) 50 mg QD morning 50 mg BID 100 No dose adjustment needed

Bile acid sequestrants

Colesevelam 1.875 g BID or 3.75 g QD 1.875 g BID or 3.75 g QD 3.75 g/day No dose adjustment
(Welchol) with meals with meals needed
Dopamine agonists
Bromocriptine 0.8 mg QD, taken within 2 hours after 1.6–4.8 mg QD 4.8 No dose adjustment
(Cycloset)
5/19/2022
waking in the morning with food needed 65
 Case 1 continuation
• GH returns in 1 month for a follow-up visit. He brings his blood
glucose readings from the past week for review in addition to
more fasting blood work. Blood glucose readings are in units
of mg/dL (mmol/L). His most recent medication list is below.
There are no changes to his health record from previous visits.
• Medications:
• Hydrochlorothiazide 25 mg by mouth once daily
• Simvastatin 20 mg by mouth once daily
• Metformin 500 mg by mouth twice daily
• VS: BP 154/96 mm Hg, P 78 beats/min, RR 18, T 38°C (100°F)
• A1c: 7.3%

67
Labs
• Total cholesterol: 240 mg/dL (6.2 mmol/L)
• HDL: 41 mg/dL (1.06 mmol/L)
• LDL: 163 mg/dL (4.22 mmol/L)
• TG: 183 mg/dL (2.07 mmol/L)
• AST: 28 U/L (0.47 µKat/L)

68
 Cont.….

• Are this patient’s blood glucose levels within target?

• What pattern seems to be established?

• What additional drug the patients need??

• Monitoring parameters to assess safety and efficacy

• Glyemic goal ???????

69
TREATMENT OF
COMPLICATIONS

70
 Complications of DM
• Acute complications of DM
 DKA and HHS
• Chronic complication of DM
 Microvascular complication

• Retinopathy, Nephropathy, Neuropathy

 Macrovascular complications
• Coronary artery disease, Peripherial vascular
disease and Cerebrovascular disease (stroke)
71
5/19/2022 72
 Diabetic retinopathy
• Diabetic retinopathy is caused by microcirculation ischemia
coupled with inappropriate growth factor release in the retina.
• This can weaken and damage the small blood vessels within
the retina, it becomes leaky.
• Pts with established retinopathy should be examined by an
ophthalmologist at least every 6 to 12 months.
• Early retinopathy may reverse with improved glycemic
control.
• Laser photocoagulation has markedly improved sight
preservation
• Uses heat from a laser to seal or destroy abnormal, leaking blood
vessels in the retina
 Intravitreal antivascular endothelial growth factor (VEGF)
therapy is also highly effective for sight preservation.
 Bevacizumab (used offlabel) and ranibizumab are antiVEGF monoclonal antibodies,
73
and aflibercept is a VEGF decoy receptor.
Diabetic retinopathy

74
 Diabetic neuropathy
• Peripheral neuropathy is most common complication in
T2DM patients.
 Neuropathy in diabetes can generally be placed into
three categories:
 Peripheral neuropathy: decrease blood supply
and nerve damage result in ulcer and finally
amputation
 Autonomic neuropathy: Gastroparesis can be
severe and debilitating.
 Paresthesias, perceived hot or cold, numbness
and pain may be predominant
75
 Diabetic neuropathy
 The feet are involved far more often than the hands.

 Improved glycemic control may alleviate some of

symptoms.
 Pharmacologic therapy is symptomatic and empiric
includes:
– Tricyclic antidepressants and anticonvulsants (e.g.,
gabapentin, pregabalin , carbamazepine),
duloxetine, venlafaxine, topical capsaicin, and
various analgesics, including tramadol and
NSAIDs. 76
Gastroparesis can be severe and debilitating.
Improved glycemic control, discontinuation of
medications that slow gastric motility, and use of
metoclopramide or low dose erythromycin may be helpful.
Diabetic diarrhea is often nocturnal and frequently
responds to a 10 to 14 day course of an antibiotic such as
doxycycline or metronidazole.
Octreotide may be useful in unresponsive cases.
Orthostatic hypotension may require
mineralocorticoids (eg, fludrocortisone) or adrenergic
agonists (midodrine).
Erectile dysfunction is common, and initial therapy
should include a trial of an oral PDE 5 inhibitor (eg,
sildenafil, vardenafil, or tadalafil).

5/19/2022 77
 Nephropathy
• Glucose and BP control are most important for
prevention of nephropathy, and BP control is most
important for retarding the progression of established
nephropathy.
• ACEI/ARBs have shown efficacy in preventing the clinical
progression of renal disease in pts with type 2 DM.
The ADA recommends a BP goal <140/90 mm Hg in patients
with nephropathy but a lower target (eg, <130/80) if it can
be achieved without undue burden or side effects.
• Diuretics are frequently necessary due to volume-expanded
states and are recommended second-line therapy.
78
 Peripheral Vascular Disease and
Foot Ulcers
• Claudication and non-healing foot ulcers are common in
type 2 DM.

• Smoking cessation, correction of dyslipidemia, and

antiplatelet therapy are important treatment strategies.

• Local debridement and appropriate footwear and foot

care are important in the early treatment of foot lesions.

• Topical treatments may be beneficial in more advanced

lesions. 79
 Coronary Heart Disease
• Multiple-risk-factor intervention (treatment of dyslipidemia and
hypertension, smoking cessation, antiplatelet therapy) reduces
macrovascular events.

• DM is CHD risk equivalent, and the goal LDL cholesterol should

be <100 mg/dL.
• An optional LDL goal in high-risk DM pts is <70 mg/dL.

• ADA recommends statin therapy, regardless of baseline

lipid or LDL-C levels in patients with documented CVD
who are over age of 40 80
Diabetic Ketoacidosis (DKA)& Hyperosmoslar
Hyperglycemia State (HHS)
 DKA and HHS are the two most serious acute life threating
complications of DM (0.2-2% mortality)
 DKA is a condition in which there is a severe deficiency of
insulin resulting in very high blood glucose.
• This is due to fat broken down as an alternative source of
energy with ketones/ketoacids as a by-product.
• Ultimately the patient end up with severe hyperglycemia
(RBS>250mg/dl), metabolic acidosis, fluid and electrolyte
abnormalities.
 HHS is a hyperglycemic emergency that occurs in T2DM due
to relative insulin deficiency and inadequate fluid intake. 81
 DKA…….
Common causes of DKA include:
 Previously undiagnosed and untreated diabetes
(T1DM)
 Interruption therapy
 Stress of intercurrent illness (e.g. infection,
myocardial infarction, stroke, surgery,
complicated pregnancy)

82
 DKA……. Clinical presentations
Symptoms
• Excessive urination
• Excessive thirst and drinking of water
• Nausea, vomiting, Abdominal pain
Signs
• Deep, Labored and fast breathing
• Low blood pressure
• Fast and weak pulse
• Alteration in mentation, confusion, coma
• Dehydration with dry skin, reduced skin turgor
• Fruity' breath (smell of acetone) in DKA

83
 Diagnosis
Investigations
• Random blood glucose : usually >300mg/dl)
• Urine glucose (usually >3+)
• Urine ketones (usually >2+)

84
DKA and HHS
 Treatment
Goal of treatment
• Replace fluid losses
• Replace electrolyte losses and restore acid-base
balance
• Replace deficient insulin
• Seek the precipitating cause and treat appropriately

86
 Management of DKA and
HHS
Fluid replacement
Initial fluid
 1000ml NS the first hour.
 Reassess for hydration status: if still severely
dehydrated, give another 1000ml NS over the next
01 hour.
Subsequent fluid: Depends on hydration status and
urine output of the patient.
 On average give about 250 mL/hr in the first 24
hrs or until patient is able to take enough oral
fluids.
 Change to D5W when RBS <250mg/dl 87
 DKA……..
Electrolyte replacement (esp. potassium)
 If initial serum K+ is below 3.3 mEq/L, hold insulin
and give K+ 20 to 30 mEq/hour IV until K+ conc. is
above 3.3 mEq/L.
 If initial serum K+ is between 3.3 and 5.3 mEq/L, give
K+ 20 to 30 mEq per liter IV fluid; maintain K+
between 4 to 5 mEq/L.
 If initial serum K+ is above 5.3 mEq/L do not give K+,
check K+ Q2 hrs.
88
Management of hyperglycemia (Insulin)

 Do not give insulin if initial serum K+ < 3.3 mEq/L;

replete K+ first.
 Insulin, 20 units of regular insulin (10 units IM, 10
units IV), followed by 5 units IM every hour in
adults, (0.1 IU/kg/h. in children) until ketoacidosis
resolves.
 Blood glucose should be checked every 1-2 hours.
 Ketoacidosis resolves SC regular insulin will be started
according to RBS (sliding scale) q4hr.
89
 Patient Case 2
J.C. a 7-year-old 30-kg was brought to the ED by her
parents because of nausea, vomiting, and a persistent
“stomach ache” secondary to the flu. For the past
week, J.C. had flu-like symptoms, resulting in a 6kg
weight loss. Initial laboratory values revealed a blood
glucose of 600 mg/dL, serum pH of 6.8 with
bicarbonate level of 13 mEq/L, plasma ketone level of
5.2 mmol/L, and positive ketonuria.
90
 Patient Case 2
J.C. was diagnosed with DKA secondary to new-onset type 1 diabetes.
In retrospect and on further questioning, J.C.’s parents realized that she
probably had symptoms as early as 4 weeks before her hospitalization.
While on a driving vacation, she drank large quantities of juice and had
to stop hourly to urinate. She began experiencing enuresis, which her
parents attributed to her increased fluid intake.
1. What signs and symptoms are consistent with the diagnosis of
T1DM?
2. What are the goals of therapy for J.C.?
3. How should J.C. be treated?
91
 Evaluation of Therapeutic
Outcomes
• The A1C is the current standard for following long-
term glycemic control for the previous 3 months.

• Pts receiving insulin should be monitored for

hypoglycemia

• Fasting lipid profiles should be obtained at each

follow-up visit if not at goal, annually if stable and at
goal, or every 2 years if the profile suggests low risk.
92
Evaluation of Therapeutic Outcomes

• Regular frequency of foot exams (each visit), urine

albumin assessment (annually), and dilated
ophthalmologic exams (yearly or more frequently
with abnormalities)
• Assessment and management of other cardiovascular
risk factors (e.g., smoking and antiplatelet therapy)
are components of sound preventive medicine
strategies.
93