Oral agents for Diabetes Mellitus type 2.
PKGhatak, MD
Diabetes-II is also called Adult diabetes; however, fundamentally the Diabetes- II is a different disease from Diabetes -I; the only connection between the two is that glucose utilization is abnormal in both diseases.
Glucose, a hexose sugar, is the principal energy-generating molecule that the human body utilizes. Glucose belongs to the carbohydrate class of food substances. Humans can also use other hexoses and pentose sugars. But under normal conditions, all forms of carbohydrates are converted to Glucose in the human intestine before it is absorbed. The Liver is the chief organ where Glucose is transformed into other sugars and glycogen, a complex carbohydrate for storage.
The Liver, in normal circumstances, converts Fat and Proteins into glucose; this process is called Neoglucogenesis.
Breastfeeding nursing mothers generate Galactose, another hexose sugar, from blood glucose to form milk sugar, Lactose.
To utilize Glucose by the tissue, the glucose molecule must pass through the cell membrane, for which Insulin plays a crucial role.
When Insulin production is altogether absent, the disease is called Diabetes mellitus-I. Whereas, in conditions where insulin production is present but insulin for one reason or another is ineffective in ferrying glucose molecules across the cell membrane, the disease is called Diabetes mellitus II.
Oral agents used in the treatment of Diabetes II.
In recent years, major advances have been made in oral antidiabetic medication. It is now almost standard, after initial attempts to control high blood sugar with a low-carbohydrate and 1500 to 18000 calorie diet, to start with Metformin. Then, if additional medication is necessary, a SG2 transport protein blocker is added.
The drugs are mentioned in order of their utilization in recent years.
Metformin:
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 anti-androgenic effect, also improves insulin resistance and helps insulin enter cells. It is a useful drug in polycystic ovary disease.
SGLT-2 Inhibitors:
Canagliflozin, brand name Invokana. Canagliflozin interferes with Sodium-Glocose contraspoters (SGLT-2). SGLT-2 interferes with the reabsorption of sugar from the glomerular filtrate in segment 3 of the proximal tubules, and blood sugar levels fall, and more and more sugar is lost in the urine.
The results in weight loss, significantly reduced HbA1c levels and lower 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 that concurrent use of Rosuvastatin and Canagliflozin may result in rhabdomyolysis and hepatotoxicity.
Dapagliflozn, brand name Farxiga. It is another SGLT-2 inhibitor. In normal conditions, SGLT-2 is responsible for 90 % of the glucose reabsorption in the renal tubules; blocking this transport mechanism results in glucose loss in the urine.
Empagliflozin, brand name Gardiance. It is the 3rd SGLT-2 approved in the USA. The mechanism of action is similar to the other two mentioned above. But it is worth remembering that SGLT-2 is a group of transporter proteins. In humans, there are 8 such SGLT-2 proteins, and each one is specifically abundant in certain organs. Though currently three SGLT-2 inhibitors are available, individual agent mainly prevent one such transporter protein in a specific organ. As a result, the toxicity and side effects are different in these drugs.
Thiazolidinediones:
This group of drugs acts by increasing the activity of Peroxisome proliferators, which increases Insulin sensitivity.
Because of hepatotoxicity and increased incidence of urinary bladder tumors, this drug was withdrawn from India and Germany; later studies cleared this drug, and now available in all countries.
Pioglitazone, brand name Actos. It is a selective agonist of Peroxisome proliferator activated receptor-gamma (PPAR-Y). These receptors are present in adipose tissue, skeletal muscle, and liver.
Rosiglitazone, brand name Avanda. It activates PPAR-y receptors and facilitates glucose and lipid metabolism.
Sulfonylureas:
There are several members in this group; at one time, these were the only effective oral agents. But the use of sulfonylureas have decresed with the arrival of severl new ganets, some of them are mentioned above. This medication works by stimulating the Beta cells of the pancreas by binding with ATP dependent Potassium channels, to incrse production of Insulin.
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 (G6P deficiency). 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.
Common drugs of this group are-
Chlopropamide, brand name Diabesese.
Glipizide, brand name Glucotrol.
Glyburide, brand name Micronase
Tolazomide, brand name Tolinase.
Tolbutamide, brand name Orinase.
Acetohexamide, brand name Dymelor.
Alpha-Glucosidase Inhibitors:
Alpha-Glucosidase Inhibitors work by delaying carbohydrate digestion and absorption, thereby lowering the postprandial glucose load.
Significant side effects of alpha-glucosidase inhibitors include bone marrow depression. Liver enzyme elevation and increased incidence of Pneumocystoides intestinalis infection and intestinal obstruction.
Two agents are available in this group: they are -
Acarbose, brand name Precose.
Miglitol, brand name Glyset.
Edited May 13, 2025