Pharmacotherapy of Diabetes

Mellitus
Dr Naser Ashraf Tadvi
Associate Professor
Kamineni Institute of Medical
Sciences
Narketpally, Nalgonda
 Diabetes
• Diabetes is a group of metabolic
disorders characterized by chronic
hyperglycemia associated with
disturbances of carbohydrate, fat and
protein metabolism due to absolute or
relative deficiency in insulin secretion
and/or action
• Diabetes causes long term damage,
dysfunction & failure of various organs
 Diagnosis of diabetes

• Fasting Plasma Glucose ≥ 126 mg / dl

• Symptoms of DM and a random blood
glucose level of ≥ 200 mg/dl
• Oral glucose tolerance test
– 2 hr after 75 gm glucose load ≥ 200 mg / dl
 Classification of Diabetes
Proposed by ADA - 1997.
• Type I:
– Absolute Insulin Deficiency due to islet cell
destruction
• Either immune mediated or idiopathic
• Type II:
– Relative insulin deficiency due to impaired -cell
function
– Marked ↑ peripheral insulin resistance
• Type III: Other Specific types
• Type IV: Gestational Diabetes
 Other specific types
A) Genetic defects of Beta cell function MODY Syndromes

B) Genetic defects in Insulin action Lipo atrophic Diabetes

C) Diseases of the Exocrine Pancreas FCPD

Pancreatitis
D) Secondary to Endocrinopathies Acromegaly
Trauma
Cushings Syndrome
Neoplasia
Steroids
Pheochromocytoma
Cystic Fibrosis
E) Drugs / Chemical induced
Thiazides
Hyperthyroidism
Hemochromatosis
Diazoxide
F) Infections Congenital Rubella
Beta Blockers
CMV
Thyroid Hormones
G) Uncommon form of Immune Mediated Diabetes.
Anti insulin Receptor Antibodies
H) Other Genetic Syndromes associated with Diabetes
Down’s Syndrome
Turners
Klinefelters
Type 2 Diabetes
β cells : insulin 65-70 %
cells : glucagon 25 %
δcells : somatostatin 10 %
PP (or F cells): pancreatic polypeptide 2 %
 Physiology of Human Insulin
Beta cell statistics
• Only 2% of the pancreas weight is
endocrine. 98 % Exocrine
• Total number of Islets…. 1 lakh
• Number of cell / Islet 1-2 thousand
• Beta cells / Islet 65-70 %
• Total Insulin storage 200 units
• Daily insulin release 40 -50 units
• 1 unit Insulin 8-10 gm. Glucose
Insulin
Discovery of insulin
 The Miracle of Insulin

Patient leonard thomson.,, February 15, 1923

December 15 1922
Biosynthesis of insulin

Preproinsulin

Proinsulin

Insulin
 Structure of insulin

21 amino acids

30 AA
Difference between human, pork, beef
insulin

Species A-chain B-chain

8th AA 10th AA 30th AA

Human THR 1LEU- THR

Pork THR ILEU ALA

Beef ALA VAL ALA

Cell at rest
Secretion of insulin
> 70 mg/ml

GLUT 2
 Bioassay of insulin
• 1 IU reduces the BSL to 45 mg/dl in fasting
rabbits
• 1 mg insulin = 28 IU
• Can also be measured by radioimmunoassay
or enzyme immunoassay
 Regulation of insulin secretion

• Direct stimulation
• Plasma glucose or Amino Acids , ketones
• Hormonal regulation
• Gastrointestinal hormones (GIP, CCK)
directly stimulate β cells
• Neural regulation
• Parasympathetic stimulates insulin release
through IP3/ DAG
• Sympathetic NS inhibits insulin release
through 2 receptor activation
 Actions of insulin

Rapid actions Intermediary actions Long term

Sec / min Few hours > 24 hrs

E.g Through DNA •↑ multiplication

Metabolic e.g •↑ differentiation
actions • ↑ GLUT synthesis of cells
• Synthesis of • Imp role in
enzymes for AA intrauterine &
metabolism extrauterine
growth
 Actions of insulin
• Metabolic:
– carbohydrate, lipid , protein, electrolyte
• Vascular
• Anti-inflammatory
• Fibrinolytic
• Growth
• Steroidogenesis
 Carbohydrate metabolism
• Over all action of insulin is to ↓ glucose level
in blood
– ↑ Transport of glucose inside the cell
– ↑ Peripheral utilization of glucose
– ↑ Glycogen synthesis
– ↓ Glycogenolysis
– ↓ Neoglucogenesis
 Lipid metabolism
• ↓ Lipolysis
• ↑ Lipogenesis
• ↑ Glycerogenesis
• ↓ Ketogenesis
• ↑ Clearance of VLDL & chylomicrons from
blood through enzyme Vascular Endothelial
Lipoprotein Lipase
 Protein metabolism
• Protein synthesis
• ↑ entry of amino acids in cells

Electrolyte metabolism
• ↑ transport of K+, Ca++, inorganic phosphates
 Other actions
• Vascular actions:
– Vasodilation ? Activation of endothelial NO
production
• Anti-inflammatory action
– Especially in vasculature
• Decreased fibrinolysis
• Growth
• Steroidogenesis
• Glucose transporters –

• GLUT 1
Non insulin mediated glucose uptake
• GLUT 3

• GLUT 2 – Beta cell – Glucose sensors

• GLUT 4 – Insulin mediated glucose uptake in

muscle & Adipose tissue
Mechanism of action of insulin
 INS Insulin molecule

Insulin Mediated Glucose Transport

Insulin subunit
Receptor
Complex Tyrosine Kinase Activation
subunit

Metabolised Stored as Glycogen

Glucose
INS

Storage vesicle
containing
GLUT 4
 Fate of insulin
• Distributed only extracellularly
• Must be given parenterally
• Addition of zinc or protein decreases its
absorption & prolongs the DOA
• Insulin released from pancreas is in
monomeric form
• Half life of insulin = 5 -9 minutes
Different types of insulin preparations

• Conventional preparations of insulin

– Produced from beef or pork pancreas
– 1 % of other proteins
– Potentially antigenic
• Highly purified insulin preparations
– Gel filtration reduces proinsulin (50-200PPM)
• Human insulins
• Newer insulin analogs
 Conventional insulin preparations
Type Onset Peak DOA
(Hr) (Hr) (Hr)
Regular insulin 0.5 -1 2-4 6-8
Short acting
Semilente 1 3-6 12-16
Intermediate Lente
1-2 8-10 20-24
acting Isophane(NPH)
Long acting Ultra lente
Protamine Zinc 4-6 14-18 24-36
Insulin (PZI)
Highly purified insulin preparations
• Single peak insulins
– Purified by gel filtration contain 50 to 200 PPM
proinsulin
– Actrapid: purified pork regular insulin
– Monotard: purified pork lente
– Mixtard: purified pork regular(30%) + isophane(70%)
• Mono component insulins
– After gel filtration purified by ion exchange
chromatography contain 20 PPM proinsulin
– Actrapid MC, Monotard MC
 Human insulins
• Human (Actrapid, monotard, insulatard, mixtard)
• Obtained by recombinant DNA technology
• Advantages
– More water soluble as well as hydrophobic
– More rapid SC absorption , earlier & more defined
peak
– Less allergy
• Disadvantages
– Costly
– Slightly shorter DOA
 Indications of human insulins
• Insulin resistance
• Allergy to conventional preparations
• Injection site lipodystrophy
• During pregnancy
• Short term use of insulin
 Newer Insulin analogs

Type Onset Peak DOA

(Hr) (Hr)
Lispro 5-15 min 1 3-5
Rapid acting Aspart 10-15 min 1 3-5
Glulisine 5-15 min 1 5-6
Long acting Glargine 1-2 hrs No peak 24 hr
Detemir 2-3 hrs 6-8 hr 24 hr
 Insulin Lispro
• Produced by Inversing proline at B28 with
lysine at B29.
• Forms weak hexamers , dissociate rapidly
• Needs to be injected immediately before,
during or even after meals
• Better control of meal time glycemia & lower
incidence of PP hypoglycemia
• Insulin aspart:
– Proline at B28 replaced by aspartic acid
– Change reduces tendency for self aggregation
• Insulin glulisine
– lysine replaces aspargine at B3 & glutamic acid
replaces lysine at position B29
 Insulin glargine
• Prepared by adding 1 glycine at A21 together
with 2 arginine residues at end of B chain
• Improved Stability
• Much better bioavailabilty
• Smooth peakless effect is obtained
• Fasting & interdigestive BGL effectively
lowered irrespective of time of day
• Lower hypoglycemic episodes
• Cannot be mixed with other insulins
 Insulin detemir
• Soluble long acting basal insulin analog with
flat action profile and prolonged duration
• Threonine in B30 ommited & C14 fatty acid
chain attached to amino acid B29
• Prolonged action
– Strong self association
– Albumin binding
– Fatty acid side chain
 Action Profiles of Insulins
Aspart, glulisine, lispro 4–5 hours
Plasma Regular 6–8 hours
insulin NPH 12–16 hours
levels
Detemir ~14 hours
Ultralente 18–20 hours
Glargine ~24 hours

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Hrs
Danne T et al. Diabetes Care. 2003;26:3087-3092
 Insulin analogs score over
conventional insulins
• Less nocturnal hypoglycemia
• Less weight gain
• Better efficacy (?)
• More physiological action profiles
• Less premeal lag time (0-15 mts)
• Lispro & Glulisine even after meals
• Better PP glucose control
• Less intra-patient/inter-patient variability
• Improved predictability, tolerability, and flexibility
 Adverse effects of insulin
• Hypoglycemia
• Local reactions
– Lipodystrophy
– Lipoatrophy
• Allergy
• Obesity
• Insulin induced edema
 Drug interactions of insulin
• Non selective beta blockers
• Thiazides,furosemide, corticosteroids, OCP ,
nifedipine ↑ BSL
• Alcohol Precipitates hypoglycemia
• Salicylates, lithium, theophylline, may
accenuate hypoglycemia
 Uses of insulin
• Diabetes mellitus
– Must for type I diabetics
– Can be used in type II diabetics
• Diabetic ketoacidosis
• Hyperosmolar non ketotic hyperglycemic
coma
Indications of insulin in type II DM
• Primary or secondary failure of oral
hypoglycemics
• Pregnancy
• Perioperative period
• CKD
• Steroid therapy
• LADA
• Fasting > 300 mgms HbA1c > 10
• Unintentional wt loss with or with out ketosis
• Type 2 with DKA ( severe beta cell dysfunction)
Recommended sites for S/C Insulin injections
 Initial Insulin dosage in T1DM

• 0.5 U/kg/day with negative to

moderate ketones
• 0.7 U/kg/day with large ketones
 Clinical case

• 14 yrs old, Chitra

• 3Ps & weight loss – 10 days duration
• RBS 418 mg %
• 36 kg wt
• No marked dehydration
• T1DM- No ketoacidosis
• Proceed?
 Insulin dose for this child

• (0.5 U/kg/day with negative to moderate

ketones)
• 36 kg wt
• No ketoacidosis
• 36 X 0.5 = 18 U/day
 18 U/day as “Four-shot-per-day”

• Basal-Bolus therapy
• Ideal for better control & flexible lifestyle
• 50% Basal dose= 9 U at bedtime (NPH,G,D)
• 50% Bolus dose = 9 U premeals (R,A,L,Glu)
3U Prebreakfast
3U Prelunch
3U Predinner
 18 U/day as “Five-shot-per-day”
• Basal-Bolus therapy
• Ideal for better control & flexible lifestyle but
“too many shots”
• 50% Basal dose= 9 U divided as 5 U
prebreakfast + 4 U at bedtime (G or D)
• 50% Bolus dose = 9 U premeals (R,A,L,Glu)
3U Prebreakfast
3U Prelunch
3U Predinner
 18 U/day as “Two-shot-per-day”
Split mixed regimen

• 2/3 prebreakfast (12 U)

• 1/3 predinner (6 U)
• Prebreakfast: 8 U NPH + 4 U Regular (A,L,G)
• Predinner: 3 U NPH + 3 U Regular
“8 N/4 R - 0 - 3N/3R”
18 U/day as “Three-shot-per-day”

• 2/3 prebreakfast (12 U)

• 8 U NPH + 4 U Regular (A,L,Glu)

• 1/3 peridinner (6 U)
• 3 U Regular ( or A,L,Glu) Predinner
• 3 U NPH at bedtime
 How to initiate insulin treatment in type 2

• Start with 0.2 units / kg (or)

• Body weight divided by 5 (or)

• Dose = FBS-50 (or)

10
• Average fasting blood sugar divided by 18
 Continuous I.V. insulin infusion

• Admit the patient

• Insulin I.V.drip
• Achieve & maintain euglycemia
• Calculate the insulin required for 12-24 hrs
• 80% of that used as O.P. therapy
• Ex., 40 U to maintain euglycemia for 24 hrs
• 80% (30 U/day) used as outpatient therapy
 Pathogenesis of DKA
Insulin deficiency Absolute / relative
+
Counter hormone excess
↓ Anabolism ↑ catabolism
↑ Glycogenolysis
↓Peripheral ↑ Glycolysis
utilization of Glucose ↑Gluconeogenesis

Hyperglycemia Dehydration
↓ Fluid intake
Heavy Glucosuria Loss of water
(osmotic diuresis) & electrolytes Hyperosmolarity
 Pathogenesis of DKA
(How ketoacidosis occurs)
↑ Lipolysis Hyperketonemia

↑ FFA to liver ↓ Alkali reserve

↑ Acetyl coA
Acidosis

↑ Acetoacetyl coA

Acetoacetate -Hydroxy
butrate Acetone
 Treatment of DKA
• Fluid therapy
• Rapid acting regular insulin
• Potassium
• Bicarbonate
• Phosphate
• Antibiotics
• Treatment of precipitating cause
• General measures
 Fluid therapy
• Adequate tissue perfusion is necessary insulin
action
• Normal saline is fluid of choice for initial
rehydration
– 1 litre in first hour
– Next 1 L in next 2 hours
– 2 litres in next 4 hours
– 2 litres in next 8 hours
• i.e 4 to 6 litres in 24 hours
• When BSL reaches 300 mg% fluid should be
changed to 5 % dextrose with concurrent insulin
 Insulin in DKA
• Regular/ short acting insulin IV treatment of
choice
• Loading dose = 0.1-0.2 U/kg IV bolus
• Then 0.1 U /kg/hr IV by continuous infusion
• Rate doubled if no significant fall in BSL in 2 hr
• 2-3 U/hr after BSL reaches 300mg%
• If patient becomes fully conscious encouraged
to take oral food & SC insulin started
 Potassium replacement
• In initial stage of treatment potassium not
administered because in DKA it remains
normal or ↑
• In presence of insulin infusion Sr potassium ↓
hence 10 mEq/L potassium can be added with
3rd bottle of normal saline
• Sr K+ < 3.3 mEq/L : 20 -30 mEq/hr
 Bicarbonates & phosphates
• Bicarbonates
– If blood pH > 7.1 no need of sodium bicarbonate
– In presence of severe acidosis 50 mEq of sodium
bicarbonate added to IV fluid
• Phosphates
– Non availability of ideal preparation
– Replacement not very essential unless < 1 mEq/L
– potassium phosphate 5-10 m mol/hr
 Hyperosmolar Non Ketotic Coma
• Usually occurs in type II
• Dehydration with severe hyperglycemia
without ketoacidosis, because insulin inhibits
hormone sensitive lipase
• The general principle of T/t is same as for DKA
except that pt needs more faster fluid
replacement
– Half NS preferred 2 Lit in 2 Hrs followed by 1 Lit in
next 2 hrs
• Low dose heparin to prevent vascular
thrombosis & intravascular coagulation
 Insulin resistance
• State in which normal amount of insulin
produces subnormal amount of insulin
response
– ↓ insulin receptors
– ↓ affinity for receptors
• May be acute or chronic
• Requirement of > 200 Units of insulin per day
in absence of stress
• Common in type II diabetics & obese
 Newer insulin delivery devices
• Prefilled insulin syringes
• Pen devices
• Jet injectors
• Inhaled insulin
• Insulin pumps
• External artificial pancreas
• Insulin complexed with liposomes:
intraperitoneal, rectal, oral
40 units/ml
100 units/ml

Tuberculin syringe
 PEN INJECTORS
• Easy to carry
• Easier to accurately measure dose
• more expensive than vials

JET INJECTORS
Needleless system.
Uses high pressure air to force a tiny
stream of insulin through the skin
 Insulin Pump
Pro Con
• Simplified insulin • More DKA
dosing • More severe
• Precise delivery hypoglycemia
• Greater impact in those
with highest starting
A1c
• Slightly less insulin use
per day
 Inhaled Insulin (Exubera)
Advantages
 Improved pt convenience
 Faster onset of action compared to Regular SC insulin
 No needles risk of infection
 Potential earlier onset of insulin therapy in Type 2 DM
 Oral antidiabetic drugs
• Sulfonylureas:
• Meglitinides:
• Biguanides :
• Thiazolidinediones:
• -glucosidase inhibitors:
 Sulfonylureas
I Generation
– Tolbutamide
– Chlorpropamide
II Generation
– Glipizide
– Gliclazide
– Glibenclamide (Glyburide)
– Glimepiride
 Mechanism of action

• Release of insulin by acting on SUR1 receptors

• Primarily augment phase 2 of insulin secretion
• Presence of at least 30% functional -cells
essential for their action.
• Minor action: ↓ glucagon secretion
• Extra pancreatic action: ↑sensitivity of
peripheral tissue to insulin by ↑insulin receptors
 Pharmacokinetics
• Well absorbed orally
• Highly bound to plasma proteins > 90%
• Have low volume of distribution
• Cross placenta C/I in pregnancy
• Metabolized in liver
• Excreted in urine
 Daily dose & Duration of action
Sulfonylureas Doses No of DOA
doses/day (hrs )
1 Tolbutamide 0.5 – 2 g 2-3 6-8
2 Chlorpropramide 0.1 to 0.5 g 1 36 -48
3 Glibenclamide 5 to 15 mg 1-2 18-24
4 Gliclazide 40- 240 mg 1-2 12-24
5 Glipizide 5 to 40 mg 1-2 12-18
6 Glimepiride 1 to 6 mg 1 Upto 24
 Individual Sulfonylurea
Sulfonylureas Special points
1 Tolbutamide Short acting, low potency , hypoglycemia
least likely
2 Chlorpropramide ↑Hypoglycemia, ↑ADH , Disulfiram Like
Reaction, Cholestatic jaundice
3 Glibenclamide Potent but slow acting, may work when
others fail
4 Gliclazide Antiplatelet, antioxidant action, may delay
Retinopathy, less weight gain
5 Glipizide Fast acting, hypoglycemia & weight gain less
likely, prefered in elderly
6 Glimepiride More extrapancreaatic action, less
hyperinsulinemia, less hypoglycemia
 GLIMEPIRIDE
1) Lesser risk of hypoglycemia
2) Insulin sparing effect (Significant extra pancreatic
effects)
3) Relatively safe in elderly and mild renal failure
4) Antiplatelet and antifibrinolytic activity
5) Little or no weight gain
6) FDA approved combination therapy with insulin
7) Safe and effective for use in the pediatric
population
8) ↑ Levels of plasma adiponectin & ↓ TNF α
9) Stimulates GLUT4 expression
 Why Glibenclamide is more potent and
longer acting than other SU
1. May accumulate within cells and directly stimulate
exocytosis of insulin granules
2. Greater/longer binding to SUR-1 receptors
3. Slower absorption and distribution
4. Inhibition of hepatic insulinase
5. Suppression of several counter-regulatory hormones
6. More suppression of HGO
7. May stimulate insulin synthesis
 Adverse effects
• Hypoglycemia:
• GI disturbances: Nausea, vomiting, metallic
taste, diarrhoea & flatulence
• Weight gain
• Hypersensitivity
• Not safe in pregnancy
• Chlorpropamide:
– cholestatic jaundice, dilutional hyponatremia,
antabuse reaction
 Contraindications
1. Allergy to SU
2. Renal failure:
3. Significant hepatic dysfunction
4. Severe infections, stress, trauma, major
surgery, CVA, AMI
5. Pregnancy (except Glibenclamide)
6. T1DM
 Drug interactions
• Drugs that ↑ SU action
– Salicylates, sulfonamides
– Cimetidine , warfarin, sulfonamides
– Propranolol
• Drugs that ↓ SU action
– Phenytoin, phenobarbitone , rifampicin
– Corticosteroids, thiazides, furosemide, OCP
 Selection of SU
Clinical conditions Agents
Fasting & postprandial Long acting/Intermediate acting Su.
hyperglycemia
Only postprandial hyperglycemia Glipizide

Renal impairment Glipizide

GDM Glibenclamide

Elderly (> 65) Avoid Glibenclamide, chlorpropamide

Alcoholics Avoid chlorpropamide

DM & IHD Avoid Glibenclamide.

DM, HT & Edema legs Avoid chlorpropamide

SU + other antihyperglycemic agents
 SU + Metformin (best)
 SU + Glitazones (best)
 SU + AGI (better)
 SU + 2 or more drugs (good)
 SU + Insulin (good)
 SU + Meglitinides (bad)
 SU + SU (worst)
 Meglitinide analogs
• Quick & short acting insulin releasers
• MOA: same as Sulfonylureas but act through
different receptor SUR2
• Mainly used to control Post prandial
hyperglycemia
• Less hypoglycemia
 Repaglinide
• Well tolerated in elderly patients in renal
impairment
• Adverse effects:
– Mild headache, dyspepsia, arthralgia, headache
• Indicated in type II DM
• Dose : start 0.5mg with meals can ↑ 16mg/day
 Nateglinide
• Stimulates first phase of insulin secretion
• More rapid acting & shorter duration than
repaglinide
• Mainly used in post prandial hyperglycemia
without producing late phase hypoglycemia
• Little effect on fasting BSL
• Adverse effects: diziness, nausea, flu like
symptoms
• Dose: 60 to 180 mg TDS with meals
 Biguanides
• Metformin & phenformin
• Little or no hypoglycemia
• Also improves the lipid profile in type II
diabetic patients
• Metformin dose = 0.5 to 2.5 g/day in 2-3
divided doses
 Mechanism of action
• Suppress hepatic & renal gluconeogenesis
• ↑ uptake & utilization of glucose by skeletal
muscles which reduces insulin resistance
• Inhibit alimentary absorption of glucose
• Interfere with mitochondrial respiratory chain
& promote peripheral glucose utilization by
enhancing anaerobic glycolysis
 Pharmacokinetics
• Taken orally , well absorbed through GI tract
• Not metabolized at all
• Excreted unchanged in urine
 METFORMIN - INDICATIONS
• Obese Type 2 Diabetes.

• Secondary Sulfonylurea Failure state.

• To reduce Insulin requirements.

• Can be combined with Sulfonylureas,

Glitazones, Insulin.
 Adverse effects
• Anorexia, nausea, vomiting, diarrhoea
• Metallic taste
• Loss of weight
• Skin rashes
• Lactic acidosis: rare
• Vitamin B12 deficiency: due to malabsorption
Usually does not cause hypoglycemia even in
large doses
 Contraindications of metformin
• Renal failure –
( Sr. Crt > 1.5 / Crt. Clearance < 40

• Advanced Liver Disease.

• Alcohol abusers.

• Cardiac Disease.

• Pregnancy.
 Thiazolidinediones (Glitazones)
Rosiglitazone & pioglitazone Selective agonists of PPAR

Bind to nuclear PPAR

Activate insulin responsive genes - regulate

carbohydrate & lipid metabolism

Sensitize the peripheral tissues to insulin

↓blood glucose by

Inhibit hepatic Promote

↑ Glucose transport into
gluconeogenesis lipogenesis
muscle & adipose tissue
 Thiazolidinediones
• Hyperglycemia, hyperinsulinemia, and
elevated HbA1c levels are improved.
• Pioglitazone has no effect on LDL levels, ↓
triglyceride & ↑ HDL
• Rosiglitazone has inconsistent effect on lipid
profile it ↑ HDL & LDL levels
• The TZDs lead to a favorable redistribution of
fat from visceral to subcutaneous tissues.
 Pharmacokinetics
• Both Rosiglitazone & pioglitazone are
completely absorbed from GIT
• Highly bound to plasma proteins (>95%)
• Rosiglitazone metabolized by CYP2C8,
Pioglitazone metabolized by CYP2C8 & CYP3A4
• Drug interactions less with rosiglitazone
• Metabolites of rosiglitazone are excreted in
urine and those of pioglitazone in bile
• Pioglitazone:
– 15 to 45 mg once daily orally
• Rosiglitazone:
– 4 to 8 mg once daily orally
• Pt who benefit most are type II DM with
substantial amount of insulin resistance
• Also used in PCOD
• Monotherapy – Hypoglycemia rare
• Add-on Therapy – readjust dosage.
• Takes one month to act
 Adverse effects
• Weight gain: due to fluid retention & edema
• ↑ Extracellular fluid volume
• Worsening of CHF
• ↑ Deposition of subcutaneous fat
• Mild anemia: due to hemodilution
• Hepatotoxicity : rare
• Rosiglitazone: ↑risk of fractures especially in
elderly women
 Contraindications
• Liver disease
• Congestive heart failure
• Pregnancy
• Lactating mother
• Children
 Alpha glucosidase inhibitors
• Acarbose
• Miglitol
• Voglibose
 Mechanism of action
Dietary Carbohydrates (Starch)
Glucosidase
Pancreatic amylase
inhibitors
Oligosaccharides/ Maltose, Isomaltose,
Disaccharides Sucrose

X
glucosidase enzymes (in
the lining of cells of
intestinal villi)

Monosaccharides (Glucose, fructose)

Absorbed in lower part of intestine

10
4
 Acarbose
• Complex oligosaccharide
• Inhibits -glucosidase as well as -amylase
• Reduces postprandial hyperglycemia without
increasing insulin levels
• Regular use reduces weight
• In prediabetics reduces occurrence of type II
DM, hypertension & cardiac disease
• Dose: 50 to 100 mg TDS
• Given just before food or along with food
 Adverse effects
• Flatulence, diarrhoea, abdominal pain
• Do not cause hypoglycemia by themselves but
may cause if used with Sulfonylureas
• If hypoglycemia occurs should not be treated
with routine sugar (sucrose),
• Glucose should be used
Contraindicated in inflammatory bowel disease
& intestinal obstruction
 Voglibose

• Advantages over Acarbose and Miglitol

– 20-30 times more potent then acarbose
– Does not affect digoxin bioavailability unlike
acarbose
– No dosage adjustment required in renal
impairment patients unlike miglitol
– Superior tolerability
– Dose: 0.2 to 5 mg
10
7
 Newer drugs for Type II DM
• GLP-1 Analogues • Amylin analog:
– Exenatide Pramlintide
– Liraglutide
• DPP-IV Inhibitors
– Sitagliptin
– Vildagliptin
– Alogliptin
 Exenatide
• Synthetic GLP I analogue resistant to DDP IV
• ↑ Post prandial insulin release
• Supresses glucagon release
• Supresses appetite and slows gastric emptying
• injected SC twice daily 1 hour before meals
acts for 6 to 10 hours
• Nausea is important side effect
 Sitagliptin
• Orally active inhibitor of DPP-4
• Prevents degradation of endogenous GLP-I
• Dose: 100mg a da
• Mainly used in post prandial hyperglycemia
• No action on weight and lipids
• Costly
 Pramlintide
• Synthetic amylin analog
• Improves overall glycaemic control,↓ PPG
• Reduces BW : anorectic action
• Well tolerated
• Given SC before meals
• SE: GI disturbances/Less hypoglycemia when
used alone
• Can be used in type I DM
Principles of treatment of Type 2 DM

Grade Diabetes Mellitus as mild, moderate or severe

NB: FBG (150 -200 ---mild ) HbA1c < 8
( 200-250 --- Moderate) HbA1c 8 - 9
( more than 250 severe) HbA1c 9 - 10
For severe DM start on insulin if there is wt loss &
ketosis
For mild & moderate DM use metformin if obese &
sulfonylureas if not obese
Principles of treatment of Type 2 DM

• Classify obese non obese

• Assess Liver function is normal or

abnormal

• Assess the kidney function

If diabetes not controlled

Look for SU failure

Occult infection – TB – UTI

Drug history and compliance

Food history – hypoglycaemia

and compliance
cardiac problem – avoid glitazones

if in failure avoid metformin

Renal problem – avoid metformin

Liver problem – avoid glitazone

and metformin

In general

patients with complication

Short acting SU or insulin

Be ware of other drugs

- Diuretics

- Corticosteroid

- Other hormones

- ACE inhibitors