DRUGS USED IN THE MANAGEMENT OF

DIABETES MELLITUS

LMO MWANZA
 Introduction
Diabetes mellitus (DM) is a metabolic disorder of multiple etiology
characterized by hyperglycemia with carbohydrates, fat, and
protein metabolic alterations that result from a decrease in the
circulating concentration of insulin (insulin deficiency) and a
decrease in the response of peripheral tissues to insulin (insulin
resistance)
Types of diabetes
Type 1 DM: An auto-immune disorder where antibodies destroy
the beta cells of the Islets of Langerhans. It usually occurs in
young children and adolescents.
Type 2 DM: DM of maturity onset in which there is both reduced
sensitivity to insulin and impaired regulation of insulin secretion

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Other types of DM

Secondary causes of DM
• Exocrine pancreas disease: pancreatitis
• Genetic syndromes: Downs, Turners
• Infections: CMV, Congenital rubella
• Drugs: glucocorticoids, phenytoin, beta agonists
• Endocrinopathies: Cushing's, Acromegaly
Gestational DM
• Presents only during pregnancy
• Increased risk of developing diabetes post partum

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 Definition of diabetes mellitus

Indicator American SI
(mg/dL) (mmo/L)

Normal 65 - 99 3.6 – 5.5

Glucose – Fasting
DM > 126 > 7.0

Random (with
DM > 200 > 11.1
symptoms)

GTT (2 hr) DM > 200 > 11.1

HbA1c DM > 6.5%

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Therapy of diabetes mellitus

• Diet
• Exercise
• Insulin and its enhancers
• Oral hypoglycemic drugs

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Insulin

• Insulin is synthesized by the beta cells in the Islets of

Langerhans in the pancreas
• The primary structure of insulin is made from two
polypeptide chains named subunit A and B. Subunit A
consists of 21 amino acids, whereas subunit B consists of 30
amino acids
• Insulin is metabolized in the liver, kidney and muscle

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Modulation of insulin synthesis and release

The synthesis and release of insulin is modulated by:

• Glucose (most important), amino acids, fatty acids and ketone
bodies stimulate release
• Glucagon and somatostatin inhibit release
• α-Adrenergic stimulation inhibits release (most important)
• β-Adrenergic stimulation promotes release
• Elevated intracellular Ca2+ promotes release

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Actions of insulin

Carbohydrate metabolism
• Stimulates the uptake and metabolism of glucose in the
peripheral tissues, especially skeletal muscles and adipose tissue
• Inhibits glucose production in the liver by inhibiting
gluconeogenesis and glycogenolysis
Lipid metabolism
• Inhibits lipolysis in adipose tissue
• Promotes the synthesis of triglycerides
Protein metabolism
• Facilitates amino acid uptake and protein synthesis
• Inhibits protein breakdown
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Mechanism of action of insulin

• Insulin acts by binding to specific receptors, which are present

on almost all cells in the body

• The binding stimulates tyrosine kinase activity of the receptor,

which in turn activates phosphorylation and
dephosphorylation. These reactions stimulate or inhibit the
enzymes involved in the metabolic actions of insulin.

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Insulin preparations

1. Rapid acting (ultra-short acting): insulin glulisine, insulin

aspart, insulin lispro (insulin analogues)

2. Short acting: regular insulin (soluble insulin)

3. Intermediate acting: isophane insulin, lente insulin

4. Long acting: insulin glargine and insulin determir (insulin

analogues), ultralente

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 SHORT ACTING
[Regular insulin (soluble insulin)]
• Crystalline zinc insulin
• Onset: 30 – 60 minutes
• Peak: 2 – 3 hours
• Duration: 6 – 8 hours
• Route of administration: SC, IM and IV
• Administered 30-45 minutes before a meal
• It is the insulin preparation used in diabetic emergencies (e.g.
diabetic ketoacidosis) and in the management for rapidly changing
insulin requirements (e.g. post surgery, acute infection)
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 RAPID ACTING
(Insulin lispro, insulin aspart and insulin glulisine)
• Have more rapid absorption, and rapid onset and offset compared
to regular insulin
• Have rapid onset and ultra short duration of action
• Onset: 5-15 minutes
• Peak: 60-90 minutes
• Duration: 3-5 hours
• Allow for possibility of more flexible treatment regimens
• Have low risk of hypoglycemia

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Insulin lispro, insulin aspart and insulin glulisine …. cont’d

• Advantages include: (1) increased convenience-can take just

prior to meal (2) better postprandial glycemic control (3) less
often associated with hypoglycaemia
• Disadvantages include: (1) short duration of action-can be
problematic in Type 1 diabetic without basal insulinization (2)
more expensive than regular insulin (double the cost)
• Ultra-short acting insulins analogues are given 15 min before
or immediately after starting a meal
• Given SC only

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 INTERMEDIATE ACTING
(Lente insulin)

• Onset is slower but more sustained than regular insulin

• Onset: 2 – 4 hours
• Peak: 4 – 12 hours
• Duration: 12 – 20 hours
• Given SC only
• Has not been produced since 2005

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Isophane insulin (Neutral protamine Hagedorn [NPH])

• A suspension of crystalline zinc insulin combined with

protamine (a polypeptide). The conjugation with protamine
delays its onset of action and prolongs it action.
• Onset: 2 - 4 hours
• Peak: 4 – 10 hours
• Duration: 12 – 18 hours
• Given SC only
• NPH insulin is usually mixed with regular insulin for twice daily
administration
• Can also be given in combination with lispro, aspart or
glulisine insulin
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 LONG ACTING
(Ultralente insulin)

• A suspension of zinc insulin forming large particles which

dissolve slowly, delaying onset and prolonging duration of
action
• Onset: 6 – 10 hours
• Peak: 10 – 16 hours
• Duration: 18 – 24 hours
• Given SC only

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Insulin glargine

• Precipitates at the injection site and this extends its duration

of action

• Onset: 2 – 4 hours

• Has a flat, prolonged hypoglycemic effect (i.e. it has no peak)

• This maximum activity is maintained for 11 – 24 hours

• Duration: 20 – 24 hours

• Given SC only

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Detemir insulin

• Has a fatty acid complexed with insulin resulting in slow

dissolution
• Properties similar to insulin glargine
• Associated with less hypoglycemia than NPH insulin
• Dose-dependent onset of 1-2 hours
• Duration: 20 hours
• Given twice daily to obtain a smooth background insulin level
• Given SC only

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Insulin dosing

Initial dose
0.5-1 unit/kg per day SC
Maintenance dose
Adjust doses to achieve pre-meal and bed time glucose level of
4.4-7.8 mmol/L
Dosage adjustment in renal impairment
• Creatinine clearance 10-50 ml/min: administer 75% of normal
dose
• Creatinine clearance < 10 ml/min: administer 25-50% of
normal dose
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Adverse effects of insulin

• Hypersensitivity reactions: treated with histamine H1 receptor

antagonist and glucocorticoids
• Hypoglycemia: the most frequent and important adverse effect
of insulin
• Lipodystrophy (lipo-atrophy and lipohypertrophy )at injection
sites
• Insulin resistance: with chronic insulin resistance, there is need
for >200 units/day. Acute insulin resistance is induced by stress.
Insulin resistance, hypersensitivity reactions and lipodystrophy are
less experienced with human insulins produced by recombinant
DNA technology

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Drug interactions affecting insulin

Drugs that decrease hypoglycemic effect

• Acetazolamide
• Thiazide and loop diuretics
• Oral contraceptives
• Adrenergic beta2 receptor agonists: salbutamol and epinephrine
• Phenothiazine
• Asparaginase
• Corticosteroids
• Protease inhibitors
• Lithium
• Thyroid hormones
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Drug interactions affecting insulin …. cont’d

Drug that increase hypoglycemic effect

• Alcohol (ethanol)
• Fluoxetine
• Sulphonamides
• β blockers (can mask the symptoms of hypoglycaemia)
• Clonidine
• Pentamidine and quinine (stimulates pancreatic beta cells to
release insulin)

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Insulin contraindications

• Hypoglycaemia

• Allergy or sensitivity to any ingredient of the product

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Non-Insulin anti-hyperglycemic agents

• Biguanides

• Sulfonylureas

• Meglitinides

• Thiazolidinediones

• Alpha-glucosidase inhibitors

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 Biguanides
Class Biguanides
Compound Metformin
Mechanism Activates AMP-kinase
Action(s) • Hepatic glucose production 
• Intestinal glucose absorption 
• Insulin action 
Glucose • Fasting
Lowering • Post Prandial
Effect
Advantages • No weight gain
• No hypoglycemia
• Reduction in cardiovascular events and mortality
• Can be combined with insulin to reduce insulin
requirements
Disadvantag • Gastrointestinal side effects (nausea, diarrhea,
es abdominal cramping)
• Lactic acidosis (rare) 25
Vitamin B deficiency
Metformin …. cont’d

Clinical use
• Oral anti-diabetic drug of choice in obese type II DM patients
• Can be used as monotherapy, and in combinations with insulin,
insulin secretagogues and thiazolidinediones
Contraindications
• Conditions that predispose to lactic acidosis: renal or hepatic
impairment, alcoholism, chronic lung disease, heart failure,
sepsis, metabolic acidosis (predisposing factors to lactic acidosis)
• Others contraindications: malabsorption, GI intolerance, marked
weight loss, vitamin B12 deficiency

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Sulfonylureas
Class Sulfonylureas
Compound • 1st generation: tolbutamide, chlorpropamide
• 2nd generation: glibenclamide (glyburide),
glipizide, gliclazide (more potent than 1st
generation)
• 3rd generation: glimepiride (most potent)
Mechanism Closes KATP channels on β-cell plasma
membranes
Action(s)  Insulin secretion
Advantages • Generally well tolerated
• Reduction in cardiovascular events and
mortality
Disadvanta • Relatively glucose-independent stimulation of
ges insulin secretion: Hypoglycemia, including
episodes necessitating hospital admission
and causing death
• Weight gain
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• Primary and secondary failure
Sulfonylureas: pharmacodynamics

Mechanism of action
• Stimulate insulin release from beta cells via binding to the
sulfonylurea (SU) receptor (which is the K+ATP channel)
• Binding of the drug makes the channel close. This results in
reduced K+ efflux leading to depolarisation
• Depolarisation opens Ca2+ channels, resulting in insulin release
from the beta cells
Additional effects
• They reduce serum glucagon levels
• They block K+ channels in extra-pancreatic tissues

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Sulfonylureas: duration of action

Short acting (given three times daily)

• Tolbutamide (DOA 6 – 8 hours)
Intermediate acting (given once or twice daily)
• Glibenclamide (DOA 18 – 24 hours)
• Glipizide (DOA 12 – 18 hours)
• Glimepiride (DOA 12 – 24 hours)
Long acting (given once daily)
• Chlorpropamide (36 – 48 hours)

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Sulfonylureas: adverse effects

Hypoglycemia
• Most frequent adverse reaction
• Consider dose, patient's age, kidney/liver dysfunction, half-life of
the drug and drug interactions
• Most often seen with chlorpropamide
• Elderly patients with impaired hepatic or renal functions are
particularly susceptible. Tolbutamide, the short acting SU, is less
likely to cause hypoglycaemia, and is therefore preferred in
patients who are susceptible to hypoglycaemia.
• These cases of hypoglycemia are treated by IV glucose infusion

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Sulfonylureas: other adverse effects

• Increased appetite and weight gain: insulin secretion-related

effect. Can be a major problem in obese patients with
metabolic syndrome.
• GIT disturbances: nausea and vomiting (more common with
1st generation SUs)
• Dermatological reactions (more common with 1st generation
SUs)
• Other adverse effects: cholestatic jaundice, hepatic damage,
disulfiram-like effects, anti-diuretic hormone effect
(chlorpropamide) and leukopenia

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Sulfonylureas: contraindications

• Type 1 diabetes mellitus

• Pregnancy and lactation

• Significant hepatic or renal failure

• Glibenclamide is contra-indicated in all degrees of renal

impairment

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Sulfonylureas: clinical use

• The sulfonylureas are used as adjuncts to diet and exercise in

patient with Type II DM
• Although they are occasionally used as monotherapy,
sulfonylureas are more commonly used in combination with
other oral anti-diabetic agents in patient who do not reach
glycemic goals
• General dosing guidelines are to start with low dose and
titrate according to patient response while monitoring for
signs and symptoms of hypoglycemia
• Use caution in patient with renal and hepatic impairment

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Meglitinides

Class Meglitinides
Compound • Repaglinide
• Nateglinide
Mechanism Closes KATP channels on β-cell plasma
membranes
Action(s) Insulin secretion 
Advantage Accentuated effects around meal
s ingestion
Disadvanta • Hypoglycemia, weight gain
ges • Dosing frequency

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Meglitinides (nateglinide and repaglinide)

• Have a rapid onset and short duration of action compared to

sulfonylureas
• Nateglinide has a more rapid onset onset of action and is
more specific for pancreatic potassium channels than
repaglinide
• These drugs are metabolized by the liver and should not be
used in patients with hepatic impairment

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Meglitinides …. cont’d

Clinical use
• Used in the management of Type II DM
• Often combined with biguanides or thiazolidinediones
• Administered shortly before meals
Meglitinides are useful in the following:
• Elderly patients in whom hypoglycaemia is a concern
• Patients with renal failure or mild hepatic impairment
• Patients taking low-dose sulphonylureas who encounter
problems with hypoglycaemia
• Patients with irregular meal patterns

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Thiazolidinediones (TZD)

Class Thiazolidinediones (Glitazones)

Compound Pioglitazone
Mechanism Activates the nuclear transcription
factor PPAR-
Action(s) Peripheral insulin sensitivity 
Advantages • No hypoglycemia
• HDL cholesterol 
• Triglycerides 
Disadvantag • Weight gain
es • Edema
• Heart failure (Contraindicated with
stage III and IV)
• Bone fractures
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Thiazolidinediones (TZD)

Class Thiazolidinediones (Glitazones)

Compound Rosiglitazone
Mechanism Activates the nuclear transcription factor
PPAR-
Action(s) Peripheral insulin sensitivity 
Advantages No hypoglycemia
Disadvantag • LDL cholesterol 
es • Weight gain
• Edema
• Heart failure (CI with stages III and IV)
• Bone fractures
• Increased cardiovascular events
(mixed evidence)
• FDA warnings on cardiovascular safety
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Thiazolidinediones
TZDs act by increasing tissue sensitivity to insulin.
TZDs are agonists on peroxisome proliferator-activated receptor γ.
Activation of these receptors induces the synthesis of genes which
enhance insulin action.
TZDs predominantly affect liver, skeletal muscle and adipose tissue:
• Liver: reduce gluconeogenesis
• Muscle: increase glucose uptake
• Adipose tissue: increase glucose uptake and decrease fatty acid
synthesis
TZDs reduce plasma glucose and triglycerides
Actions of TZDs require the presence of insulin
Enhance effectiveness of both endogenous and exogenous insulin 39
TZDs …. cont’d

Clinical effects and use

• Glucose lowering effect is slow in onset: maximum
therapeutic effect is achieved in 6 – 12 weeks
• Used as adjuvants to sulfonylureas or metformin in Type II DM
• Euglycemics rather than hypoglycaemics
• Liver function should be monitored regularly
Adverse effects
• Weight gain, anaemia, headache, fatigue, GIT disturbances
• May cause oedema and precipitate or worsen heart failure
(contraindication)

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Alpha-glucosidase inhibitors

Class Alpha-glucosidase inhibitors

Compound • Acarbose
• Miglitol
Mechanism Inhibit intestinal alpha-glucosidase, the
enzyme that breaks down starch,
oligosaccharides and disaccharides before
they can be absorbed
Action(s) Intestinal carbohydrate digestion and
absorption slowed thus decreasing
postprandial glucose levels
Advantage • Nonsystemic medication
s • Postprandial glucose 
Disadvanta • Gastrointestinal side effects (gas,
ges flatulence, diarrhea)
• Dosing frequency 41
Alpha-glucosidase inhibitors …. cont’d

Advantages
• Selective for postprandial hyperglycaemia
• Do not cause hypoglycaemia
Clinical use
• Can be used as monotherapy in Type II DM and in combination with all
drug classes including insulin
• Taken just before ingestion of first portion of the meal
Adverse effects
GIT disturbances – flatulence, diarrhea, abdominal pain
Contra-indications
• Inflammatory bowel disease (ulcerative colitis or Crohn's disease)
• Intestinal obstruction
• Kidney disease

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 Treatment targets in DM

Target Treatment AACE/ACE ADA 2012

Goal 2011
A1c ≤ 6.5% < 7%

Fasting Plasma Fasting < Preprandial 3.9 – 7.2

Glucose 6.1mmol/L mmol/L

Postprandial Plasma 2-hr postprandial < Peak < 10 mmol/L

Glucose 7.8 mmol/L

*Individualize goals based on these values.

†Postprandial glucose measurements should be made 1–2 h after
the beginning of the meal, generally peak levels in patients with
diabetes
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Type I DM pharmacotherapy

Aim: to maintain blood glucose as close to normal as possible,

and to avoid wide swings in their levels (that contribute to long-
term complications)
• Requires adherence to special diet and regular living habits
• Compliance is essential
• Standard therapy: twice daily
• Intensive therapy: 3 or more daily doses
• Usually combination of short acting insulin (mimic post
prandial insulin secretion) and long acting preparations (basal
secretion, antagonize glucose released from the liver)
• Therapy monitoring: blood glucose (self-monitoring improves
compliance) and glycated hemoglobin (HbA1c)

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Type II DM pharmacotherapy

Aim: To maintain blood glucose within normal limits and to

prevent the development of chronic complications
Diet + weight reduction + pharmacological approach
Drugs in Type II DM
• Oral hypoglycemic agents is the standard treatment
• Insulin in specific situations only, such as acute complications
(stress, infection, surgery, disease, pregnancy) and when the
disease is finally worsening beyond manageability with oral
medications

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Management of Type II DM

• Metformin + lifestyle changes at diagnosis (providing no

contraindication to metformin)
• Medications are ALWAYS to be used in combination with
healthy meal planning and regular physical activity (150
minutes per week)
• If marked elevation of HbA1c/blood glucose and/or
symptomatic consider insulin (+/– other agents) from the outset
• If non-insulin monotherapy at maximal tolerated dose does not
achieve/maintain the HbA1c goal over 3–6 months, add a
second oral agent, or insulin
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Management of type II DM …. cont’d

Use of Oral Agents to Optimize Glycemic Control

• Choice of oral agents needs to be matched with patient
characteristics (thin vs. obese) as well as concurrent medical
conditions (renal, hepatic, cardiopulmonary status)
• Diabetes is a progressive disease, and will require an
increasing number of agents and/or addition of insulin as the
duration of diabetes increases
• Each oral agent can only improve HbA1c a maximum of 2%, so
if poor control persists on multiple agents, insulin is needed

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Management of type II DM …. cont’d

Failure of a single oral agent

• Type 2 diabetes is a progressive disease, with continued loss of beta
cell function over time
• Need to progress to multi-drug therapy or add insulin in order to
maintain a similar level of glycemic control
• If glycemic goals are not met with agent in one class, we must add
second agent with different mechanism of action or add insulin
• America Diabetes Association consensus algorithm recommends
addition of a sulfonylurea, thiazolidinedione, or insulin if metformin
therapy is not effective in getting patients to achieve the desired
glycaemic goals

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 ENDE
“Happiness comes when your work and words are of
benefit to others”

[Gautama Buddha]

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