Antidiabetics

The endocrine system is composed of endocrine glands like the thyroid gland, pituitary gland and adrenal gland which produce hormones. The hypothalamus and pituitary gland are involved in regulation of the activity of most hormones in the body. Hormones regulate many body functions like glucose metabolism, growth, pubertal changes and menstrual cycle. Synthetic versions of natural hormones are available for medical use. The commonly used hormones and their analogues are discussed below.

Drugs used to treat diabetes: These include insulin and oral hypoglycemics that are used to control blood glucose levels.

Insulin: Insulin is an injectable medication that decreases blood glucose levels. It is administered subcutaneously. Only regular insulin can be administered intravenously. Insulin is available in multiple forms which vary in the time to onset and duration of action. The most common adverse effect of insulin is hypoglycemia or low blood sugar. Other effects include weight gain, hypersensitivity, and lipodystrophy. Lipodystrophy leads to the formation of fatty swellings or lumps at the site of insulin injections. Insulin is the only available medication to lower blood glucose levels in type 1 diabetics.

Rapid acting insulins: Their onset of action is within 5-30 minutes and action lasts for up to 4 hours. Examples include lispro insulin (Humalog), aspart insulin (Novolog), glulisine (Apidra) and inhaled technosphere insulin (Afrezza).

Short acting insulins: Their onset of action is within 1 hour and lasts for about 5-8 hours. Examples include regular human insulin (Humulin R, Novolin R).

Intermediate acting insulins: Their onset of action is within 2 hours and lasts for about 12-16 hours. Examples include NPH (neutral protamine Hagedorn) or isophane insulin (Humulin N, Novolin N).

Long acting or basal insulins: Their onset of action is within 2-4 hours and lasts for 24-42 hours. Examples include detemir (Levemir), glargine (Lantus, Basaglar), and degludec (Tresiba).

Insulin mixtures: Many brands contain a combination of insulins to better regulate blood glucose like fast acting with slow acting. Examples are Humalog Mix 50/50 (lispro insulin and insulin lispro protamine), Humulin 70/30 (isophane insulin and regular insulin), Novolog Mix (insulin aspart protamine and insulin aspart). The numbers indicate the percentage of each insulin type in the mix e.g., 70/30 means there is 70% of one insulin type mixed with 30% of another insulin type.

Oral hypoglycemics: Oral hypoglycemic agents, also called OHAs are oral drugs that are used in the management of diabetes mellitus. There are many different types of OHAs as discussed below.

Metformin (biguanide): Metformin decreases blood glucose levels by decreasing the intestinal absorption of glucose. It also improves insulin sensitivity. Metformin is commonly used in the management of pre-diabetes as well as type 2 diabetes to lower HbA1c levels. It is also used in polycystic ovarian syndrome (PCOS) as it is often associated with pre-diabetes. Common brands include Glucophage, Glumetza, Fortamet, and Riomet. Adverse effects include lactic acidosis, metallic taste in the mouth, vitamin B12 deficiency, nausea, vomiting, diarrhea, abdominal pain, muscle cramps, and mental status changes. Metformin should be discontinued before surgery or administration of contrast media to prevent lactic acidosis.

Sulfonylureas: Sulfonylureas are oral hypoglycemics that reduce blood sugar levels by blocking ATP sensitive K+ channels (KATP) on the pancreatic beta cells, which causes insulin secretion. Hence, they are also called insulin secretagogues. Adverse effects include hypoglycemia, weight gain, decreased white blood cell count, skin allergie,s and alcohol intolerance. They are contraindicated in sulfa allergies, advanced renal, or hepatic failure. Caution should be used while co-prescribing with beta blockers which may mask the effects of hypoglycemia like tachycardia and tremors. Examples include glipizide (GlipiZIDE XL, Glucotrol), glimepiride (Amaryl), and glyburide (DiaBeta, Glynase).

Thiazolidinediones: They activate a transcription factor PPAR gamma which results in increased transcription of genes involved in glucose metabolism. They increase insulin sensitivity. Adverse effects include weight gain, edema, fluid retention, heart failure and osteoporosis. Examples include pioglitazone (Actos) and rosiglitazone (Avandia). They are contraindicated in patients with severe heart failure.

Meglitinides: Like sulfonylureas, meglitinides increase insulin secretion from the pancreatic beta cells by blocking K+ channels. Adverse effects include weight gain, hypoglycemia, and hepatotoxicity. Examples include repaglinide (Prandin) and nateglinide (Starlix).

Incretin mimetics or GLP 1 receptor agonists: They bind to GLP 1 receptors and increase insulin secretion and slow gastric emptying. They are similar to incretin hormones that are naturally produced in the body and increase insulin secretion. They cause weight loss. Adverse effects include GI upset, pancreatitis, and rarely, pancreatic cancer. Examples include liraglutide (Victoza, Saxenda), semaglutide (Ozempic, Wegovy), tirzepatide (Mounjaro), dulaglutide (Trulicity) and exenatide (Bydureon).

DPP 4 (dipeptidyl peptidase) inhibitors or gliptins: They enhance the effect of incretin GLP 1, by inhibiting DPP 4 enzyme that degrades GLP 1. They increase insulin secretion and delay gastric emptying. Adverse effects include GI upset, diarrhea, constipation, nasopharyngitis, URTI, arthralgia, headache, dizziness, pancreatitis, and acute renal failure. Examples include sitagliptin (Januvia), linagliptin (Tradjenta), saxagliptin (Onglyza,) and alogliptin (Nesina).

SGLT 2 inhibitors: They inhibit SGLT 2 or sodium dependent glucose cotransporter in the proximal tubule of the kidney and decrease renal glucose reabsorption to decrease blood glucose levels. They promote weight loss. Adverse effects include UTIs, vulvovaginitis especially candidal, dehydration and diabetic ketoacidosis. Examples include dapagliflozin (Farxiga), empagliflozin (Jardiance) and canagliflozin (Invokana).

Alpha glucosidase inhibitors: They inhibit the enzyme alpha glucosidase that breaks down glucose, and decreases glucose absorption. Adverse effects include gas, bloating, flatulence, abdominal discomfort and diarrhea. They should not be used in Inflammatory Bowel Disease and malabsorption syndromes. Examples include acarbose (Precose) and miglitol (Glyset).

Amylin analogue: It slows gastric emptying by activation of amylin receptors in the brain and acts on the hypothalamus to decrease appetite. It leads to decreased postprandial rise in blood glucose. It causes weight loss. Adverse effects include hypoglycemia. The only available drug in this class is pramlintide (Symlin).

Antidiabetic combinations: Combination antidiabetics are composed of drugs from two or more classes with different mechanisms of action. Combinations help to improve compliance and increase efficiency.