Oral agents for Diabetes Mellitus 2

Oral agents for Diabetes Mellitus type 2.

              PKGhatak,MD  

 

Oral Drug Treatment of Diabetes type II.

Several new oral hypoglycemic agents are introduced in the treatment of Diabetes Mellitus 2 (DM2). Some agents provide beneficial therapeutic effects on many vital systems. The mechanism of action of the newer agents is very different from previous drugs. A useful summary of all currently used oral DM2 agents is discussed.

The list of oral DM2 drugs is arranged alphabetically and the essential mode of action is mentioned.

Acarbose. Brand name – precose. Acarbose lowers blood sugar by preventing the breakdown of starch into sugar in the small intestine by inhibiting enzyme Acarbose glycoside hydrolases, and alpha-glucosidase enzymes in the brush border of the small intestines. It also inhibits pancreatic alpha-amylase. The net effect is less sugar is available for intestinal absorption.

Canagliflozin. Brand name – Invokana. It specifically interferes with sodium -glucose cotransporters (SGLT2). SGLT-2 inhibition lowers the renal glucose threshold (i.e., the plasma glucose concentration which exceeds the maximum glucose reabsorption capacity of the kidney). By lowering the renal glucose threshold glucose is lost in the urine.

The results in weight loss, significantly reduced HbA1c levels and lowers BP, lowers oxygen radicals and inflammatory mediators. Improvement in β-cell glucose sensitivity and insulin secretion is observed. A decrease in tissue glucose disposal and an increase in endogenous glucose production are noted.

Recent reports caution concurrent use of Rosuvastatin and Canagliflozin may result in rhabdomyolysis and hepatotoxicity.

Chlorpropamide. Brand name – Diabinese. It is a sulfonylurea. The way chlorpropamide lowers blood sugar is not clearly understood. However, it appears to lower blood glucose by stimulating the release of insulin from the pancreas.

Dapagliflozin. Brand name – Farxiga. Dapagliflozin inhibits subtype 2 of the sodium-glucose transport 2 system which is responsible for at least 90% of the glucose reabsorption in the kidney. Blocking this transporter mechanism causes blood glucose to be eliminated through the urine.

Glibenclamide. Brand name – Diabeta, and Glyburide. It is a sulfonylurea.

Glibenclamide appears to lower blood glucose acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. It causes the pancreas to release more insulin into the bloodstream by inhibiting the ATP-sensitive K+ channels, which leads to depolarization of the cells and insulin secretion. The same way acts on the

extra-pancreatic site in the liver, skeletal muscle, heart muscle and smooth muscle.

Glimepiride. Brand name- Amaryl. It is a sulfonylurea. Glimepiride helps the pancreas to release insulin, known as a secretagogue. It lowers blood sugar by stimulating the release of insulin by pancreatic beta cells and by inducing increased activity of intracellular insulin receptors.

Gliclazide. Not approved in the USA.

It is a sulfonylurea. Gliclazide lowers blood glucose by stimulating the release of insulin from the pancreas and increasing sensitivity to insulin at receptor sites. Gliclazide stimulates insulin secretion through the beta cell sulphonyl urea receptor, and possibly through a direct effect on intracellular calcium transport and improves the abnormal first phase insulin release in and also has an effect on the second phase.

Glipizide. It is a sulfonylurea. Brand name - Glucotrol. Glipizide helps the release of insulin from the pancreas. This decreases the blood sugar levels by partially blocking potassium channels among beta cells of pancreatic islets of Langerhans. By blocking potassium channels, the cell depolarizes, which results in the opening of voltage-gated calcium channels. The resulting calcium influx encourages insulin release from beta cells.

Lateglinide. Brand name – Starlix. Nateglinide is an amino-acid derivative that lowers blood glucose levels by stimulating insulin secretion from the active beta cells of the pancreas. Lateglinide interacts with the ATP-sensitive potassium (K+ATP) channel on pancreatic beta-cells. It works by helping to restore the body's proper response to insulin thereby lowering blood sugar.

Metformin. Brand name – Glucophage. It is a Biguanide. The pharmacological actions of metformin are different from other classes of oral agents. It decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Metformin has an antiandrogenic effect, also improves insulin resistance and helps insulin enter cells. It is a useful drug in polycystic ovary disease.

Miglitol. Brand name – Glyset. It is an Iminosugar. In contrast with Sulfonylureas, it does not enhance insulin secretion. It forms a reversible inhibition of membrane-bound intestinal α-glucoside hydrolase enzymes. It belongs to a class of drugs called alpha-glucosidase inhibitors which also includes acarbose. The pancreatic enzymes digest the large carbohydrates down into smaller carbohydrates called oligosaccharides. The cells lining the small intestine then release alpha-glucosidase enzymes that further digest the oligosaccharides into single sugars, like glucose, that can be absorbed.

Miglitol is a man-made oligosaccharide designed to slow down the actions of alpha-amylase and alpha-glucosidase enzymes thereby slowing the appearance of sugar in the blood after a meal. Miglitol does not cause weight gain that is frequent with sulfonylureas.

Pioglitazone. Brand name – Actos. Pioglitazone was pulled out of the market in India, France and Germany because of the higher incidence of bladder cancer and heart disease. The subsequent study did not find an increase in bladder cancer and now the drug is available worldwide. 

Pioglitazone selectively stimulates the nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-γ) and to a lesser extent PPAR-α. It modulates the transcription of the genes involved in the control of glucose and lipid metabolism in the muscle, adipose tissue, and the liver.

Repaglinide. Brand name – Prandin. It is a Meglitinide. Repaglinide lowers blood glucose by stimulating the release of insulin from the beta islet cells of the pancreas. This is done by closing ATP-dependent potassium channels in the membrane of the beta cells. When taken just prior to meals, it promotes the release of insulin that normally occurs with meals and is responsible for preventing blood glucose levels from becoming high. Repaglinide is different because it has a rapid onset of action and a short duration of action. It lowers lower HbA1c levels. It is an inducer of cytochrome P450,3A4. Repaglinide's 98% is bound to serum proteins. It forms a weaker bound Potassium (K+) channel of Bets cells of the pancreas. Increased intracellular K+ and makes the gate for calcium (ca++) gates open and insulin is secreted.

 

Tolbutamide. Brand name – Orinase. It is a sulfonylurea. It appears to lower blood glucose acutely by stimulating the release of insulin from the pancreas.

Tolazamide. Brand name – Tolinase. Tolazamide is a sulfonylurea. It lowers blood glucose acutely by stimulating the release of insulin from the pancreas.

Voglibose. Brand name – Voglib. Voglibose is an alpha-glucosidase inhibitor used for lowering post-prandial blood glucose levels. It forms a reversible inhibition of a glycosidase in the intestinal enterocytes of the small intestine and prevents Glucose absorption in the small intestine.

General consideration for all oral diabetic agents.

The patients must be sure that their oral intake of food and drinks is going to be the same as the day before. Otherwise, hypoglycemia may ensure; that must be avoided.

Gastrointestinal diseases like malabsorption syndrome, Crohn's disease, and intestinal obstruction require careful consideration before embarking on oral diabetic therapy.

Common side effects of Sulfonylureas.

Skin rashes from sun exposure, weight gain, episodes of low blood sugar, gastrointestinal upset, nausea and vomiting. Dark urine and hemolytic anemia in patients with glucose 6 phosphatase deficiency (G6PDeficiency). Concomitant administration of other sulfa drugs tilts the free vs protein bound sulfonylurea in favor of the free form which results in more therapeutic action and hypoglycemic episodes.

Significant adverse effects of some agents.

Acarbose. Side effects. GI. Bone marrow depression. Liver enzyme elevation.

Special feature. Increased incidence of Pneumatosis cystoides intestinalis and rarely intestinal obstruction.

Canagliflozin and Dapagliflozin.

Precautions. Rapid renal function deterioration.

Side effects. Repeated yeast infection of the genitourinary tract, necrotizing fasciitis of the genital area  ( Fournier gangrene), loss of bone density, bone fractures, diabetes ketoacidosis, dehydration, and increased incidence of gangrene of limbs.

Advantage. Weight loss lowers the incidence of congestive heart failure (CHF), fewer strokes and heart attacks.

Metformin.

Advantage. Weight reduction, less incidence of diabetic ketoacidosis, lowers the incidence of cardiovascular events, lowers LDL cholesterol and triglyceride. Useful in polycystic ovary.

Pioglitazone.  Advantages of Pioglitazone use are - lowering A1c, improved uptake of glucose by muscle cells decreased turning out sugar by the liver, improving hepatic cell accumulation of fat as seen in Non-alcoholic fatty liver diseases. Side effects. Weight gain and edema of extremities. Rise in LDL cholesterol. Higher incidence of bladder cancer and congestive heart failure. It was withdrawn in Canada, India and other countries but is now cleared for the treatment of DMII worldwide.

Among all these oral diabetic agents two products are outstanding.

Metformin and Gliflozin.

Metformin. It is widely used all over the world. In its extensive use, the incidence of Ketoacidosis is rare, in contrast with the previous generation of biguanide, phenformin. Because it is priced reasonably and safe and effective it has become the number one oral agent.

Canagliflozin and Dapagliflozin. It is marketed heavily as a cardioprotective drug and also lowers bad cholesterol. It is helpful in weight reduction and the incidence of CHF is less than sulfonylureas. But the retail price is beyond the reach of most people of the world who have to pay in their own pocket.

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