Pharmacotherapy of diabetes mellitus

Pharmacotherapy of Diabetes Mellitus

Dr Naser Ashraf TadviAssociate 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 DiabetesProposed 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

B) Genetic defects in Insulin action

C) Diseases of the Exocrine Pancreas

D) Secondary to Endocrinopathies

E) Drugs / Chemical induced

F) Infections

G) Uncommon form of Immune Mediated Diabetes.

H) Other Genetic Syndromes associated with Diabetes

MODY Syndromes

Lipo atrophic Diabetes

FCPDPancreatitis

TraumaNeoplasia

Cystic FibrosisHemochromatosis

AcromegalyCushings SyndromePheochromocytoma

HyperthyroidismSteroids

ThiazidesDiazoxide

Beta BlockersThyroid Hormones

Congenital RubellaCMV

Anti insulin Receptor Antibodies

Down’s SyndromeTurners

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

• 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

Beta cell statistics

Insulin

Discovery of insulin

Patient leonard thomson.,, February 15, 1923 December 15 1922

The Miracle of Insulin

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

• 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

Regulation of insulin secretion

Actions of insulin

Rapid actions Intermediary actions Long term

Sec / min Few hours > 24 hrs

E.g Metabolic actions

•↑ multiplication•↑ differentiation of cells • Imp role in intrauterine & extrauterine growth

Through DNAe.g • ↑ GLUT synthesis• Synthesis of enzymes for AA metabolism

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

Insulin Mediated Glucose Transport

G

INS

aa

bb

InsulinRecepto

rComplex

INSaa bb

a subunit

b subunit

Insulin molecule

Storage vesiclecontaining

GLUT 4

Glucose

Tyrosine Kinase Activation

Metabolised

Stored as Glycogen

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

(Hr)Peak (Hr)

DOA (Hr)

Short acting Regular insulin Semilente

0.5 -1 1

2-4 3-6

6-8 12-16

Intermediate acting

Lente Isophane(NPH) 1-2 8-10 20-24

Long acting Ultra lente Protamine Zinc Insulin (PZI)

4-6 14-18 24-36

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 (Hr)

DOA (Hr)

Rapid acting Lispro Aspart Glulisine

5-15 min 10-15 min5-15 min

111

3-53-55-6

Long acting Glargine Detemir

1-2 hrs 2-3 hrs

No peak 6-8 hr

24 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

0 1 2 53 4 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Plasmainsulinlevels

Regular 6–8 hours

NPH 12–16 hours

Ultralente 18–20 hours

Hrs

Aspart, glulisine, lispro 4–5 hours

Glargine ~24 hours

Detemir ~14 hours

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

↓Peripheral utilization of Glucose

Hyperglycemia

Heavy Glucosuria (osmotic diuresis)

Loss of water & electrolytes

↑ Glycogenolysis ↑ Glycolysis ↑Gluconeogenesis

Dehydration

+

Hyperosmolarity

↓ Fluid intake

Pathogenesis of DKA (How ketoacidosis occurs)

↑ FFA to liver

↑ Acetyl coA

↓ Alkali reserve

↑ Lipolysis

↑ Acetoacetyl coA

Acetoacetate -Hydroxy butrate Acetone

Hyperketonemia

Acidosis

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 INJECTORSNeedleless system. Uses high pressure air to force a tiny stream of insulin through the skin

Insulin Pump Pro• Simplified insulin

dosing• Precise delivery• Greater impact in those

with highest starting A1c

• Slightly less insulin use per day

Con• More DKA• More severe

hypoglycemia

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 doses/day

DOA (hrs )

1 Tolbutamide 0.5 – 2 g 2-3 6-82 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 12-245 Glipizide 5 to 40 mg 1-2 12-186 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 hypoglycemia2) Insulin sparing effect (Significant extra pancreatic

effects)3) Relatively safe in elderly and mild renal failure4) Antiplatelet and antifibrinolytic activity5) Little or no weight gain6) FDA approved combination therapy with insulin7) Safe and effective for use in the pediatric

population8) ↑ Levels of plasma adiponectin & ↓ TNF α9) 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 SUClinical conditions Agents

Fasting & postprandial hyperglycemia

Long acting/Intermediate acting Su.

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

↑ Glucose transport into muscle & adipose tissue

Inhibit hepatic gluconeogenesis

Promote lipogenesis

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

104

Dietary Carbohydrates (Starch)

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

Pancreatic amylase

Absorbed in lower part of intestine

Monosaccharides (Glucose, fructose)

Oligosaccharides/ Disaccharides

Maltose, Isomaltose, Sucrose

X

Glucosidase inhibitors

Mechanism of action

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

107

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

Newer drugs for Type II DM

• GLP-1 Analogues – Exenatide– Liraglutide

• DPP-IV Inhibitors– Sitagliptin– Vildagliptin– Alogliptin

• Amylin analog:Pramlintide

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 - 10For severe DM start on insulin if there is wt loss &

ketosisFor mild & moderate DM use metformin if obese &

sulfonylureas if not obese

• Classify obese non obese

• Assess Liver function is normal or

abnormal

• Assess the kidney function

Principles of treatment of Type 2 DM

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