Anti-diabetic Drugs- September 2015

OBAT ANTIDIABET

LAB FARMAKOLOGI FK UBUMI KALSUM

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DefinisiApakah Diabetes itu ??

DEFINISI :

Kumpulan gejala penyakit yang timbul pada seseorang yang disebabkan oleh peningkatan kadar gula darah akibat penurunan sekresi insulin yang disebabkan oleh kerusakan sel beta pancreas dan resistensi insulin ( PERKENI)

– Apabila hormon insulin yang dihasilkan oleh sel beta pankreas tidak mencukupi untuk merubah glukose menjadi energi, maka glukose akan tetap dalam darah dan kadarnya akan meningkat

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Diabetes DiagnosisCategory FPG (mg/dL) 2h 75g OGTT A1C

Normal <100 <140 <5.7

Prediabetes 100-125 140-199 5.7-6.4

Diabetes >126 >200 >6.5

Fasting Plasma Glucose (FPG)

Oral Glucose Tolerance Test (OGTT )

Diabetes Care 34:Supplement 1, 2011Diabetes Care 34:Supplement 1, 2011https://www.aace.com/publications/guidelines 2011 2011

https://www.aace.com/publications/guidelines

Klasifikasi Diabetes Mellitus Berdasarkan Etiologinya American Diabetes Association ( ADA, 2003)

1. Diabetes Mellitus Tipe 1:Destruksi sel β umumnya menjurus ke arah defisiensi insulin absolut, melalui proses imunologik (Otoimunologik) dan Idiopatik

2.Diabetes Mellitus Tipe 2Bervariasi, mulai yang predominan resistensi insulin disertai defisiensi insulin relatif sampai yang predominan gangguan sekresi insulin bersama resistensi insulin

3. Diabetes Mellitus GestasionalDiabetes mellitus yang muncul pada masa kehamilan, disebabkan oleh hormon yang disekresikan plasenta yang akan menghambat kerja insulin, umumnya bersifatsementara, tetapi merupakan faktor risiko untuk DM Tipe 2

4. Diabetes Mellitus Tipe Lain-Defek genetik fungsi sel β-Penyakit pankreas-Autoimun

5. Gangguan Toleransi GlukosaA. IFG (Impaired Fasting Glucose) = GPT (Glukosa Puasa Terganggu)B. IGT (Impaired Glucose Tolerance) = TGT (Toleransi Glukosa terganggu)

DRUGS FOR THE TREATMENT OF DRUGS FOR THE TREATMENT OF DIABETES MELLITUSDIABETES MELLITUS

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Generasi 2

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DIABETES MELLITUS TIPE 1 : - Jarang / populasinya sedikit (5-10 % dari penderita

diabetes mellitus)

- Gangguan produksi insulin pada DM Tipe 1 umumnya terjadi karena kerusakan sel-sel β pulau Langerhans yang disebabkan oleh reaksi otoimun, virus, dsb

- Destruksi otoimun dari sel-sel β pulau Langerhans kelenjar langsung mengakibatkan defisiensi sekresi insulin.

DIABETES MELLITUS TIPE 2

- sangat umum terjadi

- populasinya 90 – 95 % penderita Diabetes Mellitus

- Etiologinya belum terungkap dengan jelas, kebanyakan karena pola hidup, faktor genetik dan pengaruh lingkungan.

- sel-sel sasaran insulin gagal atau tak mampu merespon insulin secara normal. Keadaan ini lazim disebut sebagai “Resistensi Insulin”.

Diabetes gestasional

Diabetes pada kehamilan- Diabetes / intoleransi glukosa yang terjadi pada masa

kehamilan- Umumnya timbul pada atau setelah trimester ke 2- Sekitar 4-5 % wanita hamil menderita DM- Berlansung sementara dan dapat pulih setelah

kehamilan

Akibat DM gestasional•Malformasi kongenital•Berat badan bayi berlebih•Resiko mortalitas perinatal

Perbedaan dm TIPE 1 DAN DM TIPE 2

Mula muncul Umumnya masa kanakkanakdan remaja,walaupun ada juga padamasa dewasa < 40 tahun

Pada usia tua, umumnya> 40 tahun

Keadaan klinis saatdiagnosis

Berat Ringan

Kadar insulin darah

Rendah, tak ada Cukup tinggi, normal

Berat badan Biasanya kurus Gemuk atau normal

Pengelolaan yangdisarankan

Terapi insulin, diet,olahraga

hipoglikemik oralDiet, olahraga,

PatofisiologiFungsi insulin :

Berikatan dengan reseptor pada sel / jaringan untuk membuka jalan bagi masuknya glukosa darah ke dalam sel untuk dirubah menjadi tenaga.

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Characteristic Type 1 ( 10% ) Type 2

Onset (Age) Usually < 30 Usually > 40

Type of onset Abrupt Gradual

Nutritional status Usually thin Usually obese

Diet Mandatory with insulin Mandatory with or without drug

Hypoglycemic drugs Should not be used Clinically indicated

Clinical symptoms Polydipsia, polyphagia, polyurea, Wt loss

Often asymptomatic

Ketosis Frequent Usually absent

Endogenous insulin Absent Present, but relatively ineffective

Related lipid abnormalities

Hypercholesterolemia frequent, all lipid fractions elevated in ketosis

Cholesterol & triglycerides often elevated; carbohydrate- induced hypertriglyceridemia common

Insulin therapy Required Required in only 20 - 30% of patients

• Glucose homeostasis

Figure 26.8

Insulin

Beta cellsof pancreas stimulatedto release insulin into

the blood

Bodycells

take up moreglucose

Blood glucose leveldeclines to a set point;

stimulus for insulinrelease diminishes

Liver takesup glucose

and stores it asglycogen

High bloodglucose level

STIMULUS:Rising blood glucoselevel (e.g., after eating

a carbohydrate-richmeal) Homeostasis: Normal blood glucose level

(about 90 mg/100 mL) STIMULUS:Declining blood

glucose level(e.g., after

skipping a meal)

Alphacells of

pancreas stimulatedto release glucagon

into the blood

Glucagon

Liverbreaks down

glycogen and releases glucose

to the blood

Blood glucose levelrises to set point;

stimulus for glucagonrelease diminishes

ATP/ADP binding sites

K+ K+ K+ K+ K+ K+ K+ K+

K+ K+ K+

Phosphorylation

site

Ca2+ channel opened

Ca2+ /Calmodulin-dependent kinase

GLUT2

Insulin containing secretory granules

ß-cell plasma membr

ane

Glucose

Gluc-6P

ATP

K+ channel clodsed

Ca2+Ca2+ Ca2+

Protein Kinase C

Protein phosphorelation

Exocytosis

Glucose

Glucokinase

+ + +

– – –

GLUCOSE REGULATION ON INSULIN SECRETION

INSULIN

INSULIN

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Mechanism of Insulin Action• Insulin binds to specific high

affinity membrane receptors with tyrosine kinase activity

• Phosphorylation cascade results in translocation of Glut-4 (and some Glut-1) transport proteins into the plasma membrane.

• It induces the transcription of several genes resulting in increased glucose catabolism and inhibits the transcription of genes involved in gluconeogenesis.

• Insulin promotes the uptake of K+into cells.

Insulin: Actions• Increases glucose uptake in to cells• Increases glycolysis• Increases glycogen synthesis• Reduces glycogen breakdown• Reduces gluconeogenesis

• Reduces lipolysis• Increases fatty acid synthesis• Increases cholesterol & LDL synthesis

• Increases amino acid transport• Increases protein synthesis• Reduces protein breakdown• K+ uptake into cell

INSULIN DEFICIENCY – DIABETES MELLITUS

GLUCOSE UPTAKE

HYPERGLYCEMIA

GLYCOSURIA

DEHYDRATION,

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AA

mobilization

PLASMA AA

LIPOLYSIS

PLASMA FFA

KETOSIS

ACIDOSIS

GlucoseGlucose

The biphasic insulin response

Adapted from Howell SL. Chapter 9. In: Pickup JC, Williams G (Eds). Textbook of Diabetes. Oxford. Blackwell Scientific Publications 1991: 72–83.

Insulin preparations

Short acting onset 30 mins Humulin Speak 2-4 hours Actrapidduration 8 hours

Intermediate onset 1-2 hours Insulatard(zinc) peak 4-12 hours Humulin I

duration 16-24 hoursLong acting onset 1-2 hours Human Ultratard(protamine) peak 4-12 hours Humulin Zn

duration 20-35 hoursAnalogue onset 0-15mins Humalog(designer) peak 1-2 hours Novorapid

duration 4-6 hours

Methods of Adminisration• Insulin Syringes

• Pre-filled insulin pens

• External insulin pump

Under Clinical Trials• Oral tablets

• Inhaled aerosol

• Intranasal, Transdermal

• Insulin Jet injectors

• Ultrasound pulses

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Insulin Administration

Pharmacology for Technicians by Ballington, Lauglin. EMC Paradigm 2006, Fig. 14.9

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SIDE EFFECTS OF INSULIN THERAPY

1. Severe Hypoglycemia (< 50 mg/dl )– Life threatening

Overdose of insulin

Excessive (unusual) physical exercise

2. Local or systemic allergic reactions (rare)

3. Lipodystrophy at injection sites

4. Insulin resistance

4. Hypokalemia

ORAL ANTI-DIABETIC DRUGS

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Oral Anti-Diabetic Drugs

All taken orally in the form of tablets.

Patients with type II diabetes have two physiological defects:

1. Abnormal insulin secretion

2. Resistance to insulin action in target tissues associated with decreased number of insulin receptors

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GlucoseGlucose

LiverLiver

Peripheral TissuesPeripheral Tissues(Muscle)(Muscle)

PancreasPancreas

Receptor +Receptor +post receptor post receptor

defectdefect

Increased Increased glucoseglucose

productionproduction

Impaired insulinImpaired insulinsecretionsecretion

InsulinInsulinresistanceresistance

P.P.3030

Causes of Hyperglycemia in Type 2 Diabetes

©©1997 PPS1997 PPS

Type 2 diabetes: the role of insulin resistance and -cell failure

Insulin resistanceInsulin resistance

HyperinsulinaemiaHyperinsulinaemia

Increasing insulin Increasing insulin resistance resistance

Type 2 diabetesType 2 diabetes

Impaired glucose toleranceImpaired glucose tolerance

Adapted from: Reaven GM. Adapted from: Reaven GM. Diabetes Diabetes 1988;37:1595–1607 and Beck-Nielsen H, Groop LC.1988;37:1595–1607 and Beck-Nielsen H, Groop LC. J Clin Invest J Clin Invest 1994;94:1714–1721 1994;94:1714–1721

-cell failure-cell failure++

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Oral Antidiabetic Drugs

● Classification

Sulfonylureas

Meglitinides

Biguanides

α-glucosidase inhibitors

Thiazolidinediones

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Tolbutamid short-acting

Acetohexamide

intermediate-acting

Tolazamide intermediate-

acting

Chlorpropamide

long- acting

Absorption Well Well Slow Well

Metabolism Yes Yes Yes Yes

Metabolites Inactive* Active +++ ** Active ++ ** Inactive **

Half-life 4 - 5 hrs 6 – 8 hrs 7 hrs 24 – 40 hrs

Duration of action

Short

(6 – 8 hrs)

Intermediate

(12 – 20 hrs)

Intermediate

(12 – 18 hrs)

Long

( 20 – 60 hrs)

Excretion Urine Urine Urine Urine

FIRST GENERATION SULPHONYLUREA COMPOUNDS

* Good for Px with renal impairment Good for Px with renal impairment

** Px with renal impairment can expect long t1/2

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Glipizide

Short- acting

Glibenclamide

(Glyburide)

Long-acting

Glimepiride

Long-acting

Absorption Well Well Well

Metabolism Yes Yes Yes

Metabolites Inactive Inactive Inactive

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

Duration of action

10 – 16 hrs 12 – 24 hrs 12 – 24 hrs

Excretion Urine Urine Urine

SECOND GENERATION SULPHONYLUREA COMPOUNDS

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MECHANISM OF ACTION OF SULPHONYLUREAS

1) Release of insulin from β-cells

2) Reduction of serum glucagon concentration

3) Potentiation of insulin action on target tissues

DeFronzo RA. DeFronzo RA. Diabetes. Diabetes. 1988;37:667-687.1988;37:667-687.Lebovitz HE. In Lebovitz HE. In Joslin's Diabetes MellitusJoslin's Diabetes Mellitus. 1994:508-529. 1994:508-529

Blood glucoseBlood glucose


1. 1. Intestine: glucose absorptionIntestine: glucose absorption 2. 2. Muscle and adipose tissue:Muscle and adipose tissue:glucose uptakeglucose uptake

44 . Liver: hepatic. Liver: hepaticglucose outputglucose output

3. Pancreas: insulin secretion3. Pancreas: insulin secretionSulfonylureas insulin Sulfonylureas insulin

secretionsecretion


Sulfonylureas: Mechanism of Action

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SIDE EFFECTS OF SULPHONYLUREAS

1) Nausea, vomiting, abdominal pain, diarrhea

2) Hypoglycaemia

3) Dilutional hyponatraemia & water intoxication (Chlorpropamide)

4) Disulfiram-like reaction with alcohol (Chlorpropamide)

5) Weight gain

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SIDE EFFECTS OF SULPHONYLUREAS (contd.)

6) Blood dyscrasias

(not common; less than 1% of patients)

- Agranulocytosis

- Haemolytic anaemia

- Thrombocytopenia

7) Cholestatic obstructive jaundice (uncommon)

8) Dermatitis (Mild)

9) Muscle weakness, headache, vertigo (not common)

10) Increased cardio-vascular mortality with

longterm use ??

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CONTRAINDICATIONS OF SULPHONYLUREAS

1) Type 1 DM ( insulin dependent)

2) Parenchymal disease of the liver or kidney

3) Pregnancy, lactation

4) Major stress

5) DM 2 + complication

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DRUGS THAT AUGMENT THE HYPOGLYCEMIC ACTION OF SULPHONYLUREAS

WARFARIN

SULFONAMIDES

SALICYLATES

PHENYLBUTAZONE

PROPRANOLOL

ALCOHOL

CHLORAMPHENICOL

FLUCONAZOLE

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DRUGS THAT ANTAGONIZE THE HYPOGLYCEMIC ACTION OF SULPHONYLUREAS

DIURETICS (THIAZIDE, FUROSEMIDE) DIAZOXIDE

CORTICOSTEROIDS

ORAL CONTRACEPTIVES

PHENYTOIN, PHENOBARB., RIFAMPIN

ALCOHOL ( chronic px )

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MEGLITINIDES

e.g. Repaglinide, Nateglinide

PHARMACOKINETICS

Taken orally

Rapidly absorbed ( Peak approx. 1hr )

Metabolized by liver

t1/2 = 1 hr

Duration of action 4-5 hr

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MEGLITINIDES (Contd.)

MECHANISM OF ACTION

Bind to the same KATP Channel

as do Sulfonylureas,

to cause insulin release from β-cells.




1. 1. Intestine: glucose absorptionIntestine: glucose absorption

3.3. Pancreas: insulin secretionPancreas: insulin secretion

MeglitinidesMeglitinidesInsulin secretionInsulin secretion

4.4. Liver: hepatic Liver: hepatic glucose outputglucose output

2.2. Muscle and adipose tissue:Muscle and adipose tissue:glucose uptakeglucose uptake

Wolffenbuttel BHR. Wolffenbuttel BHR. Eur J Clin PharmacolEur J Clin Pharmacol. 1993;45:113-116.. 1993;45:113-116.

CC

Meglitinides: Mechanism of Action

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MEGLITINIDES (Contd.)

CLINICAL USE

Approved as monotherapy and in combination with metformin in type 2 diabetes

Taken before each meal, 3 times / day

Does not offer any advantage over sulfonylureas;

Advantage: Px allergic to sulfur or sulfonylurea

SIDE EFFECTS:

Hypoglycemia

Weight gain ( less than SUs )

Caution in px with renal & hepatic impairement.

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BIGUANIDES e.g. Metformin

PHARMACOKINETICS

Given orally

Not bind to plasma proteins

Not metabolized

Excreted unchanged in urine

t 1/2 2 hr

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BIGUANIDES (Contd.)

MECHANISM OF ACTION

1. Increase peripheral glucose utilization

2. Inhibits gluconeogenesis

3. Impaired absorption of glucose from the gut

DeFronzo RA et al.DeFronzo RA et al. J Clin Endocrinol Metab. J Clin Endocrinol Metab. 1991;73:1294-1301.1991;73:1294-1301.




1.1. Intestine: glucose absorptionIntestine: glucose absorption

3. 3. Pancreas: insulin secretionPancreas: insulin secretion

4. Liver: hepatic4. Liver: hepatic

glucose outputglucose output

Metformin HGOMetformin HGO

2. Muscle and adipose tissue:2. Muscle and adipose tissue:glucose uptakeglucose uptake

Metformin glucose utilizationMetformin glucose utilization

Metformin: Mechanism of Action

Advantages of Metformin over SulfonylureaDoes not cause hypoglycemia ( why ? )Does not result in wt gain ( why ? )

( Ideal for obese px )

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1. Metallic taste in the mouth2. Gastrointestinal (anorexia, nausea, vomiting,

diarrhea, abdominal discomfort) 3. Vitamin B 12 deficiency (prolonged use)4. Lactic acidosis ( rare – 01/ 30,000-exclusive in

renal & hepatic failure)

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BIGUANIDES (Contd.)

SIDE EFFECTS1. Metallic taste in the mouth2. Gastrointestinal (anorexia, nausea, vomiting,

diarrhea, abdominal discomfort) 3. Vitamin B 12 deficiency (prolonged use)4. Lactic acidosis ( rare – 01/ 30,000-exclusive in

renal & hepatic failure)

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1. Hepatic impairment2. Renal impairment3. Alcoholism4. Heart failure

INDICATIONS

1. Obese patients with type II diabetes2. Alone or in combination with sulfonylureas

BIGUANIDES (Contd.) CONTRAINDICATIONS

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α-GLUCOSIDASE INHIBITORS

e.g. Acarbose

PHARMACOKINETICS

Given orally

Not absorbed from intestine except small amount

t1/2 3 - 7 hr

Excreted with stool

α-Glucosidase InhibitorsThis enzyme hydrolyses

oligosaccharides to monosaccharides which are then absorbed. Acarbose also inhibits pancreatic amylase. The normal post-prandial glucose rise is blunted, glucose levels rise modestly and remain slightly elevated for a prolonged period, less of an insulin response is required and hypoglycemia is avoided; use with other agents may result in hypoglycemia. Sucrase is also inhibited by these drugs.

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MECHANISM OF ACTION

Inhibits intestinal alpha-glucosidases and delays carbohydrate absorption, reducing postprandial increase in blood glucose

α-GLUCOSIDASE INHIBITORS(Contd.)

1. Intestine: glucose absorption1. Intestine: glucose absorptionAcarbose glucose absorption secondaryAcarbose glucose absorption secondary

to digestion of carbohydrateto digestion of carbohydrate


4. 4. Liver: hepaticLiver: hepaticglucose outputglucose output

Amatruda JM. In: Amatruda JM. In: Diabetes MellitusDiabetes Mellitus. 1996.. 1996.



3 .Pancreas: insulin secretion3 .Pancreas: insulin secretion

2. 2. Muscle and adipose Muscle and adipose tissue: glucose uptaketissue: glucose uptake

-Glucosidase Inhibitors :Mechanism of Action

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SIDE EFFECTSFlatulenceLoose stool or diarrheaAbdominal painAlone does not cause hypoglycemia


INDICATIONSPatients with Type II inadequately controlled by diet with or without other agents( SU, Metformin) Can be combined with insulin

may be helpful in obese Type II patients (similar to metformin)

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INDICATIONS

Patients with Type II inadequately controlled by diet with or without other agents( SU, Metformin) Can be combined with insulin may be helpful in obese Type II patients (similar to metformin)


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THIAZOLIDINEDIONE DERIVATIVES

New class of oral antidiabetics insulin

sensitizer e.g.: Rosiglitazone, Pioglitazone

PHARMACOKINETICS- 99% absorbed- Metabolized by liver- 99% of drug binds to plasma proteins- Half-life 3 – 4 h- Eliminated via the urine 64% and feces 23%

Whitcomb RW et al. In: Whitcomb RW et al. In: Diabetes Mellitus. Diabetes Mellitus. 1996.1996.Cavaghan MK et al. Cavaghan MK et al. J Clin InvestJ Clin Invest. 1997;100:530-537.. 1997;100:530-537.

Ehrmann DA et al. Ehrmann DA et al. J Clin Endocrinol MetabJ Clin Endocrinol Metab. 1997;82:2108-2116.. 1997;82:2108-2116.


Intestine: glucose absorptionIntestine: glucose absorption

Pancreas: insulin secretionPancreas: insulin secretion

Muscle and adipose tissue:Muscle and adipose tissue:

ThiazolidinedionesThiazolidinediones

insulin resistanceinsulin resistance

glucose uptakeglucose uptake

Liver: hepaticLiver: hepatic

glucose outputglucose output

ThiazolidinedionesThiazolidinediones

HGOHGO

Thiazolidinediones: Mechanism of Action

Improve Improve -cell-cell

functionfunction

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MECHANISM OF ACTION

- Increase target tissue sensitivity to insulin by: reducing hepatic glucose output & increase

glucose uptake & oxidation in muscles & adipose tissues.

They do not cause hypoglycemia (similar to metformin and acarbose ) .

THIAZOLIDINEDIONE DERIVATIVES (Contd.)

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ADVERSE EFFECTS

- Mild to moderate edema

- Weight gain

- Headache

- Myalgia

- Hepatotoxicity ?

THIAZOLIDINEDIONE DERIVATIVES(Contd.)

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INDICATIONS

Type II diabetes alone or in combination with

metformin or sulfonylurea or insulin in patients resistant to insulin treatment.

THIAZOLIDINEDIONE DERIVATIVES(Contd.)

Thiazolidinediones

• Counteract insulin resistance

• Bind to PPAR-gamma (receptor), forming a complex promoting transcription of genes sensitive to insulin.

• Receptors are present in skeletal muscle, adipose tissue &liver, thereby promoting uptake of fatty acids &glucose at these sites

Insulin Sensitizers

Two classes of oral hypoglycemics work by improving insulin target cell response; the biguanides and thiazolidinediones.

Biguanides:• Metformin is classified as an insulin sensitizer, it increases

glucose uptake and utilization by target tissues. It requires the presence of insulin to be effective but does not promote insulin secretion. The risk of hypoglycemia is greatly reduced.

Thiazolidinediones• These agents are insulin sensitizers, they do not promote

insulin secretion from β-cells but insulin is necessary for them to be effective. Pioglitazone and rosigglitazone are the two agents of this group.

Insulin SensitizersThiazolidinediones

(Glitazones)• These agents are

insulin sensitizers, they do not promote insulin secretion from β-cells but insulin is necessary for them to be effective. Pioglitazone and rosigglitazone are the two agents of this group.

Sites of Action by Therapeutic Options

Adapted from Sonnenberg and Kotchen Adapted from Sonnenberg and Kotchen Curr Opin Nephrol HypertensCurr Opin Nephrol Hypertens 1998;7(5):551-555. 1998;7(5):551-555.

INCREASEINCREASE

GLUCOSEGLUCOSE

ABSORPTIOABSORPTIONN MUSCLEMUSCLE

PANCREASPANCREAS

ADIPOSE ADIPOSE TISSUETISSUE

LIVELIVERR

INTESTINEINTESTINE

HYPERGLYCEMIAHYPERGLYCEMIA DECREASEDDECREASED PERIPHERAL PERIPHERAL

GLUCOSE GLUCOSE UPTAKEUPTAKE

IINCREASEDNCREASED GLUCOSE GLUCOSE

PRODUCTIONPRODUCTION

DECREASED DECREASED INSULIN INSULIN

SECRETIONSECRETION

Therapy:Therapy:

ThiazolidinedionThiazolidinedioneses

(Biguanides)(Biguanides)

Therapy:Therapy:

SulfonylureasSulfonylureas

MeglitinidesMeglitinides

InsulinInsulin

Therapy:Therapy:

BiguanidesBiguanides

ThiazolidinedionThiazolidinedioneses

Therapy:Therapy:

Alpha-glucosidaseAlpha-glucosidase

inhibitorsinhibitors

Stepwise management of type 2 diabetes

Insulin ± oral agentsInsulin ± oral agents

Oral combinationOral combination

Oral monotherapyOral monotherapy

Diet & exerciseDiet & exercise

STEP WISE MANAGEMENT OF DIABETES MELITUS

DiagnosisDiagnosis

Health educationHealth education

Diet, exercise, weight Diet, exercise, weight control control

Oral agent monotherapyOral agent monotherapy

SU, metformin, meglitinide, thiazolidinedione, SU, metformin, meglitinide, thiazolidinedione, acarboseacarbose

Oral agent combination therapy (2 different Oral agent combination therapy (2 different classes)classes)

Insulin + oral Insulin + oral agentagent

InsulinInsulin

Anti-diabetic Drugs- September 2015

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