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Antidiabetic drugs (other than insulin)

The drugs reducing hyperglycemia can be classified in three groups:

• directly acting insulomimetics which activates insulin receptors
• indirectly acting insulinomimetics which increase insulin release such as sulfonylureas or which potentiate the effect of insulin such as metformin
• drugs which act directly on the metabolism of glucose like the inhibitors of glucosidases and inhibitors of aldose reductase.

Directly acting insulomimetics or agonists

There is at present no available drug other than insulin itself to activate directly insulin receptors.

Many studies are ongoing to find nonpeptide drugs able to activate insulin receptors.

Vanadium, in the form of vanadate, with pharmacological doses, has a direct and indirect insulinomimetic effect, but it is not released on the market. Its therapeutic interest, which seems real remains to be confirmed.

Insulin secretagogues , Sulfonylureas

The first insulin secretagogues used as drugs were sulfonylureas.

The hypoglycemic action of sulphamides was discovered in Montpellier about 1945 by Janbon who observed the hypoglycemic action of a sulphamide used as antibacterial, and by Loubatière who specified the mechanism of action by showing that the hypoglycemic action resulted from an increase in insulin secretion by the pancreas.

Effects

Sulfonylureas stimulate insulin secretion by beta cells of the pancreas by sensitizing them to the action of glucose.

They bind to a receptor located on the plasma membrane adjacent to potassium channels, called SUR (sulfonylurea receptor) whose possible endogenous transmitter is not known. SUR activation inhibits ATP-sensitive K+ channels leading to a reduced efflux of potassium. The rise of intracellular potassium concentration which follows creates a sufficient cellular depolarization to elicit the opening of voltage-dependant calcium channels. It is ultimately the increase in intracellular Ca2+ which elicits insulin secretion.

Sulfonylureas can, moreover, inhibit glucagon secretion and sensitize target tissues to the action of insulin.

Sulfonylureas are administered by oral route, bind to plasma proteins, have plasma half-lives varyingfrom five to ten hours, except for chlorpropamide and carbutamide where it exceeds thirty hours. They are metabolized primarily by the liver. Numerous pharmacokinetic interactions have been reported.

Sulfonylureas of second generation, glipizide, glibenclamide, gliclazide, glibornuride and glimepiride, are active with doses much lower than the first ones, tolbutamide, chlorpropamide and carbutamide.

Use

Sulfonylureas are used for the treatment of type 2 diabetes mellitus when diet modification has not been sufficient to achieve an appropriate control... In the noninsulin-dependant diabetics who have already an hyperinsulinemia, a sensitizing of tissues to the action of insulin by metformin, for example, seems preferable to a stimulation of insulin secretion.

Sulfonylureas have adverse effects, for example:

• Hypoglycemia, especially in the event of overdose by too high dosage or inhibition of their catabolism or suppression of one meal following an unusual physical exercise
• Digestive disorders (nausea, vomiting, cholestase)
• Blood disorders (hemolytic anemia)
• Disulfiram type reactions after alcool intake, known as or Antabuse effect, especially with chlorpropamide
• Hyponatremia, by potentiation of the effect of antidiuretic hormone.

Insulin secretagogues, glinides derivatives

Other compounds not having a sulphamide group such as nateglinide and repaglinide increase insulin secretion. Their hypoglycemic action is faster and shorter than that of sulfonylureas.

Taken before meals they avoid the post-prandial hyperglycemia but their advantages and disadvantages over the long term compared to sulfonylureas are still to be defined.

Nateglinide is a phenylalanine derivative.

Enhancers of insulin effects, metformin

The drugs which potentiate the effects of insulin are metformin and thiazolidinediones derivatives.

Metformin is a biguanide. It decreases hyperglycemia without risk of hypoglycemia because it does not lower glycemia in healthy subjects. It has an antihyperglycemic effect. Contrary to sulfonylureas, metformin does not stimulate insulin secretion. It can thus be regarded as a potentialisator of insulin.

Its mechanism of action is complex. It acts in the presence of insulin:

• by increasing glucose uptake and utilization by tissues, in particular by skeletal muscles
• by decreasing hepatic glucose production: it decreases hepatic gluconeogenesis, i.e. formation of glycogen from the amino acids and lipids.
• By decreasing intestinal absorption of glucose

Clinical trials show that metformin in diabetics reduces the fasting glycemia, glycosylated hemoglobin, blood cholesterol and triglycerides.

Metformin is not metabolized by biotransformations. It is present in the plasma in a free form, unbound toproteins. Its plasma half-life is about two to four hours. It is eliminated by the kidney and, in the event of renal impairment, risks to accumulating. The renal impairment is thus a contraindication to its prescription.

It is indicated in the treatment of type 2 diabetes mellitus not balanced by an adapted life style, particularly in overweight subjects. It is sometimes used as additive to insulin therapy in the treatment of insulin-dependant diabetes. Metformin could delay the mortality of the diabetics, especially the obese.

The most severe adverse effect of metformin is lactic acidosis, which can be fatal. Its premonitory signs are cramps, digestive disorders, intense abdominal pains, asthenia. These signs must lead to discontinuation of treatment and hospitalization. This lactic acidosis is seen especially in patients with renal or hepatic impairment. The diagnosis is confirmed by determination of blood lactic acid.

It can have other adverse effects: various digestive disorders, nausea, vomiting, diarrhea, especially at the beginning of treatment.

Metformin must be stopped before a radiological examination using iodized contrast agents because they are hyperosmolar and create a cellular dehydration, likely to induce lactic acidosis.

Enhancers of insulin effects, thiazolidinedione derivatives

The first drug of the thiazolidinedione group, also called glitazones was troglitazone. It does not stimulate insulin secretion but potentiates its action, decreasing hyperglycemia and blood concentration of glycosylated hemoglobin. It was an interesting drug but it was taken off the market because of its hepatic toxicity The new analogues of troglitazone, pioglitazone and rosiglitazone, are better tolerated.

Glitazones are selective agonists of PPAR gamma receptors (Peroxisome Proliferator Activated Receptor gamma) which, activated, form heterodimers with retinoid receptors and modulate gene transcription and synthesis of proteins (enzymes, carriers like Glut-4) implicated in the metabolism of glucose and fatty acids in particular. They stimulate the release of adiponectin by adipocytes.

Chemical formula of rosiglitazone with the explanation of the thiazolidinedione term:

During clinical studies of rosiglitazone and pioglitazone certain biological parameters improved: decrease of hyperglycemia, glycosylated hemoglobin, plasma free fatty acids. But there are not yet data showing the possible reduction in complications of diabetes mellitus or reduction in overall mortality. In addition its possible adverse effects are to be taken into account: fluid retention and congestive heart failure, hepatic disturbances (check liver enzymes regularly), weight gain, anemia, in particular.

These 2 drugs are used in the treatment of type 2 diabetes mellitus, usually in complement of metformin or an hypoglycemic sulphamide.

Inhibitors of the digestive absorption of carbohydrates, alpha-glucosidase inhibitors

The intestinal alpha-glucosidases, membrane-bound enzymes , located in the intestinal brush borde, release glucose in the intestine by hydrolysis of starch residues, oligosaccharides and disaccharides. This hydrolysis is necessary for the digestive absorption of carbohydrates because only monosaccharides like glucose and fructose are absorbed.

Inhibition of alpha-glucosidases by products such as acarbose, miglitol or emiglitate, reduces and delays the digestive absorption of glucose and decreases post-prandial hyperglycemia.

Acarbose is a pseudo-tetrasaccharide which binds with high affinity to alpha-glucosidases and inhibits them. Its effect is reversible because it is hydrolyzed and inactivated by bacterial amylases and other enzymes. Acarbose is only slightly absorbed by the digestive tract. Acarbose has no inhibitory activity against lactase and consequently would not be expected to induce lactose intolerance.

Miglitol like acarbose is an alpha-glucosidase inhibitor but in contrast to acarbose it is absorbed by the digestive tract with a bioavailability which can reach 90% when the administered dose is low. The absorbed part is distributed mainly in the extracellular space, is not metabolised and is eliminated by the kidney.

One can prescribe an alpha-glucosidase inhibitor in the treatment of type 2 diabetes mellitus, alone or in combination with other antidiabetics..

The principal disadvantage of acarbose and miglitol is digestive disturbances: abdominal flatulence, diarrhea, pain, especially at the beginning of treatment. Acarbose could exceptionally cause an ileus and hepatotoxicity.

In addition, a diet enriched in vegetable fibers improves control of glycemia, decreases hyperinsulinemia and plasma lipids in type 2 diabetics.

Aldose reductase inhibitors

An excess of intracellular sorbitol and fructose deteriorates the cell, perhaps by an osmotic effect involving a water call and cellular swelling, with rupture of the plasma membrane. The depletion in the cell of taurine and myoinositol which is involved, in particular in the synthesis of PIP2, would also take part in its damage.

It was thought that the inhibition of aldose reductase by compounds such as tolrestat, imirestat, ponalrestat, would decrease certain harmful consequences of hyperglycemia but the clinical results have been quite disappointing. A more recent derivative, lidorestat, is perhaps more interesting.

Vitamin C, in low doses, about 100 mg/day, could inhibit aldose reductase and reduce sorbitol accumulation in erythrocytes.

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