1) Diabetes mellitus is a metabolic disorder characterized by hyperglycemia due to defects in insulin secretion, insulin action, or both. It is classified into type 1, type 2, gestational diabetes, and other specific types. 2) Type 1 diabetes is caused by autoimmune destruction of pancreatic beta cells leading to absolute insulin deficiency. Type 2 diabetes involves insulin resistance and relative insulin deficiency. 3) Treatment of diabetes involves lifestyle modifications, glucose monitoring, and pharmacologic therapies including insulin and various oral hypoglycemic agents. The goals of treatment are to achieve optimal glycemic control and prevent complications.

1. Diabetes Mellitus
Korinan Fanta (B. Pharm, MSc.)
Lecturer and Clinical Pharmacist
Korinan.taressa@ju.edu.et
Jimma, Ethiopia
5/11/2023 1

2. Learning Objective
1. Distinguish clinical differences between different type
of DM.
2. List risk factors of type2 DM
3. List screening and diagnostic criteria for diabetes.
4. Discuss therapeutic goals for blood glucose and blood
pressure for a patient with diabetes.
5. Recommend nonpharmacologic therapies for DM patients
6. Select appropriate insulin therapy based on onset, peak,
and duration of action.
7. Discuss the signs, symptoms, and treatment of
hypoglycemia
8. Compare oral agents used in treating diabetes by their
mechanisms of action, time of action, side effects,
contraindications, and effectiveness.
9. Define diabetic ketoacidosis and discuss treatment goals.
10. Develop a comprehensive therapeutic monitoring plan for
a patient with diabetes based on patientspecific factors.
5/11/2023 2

3. The pancreas
®The pancreas is composed of two major
types of tissues;
1. Acini (80%), secrete digestive juices into
the duodenum
2. Islets of Langerhans (2%), secrete insulin
and glucagon directly into the blood.
– These are crucial for normal regulation of
glucose, lipid, and protein metabolism
– Islets contain three major types of cells,
alpha, beta, and delta cells
® Pancreas also secretes other hormones with unknown
functions [amylin, somatostatin, and pancreatic
polypeptide] 3

4. The pancreas
4

5. The pancreatic insulin
® Produced in response to
changes in blood glucose
level.
® It is a polypeptide
containing 51 amino acids
arranged in two chains (A
and B) linked by disulphide
bridge.
@ C peptide binds to a
membrane structurer and
elicits
 Sodium-potassium adenosine
triphosphatase and
5

6. • Hyperglycemia results in
increased intracellular
ATP levels closes the ATP-
dependent K channels.
• Decreased outward K
current through this
channel results in
depolarization of the β cell
and opening voltage–
dependent Ca channels.
• The resultant influx of Ca
triggers the release of
The pancreatic insulin
6

7. 7

8. 5/11/2023 8

9. Diabetes Mellitus
® Diabetes mellitus (DM) is a group of
metabolic disorders characterized by
hyperglycemia.
that results from defects in insulin secretion,
insulin action (sensitivity), or both
® There is also concomitant alteration of fat
and protein metabolism.
5/11/2023 9

10. DM CLASSIFICATION
Diabetes can be classified into the following general
categories:
1. Type 1 diabetes
 Due to autoimmuneb-cell destruction, usually leading to
absolute insulin deficiency)
2. Type 2 diabetes
 Due to a progressive loss of b-cell insulin secretion
frequently on the background of insulin resistance)
3. Gestational diabetes mellitus (GDM)
 Diabetes diagnosed in the second or third trimester of
pregnancy that was not clearly overt diabetes prior to
5/11/2023 10

11. Classification….
4. Specific types of diabetes due to other causes, e.g.,
 Monogenic diabetes syndromes
 Neonatal diabetes
 Maturity-onset diabetes of the young [MODY]),
 Diseases of the exocrine pancreas
 Cystic fibrosis and
 Pancreatitis
 Drug- or chemical-induced diabetes
 Glucocorticoid use, in the treatment of HIV/AIDS, or
after organ transplantation)
5/11/2023 11

12. DM CLASSIFICATION
Type 1 DM
® Caused by an absolute deficiency of insulin due to
 Autoimmune destruction of the β-cells of the pancreas
® Most commonly presents in children and adolescents;
 however, it can occur at any age.
® Typically present with symptoms (the 4 P) and
ketoacidosis
® No micro or macrovascular complication at first
diagnosis
® It account for 5-10% all DM cases
® Treated by exogenous insulin replacement
5/11/2023 12

13. DM classification…
Type 2 DM
® Combination of some degree of insulin
resistance with a relative lack of insulin
secretion
 With a progressive loss of β-cell over time they become insulin
dependent
® Most of type 2 dm patients have risk factors such
as
 Abdominal obesity
 Hypertension
 Dyslipidemia
 Elevated level of plasminogen activator inhibitor-1 (PAI-
1)
® Type 2 diabetes has a strong genetic predisposition
5/11/2023 13

14. DM Classification…
® Patients with type 2 diabetes are asymptomatic for long term
or present with HHS
® Type 2 DM patients are at increased risk of developing :
 Macrovascular complications
 Microvascular complications
Gestational diabetes mellitus (GDM)
® glucose intolerance which is first recognized during pregnancy
Other Specific Types of DM (<5%DM)
® Genetic defects of β-cell function/ insulin action, Diseases or
drugs
5/11/2023 14

15. 5/11/2023 15

16. EPIDEMIOLOGY
® 34.2 million Americans—just over 1 in 10—have
diabetes.
® 88 million American adults—approximately 1 in 3—
have pre-diabetes.
® For ages 10 to 19 years, incidence of type 2
diabetes.
This has been attributed to obesity, dietary habits,
and urban life style (this is also true for Ethiopia!)
® In Ethiopia, DM prevalence varies ranging from
0.3% at Debre Berhan Referral Hospital to 7.0%
in Harar town.
5/11/2023 16

17. Pathophysiology
® DM is caused by abnormality in the secretion of insulin,
glucagon, and other hormones.
 Results in abnormal carbohydrate, protein and fat
metabolism.
® In the fasting state 75% of total body glucose to the
brain and peripheral nerves that do not require insulin.
 The remaining 25% of glucose metabolism takes place in the
liver, muscle, and adipose tissue which is dependent on
insulin.
® In the fed state, carbohydrate ingestion increases the
plasma glucose concentration and stimulates insulin
5/11/2023 17

18. Pathophysiology
® Approximately 85% of glucose production is
derived from the liver, and the remaining amount
is produced by the kidney in fasting state.
® Glucagon, produced by pancreatic α cells, is
secreted in the fasting state to oppose the action
of insulin.
It stimulate hepatic glucose production and
glycogenolysis
® Appropriate secretion of both hormones is needed
5/11/2023 18

19. 5/11/2023 19
Type 1 DM Pathophysiology

20. Pathogenesis: type 2 diabetes
®A combination of insulin deficiency, insulin
resistance, and other hormonal
irregularities, primarily involving glucagon.
®Obesity: visceral fat leads to the release
of
@Bioactive peptides (adipokines), inflammatory
mediators, and free fatty acids
@Contribute to inflammation, insulin resistance,
elevations in blood pressure, dyslipidemia (decreased
HDL level, and increased TG and LDL levels),
impaired thrombolysis, and further increases in body
weight
Contribute to cardiometabolic risk and
cardiovascular disease among patients with
20

21. Pathogenesis: type 2 diabetes
®Individuals are characterized by multiple
defects including
1. Defects in insulin secretion
2. Insulin resistance involving muscle, liver, and
adipocyte
3. Excess glucagon secretion
4. Glucagon-like peptide-1 (GLP-1) deficiency and
possibly resistance
GLP-1
» Its Insulinotropic action is glucose
dependent
 Glucose concentrations must be >90
mg/dl to enhance insulin secretion
» Suppresses glucagon secretion, slows
gastric emptying, and reduces food intake
by increasing satiety 21

22. Pathogenesis …type 2 diabetes
® Failure of insulin to
normalize plasma
glucose, dysglycemia,
including
prediabetes and
diabetes, can ensue
® Both β-cell mass and
function in the
pancreas are
reduced.
® People will lose ~5%
to 7% of β-cell
function per year of
diabetes.
® The reasons
@Glucose toxicity
@Lipotoxicity
@Insulin resistance
@Age
@Genetics; and
@Incretin deficiency.
22

23. Pathogenesis: type 2 diabetes
®The exact pathogenesis of type 2 is the
least understood
®Hyperglycemia: due to
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
23

24. Pathogenesis: type 2 diabetes
® Over time, β-cells lose their ability to
respond to elevated glucose concentrations
Leading to increasing loss of glucose control
In patients with severe hyperglycemia, the
amount of insulin secreted in response to glucose
is diminished and insulin resistance is worsened
(glucose toxicity)
® Hyperinsulinemia over time leads to down
regulation of insulin receptor
24

25. CLINICAL PRESENTATION
® Symptoms such as polyuria, polydipsia,
polyphagia, weight loss, and lethargy
Are more common in type 1 DM and about 40% also
present with ketoacidosis.
® Patients with type 2 DM often present without
symptoms
However, they present with microvascular and
Macrovascular complications at the time of diagnosis
suggest longstanding hyperglycemia.
5/11/2023 25

26. Type 2 DM risk factors
® Physical inactivity
® First degree relative with diabetes
® High risk ethnicity/race, (blacks)
® Women who delivered a baby heavier than 4 kg
or have a history of GDM,
® Hypertension,
® Dyslipidemia (high triglycerides, low HDL),
® Women with polycystic ovary syndrome,
® Diagnosed with pre-diabetes (see table: 1)
® Presence of acanthosis nigricans, or a history of
CVD.
5/11/2023 26

27. Screening for DM
® Screening for type 1 DM in the asymptomatic state is
not recommended.
® Children and Adolescents
 Overweight Children and Adolescents those who have at
least 2 or more risk factor for type 2 DM should be
screened at 10 years of age or at the onset of puberty if
it occurs at a younger age
® Adults without risk factors should be screened for type
2 DM starting at age 45 years and then every 3 years.
(Table 1)
 Age is a risk factor for type 2 DM
5/11/2023 27

28. 5/11/2023 28
Table: 1 Criteria for screening for type 2 DM/prediabetes in adults

29. 5/11/2023 29
Table: Risk-based screening for type 2 diabetes or prediabetes in
asymptomatic children and adolescents

30. Pre- diabetes
5/11/2023 30
Table: 3 Criteria defining
prediabetes

31. 5/11/2023 31
Table: 3 Criteria for Diagnosis of DM

32. 5/11/2023 32

33. Blood glucose goal
®Summary of glycemic recommendations
for many non-pregnant adults with
diabetes
5/11/2023 33

34. BG goal…
®HbAlc goal should be individualized, with
<6.5% if
Achieved without significant hypoglycemia or
Adverse effects in younger,
Long-life expectancy, and
No CVD patients.
®Less stringent HbAlc goal <8% may be
appropriate in patients with:
A history of severe hypoglycemia,
Limited life expectancy,
Advanced micro/macrovascular complications
or comorbidities,
5/11/2023 34

35. 5/11/2023 35
Rx

36. Treatment: General
®Glycemic control is fundamental to the
management of diabetes
®Goals of Therapy
Short-term Goals
Establish and maintain optimum glycemic control
No severe or nocturnal hypoglycemia episodes
Control symptoms of polydipsia, polyphagia, and
polyuria
Keeping patients free of urine ketones
Achieve optimal control of co-morbidities [hypertension
and dyslipidemia]
5/11/2023 36

37. Rx Goal
®Long-term goals of therapy:
Reduce risk for microvascular
Retinopathy, neuropathy, and nephropathy
and
Macro vascular complications
Coronary heart disease, stroke, and peripheral vascular disease
Reduce mortality
5/11/2023 37

38. Nonpharmacologic Therapy
®Medical Nutrition Therapy
A meal with moderate carbohydrates and low in
saturated fat (less than 7% of total calories)
Essential vitamins and minerals is recommended.
Caloric restriction for overweight or obese
patients with type 2 DM to promote weight loss.
For type 1 DM balanced diet is recommended
to achieve and maintain a healthy body weight.
@With Physiologically regulating insulin administration
5/11/2023 38

39. Lifestyle modification
® Physical Activity
 Aerobic exercise improves insulin sensitivity,
Improve glucose control
reduces cardiovascular risk,
contributes to weight loss or maintenance, and
improves well-being.
At least 150 min/wk of moderate (50%-70%
maximal heart rate) intensity exercise spread over
at least 3 days a week with no more than 2 days
between activity.
5/11/2023 39

40. Lifestyle modification
Alcohol
®The ADA’s recommendation for alcohol
is consistent with general
recommendations of no more than two
alcoholic drinks/day for men or one
drink/day for women
Sodium restriction
®The ADA recommends a reduced sodium
intake of less than 2,300 mg/day in
normotensive and hypertensive
5/11/2023 40

41. 5/11/2023 41

42. Insulin
Pharmacokinetics:
® The route of administration for insulin is primarily via
SC injection
® Regular insulin , can be administered by any
parenteral route
® insulin aspart and insulin lispro may be used via IV
route if they are first diluted.
® Afrezza (insulin human) available as a powder for
inhalation
5/11/2023 42

43. ®Endogenous insulin is mainly metabolized
in liver (60%) and the rest in kidney
®In contrast, exogenous insulin majorly
(60%) metabolized in kidney and the
rest cleared by liver.
5/11/2023 43

44. Pharmacodynamic
®The most important differences among
insulin products relate to their onset,
peak, and duration of action
®Current insulin products can be
categorized as :
Rapid-acting,
Short-acting,
Intermediate-acting, and
Long-acting insulin
5/11/2023 44
Next Slide

45. insulin

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48. 5/11/2023 48
Insulin injection site

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51. 5/11/2023 51

52. Type 1 DM Rx
Insulin Therapy
® Because the hallmark of type 1 diabetes is
absent or near-absent b-cell function, insulin
treatment is essential for individuals with
type 1 diabetes.
® Typical doses ranging from 0.4 to 1.0
units/kg/day.
@ 0.5 units/kg/day as a typical starting dose in patients with
type 1 diabetes who are metabolically stable.
@ Starting dose can be increased to 0.7-1.5 units/KG in
5/11/2023 52

53. Type 1 DM Rx
® Higher amounts are required during puberty,
pregnancy, and medical illness
® Half administered as prandial insulin (short or rapid
acting)
given to control blood glucose after meals and the
other
® Half as basal insulin to control glycemia in the
periods between meal absorption. (intermediate or
long acting)
5/11/2023 53

54. SMBG
Patients with Type 1 diabetes
Pregnant patients
difficulty recognizing hypoglycemia
Patients who are using physiologic
Type 2 diabetes who are on therapy that can cause
hypoglycemia
Type 2 diabetes who are engaged in self-
management of their diabetes
5/11/2023 54

55. Insulin Dosing Regimens
1. Conventional dosing
Less commonly used in patients with Type 1 diabetes.
 Involves injecting a mixture of NPH and Regular
insulin twice daily, before breakfast and before
dinner.
This type of insulin regimen does not mimic
physiologic insulin release.
After the TDD calculated 2/3 of the TDD should be
administered before breakfast and 1/3 is given
before dinner or at bed time.
5/11/2023 55

56. Insulin Regimen
2. Basal-bolus regimen (MDI)
® a combination of intermediate- or long-acting insulin
and a rapid-acting insulin to provide prandial
coverage.
® Patients on more advanced regimens learn to adjust
the bolus insulin dose based on anticipated
carbohydrate intake and physical activity.
5/11/2023 56

57. Insulin…
® Approximately 50% of total daily insulin
replacement should be in the form of basal
insulin
and
® The other 50% in the form of bolus insulin,
divided between meals.
Bolus insulin doses should be 20% of total dose prior
to breakfast, 15% prior to lunch, and 15% prior to
supper.
5/11/2023 57

58. 5/11/2023 58

59. Insulin Regimen…
3. Continuous subcutaeous insulin infusion
(insulin pump)
 Use a rapid-acting insulin analog is the most sophisticated
and precise method for insulin delivery.
 Can calculate recommended bolus doses of insulin based on
carbohydrate intake.
 paired to continuous glucose monitoring (CGM), which allows
calculation of a correction insulin dose,
 alert the patient to hypoglycemia and hyperglycemia.
 With “Close-loop” add on the pump automatically makes
insulin-dosing decisions
5/11/2023 59

60. 5/11/2023 60

61. Insulin side effect
® Hypoglycemia
All DM patients should be instructed how to recognize
and treat hypoglycemia
patients should be advised to follow the “rule of 15.” If
hypoglycemia is identified
 the patient should consume 15 g of simple carbohydrate
and then retest their BG 15 minutes later.
If the blood glucose remains less than 70 mg/dL (3.9
mmol/L), the patient should consume 15 g 0f
carbohydrate and repeat the rule of 15 until their BG is
has normalized
5/11/2023 61

62. 5/11/2023 62

63. 5/11/2023 63

64. Insulin side effect
® Insulin allergies
Traditional side effect before human insulin
develop and quality maintained.
Are uncommon with human insulin
® Lipohypertrophy
Occur by injecting insulin in the same site
repeatedly
Insulin absorption from an area of lipohypertrophy
is unpredictable. So it is not advisable to inject
insulin at this site.
5/11/2023 64

65. Pancreas transplant
® Pancreas transplant
® Islet cell transplant
Require life long immunosuppressive therapy
So it used in patients who require
immunosuppressive therapy for other reasons,
such as renal transplants
within 2 years following a pancreas transplant,
above 80% will need to reinitiate some form of
insulin therapy.
5/11/2023 65

66. Type 2 DM Rx
®Currently, nine classes of oral agents are
approved for the treatment of type 2
diabetes:
1. Biguanides,
2. Meglitinides,
3. Thiazolidinediones [TZDs] or glitazones),
4. DPP-4 inhibitors,
5. SGLT2 inhibitors,
6. Sulfonylureas.
7. α-glucosidase inhibitors
8. dopamine agonists,
9. bile acid sequestrants, and
5/11/2023 66
Injection
•Insulin
•GLP-1,and
•Amylomimetics

81. Type 2 diabetes management
® Metformin is the preferred initial pharmacologic
agent for the treatment of type 2 diabetes
® Once initiated, metformin should be continued as
long as it is tolerated and not contraindicated
® Long-term use of metformin may be associated
with biochemical Vit. B12 deficiency, and periodic
measurement of Vit. B12 levels should be
considered in metformin-treated patients,
especially in those with anemia or peripheral
neuropathy.

82. Management….
®The early introduction of insulin should
be considered if there is
Evidence of ongoing catabolism (weight
loss),
If symptoms of hyperglycemia are present,
When A1C levels >10% or blood glucose
levels (>300 mg/dL) are very high.
Pregnant women
Patients with critical illness

83. Management….
 Consider initiating dual therapy in patients with newly
diagnosed type 2 diabetes who have A1C >1.5% above their
glycemic target.
 Among patients with type 2 diabetes who have established
ASCVD, GLP-1 receptor agonists drugs with established CVD
should be added.
® Liraglutide ,dulaglutide and Semaglutide
Or
 SGLT2 inhibitor (Empagliflozin > Canagliflozin) should be
added

84. Management…..
Among DM patients with ASCVD in whom HF
coexists or is of special concern, SGLT2
inhibitors are recommended
® Empagliflozin > Canagliflozin
For patients with type 2 diabetes and CKD, with
or without CVD, consider the use of
SGLT2 inhibitor (Empagliflozin > Canagliflozin)
if contraindicated or not preferred…
 GLP-1 receptor agonist (Liraglutide >Semaglutide>Exenatide)
5/11/2023 84

85. Type2 diabetes management algorithm

86. Type2 diabetes management algorithm

87. Further information on
Metformin
&
sulfonylurea

88. Metformin
® Metformin is an oral medication that reduces
plasma glucose via multiple mechanisms.
® Dosages of IR metformin: 500 mg QD or BID
with food and titrate to a target dosage of
1000 mg BID.
Max. dose of metformin is 2550 mg per day
5/11/2023 88

89. METFORMIN
® Metformin remains the first-line medication
for management of type 2 diabetes Coz:
High efficacy in lowering HbA1c
Good safety profile
Low cost
No hypoglycemia
Modest weight reduction
CVD prevention
5/11/2023 89

90. Pharmacology: Biguanides
Metformin
• Enhances insulin sensitivity of mainly hepatic but also
peripheral (muscle) tissues.
 Allows for an increased uptake of glucose into these insulin-sensitive
tissues.
• Has no direct effect on the β cells, although insulin levels are
reduced, reflecting increases in insulin sensitivity.
• Logical in overweight/obese patients, if tolerated and not
contraindicated, as it is the only oral anti-hyperglycemic
medication potentially proven to reduce the risk of total
mortality
90

91. Pharmacology…pharmacokinetics
® Approximately 50% to 60% oral bioavailability, low lipid
solubility, and a volume of distribution that approximates body
water.
® It is not metabolized and does not bind to plasma proteins.
® Eliminated by renal tubular secretion and glomerular
filtration.
® The average plasma half-life of metformin is 6 hours, although
pharmacodynamically, metformin’s anti-hyperglycemic effects
last more than 24 hours.
91

92. Pharmacology…efficacy
• Consistently reduces
 HbA1c levels by 1.5% to 2% and FPG levels by 60 to 80 mg/dL in drug-naïve
patients, and
• Retains the ability to reduce FPG levels when they are extremely high (>300
mg/dL).
• Also has positive effects on several components of the insulin resistance
syndrome.
 It decreases plasma TGs and LDL-C by approximately 8% to 15%, in addition to
increasing HDL-C very modestly (2%).
• Metformin causes a modest reduction in weight (2 to 3 kg).
92

93. Pharmacology…efficacy
Microvascular Complications
• Found to reduce microvascular complications in the
UKPD study
Macrovascular Complications
• Reduced macrovascular complications in obese
subjects.
• It significantly reduced all-cause mortality and risk of
stroke
• Has also reduced diabetes-related death
93

94. Pharmacology…adverse effects
• Metformin causes GI side effects, including abdominal
discomfort, stomach upset, and/or diarrhea, in
approximately 30% of patients.
• Anorexia and stomach fullness is likely part of the reason loss
of weight is noted with metformin.
• These side effects are usually mild and can be minimized by
slow titration.
• GI side effects also tend to be transient, lessening in severity
over several weeks.
• If encountered, make sure patients are taking metformin with
or right after meals, and reduce the dose to a point at which
no GI side effects are encountered.
• Increases in the dose may be tried again in several weeks.
• Anecdotally, extended-release metformin (Glucophage XR)
may lessen some of the GI side effects.
94

95. Pharmacology…adverse effects
• Metallic taste, interference with vitamin B12
absorption, and hypoglycemia during intense exercise
have been documented, but are clinically uncommon.
• Metformin therapy rarely (3 to 9 cases per 100,000
patient-years) causes lactic acidosis.
• Any disease state that may increase lactic acid
production or decrease lactic acid removal may
predispose to lactic acidosis.
• Tissue hypo-perfusion, such as that due to congestive heart
failure, severe lung disease, hypoxic states, shock, or
septicemia, via increased production of lactic acid, and
severe liver disease or alcohol, via reduced removal of lactic
acid in the liver.
95

96. Pharmacology…adverse effects
• The clinical presentation of lactic acidosis is often
nonspecific flu-like symptoms; thus, the diagnosis is
usually made by laboratory confirmation of high lactic
acid levels and acidosis.
• Metformin use is contraindicate renal insufficiency
 A serum creatinine of >1.4 mg/dL in women
 And >1.5 mg/dL in men or greater, as it is renally eliminated.
• Elderly patients, who often have reduced muscle mass,
should have their glomerular filtration rate estimated by
a 24-hour urine creatinine collection.
• If the estimated glomerular filtration rate is less than 60
mL/min, metformin use should be carefully evaluated.
96

97. Pharmacology…adverse effects
®Evidence has reported that metformin may be
fairly safe in moderate renal insufficiency.
®Metformin use can be modified based on the
estimated glomerular filtration rate,
GFR<60 mL/min/1.73 m2 : monitor renal function
every 3 to 6 months
30 <GFR<45 to mL/min/1.73 m2: limit dose to 50%
of maximal dose
GFR<30 mL/min/1.73 m2: stop metformin
97

98. Dosing and administration
®Immediate-release metformin
500 mg twice a day with the largest meals to
minimize GI side effects.
 May be increased by 500 mg as tolerated until glycemic goals
or 2,500 mg/day is achieved
®Metformin 850 mg
 May be dosed daily, and then increased every 1 to 2 weeks to
the maximum dose of 850 mg three times a day (2,550
mg/day).
®Approximately 80% of the glycemic-lowering
effect may be seen at 1,500 mg, and 2,000
mg/day is the maximal effective dose.
98

99. Dosing and administration
®Extended-release metformin
Can be initiated at 500 mg a day with the evening meal
and titrated by 500 mg as tolerated to a single evening
dose of 2,000 mg/day.
®Extended-release metformin 750-mg tablets
May be titrated as tolerated to the maximum dose of
2,250 mg/day, although, 1,500 mg/day provides the
majority of the glycemic-lowering effect.
Twice-daily to three-times-a day dosing of extended-
release metformin may help to minimize GI side effects
and improve glycemic control,
99

100. METFORMIN
® Gastrointestinal side effect are common and dose
dependent
® Metformin should not be used in patients with stage 4 or 5
CKD.
® Metformin should be omitted in the setting of severe
illness, vomiting or dehydration.
 due to increased risk of lactic acidosis
® Metformin may result in lower serum vit.B12 concentration.
 Supplementation is generally recommended in anemic or
neuropathy
5/11/2023 100

101. Pharmacology…sulfonylureas
• MOA: enhancement of insulin secretion.
• Bind to a specific sulfonylurea receptor (SUR) on pancreatic β
cells.
• Elevated secretion of insulin from the pancreas travels via the
portal vein and subsequently suppresses hepatic glucose production
• First-generation: acetohexamide, chlorpropamide,
tolazamide, and tolbutamide.
• Each of these agents is lower in potency relative to the
second-generation drugs: glimepiride, glipizide, and
glyburide
• All sulfonylureas are equally effective at lowering
BG when administered in equipotent doses
101

102. Pharmacology…pharmacokinetics
® All are metabolized in the liver, some to active and
others to inactive metabolites.
® Glyburide metabolites are active, whereas glipizide and
glimepiride do not have active metabolites.
® Cytochrome P450 (CYP450) 2C9 is involved with the
hepatic metabolism of the majority of sulfonylureas.
® Agents with active metabolites or parent drug that are
renally excreted require dosage adjustment or use with
caution in patients with compromised renal function.
102

103. Pharmacology…efficacy
 HbA1c
• Will fall 1.5% to 2% in drug-naïve patients,
• FPG reductions of 60 to 70 mg/dL
• But dependent on baseline values and duration of diabetes.
• A majority of patients will not reach glycemic goals with
sulfonylurea monotherapy.
• Patients with inadequate control on a sulfonylurea
usually fall into two groups:
1. Those with low C-peptide levels and high (>250 mg/dL) FPG
levels.
• Often primary failures on sulfonylureas (<30 mg/dL drop of FPG)
and have significant glucose toxicity or LADA.
103

104. Pharmacology…efficacy
2. Those with a good initial response (>30 mg/dL drop of FPG),
but which is insufficient to reach their glycemic goals.
@Over 75% of patients fall into the second group.
@Factors that portend a positive response include:
1. Newly diagnosed patients with no indicators of type 1 DM,
2. High fasting c-peptide levels, and
3. Moderate fasting hyperglycaemia (<250 mg/dL )
104

105. Pharmacology…efficacy
Microvascular Complications
• A reduction of microvascular complications in
type 2 DM patients in the UKPDS.
Macrovascular Complications
• The UKPDS reported no significant benefit or
harm in newly diagnosed type 2 DM patients
given over 10 years.
105

106. Adverse effects
• The most common side effect of sulfonylureas is
hypoglycemia.
• Pre-treatment FPG is a strong predictor.
The lower the FPG is on initiation, the higher the potential for
hypoglycemia.
• The following are also more likely to experience
hypoglycemia
 Who skip meals, exercise vigorously, or lose substantial amounts of weight
• Hyponatremia (serum sodium <129 mEq/L)
• Associated with tolbutamide, but it is most common
with chlorpropamide (5%) .
Is due to increase in antidiuretic hormone secretion
Risk factors include age >60 years, female gender, and
concomitant use of thiazide diuretics
106

107. Adverse effects
• Weight gain is common with sulfonylureas.
• In essence, patients who are no longer glycosuric and who
do not reduce caloric intake with improvement of BG will
store excess calories.
• Other notable, although much less common, adverse
effects are skin rash, hemolytic anemia, GI upset,
and cholestasis.
• Disulfiram-type reactions and flushing have been
reported with tolbutamide and chlorpropamide when
alcohol is consumed
107

108. Dosing and administration
®Lower dosages are recommended for most agents
in elderly patients and those with compromised
renal or hepatic function.
®The dosage can be titrated as soon as every 2
weeks based on FPG values (use a longer interval
with chlorpropamide) to achieve glycemic goals.
®This is possible due to the rapid increase of
insulin secretion in response to the sulfonylurea.
®The maximal effective dose of sulfonylureas
tends to be about 60% to 75% of their stated
maximum dose
108

109. Macrovascular Disease: management
®Blood pressure control, lipid management, and
aspirin therapy
Will reduce risk of coronary heart disease, stroke, and
peripheral vascular disease
®Blood pressure control:
Goal: blood pressure <140/80 mmHg (if renal disease
<130/80 mmHg)
Medical nutritional therapy
ACE inhibitors or angiotensin receptor blockers
(ARBs) are first line agents in patients with
hypertension and diabetes
Diuretics, Hydrochlorothiazide are synergistic combo
109

110. Macrovascular Disease: management
®Lipid management:
Goal: LDL <100 mg/dL (optional goal for high-risk
patients: <70 mg/dL); total cholesterol <200 mg/dL;
HDL >40 mg/dL; triglycerides <150 mg/dL.
 Medical nutritional therapy: follow dietary
recommendations
HMG-CoA reductase inhibitors (statins) if LDL >130
mg/dL; Fibrates if triglycerides >500 mg/dL
@Over the age of 40 with a total cholesterol ≥135mg/dL, statin
therapy to achieve an LDL reduction of ~30% regardless of
baseline LDL
110

111. Macrovascular Disease: management …goals
111

112. Micro vascular disease: Management
®Prevention and recognition of retinopathy,
neuropathy , foot care, and nephropathy
Periodically evaluate after a baseline assessment
Optimize glucose and blood pressure control to reduce
the risk and/or slow the progression of nephropathy
Neuropathy is most common complaint and need to be
managed pharmacologically and non-
pharmacologically based on severity
Nephropathy is a progressive kidney disease that takes
several years to develop
112

113. 5/11/2023 113

114. Acute complications: DKA
®Due to:
Severe insulin deficiency
Excess counter regulatory hormones
oGlucagon
oEpinephrine
oCortisol
oGrowth hormone
114

115. DKA
® In DKA, an absolute or relative insulin
deficiency promotes lipolysis and metabolism of
free fatty acids to
β-hydroxybutyrate, acetoacetic acid, and acetone
in the liver.
® Physiologic stress contributes to the
development of DKA by stimulating release of
insulin counter-regulatory hormones including
glucagon,
catecholamines,
glucocorticoids, and
growth hormone..
5/11/2023 115

116. Insulin deficiency
Glucose uptake
(Tubular load exceeds 220mg/min)
normal=120mg/min Proteolysis
Lipolysis
Amino Acids
Glycerol
Free fatty acids
Gluconeogenesis
Glycogenolysis
Hyperglycemia
Ketogenesis
Acidosis
Osmotic diuresis Dehydration
Mechanism of DKA induced
ketosis/dehydration
116

117. DKA precipitating factors
1. Failure to take
insulin
2. Failure to increase
insulin
Illness/Infection
@ Pneumonia
@ MI
@ Stroke
Acute stress
@ Trauma
@ Emotional
3. Medical Stress
Counter regulatory
hormones
@ Oppose insulin
@ Stimulate glucagon
release
4. Hypovolmemia
Increases glucagon and
catecholamine
@ Decreased renal blood
flow
@ Decreases glucagon
degradation by the kidney
117

118. Signs and symptoms of DKA
® Polyuria, polydipsia
Enuresis
® Dehydration
Tachycardia
Orthostasis
® Abdominal pain
Nausea
Vomiting
® Fruity breath
Acetone
® Kussmaul breathing
@ Air hunger
® Mental status
changes
Combative
Drunk
Coma
118

119. DKA diagnosis
119

120. Treatment…DKA
Metabolic treatment targets
Reduce blood ketone concentration by 0.5mmol/L/hr.
Increase venous bicarbonate by 3.0mmol/L/hr.
Reduce capillary blood glucose by 50-70mg/dl/hr.
Maintain potassium between 4.0 and 5.5mmol/L
120

121. Treatment… fluids and electrolytes
® Fluid replacement
Restores perfusion of the tissues
@Lowers counter regulatory hormones
Average fluid deficit 3-5 liters
® Initial resuscitation
1-2 liters of normal saline over the first 2 hours
Slower rates of 500ml/hr. x 4 hr. or 250 ml/hr. x 4 hours
@When fluid overload is a concern
® If hypernatremia develops ½ NS can be used
121

122. Treatment…fluids and electrolytes
®Hyperkalemia initially present
Resolves quickly with insulin drip
Once urine output is present and K<5.0, add 20-
40 meq KCL per liter.
®Phosphate deficit
May want to use Kphos
®Bicarbonate not given unless pH <7 or
bicarbonate <5 mmol/L
122

123. Treatment…insulin therapy
® IV bolus of 0.1-0.2 units/kg (~ 10 units) regular
insulin
® Follow with 0.1 unit/kg/hr regular insulin infusion
® Glucose levels
Decrease 75-100 mg/dl hour
Minimize rapid fluid shifts
® Continue IV insulin until urine is free of ketones
123

124. Treatment…glucose administration
®Supplemental glucose
Hypoglycemia occurs
@Insulin has restored glucose uptake
@Suppressed glucagon
Prevents rapid decline in plasma osmolality
@Rapid increase in insulin could lead to cerebral edema
®Glucose decreases before ketone levels
decrease
®Shift 0.9NS to5%dextrose when plasma
glucose <250 mg/dl
124

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Thank you