Category:Antihyperglycemic agents

An antihyperglycemic agent is a medicine used to lower the blood glucose concentration in a person with diabetes mellitus. The category includes the insulins and the several classes of non-insulin agents that act on hepatic glucose production, on peripheral insulin sensitivity, on incretin signalling, on renal glucose reabsorption, and on islet insulin secretion.

The disease has been described for as long as there has been medicine. The Ebers papyrus of about 1550 BCE records a condition of polyuria that may be diabetes mellitus, and the Indian physicians Sushruta and Charaka in the first millennium BCE noted that the urine of such patients was sweet enough to attract ants. The English physician Thomas Willis in 1674 added the second word of the name when, having tasted the urine of one of his patients, he reported that it was "wonderfully sweet as if it were imbued with honey or sugar."^[1] A century later, in 1776, the Liverpool physician Matthew Dobson showed that the sweetness was due to sugar by evaporating a sample of his patient's urine to a sticky residue.^[2] The pancreas entered the story in 1869, when the 22-year-old medical student Paul Langerhans described, in his Berlin doctoral thesis, the clusters of clear cells scattered through the pancreatic acinar tissue that would later be named the islets of Langerhans. Twenty years later, in 1889, Oskar Minkowski and Joseph von Mering at Strasbourg removed the pancreas from a dog to test the digestive function of pancreatic juice and inadvertently produced the first experimental diabetes; the urine of the pancreatectomised animal attracted flies in such numbers that the laboratory cleaner remarked on it.

The breakthrough was made in the summer of 1921 at the University of Toronto. The orthopedic surgeon Frederick Banting had proposed that the failure of earlier pancreatic-extract trials was due to digestion of the islet hormone by the pancreas's own proteolytic enzymes, and the physiologist John Macleod gave him laboratory space, a medical student named Charles Best, and a supply of dogs to test the idea over the summer break. Banting and Best, by ligating the pancreatic duct to atrophy the acinar tissue and then extracting the remaining islets, prepared a substance they called isletin that lowered the blood sugar of diabetic dogs. The biochemist James Collip joined the team in December to purify the extract; on 11 January 1922 a 14-year-old patient at the Toronto General Hospital named Leonard Thompson received the first injection. The first batch was too impure and produced an abscess; the second, prepared by Collip, lowered Thompson's blood glucose from 520 to 120 mg/dL and restored him from a moribund state.^[3] Banting and Macleod shared the 1923 Nobel Prize, an award disputed publicly by Banting, who split his share with Best, while Macleod split his with Collip. Insulin was given to the patent of Eli Lilly for one dollar, on the condition that the medicine be made available at the lowest possible price.

Insulin remained, for the next sixty years, an animal-source medicine. Beef and pork pancreas extract, increasingly purified, supplied the world's diabetics into the 1980s, when recombinant human insulin (Eli Lilly's Humulin, 1982) became the first commercial product of the new biotechnology industry. The protein could now be modified, and the engineered insulin analogues followed: insulin lispro (Lilly, 1996), with the proline and lysine of positions B28 and B29 reversed to disrupt dimerization and accelerate absorption; aspart (Novo Nordisk, 2000); the long-acting glargine (Sanofi, 2000), pH-precipitating subcutaneously to form a slow-release depot; detemir (Novo Nordisk, 2005), albumin-bound through a fatty-acid side chain; and the ultra-long-acting degludec (Novo Nordisk, 2013), with a half-life beyond 24 hours.

The first effective oral antihyperglycemic was a sulfonamide. In 1942 the Montpellier physician Marcel Janbon, treating typhoid patients with the sulfonamide IPTD, observed unexplained hypoglycemia and reported it as a side effect. Pharmacological investigation by Auguste Loubatières in the same city established that the compound stimulated insulin secretion from the pancreatic beta cell. The sulfonylurea class, developed at Hoechst (tolbutamide, 1956; glibenclamide, 1969) and at subsequent firms, became the standard oral medicine for type-2 diabetes for forty years. Glipizide (1972), glimepiride (1995), and the related meglitinides extended the class.

The principal medicine of modern type-2 diabetes management came by a different route. The European folk remedy Galega officinalis, the French lilac or goat's rue, had been used for diabetic symptoms since the Middle Ages; the active component was identified as guanidine in 1918, and the substituted biguanide metformin was first synthesized by Werner and Bell in 1922 but ignored for thirty years. The Parisian physician Jean Sterne published the first clinical trial of metformin in 1957 under the trade name Glucophage; the medicine was approved in Europe shortly after but did not reach the United States until 1995, in part because of the contemporary withdrawal of phenformin (a related biguanide) for lactic acidosis. The UK Prospective Diabetes Study of 1998 demonstrated that metformin reduced cardiovascular mortality independently of its glucose-lowering effect, and it has been the first-line oral medicine for type-2 diabetes since.^[4]

The pharmacopoeia of antihyperglycemic agents expanded in three waves over the next two decades. The thiazolidinediones, PPAR-gamma agonists that improve peripheral insulin sensitivity, were introduced with troglitazone in 1997, rosiglitazone and pioglitazone in 1999; troglitazone was withdrawn for hepatotoxicity in 2000 and rosiglitazone restricted in 2010 for an apparent cardiovascular signal, leaving pioglitazone as the survivor of the class. The incretin agents arrived in two forms: the DPP-4 inhibitors, blocking the enzymatic degradation of endogenous GLP-1 and GIP, beginning with sitagliptin at Merck in 2006 and followed by saxagliptin (2009), linagliptin (Boehringer Ingelheim, 2011), and alogliptin (2013); and the GLP-1 receptor agonists, first identified through the isolation of exendin-4 from the saliva of the Gila monster Heloderma suspectum by John Eng at the Bronx VA in 1992,^[5] developed clinically as exenatide (Byetta, 2005) and extended by liraglutide (Novo Nordisk, 2010), semaglutide (2017, in injectable and 2019 oral forms), and the dual GIP/GLP-1 agonist tirzepatide (2022).

The most recent class, and the one that has most reorganised cardiovascular and renal practice in addition to glycemic, is the sodium-glucose cotransporter-2 inhibitors. The story begins with phlorizin, a glycoside isolated from the bark of the apple tree by Petersen in 1835 and noted in the nineteenth century to cause glucosuria in healthy people. The selective SGLT2 inhibitors dapagliflozin (AstraZeneca, 2014), empagliflozin (Boehringer Ingelheim, 2014), and canagliflozin (2013) were developed for glycemic control, but the 2015 EMPA-REG OUTCOME trial of empagliflozin in patients with type-2 diabetes and established cardiovascular disease showed a marked reduction in cardiovascular mortality and in heart-failure hospitalization that has driven the class into use in heart failure with both reduced and preserved ejection fraction, independent of diabetes status.^[6]

By mechanism:

• Insulins: aspart, lispro (rapid-acting); glargine, detemir (long-acting); degludec (ultra-long-acting); plus regular and NPH human insulins
• Biguanides: metformin
• Sulfonylureas (also indexed as insulin secretagogues): glimepiride, glipizide
• Thiazolidinediones: pioglitazone
• DPP-4 inhibitors: linagliptin, sitagliptin
• SGLT2 inhibitors: dapagliflozin, empagliflozin
• GLP-1 receptor agonists and the dual GIP/GLP-1 agonists (collected separately when their individual pages are built): semaglutide, liraglutide, exenatide, dulaglutide, tirzepatide
• Alpha-glucosidase inhibitors, the meglitinides, the amylin analogue pramlintide, and the bile-acid sequestrant colesevelam (which has a modest glycemic effect) are listed on their respective medicine pages

The boundary of this category is "medicine taken to lower the blood glucose in a person with diabetes mellitus." Medicines used to treat hypoglycemia (intravenous dextrose, intramuscular glucagon, oral carbohydrate preparations) are not included; they are collected under hormones or under general supportive medications. The dietary supplements and herbal products marketed for blood-sugar control (chromium, bitter melon, fenugreek, banaba leaf, and others) are not collected here, as their place in clinical care is uncertain and their regulatory standing differs from that of prescription medicines. The pancreatic islet cell transplantation procedure and the closed-loop insulin pump are devices and procedures, not medicines, and although they share the therapeutic goal of this category they are not collected here.

This category page is an encyclopedia article about its subject. The actual index of medicines belonging to the category is generated automatically by the wiki engine, from category-membership declarations on the individual medicine pages, and appears at the foot of the page below the references.