ORAL HYPOGLYCAEMIC AGENT

PRESENTER:UDIGWE CHIOMA

OUTLINE

• INTRODUCTION• CLASSIFICATION• MECHANISMS OF ACTION,INDICATIONS,

BENEFITS AND RISKS OF EACH CLASS.• CONTRAINDICATIONS TO USE OF OHA.• TARGETS OF TREATMENT WITH OHA.• CONCLUSION.

INTRODUCTION• Oral hypoglycemic agents are the group of drugs that may be

takensingly or in combination to lower the blood glucose in type 2

diabetes.• Type 2 diabetes can be due to increased peripheral resistance

to insulinor to reduced secretion of insulin.• They should be used together with changes in diet and

lifestyle to achieve good glycaemic control.• It is customary to monitor such changes for three months

before considering medication.

• Oral hypoglycaemic agent are not usually used in type 1 diabetics but metformin may be of use in combination with insulin for overweight type 1 diabetics.

What is the role of an ideal OHA?

Conserve islet cell function - delay the subsequent use of insulin.Improve patient compliance- single daily

dosing.Reduce the incidence of hypoglycaemic events

CLASSIFICATION• Based on their mechanisms of action, oral hypoglycaemic

agents are broadly classified into four major groups.1. Those that increase insulin secretion eg

sulphonyureas,meglitinides,incretin-based therapies.2. Reduce glucose production eg

biguanides,thiazolidinediones.3. Increase insulin sensitvity eg

biguanides,thiazolidinediones.4. Delay glucose absorption eg alpha-glucosidase

inhibitors.

BIGUANIDES• Metformin, representative of this class of agents, reduces hepatic

glucose production and improves peripheral glucose utilization slightly.

• Metformin activates AMP-dependent protein kinase and enters cells through organic cation transporters .

• Metformin reduces fasting plasma glucose and insulin levels,improves lipid profile and promotes modest weight loss..

• The initial starting dose of 500 mg once or twice a day can be increased to 1000 mg bid.

. An extended-release form is available and may have fewer gastrointestinal side effects (diarrhea, anorexia, nausea, metallic taste).

• Metformin is effective as monotherapy and can be used in combination with other oral agents or with insulin.

The major toxicity of metformin, lactic acidosis is very rare and can be prevented by careful patient selection.

Vitamin B12 levels are 30% lower during metformin treatment. Metformin should not be used in patients with renal

insufficiency [GFR < 60 mL/min], any form of acidosis, CHF, liver disease, or severe hypoxemia.

Metformin should be discontinued in patients who are seriously ill, in patients who can take nothing orally, and in those receiving radiographic contrast material.

• Benefits and indications: Metformin is the only oral hypoglycaemic shown to reduce macrovascular complications and death.

• It is associated with fewer hypoglycaemic attacks than sulphonylureas and does not cause weight gain.

• It is more effective than sulphonylureas in reducing any diabetes endpoint, all-cause mortality, and stroke.

• These improvements have not been explained entirely on the basis of glycaemic control.

• Risks: Metformin can increase susceptibility to lactic acidosis.

• It’s use is contraindicated in patients with impaired renal or hepatic function and in those who drink alcohol in excess.

• Gastrointestinal side-effects occur commonly with metformin at higher doses, and may necessitate a change of drug

.

SULPHONYLUREAS

• Generation I: Tolbutamide, Chlorpropamide, Tolazamide.

• Generation II: Glibenclamide, Glipizide, Gliclazide, Gliquidone.

• Generation III: Glimepiride.

• Sulphonylureas stimulate insulin secretion by interacting with the ATP-sensitive potassium channel on the beta cell .

• These drugs are most effective in individuals with type 2 DM of relatively recent onset (<5 years), who have residual endogenous insulin production

• . First-generation sulfonylureas (chlorpropamide, tolazamide, tolbutamide; have a longer half-life, a greater incidence of hypoglycemia, more frequent drug interactions, and are now rarely used. Second-generation sulfonylureas have a more rapid onset of action and better coverage of the postprandial glucose rise.

• . Sulfonylureas reduce both fasting and postprandial glucose and should be initiated at low doses and increased at 1- to 2-week interval.

• In general, sulfonylureas increase insulin acutely and thus should be taken shortly before a meal; with chronic therapy, though, the insulin release is more sustained.

• Benefits and indications: – Sulphonylureas may be used as a first-line drug

where oral hypoglycaemic medication is required, particularly in patients who cannot tolerate metformin or in whom it is contra-indicated.

– Newer drugs in this group, such as glipizide and glimipramide, appear to afford similar efficacy as the older drugs such as gliclazide.

– Chlorpropamide is no longer recommended, as it has more side-effects than other members of this group.

• Risks: – The main risk with sulphonylureas is hypoglycaemia. This is increased in

older age groups, mild-to-moderate hepatic impairment, and renal impairment.

– Glibenclamide, a long-acting sulfonylurea, is associated with a greater risk of hypoglycaemia and therefore should be avoided in the elderly, and shorter-acting alternatives, such as gliclazide should be used instead.

– Hypoglycaemia is usually related to delayed meals, increased physical activity,alchol intake or renal insufficiency.

– Some drugs can potentiate the hypoglycaemic effect of sulphonylureas by displacing them from their plasma protein binding sites e.g. salicylates,phenylbutazone and anti –fungal agents.

– Other problems can include weight gain, liver dysfunction and gastrointestinal disturbance.

ALPHA-glucosidase inhibitors.Alpha-Glucosidase inhibitors (acarbose and miglitol) reduce postprandial hyperglycemia by delaying glucose absorption; they do not affect glucose utilization or insulin secretion .

Postprandial hyperglycemia, secondary to impaired hepatic and peripheral glucose disposal, contributes significantly to the hyperglycemic state in type 2 DM.

These drugs, taken just before each meal, reduce glucose absorption by inhibiting the enzyme that cleaves oligosaccharides into simple sugars in the intestinal lumen.

Therapy should be initiated at a low dose (25 mg of acarbose or miglitol) with the evening meal and may be increased to a maximal dose over weeks to months (50–100 mg for acarbose or 50 mg for miglitol with each meal)

. The major side effects (diarrhea, flatulence, abdominal distention) are related to increased delivery of oligosaccharides to the large bowel and can be reduced somewhat by gradual upward dose titration.

alpha-Glucosidase inhibitors may increase levels of sulfonylureas and increase the incidence of hypoglycemia.

. These agents should not be used in individuals with inflammatory bowel disease, gastroparesis, or a serum creatinine >177 mol/L (2 mg/dL).

This class of agents is not as potent as other oral agents in lowering the A1C but is unique because it reduces the postprandial glucose rise even in individuals with type 1 DM. If hypoglycemia from other diabetes treatments occurs while taking these agents, the patient should consume glucose since the degradation and absorption of complex carbohydrates will be retarded by the drug.

THIAZOLIDINEDIONES• Thiazolidinediones reduce insulin resistance by binding to the PPAR- (peroxisome

proliferator-activated receptor ) The PPAR- receptor is found at highest levels in adipocytes but is expressed at lower levels in many other tissues.

• Agonists of this receptor regulate a large number of genes, promote adipocyte differentiation, reduce hepatic fat accumulation, and promote fatty acid storage .

• Thiazolidinediones promote a redistribution of fat from central to peripheral locations.

• Circulating insulin levels decrease with use of the thiazolidinediones, indicating a reduction in insulin resistance.

• Although direct comparisons are not available, the two currently available thiazolidinediones appear to have similar efficacy; the therapeutic range for pioglitazone is 15–45 mg/d in a single daily dose, and for rosiglitazone the total daily dose is 2–8 mg/d administered either once daily or twice daily in divided doses.

• The prototype of this class of drugs, troglitazone, was withdrawn from the U.S. market after reports of hepatotoxicity and an association with an idiosyncratic liver reaction that sometimes led to hepatic failure. Although rosiglitazone and pioglitazone do not appear to induce the liver abnormalities seen with troglitazone,

• the FDA recommends measurement of liver function tests prior to initiating therapy with a thiazolidinedione and at regular intervals (every 2 months for the first year and then periodically).

• Rosiglitazone raises LDL, HDL, and triglycerides slightly.• Pioglitazone raises HDL to a greater degree and LDL a lesser degree

but lowers triglycerides. The clinical significance of the lipid changes with these agents is not known and may be difficult to ascertain since most patients with type 2 diabetes are also treated with statin.

• Benefits and indications: – TDZs are usually used in combination with a sulphonylurea or metformin.– It has also been licensed as monotherapy.– The combination with metformin or a sulphonylurea should only be used in

patients unable to tolerate metformin and sulphonylurea in combination therapy, or in whom either metformin or a sulphonylurea is contra-indicated. • In such cases, the TDZ should replace whichever drug in the combination is poorly

tolerated or contra-indicated.• A TDZ plus metformin is a useful combination for obese patients. The introduction of

a TDZ may cause a deterioration of blood glucose control temporarily when used in combination therapy.

– Pioglitazone may be considered with insulin therapy in patients who have previously had a marked glucose-lowering response to TDZ therapy or in those on high-dose insulin therapy and whose blood glucose is inadequately controlled.

• Risks:Do not commence or continue a TDZ in patients who have heart failure, or who are at higher risk of fracture: – Cardiovascular: the risk of heart failure is increased when pioglitazone is combined with insulin and in

patients with a history of cardiovascular disease. Patients who take pioglitazone should be closely monitored for signs of heart failure, and treatment should be stopped immediately if any deterioration in cardiac status occurs. Pioglitazone should not be used in patients with heart failure or a history of heart failure.

– Risk of bladder cancer: there is a small increased risk of bladder cancer associated with pioglitazone use. Pioglitazone should not be used in patients with active bladder cancer, a past history of bladder cancer or for patients with uninvestigated macroscopic haematuria. .

– There have been rare reports of liver failure, but large-scale trials have shown no difference in incidence between TDZs and other oral hypoglycaemics.Baseline LFTs and periodic monitoring are recommended.

– There is an increased risk of fractures, especially in women– It is also associated with weight gain(2-3kg),small reduction in the hematocrit and a mild increase in

plasma volume..• Only continue with a TDZ if there has been a beneficial metabolic response (HbA1c falling

0.5% in 6 months).

MEGLITINIDES

• The two meglitinides in use are Repaglinide and Nateglinide. They are relatively short-acting stimulators of insulin secretion (<6 hours).

• They act by binding to various sites on pancreatic beta cells.

• They stimulate endogenous insulin secretion through the sulphonylurea receptor and is taken immediately before food.

• Benefits and indications: – Meglitinides are characterised by short duration and rapid

onset of action, which requires them to be taken before a main meal.

– Repaglinide may be suitable as monotherapy for non-obese patients in whom metformin is contra-indicated or not tolerated, or in combination with metformin.

– Nateglinide is licensed only for use in combination with metformin.

• Risks: as with the sulfonylureas, the main risk with meglitinides is hypoglycaemia.

DIPEPTIDYLPEPTIDASE-4 INHIBITORS

• Examples of DPP-4 inhibitors are sitagliptin,vildagliptin and saxagliptin.

• They are incretin-based therapies.• They are inhibitors of the enzyme

dipeptidylpeptidase 4 which degrades GLP-1.• By inhibiting the enzyme ,they prolong the

action of GLP-1.

• GLP-1 actions include stimulating insulin secretion in a glucose-dependent manner’

• Suppresses glucagon secretion.• Delays gastric emptying.• Reduces appetite and encourages weight loss.

• Benefits and indications: – They may be appropriate ahead of a TDZ when the latter is contra-indicated, or if

further weight gain would cause or exacerbate significant problems associated with a high body weight.

– In these circumstances, they are considered as a third-line therapy in combination with metformin and sulfonylurea when glycaemic control is still inadequate.

– They can be considered second-line with metformin in patients at particular risk of hypoglycaemia (elderly patients living alone; other patients working at heights or with heavy machinery), or second-line in combination with a sulfonylurea in patients intolerant of metformin.

– They are most useful in obese patient.• Risks:

– Hypersensitivity reactions may occur (anaphylaxis, angioedema and Stevens-Johnson syndrome).

Pharmacology – Bile Acid Sequestrants

.

Class Bile acid sequestrantsCompound Colesevelam (Welchol®)Mechanism Binds bile acids/cholesterolAction(s) Bile acids stimulate receptor on liver to produce

glucoseResults • Lowers fasting and post prandial glucoseAdvantages • No hypoglycemia

• LDL cholesterol Disadvantages • Constipation

• Triglycerides • May interfere with absorption of other

medicationsCost High

Agents Mechanism of action

Examples AIC reduction

Agent specific adv.

Agent specific disadv.

Contraindication

Biguanides Decrease hepatic glucose production

Metformin 1-2 Weight neutral, do not cause hypoglycemia, inexpensive

Diarrhoea,nausea,lactic acidosis

Serum creatnine>1.5mg/dl in men,>1.4mg/dl in women, radiographic studies,acidosis,CHF,seriously ill pxts

Apha-glucosidase inhibitors

Reduce GI glucose absorption

Acarbose, Miglitol

0.5-0.8 Reduce postprandial glycaemia

Flatulence,nausea,abdominal bloating

Renal/liver disease

DPP-4 INHIBITORS

Prolong endogenous GLP-1 action

Saxagliptin, sitagliptin,vildagliptin

0.5-0,8 Do not cause hypoglycemia

Reduce dose with renal disease.

Agents Mechanism of action

Examples AIC reduction

Agent specific adv.

Agent specific disadv.

Contraindication

Sulphonylureas

Increase insulin secretion

Glibenclamide,glyburide

1-2 inexpensive Hypoglycaemia,weight gain.

Renal, liver disease

Meglitinides

Increase insulin secretion

Repaglinide,Nateglinide

1-2 Short onset of action, lower post prandial glucose

Hypoglycaemia

Renal/ liver disease

Thiazolidinediones

Decrease insulin resistance, increase glucose utilization

Rosiglitazone,pioglitazone.

0.5-1.4 Lower insulin requirement.

Peripheral oedema,wt gain,fractures,macula oedema,increase cvs risk

CHF,liver dx.

• Bile acid sequestrants: are well established for the treatment of dyslipidaemia, and reduce the risk of cardiovascular disease. They also reduce glucose concentrations in patients with type 2 diabetes. The mechanism of action is not known.

• Dopamine D2-receptor agonists :Bromocriptine is an ergot alkaloid dopamine-D2receptor agonist Although bromocriptine quick release has only been licensed since 2010 by the US Food and Drug Administration (FDA) for the treatment of type 2 diabetes as an adjunct to lifestyle changes, its effects on glycaemic variables have been noted since 1980.

• Bromocriptine produces its effects without increasing insulin concentrations, possibly by altering the activity of hypothalamic neurons to reduce hepatic gluconeogenesis through a vagally mediated route.

NEWER AGENTS .

DETERMINANTS OF OHA USEAGE1)Body Mass Index : Metformin, Gliptins BMI> 22kg/m2 2)Presence of GI symptoms: Sulpha, Gliptins, Glitazones

3)Renal Dysfunction: Gliptins, Glitazones(+/-),Sulpha (variable)

4) Aging Meglitinides, Gliptins(?)

5) Hepatic Dysfunction Nateglinide, Saxagliptin(?)

6) Compliance Gliptins, Glitazones,

7) Cost Metformin, Sulphas, Glitazones

CONCLUSION

In conclusion,OHA are agents that help in lowering blood glucose in DM, more useful in type 2 DM.the different classes target the various pathophysiological mechanisms involve in type2 dm.the main limitation to the usage of available OHA is their inability to alter the progressive nature of the dx. Efforts should be geared towards developing drugs that will address this problem.

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