Patient Preference and Adherence
`
`Open Access Full Text Article
`
`Dovepress
`open access to scientific and medical research
`
`R e v i e w
`
`exenatide once weekly: clinical outcomes
`and patient satisfaction
`
`Biju Jose1
`Abd A Tahrani1,2
`Milan K Piya1,2
`Anthony H Barnett1,2
`1Department of Diabetes and
`endocrinology, Heart of england NHS
`Foundation Trust, Birmingham, UK;
`2School of Clinical and experimental
`Medicine, University of Birmingham,
`Birmingham, UK
`
`Correspondence: Abd A Tahrani
`The MiDRU, Birmingham Heartlands
`Hospital, Birmingham B9 5SS, UK
`Tel +44 7801549960
`email a.a.tahrani@bham.ac.uk
`
`Background: Type 2 diabetes mellitus (T2DM) is a complex disorder in which interactions
`between environmental and genetic factors result in the development of insulin resistance (in
`most cases) and progressive pancreatic β-cell failure. The currently available oral anti-diabetes
`treatments are effective as monotherapy; however, due to the progressive decline in β-cell
`function, most patients will require the use of combination therapy and eventually insulin to
`reach glycemic targets. These therapeutic options are not without undesirable side effects such
`as weight gain and hypoglycemia. Furthermore, T2DM is associated with impaired quality of
`life (QOL) and poor compliance with treatment. Hence, there is a need for anti-diabetes agents
`that result in sustained improvements in glycemic control without hypoglycemia or weight
`gain and have a positive impact on patients QOL and thereby hopefully improve compliance.
`Incretin-based therapy is the latest addition to anti-diabetes treatments which addresses some
`of the shortcomings of older treatments.
`Aims: To review the evidence for the use of exenatide once-weekly.
`Methods: We have searched Medline using the terms “exenatide”, “exenatide once-weekly”,
`and “exenatide LA”.
`Results: Exenatide once-weekly is an incretin mimetic that is currently undergoing phase 3
`clinical trials, and has been shown to improve glycemic parameters (HbA1c and fasting and
`postprandial glucose levels), with low risk of hypoglycemia, causes weight loss, and use was
`associated with improvements in patient satisfaction which might have a positive impact on
`treatment compliance.
`Conclusions: Exenatide once-weekly is effective, well tolerated in patients with T2DM and
`should be a useful addition to the available range of anti-diabetes treatments.
`Keywords: diabetes mellitus, incretins, exenatide once-weekly, quality of life, treatment
`satisfaction
`
`Introduction
`Type 2 diabetes mellitus (T2DM) is a global epidemic with an estimated worldwide
`prevalence of 6% (246 million people) in 2007 that is forecasted to rise to 7.3%
`(380 million) by 2025.1,2 The health, social, and economic burden of T2DM is great;3–5
`it continues to pose a major challenge to healthcare provision around the world.
`The development of insulin resistance (IR) and pancreatic β-cell dysfunction due to
`various environmental and genetic factors results in onset of T2DM.6,7 Despite obesity
`being the single most important contributor to IR, most obese insulin-resistant individu-
`als do not develop T2DM8,9 because their β-cells are capable of producing sufficient
`insulin to maintain euglycemia.9–13 This suggests that the failure of β-cells to secrete
`sufficient insulin to overcome IR is the key step in the development and progression
`
`submit your manuscript | www.dovepress.com
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`DOI: 10.2147/PPA.S7494
`
`Patient Preference and Adherence 2010:4 313–324
`© 2010 Jose et al, publisher and licensee Dove Medical Press Ltd. This is an Open Access article
`which permits unrestricted noncommercial use, provided the original work is properly cited.
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`of T2DM.6,7,9,10 Pancreatic α-cell dysfunction manifesting as
`non-suppressed glucagon secretion in the presence of hyper-
`glycemia is also manifest in patients with T2DM.14
`Several pharmacological agents have been developed
`to treat patients with T2DM. They either improve insulin
`resistance (biguanides, glitazones), stimulate insulin secre-
`tion from the β-cell (sulfonylureas, metaglinides), or decrease
`glucose absorption from the gut (α-glucosidase inhibitors).15
`The initial improvements in glycemic control observed with
`these agents as monotherapy are not sustained because of the
`progressive nature of the disease due to the continuing decline
`in β-cell function.9,16 This often necessitates the use of com-
`bination therapy and eventually insulin. Furthermore, current
`agents may be associated with undesirable side effects includ-
`ing gastrointestinal (metformin, α-glucosidase inhibitors),
`weight gain (sulfonylureas, metaglinides, glitazones, and
`insulin), and hypoglycemia (sulfonylureas, metaglinides,
`and insulin).17 These side effects may contribute to further
`worsen the already impaired health-related quality of life
`(QOL) found in patients with T2DM18 and may contribute to
`poor compliance common in this group of patients.19
`Treatment acceptability and adherence are particularly
`important in the management of T2DM. A systematic review
`showed that many patients took less than their prescribed dose
`of insulin and/or oral anti-diabetes medications20 and that a
`substantial proportion of patients had difficulty in dealing
`with various elements of the chronic disease management,
`particularly adhering to a strict drug regimen.21,22
`Taking the above into account, there is a need for new
`pharmacological agents that are well tolerated with sustain-
`able impact on glycemic control, and with very low risk of
`hypoglycemia, cause weight loss (or at least no weight gain)
`and thereby encourage patient adherence to therapy. Incretin-
`based therapy is the latest class of anti-diabetes medications
`to become available and addresses some of the shortcomings
`of conventional anti-diabetes treatments. Incretin-based ther-
`apy can be given either orally (dipeptidyl peptidase-4 (DPP-4)
`inhibitors) or via a subcutaneous injection ( glucagon-like
`peptide (GLP-1) analogues/ mimetics). They improve glyce-
`mic control with favorable impact on weight and low risk of
`hypoglycemia (apart from when used with sulfonylureas).23
`In addition, animal studies have shown that some of these
`agents improve β-cell survival,23 which if true in humans
`might result in a more sustained impact on glycemic control.
`GLP-1 analogs/mimetics are given in once- or twice-daily
`dosing regimes. However, other drugs are in development
`in this category that require administration once weekly
`or even less frequently.23 Such a dosing regimen might be
`
`highly acceptable to patients and encourage compliance
`with treatment.
`In this article, we aim to review the available data regard-
`ing the once-weekly use of exenatide in the management of
`T2DM and the potential patient considerations for the use of
`this drug. Further details regarding incretin-based therapies
`are not within the scope of this article and can be found
`elsewhere.24–27
`
`Incretins
`Incretins are hormones that are released from the gut in response
`to ingestion of food.28 The incretin effect was first described
`in 1964, when it was observed that the insulin response to oral
`glucose challenge was substantially higher than to an intrave-
`nous glucose load.29 The incretin response accounts for at least
`50% of insulin secretion in healthy individuals.30
`Glucose-dependent insulinotropic polypeptide (GIP) was
`the first incretin to be isolated and characterized.31,32 It is a
`42 amino acid peptide secreted in the bioactive form from
`the K-cells in duodenum and jejunum in response to inges-
`tion of carbohydrates and lipids.33 The second incretin to be
`isolated was GLP-1, which is cleaved from pro-glucagon
`and secreted from the L-cells in the distal ileum and colon.33
`GLP-1 levels are reduced in patients with T2DM, unlike GIP
`levels which are maintained.34
`Both GIP and GLP-1 facilitate glucose-dependent insulin
`secretion through their action on pancreatic β-cells. GLP-1
`increases insulin gene transcription as well as all the steps of
`insulin biosynthesis.35 In addition, GLP-1 results in glucose-
`dependent glucagon suppression, delays gastric emptying,
`increases satiety, and possibly reduces insulin resistance.36,37
`There is also evidence that GLP-1 increases β-cell mass in
`animal studies.38
`GLP-1 secretion is reduced in patients with T2DM.39
`Although there is a blunting of GLP-1 secretory response in
`these patients, their response to exogenous GLP-1 is intact.23
`A continuous 6-hour intravenous infusion of GLP-1 in the
`fasting state, leading to GLP-1 levels 2–3 times higher than
`normally seen after meals, resulted in lowering of glucose and
`glucagon levels, with increases in insulin secretion without
`any hypoglycemic events in patients with poorly controlled
`T2DM.40 Subcutaneous GLP-1 was also shown to have a
`similar glucose-lowering effect when administered pre-meal
`in patients with T2DM.41
`Incretins are rapidly metabolized by the enzyme DPP-4,
`and thus have extremely short half-lives (GIP , 2 minutes
`and GLP-1 5–7 minutes).42,43 The short half-life of these natu-
`rally occurring incretins limited their clinical use. This led
`
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`exenatide once weekly
`
`to the development of various modifications of the amino
`acids of GLP-1, rendering them DPP-4 resistant. Exenatide
`(Byetta®; Eli Lilly), a synthetic analog of exendin-4, was the
`first-in-class incretin mimetic. Liraglutide (Victoza®; Novo
`Nordisk), an analog of human GLP-1, is a fatty acid derivative
`of GLP-1 that has been approved for clinical use more
`recently. There are several long-acting once-weekly prepa-
`rations currently in phase 3 clinical trials – exenatide once-
`weekly (Byetta®; Eli Lilly), albiglutide ( GlaxoSmithKline)
`and taspoglutide (Ipsen and Roche), all of which show
`promising results. Research has also targeted developing
`inhibitors of the DPP-4 enzyme. The currently available
`DPP-4 inhibitors are sitagliptin (Januvia®; Merck & Co),
`vildagliptin (Galvus®; Novartis) and saxagliptin (Onglyza®;
`Bristol-Myers Squibb and Astra-Zeneca). Alogliptin (Takeda)
`and linagliptin (Ondero®; Boehringer Ingelheim) are cur-
`rently undergoing phase 3 clinical trials.
`Exenatide, a synthetic version of the naturally occurring
`salivary peptide isolated from the Gila monster (Heloderma
`suspectum), is a partial structural analog of human GLP-1
`and has 53% amino acid sequence homology with human
`GLP-1.44 It contains a glycine at position 2, in contrast to
`human GLP-1, which has an alanine at position 2, thus
`making the molecule DPP-4 resistant, in turn conferring a
`longer half-life.44 Exenatide has a half-life of 3.3–4.0 hours
`and clinical effects lasting for up to 8 hours.45–47 Exenatide
`treatment results in significant reductions in fasting plasma
`glucose (FPG) and post-prandial glucose (PPG) in patients
`with T2DM.48–51 In addition, it results in slowing of gastric
`emptying (which contributes to the reductions in PPG),52
`appetite suppression53 and weight loss.54
`The AC2993 Diabetes Management for Improving
`Glucose Outcomes (AMIGO) trials were three 30-week
`randomized, triple-blind, placebo-controlled, multicenter
`trials that had similar design and examined the impact of
`exenatide treatment on glycemic control in patients with
`T2DM. 48,55,56 They enrolled subjects aged 16–75 years who
`were poorly controlled on metformin and/or sulfonylurea
`with HbA1c 7.5%–11%. In the AMIGO trials, patients
`were randomized to placebo, exenatide 5 µg or exenatide
`10 µg while continuing metformin and/or sulfonylurea. By
`week 30, exenatide 10 µg resulted in mean HbA1c reduc-
`tion of −0.8% ± 0.1% to −0.9 ± 0.1% compared with a
`−0.16% ± 0.1% to 0.08% ± 0.1% in placebo.55 The effects
`of exenatide on glycemic control appeared to be sustainable
`as reductions achieved at 30 weeks (−1.0% ± 0.1%) were
`maintained at 82 weeks57 and 3 years58 in the open-label
`extensions of the AMIGO trials.
`
`The open-label extensions of the AMIGO trial also
`showed that exenatide treatment promotes progressive weight
`loss up to 82 weeks (−2.1 ± 0.3 kg versus −4.0 ± 0.3 kg for
`exenatide 10 µg week 30 versus week 82 respectively).57,59
`Furthermore, a subset of patients who had 3.5 years of
`exenatide exposure had reductions in triglycerides of 12%
`(P = 0.0003); LDL-C decreased by 6% (P , 0.0001), and
`HDL-C increased by 24% (P , 0.0001).59
`Exenatide is generally well tolerated long term, but the
`most commonly reported adverse events (AEs) (mostly in the
`first few weeks of treatment) are nausea, vomiting, diarrhea,
`headache, dizziness, and dyspepsia.60 In a recent meta-
`analysis, exenatide was associated with a significant increase
`in the proportion of patients experiencing hypoglycemia in
`placebo-controlled trials (OR: 2.92 (1.49–5.75), P = 0.002).
`This excess, however, was only observed when exenatide was
`combined with sulfonylureas.61 Concerns about acute pancrea-
`titis have been raised in patients using exenatide. However,
`a 1-year follow-up study of patients who were initiated on
`exenatide, sitagliptin, glyburide, or metformin showed the risk
`of acute pancreatitis to be comparable between the cohorts.62
`Nonetheless, the FDA has changed the labeling on the drug
`to warn about possibility of acute pancreatitis particularly
`in susceptible patients, based on post-marketing analysis
`s howing 30 reported cases of pancreatitis in 2007 and 6 cases
`of necrotizing hemorrhagic pancreatitis in 2008.60 The FDA
`also warns that exenatide should not be used in patients with
`severe renal impairment (creatinine clearance , 30 mL/min)
`or end-stage renal failure, and should be used with caution
`in those with renal transplant or moderate renal impairment
`(creatinine clearance 30–50 mL/min).60
`Although exenatide is relatively well tolerated and effec-
`tive in improving glycemic control with favorable impact on
`weight and low risk of hypoglycemia, the main drawback is
`that it needs to be administered by twice-daily injections.
`As a result, the development of exenatide once-weekly is
`now in progress.
`
`Exenatide once-weekly
`Chemistry
`Exenatide once-weekly uses a sustained release drug
`delivery system. Molecules of exenatide are encapsulated
`in injectable microspheres of poly (D, L lactic-co-glycolic
`acid), a biodegradable polymeric matrix commonly used in
`extended release preparations.63 This poly-lactide-glycolide
`and exenatide microsphere suspension allows gradual drug
`delivery at a controlled rate by diffusion and erosion of the
`microspheres.63,64
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`Pharmacokinetics
`Mean plasma concentration of exenatide once-weekly (0.8 or
`2 mg) reached clinically significant levels (at which exenatide
`lowers blood glucose) by week 2 in a 15-week phase 2 study
`of 45 adults (60% men, 60% Caucasians) whom glycemic
`control was suboptimal (HbA1c 8.5% ± 1.2%) with metformin
`and/or life-style changes.64,65 By week 6, exenatide once-
`weekly attained a maximum concentration higher than that
`attained by a single injection of exenatide 10 µg (a steady state
`concentration of 232 pg/mL versus 211 pg/mL).59 Six weeks
`after stopping treatment, the serum concentration of exenatide
`once-weekly declined steadily to insignificant levels.64
`In a randomized, double-blind, parallel study in Japanese
`patients with T2DM (59% men, aged 58 ± 9 years), the AUC
`(0–8 hours) of exenatide once-weekly on day 1 was 187.6
`(133.7–263.3) pg * h/mL and 405.6 (278.4–590.8) pg * h/mL
`for 0.8 mg and 2 mg respectively.66 The Cmax on day
`1 was 64.3 (38.3–107.8) pg/mL for 0.8 mg and 137.3
`(74.6–252.6) pg/mL for 2 mg of exenatide once-weekly.
` Geometric mean (90% CI) steady-state plasma concentrations
`were 81.2 (68.3–96.4) pg/mL and 344.5 (256.5–462.7) pg/mL
`with 0.8 mg and 2.0 mg respectively (Figure 1).66
`The diabetes therapy utilization researching changes
`in A1c, weight, and other factors through intervention with
`Exenatide once-weekly (DURATION)-1 study (described
`below) showed that plateau concentrations of exenatide
`
`were achieved after 6–10 weeks of exenatide once-weekly
`with a geometric mean steady state plasma concentration of
`71.7 pmol/L.67
`
`Clinical efficacy
`impact on glycemic parameters
`There are 3 published randomized controlled trials that
`assessed the impact of exenatide once-weekly on glycemic
`parameters (Table 1). Exenatide once-weekly produced sig-
`nificant reductions in HbA1c, FPG, and PPG when used in
`drug-naïve patients or patients treated with one or more oral
`anti-diabetes therapy.64,66,67
`The DURATION-1 study was a randomized, open-label,
`non-inferiority study that compared exenatide 2.0 mg
`weekly to exenatide 10 µg twice daily in patients with
`T2DM. 303 patients were enrolled and 295 (53% men, 78%
` Caucasians) were randomized.67 All patients underwent a
`3-day lead-in period with exenatide 5 µg twice daily, after
`which they were randomized to either exenatide 2.0 mg once-
`weekly or exenatide 5 µg twice daily for 28 days, followed by
`exenatide 10 µg twice daily. Participants had a mean age of
`55 ± 10 years with a mean BMI of 35 ± 5 kg/m2. The baseline
`anti-diabetes treatment included metformin (73%), sulfo-
`nylurea (37%), and thiazolidinediones (16%) alone or in
`combination.67 By week 10, there were significantly greater
`reductions in HbA1c in the once-weekly group compared
`
`Last injection
`
`1200
`
`1000
`
`800
`
`600
`
`400
`
`200
`
`0
`
`Mean exenatide concentration (pg/mL)
`
`0
`
`2
`
`4
`
`6
`
`8
`
`10
`Weeks
`
`12
`
`14
`
`16
`
`18
`
`20
`
`Figure 1 Mean (±SD) plasma exenatide trough concentration-versus-time profiles in pharmacokinetic evaluable patients receiving exenatide once weekly 0.8 mg (closed
`triangles) (n = 8) or exenatide once weekly 2.0 mg (closed circles) (n = 6). Reproduced with permission from iwomoto K, et al. Endocr J. 2009;56(8):951–962.66
`
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`exenatide once weekly
`
`−28.5 ± 38.4 mg/dL
`Not reported
`−20.5 ± 20.4 mg/dL
`Not reported
`−0.4 ± 0.3
`
`−75.8 ± 42.9 mg/dL
`Not reported
`−25.2 ± 10.9 mg/dL
`Not reported
`−1.0 ± 0.7
`
`10
`TZD-20%
`SU-50%
`BG-0%
`Placebo QW
`
`10
`TZD-10%
`SU-30%
`BG-20%
`0.8 mg Ex QW
`
`TZD-11%
`SU-6%
`BG-0%
`2.0 mg Ex QW
`FPG 156.1 ± 29.1 mg/dL
`Diabetes duration 6 ± 5 years
`Men 58.6%
`Age 58 ± 9
`10 weeks
`
`Phase 1, randomized, placebo controlled
`Iwamoto et al66
`
`Not reported
`−0.8 ± 1.5 kg
`(26.3 ± 2.9 kg/m2)
`69.7 ± 13.4 kg
`Not reported
`
`−111.1 ± 48.5 mg/dL
`Not reported
`−50.8 ± 27.8 mg/dL
`Not reported
`−1.5 ± 0.7
`7.4 ± 0.8%
`
`9
`
`Not reported
`−1.6 ± 1.6 kg
`
`Not reported
`
`Not reported
`−0.3 ± 2.2 kg
`
`Not reported
`
`Abbreviations: FPG, fasting blood glucose; PPG, post prandial blood glucose; Ex, exenatide; QW, once weekly; BD, twice daily; NS, not significant; SU, sulfonylurea; TZD, thiazolidinedione; BG, biguanide.
`P value
`weight change
`(BMi)
`Baseline weight
`P value
`
`−3.6 (Se 0.5) kg
`
`(subset n = 51)
`−6.9 (Se 0.5) mmol/L
`
`−1.4 (Se 0.5) mmol/L
`
`−1.5 ± 0.1
`
`130
`TZD-17%
`SU-37%
`Metformin-69%
`10 µg Ex BD
`
`0⋅89
`−3.7 (Se 0.5) kg
`(34 kg/m2)
`102 (SD 20) kg
`Not reported
`(subset n = 51)
`−5.3 (Se 0.5) mmol/L
`,0.001
`−2.3 (Se 0.5) mmol/L
`0⋅0023
`−1.9 ± 0.1
`8.4%
`129
`TZD-15%
`SU-37%
`Metformin-77%
`2.0 mg Ex QW
`FPG 9 ± 2 mmol/L
`Diabetes duration 6.7 ± 5.0 years
`Men 58%
`Age 55
`30 weeks
`non-inferiority
`Phase 2, randomized, open-label,
`Drucker et al67
`
`–
`
`−0.03 ± 0.7 kg
`
`NS vs placebo
`−0.04 ± 0.7 kg
`
`,0.05 vs placebo
`−3.8 ± 1.4 kg
`
`Not reported
`
`Not reported
`
`106 ± 20 kg
`Not reported
`
`–
`
`+1.0 ± 0.7 mmol/L
`
`+0.4 ± 0.3
`
`12
`
`Not reported
`,0.001 vs placebo,0.001 vs placebo
`−2.2 ± 0.5 mmol/L
`−2.4 ± 0.9 mmol/L
`,0.001 vs placebo,0.001 vs placebo
`−1.7 ± 0.3
`8.5 ± 1.2%
`15
`
`−1.4 ± 0.3
`
`16
`
`Not reported
`
`Metformin-53%
`Metformin-64%
`2.0 mg Ex QW0.8 mg Ex QWPlacebo QW
`FPG 9.9 ± 2.3 mmol/L
`Diabetes duration 5 ± 4 years
`Men 60%
`Age 17–85
`15 weeks
`
`Metformin-63%
`
`PPG change
`P value
`FPG change
`P value
`HbA1c change (%)
`Baseline HbA1c
`evaluable number
`
`treatment
`Baseline
`Study groups
`
`characteristics
`Baseline
`Duration
`
`Design
`Study
`Table 1 Designs and clinical outcomes of the published exenatide once-weekly studies
`
`Phase 2, randomized, placebo controlled
`Kim et al64
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`with the twice-daily group, which continued to be the case
`until study end (week 30) (Table1). A greater proportion of
`patients randomized to exenatide once-weekly achieved target
`HbA1c # 7.0% (77% versus 61%; P = 0.0039). Exenatide
`once-weekly also resulted in greater reductions of FPG and
`2-hour PPG (measured during a mixed meal tolerance test)
`(Table 1).67
`In another randomized, placebo-controlled, phase 2 trial,
`45 (60% male) drug-naïve or metformin-treated patients with
`T2DM were randomized to 2.0 mg or 0.8 mg exenatide once-
`weekly or placebo.64 HbA1c reductions were apparent in both
`the exenatide once-weekly groups from week 3 onwards and
`continued to improve until study end (Table 1). 86% of the
`2.0 mg group and 36% of the 0.8 mg group achieved target
`HbA1c 7.0% or less compared with 0% in the placebo group.64
`In addition, by week 15, exenatide once-weekly (2.0 mg or
`0.8 mg) resulted in significant reductions in FPG and PPG
`(based on self monitored blood glucose profiles) compared
`with placebo.
`Exenatide once-weekly was also examined in a Japanese
`population in a 10-week randomized, placebo-controlled,
`double-blind, parallel study in patients with T2DM
` suboptimally controlled by life style and/or biguanide,
`sulfonylurea, thiazolidinedione, or combinations of these
`agents.66 Patients continued their baseline medications
` during this study. Patients were randomized in a 1:1:1 ratio
`to subcutaneous placebo once weekly, exenatide once weekly
`0.8 mg, or exenatide once weekly 2.0 mg.66 At week 10, there
`was significant reduction in HbA1c in the exenatide once-
`weekly groups compared with placebo (Table 1). Similarly,
`FPG and PPG concentrations showed clinically relevant
`reductions in the exenatide once-weekly groups compared
`with placebo (Table 1).
`The impact of exenatide once weekly seems to be sustain-
`able up to 2 years following initiating treatment.68,69 In the
`open-label extension of the DURATION-1 trial, 258 patients
`entered the 22-week open-ended assessment phase (n = 128
`exenatide once weekly only; n = 130 switched from daily
`to once weekly exenatide).68 Exenatide once weekly main-
`tained the HbA1c improvements through the 52 weeks
`(−2.0% [−2.1% to −1.8%]). Patients switching from daily
`to weekly exenatide achieved further HbA1c improvements,
`but both groups had a mean HbA1c of 6.6% at study-end. At
`week 52, 71% and 54% of all patients achieved an A1c , 7.0%
`and #6.5%, respectively.68 This glycemic improvement
`was achieved without any major hypoglycemia. A further
`open-label extension of the DURATION-1 trial involving
`135 patients who have completed 2 years treatment with
`
`2 mg exenatide once weekly showed that the initial improve-
`ments in HbA1c were maintained at 2 years with 66% and
`42% of patients achieving an HbA1c #7.0% and #6.5%,
`respectively.69
`
`impact on weight
`Similar to exenatide twice-daily treatment, exenatide once
`weekly results in significant weight loss (Table 1). In the
`study by Kim et al exenatide once weekly 2 mg resulted in
`a weight loss of 3.8 ± 1.4 kg (mean ± SE) from baseline by
`week 15 (P , 0.05, compared with the placebo).64 In the
`DURATION-1 trial, the weekly exenatide treatment group
`had a weight change of −3.7 kg (SE 0.5) at week 30, which
`was comparable to the twice-daily exenatide treatment
`(−3.6 kg [SE 0.5]).67
`However, in the Japanese study, exenatide once weekly
`resulted in a weight neutral effect, while the placebo group
`lost 1.6 kg (Table 1).66 This effect was seen in earlier exenatide
`twice daily studies in Japanese subjects.70 The authors hypoth-
`esize that the leanness of the Japanese cohort could contribute
`to this apparent neutral effect on weight.
`The impact of exenatide once weekly on weight seems
`to be sustainable. At 52 weeks, body weight was reduced
`by .4 kg.68 In the 2-year open-label extension of the
`DURATION-1 study, there was significant reduction in
`body weight from baseline (−3.6 ± 0.6 kg; 95% CI: −4.8
`to −2.3 kg) by 2 years.69
`
`impact on cardiovascular risk factors
`Exenatide once weekly resulted in significant reductions in
`lipids and blood pressure (Table 2).67
`The 2-year open-label extension of the DURATION-1
`study reported that exenatide once weekly improved
`serum lipids (triglycerides: −18%, 95% CI −24% to
`−12%; total cholesterol: −0.25 ± 0.09 mmol/L, 95% CI
`−0.42 to −0.07 mmol/L). These subjects were also able to
`maintain a significant reduction in systolic blood pressure
`(−3.2 ± 1.2 mmHg; 95% CI −5.5 to −0.8 mmHg) throughout
`the treatment period.69
`
`impact on glucagon and other incretin-related effects
`Exenatide once weekly resulted in more glucagon suppression
`than exenatide twice daily.67 In the DURATION-1 study, glu-
`cagon levels changed by −18⋅0 (SE: 2⋅9) ng/L (from a baseline
`of 103 (3⋅1) ng/L) and −6⋅4 (2⋅9) ng/L (from a baseline of 99⋅0
`(3⋅0) ng/L) for exenatide once weekly and exenatide twice daily
`respectively (P , 0.05).67 The impact of exenatide once weekly
`on satiety and gastric emptying has not been examined.
`
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`exenatide once weekly
`
`Adverse events
`Hypoglycemia
`There were no significant events of hypoglycemia reported
`with exenatide once weekly in the DURATION-1 study or
`its open-label extensions.67–69 In the Japanese study, patient-
`reported hypoglycemia was reported in 2 patients. Both of
`these patients were on concomitant sulfonylurea therapy.66
`In the earlier study by Kim et al patient-reported hypo-
`glycemia was reported in 25% with exenatide once weekly
`0.8 mg, of which only one was confirmed with a blood glu-
`cose level of 3.1 mmol/L and all were mild, and 0% in the 2.0
`mg group; patients in the placebo arm had no hypoglycemia
`events.64
`
`Other Aes
`The common AEs are summarized in Table 3. Nausea was
`the most commonly reported side effect. Other AEs included
`vomiting, diarrhea, injection-site pruritus, and bruising.
`Elevated blood amylase levels were reported in 2 patients
`in the exenatide 0.8 mg once-weekly group, but these were
`not associated with any clinical symptoms of pancreatitis.
`Baseline to week 10 elevations in amylase levels did not
`reach significance in any of the groups, and no cases of
`pancreatitis were reported. There were no clinically relevant
`AEs relating to vital signs, ECG, or blood results. There were
`no withdrawals from the study due to AEs.
`In the 2-year open-label extension of the DURATION-1
`study, mild nausea diminished over time, occurring in only 8%
`of patients during the open-ended treatment period compared
`with 26.4% patients during the 30-week study period.69
`Overall, exenatide once weekly was well tolerated with
`no serious patient-reported AEs in any of the 3 published
`studies. Mild nausea and injection-site pruritus were com-
`monly encountered. Incidences of hypoglycemia were mild.
`So far, no cases of acute pancreatitis have been reported in
`any of the studies.
`
`Anti-exenatide antibodies
`The development or presence of antibodies did not have any
`clinical effect on the incidence of hypoglycemia or change in
`HbA1c in any of the available studies.64,66,67 Kim et al reported
`that 67% of subjects receiving exenatide once weekly had
`anti-exenatide antibodies at week 15, but no association could
`be found with safety or efficacy in individual patient profile.64
`DURATION-1 reported that anti-exenatide antibody levels
`were higher with exenatide once a week compared with twice-
`daily exenatide (P = 0⋅0002); however, there were significant
`reductions in mean HbA1c over 30 weeks in patients with
`
`Not reported
`−5.5 to −0.8
`Not reported
`Not reported
`−0.42 to −0.07
`−24% to −12%
`
`Not reported
`−3.2 ± 1.2
`Not reported
`Not reported
`−0.25 ± 0.09
`−18%
`baseline (SE)
`Change from
`
`Baseline (SE)
`95% CI
`2 yr DURATION-1 open label extension69
`Exenatide once a week (N = 135)
`
`Not reported
`Not reported
`Not reported
`Not reported
`Not reported
`Not reported
`
`−3.1 to −0.3
`−5.5 to 1.3
`−0.07 to 0.13
`−0.06 to −0.01
`−0.22 to 0.02
`−16 to −4
`
`95% CI
`
`−1.7 (0.7)
`−3.4 (1.1)
`+0.03 (0.05)
`−0.03 (0.01)
`−0.10 (0.06)
`−11% (0.03)
`baseline (SE)
`Change from
`
`0.6 (0.6)
`0.5 (1.2)
`0.6 (0.08)
`0.20 (0.02)
`0.72 (0.10)
`1.78 (0.09)
`
`−3.1 to −0.3 79
`−6.9 to −2.6 129
`−0.23 to −0.03 2
`−0.05 to +0.01 1
`−0.42 to −0.194
`−20 to −9
`
`Baseline (SE)
`DURATION-167
`Exenatide twice a day (N = 147)
`
`95% CI
`
`Baseline (SE)
`DURATION-167
`Exenatide once a week (N = 148)
`
`Abbreviations: SE, standard error; CI, confidence interval; BP, blood pressure; HDL-C, HDL cholesterol; LDL-C, LDL cholesterol.
`Diastolic BP (mm Hg)
`Systolic BP (mm Hg)
`LDL-C (mmol/L)
`HDL-C (mmol/L)
`Total cholesterol (mmol/L)
`Triglycerides (mmol/L) or (%)
`
`−1.7 (0.7)
`−4.7 (1.1)
`−0.13 (0.05)
`−0.02 (0.01)
`−0.31 (0.06)
`−15% (0.03)
`baseline (SE)
`Change from
`
`77.7 (0.7)
`127.8 (1.1)
`2.37 (0.07)
`1.14 (0.02)
`4.49 (0.09)
`1.88 (0.10)
`
`Table 2 Comparison of cardiovascular parameters in exenatide once weekly (30-week original study and 2-year open-label extension) and twice daily
`
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`Table 3 Most common Aes from the 3 published studies on exenatide once weekly
`AE
`Kim et al64
`Drucker et al67
`10 µg Ex
`Placebo
`0.8 mg Ex
`2.0 mg Ex
`2.0 mg Ex
`QW
`QW
`QW
`QW
`BD
`15%
`19%
`27%
`26.4%
`34.5%
`Nausea
`–
`–
`–
`10.8%
`18.6%
`vomiting
`0%
`19%
`13%
`13.5%
`13.1%
`Gastroenteritis/diarrhea
`–
`–
`–
`17.6%
`1.4%
`injection-site pruritus
`0%
`13%
`7%
`4.7%
`10.3%
`injection site bruising/induration
`–
`–
`–
`10.8%
`6.2%
`Constipation
`–
`–
`–
`8.1%
`17.2%
`Upper respiratory tract infection
`Abbreviations: Ae, adverse event; ex, exenatide; Qw, once weekly; BD, twice daily.
`
`Iwamoto et al66
`2.0 mg Ex
`0.8 mg Ex
`QW
`QW
`33.3
`0
`11.1
`0
`–
`–
`44.4
`40
`88.9
`90
`–
`–
`–
`–
`
`Placebo
`QW
`0
`10
`–
`20
`60
`–
`–
`
`negative, low titer (1/25 to 1/125), and high titer (.1/625)
`antibodies in the exenatide once-weekly group compared
`with twice daily (Figure 2).67 Anti-exenatide antibodies were
`present in 60.0% (6/10) and 77.8% (7/9) of patients in the
`exenatide once-weekly 0.8 mg and exenatide once-weekly
`2.0 mg groups, respectively, at any point during the Japanese
`study. But this did not have any clinical effect on hypoglycemia
`or HbA1c change (data not available).66
`
`Ongoing clinical trials
`DURATION-2, a head-to-head comparative study of
`exenatide once weekly against sitagliptin or pioglitazone is
`a 26-week, double-blinded, phase 3, superiority study involv-
`ing 491 patients whose diabetes was suboptimally controlled
`on metformin. Preliminary results were presented at the
` European Association for the Study of Diabetes annual meet-
`ing in 2008 and American Diabetes Association conference in
`
`8.5
`N = 38
`
`8.5
`N = 76
`
`8.3
`N = 75
`
`8.2
`N = 57
`
`8.1
`N = 35
`
`8.2
`N = 14
`
`−0.8%
`
`−1.4%
`
`−1.5%
`
`−1.7%
`
`−1.9%
`
`−2.0%
`
`Exenatide once a week (N = 148)
`
`Exenatide twice a day (N = 147)
`
`0
`
`−0.5
`
`−1.0
`
`−1.5
`
`−2.0
`
`Least square mean (SE) change in A1c (%)
`
`Negative
`
`Low
`
`High
`
`Figure 2 intention-to-treat subanalysis (N = 295) of change in HbA1c (least square mean (Se) by antibody status). Negative antibodies were not detectable in repeated
`analyses throughout the 30 weeks; low titer (#1/625) at any point during the 30 weeks; and high titer ($1/625) at any point during the 30 weeks; HbA1c reductions of −1.4%
`were observed in patients treated once a week in the high titer group. Reprinted from Drucker DJ, Buse JB, Taylor K. DURATiON-1: exenatide once weekly produces
`sustained glycemic control and weight loss over 52 weeks. The Lancet. 372:1240–1250, Copyright © 2008, with permission from elsevier.
`
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`exenatide once weekly
`
`2009, yet to be published.71,72 HbA1c reduction and weight loss
`was superior to the comparator arms; at 26 weeks the chang