Oral Hypoglycaemic Drugs

ORAL HYPOGLYCAEMIC DRUGS

These drugs lower blood glucose levels and are effective orally. The chief draw back of insulin is—it must be given by injection. Orally active drugs have always been searched.

The early sulfonamides tested in 1940s produced hypoglycaemia as side effect. Taking this lead, the first clinically acceptable sulfonylurea tolbutamide was introduced in 1957. Others followed soon after. In the 1970s many so called ‘second generation’ sulfonylureas have been developed which are 20–100 times more potent. Clinically useful biguanide phenformin was developed parallel to sulfonylureas in 1957. Recently 3 newer classes of drugs, viz. α glucosidase inhibitors, meglitinide analogues and thiazolidinediones have been inducted.

SULFONYLUREAS

First generation   

Tolbutamide        

Chlorpropamide   

Second generation

Glibenclamide

(Glyburide)

Glipizide

Gliclazide

Glimepiride

BIGUANIDES

Metformin

MEGLITINIDE / PHENYL ALANINE ANALOGUES

Repaglinide         

Nateglinide

THIAZOLIDINEDIONES

Rosiglitazone

Pioglitazone

α GLUCOSIDASE INHIBITORS

Acarbose             

Miglitol

SULFONYLUREAS

The generic formula of sulfonylureas is—

All have similar pharmacological profile—sole significant action being lowering of blood glucose level in normal subjects and in type 2 diabetics, but not in type 1 diabetics.

Mechanism Of Action

Sulfonylureas provoke a brisk release of insulin from pancreas. They act on the so called ‘sulfonylurea receptors’ (SUR1) on the pancreatic β cell membrane—cause depolarization by reducing conductance of ATP sensitive K+ channels. This enhances Ca2+ influx degranulation. The rate of insulin secretion at any glucose concentration is increased. In type 2 DM the kinetics of insulin release in response to glucose or meals is delayed and subdued. The sulfonylureas primarily augment the 2nd phase insulin secretion with little effect on the 1st phase. That they do not cause hypoglycaemia in pancreatectomised animals and in type 1 diabetics (presence of at least 30% functional β cells is essential for their action) confirms their indirect action through pancreas.

A minor action reducing glucagon secretion, probably by increasing insulin and somatostatin release has been demonstrated. Hepatic degradation of insulin is slowed.

Extrapancreatic Action After chronic administration, the insulinaemic action of sulfonylureas declines probably due to down regulation of sulfonylurea receptors on β cells, but improvement in glucose tolerance is maintained. In this phase, they sensitize the target tissues (especially liver) to the action of insulin. This is due to increase in number of insulin receptors and/or a postreceptor action—improving translation of receptor activation. It is hypothesized that long term improvement in carbohydrate tolerance leads to a decreased insulin concentration in blood which reverses the down regulation of insulin receptors—apparent increase in their number. A direct extrapancreatic action of sulfonylureas to increase insulin receptors on target cells and to inhibit gluconeogenesis in liver has been suggested, but appears to have little clinical relevance.

Pharmacokinetics

All sulfonylureas are well absorbed orally, and are 90% or more bound to plasma proteins: have low volumes of distribution (0.2–0.4 L/kg). Some are primarily metabolized—may produce active metabolite; others are mainly excreted unchanged in urine. Accordingly they should be used cautiously in patients with liver or kidney dysfunction.

The distinctive features of different sulfonylureas are given in Table 19.2.

Interactions

Drugs that enhance sulfonylurea action (may precipitate hypoglycaemia) are—

a.     Displace from protein binding: Phenylbutazone, sulfinpyrazone, salicylates, sulfonamides, PAS.

b.     Inhibit metabolism/excretion: Cimetidine, sulfonamides, warfarin, chloramphenicol, acute alcohol intake (also synergises by causing hypoglycaemia).

c.      Synergise with or prolong pharmacodynamic action: Salicylates, propranolol (cardioselective β₁ blockers less liable), sympatholytic antihypertensives, lithium, theophylline, alcohol (by inhibiting gluconeogenesis).

Drugs that decrease sulfonylurea action (vitiate diabetes control) are—

a.     Induce metabolism: Phenobarbitone, phenytoin, rifampicin, chronic alcoholism.

b.     Opposite action/suppress insulin release: Corticosteroids, diazoxide, thiazides, furosemide, oral contraceptives.

Adverse Effects

Incidence of adverse effects is quite low (3–7%).

1. Hypoglycaemia It is the commonest problem, may occasionally be severe and rarely fatal. It is more common in elderly, liver and kidney disease

patients and when potentiating drugs are added. Chlorpropamide is a frequent culprit due to its long action. Tolbutamide carries lowest risk due to its low potency and short duration of action. Lower incidence is also reported with glipizide, glibenclamide, glimepiride.

Treatment is to give glucose, may be for a few days because hypoglycaemia may recur.

2. Nonspecific side effects Nausea, vomiting, flatulence, diarrhoea or constipation, headache, paresthesias and weight gain.

3. Hypersensitivity Rashes, photosensitivity, purpura, transient leukopenia, rarely agranulocytosis.

Chlorpropamide in addition causes cholestatic jaundice, dilutional hyponatremia (sensitises the kidney to ADH action), intolerance to alcohol in predisposed subjects (flushing and a disulfiram like reaction); other sulfonylureas are less prone to this interaction.

Tolbutamide reduces iodide uptake by thyroid but hypothyroidism does not occur.

Safety of sulfonylureas during pregnancy is not established—change over to insulin. They are secreted in milk: should not be given to nursing mothers.

BIGUANIDES

Two biguanide antidiabetics, phenformin and metformin were introduced in the 1950s. Because of higher risk of lactic acidosis, phenformin was withdrawn in many countries and has been banned in India since 2003.

The generic formula of biguanides is:

They differ markedly from sulfonylureas: cause little or no hypoglycaemia in nondiabetic subjects, and even in diabetics episodes of hypoglycaemia due to metformin are rare. They do not stimulate pancreatic β cells. Metformin is reported to improve lipid profile as well in type 2 diabetics.

Mechanism Of Action

It is not clearly understood. Biguanides do not cause insulin release, but presence of some insulin is essential for their action. Explanations offered for their hypoglycaemic action are—

1)    Suppress hepatic gluconeogenesis and glucose output from liver: the major action.

2)   Enhance insulinmediated glucose disposal in muscle and fat. Though they do not alter translocation of GLUT4 (the major glucose transporter in skeletal muscle), they enhance GLUT1 transport from intracellular site to plasma membrane. The effect thus differs from that of insulin.

3)    Retard intestinal absorption of glucose, other hexoses, amino acids and vit B₁₂.

4) Interfere with mitochondrial respiratory chain—promote peripheral glucose utilization by enhancing anaerobic glycolysis. However, metformin binds less avidly to mitochondrial membrane.

Actions 3 and 4 appear to contribute little to the therapeutic effect.

Pharmacokinetics

The important features are given in Table 19.2. Clearance of metformin approximates g.f.r. It accumulates and increases the risk of lactic acidosis in renal failure.

Adverse Effects

Abdominal pain, anorexia, nausea, metallic taste, mild diarrhoea and tiredness are the frequent side effects. Metformin does not cause hypoglycaemia except in overdose.

Lactic acidosis Small increase in blood lactate occurs with metformin, but lactic acidosis is rare (<1 per 10,000 patient years) because it is poorly concentrated in hepatic cells. Alcohol ingestion can precipitate severe lactic acidosis.

Vit B₁₂ deficiency due to interference with its absorption can occur with high dose of metformin.

In addition to general restrictions for use of oral hypoglycaemics (see below), biguanides are contraindicated in hypotensive states, cardiovascular, respiratory, hepatic and renal disease and in alcoholics because of increased risk of lactic acidosis.

MEGLITINIDE / DPHENYLALANINE ANALOGUES

These are recently developed quick and short acting insulin releases.

Repaglinide

It is a meglitinide analogue oral hypoglycaemic designed to normalise mealtime glucose excursions. Though not a sulfonylurea, it acts in an analogous mannerby binding to sulfonylurea receptor as well as to other distinct receptors → closure of ATP dependent K+ channels → depolarisation → insulin release.

Repaglinide induces rapid onset shortlasting insulin release. It is administered before each major meal to control postprandial hyperglycaemia; the dose should be omitted if a meal is missed. Because of short lasting action it may have a lower risk of serious hypoglycaemia. Side effects are mild headache, dyspepsia, arthralgia and weight gain.

Repaglinide is indicated only in type 2 DM as an alternative to sulfonylureas, or to supplement metformin/longacting insulin. It should be avoided in liver disease.

Nateglinide

This D-phenylalanine derivative principally stimulates the 1st phase insulin secretion resulting in rapid onset and shorter duration of hypoglycaemic action than repaglinide. Ingested 10–20 min before meal, it limits postprandial hyperglycaemia in type 2 diabetics without producing late phase hypoglycaemia. There is little effect on fasting blood glucose level. Episodes of hypoglycaemia are less frequent than with sulfonylureas. Side effects are dizziness, nausea, flu like symptoms and joint pain. It is used in type 2 DM along with other antidiabetics, to control postprandial rise in blood glucose.

THIAZOLIDINEDIONES

Two thiazolidinediones Rosiglitazone and Pioglitazone are available. This novel class of oral antidiabetic drugs are selective agonists for the nuclear peroxisome proliferator activated receptor γ (PPARγ) which enhances the transcription of several insulin responsive genes. They tend to reverse insulin resistance by stimulating GLUT4 expression and translocation: entry of glucose into muscle and fat is improved. Hepatic gluconeogenesis is also suppressed. Activation of genes regulating fatty acid metabolism and lipogenesis in adipose tissue contributes to the insulin sensitizing action. Adipocyte turnover and differentiation may also be affected. Thus, fatty tissue is a major site of their action. The magnitude of blood glucose reduction is somewhat less than sulfonylureas and metformin. Improved glycaemic control results in lowering of circulating HbA_1C and insulin levels in type 2 DM patients.

Pioglitazone lowers serum triglyceride level and raises HDL level without much change in LDL level, probably because it acts on PPARα as well. The effect of rosiglitazone on lipid profile is inconsistent.

Both pioglitazone and rosiglitazone are well tolerated; adverse effects are plasma volume expansion, edema, weight gain, headache, myalgia and mild anaemia. Monotherapy with glitazones is not associated with hypoglycaemic episodes. Few cases of hepatic dysfunction and some cardiovascular events have been reported; CHF may be precipitated or worsened. Monitoring of liver function is advised. They are contraindicated in liver disease and in CHF. Rosiglitazone has been found to increase the risk of fractures, especially in elderly women.

Rosiglitazone is metabolized by CYP2C8 while pioglitazone is metabolized by both CYP2C8 and CYP3A4. Failure of oral contraception may occur during pioglitazone therapy. Ketoconazole inhibits metabolism of pioglitazone. Drug interactions are less marked with rosiglitazone.

The thiazolidinediones are indicated in type 2 DM, but not in type 1 DM. They reduce blood glucose and HbA_1c without increasing circulating insulin. Some patients may not respond (non-responders), especially those with low baseline insulin levels. Glitazones are primarily used to supplement sulfonylureas/metformin and in case of insulin resistance. They may also be used as monotherapy (along with diet and exercise) in mild cases. Reduction in mortality due to myocardial infarction and stroke (macrovascular complications) has been obtained in type 2 DM.

Several reports associating precipitation of CHF after combined use of glitazones with insulin have appeared; avoid such combinations. They should not be used during pregnancy. The Diabetes Prevention Programme (2005) has shown that glitazones have the potential to prevent type 2 DM in prediabetics.

GLUCOSIDASE INHIBITORS

Acarbose

It is a complex oligosaccharide which reversibly inhibits αglucosidases, the final enzymes for the digestion of carbohydrates in the brush border of small intestine mucosa. It slows down and decreases digestion and absorption of polysaccharides and sucrose: postprandial glycaemia is reduced without increasing insulin levels. Regular use tends to lower Hb A_1c, body weight and serum triglyceride. These beneficial effects, though modest, have been confirmed in several studies. Further, the stopNIDDM trial (2002) has shown that longterm acarbose treatment in prediabetics reduces occurrence of type 2 DM as well as hypertension and cardiac disease. In diabetics, it reduces cardiovascular events.

Acarbose is a mild antihyperglycaemic and not a hypoglycaemic; may be used as an adjuvant to diet (with or without a sulfonylurea) in obese diabetics. Dose 50–100 mg TDS is taken at the beginning of each major meal. It is minimally absorbed, but produces flatulence, abdominal discomfort and loose stool in about 50% patients due to fermentation of unabsorbed carbohydrates.

GLUCOBAY 50, 100 mg tabs, ASUCROSE, GLUCAR 50 mg tabs.

Miglitol is similar to acarbose, and is more potent in inhibiting sucrase.