PHARMACOLOGY OF DIABETES

MELLITUS

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Diabetes mellitus is defined as an elevated blood glucose
associated with
◦ absent or inadequate pancreatic insulin secretion, with or
without concurrent impairment of insulin action.

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Pancreatic islet cells and their secretory products

09-Sep-22 3
The disease states underlying the diagnosis of diabetes
mellitus are now classified into four categories:
◦ Type 1,
◦ Type 2,
◦ Other, and
◦ Gestational diabetes mellitus

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The hallmark of type 1 diabetes is
◦ Selective beta cell (B cell) destruction and

◦ Severe or absolute insulin deficiency.

◦ Immune-mediated (type 1a) and

◦ Idiopathic causes (type 1b).

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The immune form is
◦ The most common form of type 1 diabetes

◦ The onset can occur at any age

◦ Most patients are younger than 30 years

◦ Found in all ethnic groups

◦ Only 10–15% of patients have a positive family history

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 ◦ Develop diabetic ketoacidosis

• It develops because of accelerated fat breakdown to

acetyl-CoA, which, in the absence of aerobic
carbohydrate metabolism, is converted to acetoacetate
and beta-hydroxybutyrate (which cause acidosis) and
acetone (a ketone)

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Type 2 diabetes is characterized by

◦ Tissue resistance to the action of insulin combined with a

relative deficiency in insulin secretion.

◦ May not require insulin to survive, but 30% or more will

benefit from insulin therapy to control blood glucose.

◦ Develop nonketotic hyperosmolar coma

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Gestational diabetes (GDM) is defined as any abnormality in
glucose levels noted for the first time during pregnancy.

During pregnancy, the placenta and placental hormones

create an insulin resistance that is most pronounced in the
last trimester.

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 complications of Dm
◦ Results of disease of blood vessels,either

◦ Large (macrovascular disease) or

◦ Small (microangiopathy).

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Macrovascular disease consists of acclerated atheroma
◦ Which predispose heart disease, hypertension, and stroke

◦ Which is much more common and severe in diabetic

patients.

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Microangiopathy particularly affects the
◦ Retinopathy,

◦ Nephropathy, and

◦ Neuropathy

Coexisting hypertension promotes progressive renal damage.

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 non Drug treatment
• Exercise

• Dietary modification

• Weight reduction

•Diet and exercise are important components of therapy in

patients with type 1 diabetes

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 Drug treatment-insulin
Insulin is a small protein ,contains 51 amino acids arranged in
two chains (A and B) linked by disulfide bridges

there are species differences in the amino acids of both

chains.

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Proinsulin is processed within the golgi apparatus of beta
cells and packaged into granules

It is hydrolyzed into insulin and c-peptide by removal of

four amino acids

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. Insulin is released from pancreatic beta cells at
◦ A low basal rate and

◦ A much higher stimulated rate in response to a variety of

stimuli, especially glucose

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•Hyperglycemia results in
• Increased intracellular ATP levels

• which close the ATP-dependent potassium channels

• Decreased outward potassium efflux results

• in depolarization of the beta cell

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 • Opening of voltage-gated calcium channels.

• The resulting increased intracellular calcium triggers

secretion of the hormone

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The liver and kidney are the two main organs that remove
insulin from the circulation.

The liver normally clears the blood of approximately 60%

of the insulin released from the pancreas by virtue of its
location as the terminal site of portal vein blood flow, with
the kidney removing 35–40% of the endogenous hormone.

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In insulin-treated diabetics receiving SC insulin injections,
this ratio is reversed, with as much as 60% of exogenous
insulin being cleared by the kidney and the liver removing
no more than 30–40%.

The half-life of circulating insulin is 3–5 minutes.

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After insulin has entered the circulation, it diffuses into
tissues, where it is bound by specialized receptors that are
found on the membranes of most tissues.
◦ The primary target tissues regulating energy metabolism,
ie, liver, muscle, and adipose tissue.

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The receptors bind insulin with high specificity and affinity

The full insulin receptor consists of two covalently linked

heterodimers, each containing
◦ an α subunit, constitutes the recognition site

◦ a β subunit ,contains a tyrosine kinase.

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The binding of an insulin molecule to the α subunits at the
outside surface of the cell activates the receptor

through a conformational change brings the catalytic loops

of the opposing cytoplasmic β subunits into closer proximity.

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This facilitates mutual phosphorylation of tyrosine residues
on the β subunits

Tyrosine kinase activity directed at cytoplasmic proteins

◦ Translocation of glucose transporters especially GLUT 4

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Insulin receptor substrate

Mitogen-activated protein

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 effects of insulin

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characteristics of insulin preparations

Insulin preparations differ in a number of ways,

◦ Recombinant DNA production techniques

◦ Amino acid sequence

◦ Concentration

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 ◦ Solubility

◦ Appearance (clear or cloudy), and

◦ The time of onset of action

◦ Duration of their biologic action

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Four principal types of injected insulin's are available:
◦ Rapid-acting, with very fast onset and short duration;

◦ Short-acting, with rapid onset of action;

◦ Intermediate-acting; and

◦ Long-acting, with slow onset of action

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extent anD Duration of action of various types of insulin

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 after subcutaneous injection

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All insulins should be refrigerated and brought to room
temperature just before injection.

Insulin glargine and insulin detemir are clear, soluble long-

acting insulins.

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Injected rapid-acting and short-acting insulins are
dispensed as

clear solutions at neutral pH and

contain small amounts of zinc to improve their stability and

shelf life.

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Injected intermediate-acting NPH insulins
◦ dispensed as a turbid suspension at neutral pH with
protamine in phosphate buffer (neutral protamine
Hagedorn [NPH] insulin).

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With the exception of NPH insulins, all insulins available
today are supplied as clear, colorless solutions.

Because NPH insulins are suspensions, their particles must

be evenly dispersed prior to loading the syringe

The most common sites of SC injection are the upper arm,

thigh, and abdomen.

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The goal of subcutaneous insulin therapy is to
◦ Replicate normal physiologic insulin secretion

◦ Replace the background or basal (overnight, fasting, and

between-meal) as well as bolus or prandial (mealtime)
insulin.

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• Insulin is destroyed in the GIT, and must be given
parenterally (s.c., i.v., i.m.) or inhalational

• Owing to its peptide structure, insulin would be

inactivated by the digestive system if it were given by
mouth

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Intensive regimens involving multiple daily injections (MDI)
◦ To restore near-normal glucose patterns throughout the
day

◦ Minimizing the risk of hypoglycemia.

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 ◦ Long-acting insulin analogs to provide basal or background
coverage, and

◦ Rapid-acting insulin analogs to meet the mealtime

requirements.

Most insulins are available in a concentration of 100 U/mL

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mixtures of insulins

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Mass production of human insulin and insulin analogs by
Recombinant DNA techniques is carried out by inserting
the human or a modified human proinsulin gene into
escherichia coli or yeast

Treating the extracted proinsulin to form the insulin or

insulin analog molecules.

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 insulin Delivery systems
•Standard delivery
• The standard mode of insulin therapy is subcutaneous
injection using conventional disposable needles and
syringes.

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•Portable pen injectors
• To facilitate multiple subcutaneous injections of insulin,
particularly during intensive insulin therapy
• Well accepted by patients because they eliminate the
need to carry syringes and bottles of insulin to the
workplace and while traveling.

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•Continuous subcutaneous insulin infusion devices (CSII,
insulin pumps)
• Are external open-loop pumps for insulin delivery.

• Have a user-programmable pump that delivers

individualized basal and bolus insulin replacement doses
based on blood glucose

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Inhaled insulin
• Peak levels are reached in 12 -15 minutes

• Significantly faster in onset and shorter in duration than

subcutaneous insulin.

• Adverse effect of inhaled insulin was cough

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 insulin regimens
Intensive insulin therapy
◦ Prescribed for almost everyone with type 1 diabetes

◦ Many with type 2 diabetes

Generally, the total daily insulin requirement in units is

equal to 0.55 times the person’s weight in kilograms.

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With improved purification techniques, the unit is presently

defined on the basis of weight, and present insulin

standards used for assay purposes contain 28 units per

milligram.

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Approximately half the total daily insulin dosage covers the
background or basal insulin requirements,

The remainder covers meal and snack requirement

This is an approximate calculation and has to be

individualized.

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In intensive insulin regimens, the meal or snack and high
blood sugar correction boluses are prescribed by formulas.

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The patient uses the formulas to calculate the rapid-acting
insulin bolus dose by considering
◦ how much carbohydrate is in the meal or snack,

◦ the current plasma glucose, and

◦ the target glucose.

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The formula for the meal or snack bolus is expressed as an
insulin-to-carbohydrate ratio
◦ How many grams of carbohydrate will be disposed of by 1
unit of rapid acting insulin.

Continuous subcutaneous insulin infusion devices provide

the most sophisticated and physiologic insulin replacement.

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Conventional insulin therapy

Conventional insulin therapy is

◦ usually prescribed only for certain people with type 2
diabetes who are felt not to benefit from intensive
glucose control.

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 ◦ The insulin regimen ranges from one injection per day to
many injections per day, using intermediate- or long-
acting insulin alone or with short- or rapid-acting insulin
or premixed insulins.

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Insulin is required by
• All patients with type 1 diabetes

• Some with type 2 diabetes.

• Treatment of hyperkalemia

• Because of its ability to promote cellular uptake of

potassium

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insulin treatment of special circumstances

Diabetic Ketoacidosis
◦ Aggressive intravenous hydration and insulin therapy and

◦ Maintenance of potassium and other electrolyte levels.

◦ Fluid therapy generally begins with normal saline.

◦ Regular human insulin should be used for intravenous

therapy with a usual starting dosage of about 0.1 U/ kg/h.

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Hyperosmolar hyperglycemic syndrome

It is diagnosed in persons with type 2 diabetes and is

characterized by profound hyperglycemia and dehydration.

A plasma glucose of over 600 mg/dl, and a calculated serum

osmolality higher than 320 mmol/l.

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Persons with HHS are not acidotic

The treatment is

aggressive rehydration and restoration of glucose and

electrolyte homeostasis

Low-dose insulin therapy may be required.

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 complications of insulin therapy
Hypoglycemic reactions are the most common complication
of insulin therapy.
Inadequate carbohydrate consumption,

Unusual physical exertion, or

Too large a dose of insulin.

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All the manifestations of hypoglycemia are relieved by
Glucose administration.

Dextrose tablets, glucose gel, or any sugar-containing

beverage or food may be given (mild)

Give 20–50 ml of 50% glucose solution by intravenous

infusion over a period of 2–3 minutes (severe)

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 1 mg of glucagon injected either subcutaneously or
intramuscularly

Small amounts of honey or syrup can be inserted into the

buccal pouch.

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Insulin allergy
◦ An immediate type hypersensitivity, is a rare condition in
which local or systemic urticaria results from

◦ Histamine release from tissue mast cells sensitized by

anti-insulin ige antibodies.

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 ◦ Because sensitivity is often to noninsulin protein
contaminants,

◦ the human and analog insulins have markedly reduced the

incidence of insulin allergy, especially local reactions.

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 Immune insulin resistance

A low titer of circulating IgG anti-insulin antibodies that

neutralize the action of insulin to a negligible extent
develops in most insulin-treated patients.

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 Lupus erythematosus

• The titer of insulin antibodies leads to insulin resistance

and may be associated with other systemic autoimmune
processes

Hypokalemia
Weight gain

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Lipodystrophy at injection sites
◦ Injection of animal insulin preparations

◦ Hypertrophy of subcutaneous fatty tissue remains a

problem if injected repeatedly at the same site.

◦ Corrected by avoiding the specific injection site or by

liposuction

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 oral antiDiabetic agents
For the treatment of persons with type 2 diabetes:
◦ Agents that bind to the sulfonylurea receptor and
stimulate insulin secretion

◦ (sulfonylureas, meglitinides, d-phenylalanine derivatives);

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 ◦ Agents that lower glucose levels by their actions on liver,
muscle, and adipose tissue

◦ (biguanides, thiazolidinediones)

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 ◦ Agents that principally slow the intestinal absorption of
glucose

◦ (α-glucosidase inhibitors);

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 ◦ Agents that mimic incretin effect or prolong incretin
action

◦ (glucagon-like peptide-1 [GLP-1] receptor agonists,

dipeptidyl peptidase-4 [DPP-4] inhibitors),

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 ◦ Agents that inhibit the reabsorption of glucose in the
kidney

◦ (sodium-glucose co-transporter inhibitors [sglts]), and

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 sulfonylureas
•They increase insulin release from the pancreas

•They bind to a high affinity sulfonylurea receptor that is

associated with a beta-cell inward rectifier ATP-sensitive
potassium channel

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•Binding of a sulfonylurea
• Inhibits the efflux of potassium ions through the channel
and results in depolarization.

• Depolarization opens a voltage-gated calcium channel

• Results in calcium influx

• The release of preformed insulin.

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regulation of insulin release in humans

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Sulfonylureas are metabolized by the liver and, with the

exception of acetohexamide, the metabolites are either

weakly active or inactive.

The metabolites are excreted by the kidney and partly

excreted in the bile. (2nd generation)

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The second-generation have greater affinity for their
receptor compared with the first-generation
The lower effective doses and plasma levels

The lower the risk of drug-drug interactions

plasma binding sites or hepatic enzyme action.

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 first-generation sulfonylureas
Tolbutamide Acetohexamide Tolazamide Chlorpropamide

Absorption Well Well Slow Well

Metabolism Yes (rapid) Yes Yes Yes (slow)
Metabolites Inactive Active Active Active
Half-life 4 - 5 hrs 6 – 8 hrs 7 hrs 32 hrs
Duration of Short Intermediate Intermediate Long
action (6 – 10 hrs) (8 – 24hrs) (12 – 18 hrs) ( 20 – 60 hrs)
Excretion Urine Urine Urine Urine
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 seconD-generation sulfonylureas
They are 100–200 times more potent than tolbutamide.

All of the have inactive metabolites

They should be used with caution in patients with

cardiovascular disease or in elderly patients, in whom
hypoglycemia

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 seconD generation sulphonylurea
Glipizide Glibenclamide Glimepiride

(Glyburide)

Absorption Well (food delay) Well Well

Metabolism Yes (90%) Yes Yes

Metabolites Inactive Inactive Inactive

Half-life 2– 4 hrs Less than 3 hrs 5 - 9 hrs

Duration of action 10 – 16 hrs 12 – 24 hrs 12 – 24 hrs

Short- acting
Excretion Urine (10%) Urine Urine
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 siDe effects of sulphonylureas
• Nausea, vomiting, abdominal pain, diarrhea

• Hypoglycaemia

• Dilutional hyponatraemia and water intoxication

(Chlorpropamide)

• Disulfiram-like reaction with alcohol (Chlorpropamide)

• Weight gain
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• Blood dyscrasias (not common; less than 1% of patients)

- Agranulocytosis

- Haemolytic anaemia

- Thrombocytopenia

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• Cholestatic obstructive jaundice (uncommon)

• Dermatitis (Mild)

• Muscle weakness, headache, vertigo (not common)

• Increased cardio-vascular mortality with long-term use ??

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 meglitiniDe analogs
Repaglinide is the first member of the meglitinide group of
insulin secretor

They modulate beta cell insulin release by regulating

potassium efflux through the potassium channels

Repaglinide has a very fast onset of action

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The duration of action is 5–8 hours.

It is hepatically cleared by CYP3A4 with a plasma half-life

of 1 hour.

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The drug should be taken just before each meal

Hypoglycemia is a risk if the meal is delayed or skipped or

contains inadequate carbohydrate.

This drug should be used cautiously in individuals with renal

and hepatic impairment.

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Because of its rapid onset, repaglinide is indicated for use
in controlling postprandial glucose excursions.
◦ Monotherapy or in combination with biguanides.

There is no sulfur in its structure, so repaglinide may be

used in type 2 diabetics with sulfur or sulfonylurea allergy.

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 D-phenylalanine Derivative
Nateglinide stimulates rapid and transient release of insulin
from beta cells through closure of the ATP-sensitive K+
channel.

It is absorbed within 20 minutes after oral administration

with a time to peak concentration of less than 1 hour

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It is metabolized in the liver by CYP2C9 and CYP3A4 with a
half-life of about 1 hour.

The overall duration of action is about 4 hours.

It is taken before the meal and reduces the postprandial

rise in blood glucose levels.

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 Nateglinide is efficacious when given
◦ Alone or in combination with non secretor oral agents
(such as metformin).

Hypoglycemia is the main adverse effect.

It can be used in patients with renal impairment and in the

elderly.
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 biguaniDes
Metformin is the only biguanide currently available

The mechanism of action of the biguanides remains elusive,

◦ Activate the enzyme AMP-activated protein kinase
(AMPK)

◦ Reduce hepatic glucose production

◦ Blockade of hepatic gluconeogenesis

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Patients with type 2 diabetes have considerably
◦ Less fasting hyperglycemia

◦ Lower postprandial hyperglycemia after administration of

biguanides

◦ Hypoglycemia during biguanide therapy is rare.

◦ More appropriately termed “euglycemic” agents

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Metformin has
◦ A half-life of 1.5–3 hours,

◦ Is not bound to plasma proteins,

◦ Is not metabolized, and

◦ Is excreted by the kidneys as the active compound.

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Due to its blockade of gluconeogenesis, the drug may
◦ Impair the hepatic metabolism of lactic acid

◦ Increase the risk of lactic acidosis, which appears to be

a dose-related complication.

In patients with renal insufficiency(biguanides accumulate)

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Metformin is advantages over insulin or sulfonylureas in
treating hyperglycemia
◦ An insulin-sparing agent and

◦ Doesn’t increase body weight

◦ Doesn't provoke hypoglycemia

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Biguanides are
◦ Recommended as first-line therapy for type 2 diabetes.
◦ Indicated for use in combination with
◦ Insulin secretor
◦ Thiazolidinediones in type 2 diabetics in whom oral
monotherapy is inadequate.

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The most common toxic effects of metformin are
• Gastrointestinal (anorexia, nausea, vomiting, abdominal
discomfort, and diarrhea) (20% of patients)-common

• Vitamin B12 deficiency (Peripheral neuropathy or

macrocytic anemia)- interferes with the calcium-
dependent absorption Vitamin B12

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•Lactic acidosis can sometimes occur
• It is more likely to occur

• In conditions of tissue hypoxia

• In renal insufficiency

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 Phenformin (an older biguanide) was discontinued because
of its association with lactic acidosis.

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 thiaZoliDineDiones
They act to decrease insulin resistance.

They are ligands of peroxisome proliferator-activated

receptor gamma (PPAR-γ), part of the steroid and thyroid
superfamily of nuclear receptors.

These PPAR receptors are found in muscle, fat, and liver.

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PPAR-γ receptors modulate the expression of the genes
involved in
◦ Lipid and glucose metabolism,

◦ Insulin signal transduction, and

◦ Adipocyte and other tissue differentiation.

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 ◦ Increased glucose transporter expression (GLUT 1 and
GLUT 4),

◦ Decreased free fatty acid levels

◦ Decreased hepatic glucose output

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Two thiazolidinediones are currently available: pioglitazone
and rosiglitazone

An earlier compound, troglitazone, was withdrawn from the

market because of hepatic toxicity thought to be related
to its side chain.

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Pioglitazone
◦ Is absorbed within 2 hours of ingestion

◦ Is metabolized by CYP2C8 and CYP3A4 to active

metabolites

◦ As a monotherapy and in combination with metformin,

sulfonylureas, and insulin for the treatment of type 2
diabetes.
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Rosiglitazone is
◦ rapidly absorbed and highly protein-bound.

◦ is metabolized in the liver to minimally active metabolites,

predominantly by CYP2C8 and to a lesser extent by
CYP2C9.

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 ◦ As monotherapy, in double combination therapy with a
biguanide or sulfonylurea, or in quadruple combination
with a biguanide, sulfonylurea, and insulin.

The combination of a thiazolidinedione and metformin has

the advantage of not causing hypoglycemia.

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Pioglitazone lowers triglycerides and increases HDL
cholesterol without affecting total cholesterol and low-
density lipoprotein (LDL) cholesterol.

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Rosiglitazone increases total cholesterol, HDL cholesterol,
and LDL cholesterol but does not have significant effect on
triglycerides.

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Troublesome side effects
◦ Increased the risk of angina pectoris or myocardial
infarction.

◦ Fluid retention occurs in about 3–4 % patients

◦ Loss of bone mineral density

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 ◦ Anemia, which might be due to a dilutional effect of
increased plasma volume rather than a reduction in red
cell mass.

◦ Weight gain occurs, especially when used in combination

with a sulfonylurea or insulin.

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 α-glucosiDase inhibitors
The α-glucosidase inhibitors competitively
◦ Inhibit the intestinal α-glucosidase enzymes

◦ Reduce postmeal glucose excursions by delaying the

digestion and absorption of starch and disaccharides

◦ Acarbose , miglitol and voglibose

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Prominent adverse effects of α-glucosidase inhibitors
Flatulence, diarrhea, and abdominal pain
◦ Appearance of undigested carbohydrate in the colon
that is then fermented into short-chain fatty acids,
releasing gas.

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 ◦ Hypoglycemia may occur with concurrent sulfonylurea
treatment

◦ Not a problem with monotherapy or combination

therapy with a biguanide

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combination therapy in type 2 Diabetes
• To achieve glycemic control, a stepwise approach is often
used.

• Drug selection in type 2 diabetes can be complex,

• Owing to the many options that are available.

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• Furthermore, because the disease is progressive, therapy
needs to be more aggressive as time passes
• Progressive decrease in beta-cell mass,

• Reduction in physical activity,

• Decline in lean body mass, or

• Increase in ectopic fat deposition

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Implement lifestyle changes: caloric and carbohydrate
restriction, exercise, and weight loss.

Initiate therapy with just one oral hypoglycemic drug.

◦ For lean patients, try a sulfonylurea.

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 • Because lean patients are usually insulin deficient, and
sulfonylureas stimulate insulin release

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•For obese patients, try metformin.

•Because in obese patients, insulin's target cells tend to be

insulin resistant.

•Metformin can reduce insulin resistance, and has the added

benefit of suppressing appetite, which can help the patient
lose weight.

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• Treat with two oral hypoglycemic drugs.
◦ The three most popular combinations are

◦ Metformin plus a sulfonylurea,

◦ Metformin plus a thiazolidinedione, and

◦ Sulfonylurea plus a thiazolidinedione.

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•Treat with three oral hypoglycemic drugs (e.g., metformin
plus a sulfonylurea plus a thiazolidinedione)

•Treat with an oral hypoglycemic plus insulin.

• For lean patients, try a sulfonylurea plus insulin.

• For obese patients, try metformin plus insulin.

•Treat with insulin alone. Increase the dose as needed.

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