Pharmacotherapy of

Diabetes Mellitus
By:
Ameha Zewudie, [Assistant professor
of Clinical Pharmacy]
Introductory Case:

 A 39-year-old man with a 2-year history of

type 2 diabetes mellitus presents for care. He
has no microvascular or macrovascular
complications. His family history is positive for
type 2 diabetes and cardiovascular disease in
his mother and older brother. On examination,
his weight is 99.8 kg, with a BMI of 37, and his
BP is 125/85 mm Hg. His glycated hemoglobin
level is 8.9%, Sr Cr 1.0 mg /dL, low-density
lipoprotein (LDL) cholesterol 88 mg /dL
2
Introductory Case: (cont.)

, high-density lipoprotein (HDL) cholesterol 45 mg/dL,

and triglyceride level 130 mg /dL ; he does not have
microalbuminuria. His medications include metformin
(500 mg twice daily), glipizide (5 mg twice daily),
simvastatin (20 mg daily), and lisinopril (10 mg daily).
Which one of the following
interventions/recommendations will help to
improve his glycemic control?

3
Introductory Case: (cont.)

A. His BP and Lipid levels are well controlled with the

current interventions
B. Recommend an exercise program (preferably at least
150 minutes per week) with the aim of gradual weight
loss (perhaps 4.5 to 6.8 kg over the next year)
C. Increase the dose of metformin to 2000 mg daily
while diet and exercise are actively pursued
D. If choices B and C are effective, plan to decrease or
discontinue glipizide
E. On serial follow ups, if glycated hemoglobin level
remains high, addition of another oral agent unlikely
will reduce the HbA1c and require adding bed time
NPH insulin
F. All of the above interventions 4
Unit Learning Objectives
Define Diabetes Mellitus
Compare and contrast type 1 and type 2 DM
List the diagnostic and screening criteria for type 1& 2 DM
Identify common concomitant conditions and complications
Apply non-pharmacologic and pharmacologic treatment
interventions and goals for diabetes mellitus
Construct rationale therapeutic regimens for treatment of
DM
Develop treatment regimens for complications associated
with diabetes mellitus
Evaluate therapeutic outcomes of pharmacotherapy of
diabetes mellitus
5
Definition: Diabetes Mellitus

 A group of metabolic disorders characterized

by hyperglycemia
 Associated with abnormalities in carbohydrate,
fat, and protein metabolism
 Results in chronic complications including
Microvascular
• retinopathy, neuropathy, and nephropathy
Macrovascular
• coronary heart disease, stroke, and peripheral
vascular disease
6
Epidemiology

 Medical management of persons with diabetes

is costly
2007 , US data - total cost of diabetes was ≈ $174
billion, with 1 out of 5 health care dollars being
spent on people with diabetes
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
7
8
Diabetes Classification
 Type 1 diabetes
caused by an absolute deficiency of insulin
 Type 2 diabetes
defined by the presence of insulin resistance with an
inadequate compensatory increase in insulin secretion
 Gestational diabetes mellitus (GDM)
is used to describe glucose intolerance that has its onset
during pregnancy
 Other specific types: drug-induced, genetic defects
of beta cell function, disease of the exocrine
pancreas…etc..
9
Comparisons: Type 1& 2 DM
 Type 1 Diabetes  Type 2 Diabetes Mellitus:
Mellitus: 90-95% of all diabetes
5-10% of all diabetes Cxterized by both insulin
cases resistance and relative
β-cell destruction usually (rather than absolute)
insulin deficiency
leading to absolute insulin
deficiency (either immune Occurs when a life-style of
mediated or idiopathic) excessive calories,
inadequate exercise, and
Generally develops in
obesity is superimposed
early childhood or early upon a susceptible genotype
adulthood Typically occurs after age 40
• Mean age of onset: 8-12
years
10
11 10/18/24
 Drug- or chemical

 Nicotinic acid
 Glucocorticoids
 Thyroid hormone
 β-Adrenergic agonists
 Thiazides
 Phenytoin
 Interferon alpha

12 10/18/24
 PATHOGENESIS

Type 1 Diabetes Mellitus

 Type 1 DM is characterized by an absolute deficiency of
pancreatic β-cell function.
 Most often this is the result of an immune-mediated
destruction of pancreatic β cells, but rare unknown or
idiopathic processes can contribute.
What is evident are four main features:
 a long preclinical period marked by the presence of
immune markers when β-cell destruction is thought to
occur.
 Hyperglycemia when 80% to 90% of β cells are
destroyed.
 Transient remission (the so-called honeymoon phase).
 Established disease with associated risks for
13 complications and death. 10/18/24
Proposed Scheme of Natural History of
Beta -Cell Defect

14
 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 (Latent autoimmune diabetes in adults)
late age presentation
15
 The autoimmune process is mediated by macrophages
and T lymphocytes with circulating autoantibodies to
various β-cell antigens.
 The most commonly detected antibody associated with
type 1 DM is the islet cell antibody.
 Other more readily measured circulating antibodies
include insulin autoantibodies, antibodies directed
against glutamic acid decarboxylase, insulin and several
others.
 More than 90% of newly diagnosed persons with type 1
DM have one or another of these antibodies.
 These antibodies are generally considered markers of
disease rather than mediators of β-cell destruction.
 Destruction of pancreatic β-cell function causes
16
hyperglycemia because of an absolute deficiency of
10/18/24
both insulin and amylin.
 Insulin lowers blood glucose by a variety of
mechanisms including:
stimulation of tissue glucose uptake
 suppression of glucose production by the liver, and
 suppression of free fatty acid release from fat cells.
 Amylin, a glucoregulatory peptide hormone co-
secreted with insulin, plays a role in lowering
blood glucose by
slowing gastric emptying,
suppressing glucagon output from pancreatic α cells,
and
increasing satiety.

17 10/18/24
Normal Insulin Action

 In the fasting state 75% of total body glucose

disposal takes place in non–insulin-dependent
tissues: the brain and splanchnic tissues (liver and
gastrointestinal [GI] tissues).
 The remaining 25% of glucose metabolism takes
place in muscle, which is dependent on insulin.
 In the fasting state approximately 85% of glucose
production is derived from the liver, and the
remaining amount is produced by the kidney.
 Glucagon, produced by pancreatic α cells, is
secreted in the fasting state to oppose the action
of insulin and stimulate hepatic glucose 10/18/24

production.
  In the fed state, carbohydrate ingestion increases
the plasma glucose concentration and stimulates
insulin release from the pancreatic β cells.
 Although fat tissue is responsible for only a small
amount of total body glucose disposal, it plays a
very important role in the maintenance of total
body glucose homeostasis.
 Small increments in the plasma insulin
concentration exert a potent antilipolytic effect,
leading to a marked reduction in the plasma free
fatty acid (FFA) level.
 The decline in plasma FFA concentration results in
increased glucose uptake in muscle and reduces
hepatic glucose production.
 Thus a decrease in the plasma FFA concentration
19
lowers plasma glucose by both decreasing10/18/24its
production and enhancing the uptake in muscle.
20 10/18/24
Pathogenesis: Type 2 Diabetes
[1]
 Central adiposity contributes too many of the
pathophysiologic features of type 2 diabetes
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
high-density lipoprotein level, and increased triglyceride
and low-density lipoprotein levels), impaired
thrombolysis, and further increases in body weight
Contribute to cardiometabolic risk and cardiovascular
disease among patients with type 2 diabetes
21
Pathogenesis: Type 2 Diabetes
[2]
 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
22
 Type 2 Diabetes Mellitus

 Type 2 diabetic individuals are characterized by:

(1) defects in insulin secretion; and
(2) insulin resistance involving muscle, liver, and the adipocyte.
Impaired Insulin Secretion
 Impaired insulin secretion is a uniform finding in type 2
diabetic patients.
 As the FPG concentration increases from 80 to 140 mg/dL, the
fasting plasma insulin concentration increases progressively.
 When the FPG concentration exceeds 140 mg/dL, the β cell is
unable to maintain its elevated rate of insulin secretion, and
the fasting insulin concentration declines.
 This decrease in fasting insulin leads to an increase in hepatic
glucose production overnight, which results in an elevated FPG
concentration.
23 10/18/24
Pathogenesis: Type 2 Diabetes
[3]
 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
 Read hand out …… on metabolic syndrome
24
25 10/18/24
The incretin effect

 In nondiabetic control individuals, 73% more

insulin is released in response to an oral
glucose load
 This increased insulin secretion in response to
an oral glucose stimulus is referred to as “the
incretin effect” and suggests that gut derived
hormones when stimulated by glucose lead to
an increase in pancreatic insulin secretion.
 The incretin effect is blunted in diabetic
patients
26
Site of Insulin Resistance in Type 2 Diabetes

 Following glucose ingestion, insulin is secreted into

the portal vein and carried to the liver, where it
suppresses glucagon secretion and reduces hepatic
glucose output.
 Type 2 diabetic patients fail to suppress glucagon in
response to a meal and can even have a paradoxical
rise in glucagon levels.
 Thus, hepatic insulin resistance and
hyperglucagonemia result in continued production of
glucose by the liver.
 Therefore, type 2 diabetic patients have two sources
of glucose in the postprandial state:
 one from the diet and
27  The other from continued glucose production from the 10/18/24
liver.
Peripheral (Muscle)

 Muscle is the major site of glucose disposal in man,

an approximately 80% of total body glucose uptake
occurs.
 In type 2 diabetic subjects, the onset of insulin action
is delayed for 40 minutes, and the ability of insulin to
stimulate leg glucose uptake is educed by 50%.
 Therefore the primary site of insulin resistance in type
2 diabetic subjects resides in muscle tissue.
 Peripheral (Adipocyte)
 In obese nondiabetic and diabetic humans, basal
plasma FFA levels are increased and fail to suppress
normally after glucose ingestion.
 FFAs are stored as triglycerides in adipocytes and
serve as an important energy source during
28 conditions of fasting. 10/18/24
Visceral adipose tissue (VAT)

 Resulting in an increase in FFA production.

 Stimulate the production of very-low-density
lipoproteins and decrease insulin sensitivity in
peripheral
 Produces TNF-α, interleukin 6,
angiotensinogen, and resistin, which
contribute to insulin resistance, hypertension,
and hypercoagulability.

29
30 10/18/24
Classical Clinical Presentation of
Diabetes Mellitus
Characteristic Type 1 DM Type 2 DM
Age <30 years >30 years
Onset Abrupt Gradual
Body habitus Lean Obese or history of
obesity
Insulin resistance Absent Present
Autoantibodies Often present Rarely present
Symptoms Symptomatic Often
asymptomatic
Ketones at diagnosis Present Absent
Need for insulin Immediate Years after
therapy diagnosis
Acute complications Diabetic Hyperosmolar
ketoacidosis hyperglycemic
31
state
Screening for Diabetes

 Type 2 Diabetes Mellitus

 The American Diabetes Association (ADA) recommends
screening for type 2 DM at any age in
 individuals who are overweight (BMI ≥25 kg/m2) and have at least
one of the following risk factors.
 Phy21sical inactivity, first-degree relative with diabetes or high-risk
ethnicity/race, women who have delivered a baby >9 lb (>4 kg)
 a history of GDM, hypertension, high triglycerides, low HDL
 women with polycystic ovary syndrome
 Prediabetes, acanthosis nigricans, a history ofcardiovascular disease
(CVD
 Adults with outrisk factors should be screened starting at age 45
years…why?
 diabetes should guide the clinician. Repeat testing every 3 to 5 years 32
is cost-effective.
Screening for Diabetes
Type 1 : not recommended, low prevalence, acute
symptoms
Type 2 : FPG recommended , alternative: OGTT -
more costly, less convenient, less reproducible;
HbA1c not recommended - no gold standard assay,
but useful in monitoring glycemic control after
diagnosis

33
Diagnostic Criteria:
 Classic signs and symptoms of diabetes (polyuria,
polydipsia, ketonuria, and unexplained weight loss)
combined with random plasma glucose (RBS) ≥200
mg/dL
 A Fasting plasma glucose (FPG) ≥126 mg/dL--- Fasting
means no caloric intake for at least 8 hours.
 After a standard oral glucose challenge (75 g glucose
for an adult or 1.75 g/kg for a child), the venous
plasma glucose concentration is ≥200 mg/dL at 2
hours and >200 mg/dL at least one other time during
the test (0.5, 1, 1.5 hours)
 OGTT (oral glucose tolerance test)
34
35 10/18/24
36 10/18/24
Treatment: General
 Glycemic control is fundamental to the
management of diabetes
UKPDS, DCCT trails showed that improved glycemic
control is associated with sustained decreased rates of
retinopathy, nephropathy, and neuropathy
 Goals of Therapy
Short-term Goals of Therapy
• Establish and maintain optimum glycemic control
• No severe or nocturnal hypoglycemia episodes
• Control symptoms of polydipsia, polyphagia, and polyuria
• Patient is negative for ketones in the urine ( for Type 1
DM)
37
• Achieve optimal control of co-morbidities such as
Treatment: cont’d……

 Long-term Goals of Therapy:

Reduce risk for microvascular (retinopathy,
neuropathy, and nephropathy) and macrovascular
complications (coronary heart disease, stroke, and
peripheral vascular disease)
Reduce mortality
 The overall goal of diabetes management is
to prevent acute and chronic complications
Periodic assessments of HbA1c coupled with regular
measurement of fasting, preprandial, and postprandial
glucose levels should be utilized to assess therapy
38
Achieve :
 Strive for glycemic control achieved in DCCT and
UKPDS
 Try to keep patients free of symptoms associated
with hyperglycemia
 Maintain normal growth and development in
children
 Eliminate or minimize all other cardiovascular risk
factors (obesity, hypertension, tobacco use, and
hyperlipidemia
 Try to integrate the patient into the health care
team through intensive education
39
Cont’d…
 Near-normal glycemia
will reduce the risk for development of microvascular
disease complications
 Aggressive management of traditional
cardiovascular risk factors (i.e., smoking cessation,
treatment of dyslipidemia, intensive blood pressure
control, and antiplatelet therapy)
are needed to reduce the likelihood of development of
macrovascular disease
 Diabetic ketoacidosis and hyperosmolar
hyperglycemic state
are severe manifestations of poor diabetes control, almost
40
always requiring hospitalization
Non-pharmacologic Therapy:

 Diet: Medical nutrition therapy

is recommended for all persons with DM and along
with activity, is a cornerstone of treatment
 Type 1 DM, the focus is on regulating insulin
administration with a balanced diet to achieve and
maintain a healthy body weight
Type 2 DM often require caloric restriction to
promote weight loss, and portion size and
frequency are often issues

41
 Physical Activity:
In general, most patients with DM can benefit from
increased activity
Aerobic exercise improves insulin sensitivity and
glycemic control in the majority of individuals, and
reduces cardiovascular risk factors, contributes to
weight loss or maintenance, and improves well-
being
Physical activity goals include at least 150
minutes/week of moderate (50%–70% maximal
heart rate) intensity exercise
42
Pharmacotherapy of Type 1
Diabetes Mellitus
 Glycemic goals:
Goals for pts < 6 years:
• pre meal goal: 100-180mg/dl; bed time: 110-
200mg/dl; HbA1c: < 8.5%
 Goals for pts 6- 12 years:
• Pre-meal goal: 90-180mg/dl; bedtime: 100-180mg/dl;
HbA1c: < 8%
Goals for pts 13- 19 years:
• Pre-meal goal:90-130mg/dL; Bed time:90 – 150mg/dL;
HbAlc: < 7.5%
Goals for patients > 19 years old:
• pre meal goal: 70-140mg/dl; bed time: 100- 160mg/dl;
43
HbA1c: < 7.0%
Goals in hypertension and
dyslipidemia management in
type 1 DM pts:

44
Pharmacologic Treatment:
Insulins
 Pharmacology: stimulates peripheral glucose
uptake and inhibits hepatic glucose production
 Dosage guidelines:
Insulin is normally injected subcutaneously (SC)
Only regular insulin may be injected intravenously (IV)
The number and size of daily doses, time of
administration, and diet and exercise require continuous
medical supervision
Insulin is prepared as a 100 Units/mL solution (or
suspension) in a 10 mL vial
 Dosage adjustments are made on the basis of
clinical symptoms, diet, physical activity, blood 45
glucose levels, and HbA1C values
  Clearly one two injection of any insulin preparation daily
will in no way mimic normal physiology, and therefore is
unacceptable.
 Injection regimens that begin to approximate physiologic
insulin release start with “split-mixed” injections of a
morning dose of NPH and regular insulin before
breakfast, and again before the evening meal.
 The presumption is made that the morning NPH insulin
gives 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 the evening regular covers the evening
meal.
 The basal-bolus concept is an attempt to replicate normal
insulin physiology with a combination of intermediate- or
longacting insulin to give the basal component, and
short-acting insulin to give the bolus component. 10/18/24
46
 Empirically, patients can begin on ~0.6 unit/kg per day
with basal insulin 50% of total dose and prandial insulin
20% of total dose prebreakfast, 15% prelunch, and 15%
presupper.
 Type 1 DM patients generally require between 0.5 and 1
unit/kg per day.
 During the honeymoon phase it can fall to 0.1 to 0.4
units/kg.
 Insulin pump therapy (continuous subcutaneous insulin
infusion [CSII], generally using lispro or aspart insulin is
the most sophisticated form of basal bolus insulin
delivery system.
 For patients insisting on two injections daily, NPH and
regular insulin (starting at 0.6 units/kg with two-thirds in
the morning, two-thirds of morning dose as NPH, and
47 one-half of evening dose as NPH) may be sufficient. 10/18/24
Insulin Action Times
Type of Onset Peak Duration Maximum Appearan
Insulin (Hours) (Hours) (Hours) Duration ce
(Hours)
Rapid acting
Aspart 15–30 min 1–2 3–5 5–6 Clear
Lispro 15–30 min 1–2 3–4 4–6 Clear
Glulisine 15–30 min 1–2 3–4 5–6 Clear

Short-acting
Regular 0.5–1.0 2–3 4–6 6–8 Clear
Intermediate acting
NPH 2–4 4–8 8–12 14–18 Cloudy
Long acting
Detemir 2 hours — 14–24 24 Clear
48
Glargine 4–5 — 22–24 24 Clear
Two methods of insulin
administration
 Conventional therapy
At least 2 injections of mixed insulins per day
Starts at Insulin Stage 2 and moves to Insulin Stage 3 if
necessary
Food intake is timed to match insulin action
Three meals at specific times and snacks are required
 Intensive therapy
4 injections/day
Starts at Physiologic Insulin Stage 4
Insulin altered to match food plan and lifestyle of patient
Bolus insulin with meals and basal insulin at bedtime
Closer to mimicking physiologic insulin patterns 49
Insulin Stage 2 (Conventional
therapy with 2 injections/day)
 Initial: 0.5 Units/kg for negative to moderate
ketones and 0.7 Units/kg for large ketones
 The insulin schedule is either R/N – 0 – R/N – 0
or RA/N – 0 – RA/N – 0 (AM and PM doses are
about 10 hours apart)
 Initial dosage titration is done on the second
day of treatment
AM MIDDAY PM BED TIME
Insulin dose 2/3 0 1/3 0
Distribution
R/N or RA/N ratio 1:2 -------- 1:1 -------
50
 Maximum:
 total daily insulin >1.5 Units/kg. Consider moving
to the next stage if the patient has not shown
monthly improvement in self-monitoring blood
glucose of 15-30 mg/dL and/or HbA1C of 0.5-1%
within 12 months of adjusting treatment
Move patient to the next stage if at any time the
patient is experiencing persistent AM
hyperglycemia and/or nocturnal hypoglycemia
 Read : handout on empiric insulin dose, etc

51
 Most patients have a local reaction that will dissipate
over time.
 If the allergic reaction does not improve or is systemic,
insulin desensitization can be carried out.
 Because insulin absorption from an area of
lipohypertrophy is unpredictable, avoidance of injections
into these areas is mandatory.
 Several common errors can occur in the therapy of
patients with type 1 DM, causing erratic glucose
fluctuations:
 Failure to take into account peaks of insulin action when using
a peaking insulin and planning meals and/or activity.
 Random rotation of insulin injection sites.
52 10/18/24
 Overinsulinization is a very common problem.
 Adverse Effects.
 The most common adverse effects reported
with insulin are hypoglycemia and weight gain.
 Patients with type1DM tend to have more
hypoglycemic events compared to type2 DM
patients.
 Lipohypertrophy is caused by many injections
into the same injection site.
 Lipoatrophy, in contrast, is thought to be
caused by insulin antibodies, with destruction of
fat at the site of injection.
53 10/18/24
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 <130/80 mmHg (if renal
disease <120/75 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
54
Cont’d…..

 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

55
Micro vascular disease:
Management
 Prevention and recognition of retinopathy,
neuropathy and 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

56
Pharmacotherapy of Type 2
Diabetes Mellitus
 Glycemic goals:
HbA1C goals: <7 % ; Pre-prandial plasma glucose goals: 90-
130 mg/dL; Postprandial plasma glucose: <180 mg/dL
 BP control, Lipid management goals: look under type
1 DM
 Five treatment regimens for type 2 diabetes:
1. Medical nutritional therapy:
• Helps patients achieve goals through a food and activity plan
2. Oral agent monotherapy:
• If patients have an HbA1C <9%, usually monotherapy is used

57
 Start oral agent therapy if :
The patient is newly diagnosed with fasting plasma
glucose between 200-300 mg/dL or casual plasma
glucose between 250-350 mg/dL,
The patient has reached glycemic goals of therapy
and wants to replace low-dose insulin (<0.2
Units/kg).

58
 Select the oral agent based on
clinical indicators
Clinical Indicators Pharmacological
Class
Insulin Resistance Obesity, hypertension, Metformin or
elevated fasting Thiazolidinedione

plasma glucose,
elevated
triglycerides, low HDL
Insulin Deficiency Leaner, elevated post- Sulfonylurea,
prandial plasma
Meglitinides,
glucose, symptoms
Or Alpha-glucosidase
59
inhibitor
 The patient may move to combination of oral agents
(regimen 3) or combination oral agents and insulin
(regimen 4), while continuing medical nutritional therapy
 3. Combination of oral agents from different
classes:
 If patients have an HbA1C between 9-11%, use a
combination of oral agents from different classes
Add a second oral agent after maximum effective dose
of the first oral agent
Patients should take one drug associated with insulin
resistance and one with insulin deficiency
• (i.e., metformin and sulfonylurea or metformin and
repaglinide or thiazolidinedione and sulfonylurea). 60
 4. Combination of oral agent and insulin:
If the patient’s morning fasting plasma glucose
>300 mg/dL, add bedtime NPH or glargine
The patient may move to insulin (regimen 5)
 5. Insulin:
Initiate insulin therapy immediately if fasting
plasma glucose >300 mg/dL or casual plasma
glucose >350 mg/dL without regard to symptoms
With these levels of glucose levels, medical
nutritional therapy or oral agents alone will not be
sufficient to reach glycemic goals
61
Approximate Glucose-lowering
Potential of Type 2 Diabetes
Therapies
Treatment Fasting plasma HbA1C
glucose reduction
reduction
(mg/dl)
Medical 30-60
Nutritional
Therapy
Sulfonylurea 50-60 1- 2%
Metformin 50-60 1-2%
Meglitinide ~60 1-2 %
Thiazolidinedion 50-60 1-2%
62
Pharmacology
 Biguanides:
Metformin (immediate release or oral solution)
• Initial: 500 mg twice daily (given with the morning
and evening meals) or 850mg once daily.
• Adjustments: Gradually increase dosage at
intervals of 1-2 weeks
• 500 mg tablet: One tablet/day at weekly intervals
• 850 mg tablet: One tablet/day every other week
• Oral solution: 500 mg twice daily every other week
• The clinically effective dose is 2000 mg/day. If a dose >
2000 mg/day is required, it may be better tolerated in
three divided doses.
Maximum: 2550 mg/day. 63
 Metformin and glyburide :
Glyburide 1.25 mg/metformin HCl 250 mg; glyburide
2.5mg/metformin HCl 500 mg; glyburide 5 mg/
metformin HCl 500 mg
No prior treatment with sulfonylurea or metformin:
• Initial: glyburide 1.25 mg/metformin 250 mg once
daily with a meal; patients with HbA1C >9% or
fasting plasma glucose >200 mg/dL may start with
glyburide 1.25mg/ metformin 250 mg twice daily.
Maximum: glyburide 10 mg/metformin 2000 mg daily.

64
Previously treated with a sulfonylurea or metformin
alone:
• Initial: glyburide 2.5 mg/metformin 500 mg twice
daily or glyburide 5 mg/metformin 500 mg twice
daily.
• When switching patients previously on a sulfonylurea
and metformin together, do not exceed the daily dose
of glyburide (or glyburide equivalent) or metformin.
• Adjustments: Increase at increments no greater
than 5 mg/500 mg.
• Maximum: glyburide 20 mg/metformin 2000 mg
daily
65
 Sulfonylureas:
• Glyburide
• Non-micronized tablets
• Initial: 2.5-5 mg/day, administered with breakfast or the first
main meal of the day. In patients more sensitive to
hypoglycemic drugs, start at 1.25 mg/day. Serum insulin
levels begin to increase 15-60 minutes after a single dose.
• Adjustments: Increase in increments of no more than 2.5
mg/day at weekly intervals based on the patient’s blood
glucose response. Maintenance: 1.25-20 mg/day
given as single or divided doses
• Maximum: 20 mg/day
• Renal impairment of Clcr <50 mL/minute: Not
recommended.
66
 Safety concerns: Biguanides and sulfonylureas
67
DRUG THERAPY PROBLEMS : US
data

68
  Gestational DM
 Dietary therapy to minimize wide fluctuations in
blood glucose is of paramount importance.
 If FPG is >105 mg/dL, or if 2-hour postprandial
plasma glucose levels are >130 mg/dL, insulin
therapy is usually begun.
 One shot of NPH or a mixture of NPH and regular
insulin in a 2:1 ratio given before breakfast may
be adequate to reach glucose targets.
PAINFUL DIABETIC NEUROPATHY
 To control the pain amitriptyline, should be
added particularly in younger healthier patients,
because of its effectiveness and low cost.
69 10/18/24
 Monitoring complications

 Current recommendations continue to advocate

yearly dilated eye examinations in type 2 DM, and
 an initial eye examination in the first 3 to 5 years
in type 1 DM, then yearly thereafter.
 The feet should be examined and the blood
pressure assessed at each visit.
 A urine test for microalbumin once yearly is
appropriate.
 Yearly testing for lipid abnormalities, and more
frequently if needed to achieve lipid goals, is
recommended.
70 10/18/24
Key concepts
 Diabetes mellitus (DM) is a group of metabolic
disorders of fat, carbohydrate, and protein
metabolism that results from defects in insulin
secretion, insulin action (sensitivity), or both
 The incidence of type 2 DM is increasing
 The two major classifications of DM are type 1
(insulin deficient) and type 2 (combined insulin
resistance and relative deficiency in insulin
secretion)
They differ in clinical presentation, onset, etiology, and
progression of disease. Both are associated with
microvascular and macrovascular disease complications71
 Diagnosis of diabetes is made by 3- 4 criteria:
 fasting plasma glucose>/= 126 mg/dL; a 2-hour value
from a 75-g oral glucose tolerance test 200 mg/dL; a
casual plasma glucose level of >/=200 mg/dL with
symptoms of diabetes; or a HbAlc >/=6.5%. The
diagnosis should be confirmed by repeat testing if
obvious hyperglycemia is not present
 Goals of therapy in DM are directed toward attaining
normoglycemia (or appropriate glycemic control based on
the patient's comorbidities), reducing the onset and
progression of retinopathy, nephropathy, and neuropathy
complications, intensive therapy for associated
cardiovascular risk factors, and improving quality and
72
quantity of life
 Metformin should be included in the therapy for all
type 2 DM patients, if tolerated and not
contraindicated, as it is the only oral
antihyperglycemic medication proven to reduce the
risk of total mortality.
 Intensive glycemic control is paramount for reduction
of microvascular complications (neuropathy,
retinopathy, and nephropathy) in type 1 & 2 DM
 Control of hypertension in patients with diabetes will
not only reduce the risk of retinopathy and
nephropathy, but also reduce cardiovascular risk.
73
 Short-term (3–5 years), intensive glycemic control
does not lower the risk of macrovascular events
 Microvascular event reduction may be sustained,
and macrovascular events reduced by improved
early glycemic control. Significant reductions in
macrovascular risk may take 15 to 20 years
 Type 1 DM treatment necessitates insulin
therapy. Currently, the basal-bolus insulin
therapy or pump therapy in motivated individuals
often leads to successful glycemic outcomes

74