In Brief This article provides an overview of the development of insulins, oral agents, and noninsulin injectable agents used in the management of hyperglycemia in patients with diabetes. It also briefly reviews the pharmacological impact and salient side effects of these medications. A Brief History of the Development of Diabetes Medications The management of diabetes has one patient in the first month of his changed dramatically during the past practice (a patient seeking a prescrip- John R. White, Jr., PA-C, PharmD several thousand years. The option tion for ethanol), Banting embarked preferred by “experts” of the pha- upon a career in academics. raoh of Egypt 3,500 years ago was One of his first teaching assign- a mixture of “water from the bird ments involved carbohydrate pond,” elderberry, fibers from the asit metabolism. This led to his interest in plant, milk, beer, cucumber flower, diabetes and his erroneous assump- and green dates.1 Although our thera- tion that one needed to surgically peutic options today are significantly ligate the pancreatic duct and then more effective, they will likely be wait 6–8 weeks before extracting considered arcane by our successors anything that might be useful from 100 years from now if the current the endocrine portion of the gland. trajectory in treatment development Over time, and without the ligation continues. Clearly, however, the cur- step, he was able to extract a substance rent pharmacological armamentarium from canine pancreas glands that had used to manage diabetes has resulted an impact on hyperglycemia in other in a dramatic reduction in morbidity diabetic animals. and mortality. This article provides Banting and his student, Charles a brief overview of the development Best, continued working on various history and effectiveness of various extraction processes. By December agents used in the pharmacological 1921, they were using a process that management of diabetes. combined equal parts of ground-up beef pancreas and slightly acidic alco- Insulin hol. The solution was filtered, washed Before the 1920s, there were no effec- twice with toluene, and filter steril- tive pharmacological agents for the ized. This test solution was given to management of diabetes. Because of dogs to determine potency. this, type 1 diabetes was a fatal mal- Leonard Thompson was the first ady. This changed dramatically with patient to receive insulin. He was a Frederick Banting’s work. 14-year-old boy who weighed 65 lb, Dr. Banting served as a surgeon was pale, smelled of acetone, was los- in World War I. Captain Banting ini- ing hair, had a distended abdomen, tially spent some time in hospitals in and was later described as looking like England, but later was sent to the front the victim of a concentration camp. as a battalion medical officer, where he On 11 January 1922, a young house was wounded by shrapnel. He received officer, Ed Jeffery, injected 7.5 cc of a Military Cross for his courage in Banting and Best’s extract (described action.2 After returning from the war, as a thick brown muck) into each but- Dr. Banting opened an office outside tock of the patient. A sterile abscess of Toronto, Canada. After seeing only developed at the site of one of the 82 Diabetes Spectrum Volume 27, Number 2, 2014 injections, but the patient’s blood glu- and semilente and is intermediate there was a resurgence in interest cose dropped. acting. in the biguanides. In the 1960s and FROM After that injection, the push All insulin preparations avail- 1970s, phenformin was widely studied to perfect the extraction process able before 1983 were derived from in the United States, while metformin animal sources (primarily beef and was studied in France and buformin and commercialize insulin was on. R 9 Banting’s team entered into an agree- pork). This changed in 1983, when was studied in Germany. Although ESEARCH TO PRACTICE/PHARMACOTHERA ment with Eli Lilly and Company, the first recombinant medication, phenformin and buformin were used and, by July 1922, the first bottles human insulin, was approved.5 One clinically, their relationship to lactic of Lilly’s Iletin (insulin) arrived in of the primary problems at the time of acidosis led to their withdrawal from Banting’s office. Insulin was commer- the release of human insulin was the the market in most countries. cially available in the United States by pharmacokinetic/pharmacodynamic Metformin was introduced in 1959 1923. profiles of the available insulins. The as an antihyperglycemic agent but was The next major advancement in search for a “flat” basal insulin and a not approved in the United States until insulin was its crystallization in 1926.3 rapid-acting insulin that more closely the 1990s. Today, metformin is the The technique of insulin crystalliza- approximated physiological insulin only clinically significant biguanide tion led to improved soluble (regular) secretory patterns accelerated after the and is the most widely used antihy- insulin purity and also opened the release of human insulin. perglycemic agent in the world. Its door to insulin formulation modi- In 1996, the first rapid-acting primary mechanism of action is its fications with different time-action human insulin analog, lispro, was ability to reduce hepatic glucose pro- profiles. There was a great need for approved.5 This was followed in the duction, but it also reduces glucose via an extended-action insulin. With past 15 years with a succession of a mild increase in insulin-stimulated 7 the availability of only rapid-acting additional insulin analogs, including glucose uptake. This medication is insulin, patients required multiple the rapid-acting insulins aspart and generally well tolerated and is typically daily injections and had to be awak- glulisine and the long-acting basal associated with a significant reduction 7 ened at night for injections. Children analogs glargine and detemir. The in A1C levels (~ 1.5%). not awaked for nighttime injections U.S. Food and Drug Administration Sulfonylureas were at risk for a significant reduc- (FDA) declined to approve degludec, an ultra-long-acting insulin (dura- The history of the sulfonylureas (SUs) P tion in growth, or diabetic dwarfism Y O tion of 42 hours), in 2013. However began in 1937 with the observation syndrome. Children with diabetic of the hypoglycemic activity of syn- this compound is available in Europe F dwarfism syndrome, which was 10 thetic sulfur compounds. Five years AN PRESENT, DIABETES: PAST, also known as Mauriac’s syndrome, and will probably be resubmitted for 6 later, Marcel Janbon and his col- suffered from stunted growth, hepa- approval in the United States. 4 In addition to the formulation leagues were treating patients with the tomegaly, and delayed puberty. In antibiotic para-amino-sulfonamide- 1936, the first commercially avail- changes described above, myriad advancements in the area of insulin isopropyl-thiodiazole for typhoid and able, extended-action insulin, PZI 11 delivery devices and routes of admin- observed hypoglycemia. In 1946, (protamine zinc insulin), was released. istration have been made or are being Auguste Loubatieres confirmed that This formulation was composed of an worked on, including better syringes, aryl SU compounds stimulated release amorphous combination of protamine, pulmonary insulin, insulin pumps, of insulin and therefore required some zinc, and insulin. PZI continues to be and closed-loop insulin delivery sys- pancreatic β-cell function to elicit an used today in the management of cats 3,10 tems. Insulin is widely used today in effect. with diabetes.3 patients with type 1 or type 2 diabe- In the 1950s, the first SU, tolbu- The next major development in 11 tes and is arguably the most effective tamide, was marketed in Germany. insulin formulation came in 1946, and predictable (in most, but not all This was followed by the introduction when the Nordisk Insulin Laboratory cases) of all of the current antihy- of the other first-generation agents: in Denmark released the second perglycemic agents. chlorpropamide, acetohexamide, and extended-action insulin, NPH (neutral tolazamide. The next advancement 3 protamine Hagedorn). This insulin Biguanides in SU therapy in the United States D contained ~ 10% of the protamine French lilac, or goat’s rue (Galega did not occur until the release of the FUTURE found in PZI along with zinc insulin officinalis), was used as a folk rem- more potent second-generation agents crystals. This insulin was shorter act- edy for diabetes in Southern and glipizide and glyburide in 1984. These ing than PZI and could be combined Eastern Europe during medieval agents had been in use in Europe for with regular insulin. times.7 In the early 20th century, several years before this.11 The next SU In 1956, the lente series of insulin the antihyperglycemic moiety in this agent, glimepiride, which is sometimes was introduced: ultralente, lente, and plant, guanidine, was isolated. Frank referred to as a third-generation agent, semilente. These formulations were et al.8 synthesized a guanidine com- was released in 1995. synthesized by altering the content of pound called Synthalin in Germany SUs are widely used, generally safe, the excess zinc. Ultralente is a micro- and used it to treat diabetes during inexpensive, and relatively predict- crystalline formulation that is long the 1920s.3 Homologs of guanidine able. Their primary use-limiting side acting. Semilente is more amorphous (e.g., Synthalin) were used for a short effect is hypoglycemia, although they than ultralente and has a time-action period but were hepatotoxic, and the are also associated with weight gain. profile that is slightly slower in onset use of these compounds all but ended Generally, an A1C reduction of 1–2% than regular insulin. Lente is com- with the discovery and proliferation can be expected in a responsive patient posed of a 70:30 mixture of ultralente of insulin.