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
`
`John R. White, Jr., PA-C, PharmD
`
`82
`
`The management of diabetes has
`changed dramatically during the past
`several thousand years. The option
`preferred by “experts” of the pha-
`raoh of Egypt 3,500 years ago was
`a mixture of “water from the bird
`pond,” elderberry, fibers from the asit
`plant, milk, beer, cucumber flower,
`and green dates.1 Although our thera-
`peutic options today are significantly
`more effective, they will likely be
`considered arcane by our successors
`100 years from now if the current
`trajectory in treatment development
`continues. Clearly, however, the cur-
`rent pharmacological armamentarium
`used to manage diabetes has resulted
`in a dramatic reduction in morbidity
`and mortality. This article provides
`a brief overview of the development
`history and effectiveness of various
`agents used in the pharmacological
`management of diabetes.
`
`Insulin
`Before the 1920s, there were no effec-
`tive pharmacological agents for the
`management of diabetes. Because of
`this, type 1 diabetes was a fatal mal-
`ady. This changed dramatically with
`Frederick Banting’s work.
`Dr. Banting served as a surgeon
`in World War I. Captain Banting ini-
`tially spent some time in hospitals in
`England, but later was sent to the front
`as a battalion medical officer, where he
`was wounded by shrapnel. He received
`a Military Cross for his courage in
`action.2 After returning from the war,
`Dr. Banting opened an office outside
`of Toronto, Canada. After seeing only
`
`one patient in the first month of his
`practice (a patient seeking a prescrip-
`tion for ethanol), Banting embarked
`upon a career in academics.
`One of his first teaching assign-
`m e nt s i nvolve d c a rb ohyd rat e
`metabolism. This led to his interest in
`diabetes and his erroneous assump-
`tion that one needed to surgically
`ligate the pancreatic duct and then
`wait 6–8 weeks before extracting
`anything that might be useful from
`the endocrine portion of the gland.
`Over time, and without the ligation
`step, he was able to extract a substance
`from canine pancreas glands that had
`an impact on hyperglycemia in other
`diabetic animals.
`Banting and his student, Charles
`Best, continued working on various
`extraction processes. By December
`1921, they were using a process that
`combined equal parts of ground-up
`beef pancreas and slightly acidic alco-
`hol. The solution was filtered, washed
`twice with toluene, and filter steril-
`ized. This test solution was given to
`dogs to determine potency.
`Leonard Thompson was the first
`patient to receive insulin. He was a
`14-year-old boy who weighed 65 lb,
`was pale, smelled of acetone, was los-
`ing hair, had a distended abdomen,
`and was later described as looking like
`the victim of a concentration camp.
`On 11 January 1922, a young house
`officer, Ed Jeffery, injected 7.5 cc of
`Banting and Best’s extract (described
`as a thick brown muck) into each but-
`tock of the patient. A sterile abscess
`developed at the site of one of the
`
`In Brief
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`

`injections, but the patient’s blood glu-
`cose dropped.
`After that injection, the push
`to perfect the extraction process
`and commercialize insulin was on.
`Banting’s team entered into an agree-
`ment with Eli Lilly and Company,
`and, by July 1922, the first bottles
`of Lilly’s Iletin (insulin) arrived in
`Banting’s office. Insulin was commer-
`cially available in the United States by
`1923.
`The next major advancement in
`insulin was its crystallization in 1926.3
`The technique of insulin crystalliza-
`tion led to improved soluble (regular)
`insulin purity and also opened the
`door to insulin formulation modi-
`fications with different time-action
`profiles. There was a great need for
`an extended-action insulin. With
`the availability of only rapid-acting
`insulin, patients required multiple
`daily injections and had to be awak-
`ened at night for injections. Children
`not awaked for nighttime injections
`were at risk for a significant reduc-
`tion in growth, or diabetic dwarfism
`syndrome. Children with diabetic
`dwarfism syndrome, which was
`also known as Mauriac’s syndrome,
`suffered from stunted growth, hepa-
`tomegaly, and delayed puberty.4 In
`1936, the first commercially avail-
`able, extended-action insulin, PZI
`(protamine zinc insulin), was released.
`This formulation was composed of an
`amorphous combination of protamine,
`zinc, and insulin. PZI continues to be
`used today in the management of cats
`with diabetes.3
`The next major development in
`insulin formulation came in 1946,
`when the Nordisk Insulin Laboratory
`in Denmark released the second
`extended-action insulin, NPH (neutral
`protamine Hagedorn).3 This insulin
`contained ~ 10% of the protamine
`found in PZI along with zinc insulin
`crystals. This insulin was shorter act-
`ing than PZI and could be combined
`with regular insulin.
`In 1956, the lente series of insulin
`was introduced: ultralente, lente, and
`semilente. These formulations were
`synthesized by altering the content of
`the excess zinc. Ultralente is a micro-
`crystalline formulation that is long
`acting. Semilente is more amorphous
`than ultralente and has a time-action
`profile that is slightly slower in onset
`than regular insulin. Lente is com-
`posed of a 70:30 mixture of ultralente
`
`and semilente and is intermediate
`acting.
`All insulin preparations avail-
`able before 1983 were derived from
`animal sources (primarily beef and
`pork). This changed in 1983, when
`the first recombinant medication,
`human insulin, was approved.5 One
`of the primary problems at the time of
`the release of human insulin was the
`pharmacokinetic/pharmacodynamic
`profiles of the available insulins. The
`search for a “flat” basal insulin and a
`rapid-acting insulin that more closely
`approximated physiological insulin
`secretory patterns accelerated after the
`release of human insulin.
`In 1996, the first rapid-acting
`human insulin analog, lispro, was
`approved.5 This was followed in the
`past 15 years with a succession of
`additional insulin analogs, including
`the rapid-acting insulins aspart and
`glulisine and the long-acting basal
`analogs glargine and detemir. The
`U.S. Food and Drug Administration
`(FDA) declined to approve degludec,
`an ultra-long-acting insulin (dura-
`tion of 42 hours), in 2013. However
`this compound is available in Europe
`and will probably be resubmitted for
`approval in the United States.6
`In addition to the formulation
`changes described above, myriad
`advancements in the area of insulin
`delivery devices and routes of admin-
`istration have been made or are being
`worked on, including better syringes,
`pulmonary insulin, insulin pumps,
`and closed-loop insulin delivery sys-
`tems. Insulin is widely used today in
`patients with type 1 or type 2 diabe-
`tes and is arguably the most effective
`and predictable (in most, but not all
`cases) of all of the current antihy-
`perglycemic agents.
`
`Biguanides
`French lilac, or goat’s rue (Galega
`officinalis), was used as a folk rem-
`edy for diabetes in Southern and
`Eastern Europe during medieval
`times.7 In the early 20th century,
`the antihyperglycemic moiety in this
`plant, guanidine, was isolated. Frank
`et al.8 synthesized a guanidine com-
`pound called Synthalin in Germany
`and used it to treat diabetes during
`the 1920s.3 Homologs of guanidine
`(e.g., Synthalin) were used for a short
`period but were hepatotoxic, and the
`use of these compounds all but ended
`with the discovery and proliferation
`of insulin. However, in later years,
`
`there was a resurgence in interest
`in the biguanides. In the 1960s and
`1970s, phenformin was widely studied
`in the United States, while metformin
`was studied in France and buformin
`was studied in Germany.9 Although
`phenformin and buformin were used
`clinically, their relationship to lactic
`acidosis led to their withdrawal from
`the market in most countries.
`Metformin was introduced in 1959
`as an antihyperglycemic agent but was
`not approved in the United States until
`the 1990s. Today, metformin is the
`only clinically significant biguanide
`and is the most widely used antihy-
`perglycemic agent in the world. Its
`primary mechanism of action is its
`ability to reduce hepatic glucose pro-
`duction, but it also reduces glucose via
`a mild increase in insulin-stimulated
`glucose uptake.7 This medication is
`generally well tolerated and is typically
`associated with a significant reduction
`in A1C levels (~ 1.5%).7
`
`Sulfonylureas
`The history of the sulfonylureas (SUs)
`began in 1937 with the observation
`of the hypoglycemic activity of syn-
`thetic sulfur compounds.10 Five years
`later, Marcel Janbon and his col-
`leagues were treating patients with the
`antibiotic para-amino-sulfonamide-
`isopropyl-thiodiazole for typhoid and
`observed hypoglycemia.11 In 1946,
`Auguste Loubatieres confirmed that
`aryl SU compounds stimulated release
`of insulin and therefore required some
`pancreatic β-cell function to elicit an
`effect.3,10
`In the 1950s, the first SU, tolbu-
`tamide, was marketed in Germany.11
`This was followed by the introduction
`of the other first-generation agents:
`chlorpropamide, acetohexamide, and
`tolazamide. The next advancement
`in SU therapy in the United States
`did not occur until the release of the
`more potent second-generation agents
`glipizide and glyburide in 1984. These
`agents had been in use in Europe for
`several years before this.11 The next SU
`agent, glimepiride, which is sometimes
`referred to as a third-generation agent,
`was released in 1995.
`SUs are widely used, generally safe,
`inexpensive, and relatively predict-
`able. Their primary use-limiting side
`effect is hypoglycemia, although they
`are also associated with weight gain.
`Generally, an A1C reduction of 1–2%
`can be expected in a responsive patient
`with type 2 diabetes.7
`
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`

`Thiazolidinediones
`Thiazolidinediones (TZDs), which are
`also known simply as “glitazones,”
`were initially introduced to the U.S.
`market in 1996. These agents are
`peroxisome proliferator–activated
`receptor-γ activators whose mecha-
`nisms of action are enhancement of
`skeletal muscle insulin sensitivity and
`reduction in hepatic glucose produc-
`tion.12 These agents do not increase
`the risk of hypoglycemia and have a
`more durable effect than metformin
`or SUs.12
`Troglitazone was the first agent in
`this category to be approved by the
`FDA.13 As troglitazone use increased,
`idiosyncratic hepatic failure began to
`be reported. By March 2000, the FDA
`had received reports of 63 hepatic fail-
`ure cases resulting in death in patients
`treated with troglitazone, and shortly
`thereafter, the drug was removed from
`the market.14
`Two other TZDs, pioglitazone and
`rosiglitazone, which are currently on
`the market, have each been linked to
`nonhypoglycemic issues. Both agents
`have been linked to fluid retention
`and must be used with caution in
`patients with congestive heart failure.
`Pioglitazone has been shown to poten-
`tially have a modest beneficial impact
`on cardiovascular disease but has
`also been associated with a possible
`increase in the incidence of bladder
`cancer.12 Until recently, rosiglitazone
`was not widely available because of
`concerns that it was associated with an
`increased risk of myocardial infarction
`(MI). The FDA, which had previously
`placed restrictions on rosiglitazone,
`began to ease those restrictions in
`November 2013. Their change in
`position was based on the findings
`of the large Rosiglitazone Evaluated
`for Cardiovascular Outcomes and
`Regulation of Glycemia in Diabetes
`(RECORD) study, which concluded
`that people treated with rosiglitazone
`did not have an elevated risk of MI
`compared to patients taking other
`antihyperglycemic medications.15
`TZDs are typically associated with
`an A1C decrease of 0.5–1% in most
`patients.7 There are no significant dif-
`ferences in A1C lowering between
`pioglitazone and rosiglitazone.
`
`α-Glucosidase Inhibitors
`α-Glucosidase inhibitors (AGIs)
`exert a local effect on the brush bor-
`der of the small intestine, inhibiting
`α-glucosidase enzymes, which are
`
`responsible for the breakdown of
`oligosaccharides, trisaccharides, and
`disaccharides. These enzymes include
`maltase, isomaltase, gluocoamy-
`lase, and sucrase. Inhibition of these
`enzyme systems effectively reduces
`the rate of absorption of carbohy-
`drates but does not alter the absolute
`absorption. The result is reduced post-
`prandial glucose levels, with a modest
`effect on fasting glucose.7 The reduc-
`tion of A1C observed with AGIs is
`typically 0.5–1.0%.
`The first drug in this category to
`reach the market was acarbose, which
`was approved by the FDA in 1995. A
`second AGI, miglitol, was approved
`in 1996. These drugs are available but
`not widely used, probably because of
`their modest impact on A1C, their
`need for multiple daily doses, and their
`gastrointestinal (GI) side effects.7,12
`
`Meglitinides
`T he meg l it i n ide s (a lso c a l led
`“glinides”) have a mechanism of
`action similar to that of the SUs but
`are structurally unrelated to SUs.
`This class of medication lowers blood
`glucose levels by stimulating insulin
`release from the pancreas.7 As with
`the SUs, glinide-induced insulin stim-
`ulation is dependent on functioning
`pancreatic β-cells. However, the effect
`of these drugs is glucose dependent
`and diminishes at low glucose concen-
`trations. The glinides bind to receptors
`in the pancreas, but the configura-
`tion of their binding is different from
`that observed with SUs. The glinides
`have a more rapid onset and a shorter
`duration of action than the second-
`generation SUs, which necessitates
`multiple daily dosing.
`Glinides can cause hypoglycemia,
`but they do so at a rate lower than that
`observed with the SUs. A1C reduction
`from glinides is generally between 1
`and 1.5%.7,11 The first agent in this
`class, repaglinide, was approved by
`the FDA in 1997, and a second agent,
`nateglinide, was approved in 2000.11
`
`Glucagon-Like Peptide-1
`Receptor Agonists
`The idea of an “incretin effect” was
`long known and based on experi-
`mental data demonstrating a greater
`insulin response with oral glucose
`administration versus intravenous glu-
`cose administration. The generalities
`of the incretin-insulin pathway were
`worked out by the 1980s. Two key
`studies evaluated the impact of native
`
`glucagon-like peptide-1 (GLP-1) in
`normal subjects and in patients with
`type 2 diabetes.16,17 Both of these trials
`demonstrated a significant increase in
`insulin response and in the reversal of
`hyperglycemia in patients with type 2
`diabetes who were hyperglycemic and
`received native GLP-1.
`GLP-1 and its analogs reduce
`glucose levels via a glucose-linked
`enhancement of insulin secretion.
`The short half-life (1–2 minutes) of
`native GLP-1 (because of its rapid
`degradation by the enzyme dipeptidyl
`peptidase-4 [DPP-4; discussed below])
`led to the search for GLP-1 analogs
`and DPP-4 inhibitors. One analog,
`exendin-4, was isolated from the sali-
`vary gland venom of the Gila monster
`(Heloderma suspectum).7
`Exenatide, a synthetically pro-
`duced form of exendin-4, was the
`first GLP-1 receptor agonist to become
`available for clinical use in 2005.18 A
`second GLP-1 receptor agonist, lira-
`glutide, was approved in 2010. In
`2012, a long-acting (once-weekly)
`form of exenatide was approved. A
`new drug application (NDA) for dula-
`glutide, another once-weekly GLP-1
`agonist, was submitted to the FDA in
`October 2013.19
`Other agents in this class are cur-
`rently under development, including
`lixisenatide and albiglutide. The NDA
`for lixisenatide was submitted to the
`FDA but later rescinded in 2013. It is
`expected that the NDA for lixisenatide
`will be resubmitted in 2015.20
`GLP-1 receptor agonists, which
`are all administered subcutaneously,
`are generally associated with 0.5–1%
`reductions in A1C levels.7,11 Weight
`loss is one advantage of treatment
`with incretin-based agents. However,
`these compounds can cause significant
`GI side effects, particularly early in
`therapy, and concerns about associa-
`tions between GLP-1 receptor agonists
`and pancreatitis are ongoing.
`
`DPP-4 Inhibitors
`As noted above, with the elucida-
`tion of the incretin-insulin pathway,
`researchers became interested in the
`development of DPP-4 inhibitors,
`agents that could be taken orally and
`would prolong the circulating half-life
`of endogenous incretins. The first of
`these agents to become available in the
`United States was sitagliptin, which
`was approved in 2006.21 This was fol-
`lowed by the release of saxagliptin and
`linagliptin. Alogliptin was approved
`
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`

`Figure 1. History of diabetes medications.
`
`by the FDA in 2013. Vildagliptin has
`been approved for use in Europe but
`is not available in the United States.
`These compounds are associ-
`ated with an A1C reduction of
`~ 0.8%.10 They are weight neutral
`and do not tend to cause hypogly-
`cemia.7 However, pancreatitis has
`been reported in patients treated with
`DPP-4 inhibitors.11
`
`Amylin Agonists
`The endogenous neuroendocrine hor-
`mone amylin was discovered in 1987.
`Amylin is co-secreted with insulin by
`the β-cells in equimolar amounts.7
`Patients with type 2 diabetes have
`reduced amounts of amylin, whereas
`patients with type 1 diabetes have
`essentially no amylin.11 The only amy-
`lin analog currently on the market is
`pramlintide, which was approved by
`the FDA in 2005. Its physiological
`effect includes weight loss, delayed
`gastric emptying, and a reduction in
`both postprandial glucose and gluca-
`gon. The primary side effect is nausea.
`Pramlintide has a modest effect
`on A1C reduction of ~ 0.5%. This
`compound is usually reserved for
`use in patients with type 1 diabetes
`treated with intensive insulin ther-
`apy.11 It reduces postprandial glucose
`excursions via the mechanisms men-
`tioned above.
`
`Bromocriptine
`Bromocriptine is a dopamine ago-
`nist that was approved for use in the
`
`United States as an antihyperglycemic
`medication in 2009.12 Its mechanism
`is not certain but may be related to
`its dopaminergic activity in the brain
`and the subsequent inhibition of sym-
`pathetic tone.11 Its impact on glycemia
`is modest, with A1C reductions of up
`to 0.7%.11
`
`Colesevelam
`Colesevelam is an interesting com-
`pound that has a dual effect of
`lowering LDL cholesterol and reduc-
`ing blood glucose levels. This drug
`was specifically developed for its
`ability to bind bile acids, effectively
`removing them from circulation and
`resulting in reductions in LDL cho-
`lesterol. The mechanism of action of
`the glucose lowering observed with
`this compound is not known. The
`drug was approved by the FDA for
`use in patients with type 2 diabetes
`in 2008.11
`Colesevelam is typically associated
`with an A1C reduction of ~ 0.5% and
`LDL cholesterol reduction of 13%.7
`Its side effects are similar to those
`encountered with AGIs and are pri-
`marily gastrointestinal. Also, it should
`be noted that colesevelam may cause a
`slight increase in triglycerides.
`
`Sodium Glucose
`Co-Transporter 2 Inhibitors
`The sodium glucose co-transporter
`2 (SGLT-2) inhibitors are a novel
`group of compounds that antagonize
`a high-capacity, low-affinity glucose
`
`transporter found primarily in the kid-
`ney.22 This transporter is responsible
`for ~ 90% of glucose reabsorption
`in the kidney. When this transporter
`is antagonized, excess glucose in the
`renal tubules is not reabsorbed, and
`glucose is excreted in the urine. This
`results in a net loss of glucose and a
`reduction in hyperglycemia.
`A recent meta-analysis of placebo-
`controlled studies evaluating SGLT-2
`inhibitors reported A1C reductions
`of 0.5–0.6% in patients treated with
`these agents.23 In addition to reduc-
`ing hyperglycemia, SGLT-2 inhibitors
`have also been associated with slight
`reductions in weight and BMI.
`The primary side effect of SGLT-2
`inhibition is an increase in urinary
`or genital infections. These infec-
`tions are much more common than in
`placebo-treated patients (about four
`times as many) but are usually mild.23
`Canagliflozin was the first SGLT-2
`inhibitor to be approved by the FDA,
`in March 2013.24 Dapagliflozin was
`approved in the United States in early
`2014. Empagliflozin and other SGLT-2
`inhibitors are under development.
`
`Conclusion
`There are now 11 different categories
`of medications directed at the man-
`agement of hyperglycemia in patients
`with diabetes. These compounds
`have been developed during the past
`90 years (Figure 1), and among these
`categories, myriad subtypes exist.
`
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`

`Additionally, the potential permu-
`tations of various combinations of
`these agents is staggering and can be
`bewildering to the clinicians trying to
`design the optimum therapy regimen
`for a given patient.
`We continue to struggle, as we
`should, with questions of efficacy
`and the potential detrimental effects
`of antihyperglycemic medications. At
`the same time, we should be mindful
`of the fact that the outlook for patients
`with diabetes today is much better
`than what they would have encoun-
`tered in the 1920s or even in the
`1970s. A recent poster presented at the
`European Association for the Study of
`Diabetes 2013 meeting reported that
`the life expectancy of people with type
`1 diabetes (aged 20–24 years) is about
`11–14 years less than that of individu-
`als without diabetes.25 This is in stark
`contrast to data presented in 1975
`that reported a 27-year difference in
`life expectancy between patients with
`type 1 diabetes and those without dia-
`betes.26 Clearly, we are headed in the
`right direction, with the goal of having
`no gap between the two populations
`in terms of life expectancy or even
`the outright prevention of all types
`of diabetes. In the interim, advances
`in pharmacotherapy have made, and
`future advances will continue to make,
`a positive difference in the lives of
`our patients.
`
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`John R. White, Jr., PA-C, PharmD,
`is a professor in and chair of the
`Department of Pharmacotherapy
`at Washington State University
`in Spokane.
`
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`MPI EXHIBIT 1108 PAGE 5
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`MPI EXHIBIT 1108 PAGE 5
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