`
`Overview of Glucagon-Like Peptide-1
`Receptor Agonists for the Treatment of
`Patients with Type 2 Diabetes
`
`Kelvin Lingjet Tran, DO; Young In Park, DO; Shalin Pandya, DO; Navin John Muliyil, DO; Brandon David
`Jensen, DO; Kovin Huynh, DO; Quang T. Nguyen, DO, FACP, FACE, FTOS
`
`BACKGROUND: It is estimated that 29.1 million people or 9.3% of the US population have diabetes,
`which contributes to considerable medical and financial burden. Type 2 diabetes mellitus is characterized
`by insulin resistance and insulin secretion impairment leading to hyperglycemia. The presence of insulin
`resistance is strongly correlated with obesity.
`OBJECTIVE: This article reviews the available glucagon-like peptide-1 (GLP-1) receptor agonists and
`their role in the management of patients with diabetes, to help guide the selection of the most suitable
`agent for the individualized treatment of patients with type 2 diabetes.
`DISCUSSION: This article reviews the evidence from phase 3 clinical trials for each of the 5 GLP-1 re-
`ceptor agonists by comparing them against one another and with other existing therapies, including
`metformin, dipeptidyl peptidase-4 (DPP-4) inhibitors, and sulfonylureas. Incretin-based therapies have
`emerged as attractive agents for the treatment of type 2 diabetes. They target the GLP-1 hormone, which
`is partly responsible for insulin release and for attenuating hyperglycemia during meals (ie, the incretin ef-
`fect). The 2 classes of incretin-based therapy currently available are GLP-1 receptor agonists and DPP-4
`inhibitors, which prevent the breakdown of GLP-1. Both classes are attractive options, given their glu-
`cose-lowering effects without the adverse effects of hypoglycemia and weight gain. The different mecha-
`nisms of action of these therapies result in generally greater efficacy with GLP-1 receptor agonists, albeit
`at the expense of slightly increased gastrointestinal symptoms. These agents exert their effects by improv-
`ing glucose-dependent insulin release, suppressing glucagon release, suppressing hepatic glucose output,
`and decreasing the rate of gastric emptying, thereby reducing appetite. Currently, 5 GLP-1 receptor ago-
`nists are available, including exenatide, liraglutide, albiglutide, dulaglutide, and lixisenatide; semaglutide
`may soon become available as the newest agent. With the exception of the investigational oral semaglu-
`tide, which has shown promising results, the other 5 agents are administered as subcutaneous injections,
`at different dosing intervals.
`CONCLUSION: Currently, 5 GLP-1 receptor agonists are available for use in the United States. Although
`they are all in the same drug class, some significant differences exist among the various GLP-1 receptor
`agonists. The choice of a specific GLP-1 receptor agonist will depend on the patient preferences, poten-
`tial adverse effects, and cost.
`
`KEY WORDS: albiglutide, diabetes, DPP-4 inhibitors, dulaglutide, exenatide, GLP-1 receptor agonists,
`incretin- based therapy, insulin, liraglutide, lixisenatide, metformin, semaglutide, sulfonylureas, type 2 diabetes
`
`Stakeholder Perspective,
`page 187
`
`Am Health Drug Benefits.
`2017;10(4):178-188
`www.AHDBonline.com
`
`Manuscript received April 3, 2017
`Accepted in final form April 21, 2017
`
`Disclosures are at end of text
`
`It is estimated that 29.1 million people or 9.3% of the
`
`US population have diabetes, which contributes to
`considerable medical and financial burden.1 Type 2
`
`Dr Tran, Dr Park, Dr Pandya, Dr Muliyil, Dr Jensen,
`and Dr Huynh are Residents, Department of Internal
`Medicine, Valley Hospital Medical Center, Las Vegas, NV;
`Dr Nguyen is Medical Director, Las Vegas Endocrinology,
`Clinical Associate Professor, Clinical Education, AZCOM,
`and Adjunct Associate Professor of Endocrinology, Touro
`University Nevada.
`
`diabetes mellitus is characterized by insulin resistance,
`and by some impairment in insulin secretion leading to
`hyperglycemia. The presence of insulin resistance is
`strongly correlated with obesity.1
`A significant challenge in the treatment of diabetes is
`avoiding the development of hypoglycemia, particularly
`with sulfonylureas and insulin. Complications of hypo
`glycemia include unconsciousness, brain damage, and
`even death if untreated.1 Another adverse effect associ
`ated with the treatment of diabetes is weight gain, which
`occurs with most antidiabetes agents, including sulfonyl
`
`178
`
`CLINICAL
`
`l American Health & Drug Benefits l www.AHDBonline.com
`
`June 2017 l Vol 10, No 4
`
`Copyright © 2017 by Engage Healthcare Communications, LLC; protected by U.S. copyright law.
`Photocopying, storage, or transmission by magnetic or electronic means is strictly prohibited by law.
`
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`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
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`
`
`
`urea, insulin, and thiazolidinediones.2 Because obesity is
`closely linked to diabetes, these agents’ efficacy in treat
`ing diabetes become partly limited because of their link
`to weight gain.2
`Cost is also an important consideration when selecting
`among the many antidiabetes medications. Table 1 com
`pares the costs of diabetic agents. Glucagonlike peptide
`(GLP)1 receptor agonists are generally the most expen
`sive agents. Of note, the cost of Soliqua 100/33 (insulin
`glargine and lixisenatide injection), which is a combina
`tion of insulin glargine and a GLP1 receptor agonist, is
`comparable to other GLP1 receptor agonists that are
`given as monotherapy. The cost of individual antidiabetes
`agents may vary depending on insurance coverage, al
`though coupons are often available for a significant cost
`reduction. Although the cost of diabetes medications (and
`associated supplies) is significant (12% of the overall cost
`of treating diagnosed diabetes), the costs of treating the
`complications of diabetes (18%) and of diabetesrelated
`inpatient care (43%) are even greater.3 Therefore, it is
`more costeffective for patients when their diabetes is ap
`propriately controlled with medications, as necessary.
`
`The Rationale for GLP-1 Receptor Agonists
`The pathology of type 2 diabetes involves inherited
`traits and environmental factors. The vast majority of pa
`tients with type 2 diabetes have a genetic risk for insulin
`resistance; however, the risk for diabetes also worsens with
`increasing age and weight.2 Obese patients have more ad
`ipocytes, which release leptin, adiponectin, tumor necrosis
`factor–alpha, and resistin, and these hormones are thought
`to further contribute to insulin resistance.
`During periods of hyperglycemia, there is an increase
`in glucose transport into betacells of the pancreas,
`which leads to insulin secretion. It is wellrecognized
`that continued poor control of hyperglycemia leads to a
`decline in betacell function, which is likely a result of
`decreased insulin gene expression and decreased produc
`tion of insulin. Therefore, it is important that lifestyle
`changes and treatments are implemented to maintain
`euglycemia. Uncontrolled diabetes will eventually lead
`to complications, such as microvascular disease (ie, reti
`nopathy, nephropathy, and neuropathy), and cardiovas
`cular (CV) events and hypertension.
`Insulin secretion occurs in 2 phases. The first phase
`occurs after a meal, manifested as an immediate rise in
`insulin lasting approximately 10 minutes. This is fol
`lowed by a second phase, in which insulin is released
`more slowly for a prolonged period. Patients with type 2
`diabetes have markedly reduced firstphase insulin secre
`tion, which likely explains why the majority have per
`sistently elevated postprandial glucose concentrations
`despite relatively normal fasting glucose levels.4,5 The
`
`KEY POINTS
`➤ This article reviews the available glucagonlike
`peptide1 (GLP1) receptor agonists and their role
`in the management of patients with diabetes.
`➤ Clinical trials demonstrate the superiority of
`GLP1 receptor agonists to other antidiabetes drugs
`in HbA1c reduction, blood pressure reduction, and
`weight loss, without hypoglycemia risk.
`➤ The 5 GLP1 receptor agonists available include
`exenatide, liraglutide, albiglutide, dulaglutide,
`and lixisenatide.
`➤ A new, oral agent, semaglutide, is currently under
`FDA review and may soon become available as
`the newest GLP1 receptor agonist.
`➤ The GLP1 receptor agonists are valuable options
`for the treatment of type 2 diabetes as adjunctive
`therapy or as monotherapy.
`
`Table 1 Costs of Diabetes Medications, by Class
`Drug/drug class
`Cost of 30-day supply, range, $
`
`Metformin
`
`Insulin
`
`Sulfonylureas
`
`Pioglitazone
`
`DPP-4 inhibitors
`
`SGLT-2 inhibitors
`
`GLP-1 receptor agonists
`
`5-9
`
`145-650
`
`9-15
`
`12-17
`
`173-397
`
`432-443
`
`492-684
`
`DPP-4 indicates dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; SGLT-2, sodium-
`glucose cotransporter-2.
`Source: Cost obtained from GoodRx based on 30-day supply.
`
`betacells in the pancreas respond to this by increasing
`secondphase insulin response.6 However, prolonged ele
`vation of insulin from persistent hyperglycemia leads to
`betacell toxicity and ultimately contributes to insulin
`resistance.7 Interventions that mimic normal firstphase
`insulin secretion, rather than the second phase, have
`been correlated with improved glucose tolerance.8
`GLP1 is a naturally occurring hormone responsible
`for the incretin effect. The incretin effect is a response to
`release more insulin because of high glucose levels after
`a meal. Studies suggest that patients with type 2 diabetes
`have an attenuated incretin effect, possibly because of
`reduced levels of active GLP1.9 Evidence shows that
`GLP1 regulates the expression of betacell genes by in
`hibiting betacell apoptosis, preventing betacell glucolip
`otoxicity, and improving betacell function.10 GLP1 has
`been shown to suppress glucagon release and hepatic
`glucose output.10 GLP1 also decreases the rate of gastric
`
`179
`
`Medication Adherence and Persistence in Diabetes
`
`Vol 10, No 4 l June 2017
`
`www.AHDBonline.com l American Health & Drug Benefits l
`
`Copyright © 2017 by Engage Healthcare Communications, LLC; protected by U.S. copyright law.
`Photocopying, storage, or transmission by magnetic or electronic means is strictly prohibited by law.
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`
`Table 2 Phase 3 DURATION Trials with Exenatide ER16-22
`Trial
`Study drug
`Exenatide ER outcomes vs comparator drugs
`
`DURATION-1
`
`Exenatide ER 2 mg
`vs exenatide 10 mcg
`twice daily
`
`DURATION-2
`
`DURATION-3
`
`DURATION-4
`
`DURATION-5
`
`DURATION-6
`
`Exenatide ER vs
`pioglitazone vs
`sitagliptin; all
`agents taken
`with metformin
`
`Exenatide ER vs
`insulin glargine,
`titrated to goal
`<100 mg/dL
`
`Exenatide ER vs
`metformin vs
`pioglitazone vs
`sitagliptin; all in
`treatment-naïve
`patients
`
`Exenatide ER vs
`exenatide; this
`is similar to
`DURATION-1
`
`Exenatide ER
`vs liraglutide
`
`Greater HbA1c reduction: –1.9% vs –1.5%
`Greater reduction in lipid profile, total cholesterol, triglycerides
`Better glucose control, body weight reduction, systolic blood
`pressure reduction
`Reduced nausea
`
`Greater HbA1c reduction w/ exenatide ER: –1.5% vs –0.9%
`vs –1.2%
`Greater weight loss: –2.3 kg vs –0.8 kg vs +2.8 kg
`Less nausea (5% vs 10.8% vs 9.6%)
`No hypoglycemia w/ exenatide ER
`
`Greater HbA1c reduction w/ exenatide ER: –1.5% vs –1.3%
`3 × lower hypoglycemia rate w/ exenatide ER
`
`HbA1c reduction: –1.53% vs 1.48% vs 1.63% vs 1.15%
`Weight loss: –2.0 kg vs –2.0 kg vs +1.5 kg vs –0.8 kg
`Nausea & diarrhea: 11.3% and 10.9% w/ exenatide ER
`No major hypoglycemia occurred
`
`At 24 weeks, greater HbA1c reduction: –1.6% vs –0.9%
`Greater fasting glucose reduction: –35 mg/dL vs –12 mg/dL
`Similar weight reduction, adverse effects
`
`Greater HbA1c reduction w/ liraglutide: –1.48% vs –1.28%
`More patients reached goal w/ liraglutide: 60% vs 53%
`Greater weight loss w/ liraglutide
`
`ER indicates extended-release; HbA1c, glycated hemoglobin.
`
`emptying and acid secretion, thereby reducing appetite
`and contributing to weight loss. GLP1 is degraded by
`dipeptidyl peptidase (DPP)4, resulting in a shorter half
`life, as shown in patients with type 2 diabetes and in
`healthy volunteers.11 This has led to the development of
`DPP4 inhibitors, which inhibit the degradation of GLP
`1. GLP1 had been considered a treatment modality, but
`it has a very short halflife and would require continuous
`infusions.11 This has led to the development of GLP1
`receptor agonists, which are structurally similar to the
`natural hormone to provide beneficial effects but differ
`structurally to prevent breakdown by DPP4.
`This article reviews the evidence available for current
`GLP1 receptor agonists.
`
`Exenatide
`Exenatide (Byetta) is a synthetic derivative of exen
`din4 (isolated from salivary secretions of the Gila mon
`ster lizard) with a 53% amino acid sequence overlap.12 In
`2005, it became the first GLP1 receptor agonist to re
`ceive approval by the US Food and Drug Administration
`(FDA) for the treatment of type 2 diabetes. As an ago
`nist of pancreatic betacells and resistance from DPP4
`inactivation, exenatide has a longer duration of action
`than GLP1 and more than 1000fold potency for lower
`ing glucose than GLP1.12 Exenatide has been shown to
`stimulate insulin production in response to blood glucose
`
`concentration, inhibit postprandial glucagon release,
`slow the rate of gastric emptying, slow the rate of nutri
`ent absorption in the bloodstream, and reduce appetite.12
`It is also found to promote the proliferation of betacells
`and isletcell neogenesis from precursor cells.12
`Exenatide was first introduced as a twicedaily injection
`of 5 mcg for 1 month followed by 5 mcg or 10 mcg. Phar
`macokinetics demonstrated a plasma level reaching peak
`concentrations at 2 to 3 hours after administration with
`levels remaining detectable for 6 hours after administra
`tion. Patients with type 2 diabetes who were inadequately
`controlled with a sulfonylurea and/or metformin were
`given 0.08mcg/kg subcutaneous injections of exenatide,
`which showed significant reductions in postprandial plas
`ma glucose (PPG) and glycated hemoglobin (HbA1c).12
`Exenatide was studied in the phase 3 clinical trials
`AMIGO I, II, and III.12,13 In all 3 trials, the continuation
`of previous therapy (with metformin alone, sulfonylurea
`alone, or the combination of both) was compared between
`the addition of exenatide and placebo. The exenatide
` treatment group demonstrated a significant reduction in
`PPG concentrations and HbA1c compared with the place
`bo group. Nausea was the most common adverse effect,
`with an increased rate of nausea in the exenatide groups
`versus the placebo groups. The rates of hypoglycemia in
`AMIGO I, which included patients who had received
`metformin, were equal between the exenatide and the
`placebo groups; however, in the AMIGO III study, which
`included patients who had received sulfonylurea and met
`formin combination therapy, patients receiving 10mg
`exenatide had increased hypoglycemia (28% vs 13% in
`the placebo group). No changes in heart rate, blood pres
`sure, and electrocardiograms were noted. The small in
`crease in cortisol levels normalized by day 28.12,13
`Buse and colleagues compared exenatide 5 μg twice
`daily for 4 weeks and then 10 μg twice daily thereafter
`with placebo in patients receiving insulin glargine.14 Insu
`lin glargine was titrated to achieve a fasting glucose of
`<100 mg/dL on the basis of the TreattoTarget Trial al
`gorithm. The study showed an HbA1c reduction of 1.74%
`with exenatide versus 1.04% with placebo. No significant
`increase in hypoglycemia or weight gain occurred. Simi
`lar to the AMIGO trials, exenatide was associated with
`more events of nausea (41% vs 8%, respectively) and
`vomiting (18% vs 4%, respectively) than placebo.14
`
`Exenatide ER
`A new formulation of exenatide, exenatide extended
`release (ER; Bydureon) 2mg onceweekly injection was
`approved by the FDA in 2012 as an adjunct therapy or
`monotherapy in patients with type 2 diabetes.15 Exena
`tide ER reaches therapeutic levels after 2 weeks, and
`after 6 weeks the drug attains a maximum concentration
`
`180
`
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`
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`
`June 2017 l Vol 10, No 4
`
`Copyright © 2017 by Engage Healthcare Communications, LLC; protected by U.S. copyright law.
`Photocopying, storage, or transmission by magnetic or electronic means is strictly prohibited by law.
`
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`
`
`higher than that attained by a single injection of exen
`atide 10 mcg.15 Six weeks after stopping treatment, the
`serum concentration of exenatide once weekly declines
`to insignificant levels.
`The phase 3 clinical trials of exenatide ER included
`the DURATION series, and are summarized in Table
`2.1622 DURATION1 and 5 compared exenatide twice
`daily versus exenatide ER, showing that exenatide ER
`had a greater HbA1c reduction and better glucose control
`compared with the twicedaily formulation. DURA
`TION2 and 4 compared exenatide ER with other dia
`betic oral medications, including pioglitazone, sitagliptin,
`and metformin, which demonstrated comparable efficacy
`in reducing HbA1c and significantly reducing weight.1621
`Exenatide was associated with an increase in gastro
`intestinal (GI) adverse effects, including nausea, vom
`iting, and diarrhea,1621 as is expected of the GLP1
`class. Nausea was most notable during the first few
`weeks of therapy and was minimized by gradual dose
`titration. In DURATION2 and 4, no significant dif
`ferences were reported in the rates of hypoglycemia
`between exenatide ER and metformin, pioglitazone, or
`sitagliptin.18,20 DURATION3 compared exenatide ER
`with insulin glargine, showing 3 times fewer hypoglyce
`mic events with the GLP1 inhibitor than in the insu
`lin glargine group.19
`Mild injectionsite pruritus was observed more often
`with exenatide ER, but it resolved with treatment con
`tinuation.17 Despite concerns for a possible association of
`exenatide and the other GLP1 receptor agonists with
`increased risk for pancreatitis, this was not observed in
`the DURATION trials.15
`
`Liraglutide
`Liraglutide (Victoza) is an acylated analog of GLP1
`that has 97% amino acid sequence identity to the endog
`enous GLP1 analog. In 2009, it was the second GLP1
`agonist to be approved by the FDA for the treatment of
`type 2 diabetes. Liraglutide is a longacting GLP1 recep
`tor agonist that is administered once daily as a subcutane
`ous injection in contrast to twicedaily injections of the
`first exenatide formulation.23 Liraglutide has been report
`ed to increase betacell mass in animal models via in
`creased betacell replication and reduced apoptosis.24 In a
`study with normalweight and obese rats, liraglutide was
`associated with a reduction in food intake, resulting in
`weight loss of approximately 15%.25 Preclinical studies
`showed improvement in first and secondphase insulin
`secretion, implying that liraglutide leads to improved bi
`phasic insulin secretion in response to hyperglycemia.26,27
`The Liraglutide Effect and Action in Diabetes
`(LEAD) program is comprised of 6 phase 3 clinical trials,
`which are summarized in Table 3.2833 Liraglutide, given
`
`Table 3 Phase 3 LEAD Trials with Liraglutide28-33
`Trial
`Study drug
`Liraglutide outcomes vs comparator drugs
`
`LEAD-1
`
`LEAD-2
`
`LEAD-3
`
`LEAD-4
`
`LEAD-5
`
`LEAD-6
`
`Liraglutide 1.2 mg &
`1.8 mg once daily vs
`rosiglitazone 4 mg
`once daily; all
`concurrently taking
`sulfonylurea
`
`Liraglutide 1.2 mg &
`1.8 mg vs
`glimepiride 4 mg; all
`concurrently taking
`metformin
`
`Significant HbA1c reduction w/ liraglutide 1.2 mg & 1.8 mg:
`1.1% vs –0.4% w/ rosiglitazone 4 mg
`Significant decrease in FPG & PPG w/ liraglutide vs
`rosiglitazone
`Minor hypoglycemia, <10%; nausea, <11%; vomiting, <5%;
`diarrhea, <8%
`
`Noninferior HbA1c reduction in liraglutide groups: mean
`decrease, –1%
`Body weight –2.8 kg w/ 1.8-mg liraglutide vs +1.0 kg w/
`glimepiride
`Less hypoglycemic events in liraglutide groups: 3% vs 17%
`w/ glimepiride
`Increased nausea in liraglutide groups
`
`Liraglutide 1.2 mg &
`1.8 mg once daily
`vs glimepiride 8 mg
`once daily
`
`HbA1c reductions: –0.84% & –1.23% w/ liraglutide 1.2 mg &
`1.8 mg vs 0.51% w/ glimepiride 8 mg
`No major hypoglycemic events
`Significantly less minor hypoglycemia: 8% & 12% vs 24%
`
`Liraglutide 1.2 mg &
`1.8 mg vs placebo;
`all concurrently
`taking metformin
`and rosiglitazone
`
`Liraglutide 1.8 mg
`vs insulin glargine;
`all concurrently
`taking metformin
`and glimepiride
`
`Liraglutide 1.8 mg
`vs exenatide 10 μg
`twice daily, all
`concurrently taking
`metformin and
`sulfonylurea
`
`HbA1c reduction: –1.5% vs –0.5%
`Significant FPG and PPG reductions w/ 1.2-mg & 1.8-mg
`liraglutide
`Body weight reductions: –1.0 kg & –2.0 kg w/ liraglutide 1.2
`mg & 1.8 mg vs +0.6-kg weight gain w/ placebo
`Systolic BP reductions: –6.7 mm Hg & –5.6 mm Hg w/
`liraglutide 1.2 mg & 1.8 mg vs –1.1 mm Hg w/ placebo
`Minor hypoglycemia: 7.9% & 9% vs 5.1%
`No major hypoglycemic events
`
`Significantly greater HbA1c reduction: –1.33% vs –1.09%
`Significantly greater weight loss w/ liraglutide: –1.39 kg vs
`+3.43 kg
`Systolic BP reduction: –4 mm Hg vs +0.5 mm Hg
`Major & minor hypoglycemia rates: 0.06 & 1.2 vs 0 & 1.3
`events/patient annually
`
`Significant HbA1c reduction: –1.12% vs –0.79%
`Greater FPG reduction vs exenatide
`Weight loss: 3.24 kg vs 2.87 kg (difference not significant)
`Significantly less minor hypoglycemia w/ liraglutide: 25.5%
`vs 33.6%
`2 patients taking exenatide & sulfonylurea had major
`hypoglycemia
`Less nausea w/ liraglutide
`
`BP indicates blood pressure; FPG, fasting plasma glucose; HbA1c, glycated hemoglobin; PPG,
`postprandial glucose.
`
`as adjunct therapy and as monotherapy, was associated
`with significant reductions in HbA1c levels, blood pres
`sure, fasting plasma glucose (FPG), and PPG levels.2833
`Liraglutide is superior to insulin glargine and to twicedai
`ly exenatide in HbA1c reduction. Weight loss was similar
`between the liraglutide and the exenatide groups, but
`greater weight loss was seen with liraglutide compared
`with insulin glargine.2833
`The LEAD trials showed that the risk for hypoglyce
`mia is low with liraglutide and is significantly lower than
`with a sulfonylurea or twicedaily exenatide.2833 Like
`exenatide, liraglutide was associated with increased GI
`side effects, including nausea and vomiting, which were
`generally mild and transient. A total of 3.4% of the pa
`tients receiving liraglutide in the phase 3 trial withdrew
`because of nausea.30 In general, the GI adverse effects
`can be managed by starting at lower doses of liraglutide
`and then gradually increasing the dose. Liraglutide was
`
`181
`
`Medication Adherence and Persistence in Diabetes
`
`Vol 10, No 4 l June 2017
`
`www.AHDBonline.com l American Health & Drug Benefits l
`
`Copyright © 2017 by Engage Healthcare Communications, LLC; protected by U.S. copyright law.
`Photocopying, storage, or transmission by magnetic or electronic means is strictly prohibited by law.
`
`Novo Nordisk Exhibit 2374
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`
`
`
`Table 4 Phase 3 HARMONY Trials with Albiglutide39-46
`Trial
`Study drug
`Albiglutide outcomes vs comparator drugs
`
`HARMONY-1
`
`Albiglutide 30 mg vs placebo
`
`HARMONY-2
`
`Albiglutide 30 mg vs albiglutide
`50 mg vs placebo
`
`HARMONY-3
`
`Albiglutide 30 mg vs sitagliptin
`100 mg vs glimepiride 2 mg
`vs placebo; all concurrently
`taking metformin
`
`HbA1c: –0.8% vs –0.1%
`Hyperglycemia events: 24.4% vs 47.7%
`No significant differences in weight change
`All GI events: 31.3% vs 29.8%
`Diarrhea: 11.3% vs 8.0%
`Nausea: 10.7% vs 11.3%
`Vomiting: 4% vs 4%
`
`HbA1c: –0.84% vs –1.04%
`No significant changes in weight w/ 2
`albiglutide doses
`Similar nausea, diarrhea, vomiting, hypoglycemia
`rate in all groups, including placebo
`
`HbA1c: –0.9% vs –0.4% vs –0.3% (vs placebo)
`Weight change: –1.21 kg vs –0.86 kg vs +1.17
`kg vs –1.0 kg
`Hyperglycemia rates: 25.8% vs 36.4% vs
`32.7% vs 59.2%
`Diarrhea: 12.9% vs 8.6% vs 10.9% (vs placebo)
`Nausea: 10.3% vs 6.2% vs 10.9% (vs placebo)
`
`HARMONY-4
`
`HARMONY-5
`
`Albiglutide vs insulin glargine
`titrated to fasting plasma
`glucose goal of 100 mg/dL
`
`HbA1c: –0.7% vs –0.8%
`Weight change: –1.0 kg vs +1.5 kg
`Hypoglycemia: 17.5% vs 27.4%
`
`Albiglutide 30 mg titrated up to
`50 mg vs pioglitazone 30 mg
`titrated up to 50 mg; all
`concurrently taking metformin ±
`glimepiride 4 mg
`
`HbA1c reduction: –0.87% vs placebo
`HbA1c +0.25 vs pioglitazone: not meeting
`noninferiority criteria
`Hypoglycemia: 14% vs 25% vs 14%
`Weight change: –0.42 kg vs +4.4 kg vs –0.4 kg
`
`HARMONY-6
`
`Albiglutide 30 mg titrated up to
`50 mg vs insulin lispro 3 × daily
`adjusted per glucose level
`
`HARMONY-7
`
`HARMONY-8
`
`Albiglutide 30 mg titrated up to
`50 mg vs liraglutide 0.6 mg
`titrated up to 1.8 mg; all
`concurrently taking metformin ±
`sulfonylurea ± thiazolidinedione
`
`Albiglutide vs sitagliptin with
`GFR >60 mL/min, GFR 30-59
`mL/min, GFR 15-29 mL/min; all
`± oral diabetes drugs
`
`HbA1c: –0.82% vs –0.66%
`Weight change: –7.3 kg vs +0.81 kg
`Severe hypoglycemia: 0 vs 2 events
`Nausea: 11.2% vs 1.4%
`Vomiting: 6.7% vs 1.4%
`Injection-site reaction: 9.5% vs 5.3%
`
`HbA1c: –0.78% vs –0.99%
`Injection-site reaction: 12.9% vs 5.4%
`GI adverse effects: 35.9% vs 49%
`
`HbA1c: –0.83% vs –0.52%
`Time to hyperglycemic rescue longer w/ albiglutide
`All adverse events: 51.7% vs 25.2%
`Diarrhea: 10% vs 6.5%
`Nausea: 4.8% vs 3.3%
`Vomiting: 1.6% vs 1.2%
`Hypoglycemia: 24.1% vs 15.9% (sulfonylurea:
`22.5% vs 14.2%; no sulfonylurea: 4% vs 4%)
`Weight change: –0.79 kg vs –0.19 kg
`
`GFR indicates glomerular filtration rate; GI, gastrointestinal; HbA1c, glycated hemoglobin.
`
`associated with a lower antibody formation than exena
`tide, likely because of the greater (97%) amino acid
`sequence identity than human GLP1.34 Exenatide has a
`lower sequence identity than liraglutide, which may ex
`plain the incidence of antiexenatide antibody formation
`in up to 43% of exenatidetreated patients.35
`There have been few case reports of liraglutideassoci
`ated pancreatitis. Studies in rodents have shown that
`liraglutide induces Ccell proliferation and medullary
`thyroid adenomas and carcinomas via GLP1 receptor
`agonist activation and calcitonin release, but this pattern
`was not seen in humans. Followup studies have been
`inconclusive to definitively define a causeandeffect re
`
`lationship between liraglutide and pancreatitis, because
`patients with type 2 diabetes already have a 3fold in
`creased risk for pancreatitis.36 In the LEADER trial, lira
`glutide taken for 3.5 years was associated with a 23%
`reduction in CV events, a 22% reduction in CV mortal
`ity, and a 15% reduction in allcause mortality.37
`
`Albiglutide
`Albiglutide (Tanzeum) is a GLP1 agonist that was
`approved by the FDA in 2014 as an adjunct treatment
`for diabetes; it is administered as a weekly injection.38
`Albiglutide has 97% homology to the amino acid se
`quence of GLP1. A single amino acid substitution (ala
`nine to glycine) renders albiglutide resistant to DPP4–
`mediated protein degradation, resulting in a longer
`halflife. After subcutaneous injection of a single 30mg
`dose, patients with type 2 diabetes achieved mean maxi
`mum plasma concentration 3 to 5 days after administra
`tion. Plasma concentrations reach steady state within 3
`to 5 weeks of repeated onceweekly administrations.
`Albiglutide is currently available as a 30mg and a 50mg
`onceweekly injection.38
`Albiglutide was tested in the HARMONY phase 3
`clinical trials, which comprised 8 studies (Table 4).3946
`HARMONY2 demonstrated the superiority of albiglu
`tide monotherapy to diet and exercise in glycemic con
`trol.40 In HARMONY3, onceweekly albiglutide addon
`therapy was noninferior to oncedaily sitagliptin and
`oncedaily glimepiride at reducing HbA1c levels in pa
`tients inadequately controlled with metformin alone,41
`whereas HARMONY4 and 6 demonstrated that albi
`glutide was noninferior to insulin therapy in patients in
`adequately controlled with oral antidiabetes therapy.42,44
`However, in HARMONY5, albiglutide was found to be
`inferior to pioglitazone in HbA1c reduction.43 HARMO
`NY8 revealed that albiglutide was superior to sitagliptin
`in patients with and without renal impairment.46
`Albiglutide demonstrated greater weight loss in all
`studies compared with sitagliptin, glimepiride, pioglit
`azone, and insulin therapy, although more GI adverse
`effects were reported with albiglutide compared with
`other agents.3946 All trials demonstrated no significant
`differences in rates of hypoglycemia, except in pa
`tients with impaired renal disease who used albiglu
`tide and a sulfonylurea.3946
`
`Dulaglutide
`Dulaglutide (Trulicity) is a onceweekly subcutane
`ously administered GLP1 receptor agonist approved by
`the FDA in 2014 as an adjunct to diet and exercise to
`improve glycemic control in patients with type 2 diabe
`tes.47 The initial dosage is 0.75 mg administered subcuta
`neously once weekly, which may be increased to 1.5 mg
`
`182
`
`CLINICAL
`
`l American Health & Drug Benefits l www.AHDBonline.com
`
`June 2017 l Vol 10, No 4
`
`Copyright © 2017 by Engage Healthcare Communications, LLC; protected by U.S. copyright law.
`Photocopying, storage, or transmission by magnetic or electronic means is strictly prohibited by law.
`
`Novo Nordisk Exhibit 2374
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00005
`
`
`
`once weekly for additional glycemic control. Dulaglutide
`is comprised of 2 identical GLP1 analog peptide chains
`(approximately 90% homologous to native human GLP
`1) linked to an immunoglobulin (Ig) G4 heavy chain.
`The alteration of the GLP1 analog provides protection
`against degradation by DPP4, improved solubility, and
`reduced immunogenicity. The addition of IgG4 increases
`the size of the protein, which helps decrease the rate of
`renal clearance, and the Fc fragment of IgG4 prevents
`antibody formation to further reduce the potential for
`immunologic cytotoxicity.47
`Dulaglutide has been studied in comparison with
`other antidiabetes agents and with placebo in the phase
`3 AWARD trials (Table 5).4854 These trials demon
`strate that onceweekly dosing of 1.5mg dulaglutide
`was superior to metformin, insulin glargine, and sita
`gliptin in reducing HbA1c levels; dosing with dulaglu
`tide 0.75 mg was noninferior to these agents. Patients
`in these trials experienced greater loss with 1.5mg and
`with 0.75mg dosing of dulaglutide compared with
`other agents. In patients taking dulaglutide and insulin
`concomitantly, there was either attenuation of the
`weight gain or overall weight loss compared with pa
`tients receiving placebo.4854 In AWARD6, patients
`receiving liraglutide 1.8 mg experienced greater weight
`loss than those receiving dulaglutide 1.5 mg.53
`Similar to other GLP1 receptor agonists, the most
`frequently reported adverse events with dulaglutide were
`GI in nature, including nausea, vomiting, and diarrhea.4854
`These events were generally mild to moderate, peaked at
`2 weeks, and rapidly declined over the next 4 weeks. The
`majority of adverse events were reported during the first 2
`to 3 days after receiving the initial dose and declined with
`subsequent doses. Hypoglycemic events were not common
`in patients taking dulaglutide, and occurred less frequently
`compared with patients receiving insulin therapy, as was
`shown in AWARD2 and 449,51; however, significantly
`more hypoglycemic events were reported with a sulfonyl
`urea as background therapy compared with placebo as
`demonstrated in AWARD8.4854
`Given its mechanism of action, dulaglutide was evalu
`ated for pancreatic safety. Throughout the AWARD tri
`als, 4 events were reported in patients taking dulaglutide
`(3 patients receiving dulaglutide 1.5 mg and 1 receiving
`the 0.75mg dose). Laboratory studies of pancreatic amy
`lase and lipase in these trials revealed a mean 14% to 20%
`increase in amylase and lipase levels in patients receiving
`dulaglutide; however, these events were not predictive of
`acute pancreatitis. Given the association of GLP1 ana
`logs with medullary thyroid carcinoma, thyroid safety was
`assessed as well. In the AWARD trials, only 1 case of
`medullary thyroid carcinoma in AWARD5 was reported,
`although this case was determined to be preexisting.52
`
`Table 5 Phase 3 AWARD Trials with Dulaglutide48-54
`Trial
`Study drug
`Dulaglutide outcomes vs comparator drugs
`
`Dulaglutide 1.5 mg once
`weekly vs dulaglutide 0.75
`mg vs exenatide 10 μg twice
`da