FDA approves two new

drug treatments for

diabetes mellitus

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For Immediate Release

September 25, 2015

Release
Espaol

The U.S. Food and Drug Administration today approved

Tresiba (insulin degludec injection) and Ryzodeg 70/30
(insulin degludec/insulin aspart injection) to improve
blood sugar (glucose) control in adults with diabetes
mellitus.
According to the Centers for Disease Control and
Prevention, approximately 21 million people in the
United States have been diagnosed with diabetes. Over
time, diabetes increases the risk of serious health
complications, including heart disease, blindness, nerve
and kidney damage. Improvement in blood sugar
control can reduce the risk of some of these long-term
complications.
"Long-acting insulins play an essential role in the
treatment of patients with type-1 diabetes and in
patients with type-2 diabetes with advanced disease,"
said Jean-Marc Guettier, M.D., director of the Division of
Metabolism and Endocrinology Products in the FDAs
Center for Drug Evaluation and Research. The FDA
remains committed to support the development of
innovative therapies for the treatment of diabetes.

Tresiba is a long-acting insulin analog indicated to

improve glycemic control in adults with type 1 and 2
diabetes mellitus. Dosing of Tresiba should be
individualized based on the patients needs. Tresiba is
administered subcutaneously once daily at any time of
day.
The efficacy and safety of Tresiba used in combination
with mealtime insulin for the treatment of patients with
type-1 diabetes were evaluated in two 26-week and
one 52-week active-controlled clinical trials involving
1,102 participants exposed to Tresiba. The efficacy and
safety of Tresiba used in combination with mealtime
insulin or used as add-on to common background oral
antidiabetic drugs for the treatment of patients with
type-2 diabetes were evaluated in four 26-week and
two 52-week active-controlled clinical trials involving
2,702 participants exposed to Tresiba. In participants
with type 1 and 2 diabetes who had inadequate blood
sugar control at trial entry, treatment with Tresiba
provided reductions in HbA1c (hemoglobin A1c or
glycosylated hemoglobin, a measure of blood sugar
control) in line with reductions achieved with other,
previously approved long-acting insulin.
Ryzodeg 70/30 is a mixture of insulin degludec, a longacting insulin analog, and insulin aspart, a rapid-acting
human insulin analog. It is indicated to improve
glycemic control in adults with diabetes mellitus.
The efficacy and safety of Ryzodeg 70/30 used in
combination with mealtime insulin for the treatment of
patients with type 1 diabetes were evaluated in one 26week active controlled clinical trial involving 362
participants exposed to Ryzodeg 70/30. The efficacy
and safety of Ryzodeg 70/30 administered once or
twice daily for the treatment of patients with type 2
diabetes were evaluated in four active controlled 26week clinical trials involving 998 participants exposed
to Ryzodeg 70/30. In participants with type 1 and 2

diabetes who had inadequate blood sugar control at

trial entry, treatment with Ryzodeg 70/30 provided
reductions in HbA1c equivalent to reductions achieved
with other, previously approved long-acting or premixed insulin.
Tresiba and Ryzodeg should not be used in those who
have increased ketones in their blood or urine (diabetic
ketoacidosis). Patients or caregivers should monitor
blood glucose in all patients treated with insulin. Insulin
regimens should be modified cautiously and only under
medical supervision. Tresiba and Ryzodeg may cause
low blood sugar (hypoglycemia), which can be lifethreatening. Patients should be monitored more closely
with changes to insulin dosage, co-administration of
other glucose-lowering medications, meal pattern,
physical activity, and in patients with renal impairment
or hepatic impairment or hypoglycemia unawareness.
Severe, life-threatening, generalized allergy, including
anaphylaxis, generalized skin reactions, angioedema,
bronchospasm, hypotension, and shock may occur with
any insulin.
The most common adverse reactions associated with
Tresiba and Ryzodeg in clinical trials were
hypoglycemia, allergic reactions, injection site
reactions, pitting at the injection site (lipodystrophy),
itching, rash, edema, and weight gain.
Tresiba and Ryzodeg are manufactured by Novo Nordisk
in Plainsboro, New Jersey.
The FDA, an agency within the U.S. Department of
Health and Human Services, protects the public health
by assuring the safety, effectiveness, and security of
human and veterinary drugs, vaccines and other
biological products for human use, and medical
devices. The agency also is responsible for the safety
and security of our nations food supply, cosmetics,
dietary supplements, products that give off electronic
radiation, and for regulating tobacco products.

Treating type 2 diabetes a

21st century pandemic
With the number of people diagnosed with type 2
diabetes set to double in the next ten years Dr
Valentina Gburcik, GlobalData's analyst in
cardiovascular and metabolic disorders, looks at
what this will mean for the pharmaceutical industry.
Begin DMS Content

With close to ten percent of the world's population

currently living with type 2 diabetes, this chronic
disease is clearly the pandemic of the 21st century.
The skyrocketing growth in the prevalence of this silent
killer is attributable to increased life expectancy and an
increasingly sedentary and stressful lifestyle.
The amount of people diagnosed with type 2 diabetes is
expected to almost double in the next ten years, so it is
no wonder that the pharmaceutical market in this space
is blossoming.
According to GlobalData's epidemiology-based market
forecast, the global type 2 diabetes pharmaceutical
market (including the 7MM, Brazil, China, and India) in
2012 was valued at $28.1bn, including sales of both
branded and generic drugs.
In the next ten years this market will reach $68.8bn in
2022 at a CAGR of 9.4%. In the emerging markets,

uptake of branded drugs will increase due to rapid

economic growth.

First-line therapy
The type 2 diabetes market in the 7MM, Brazil, China
and India is very mature; it is crowded with inexpensive
generics and marked by a late-stage pipeline filled with
me-too drugs.

"The global type 2 diabetes

pharmaceutical market (including
the 7MM, Brazil, China, and India) in
2012 was valued at $28.1bn."
The oldest antidiabetic drug, metformin, has long been
and will remain the first-line therapy for type 2 diabetes
due to its low cost, physicians' familiarity with it and
the availability of long-term data.
In contrast, sulfonylureas, another old and front-line
therapy, will gradually be replaced by novel therapies
with improved side-effect profiles.
Nevertheless, during the next decade, the type 2
diabetes market will not experience a fundamental shift
in the classes of drugs that are preferred by physicians.
Rapid uptake of drugs from the novel class of SGLT-2
inhibitors will occur with the global sales for whole class
in 2022 reaching 4.8bn; however, DPP-4 inhibitors and
GLP-1 receptor agonists will continue to dominate the
non-insulin type 2 diabetes space because SGLT-2
inhibitors will more often be used as a third-line
treatment.
Of all currently marketed classes, GLP-1 receptor
agonists will experience the fastest growth, growing at
a CAGR of 13.4% and reaching total peak sales of 9bn
in 2022, thanks to their weight-loss effects and another
burgeoning epidemic - obesity - a disease closely linked
with type 2 diabetes.

Global sales for the whole class of DPP-4 inhibitors will

continue growing at a slightly slower rate (CAGR of
8.9%) and reach a staggering $16.9bn in 2022.
The insulin segment of the type 2 diabetes market will
continue to grow at relatively fast pace (CAGR of 8.1%)
and will reach the value of almost $25bn in 2022,
accounting for both branded and biosimilar insulins and
insulin analogs.

Reaching the market / 'me-too' drugs

Despite a well-populated research pipeline, none of the
drugs slated to reach the market during the next ten
years will significantly diminish the level of unmet need
in type 2 diabetes.

"During the next decade, the type 2

diabetes market will not experience
a fundamental shift in the classes of
drugs that are preferred."
All currently available treatments for type 2 diabetes
are initially effective and reduce complication rates, but
they lack the ability to maintain glycemic control in the
long term because of the progressive nature of
pancreatic -cell dysfunction; this represents one of the
highest unmet needs in the type 2 diabetes space.
In addition to glycemic control, patients with type 2
diabetes should manage other cardiovascular risk
factors, including obesity, hypertension and
dyslipidemia.
Control of these factors is less than optimal in most
patients, and current therapies are only partially
addressing these problems.
As the late-stage pipeline is dominated by me-too drugs
and by drugs belonging to novel classes that are not
very different from the marketed classes, most of the

unmet needs will remain unfulfilled in the foreseeable

future.
Therefore, despite the high number of marketed
therapies, this market has a significant growth
opportunity for new patent-protected products.

Tailored treatments for type 2 diabetes

"The insulin segment of the type 2
diabetes market will continue to
grow at relatively fast pace (CAGR of
8.1%)."
Even in the absence of a revolutionary new treatment,
pharmaceutical companies still have an opportunity to
achieve considerable success in this market.
Indeed, even fourth or fifth-to-market me-too drugs will
garner significant sales, thanks to the rapidly
expanding patient population and the emphasis of the
latest therapeutic guidelines on a patient-tailored
treatment approach. In the future, companies may elect
to develop more tailored treatments for certain patient
segments, discarding the traditional blockbuster
approach and focusing on niche drugs that are aimed at
smaller groups.
Eli Lilly, for example, has already embraced this new
business model and focuses on individualised solutions
for patients.
On the other hand, companies such as Sanofi may
choose to shift their focus from therapeutic value
towards competitive pricing.
Given the stiff competition in the mature type 2
diabetes space and cost pressures that many countries'
healthcare systems face today, competing on price is
likely to become an essential strategy for many current
and future leaders in this therapy area.

While these strategies will seemingly diminish the cash

inflow for pharmaceutical companies, the rapidly
increasing type 2 diabetes market size will support the
survival of any company that has fingers in this space.
Key opinion leaders interviewed by GlobalData believe
most type 2 diabetics are not going to have sufficient
control over their lifestyles, will continue to overeat,
under-exercise and gain weight, and these patients'
need for medications will therefore increase.
For drugmakers, the sky is the limit on the value of the
type 2 diabetes market.

A 21st century
diabetes option: Will
Oramed be first to
market with oral
insulin?
By Nicole Gray July 10, 2015

The size of the diabetes treatment marketplace

has been growing at a rapid pace, and is
expected to reach $55.3 billion in 2017, from
$35.6 billion in 2012. That growth is being fueled
by an unfortunate trend---the increasing

prevalence of diabetes worldwide. According to

the International Diabetes Federation (IDF), there
are 387 million people worldwide with diabetes,
including 29.1 million people in the United States
(U.S).
With prevalence hovering at the 9% mark,
diabetes has become a major public health
threat, with large-scale societal, financial and
individual consequences, including a 1.8-fold
increased risk of heart attack, a 2-fold risk of
premature death and a significantly increased
risk of neuropathies, blindness, end-stage renal
disease and lower-limb amputations.
Enter Orameds oral insulin-in-development
Story continues below

Oramed, based in Israel, is currently one of three

companies, including Biocon and Novo Nordisk,
developing an oral insulin treatment option for
diabetes. Orameds oral insulin (ORMD-0181) is
moving into phase IIb after successful completion
of phase IIa, in which a total of 196 patients
received 2,063 doses of oral insulin, with positive
safety, tolerability and efficacy outcomes.
According to Josh Hexter, chief operating officer
of Oramed, Our oral insulin is not a substitute
for insulin injections, but rather a new, earlier
treatment option.
Based on current diabetes treatment algorithms,
most physicians and patients opt to save insulin
as a last resort. Patients are generally counseled

to modify their lifestyles before physicians add

on Metformin, sulfonylureas, thalzolidinediones,
DPP-4 inhibitors and other oral antidiabetic
treatments, before finally progressing to
injectable insulin.
However, Hexter makes the point that diabetes
clinical treatment guidelines suggest starting
insulin therapy as early as possible in order to
preserve beta-cell functioning. Theres a problem
with this recommendation: Most patients do not
want to use injectables and prefer to try other
options before committing to insulin---most likely
for the rest of their lives.
Why oral insulin is such a game-changer
Its not just a question of changing the mode of
delivery and getting the same outcomes. Barry
Mennen, MD, a Washington, D.C.-based physician
and diabetes expert, says, Oral insulin therapy
has been the Holy Grail of diabetes therapy ever
since insulin was developed as an injectable
therapeutic for diabetes.
He says, Since better mealtime blood sugar
control has been shown to be essential for better
outcomes in diabetes, more injections have been
needed for type 1 diabetes (T1DM) and about
one-fifth of patients with type 2 diabetes (T2DM).
A consistent orally-administered insulin would be
a huge game changer for patients and the overall
diabetes market.
A more natural, truly physiologic MOA
Injectable insulin is not only inconvenient, but
because it is administered into the peripheral
blood stream, which does not mirror the way

natural insulin is processed in the body, it is not

as effective as it could be. Mennen explains,
From the clinical point of view, oral insulin is
actually more physiologic than injectable since it
is absorbed via the gut and therefore passes
directly into the portal circulation (the same
system that natural insulin is secreted into from
the beta cells of the pancreas). This is important
since the liver now gets the first flush of the
insulin and can extract what it requires when the
insulin couples with its receptor sites in this key
target organ. Subcutaneous insulin gets to the
liver only after passing through the systemic
circulation. Mimicking physiology is usually a
good thing.
With insulin, which was first extracted from the
pancreas of cows and pigs and injected into
humans in the 1920s, the goal has always been
to enhance the mode of action (MOA) to give it a
faster onset of action, while also slowing its
release in order to provide the body with insulin
over a longer period of time. Novo Nordisk and
other companies have successfully developed
long-lasting insulins, with various
pharmacokinetic properties that have improved
treatment outcomes, but many patients with
diabetes are still poorly controlled.
Combating FBG overnight
Fasting blood glucose (FBG) is the major point of
reference for determining short term glycemic
control, while glycosolated hemoglobin, or A1C,
is the go-to metric for gauging long-term control.
Approximately 70% of patients with impaired FBG

develop T2DM, while almost 80% of patients who

already have T2DM fail to achieve control with
Metformin and other oral hypoglycemic
treatment options.
According to Hexter, the goal of using ORMD0181 to treat patients with T2DM is to reduce
the excessive nocturnal glucose production from
the liver by going after a nighttime dosing
indication for this population. As for patients with
T1DM, the goal is to use oral insulin, in addition
to injectable insulin, with the goal of decreasing
the number of injections a patient needs on a
daily basis.
He says, By providing a dose of hepatically
focused insulin to patients at the most
challenging time you basically nip the problem of
high morning FBG in the bud by addressing the
problem while the patient sleeps.
An innovative delivery system
According to Hexter, The goal of Orameds
delivery system is to deliver a therapeutic protein
into the body and protect it from the digestive
system, which is designed to rip apart proteins
before they can ever exert a therapeutic effect.
The system is also designed to enhance
absorption.
Towards that end, Orameds technology is
comprised of three main proprietary
components---a pH sensitive enteric coating that
only degrades in the small intestine; protease
inhibitors , which protect oral insulin from
degradation by digestive proteases and
absorption enhancers which assist with

translocation of insulin across the intestinal

membrane into the bloodstream.
Time and money
While Hexter did not provide specific financial
projections, Oramed is strategically positioned
with ORMD-0801, as well as an oral GLP-1 analog
that it is developing (ORMD-0901), to move into
phase III trials by 2017, with the goal of receiving
quality feedback from the FDA and possibly an
expedited approval pathway. Oramed is pursuing
U.S. and ex-U.S. markets.
Market research shows that the global insulin
market will reach roughly $47 billion by 2020, up
from $20 billion in 2013. Assuming successful
development and approval outcomes, Oramed
and other companies that develop oral insulin
treatments, can expect to become a core part of
the diabetes treatment paradigm, to be used as
monotherapy and as part of combination therapy.
Paradigm shift and a huge step forward for
diabetes therapeutics
While many companies call their therapies
novel or first-in-class, oral insulin will change
the way patients and physicians handle the
diabetes treatment timeline. Hexter says, The
earlier you can start insulin therapy, the better.
You want to de-burden the pancreas and preserve
beta-cell functioning. It completely changes longterm outcomes.
The implication of exerting control over blood
sugar as early as possible is not only about
preserving beta-cell functioning, but ultimately
preserving patients quality of life, staving off the

worst consequences of diabetes, saving money

and ultimately changing what it means to be
diagnosed with diabetes.

A Brief History of the

Development of Diabetes
Medications

John R. White Jr., PA-C, PharmD

Diabetes Spectrum 2014 May; 27(2): 82-86.

http://dx.doi.org/10.2337/diaspect.27.2.82

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Abstract
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.
The management of diabetes has changed dramatically during the past several
thousand years. The option preferred by experts of the pharaoh 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
therapeutic 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 current
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 effective pharmacological agents for the
management of diabetes. Because of this, type 1 diabetes was a fatal malady.
This changed dramatically with Frederick Banting's work.
Dr. Banting served as a surgeon in World War I. Captain Banting initially 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 prescription for ethanol), Banting embarked
upon a career in academics.
One of his first teaching assignments involved carbohydrate metabolism. This led
to his interest in diabetes and his erroneous assumption that one needed to
surgically ligate the pancreatic duct and then wait 68 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 alcohol. The solution was
filtered, washed twice with toluene, and filter sterilized. 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 losing 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 buttock of the patient. A sterile abscess developed at the site of one of
the injections, but the patient's blood glucose dropped.
After that injection, the push to perfect the extraction process and commercialize
insulin was on. Banting's team entered into an agreement with Eli Lilly and
Company, and, by July 1922, the first bottles of Lilly's Iletin (insulin) arrived in
Banting's office. Insulin was commercially available in the United States by 1923.
The next major advancement in insulin was its crystallization in 1926. 3 The
technique of insulin crystallization led to improved soluble (regular) insulin purity
and also opened the door to insulin formulation modifications with different timeaction 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 awakened at night for injections. Children not awaked for
nighttime injections were at risk for a significant reduction in growth, or diabetic
dwarfism syndrome. Children with diabetic dwarfism syndrome, which was also
known as Mauriac's syndrome, suffered from stunted growth, hepatomegaly, and
delayed puberty.4 In 1936, the first commercially available, 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
acting 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 microcrystalline 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 composed of a 70:30
mixture of ultralente and semilente and is intermediate acting.
All insulin preparations available 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 rapidacting 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 (duration 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 administration have been made
or are being worked on, including better syringes, pulmonary insulin, insulin
pumps, and closed-loop insulin delivery systems. Insulin is widely used today in
patients with type 1 or type 2 diabetes and is arguably the most effective and
predictable (in most, but not all cases) of all of the current antihyperglycemic
agents.
Biguanides
French lilac, or goat's rue (Galega officinalis), was used as a folk remedy
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 compound 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 antihyperglycemic
agent in the world. Its primary mechanism of action is its ability to reduce
hepatic glucose production, 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 synthetic sulfur compounds. 10 Five years later, Marcel
Janbon and his colleagues were treating patients with the antibiotic para-aminosulfonamide-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 -cell function to elicit an
effect.3,10
In the 1950s, the first SU, tolbutamide, 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 secondgeneration 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 predictable.
Their primary use-limiting side effect is hypoglycemia, although they are also
associated with weight gain. Generally, an A1C reduction of 12% can be
expected in a responsive patient with type 2 diabetes. 7
Thiazolidinediones
Thiazolidinediones (TZDs), which are also known simply as glitazones, were
initially introduced to the U.S. market in 1996. These agents are peroxisome
proliferatoractivated receptor- activators whose mechanisms of action are
enhancement of skeletal muscle insulin sensitivity and reduction in hepatic
glucose production.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 failure 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 potentially 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 0.51% in most patients. 7
There are no significant differences in A1C lowering between pioglitazone and
rosiglitazone.
-Glucosidase Inhibitors
-Glucosidase inhibitors (AGIs) exert a local effect on the brush border of the
small intestine, inhibiting -glucosidase enzymes, which are responsible for the
breakdown of oligosaccharides, trisaccharides, and disaccharides. These
enzymes include maltase, isomaltase, gluocoamylase, and sucrase. Inhibition of
these enzyme systems effectively reduces the rate of absorption of

carbohydrates but does not alter the absolute absorption. The result is reduced
postprandial glucose levels, with a modest effect on fasting glucose. 7 The
reduction of A1C observed with AGIs is typically 0.51.0%.
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
The meglitinides (also called 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 stimulation is dependent on functioning
pancreatic -cells. However, the effect of these drugs is glucose dependent and
diminishes at low glucose concentrations. The glinides bind to receptors in the
pancreas, but the configuration 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 experimental data
demonstrating a greater insulin response with oral glucose administration versus
intravenous glucose 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 (12 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 salivary gland venom of the Gila monster
(Heloderma suspectum).7
Exenatide, a synthetically produced 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, liraglutide, was approved in 2010. In 2012, a long-acting (onceweekly) form of exenatide was approved. A new drug application (NDA) for
dulaglutide, another once-weekly GLP-1 agonist, was submitted to the FDA in
October 2013.19
Other agents in this class are currently 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 0.51% 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 associations between GLP-1 receptor agonists and
pancreatitis are ongoing.

DPP-4 Inhibitors
As noted above, with the elucidation 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 followed by the release of saxagliptin
and linagliptin. Alogliptin was approved by the FDA in 2013. Vildagliptin has been
approved for use in Europe but is not available in the United States.

<img class="highwire-fragment fragment-image" alt="Figure 1."

src="http://spectrum.diabetesjournals.org/content/diaspect/27/2/82/F1.me
dium.gif" width="440" height="222"/>

Download figureOpen in new tabDownload powerpoint

Figure 1.
History of diabetes medications.
These compounds are associated with an A1C reduction of ~ 0.8%. 10 They are
weight neutral and do not tend to cause hypoglycemia. 7 However, pancreatitis
has been reported in patients treated with DPP-4 inhibitors. 11
Amylin Agonists
The endogenous neuroendocrine hormone amylin was discovered in 1987.
Amylin is co-secreted with insulin by the -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 amylin 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 glucagon. 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 therapy.11 It reduces postprandial glucose excursions via the
mechanisms mentioned above.
Bromocriptine
Bromocriptine is a dopamine agonist 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 sympathetic tone.11 Its impact on glycemia is modest,
with A1C reductions of up to 0.7%.11
Colesevelam
Colesevelam is an interesting compound that has a dual effect of lowering LDL
cholesterol and reducing 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 cholesterol. 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 primarily 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 kidney.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 0.50.6% in patients treated with these agents. 23 In
addition to reducing 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 infections 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
management 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. Additionally, the potential permutations 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 encountered 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 2024 years) is about 1114 years less than that of
individuals 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 diabetes. 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.

New Medications for

Type 2 Diabetes
Recent developments in diabetes
treatment

/#content-header
Written by Lisa M. Leontis RN, ANP-C and Amy Hess-Fischl MS,
RD, LDN, BC-ADM, CDE

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Researchers are constantly working on ways to better
control type 2 diabetes, and as they learn more about
how it works, theyre able to develop new medications,
such as the ones listed below.
Gliptins (DPP-4 Inhibitors)
Most often, youll hear gliptins referred to as DPP-4 (or
DPP-IV) inhibitors. DPP-4 inhibitors are one of the
newest classes of drugs used for type 2 diabetes.
The DPP stands for dipeptidyl peptidase IV, and its an
enzyme thats supposed to stop a certain hormone
called glucagonlike peptide-1 or GLP-1. GLP-1 tells the
beta cells to release insulin.
How they work: DPP-4 inhibitors lower blood glucose
levels by allowing more insulin to be released in the
body. There are hormones in the digestive tract that are
released when you eat; they go to your pancreas and
tell your beta cells to produce insulin. One of those
hormones, GLP-1, is quickly destroyed by the enzyme
DPP-4, which is fine for someone without diabetes.
For someone with type 2 diabetes, though, this
prevents them from getting more insulin into their

blood. A DPP-4 inhibitor, therefore, prevents the

enzyme from destroying the GLP-1 hormone.
Example of DPP-4 inhibitor:
Right now, there is only one DPP-4 inhibitor with
FDA approvalsitagliptin (Januvia).
Combination medication with metformin (Janumet)
GLP-1 Mimetics (Incretin Mimetics)
GLP-1 mimetics (also called incretin mimetics) focus on
the effects of the GLP-1 hormone that the digestive
tract releases when you eat. Researchers found a way
to get around the fact that the DPP-4 enzyme destroys
the GLP-1 hormone: they created a synthetic
(manmade) version that mimics (hence the word
mimetic) the GLP-1 hormone. Oddly enough,
researchers found that the saliva of a Gila monster (a
type of lizard) contains a hormone that mimics GLP-1,
so they created a synthetic version using that.
How they work: The DPP-4 enzyme doesnt attack the
GLP-1 mimetic because it doesnt recognize it as the
same thing as the naturally-occurring GLP-1
hormone. Therefore, your body produces more insulin
because the GLP-1 mimetic tells the beta cells to
produce insulin; it works just like the natural hormone.
Special notes: GLP-1 mimetics also make you feel fuller
fasterand you may feel fuller longer. When taking a
GLP-1 mimentic, then, you may not eat as much, and
you may lose weight.
Example of GLP-1 mimetic:
Exenatide (Byetta) is an injectable medication
thats FDA-approved to treat type 2 diabetes.
Amylin Analog

An amylin analog is a synthetic (man-made) version of

the hormone amylin. Amylin is released when insulin is
released in the pancreas, so if your body is having
trouble producing insulin, its probably also having
trouble producing amylin. The hormone amylin helps
lower blood glucose levels.
How it works: An amylin analog is injected before you
eat. It works just like the naturally-occurring hormone
amylinit reduces how much glucagon you have in
your body. Glucagon is a hormone that causes the body
to release or produce glucose. So by reducing the
glucagon level, an amylin analog reduces the blood
glucose level.
Special notes: An amylin analog can be taken with
insulin. If your body doesnt produce much insulin any
moreand you have to take insulintaking an amylin
analog at the same time can be another way to get
better blood glucose control. Amylin cannot be mixed
with insulin, so it needs to be taken as a separate
injection.
Example of amylin analog:
Pramlintide (Symlin) is an example of an FDAapproved amylin analog.
As you can see, there are many medication options if
you have type 2 diabetes. All these medications help
you control your blood glucose level, but they do it in
different ways. Discuss which medication or
medications might be right for you with your healthcare
professional.

New Drugs Promise to

Revolutionize Type 2
Diabetes Treatment
A new class of drugs could dramatically improve
Type 2 diabetes treatment by spurring diabetics
to excrete excess sugar through their urine.
Whats more, the drugs, called SGLT2 inhibitors,
boost overall health by promoting weight loss.
A reduced level of blood sugar is a major
treatment goal in Type 2 diabetes, which affects
an estimated 26 million Americans.
The disease can lead to serious complications
such as heart and kidney disease, nerve damage,
amputations, blindness, and premature death.
The FDA has green-lighted three SGLT2 inhibitors:
Canagliflozin (Invokana), approved March, 2013
Dapagliflozin (Farxiga), approved January, 2014
Empagliflozin (Jardiance), approved August, 2014
Most diabetes drugs target the liver, pancreas, or
gut to improve insulin sensitivity, reduce insulin
resistance, or stimulate insulin secretion.
But SGLT2 inhibitors work in a different way. They
have no effect on insulin. Instead, they target the
kidneys to block the reabsorption of sugar,

increase sugar excretion, thereby reducing blood

sugar levels.
They work by inhibiting a substance called
SGLT2, sodium-glucose co-transporter 2.
This transporter is responsible for reabsorbing
the majority of glucose filtered by the kidneys,
says Jean-Marc Guettier, M.D., director of the
CDCs Division of Metabolism and Endocrinology
Products.
The most recently approved SGLT2 inhibitor
Jardiance was evaluated in seven clinical trials
which included 4,480 participants.
Compared to a placebo, Jardiance significantly
improved hemoglobin A1c levels, an important
measure of blood-sugar control.
Experts say that SGLT2 inhibitors are most likely
to benefit obese patients who have normal
kidney function.
In such patients, an SGLT2 inhibitor often is just
as effective at lowering blood sugar as betterknown diabetes drugs such as metformin,
sulfonylureas, pioglitazone, or insulin.
The FDA has approved SGLT2 inhibitors for use as
stand-alone drugs or in combination with other
diabetes drugs.
Type 2 diabetes is a progressive disease and
patients often require multiple antidiabetic

agents to control glucose as disease progresses,

Dr. Guettier tells Newsmax Health.
SGLT2 inhibitors are best for patients with normal
kidney function. But theyre not as well-tolerated
in patients who have moderate kidney disease.
Theyre not recommended for patients who have
severe kidney impairment, end-stage renal
disease, or are on dialysis.
Such subjects dont benefit from SGLT2
inhibitors and shouldnt be prescribed them,
says Dr. Guettier.
Other groups who should avoid SGLT2 inhibitors
include pregnant women, children, those with
Type 1 diabetes, patients with diabetic
ketoacidosis, which increases the level of ketones
in blood or urine.
In patients with normal kidney function, SGLT2
inhibitors are associated with a welcome side
effect: weight loss.
Studies show that the drugs are associated with a
body weight loss of 2.8 percent to 5.7 percent,
which could significantly improve overall health.
Most other diabetes drugs either have no effect
on weight or can actually cause weight gain. The
only exception is metformin, which also is
associated with modest weight loss.

SGLT2 inhibitors have a mild diuretic effect

because they tend to increase urination.
In patients with hypertension, this effect may
result in a beneficial lowering of blood pressure.
In other patients, however, it may cause
lightheadedness, dizziness, or fainting.
The most common adverse side effects
associated with SGLT2 inhibitors are genital yeast
infections, urinary tract infections, dehydration,
and modestly increased levels of LDL (bad)
cholesterol.