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Home , Buformin, History of diabetes, Phenformin

In Brief This article provides an overview of the development of , oral agents, and noninsulin injectable agents used in the management of in patients with . 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 . 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 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- 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, was a fatal mal- Leonard Thompson was the first ady. This changed dramatically with patient to receive insulin. He was a ’s work. 14-year-old boy who weighed 65 lb, Dr. Banting served as a surgeon was pale, smelled of acetone, was los- in . 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 . In the 1960s and From R esearch to Practice/Pharmacothera p y o f Diabetes: Past, Present, an d Future After that injection, the push All insulin preparations avail- 1970s, was widely studied to perfect the extraction process able before 1983 were derived from in the United States, while and commercialize insulin was on. animal sources (primarily beef and was studied in France and Banting’s team entered into an agree- pork). This changed in 1983, when was studied in Germany.9 Although ment with , 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 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 , 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 were at risk for a significant reduc- (FDA) declined to approve degludec, The history of the sulfonylureas (SUs) tion in growth, or diabetic dwarfism an ultra-long-acting insulin (dura- began in 1937 with the observation syndrome. Children with diabetic tion of 42 hours), in 2013. However this compound is available in Europe of the hypoglycemic activity of syn- dwarfism syndrome, which was thetic sulfur compounds.10 Five years 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 . 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. , , and extended-action insulin, NPH (neutral . The next advancement protamine Hagedorn).3 This insulin Biguanides in SU therapy in the United States contained ~ 10% of the protamine French lilac, or goat’s rue (Galega did not occur until the release of the 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 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 . 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, , 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. However, in later years, with .7 Diabetes Spectrum Volume 27, Number 2, 2014 83 responsible for the breakdown of -like peptide-1 (GLP-1) in Thiazolidinediones (TZDs), which are oligosaccharides, trisaccharides, and normal subjects and in patients with also known simply as “glitazones,” disaccharides. These enzymes include type 2 diabetes.16,17 Both of these trials were initially introduced to the U.S. maltase, isomaltase, gluocoamy- demonstrated a significant increase in market in 1996. These agents are lase, and sucrase. Inhibition of these insulin response and in the reversal of peroxisome proliferator–activated enzyme systems effectively reduces hyperglycemia in patients with type 2 receptor-γ activators whose mecha- the rate of absorption of carbohy- diabetes who were hyperglycemic and nisms of action are enhancement of drates but does not alter the absolute received native GLP-1. skeletal muscle insulin sensitivity and absorption. The result is reduced post- GLP-1 and its analogs reduce reduction in hepatic glucose produc- prandial glucose levels, with a modest glucose levels via a glucose-linked tion.12 These agents do not increase effect on fasting glucose.7 The reduc- enhancement of insulin secretion. the risk of hypoglycemia and have a tion of A1C observed with AGIs is The short half-life (1–2 minutes) of more durable effect than metformin typically 0.5–1.0%. native GLP-1 (because of its rapid or SUs.12 The first drug in this category to degradation by the enzyme dipeptidyl was the first agent in reach the market was , which peptidase-4 [DPP-4; discussed below]) this category to be approved by the was approved by the FDA in 1995. A led to the search for GLP-1 analogs FDA.13 As troglitazone use increased, second AGI, , was approved and DPP-4 inhibitors. One analog, idiosyncratic hepatic failure began to in 1996. These drugs are available but exendin-4, was isolated from the sali- be reported. By March 2000, the FDA not widely used, probably because of vary gland venom of the had received reports of 63 hepatic fail- their modest impact on A1C, their (Heloderma suspectum).7 ure cases resulting in death in patients need for multiple daily doses, and their , a synthetically pro- treated with troglitazone, and shortly gastrointestinal (GI) side effects.7,12 duced form of exendin-4, was the thereafter, the drug was removed from first GLP-1 receptor agonist to become the market.14 available for clinical use in 2005.18 A Two other TZDs, and The meglitinides (also called second GLP-1 receptor agonist, lira- , which are currently on “glinides”) have a mechanism of glutide, was approved in 2010. In the market, have each been linked to action similar to that of the SUs but 2012, a long-acting (once-weekly) nonhypoglycemic issues. Both agents are structurally unrelated to SUs. form of exenatide was approved. A have been linked to fluid retention This class of medication lowers blood new drug application (NDA) for dula- and must be used with caution in glucose levels by stimulating insulin glutide, another once-weekly GLP-1 patients with congestive heart failure. release from the pancreas.7 As with agonist, was submitted to the FDA in Pioglitazone has been shown to poten- the SUs, glinide-induced insulin stim- October 2013.19 tially have a modest beneficial impact ulation is dependent on functioning Other agents in this class are cur- on cardiovascular disease but has pancreatic β-cells. However, the effect rently under development, including also been associated with a possible of these drugs is glucose dependent and . The NDA increase in the incidence of bladder and diminishes at low glucose concen- for lixisenatide was submitted to the cancer.12 Until recently, rosiglitazone trations. The glinides bind to receptors FDA but later rescinded in 2013. It is was not widely available because of in the pancreas, but the configura- expected that the NDA for lixisenatide concerns that it was associated with an tion of their binding is different from will be resubmitted in 2015.20 increased risk of myocardial infarction that observed with SUs. The glinides GLP-1 receptor agonists, which (MI). The FDA, which had previously have a more rapid onset and a shorter are all administered subcutaneously, placed restrictions on rosiglitazone, duration of action than the second- are generally associated with 0.5–1% began to ease those restrictions in generation SUs, which necessitates reductions in A1C levels.7,11 Weight November 2013. Their change in multiple daily dosing. loss is one advantage of treatment position was based on the findings Glinides can cause hypoglycemia, with incretin-based agents. However, of the large Rosiglitazone Evaluated but they do so at a rate lower than that these compounds can cause significant for Cardiovascular Outcomes and observed with the SUs. A1C reduction GI side effects, particularly early in Regulation of Glycemia in Diabetes from glinides is generally between 1 therapy, and concerns about associa- (RECORD) study, which concluded and 1.5%.7,11 The first agent in this tions between GLP-1 receptor agonists that people treated with rosiglitazone class, , was approved by and pancreatitis are ongoing. did not have an elevated risk of MI the FDA in 1997, and a second agent, compared to patients taking other , was approved in 2000.11 DPP-4 Inhibitors antihyperglycemic medications.15 As noted above, with the elucida- TZDs are typically associated with Glucagon-Like Peptide-1 tion of the incretin-insulin pathway, an A1C decrease of 0.5–1% in most Receptor Agonists researchers became interested in the patients.7 There are no significant dif- The idea of an “incretin effect” was development of DPP-4 inhibitors, ferences in A1C lowering between long known and based on experi- agents that could be taken orally and pioglitazone and rosiglitazone. mental data demonstrating a greater would prolong the circulating half-life insulin response with oral glucose of endogenous incretins. The first of α-Glucosidase Inhibitors administration versus intravenous glu- these agents to become available in the α-Glucosidase inhibitors (AGIs) cose administration. The generalities United States was , which exert a local effect on the brush bor- of the incretin-insulin pathway were was approved in 2006.21 This was fol- der of the small intestine, inhibiting worked out by the 1980s. Two key lowed by the release of and α-glucosidase enzymes, which are studies evaluated the impact of native . was approved 84 Diabetes Spectrum Volume 27, Number 2, 2014 From R esearch to Practice/Pharmacothera p y o f Diabetes: Past, Present, an d Future

Figure 1. medications. by the FDA in 2013. has United States as an antihyperglycemic transporter found primarily in the kid- been approved for use in Europe but medication in 2009.12 Its mechanism ney. 22 This transporter is responsible is not available in the United States. is not certain but may be related to for ~ 90% of glucose reabsorption These compounds are associ- its dopaminergic activity in the brain in the . When this transporter ated with an A1C reduction of and the subsequent inhibition of sym- is antagonized, excess glucose in the ~ 0.8%.10 They are weight neutral pathetic tone.11 Its impact on glycemia renal tubules is not reabsorbed, and and do not tend to cause hypogly- is modest, with A1C reductions of up glucose is excreted in the urine. This cemia.7 However, pancreatitis has to 0.7%.11 results in a net loss of glucose and a been reported in patients treated with reduction in hyperglycemia. DPP-4 inhibitors.11 Colesevelam A recent meta-analysis of placebo- Colesevelam is an interesting com- controlled studies evaluating SGLT-2 Agonists pound that has a dual effect of inhibitors reported A1C reductions The endogenous neuroendocrine hor- lowering LDL cholesterol and reduc- of 0.5–0.6% in patients treated with mone amylin was discovered in 1987. ing blood glucose levels. This drug these agents.23 In addition to reduc- Amylin is co-secreted with insulin by was specifically developed for its ing hyperglycemia, SGLT-2 inhibitors the β-cells in equimolar amounts.7 ability to bind bile acids, effectively have also been associated with slight Patients with type 2 diabetes have removing them from circulation and reduced amounts of amylin, whereas resulting in reductions in LDL cho- reductions in weight and BMI. patients with type 1 diabetes have lesterol. The mechanism of action of The primary side effect of SGLT-2 essentially no amylin.11 The only amy- the glucose lowering observed with inhibition is an increase in urinary lin analog currently on the market is this compound is not known. The or genital infections. These infec- , which was approved by drug was approved by the FDA for tions are much more common than in the FDA in 2005. Its physiological use in patients with type 2 diabetes placebo-treated patients (about four 23 effect includes weight loss, delayed in 2008.11 times as many) but are usually mild. gastric emptying, and a reduction in Colesevelam is typically associated was the first SGLT-2 both postprandial glucose and gluca- with an A1C reduction of ~ 0.5% and inhibitor to be approved by the FDA, gon. The primary side effect is nausea. LDL cholesterol reduction of 13%.7 in March 2013.24 was Pramlintide has a modest effect Its side effects are similar to those approved in the United States in early on A1C reduction of ~ 0.5%. This encountered with AGIs and are pri- 2014. and other SGLT-2 compound is usually reserved for marily gastrointestinal. Also, it should inhibitors are under development. use in patients with type 1 diabetes be noted that colesevelam may cause a treated with intensive insulin ther- slight increase in triglycerides. Conclusion apy.11 It reduces postprandial glucose There are now 11 different categories excursions via the mechanisms men- Sodium Glucose of medications directed at the man- tioned above. Co-Transporter 2 Inhibitors agement of hyperglycemia in patients The sodium glucose co-transporter with diabetes. These compounds 2 (SGLT-2) inhibitors are a novel have been developed during the past Bromocriptine is a dopamine ago- group of compounds that antagonize 90 years (Figure 1), and among these nist that was approved for use in the a high-capacity, low-affinity glucose categories, myriad subtypes exist. Diabetes Spectrum Volume 27, Number 2, 2014 85 Additionally, the potential permu- www.defeatdiabetes.org/about_diabetes/ 17Nathan DM, Schreiber E, Fogel H, Mojsov tations of various combinations of text.asp?id=Diabetes_Timeline. Accessed 4 S, Habener JF: Insulinotropic action of December 2013 these agents is staggering and can be glucagon-like peptide-1 (7-37) in diabetic and 6Medscape: FDA rejects Novo Nordisk’s non-diabetic patients with diabetes mellitus. bewildering to the clinicians trying to Diabetes Care 15:270–276, 1992 design the optimum therapy regimen [article online]. 11 February 2013. Available from http://www. 18Aroda VR, Ratner R: The safety and for a given patient. medscape.com/viewarticle/779077. Accessed tolerability of GLP-1 receptor agonist in We continue to struggle, as we 2 January 2014 the treatment of type 2 diabetes: a review. should, with questions of efficacy 7White JR: Overview of the medications Diabetes Metab Res Rev 27:528–542, 2011 and the potential detrimental effects used to treat type 2 diabetes. In Medications 19diatribe: Eli Lilly submits GLP-1 dula- of antihyperglycemic medications. At for the Treatment of Diabetes. White glutide to FDA and unveils injection device the same time, we should be mindful JR, Campbell RK, Eds. Alexandria. Va., [article online]. Available from http://diatribe. American Diabetes Association, 2008, us/issues/59/new-now-next/5. Accessed 4 of the fact that the outlook for patients p. 5–15 with diabetes today is much better December 2013 8Frank E, Nothnamm M, Wagner A: 20Stuart C: Sanofi pull lixisenatide’s than what they would have encoun- Über synthetische dargestellte Korper mit FDA application [article online]. tered in the 1920s or even in the Insulinartiger Wirkung auf den normallen 1970s. A recent poster presented at the und diabetisched Organismus. Klin Wchnschr Cardiovascular Business. Available from 5:2011, 1926 http://www.cardiovascularbusiness. European Association for the Study of com/topics/prevention/sanofi-pulls- Diabetes 2013 meeting reported that 9Alberti KGMM, Zimmet P, Defronzo RA: lixisenatide%E2%80%99s-fda-application. the life expectancy of people with type International Textbook of Diabetes Mellitus. Accessed 4 December 2013 2nd ed. New York, John Wiley & Sons, 1997 1 diabetes (aged 20–24 years) is about 21Neumiller JJ: Differential chemistry 10 11–14 years less than that of individu- Levine R: Sulfonylureas: background and (structure), mechanism of action, and als without diabetes.25 This is in stark development of the field. Diabetes Care 7 of GLP-1 receptor agonist contrast to data presented in 1975 (Suppl. 1):3–7, 1984 and DPP-4 inhibitors. J Am Pharm Assoc 49 that reported a 27-year difference in 11Quianzon CCL, Cheikh I: History of cur- (Suppl. 1):S14–S29, 2009 rent non-insulin medications for diabetes 22White J: Apple trees to sodium glucose life expectancy between patients with mellitus. J Community Hosp Intern Med co-transporter inhibitors: a review of SGLT-2 type 1 diabetes and those without dia- Perspect. Published online 15 October 2012. inhibition. Clinical Diabetes 28:5–10, 2010 betes.26 Clearly, we are headed in the (doi: 10.3402/jchimp.v2i3.19081) 23Monami M, Nardini C, Mannucci E: right direction, with the goal of having 12Inzucchi SE, Bergenstal RM, Buse JB, no gap between the two populations Diamant M, Farrannini E, Nauck M, Peters Efficacy and safety of sodium glucose co- in terms of life expectancy or even A, Tsapas A, Wender R, Mathhews DR: transport-2 inhibitors in type 2 diabetes: a meta-analysis of randomized clinical trials. the outright prevention of all types Management of hyperglycemia in type 2 diabetes: a patient-centered approach: posi- Diabetes Obes Metab. Electronically pub- of diabetes. In the interim, advances tion statement of the American Diabetes lished ahead of print on 29 December 2013 in pharmacotherapy have made, and Association (ADA) and the European (doi: 0.1111/dom.12244) future advances will continue to make, Association for the Study of Diabetes (EASD). 24Forbes.com: FDA approves first SGLT2 a positive difference in the lives of Diabetes Care 35:1364–1379, 2012 inhibitor for diabetes [article online]. 29 our patients. 13Kendall DM: Thiazolidinediones: the March 2013. Available from http://www. case for early use. Diabetes Care 29:154– forbes.com/sites/larryhusten/2013/03/29/fda- 157, 2006 approves-first-sglt2-inhibitor-for-diabetes. Accessed 3 January 2014 References 14Lumpkin MM: Troglitazone: presentation 1Sanders LJ: From Thebes to Toronto and the to advisory committee. Published 19 May 25Nainggolan L: Life expectancy greatly 21st century: an incredible journey. Diabetes 2000. Available from www.fda.gov/ohrms/ improved in type 1 diabetes [article online]. Spectrum 15:56–60, 2002 dockets/ac/00/slides/3615s1a.PPT. Accessed 4 25 September 2013. Available from http:// December 2013 2Bliss M: The Discovery of Insulin. Chicago, www.medscape.com/viewarticle/811610. University of Chicago Press, 1982 15Nature World News: FDA eases restric- Accessed 4 December 2013 tions on Glaxo diabetes drug Avandia. 26 3Galloway JA: Diabetes Mellitus. 9th Goodkin G: Mortality factors in diabe- Published 26 November 2013. Available ed. Indianapolis, Ind., Eli Lilly and tes: a 20 year mortality study [Abstract]. from http://www.natureworldnews. Company, 1988 J Occup Med 17:716–721, 1975 com/articles/5075/20131126/fda-eases- 4Daneman D, Drash AL, Lobes LA, Becker restrictions-glaxos-drug.htm. Accessed 4 DJ, Baker LM, Travis LB: Progressive reti- December 2013 John R. White, Jr., PA-C, PharmD, nopathy with improved control in diabetic 16Gutniak M, Orskov C, Holst JJ, Ahrén dwarfism (Mauriac’s syndrome). Diabetes is a professor in and chair of the B, Efendic S: Antidiabetogenic effect of Care 4:360–365, 1981 Department of Pharmacotherapy glucagon-like peptide-1 (7-37) in diabetic and 5Defeat Diabetes, Foundation: History of non-diabetic patients with diabetes mellitus. at Washington State University diabetes in timeline. Available from http:// N Engl J Med 326:1316–1322, 1992 in Spokane.

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