æBRIEF HISTORICAL PERSPECTIVE
`
`History of current non-insulin
`medications for diabetes mellitus
`
`Celeste C. L. Quianzon, MD and Issam E. Cheikh, MD*
`
`Division of Endocrinology, Department of Medicine, Union Memorial Hospital, Baltimore,
`MD, USA
`
`This article is a brief review of the current non-insulin agents for diabetes mellitus in the United States, namely,
`sulfonylureas, biguanides, thiazolidinediones, meglitinides, a-glucosidase inhibitors, glucacon-like peptide-1
`receptor agonists, dipeptidyl-peptidase-4 inhibitors, amylin agonists, bromocriptine, and colesevelam.
`
`Keywords: diabetes medication; history; review
`
`Received: 29 June 2012; Accepted: 3 July 2012; Published: 15 October 2012
`
`Since the introduction of sulfonylureas, multiple
`
`medications have been introduced for the treatment
`of diabetes mellitus type 2, substituting or supple-
`menting insulin. A short review of these medications is
`presented in this article.
`
`Sulfonylureas
`stimulate pancreatic b-cells
`to secrete
`Sulfonylureas
`insulin by binding to receptors that block the potassium
`ATP-dependent channels, leading to cell depolarization
`and subsequently insulin exocytosis. The hypoglycemic
`activity of synthetic sulfur compounds was noted by Ruiz
`and his colleagues in 1937 (1). In 1942, Janbon, a French
`physician, and his colleagues confirmed hypoglycemia
`in patients treated with p-amino-sulfonamide-isopropyl-
`thiodiazole for
`typhoid (1), and in August 1946,
`Lobatieres and his colleagues established that this group
`of drugs stimulated b-cell release of
`insulin (1). In
`1956, the first sulfonylurea, tolbutamide, was introduced
`commercially in Germany followed by chlorpropamide,
`acetohexamide, and tolazamide,
`the first-generation
`sulfonylureas (1, 2). In 1984, more than 14 years after
`their introduction in Europe, glyburide and glipizide,
`which are more potent second-generation sulfonylureas,
`became available in the United States (3 6). Glimepiride,
`a third-generation sulfonylurea, was introduced in 1995
`in the United States (7). The HbA1C (A1C) is decreased
`by 1 2%. Sulfonylureas have been in the market for more
`than 50 years. They are safe, cheap, and predictable, but
`the incidence of hypoglycemia, a major side effect, limits
`their use.
`
`Biguanides
`The use of biguanide can be traced back to the medieval
`times when Galega officinalis, an herb, was used to relieve
`symptoms of diabetes (8). The plant was found to contain
`guanadine, a compound with hypoglycemic properties
`but too toxic for clinical use (9). Two synthetic diguanides
`were used between 1920 and 1930 but were discontinued
`from clinical use because of their toxic nature (8). In the
`1950s, three biguanides, metformin, phenformin, and
`buformin, were introduced. Metformin and phenformin
`were introduced in the United States but were withdrawn
`in 1978 because use of phenformin led to increased
`incidences of lactic acidosis (8). In 1995, Metformin,
`which inhibits gluconeogenesis and improves peripheral
`glucose utilization, was reapproved in the United States
`after being in use in Europe for 20 years (10).
`In 1998,
`the U K Prospective Diabetes Study
`(UKPDS)-34 examined the effect of intensive glucose
`control in overweight (mean BMI, 31), type 2 diabetes
`patients treated with metformin (11). UKPD study
`showed that metformin decreased the risk of diabetes-
`related end points and was associated with less weight
`gain and lesser hypoglycemic events compared with
`sulfonylureas and insulin (11).
`Currently, metformin has been used for the first-
`line treatment of type 2 diabetes, alone or in combina-
`tion with other diabetes agents, in addition to lifestyle
`modifications (12). A1C is decreased by 1 2%. An
`important contraindication for patients treated with
`biguanides is renal
`impairment, with creatinine level
`greater than 1.4 mg/dL and 1.5mg/dL for women and
`men, respectively. Lactic acidosis, the major side effect, is
`rarely observed when metformin is administered properly
`
`Journal of Community Hospital Internal Medicine Perspectives 2012. # 2012 Celeste C. L. Quianzon and Issam E. Cheikh. This is an Open Access article
`distributed under the terms of the Creative Commons Attribution-Noncommercial 3.0 Unported License (http://creativecommons.org/licenses/by-nc/3.0/),
`permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
`Citation: Journal of Community Hospital Internal Medicine Perspectives 2012, 2: 19081 - http://dx.doi.org/10.3402/jchimp.v2i3.19081
`(page number not for citation purpose)
`
`1
`
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`Celeste C. L. Quianzon and Issam E. Cheikh
`
`such as nausea,
`side effects,
`(13). Gastrointestinal
`diarrhea, and abdominal discomfort, may occur.
`
`Thiazolidinediones
`Thiazolidinediones improve insulin sensitivity by binding
`to the peroxisome proliferator activator receptors in the
`target cell nucleus, which causes conformational changes
`with the retinoic X receptor. The discovery of thiazolidi-
`nediones was the result of the observation that patients
`with type 2 diabetes on clofibrate had lower fasting
`glucose levels (14). In the quest for formulating more
`potent fibrates in the early 1980s, Takeda Pharmaceuti-
`cals, Japan, made analogs of clofibrates that had positive
`effects on hyperglycemia, hyperinsulinemia, and hyper-
`triglyceridemia in animals with type 2 diabetes. This led
`to the discovery of the first thiazolidinedione, ciglitazone,
`which had a modest effect on glucose and significant
`effects on lipids but caused edema and lenticular opacities
`in rodents (14). Ciglitazone was never marketed. In
`1997, troglitazone became the first thiazolidinedione to
`be approved for clinical use. Though effective, it was
`withdrawn in 2000 after it was found to cause liver
`damage. Two other thiazolidinediones, rosiglitazone and
`pioglitazone, were approved in 1999 for treatment of
`type 2 diabetes. In September 2010, the US Food and
`Drug Administration (US FDA) restricted the use of
`rosiglitazone because of its potential to cause cardiovas-
`cular ischemia (15), and a recent study found that long-
`term use of pioglitazone slightly increases the risk of
`bladder cancer (16, 17).
`The use of pioglitazone, alone or in combination with
`other diabetes agents, is permitted in the United States.
`A1C is decreased by 1 1.5%. The most common side
`effect is edema, which is dose related. Pioglitazone should
`be used with caution in patients with congestive heart
`failure (CHF) stage I and II, and it is contraindicated in
`CHF stage III and IV. Anemia and osteoporosis may also
`occur.
`
`Meglitinides
`Meglitinides are non-sulfonylurea insulin secretagogues
`with short half-lives. These medications bind to the
`SUR1 binding site in the pancreas. They are given
`15 30 min premeal to target the postprandial rise in
`glucose. Repaglinide is the first agent in this class to be
`approved for use in 1997 (18) followed by nateglinide in
`2000 (19). A1C is decreased by 1 1.5%. The need for
`multiple meal-timed doses and the incidence of hypogly-
`cemia limit their use.
`
`a-Glucosidase Inhibitors
`a-Glucosidase inhibitors reversibly inhibit a-glucosidase
`enzyme present at the brush border membrane of the
`small intestine, which delays carbohydrate degradation
`and absorption, and thereby the subsequent desired effect
`
`of reduced postprandial hyperglycemia. Acarbose was
`approved by the US FDA in 1995 (20) and miglitol in
`1996 (21). The effect on A1C is modest; it decreases by
`0.5%. The need for multiple prandial dosing and gastro-
`intestinal side effects of flatus and diarrhea markedly
`limit their use.
`
`Glucagon-Like Peptide-1 Receptor Agonists
`and Dipeptidyl Peptidase-4 Inhibitors
`Glucagon-like peptide-1 (GLP-1) is a hormone secreted
`by the L cells of the small
`intestines within minutes
`following a carbohydrate- or
`fat-containing meal
`(22, 23). GLP-1 stimulates insulin synthesis and glucose-
`dependent insulin secretion. Moreover, GLP-1 suppresses
`glucagon release and delays gastric emptying (22, 23).
`It has a short half-life of 1 2 min because of rapid
`degradation by dipeptidyl peptidase-4 (DPP-4)
`(23).
`These physiologic benefits led to the development of
`GLP-1 receptor agonists and DPP-4 inhibitors for the
`treatment of type 2 diabetes (24).
`Exenatide, the first GLP-1 agonist, is a mimetic of
`exendin-4, a peptide isolated from the saliva of the Gila
`monster, and has a 53% likeness to the human GLP-1
`(25, 26). It is more resistant to DPP-4 degradation, thus
`has a longer half-life (26). Exenatide injection, twice
`daily, given 40 60 min before breakfast and dinner was
`approved in 2005 (27), and a once-weekly formulation
`was approved in January 2012 (28). Once-daily injection
`of liraglutide, a modified form of human GLP-1, with
`97% homology, was approved in 2010 (29). GLP-1
`receptor agonists decreases A1C by 1%. The most
`common side effects are gastrointestinal disorders, in-
`cluding nausea and occassional vomiting. Pancreatitis
`has also been reported (30, 31). There is concern for
`medullary thyroid cancer as it was seen in rats, though
`not reported in humans.
`There are three approved DPP-4 inhibitors: sitagliptin,
`saxagliptin, and linagliptin. They effect a modest A1C
`reduction of up to 0.8%. They are available alone or
`in combination with metformin. The near absence of
`hypoglycemia makes their use desirable. It should be
`noted that pancreatitis has been reported among patients
`using DPP-4 inhibitors (32 34).
`
`Amylin Agonists
`Amylin, a neuroendocrine hormone, was discovered in
`1987. It is co-secreted with insulin by the pancreatic
`b-cells in a molar ratio (35, 36). Patients with type 1
`diabetes have no amylin, whereas those with type 2
`diabetes have a relative deficiency (36, 37). The physio-
`logic effects of amylin include reduction of postprandial
`glucagon secretion and hepatic glucose production,
`resulting in lowering postprandial glucose levels. It also
`delays gastric emptying and mediates satiety (35 37). As
`amylin is insoluble and toxic to pancreatic b-cells, the
`
`2(
`
`Citation: Journal of Community Hospital Internal Medicine Perspectives 2012, 2: 19081 - http://dx.doi.org/10.3402/jchimp.v2i3.19081
`page number not for citation purpose)
`
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`development of a soluble amylin agonist facilitated a
`new class of diabetes medication. Pramlintide, a synthetic
`analog of amylin, was approved by the US FDA in 2005
`as an adjunct to preprandial insulin therapy (38). The
`effect on A1C is a reduction by 0.4 0.6%. Pramlintide
`reduces prandial glucose, decreases prandial glucagon,
`delays gastric emptying, and induces weight loss (35). The
`most common side effect is nausea.
`
`Bromocriptine
`Bromocriptine is an old drug with a new indication. It
`is a sympatholytic D2-receptor agonist approved in 2009
`for the treatment of type 2 diabetes as an adjunct to diet
`and exercise (39). Oral administration of bromocriptine
`once daily within 2 hours of awakening reduced post-
`prandial glucose levels (40). Its mechanism has not been
`fully understood, but it is thought to increase dopamine
`activity in the brain and inhibit excess sympathetic tone
`(40). A1C is decreased by up to 0.7%.
`
`Colesevelam
`Colesevelam is a bile-acid sequestrant that reduces LDL
`cholesterol and lowers glucose levels (41). It is given
`twice daily. The mechanism of action is not known.
`Colesevelam was approved by the US FDA in 2008 for
`treatment of type 2 diabetes (42). The reduction in
`hemoglobin A1C is a modest 0.5%.
`
`Conclusion
`Home glucose monitoring, education, and lifestyle
`changes enhance the management of all patients with
`diabetes mellitus. Advances in research, that is, diabetes
`gene therapy and human insulin-producing cell therapy,
`may personalize treatment and make cure possible.
`
`Conflict of interest and funding
`The authors have not received any funding or benefits
`from industry or elsewhere to conduct this study.
`
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`Page 00003
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`Celeste C. L. Quianzon and Issam E. Cheikh
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`
`*Issam E. Cheikh
`Division of Endocrinology
`Department of Medicine
`Union Memorial Hospital
`201 E. University Parkway
`Baltimore, MD 21218
`USA
`Email: issam.cheikh@medstar.net
`
`4(
`
`Citation: Journal of Community Hospital Internal Medicine Perspectives 2012, 2: 19081 - http://dx.doi.org/10.3402/jchimp.v2i3.19081
`page number not for citation purpose)
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`Novo Nordisk Exhibit 2360
`Mylan Pharms. Inc. v. Novo Nordisk A/S
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