sulphonylureas and meglitinides1

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History Sulfonylureas were discovered accidentally. In 1942, Janbon and colleagues noted that some sulfonamides caused hypoglycemia in experimental animals. Soon thereafter, 1-butyl-3-sulfonylurea (carbutamide) became the first clinically useful sulfonylurea for the treatment of diabetes. Although later withdrawn because of adverse effects on the bone marrow, this compound led to the development of the entire class of sulfonylureas..

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Clinical trials of tolbutamide, the first widely used member of this group, were instituted in patients with type 2 DM in the early 1950s. Since that time, approximately 20 different agents of this class have been in use worldwide

Mechanism of Action:

Mechanism of Action They act on the sulphonylurea receptors on thepancreatic ß -cells causing depolarisation by reduced conductance of ATP sensitive K+ Channels. This enhances Ca+ influx causing degranulation and insulin release. Presence of at least 30% functional b-cell is essential for their action. They also have an extra-pancreatic action of increasing sensitivity of peripheral tissues to insulin.

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Sulphonylureas , cause an increase in basal insulin secretion and enhance glucose-induced insulin secretion. The degree to which basal and meal-stimulated insulin release is enhanced may differ between compounds. Recently glimipride and glibenclamide were shown to activate the nuclear transcription factor ppar y .

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Maximal potency was about 60% of that of pioglitazone,which provides a novel explanation for insulin –sensitizing actions of SUs,which may be caused by the partial agonism at these nuclear receptors. Two clinical studies reported glimepiride increases adiponectin and reduced inflammatory cytokines such as TNF α , which is increased by activation of ppar y .


INDICATION Insulin deficient patients not over weight. BMI <25 KG/M 2 Over weight patients metformin and alpha-glucosidase inhibitors. SUs can be added where blood glucose is insufficient contld. In obese SUs are 2nd choice - since weight of 2-4 kg in many studies. In obese SUs are indicated if hyperglycemia not controlled by other agents.


EFFICACY Decrease blood glucose by an average of 30- 60mg/dl. HbA1c by 1.0 -2.5%. Over 10 years HbA1c increased by 2% in UKPDS, reflecting overall beta cell function. 25% patients with SUs achieve FPG <140. 50% -75% new patients need 2 nd agent.

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Failure rate 5% per year. Within 10 years most of them go for secondary failure, cause due to insufficient insulin due to weight gain, immobilzation , chronic inflammation or dietary factors. Long term studies show a decline in beta cells function a unmodifiable factor of T2DM.

Drug Types:

Drug Types SUs 50 years old. First generation drugs have low potency than the second generation. Potency corelates with the affinity to the SUs receptors. Second generation SUs have higher affinity. Glimepiride because of its extrapancreatic effect termed as third generation SUs.


SULPHONYLUREAS First Generation: Acetohexamide Chlorpropamide Tolbutamide Tolazamide Tolazamide Gliclazide Glimepiride Second Generation Glipizide Gliclazide Glibenclamide Gliquidone Glyclopyramide Third Generation Glimepiride

Reduction of Serum Glucagon Concentrations:

Reduction of Serum Glucagon Concentrations Chronic administration of sulfonylureas to type 2 diabetics reduces serum glucagon levels, which may contribute to the hypoglycemic effect of the drugs. The mechanism for this suppressive effect of sulfonylureas on glucagon levels is unclear but appears to involve indirect inhibition due to enhanced release of both insulin and somatostatin, which inhibit A cell secretion.

Extra Pancreatic Effects:

Extra Pancreatic Effects Improve lipid metabolism , by increased level of insulin and low level of blood glucose, an indirect method. Weight gain is due to diet, increase insulin, antilipotic and tropic changes in fat cells. Beta blockers and glitazones inhibit lipolysis and promote fat cell differentiation and proliferation.


SULFONYLUREAS Extra pancreatic effect: Increases the number of insulin receptors Increases post-receptor insulin sensitivity Increases glucolysis Increases glycogen storage in muscle and liver Decreases the hepatic output of glucose


Tolbutamide Is well absorbed but rapidly metabolized in the liver. Its duration of effect is relatively short, with an elimination half-life of 4–5 hours, and it is best administered in divided doses. Because of its short half-life, it is the safest sulfonylurea for use in elderly diabetics. Prolonged hypoglycemia has been reported rarely, mostly in patients receiving certain drugs (eg, dicumarol, phenylbutazone, some sulfonamides) that inhibit the metabolism of tolbutamide .


Chlorpropamide Half-life of 32 hours and is slowly metabolized in the liver to products that retain some biologic activity 20–30% is excreted unchanged in the urine. it is contraindicated in patients with hepatic or renal insufficiency Prolonged hypoglycemic reactions are more common in elderly patients hyperemic flush after alcohol ingestion in genetically predisposed patients and dilutional hyponatremia Hematologic toxicity (transient leukopenia, thrombocytopenia) occurs in less than 1% of patients .


Tolazamide Tolazamide is more slowly absorbed than the other sulfonylureas, and its effect on blood glucose does not appear for several hours . Its half-life is about 7 hours . Tolazamide is metabolized to several compounds that retain hypoglycemic effects. If more than 500 mg/d is required, the dose should be divided and given twice daily

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Second-Generation Sulfonylureas


Glyburide(Glibenclamide) Metabolized in the liver into products with very low hypoglycemic activity. The usual starting dosage is 2.5 mg/d or less, and the average maintenance dosage is 5–10 mg/d given as a single morning dose; maintenance dosages higher than 20 mg/d are not recommended

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Glyburide has few adverse effects other than its potential for causing hypoglycemia. Flushing has rarely been reported after ethanol ingestion and the compound slightly enhances free water clearance. Glyburide is contraindicated in the presence of hepatic impairment and in patients with renal insufficiency .


Glipizide shortest half-life (2–4 hours) For maximum effect in reducing postprandial hyperglycemia, this agent should be ingested 30 minutes before breakfast The recommended starting dosage is 5 mg/d, with up to 15 mg/d given as a single dose. An extended-release preparation (Glucotrol XL) provides 24- hour action after a once-daily morning dose (maximum of 20 mg/d) At least 90% of glipizide is metabolized in the liver to inactive products, and 10% is excreted unchanged in the urine


Glimepiride Is approved for once-daily use as monotherapy or in combination with insulin. Glimepiride achieves blood glucose lowering with the lowest dose of any sulfonylurea compound . A single daily dose of 1 mg has been shown to be effective, and the recommended maximal daily dose is 8 mg. It has a long duration of effect with a half-life of 5 hours, allowing once-daily dosing and thereby improving compliance . It is completely metabolized by the liver to inactive products

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Glimepiride translocate glucose transporters to the cell membrane by direct action. It increases insulin sensitivity . Insulin levels were low compared to glibenclamide.

Which SU to choose ??:

30 Which SU to choose ?? Glybenclamide (Daonil) is a long acting SU Incidence of hypoglycemia is high with Daonil The continuously stimulate the - cell – ↑ apoptosis Glipizide and Gliclazide need to be used twice a day Glimepiride is the best among the SU – OD Its action on - cell is short lived –less hypoglycemia

Which Sulfonylurea to choose ?: 31 Which Sulfonylurea to choose ? Sulfonylurea Effectiveness Dosage Hypogly Metabolite Glimepiride (III) * Potent - OD 1 to 8 mg Least. Inactive Gliclazide (II) Potent - BID 40 to 80 mg Less Inactive Glipizide (II) Most potent -BID 5 to 15 mg Less Active Glibenclamide (II) Long acting OD 2.5 to 15 mg More Active Chlorpropamide (I) Long acting Not in use Most Active Tolbutamide (I) Intermediate Not in use More Active * No action on KATP of Heart

Secondary Failure & Tachyphylaxis to Sulfonylureas:

Secondary Failure & Tachyphylaxis to Sulfonylureas Secondary failure, ie, failure to maintain a good response to sulfonylurea therapy over the long term—remains a disconcerting problem in the management of type 2 diabetes. A progressive decrease in B cell mass, reduction in physical activity, decline in lean body mass, or increase in ectopic fat deposition in chronic type 2 diabetes also may contribute to secondary failure


Meglitinides Do not have sulphonylurea chemical motif. Repaglinide is a benzoic acid derivative. Nateglinide is derived from amino acid tryptophane. Both ultra short acting.


Repaglinide Was approved for clinical use in 1998 These drugs modulate B cell insulin release by regulating potassium efflux through the potassium channels There is overlap with the sulfonylureas in their molecular sites of action since the meglitinides have two binding sites in common with the sulfonylureas and one unique binding site. Unlike the sulfonylureas, they have no direct effect on insulin exocytosis

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Repaglinide has a very fast onset of action, with a peak concentration and peak effect within approximately 1 hour after ingestion , Duration of action is 5–8 hours. It is hepatically cleared by CYP3A4 with a plasma half-life of 1 hour Because of its rapid onset, repaglinide is indicated for use in controlling postprandial glucose excursions . The drug should be taken just before each meal in doses of 0.25–4 mg (maximum, 16 mg/d) There is no sulfur in its structure, so repaglinide may be used in type 2 diabetic individuals with sulfur or sulfonylurea allergy


Nateglinide A D-phenylalanine derivative , is the latest insulin secretagogue to become clinically available. Nateglinide stimulates very rapid and transient release of insulin from B cells through closure of the ATP-sensitive K+ channel . It also partially restores initial insulin release in response to an intravenous glucose tolerance test. Nateglinide may have a special role in the treatment of individuals with isolated postprandial hyperglycemia , but it has minimal effect on overnight or fasting glucose levels . It is efficacious when given alone or in combination with nonsecretagogue oral agents

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It is absorbed within 20 minutes after oral administration with a time to peak concentration of less than 1 hour and is hepatically metabolized by CYP2C9 and CYP3A4 with a half-life of 1.5 hours Nateglinide amplifies the insulin secretory response to a glucose load but has a markedly diminished effect in the presence of normoglycemia . The incidence of hypoglycemia may be the lowest of all the secretagogues , and it has the advantage of being safe in individuals with very reduced renal function.

Dosing :

Dosing Start low and slow. Uptitrate every 1 -2 week. In renal insufficency it has to reduced or stopped. Meglitinides recommended only when u take food. So no food no drug.

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Theoritically SUs close ATP dependant pottasium channels possessing SURa /b subunit, present on cardiomyocytes and coronary and arterial vessel smooth muscle cells in response to hypoxia. This occurs due to closure of K- ATP channels by SUs, which enlarges the infarct area

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Glimepiride and nateglinide effects have low affinity for the cardiac SUR2b SUs receptor than for the b cell SUR1 and are a safer choice in this respect. Death after MI is due to poor left ventricular function.

Safety :

Safety Hypoglycemia is the major concern. Elderly T2DM are more prone – missing meals. Presence of renal and/or hepatic insufficency enhances the risk due to impaired gluconeogenesis. In renal insufficency accumulation of the compound due to decreased elimination causes severe hypoglycemia. up to 60ml/min of creatinine clearence needs dose reduction

Strategies for Antidiabetic Treatment:

Strategies for Antidiabetic Treatment Oral Triple Combination Therapy plus Basal Insulin or plus GLP-1-Mimeticum Oral Monotherapy Oral Dual Combination Therapy Oral Triple Combination Therapy NPG, Glargine, Levemir Metformin + Sulfonylureas + TZDs Metformin + Sulfonylureas+DPP-4-Inhib. Metformin DPP-4 Inhibitors Glinides TZDs Sulfonylureas -Glucosidase-Inhibitors Metformin + DPP-4-Inhibitors Sulfonylureas + DPP-4-Inhibitors Metformin + Sulfonylureas Sulfonylureas + TZDs Metformin + TZDs Exenatide, Liraglutide

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