Oral Hypoglycemic Agents

dr. Siham G. AltayibMSc. Community Pharmacy

Queen’s University Belfast

Achieve adequate glycaemic control. Avoid short term complications:- hypoglcaemia hyper glycaemia DKA Prevent long term complications Improve quality of life

Goals of diabetes management

The means of controlling blood glucose is 1\ Life style modifications :- 1- diet 2- exercise 3- weight loss2\ Drugs

Con.

The medication available to treat type 2 diabetes can be grouped according to their chemical class and function :

Medications that improve insulin action :1- biguanides 2- thiazolidenedones

Medications that slow glucose absorption:Alpha – glucosidase inhibitors

Options of the therapy

Medication that increase insulin secretion :1- sulphonylureas 2- meglitinide3- D-phenaylalanine drevatives

Medication that restore or duplicate incretion action on insulin secretion and glucagon suppression :

1- GLP-1 agonist2- DPP-4 inhibitors

con

Medication that provides additional insulin exogenous pharmacological insulin

It is important to note that insulin is included in this list not because oral medication faild to work or when patient is not adherent BUT insulin is typically used when

1- there is deceased endogenous insulin secretion OR

2- to decrease glucose toxicity

con

There are many clinical markers that can reflect the predominance of the various pathophysiologic component that contributes to type2 diabetes SO this can guide the selection of the treatment by the doctor . These include :

1- body habits :Apple-shaped body suggest insulin resistanceOverweight also suggest insulin resistance

Medication selection for treatment of type2 diabetes

2- Age : Aging promotes insulin resistance ( therefore the

older the person the more likely he/she is to have insulin resistabce

3- weight change : Recent loss of weight , particularly concurrent

wirth poor diabetes control suggest insulin deficiency

BMI more than 27 suggest insulin resistance

con

4 - duration of diabetes: The longer the patient has had diabetes , the

more like hood that there is insulin deficiency

5- gender: Women with type 2 diabetes lose the protection

against macrovascular disease , so attention to macrovascular risk factors is important

Con.

6- co-existing disease: Presence of other component of the insulin

resistant syndrome suggest the presence of insulin resistance (dyslipediemia , hypertension or gout)

7- side effect profile: Development of side effect from use of medication

might preclude its use e.g. metfornmin

Con.

1-duration of diabetes 2- age of the patient 3- Patient's Life style consideration 4- Degree of glycemic control( severity of

postprandial hyperglycemia) 5- other illnesses 6- Access to drug

The choice of oral therapy should be based on :

7- Economic status of the person with diabetes 8- Mutual agreement between the patient &

doctor ( willingness and ability to use the drug or inject insulin

The choice of oral therapy should be based on :

The ideal OHGA is that which ; 1- conserve islets cell function . i.e . Delay the

subsequent use of insulin

2- improve patient’s compliance ( single daily dosing )

3- reduce the incidence of oral hypoglycemic events

What is the ideal oral hypoglycemic agent?

1- oral agents are never indicated for typ1 diabetes

2- type 2 patients with acute illness 3- surgery 4- state of gastrointestinal disorders ( nausea ,

vomiting or diarrhea )

Contraindications f OHGAs.

Monotherapy should be the initial choice

The step care approach is recommended because of the progressive nature of diabetes

Important points

1- combination of OHGAs with different mechanisms can be indicated if MONOTHERAPY failed to control BG.

NEVER use 2 drugs from the same class

2- when oral therapy failed to achieve glycemic control ISULIN should be added to the regimen OR alternatively replace treatment with OHGAs.

Important points con. :

1 ] sulphonylureas:

Mechanism of action :Stimulates basal as well as glucose - mediated insulin

secretion. Thus resulting in continuous stimulation of the beta cells to release insulin

With progressive betacell failure sulphonyluras fails to control BG So additional OHGA is added or insulin may be required for glycemic contol

1\ drugs that stimulates insulin relase from pancreas ( secretogogus):

1] pancreatic effect :a) Increase insulin release from the pancreas by : stimulating the release of insulin from functioning

beta cell by blocking ATP –sensitive K chanells resulting in depolarization and calcium influx which causes microtubular contraction and release of insulin

b) Suppress the secretion of glucagon from alpha cells

Con. Mechanism of action SU.

2] Extra pancreatic effect: Potentiating of insulin action in target tissues :1- increase the number of insulin receptors2- increase post receptor insulin sensetivity 3- increase glycolysis4- increase glycogenesis ( glycogen storage in liver

and muscles )5- decrease the gluconeogensis ( glucose out put

from the liver

Con. Mechanism of action SU.

Measurement of C-peptide level gives indication of residual ß-cell function

Early use of combination has been shown to reduce glucose toxicity & preserve ß-cell mass

Pharmakokinetics :1- SU. Are well absorbed orally .2- peak plasma concentration within 2-4 hours3- they circulate by binding to plasma protein and can be

potentially interact with other drugs such as sailcylates and sulphonamides which binds to albumin

Con. sulphonylureas

4- elimination is through kidneys .so the half life can be significantly prolonged in the elderly and those with renal diseases

5- SU. Cross placenta & can stimulate foetal beta cell to secret insulin

Clinical use of SU:SU . Is indicated for type2 D. when diet alone is

insufficient to achieve glycemic control.

Treatment should be commenced at low doses and titrated every 4-7 days as needed

Con. sulphonylureas

SU. Can be used alone or in combination with other OHGA or insulin .

Early use of combination has been shown to reduce glucose toxicity & preserve ß-cell mass

A higher effect is observed with high fasting BG. And with high A1c levels

There are 2 generations of SU. The second generation agents are more potent , have

more rapid onset of action & longer duration of action

Con. sulphonylureas

Drugs that incrase sulphonyl urease action :1] by displacing from the protein binding :Phenylbutazone , sulphonamides ( trimethoprime)

2} inhibit metabolism\ excretion :Cimetidin (H2 blockers) , warfarin , chlorampheincol

3] synergize or prolong plasma pharmacodynemic action :

Salicylate ( aspirin) , probranolol , theophelline

Sulphonylureas drug interactions

Drugs which reduce sulphonylureas action :1] drugs which induce SU metabolism :Phenobarbitones , chronic alcohiolism

2] drugs that oppose \ suppress action ( insulin release ):

Corticosteroids, thiazide diuretics , furosemide . Oral contraceptives

Sulphonylureas drug interactions

1] hypoglycemia :The most serious complication ( often result from

law coloric intake )Risk of HG increase in :- elderly &Those with hepatic or renal impairemnt so

long acting SU. Should be avoided in this group of patients

- The highest incidence occures with chlorobromide & glibencalmide ( donil)

Sulphonylureas \ adverse effects

2] stimulate appitaite & weight gain 3] gasteric upset ( nausea , flatulance , diarrhoea

or constipation )4] allergic skin reaction 5] headache 6] rarely bone marrow damage

Sulphonylureas \ adverse effects

1) Pregnancy2) Hepatic or renal insufficienty 3) Major surgary 4) Severe infection 5) Sesetivity to sulpha

Sulphonylureas \ contraindication

First generation :1- Chloropromide 2- tolbutamide

Second generation :1- Gliclazide 2- glibenclamide ( donil)3- glipizide

Third genteration :Glimepride

Con. sulphonylureas

1] Glibinclamide ( donil)

2] Glimipride ( amary)

3]Gliclazide ( dimicrone)

Sulphonylureas \ commonly used

2] Non-sulphonylureas insulin secretogogues: [Meglinitides ]

Meglinitides stimulating the release of insulin from bancreas by binding to the SUR at a site different from the sulphonylurea –binding site .

They inhibit ATP dependant potassium channels in the beta cell membrane which depolarize the cell leading to opening of calcium channels and insulin secretion .

In contrast to SU this release of insulin is glucose dependant , it diminishes at low glucose concentration

1\ drugs that stimulates insulin relase from pancreas ( secretogogus):

These agents stimulate first phase insulin release in glucose dependent manner {reducing the risk of hypoglycemia}

Drugs in this group are : 1- repaglinide 2- Nateglinide Pharmakokinetics : Fast acting Short duration of action (2-6 hours) doses 2-4

dose per day

Designed to minimize meal time blood glucose peaks .( taken before the main meal) , as they help control prandial glucose) so these agents is suitable options for those who need flexible meal timing and in the elderly

Patients are advised to skip dose if meal is missed Metabolize in liver ( to inactive product ) and

excreted in bile

Con .

Con. Repaglinide : Form available in sudan is NovoNorm Strength 0.5-4.0 mg tablets \ staring dose 0.5-2

mg Given just before each major meal 15 kin. Rapid & short duration of action Improve postprandial glycemia Less likely to develop repeated hunger , frequent

eating and weight gain [unlike sulphonylureas]

Side effects: 1- hypoglycemia { rare} 2- nausea and vomiting 3- arthralgia ( joint pain)

Con.

Very rapid onset of action Shorter duration of action 1-10 minutes before meal Lower incidence of hypoglycemia than repaglinide

Nateglinide

These are drugs that improve the sensitivity to insulin in muscle , liver & fat tissues

Medication in this group share the following characteristics :

1- they require the presence of endogenous or exogenous insulin to have their effects

2- the patient must have insulin resistance 3- hence they reduce insulin resistance rather than

insulin quantity so they have good effects in higher glucose levels ..and not likely to cause significant hypoglycemia as treatments that increase insulin levels

2\ insulin sensitizers :

1- biguanides 2- thiazolidenediones

1] Biguanides : These are class of antidiabetic drugs originate

from the french lilac (flower) The only one used now and is effective is

metformin

Con.

Metformin :Use alone or in combination with other drugs Recommended as first-line drug in patient with

type2 diabetes ( guidelines)

Approved for prevention of type 2 diabetes in high risk individuals

Used for polycystic ovary syndrome : insulin resistance with ovarian hyperandrogenism

Con.

Mechanism of action :

1- decrease the intestinal absorption of CHO2- decrease hepatic glucose production 3- increase insulin-mediated peripheral glucose

uptake4- increase glucose utilization (glycogen synthesis5- increase glycolysis through anaerobic pathway

( lactic acidosis)

Con. Metformin

6- dcrease fasting plasma glucose conc. By about 60-7-mg\dl

7- lower blood glucose but not cause hypoglycemia

NB: metformin is appropriate for obese patient with type2 diabetes

Con. Mechanism of action :

pharmakokinetics :1- well absorbed from small intestine2- stable 3- doesnot bind to plasma protein 4- excreted unchanged in urine 5- can be taken in 3 doses with meal6- maximum recommended daily dose is 3g\day ( currently we don’t give more than 2g\day in divided

doses with meal )

Con. Metformin

Secondery beneficial effects : on libids :1\ small reduction in total cholestrol level2- small reduction in triglycerides 3- reduction in LDL4- increase in HDL

Con. Metformin

Side effects :Occurs in 20-25% of patientsGastrointestinal side effects:1- abdominal discomfort , bloating , nausea ,

metallic taste 2- weight loss and diarrhea observed in 10-15% of

patient , depending on dose 3- decrease absorption of vit,B 12

Con. Metformin

adverse effects :1- hypoglycemia : occurs only when combined with

other drugs 2- rarely : severe lactic acidosis particularly in

patients with CHF

Drug interaction:Cimetidine , nifedipine , frusemide

Con. Metformin

Contraindications:1- should be avoided in patients who predisposed to

lactic acidosis ( renal & hepatic disease , heart failure ..) impaired renal function serum cr. >1.4mg\dl for woman or 1.5 mg\l male

2- past history of lactic acidosis 3- chronic lung diseaseThese conditions predespose to increase lactate

production which cause hepatic lactic acidosis which is fetal.

4- all other situatios where OHGAs is contraindicated

Con. Metformin

Contraindications:5- type1 diabetes 6- surgary 7- myocardial infraction 8- elderly 9- pregnancy

Con. Metformin

Metformin in market

Metformin in market \combination

Also known as :1- PPRAs ( peroxisome prolifelator activated

receptors )2- glitazones ( TZDs.)Untilrecently there were 3 TZDs :1- pioglitazone ( Actos)2- posiglitazone ( Avandia)3- troglitazone ( rezulin)

2] Thiazlidenediones

Mechanism of action :Antihyperglycemic : 1- increase insulin sensetivity in liver and

muscle 2- do not increase insulin secretion3- reduce hepatic glucose output4-improve lipid profile 5- may induce weight gain

Con. Thiazlidenediones

Rosiglitazone :

Bioavailability of oral dose 99%Extenseivelly 98.5% bound to plasma protein

Metabolites have no significant activity

Plasma half life is 3-4 hours

Excreted in urine and stool

Use as single or divided to two doses per day

Con. Thiazlidenediones

Pioglitazone:Execreted primarily in the stool

Half life 3-7 h

Extensively 99% bound to plasma proteins

Can be given in single dose

No evidence of drug induced hepato toxicity

Con. Thiazlidenediones

Side effects :1- weight gain because of insulin like effects 2- fluid retention ( lower limb oedema )3- liver enzyme elivation ( the firstTZDs troglitazone was

withdrawn from market because of hepatotoxicity )4- most common sside effects : Headache , CHF , fatigue , slight decrease in

heamoglobin , hepatic cellular injury ( rare )

Con. Thiazlidenediones

Contraindications 1- cardiac failure 2- impaired hepatic function 3- pregnancy and lactation

Drug interaction :Not recommended to be used with oral contraceptives )

Con. Thiazlidenediones

Alpha glucosidase inhibitors AGIs) :

Acts in the proximal small intestine They reduce the rate of digestion of

polysaccarides . They reduce intestinal absorption of starch , dextrin , and disaccharides by inhibiting action of alpha glucosidase enzyme , thereby primarily lowering postprandial glucose levels .

AGIs , donot prevent absorption of complex carbohydrates but delay it

3] drugs that delay glucose absoption

There are 2 drugs :1- acarbose 2- miglitol Side effects :Gastric upset ( flatulanse , loose stool or diarrhae ,

abdominal paintolerability can be improved by slowly titrating the dose over

several days Drug interaction:Decrease metformin bioavailability when used concomitantly

Con. Alpha glucosidase inhibitors AGIs) :

Con. Alpha glucosidase inhibitors AGIs) :

Are naturally occurring hormones secreted by the intestine in response to meal when BG is elevated

Increased incretin levels signals : 1- incrase insulin secretion 2- stop hepatic glucose production

The levels of incretins increases significantly when food is ingested

4] incretins & DPP-4 inhibitors

Endogenous hormones are : 1- GLP-1 ( glucagon like peptide 1) 2-,GIP ( glucose dependant insulinotropic peptide ) 1\ GIP : 42 amino acid peptide Secreted from dudenum & proximal jejenum ) 2] GLP_1: 30 amino acid peptide Secreted from the distal GI tract ( ielum & colon)

Con. Incretins & DPP-4 inhibitors

Action : Increase insulin production from beta cells Decreas glucagon secretion )

The physiological activity of incretin is limited by the enzyme dipeptidyle peptidase-4 (DPP-4) .which rapidly degrades active incretin after its release

Consequently both GLP-1 & GIP are rapidly inactivated by the enzyme dipeptidyle peptidase-4 (DPP-4)

Con. Incretins & DPP-4 inhibitors

DPP-4 inhibitors

Mechanism of Action : Slow the inactivation of incretin hormones ( GLP-1

& GIP) Increased glucose stimulated insulin secretion Cause glucose stimulated glucagon suppression Primarily reduce postprandial glucose levels but

also has been shown to reduce fasting BG levels

DPP-4 inhibitors

SGLT-2 inhibitors

Inhibit the reabsorption of glucose by kidneys so glucose levels in urine will be increased { this is an insulin independent mechanism to lower blood glucose levels

Advantages : Improve glycemic control Weight lloss Carry low risk of hypoglycemia

SGLT-2 inhibitors

Examples : Dapagliflozin Canagliflozin

SGLT-2 inhibitors

Life style :

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