Dr Kyan_Aung

kyan_aung@imu.edu.my
 Learning outcomes
• Describe the drugs used in the management of DM
• Discuss the role of oral hypoglycaemic agents

Aims of Treatment in T2DM

To achieve optimum control of blood glucose in order to:
 relieve the symptoms of hyperglycaemia
 improve or maintain quality of life and psychological
wellbeing
 prevent or delay vascular and other complications of DM
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How to Achieve Objectives?
This requires
• Health Education to the Patient and Family
• Monitoring drug therapy, assessment of glycaemic control &
diet, and titration of dosage
• Regular Consultation with Health Care personnel (doctor,
dietician, nurse)
• Prevention / early detection of adverse effects of any
treatment.
• Lifestyle changes: Low calorie, low fat diet, exercise

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• Muscle Insulin resistance –
Biguanides,Thiazolidinedione:
↑Glucose uptake
• Adipose tissue Insulin
resistance – Biguanides,
Thiazolidinedione:
↑ Glucose utilization
• Liver – Biguanides,
Thiazolidinedione:
↓ Gluconeogenesis
• Complex carbohydrates –
Glucosidase inhibitors,
Biguanides
↓Carbohydrate absorption
• Pancreas – Sulfonylureas,
Meglitinides, DPP-4 inhibitor
(Sitagliptin), Incretin mimetics
Insulin secretagogues
Metabolic dysfunctions in type 2
diabetes and sites of drug action
Pharmacological management: SU
TWO main defects • Tolbutamide
1. Impaired secretion of insulin • Glibenclamide
2. Impaired action of insulin = glyburide
(relative insulin resistance)
TWO main classes of oral antidiabetic drugs • Gliclazide
• Glipizide
Meglitinides
Biguanides
• Metformin
TZD
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Sulfonylureas
• Efficacy: very effective, good blood glucose lowering
• Safety: hypoglycaemia, esp. newly diagnosed, weight gain
• Suitability: non-obese diabetics, those who can take meals
at regular times
Long-term effects
• Increased insulin receptor number,
• increased glucose uptake by muscle,
• reduced glycogenolysis
 MOA: SU promote insulin secretion “secretagogue”
B. Cell membrane
A. Binding of SU with receptor depolarization opens
Ca2+ channel, allowing C. Ca2+ influx causes
closes membrane-bound ATP- degranulation of b-cells
sensitive K+ efflux channels and Ca2+ entry into the cell.
of pancreas (i.e.
causes membrane depolarization secretion of insulin)

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Features of individual drugs – example SU

Note: Tall Man Letters

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How to minimise adverse effects of SU

Other Rare AE: Nausea, vomiting, diarrhoea; thrombocytopenia 9

Sulfonylureas - Contraindications

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 Sulfonylureas – Cautions
Newly diagnosed: risk of hypoglycaemia
There is beta cell recovery when blood glucose
is normalized

Tolbutamide and gliclazide have short duration

of action & metabolized in liver.
 Preferred in
 Renal impairment
 Elderly patient
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 Biguanides: Metformin

First developed in 1920s.

 Started using in the UK in 1958, US 1995.
 Most widely used anti-diabetic drug worldwide.
Do not cause hypoglycemia when used as monotherapy.
Do not cause weight gain: reduces food intake by action
on CNS which reduce appetite.

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 Biguanide: Metformin - Mechanism of action
Actions unrelated to insulin
1. CNS: ↓ appetite (↓ food intake &
results in weight loss)
2. GIT: ↓ intestinal glucose absorption
3. Liver: Inhibition of hepatic
gluconeogenesis & lipogenesis

Actions related to insulin at target

tissue
1. ↑ insulin receptor number and affinity
2. ↓ insulin resistance / ↑ insulin
sensitivity
3. ↑ glucose uptake by muscle in the
presence of insulin
Malin and Kashyap (2014) Effects of metformin on weight loss: potential
mechanisms (Review). Curr Opin Endocrinol Diabetes Obes 2014, 21:323–329 13
 Metformin: Indications
Newly diagnosed

When hypoglycemia is a risk to life: driving,

working with machinery & at heights

When meals cannot be taken on

time
Inquire about the occupation, driving and the meal pattern 14
 Features of Metformin
• Frequency of administration: 1 – 3 times / day
• Time of administration:
Strictly with meals or immediately after meals
• Suitability in renal impairment:
Reduce dose when Cr Clearance is <45 mL/min/1.73m2
Avoid when Cr Clearance is <30 mL/min/1.73m2 2
• Suitable during pregnancy and breast feeding

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 How to minimise adverse effects of Metformin
• Avoid in chronic alcoholic patients –
can increase risk of lactic acidosis
Risk Factors Adverse Effect How to minimise
• Renal insufficiency Common: Start with a low dose and gradually
Nausea, anorexia, loss increase the dose.
• Hepatic disease of appetite & diarrhoea Take with meals or immediately after
• Congestive heart meals. Avoid taking before meals.
failure Long-term Therapy: Supplementary B12
Vitamin B12 deficiency
• Sepsis Rare: Avoid in major organ failure.
• Chronic alcoholism Lactic acidosis (Phenformin) Stop during perioperative period.
Reduce daily dose to <2g in elderly.

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Metformin: Contraindications and Cautions

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Alpha-Glucosidase Inhibitors: Acarbose
• Drugs: Acarbose, miglitol, voglibose
• MOA: Delayed conversion of disaccharides to
monosaccharides in the intestines
• ↓ GI glucose absorption
• ↓ post-prandial glycaemia

• ADR: bacterial action on undigested food in the colon leads

to intolerable GIT SEs (abdominal distension, gas formation);
Liver toxicity (elevated liver enzymes)
• Contraindications: Renal / Liver disease
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 Thiazolidinediones (TZD): Glitazones
• Drugs: rosiglitazone, pioglitazone
• MOA: Binds with PPAR (which modulate
glucose and fat metabolism)
Promote glucose uptake & utilisation
↓ FFA & ↓ triglycerides
↓Insulin resistance & ↑sensitivity
Lowers insulin requirements
ADR: peripheral oedema, weight gain,
heart failure, myocardial infarction,
fractures, macular oedema
Contraindications: CHF, liver disease
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Short-Acting Insulin Secretagogue: Nonsulfonylureas -
Meglitinide group (Nateglinide, repaglinide, mitiglinide)
• MOA: ↑ Insulin secretion (by stimulating rapid and transient
release of insulin through closure of ATP-sensitive K+ channel)
• ↓ postprandial glucose
• Short onset of action, Half-life 1 hr; duration of action 4 hr
• Ingested just before meal [Note: meal must follow immediately]
• ADR: Hypoglycaemia (less with nateglinide)
• Caution: Liver disease, elderly / malnourished pt.,
• CI: diabetic ketoacidosis
NB: Nateglinide used in renal impairment; no dose adjustment
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Incretin mimetics: Dipeptidyl peptidase IV inhibitors
Incretins = GIP (Glucose dependent Insulinotropic Peptide);
GLP = Glucagon Like Polypeptide acts on GLP-1 receptor and
stimulate insulin secretion
• Drugs (Oral): Dipeptidyl peptidase IV inhibitors - sitagliptin
• MOA: Block degradation of incretin  Prolong endogenous
GLP-1 action;
• Well tolerated, do not cause hypoglycaemia;
• ADR: anaphylaxis, severe dermatitis, acute pancreatitis
• CI: renal disease; increased heart failure risk; angioedema
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Incretin mimetics: GLP-1 receptor agonists
• Drugs (Parenteral): Exenatide, liraglutide
• MOA: stimulate beta cells to increase glucose dependent
insulin secretion & reduce hepatic glucose production
[↑Insulin, ↓ glucagon, slow gastric emptying]
Promote early satiety (central effect)
• Weight loss, do not cause hypoglycaemia;

• ADR: injection, nausea, ↑ risk of hypoglycaemia

• CI: CI: Renal disease, agents that also slow GI motility
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 Effects of GLP-1 agonists
CNS: Reduce food and water intake
Increases secretion of insulin
and somatostatin
Reduces glucagon secretion
Increases glycogenesis in liver and
muscle
Increases lipogenesis
Reduces gastric acid secretion
and gastric emptying

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Sodium-glucose co-transporter-2 inhibitors (SGLT2i) and
Amylin agonists
• Sodium-glucose co-transporter-2 inhibitors (oral):
Canagliflozin, dapagliflozin, empagliflozin
• MOA: ↑ Urinary glucose excretion
• Insulin secretion and action independent
• SE: Urinary and vaginal infections, dehydration, exacerbate
tendency to hyperkalaemia
Amylin agonists (parenteral): Pramlintide
• MOA: Slow gastric emptying, ↓ glucagon
• Reduce postprandial glycemia, weight loss
• SE: Injection, nausea, ↑ risk of hypoglycemia with insulin
• CI: Agents that also slow GI motility
Oral antidiabetic drug failure
• Secondary failure: failure after some years
• Apparent secondary failure: common as result of poor
compliance to therapy and the diet
• Check compliance top therapy and the diet
• True secondary failure: not so common, is due to beta
cell exhaustion and failure to produce adequate
insulin
• Rx: a small dose of insulin (6-10 units) is given once a
day in addition to the oral drugs.

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Careful Risk–Benefit Assessment before
prescribing any medicine
Glycaemic control: Most agents lower HbA1c by ~1%
Lipid profile: Metformin lowers LDL; other agents have no effect
Weight: Metformin & GLP-1 agonists (exenatide) reduce weight
• glitazones (TZD) > sulfonylureas, meglitinides, increase weight
• DPP-4 inhibitors (sitagliptin) are weight neutral
Hypoglycaemia: sulfonylureas, glitazones & repaglinide
Adverse effects specific to agent:
• Metformin: lactic acidosis (uncommon); GI upset (common)
• glitazones (TZDs) increase risk of heart failure
• -glucosidase inhibitors > glitazones > SU: liver damage
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 Monitoring Patients

• Fasting blood glucose: fasting for 8-12 hours

• Post prandial blood glucose: At 2 hours following

a main meal (break-fast , lunch and dinner)

• Haemoglobin A1c (HbA1c): non fasting blood test,

gives the control over the previous 3 months

• Newly diagnosed patients should be tested

preferably once a week and blood glucose targets
should be achieved early preferably in one month 27
 Special situations: pregnancy and breast feeding
Type DM:
• Metformin is recommended in pregnancy & breast feeding

Gestational Diabetes:
Metformin should be discontinued after delivery
• Sulfonylureas are relatively contraindicated:
SU need to be discontinued only with the commencement of
insulin/metformin in pregnancy.

13. Management of Diabetes in Pregnancy Diabetes Care 2017;40(Suppl. 1):S114–S119 | DOI: 10.2337/dc17-S016
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Principles of Therapy

1. Start with a suitable low dose (mono -therapy)

2. Continue dietary adjustment during therapy
3. Monitor fasting blood glucose and 2 hour
postprandial blood glucose
4. Adjust the dose accordingly
5. The relevant meal (quality and quantity )
should be considered when adjusting the dose
6. Add a second drug in low dose, early if needed
7. Try to achieve targets for control early
8. Prevent adverse effects of treatment 29
 The principles of combination therapy
 Add a second oral anti-diabetes drug that has a different
mechanism of action
e.g. metformin + sulfonylurea
Two medications in low doses rather than an increase in
initial medicine to max. dosage
 Fewer side effects than mono-therapy
at higher doses
 NEVER combine 2 SUs

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 Combination Therapy
Need to adjust for individual patients based on
Preferences, Risks from polypharmacy, Risks from tight blood glucose control,
Ability to achieve long term benefits
 Summary
• Lifestyle changes FIRST: the diet, weight and exercise

• Prevent glucotoxicity by avoiding sugar containing food and drinks

• Start with a suitable oral antidiabetic drug early; metformin is

suitable in newly diagnosed

• Commonest cause of treatment failure is poor compliance to the

diet and the treatment

• Combining metformin with a low dose SU is recommended for

optimum blood glucose control

Do not delay adding insulin if the blood glucose control is poor.

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 THE END
See also: http://www.bmj.com/content/bmj/353/bmj.i1575.full.pdf 33
Review Questions

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Review Questions

Thank You 35
 True/False Questions from Med Phar Ther 4e
1. Oral hypoglycaemic drugs are only used in type 2 diabetes.
2. Glibenclamide is the drug of choice when there is no residual insulin secretion.
3. Sulfonylureas should be administered in conjunction with a dietary regimen in obese
people.
4. Glibenclamide can cause hypoglycaemia, particularly in the elderly.
5. Metformin and the sulfonylurea gliclazide cannot be taken together.
6. The meglitinides are structurally related to glibenclamide.
7. Oral hypoglycaemics given to a pregnant mother can cause hypoglycaemia in the fetus.
8. Sulfonylureas should not be given together with the antibacterial trimethoprim.
9. Insulin lispro has a longer duration of action than isophane insulin.
10. Dipeptidyl peptidase-4 (DPP-4) synthesises incretin hormones.
11. Acarbose is completely absorbed from the gut after oral administration.
12. Glucagon mobilises glucose from glycogen in the liver.
 Case Study from B & CP 13 th ed 2015
• A 56-year-old Hispanic woman presents with symptoms of fatigue,
increased thirst, frequent urination, and exercise intolerance with
shortness of breath of many months’ duration.
• Unaware of any medical problems & not taking any medications
• Family history is significant for obesity, diabetes, high blood pressure,
and coronary artery disease in both parents and several siblings.
• Five of her six children had a birth-weight of over 9 pounds.
• Physical examination reveals a BMI of 34 & BP 150/90 mm Hg.
• Lab tests: RBS 261 mg/dL; FBG 192 mg/dL. Fasting total cholesterol
264 mg/dL, TG 255 mg/dL, HDL 43 mg/dL, and LDL 170 mg/dL.

 What type of diabetes does this woman have?

 What further evaluations should be obtained?
 How would you treat her diabetes? 37
OBA from MPT 4e 2014
Ms JJ is a 55-year-old housewife with a body mass index (BMI) of
35 kg⋅m−2 . She was diagnosed with type 2 diabetes mellitus. Choose
the correct statement below.
A. The mainstay of treatment is diet and exercise.
B. Diabetes presenting in this way is a medical emergency.
C. A sulfonylurea would be the drug of first choice.
D. Pioglitazone would be the drug of first choice.
E. Treatment with metformin may increase her risk of heart disease.

See notes panel for OBAs from Katzung & Trevor's Pharmacology:
Examination & Board Review, 11e > i-Lib IMU
Pathophysiology of Hyperglycemia in
T2DM and Specific Treatment.
• Insulin
• Biguanides: metformin
• Sulfonylureas: glipizide
• Thiazolidinedione: pioglitazone
• Alpha-glucosidase inhibitors: acarbose
• GLP-1-receptor agonists: exenatide and
liraglutide
• DPP-4-inhibitors:Forsitagliptin
Self-Study
• Amylin mimimetic: pramlintide
• Dopamine agonist: bromocriptine

N Engl J Med 2012;366:1319-27.

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